Title Hydrogen peroxide delivery system
Field of the Invention
This invention relates to a delivery system, e g a dressing, comprising hydrogen peroxide for
application to a part of the human or animal body especially for treatment of skin, e g. a
wound site.
Background to the Invention
Hydrogen peroxide (H2Q2) is a known antimicrobial substance for use on the skin and in
wounds It is produced naturally in the body by white blood cells as part of the rrnmune
defence activities in response to infection and through the action of the enzyme superoxide
dismutase There are no known microbial evasion mechanisms by which microbes can escape
its effects and it has a short lifetime, very rapidly breaking down to water and oxygen in the
tissues However, excessive hydrogen peroxide can be toxic to tissue cells, and the
prevailing attitude in the medical community is that its potential toxicity is too great to justify
its regular application to skin or open wounds Even so, very carefully limited doses of
hydrogen peroxide can be used as a means to enrich the wound environment with abundant
oxygen, provided that little, if any, intact hydrogen peroxide reaches the living tissues
Catalase and other substances that break down hydrogen peroxide are present in the wound,
and in the epidermis in sufficient quantities to ensure very rapid decomposition.
For these reasons, there is a need to provide a means for delivering hydrogen peroxide to
wounds or skin, that goes beyond the direct application of a source of hydrogen peroxide as a
liquid or a film or other format, straight onto wounds or skin A more controlled method of

application is needed, if hydrogen peroxide is to be used effectively for the treatment of
wounds or skin.
In particular, if dose levels could be controlled reliably, and automatically, through a simple,
practicable mechanism, hydrogen peroxide could be used safely to great advantage Any such
mechanism would have to limit the rate of delivery of hydrogen peroxide to wounds or skin,
such that it is instantly and completely broken down to water and oxygen before appreciable
quantities can leave the dressing In this situation, it would be possible to achieve
oxygenation, without the tissues of the wound ever experiencing hydrogen peroxide exposure
In certam types of wound dressing or apparatus, hydrogen peroxide can be used to drive the
production of lodme from iodide, provided that there is a reactor compartment within the
dressing in which the reaction can take place, and that the ingress of hydrogen peroxide can be
regulated appropriately Thus, hydrogen peroxide can be utilised in the treatment of wounds
or skin conditions as an antimicrobial agent in its own right, as a means to provide oxygen or
as a means to drive iodine production in-situ for controlled iodme delivery It may be
desirable for all three functions to be provided simultaneously
Hydrogen peroxide has been used for many years as an anti-microbial substance for cleansing
wounds of all kinds and as a biologically compatible general antiseptic. It is often used for
household and surface cleaning as a more environmentally acceptable and safer alternative to
"bleach" (solutions of sodium hypochlorite). In medical applications, hydrogen peroxide-
containing ointments have been used, e.g., for treatment of leg ulcers, pressure sores, minor
wounds and infection There are, however, problems associated with hydrogen peroxide, as
currently used Hydrogen peroxide solution is unstable, being readily oxidised to water and
oxygen, further, hydrogen peroxide at high concentration can be damaging to normal skin and
to cells responsible for healing in the wound bed It is very difficult or even impossible to use
hydrogen peroxide as part of a pre-dosed wound dressing, as its instability would make for a
product with an inconveniently short shelf-life. The dosing of simple solutions of hydrogen
peroxide at the point of application would not provide a sustained delivery over a usefully

prolonged period When, it is used in wound treatment (as described in the British
Pharmacopoeia, for example) very high concentrations (typically 3 %) are needed to achieve a
-powerful antimicrobial effect over a very short time interval Even this type of short burst can
be effective, because of the antimicrobial effectiveness of hydrogen peroxide and the physical
cleaning effect of the inevitable foaming that occurs as copious amounts of gaseous oxygen are
released, but there is the further disadvantage that such high concentrations can be relatively
damaging to host cells and can impede the healing process For this reason, use of hydrogen
peroxide tends to be restricted to initial clean-up and sterilisation of wounds. Even so, it is a
natural defence substance, produced by the body's own cells (albeit at lower concentrations)
and it is increasingly recognised as an intercellular and mtracellular messenger molecule,
involved in cell to cell molecular signalling and regulation. Undoubtedly, hydrogen peroxide
is potentially a very beneficial molecule, if it can be used at the right concentrations over an
appropriate time course and with the right accessory molecules or formulations
WO2005/072784 concerns a skin dressing comprising a hydrated hydrogel material including
a source of lactate ions and a supply of glucose, which may be used in conjunction with a
superposed layer containing a supply of pre-formed hydrogen peroxide or a hydrogen
peroxide precursor substance
Summary of the Invention
The invention provides a hydrogen peroxide delivery system, comprising an upper component
comprising hydrogen peroxide, and a lower component in hydrated condition, such that when
the upper and lower components are placed in contact with each other, hydrogen peroxide
migrates towards the lower component
The delivery system is preferably free of a source of lactate ions and a supply of glucose.

