Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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ANTIMICROBIAL DYES FOR HEALTHCARE APPAREL
FIELD OF INVENTION
The present invention relates to an antimicrobial fabric for healthcare
apparel, healthcare apparel
comprising said antimicrobial fabric, and a process for treating a fabric
suitable for healthcare apparel.
BACKGROUND OF THE INVENTION
Recently, the cost to society associated with Hospital Acquired Infections
(HAT) has significantly
increased. There is a general need to control infective agents, especially in
healthcare settings. To
protect health workers, and to minimise the risk of cross contamination
between patients and healthcare
workers it is desirable to engender antimicrobial properties to routine
protective equipment, such as
gowns.
Gowns are typically made up of multiple layers. These layers can be made from
a variety of materials
such as polyethylene, polypropylene, polyester or polyurethane. Gowns may be
used by patients or
healthcare workers. The duration of wear may be very short (minutes), or may
be multiple hours ¨ for
example in a surgical setting. Such gowns provide a basic level of protection
by acting as a simple
barrier to pathogens, but unless bacterial and viruses are rapidly killed they
may grow and become a
contaminating source.
W02010/118180 claims the chemical attachment of photosensitising dyes to
fabrics for odor control.
W093/00815 discusses dyeing of polymers with photosensitising phthalocyanines,
but not cationic
dyes.
US5486274A details the preparation of pyridyl substituted phthalocyanines for
cleaning applications.
JP2005023473 details a robe or gown for medical applications, made from
functionalised synthetic
fibres coated with typical conventional biocides. It gives an example of
quaternary ammonium salts,
but claims a wide variety of biocides. It does not claim photosensitisers or
activity mediated by singlet
oxygen.
JP3247293 (1995) reports cellulose acetate fibres with antimicrobial
properties given by metals salts
such as silver or zinc.
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CN201109221 claims an antimicrobial water resistant fabric for disposable
hospital wear. It makes no
claims for the antimicrobial action being mediated by photosensitisers.
CN101285220 (2008) describes polyethylene! polypropylene fibres for a wide
variety of applications
both within and beyond healthcare. Gowns are specifically mentioned. The
antimicrobial additive is
silver.
KR20140104256 teaches a manufacturing method for an antimicrobial fabric
suitable for gowns. A
biocide is included in the manufacturing method, but not specifically claimed
in the patent.
CN108936892 (2018) reports a nano-modified resin-based operating gown
material. The fabric is
made from polyurethane / polylactic acid with zinc and bamboo cellulose
incorporated to gift
antimicrobial activity.
US2018066384 teaches that treatment of any natural or synthetic fibre with a
formulated copper sulfide
solution produces antimicrobial fibres claimed suitable for industrial,
military and healthcare clothing,
including gowns.
CN108914610 (2018) specifically claims a disposable hospital gown. The added
biocide is claimed to
be a quaternary ammonium salt or metal ion.
CN105839410 (2016) details a surgical gown produced from zinc oxide, woven
with silver wire and
coated with PHMB.
CN106235474 (2016) again details a surgical gown comprising an antimicrobial
silver cloth.
US20090081911 details a surgical gown with an outer layer of spunbond
polypropylene. This
polypropylene layer is stated to have antibacterial properties, potential by
acting as a barrier. No
additional biocides are claimed.
Singlet oxygen is a highly attractive antimicrobial agent, as due to its
potent and non-selective
mechanism of action there are no reported examples of the development of
resistance by
microorganisms.
Commonly used singlet oxygen generators can still present issues of
solubility, aggregation, singlet
oxygen generating efficiency, overall unsatisfactory antimicrobial activity
and stability.
There is therefore a need to develop suitable singlet oxygen generators to
engender healthcare apparel
with effective and efficient antimicrobial activities which are safe for the
user.
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SUMMARY OF THE INVENTION
The present invention identifies certain dyes that are suitable for depositing
on fibres that may be used
in healthcare apparel, and demonstrates their antimicrobial properties.