The upper component may be in wet or dry condition, but is preferably in dry condition for
reasons of storage stability.
The delivery system is suitable for delivery of hydrogen peroxide to a part of the human or
animal body. However, typically it will be applied to the skin, e.g. a wound site, and in this
case the delivery system takes the form of a dressing and the upper and lower components are
dressing components.
The delivery system is designed to be used as a single unit, wherein the two components are
brought together at the point of use. The lower component means the component which is
nearer the skin rn use, with the upper component being located on top of the lower dressing
component.
The components are constructed of a material that can be dispensed as a coherent entity,
whether in sheet (or film) form, or as an amorphous gel (e.g. that can be squeezed from a
dispenser) and which will stay in place when applied to a target site (e g. a wound or an area
of skin.
'Dry condition' means that there is no free water in the material, such that no significant or
measurable water loss occurs through evaporation under normal ambient conditions of
temperature, pressure and humidity. Dry condition includes desiccated condition, which is an
extra thoroughly dried condition Desiccated condition means a condition maintained by
storage in an environment enclosed by a moisture impermeable barrier, wherein the material
is kept scrupulously free of water by means of an added desiccant.
la embodiments in which the upper component is in dry condition the hydrogen peroxide is
particularly stable and is retained in the material. The upper component can be stored under
suitable conditions for an extended period of time, with the hydrogen peroxide remaining
stable therein.

Upper hydrogen peroxide-containing component
The hydrogen peroxide is incorporated in the upper component, which can be considered to be
a "carrier" material for the hydrogen peroxide. The upper component may be in a dried
form, if that is more convenient or cost effective, but it is equally acceptable for the carrier
material to be in a hydrated condition, such as a high water hydrogel The hydrogen peroxide
is preferably dispersed throughout the upper component Typically the upper component
comprises a matrix (whether in dry or hydrated condition) with the hydrogen peroxide
dispersed therein, preferably in a reasonably homogeneous manner
The upper component preferably comprises a polymer material
A preferred polymer material comprises polyvinyl alcohol (PVA) PVA has convement and
acceptable properties for skin treatment use, e.g being non-toxic. PVA is also easy to handle
and use, readily forming a film on drying of a PVA solution in water, with the resulting film
being easy to handle. PVA is also readily available and cheap. Cross-lrnkmg is not required
to form a solid material, eg. in the form of a Mm, although cross-linking may optionally be
employed PVA is available in a wide range of grades based on molecular weight and degree
of hydrolysis, which affect the physical properties of the material Appropriate grades of
PVA can be readily selected to produce a polymer product having desired properties for a
particular intended use. For example, for use in skin dressings, good results have been
obtained by use of PVA with a molecular weight in the range 100,000 to 200,000,
substantially fully hydrolysed (98-99% hydrolysed), e.g. in the form of code 36, 316-2 from
Aldrich, in non-cross-linked form
Another preferred polymer material comprises polyvinylpyrrolidone (PVP) The properties of
PVP are very similar to those of PVA, and PVP is also acceptable for skin treatment use.
PVP is readily available in a range of different molecular weights Appropriate grades of

PVP can be readily selected For example, good results have been obtained using a PVP
having a molecular weight average of 360,000, e g in the form of code PVP360 from Sigma,
in a non-crosslrnked form
Mixtures of polymer materials may be used, with the presence of at least some PVP berng
found to be beneficial for hydrogen peroxide stability
The form of the upper component may be selected to suit the intended use For use in skin
dressings, the component is conveniently in the form of a sheet, layer or film The layer or
film typically has a thickness in the range 0 01 to 1 0mm, preferably in the range 0 05 to
0 5mm.
The hydrogen peroxide may be incorporated in the upper component in the form of hydrogen
peroxide per se or hydrogen peroxide in combination with or complexed with another entity
Good results have been obtained with a hydrogen peroxide urea complex1 this is available as a
dry powder, and so is easy to handle, yet will release hydrogen peroxide
The hydrogen peroxide material may optionally include a support to provide rigidity when
wet
The hydrogen peroxide material may also include a humectant, e g glycerol or propylene
glycol, to aid in the flexibility of the dried film
The upper component is conveniently made by mixing a solution of a polymer (e g. an
aqueous solution of PVA and/or PVP) and hydrogen peroxide (e g an aqueous solution of
hydrogen peroxide urea complex), and drymg the mixture to produce a solid material, e g
forming film by a castmg procedure. Suitable techniques are well known to those skilled in the art