In particular, the present invention provides an antimicrobial fabric for
healthcare apparel comprising
a singlet oxygen generating photosensitising dye. The present invention
further provides a process for
treating a fabric suitable for healthcare apparel with a singlet oxygen
generating phthalocyanine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention identifies certain dyes which are suitable for
depositing on fibres (for example
polyethylene, polypropylene, polyester, nylon, cellulose or polyurethane) that
may be used to construct
healthcare apparel, and demonstrates their antimicrobial properties. The
healthcare apparel can be any
of patient gowns, health worker gowns, surgical gowns, all over hazmat
(hazardous material) suits,
uniforms or scrubs.
The dye of the present invention is cationic or anionic. Cationic dyes are
preferred and have been found
to have an unexpected affinity for fabrics (e.g. cellulose, polyester, nylon),
enabling their efficient
deposition without chemical attachment, and additionally sufficient water
solubility to enable dyeing.
The antimicrobial fabric or material may comprise at least one layer of
nonwoven fabric, for example
meltblown or spunbond formed polypropylene, polyethylene, polyester, cellulose
or nylon, onto which
is deposited a singlet oxygen generating photosensitising dye. Especially
preferred is where the
facemask comprises or consists of a non-woven fabric.
In this respect, the fabric or material of the apparel may incorporate the
singlet oxygen generating
photosensitising dye. "Incorporate" may include the concepts of coated,
impregnated or dyed.
Most preferably the fabric or material is comprised of multiple layers, which
may or may not be
identical.
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The present invention relates to the application of certain photosensitisers
as generators of singlet
oxygen, a method for their application to materials suitable for healthcare
apparel, and an antimicrobial
gown obtainable using the invention.
Dyes may be selected from structural classes such as phthalocyanines,
porphyrins, dipyrrole-boron
complexes (BODIPY), phenothiazines (e.g. Methylene Blue) and fluoresceins
(e.g. Rose Bengal).
Singlet oxygen generators are known to destroy microorganisms. Singlet oxygen
has a greater energy
than ground-state, triplet oxygen. The singlet and triplet states of oxygen
are distinguished by the
singlet state having two electrons of anti-parallel spins and the triplet
state having an uncoupled pair
of electrons with parallel spins. Singlet oxygen is also distinguished from
triplet oxygen because it is
a highly reactive species with a lifetime from a few microseconds to several
hundred microseconds.
During its lifetime singlet oxygen has the potential to react before being
deactivated, and therefore has
a wide number of applications, including antimicrobial applications such as in
medical gloves,
facemasks, gowns and other healthcare apparel.
Preferred singlet oxygen generating dyes according to the present invention
are phthalocyanines.
Preferably the phthalocyanine is alpha substituted.
Alternatively preferred is the phenothiazine class of dyes, for example
Methylene Blue.
The phthalocyanine nucleus may be aluminium, titanium or zinc. If aluminium or
titanium is used,
the metal may be further substituted by alkyl, aryl, alkoxy, hydroxy or
halogen. Aluminium, titanium
and zinc are chosen because they are more efficient in generating singlet
oxygen than other metals
such as copper or nickel, and they are reasonably small and so can be inserted
into the phthalocyanine
easily, with the reactions occurring under air, in good yield, as opposed to
other metals such as using
SiC14, and are easily available in bulk. The central metal atom also
influences the position of the
absorption maximum of the phthalocyanine. Zinc, titanium and aluminium are
preferred in the
compounds because their absorption is in the visible region of the spectrum
especially between 600 ¨
700 nm. The zinc compounds described herein are especially preferred.
For the phthalocyanines of the present invention each of the pendant organic
radicals linked to the
phthalocyanine nucleus may be any aromatic or heteroaromatic moiety. Any one
phthalocyanine
nucleus may carry two or more different organic radicals. This radical may be
linked to the
phthalocyanine core by a carbon or hetero-atom bridge. Examples include, but
are not limited to
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oxygen linked phenyl, pyridyl and N-alkylated pyridinium, Examples of N-
alkylated pyridines are 3-
hy droxy -1 -m ethylpyri din-1 -ium, 3 -hydroxy -1 -ethylpyri din-1 -ium, 3 -
hydroxy-l-propylpyridin-l-ium.
Further, the phthalocyanines used in the present invention preferably have
substituents to the
phthalocyanine nucleus in the alpha position, adjacent to the phthalocyanine
nucleus. This alpha
substitution decreases aggregation of the phthalocyanine. Aggregation is known
to reduce singlet
oxygen generation efficiency, and therefore this structure prevents
aggregation and increases
efficiency singlet oxygen generation and hence antimicrobial and other
activity. In addition, after
extensive research the present inventors have realised the molecules described
herein have other
desirable properties. They are more thermally stable, and stable to radical
degradation than
commercially available analogs such as Tinolux BBS and Tinolux BMC. The
phthalocyanine
according to the present invention has a structure with the following formula:
_
a
Rd. =
' '
NJ
R.
H)
F07 1.:Th 1
wherein:
M is selected from aluminium, titanium or zinc,
R = R'(a) or R"(b)
R' = Oxygen linked phenyl or pyridyl
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R" = Oxygen linked phenyl, pyridyl or N-alkylated pyridinium, and
a + b = 4
b = 1 to 4
X = C1, Br, F, methanesulphonate, ethanesulphonate, toluenesulfonate, formate,
acetate or other
inorganic or organic counter-ion or mixture thereof;
and
wherein alkylation on the pyridine nitrogen is optionally branched C1-C8
alkyl. This alkyl chain may
be further hydroxylated or fluorinated.
Most preferred are the zinc pthalocyanines illustrated below ¨
+I
bi\t¨
Nt¨Zn-
4
+I\ N
)4
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n1.1
NNL
7-)
ei-
\ ____________________________________________
¨Zn ______________________________________ N
I 7/
---. N
0
0 N
N--Zn¨N
N 0
0
The phthalocyanines used in the present invention are activated by light and
offer a sustained release
of singlet oxygen onto the gown or other apparel. It is known that singlet
oxygen is a
strong antimicrobial agent, killing most bacteria. The advantage of singlet
oxygen generating dyes is
that they are catalytic and not exhausted over time, and the singlet oxygen
they release is not persistent,
due it its very short half-life of typically a few microseconds. This has
major advantages in toxicity
and potential for development of resistant organisms. The short lifetime and
hence short diffusion
range of singlet oxygen gives this invention a significant advantage in safety
for users.
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Further, the phthalocyanines preferred in the present invention have
substituents to the
phthalocyanine nucleus in the alpha position, adjacent to the phthalocyanine
nucleus (positions
1,5,12 and 13 in Formula 1). This alpha substitution decreases aggregation of
the
phthalocyanine. Aggregation is known to reduce singlet oxygen generation
efficiency, and
therefore this structure prevents aggregation and increases efficiency singlet
oxygen generation
and hence antimicrobial and other activity. To demonstrate this,
phthalocyanine I was
compared to an analogue where the oxypyridinium residue was attached to the
phthalocyanine
core in the beta position (positions 3,6,11 and 14 in Formula 1). 25 mgs of
each were dissolved
in 1 L water, and the UV / vis absorption compared. It can be seen in the
spectra below that the
alpha substitution pattern results in much high population of the monomeric
phthalocyanine
(ca. 675 nm here) compared to the aggregated phthalocyanine (ca. 640 nm here)
than is the
case for the beta substitution, which favours the aggregate (ca. 635 nm here).
This use of alpha substitution is therefore novel and inventive over beta
substitution pattern.