Lower hydrated component
The lower component is in a hydrated condition, which means that it contains sufficient water
for the hydrogen peroxide carried in the upper component to diffuse through its structure and
to the interface with the target, e g wound or skin If the upper component is supplied in a
dry condition, it will become hydrated (wetted) by contact with the water of the lower
component. In this instance, the hydrogen peroxide will be dissolved and released into the
lower component Sufficient water is required within the lower component to form a contact
liquid junction between the material and a water source
Additionally, the lower component provides a source of moisture which can act in use to
maintain a beneficial moist environment within a target wound site.
The material of the lower component may be in the form of hydrogel, a sponge, a foam or
some other form of hydrophilic matrix that can hold sufficient water to allow a controlled
diffusion path between the hydrogen peroxide layer and the target site Preferably, the water
will contain solutes that serve to regulate the passage of hydrogen peroxide, e g. by hydrogen
bonding, which may be achieved by appropriate concentrations of polymers, e g.
polysaccharides, including glycosaminoglycans Preferably the layer will contain polyacrylic
polymers, such as poly 2-acrylarmdo-2-methylpropane sulphonic acid (polyAMPS), which
serve to impart solid gel properties as well as the ability to control transmission of hydrogen
peroxide.
The lower component can control hydrogen peroxide flux rates in numerous ways, includrng
by selection of its physical dimensions (especially depth, affecting diffusion path distance), its
water content (less water causing a slower diffusion rate), its composition (with immobilised
hydrogen bonding groups slowing hydrogen peroxide movement) and/or its surface
architecture at the mterface with the target site, e g wound site, and/or at the interface with

the upper component (affecting the contact surface areas and thereby the rate of transfer into
or out of the lower component), e,g , it may have a contoured (possibly corrugated) surface
Because the upper component releases hydrogen peroxide when wet, the water-bearing lower
component can serve as both a source of water for re-hydration/dissolution of the hydrogen
peroxide (if in dry condition) and as the means for the hydrogen peroxide to pass through the
delivery system, e.g. for delivery to a wound from a dressing The rate of
hydration/dissolution can be controlled by the combined properties of the two layers, and the
way they interact This, in turn, can regulate the rate at which hydrogen peroxide is made
available to e.g a wound, and can be used to ensure that the dosage is sufficient only to
effectively expose a wound to oxygen, rather than to hydrogen peroxide (through the effect of
tissue catalase and other hydrogen peroxide-decomposing substances in immediate contact
with the dressing)
In addition, the lower component can perform as a reactor, in which the hydrogen peroxide is
actively decomposed to oxygen and water (e.g by containing iodide ions, which undergo a
complex chemical reaction with the hydrogen peroxide, resulting in appropriate oxygen
production) The lower component can also provide the benefit of synthesising and delivering
active wound-care substances, typically by means of chemical reaction with hydrogen
peroxide For example, iodine can be synthesised in this way, through the oxidation of iodide
ions, to work as an antimicrobial agent As with hydrogen peroxide, it is helpful for the
wound to receive iodine at a controlled rate such that there is sufficient iodine to kill
microbes, but the level is low enough to avoid toxic effects on the wound tissues Another
example is provided by the delivery of allantoin, which is claimed to have a healing effect
Allantoin is unstable, so it is preferable for the transmission layer to be pre-dosed with
relatively stable urate ions, which are oxidised by mcoming hydrogen peroxide to yield
allantoin.