The phthalocyanines of Formula 1 can be prepared by reacting:
(1) a substituted 1,2-dicyanobenzene of Formula 2:
SUBSTITUTE SHEET (RULE 26)
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C N
C N
Y=F, CI, BrI,NO 2
Formula 2
wherein Z is selected from chloro, bromo and iodo or nitro and is in the 3
position (alpha) to one of
the CN groups,
with
(2) a compound aryl-OH whereby the group Z, is replaced by aryl-0 groups to
form a compound of
Formula (3). Pyridyl is illustrated for example, but this may be phenyl or
other hetero aromatic.
N2c
0
C N
C N
Formula 3
This can then be followed by reaction of one or more 1,2-dicyanobenzene
compounds of Formula 3
with an appropriate metal or metal salt optionally in an inert liquid at an
elevated temperature to form
a phthalocyanine of Formula 1.
Such reactions are fully described in GB 1489394, GB 2200650 and DE 2455675.
If an N-alkyl derivate is desired, then the alkylation of the pyridine groups
is done last. If the alkylation
process is not done to completion, some of the pyridyl substituents can remain
unalkylated and
uncharged. The process can be modified by temperature and stoichiometry to
give higher or lower
degrees of final alkylation.
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The antimicrobial phthalocyanines illustrated in present invention can be used
to coat fibres suitable
for gown manufacture and can provide effective and continuous antimicrobial
protection. In addition,
the physical properties of the gown are not significantly reduced.
The phthalocyanines used can be applied to any material suitable for gown or
healthcare apparel
construction. Examples are, but not limited to polyester, polypropylene,
polyester or polyurethane. The
application of the phthalocyanines to the fibres may be achieved via a wide
variety of methods familiar
to those skilled in the art of textile dyeing. Examples may include, but are
not limited to ¨
1) Treatment of the fibres with a solution of the dye in an organic solvent or
water
2) Treatment of the fibres with a slurry of the dye in an organic solvent or
water, combined with
appropriate co-factors, surfactants and processing conditions (e.g. time,
temperature) to
achieve dyeing
A particular advantage of the pthalocyanines preferred in this invention is
their high solubility in
selected solvents which allow facile dyeing of the desired fibres.
Without wishing to be bound by theory, the present inventors have realised
that application of the
photosensitising phthalocyanines as solutions is a particular advantage of the
invention as it maintains
the phthalocyanine in a de-aggregated state (in contrast to slurries,
suspensions or dispersions).
Aggregation is known to decrease the generation of singlet oxygen by
photosensitisers. As such, the
photosensitiser may be applied at a low weight loading per square meter of
fabric, whilst still giving
high antimicrobial activity.
In addition to the photosensitising dye, a homo or heteropolymer of
unsaturated low molecular weight
carboxylic acids (or their esters or anhydrides) may also be deposited onto
facemask material, such as
the non-woven fabric. Example monomers include acrylic, methacrylic or maleic
acids, and example
polymers include the carbomer class, such as acrylic acid homopolymers, or
maleic acid / vinyl ether
heteropolymers. Preferably the carboxylic acid polymer is deposited on the
same fabric layer as the
photosensitiser, being the outer layer of the apparel. Preferably the homo or
heteropolymer may be
deposited on the fabric first, enabling deposition of the dye without chemical
attachment.
Additionally, or alternatively a surfactant may also be included. Preferably
the surfactant is an ionic,
or alternatively a betaine type surfactant. Preferred is an ionic sulfonated
aryl surfactant, such as an
alkylbenzene sulfonate, preferably sodium dodecylbenzenesulfonate.
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While the invention has been described in terms of what is presently
considered to be the most practical
and preferred embodiments, it is to be understood that the invention needs not
be limited to the
disclosed embodiments. On the contrary, it is intended to cover various
modifications and similar
arrangements included within scope of the appended claims which are to be
accorded with the broadest
interpretation so as to encompass all such modifications and similar
structures.
The present invention will now be illustrated, but in no way limited, by
reference to the following
examples.