Typically, skin or a wound is in direct contact with the water-bearing lower component The
lower component, preferably when in the form of a hydrated hydrogel as discussed below, can
(depending on its chemical composition) act to absorb water and other materials exuded from
a wound site, enablmg the dressing to perform a valuable and useful function by removing
such materials from a wound site
The form of the lower component may be selected to suit the intended use For use in skin
dressings, the material is conveniently in the form of a sheet, layer or film. The layer or film
typically has a thickness in the range 0 01 to 1 Omm, preferably in the range 0 05 to 0 5mm
The lower component may alternatively be in the form of an amorphous gel or lotion,
preferably a hydrogel, not having a fixed form or shape, that can be deformed and shaped in
three dimensions, mcluding being squeezed through a nozzle Amorphous gels are typically
not cross-linked or have low levels of cross-linking A shear-thinnmg amorphous gel may be
used Such a gel is liquid when subjected to shear stress (e g. when being poured or squeezed
through a nozzle) but is set when static. Thus the gel may be in the form of a pourable or
squeezable component that may be dispensed, e.g from a compressible tube or a syringe-like
dispenser, comprising a piston and cylinder, typically with a nozzle of about 3mm diameter.
Such a gel may be applied in the form of a surface layer, or into a wound cavity as a fully
conformable gel that fills the available space and contacts the wound surface
This approach finds particular application in the treatment of cavity wounds by, for example,
squeezing from a tube or syringe, with the cavity being filled with the amorphous gel and an
upper component (e.g a film, possibly in rolled up condition) placed onto the gel. It is also
possible for the material to be carried in the form of rope or tape to be packed into a cavity.
On wetting of the upper component, e g by water from the gel or lotion, hydrogen peroxide
is released and reacts with catalase of the wound site to produce oxygen If the gel or lotion
includes iodide ions then either predominantly oxygen will be produced within the gel (if the

iodide ions are at a low concentration) or substantial levels of iodine and oxygen will be
generated (if the iodide ions are at a suitably increased concentration)
A typical example of an amorphous gel formulation is. 15%w/w AMPS (sodium salt), 5%w/w
glucose, 0 05%w/w potassium iodide, 0 1% zinc lactate, 0.19% polyethylene glycol
diacrylate and 0 01% hydroxycyclohexyl phenyl ketone, with the volume made up to 100%
with analytical grade DI water The reagents are thoroughly mixed and dissolved, then
polymerised for between 30-60 seconds, using a UV-A lamp delivering approximately
100mW/cm2, to form the required hydrogel This may be in the form of a flat sheet or, more
conveniently, housed in plastic syringes The amorphous gel may then be dispensed from a
syringe into a target site
Hydrogels
The lower component is preferably in the form of a hydrated hydrogel. A hydrated hydrogel
means one or more water-based or aqueous gels, in hydrated form A hydrated hydrogel can
act to absorb water and other materials exuded from a wound site, enabling the dressing to
perform a valuable and useful function by removing such materials from a wound site The
hydrated hydrogel also provides a source of moisture, that can act in use to maintain a wound
site moist, aiding healing The hydrated hydrogel also acts as a source of water, causmg
release of hydrogen peroxide Use of a hydrated hydrogel has other benefits as discussed in
WO 03/090800
Suitable hydrated hydrogels are disclosed in WO 03/090800 The hydrated hydrogel
conveniently comprises hydrophihc polymer material Suitable hydrophilic polymer materials
include polyacrylates and methacrylates, e g as supplied by First Water Ltd in the form of
proprietory sheet hydrogels, including poly 2~acrylamido-2-methylpropane sulphonic acid
(polyAMPS) or salts thereof (e g. as described in WO 01/96422), polysaccharides e.g
polysaccharide gums particularly xanthan gum (e g available under the Trade Mark Keltrol),

various sugars, polycarboxylic acids (e g available under the Trade Mark Gantrez AN-169
BF from ISP Europe), poly(methyl vinyl ether co-maleic anhydride) (e.g available under the
Trade Mark Gantrez AN 139, having a molecular weight rn the range 20,000 to 40,000),
polyvinyl pyrrolidone (eg in the form of commercially available grades known as PVP K-30
and PVP K-90), polyethylene oxide (e g available under the Trade Mark Polyox WSR-301),
polyvinyl alcohol (e g available under the Trade Mark Elvanol), cross-linked polyacrylic
polymer (e g. available under the Trade Mark Carbopol EZ-1), celluloses and modified
celluloses mcluding hydroxypropyl cellulose (e g available under the Trade Mark Klucel
EEF), sodium carboxymethyl cellulose (e.g. available under the Trade Mark Cellulose Gum
7LF) and hydroxyethyl cellulose (e g available under the Trade Mark Natrosol 250 LR)
Mixtures of hydrophilic polymer materials may be used in a gel.
In a hydrated hydrogel of hydrophilic polymer material, the hydrophrhc polymer material is
desirably present at a concentration of at least 1 %, preferably at least 2%, more preferably at
least 5%, yet more preferably at least 10%, or at least 20%, desirably at least 25% and even
more desirably at least 30% by weight based on the total weight of the gel. Even higher
amounts, up to about 40% by weight based on the total weight of the gel, may be used
A preferred hydrated hydrogel comprises poly 2-acrylamido-2-methylpropane sulphonic acid
(poly AMPS) or salts thereof, preferably in an amount of about 30 % by weight of the total
weight of the gel
The lower component can be manufactured by known means Preferably it is manufactured
by the polymerisation of AMPS monomer dissolved at the rate of about 40% w/v in a solution
buffered to a pH of about 5 5, containing any further ingredients required for controlling the
rate of hydrogen peroxide transmission or reaction, such as iodide If iodide is required
primarily only to decompose hydrogen peroxide to oxygen and water, the iodide concentration
should be about 0.01% w/v. If it is to be used both to release oxygen and synthesise iodine,