Example 1 ¨ Preparation of 3-(pyridyloxy)phthalocyanine
CN bN
CN __________________________________
DBU, 2-ethylhexanol
N¨Zn--
,
4
¨ N o
To 2-ethylhexanol (242 g) is charged 3-(oxypyridyl)phthalonitrile (145 g,
0.656 moles, 1 eq), and the
vessel purged with inert gas. Zinc chloride is charged (21 g, 0.154 moles, 94%
of theoretical charge)
followed by DBU (51 g, 0.335 moles, 0.51 eq). The reaction is heated to ca.
107 C (internal vessel
temp) for at least 16 hours. The reaction is cooled and isopropyl alcohol
(1600 mL) charged to the
reaction mixture. After cooling to room temperature, the product is isolated
by filtration and washed
with further iso-propanol, then dried in an oven.
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Example 2 ¨ Preparation of tetra-methyl (pyridiniumoxy) phthalocyanine iodide
+
z z
Me0Ts, Lil, IPA
¨ N
-Fr\
=%r
(-)4
To NMP (360 g) is charged pyridyl zinc phthalocyanine prepared in Example 1
(140 g, 1 eq, 0.147
mol) and methyl p-tolueneslufonate (120 g, 0.644 mol, 4.4 eq). The reaction is
stirred and heated to
107 - 111 C (internal vessel temperature) for 20 h, then cooled to 50 - 60 C
(internal). Meanwhile,
to a second vessel is charged iso-propanol (14 vols, 2000 mL) and lithium
iodide trihydrate (125 g,
0.668 mol, 4.54 eq). The reaction mixture is transferred to the second vessel
to precipitate the crude
product, which is isolated by filtration and washed with further iso-propanol.
The wet cake of the crude
product is recharged to a vessel with iso-propanol (8 vols, 1100 mL) and
lithium iodide trihydrate (35
g, 0.187 mol, 1.27 eq). The slurry is heated to 80 - 83 C (internal), then
cooled to room temperature.
The final product is isolated by filtration and washed with further iso-
propanol, before being dried in
an oven.
Example 3 ¨ Preparation of tetra-(2-ethylhexyl) (pyridiniumoxy)phthalocyanine
iodide
r 1+
2-ethylhexyl
bromide
N-- Zn¨ N--
- N 0
2-Et-hexy1N+
N+
I I-
2-Et-hexyl
To NMP (10 g) is charged pyridyl zinc phthalocyanine prepared in Example 1 (5
g, 1 eq, 0.0053 mol)
and 2-ethylhexyl bromide (6.09 g, 0.0315 mol, 6 eq). The reaction is stirred
and heated to 110 C (oil
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bath temperature) for 27 h, then cooled to 70 C (bath). Meanwhile, to a
second vessel is charged iso-
propanol (150 mL) and sodium iodide (3 g, 0.02 mol, 3.8 eq). The reaction
mixture is transferred to
the second vessel to precipitate the crude product, which is isolated by
filtration and washed with
further iso-propanol. The wet cake is recharged to a vessel with iso-propanol
(150 ml) and sodium
iodide (1 g, 0.0067 mol, 1.27 eq). Water (15 ml) is added, and the slurry
heated to 40 C for 3 h, then
cooled to room temperature and further stirred. The product is isolated by
filtration, then washed with
iso-propanol / water, then finally washed with further iso-propanol before
being dried in an oven.
Example 4 ¨ Preparation of 3-(4-t-butylphenoxy)phthalonitrile
NQ
CN CN
CN CN
To a slurry of potassium carbonate (47.8 g, 0.347 mol, 1.2 eq), 3-
nitrophthalonitrile (50 g, 0.289 mol)
in ethyl acetate was added 4-tert-butylphenol (45.6 g, 0.303 mol, 1.05 eq).
The mixture was heated to
reflux for 7 hours, then the organic phase extracted with water. The majority
of the ethyl acetate was
removed by distillation, and replaced with iso-propanol. The solution of the
desired product was
allowed to cool slowly until it crystallised. The product was isolated by
filtration, washed with further
iso-propanol and dried in an oven.
Example 5 ¨ Preparation of tetra(4-t-butylphenoxy)phthalocyanine
cL
CN N N
CN
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To 3-(4-t-butylphenoxy)phthalonitrile prepared in Example 5 (15 g, 0.054 mol)
is added 2-
ethylhexanol (30 ml) zinc chloride (1.77 g, 0.013 mol, 0.24 eq) and DBU (4.3
g, 0.028 mol, 0.52 eq).
The reaction is heated to 105 C (internal) for 23 hours, then cooled and
slowly dropped into stirred
methanol. The product was isolated by filtration, washed with further methanol
and dried in an oven.
Example 6 ¨ Dyeing fabric with solution of Example 2 in methanol
0.025 g of the phthalocyanine prepared in Example 2 was dissolved in 100 ml of
methanol. A 10 x 10
cm square of polypropylene fabric (suitable for gown construction) was
immersed in the solution for
15 seconds with swirling. The sample was carefully removed from the liquid,
allowing the excess to
run off. The sample was air dried.
Example 7 ¨ Dyeing fabric with solution of Example 2 in methanol
0.025 g of the phthalocyanine prepared in Example 2 was dissolved in 100 ml of
methanol. A 10 x 10
cm square of polyethylene fabric (suitable for gown construction) was immersed
in the solution for 15
seconds with swirling. The sample was carefully removed from the liquid,
allowing the excess to run
off. The sample was air dried.
Example 8 ¨ Dyeing fabric with solution of Example 3 in acetone
0.025 g of the phthalocyanine prepared in Example 3 was dissolved in 1 ml NMP
and made up to 100
ml with acetone. A 10 x 10 cm square of polypropylene fabric (suitable for
gown construction) was
immersed in the solution for 15 seconds with swirling. The sample was
carefully removed from the
liquid, allowing the excess to run off. The sample was air dried.
Example 9 ¨ Dyeing fabric with solution of Example 5 in acetone
0.025 g of the phthalocyanine prepared in Example 5 was dissolved in 100 ml of
acetone. A 10 x 10
cm square of polypropylene fabric (suitable for mask construction) was
immersed in the solution for
15 seconds with swirling. The sample was carefully removed from the liquid,
allowing the excess to
run off. The sample was air dried.
Example 10 ¨ Dyeing fabric with Carbomer, then solution of Example 2 in water
An 8.7 cm diameter disc of a polyethylene / polyester laminate fabric
(suitable for a gown, apron or
"hazmat" suit) was treated with a suspension of 150 mgs of an acrylic acid
homopolymer (for example
Carbopol 971) and 75 mgs of sodium dodecylbenzenesulfonate in 50 g water. The
disc was treated for
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1 min, then the sample was carefully removed from the liquid, allowing the
excess to run off The
sample was air dried. Next, 0.025 g of the phthalocyanine prepared in Example
2 was dissolved in 100
ml of water. 2.5 g of this solution was made up to 15 g. The disc prepared
above was treated with 4 g
of this dye solution for 1 min, then the sample was carefully removed from the
liquid, allowing the
excess to run off. The sample was air dried.
Example 11 ¨ Dyeing of fabric with Carbomer and Dye of Example 2 in water
0.025 g of the phthalocyanine prepared in Example 2 was dissolved in 100 ml of
water. To 75 ml of
this solution was added 150 mgs of an acrylic acid homopolymer (for example
Carbopol 971) and 75
mgs of sodium dodecylbenzenesulfonate. The suspension was stirred until fully
dispersed. An 18 cm
square of non-woven polypropylene fabric was dipped in this suspension for 2
min, then the sample
was carefully removed from the liquid, allowing the excess to run off The
sample was air dried.
Example 12 ¨ Microbiology performance of above fabrics
A 4.3 cm disc of the sample prepared in Example 6 was inoculated with a 0.1 ml
presentation of either
Staphylococcus aureus or Klebsiella pneumonia. After lh at 37 C under
illumination of 1500 lux, a
reduction of 5.5 Log was achieved for Staph a and 2.1 Log for Kleb p.