then the level of iodide should be from about 0 05% to about 0.2% w/v Methods for the
manufacture of this material are as described in patent number EP1631328
Use
For use on the body, the delivery system, e.g a skin dressing, may be assembled simply by
laying the upper component onto the lower component This can be carried out away from
the skin/wound surface, in which case the composite dressing is placed on the skin/wound as a
single entity, with the hydrogen peroxide upper component facing outwards, away from the
skin surface Alternatively, the lower component can be applied first to the target skin or
wound site, and then the hydrogen peroxide component can be added on top. Both
components may also be cut to size, should the dressing be too large for the area to be treated,
where the upper component remains smaller than the lower component, thus preventmg the
upper component from coming in contact with the skin or wound surface directly
Usually the lower component will be located directly on the body, but it is possible for
intervening material to be present
For most body treatments, the delivery system is used for skin treatment by being located on
or near the skin of a human or animal, e g over a wound or on a region of skin to be treated
for cosmetic or therapeutic purposes, e g for treatment of a wide range of conditions as
discussed above
If the upper component is in a dried condition (eg a PVA film), it will be automatically
supplied with water from the lower component, as soon as they are brought together at the
point of use Once rehydrated, the hydrogen peroxide can migrate into the lower component
and thence to the interface between the dressing and the wound or skin at a pre-determined
rate. If the hydrogen peroxide layer is already hydrated (e.g a 40% w/v poly AMPS hydrogel
with dissolved hydrogen peroxide) then it just remains for the hydrogen peroxide to diffuse

into and through the lower component In both situations, hydrogen peroxide is released at an
appropriate rate, with known beneficial effects as discussed above
In particular, the composite dressing may be used in a skin treatment dressing or wound
dressing.
Optional ingredients
In addition to components essential for controlling the passage of hydrogen peroxide and/or
reacting with the hydrogen peroxide to generate benefit agents in place, the dressing, and
preferably the lower component, may incorporate one or more other active ingredients such as
zinc ions, as disclosed in WO 2004/108917. Zinc ions are known to form stabilising
complexes with hydrogen peroxide, aiding delivery of hydrogen peroxide to the target site.
Zinc is also an essential, nutritional trace element, which has numerous functions in the
growth and repair of healthy tissues
In the second aspect of the invention, lactate ions may be included in the delivery system
Lactate ions have a mild buffering effect within the delivery system Lactate ions are also
believed to have an important role in stimulating angiogenesis - the growth and regeneration
of new blood vessels However, lactate ions are absent in the first aspect of the invention
In the second aspect of the invention, a source of glucose may be included in the delivery
system Glucose is believed to participate (as a metabolic precursor) in building
polysaccharides of various types that form extracellular matrix (ECM), essential to tissue
repair and healing Preferred skin-contacting layers of this sort are disclosed in our European
Patent Application No. 04250508 1 and British Patent Application No 0427444 5. However,
a source of glucose is absent in the first aspect of the invention.
Packaging

The delivery system conveniently includes, or is used with, a covering or outer layer for
adhering the dressing to the skin of a human or animal subject in known manner
The components of the delivery system are preferably separately packaged for optimal
performance prior to use, e g. bemg sealed in suitable sterile water-impervious packages, e.g
of laminated alummmm foil
Preferred embodiments
In a preferred embodiment the delivery system is a dressmg which comprises an upper
component in dry condition, in the form of a layer, comprising a hydrogen peroxide urea
complex and PVA, and a lower component which is a poly-AMPS hydrogel in the form of a
layer
The invention will be further described, by way of illustration, in the following examples
which refer to the accompanying drawings, in which
Figure 1 is a graph of current (in micro Amps) versus time (in rm'ns) showing iodine
production from a polymer film rn accordance with the invention in combination with an
iodine-contarmng hydrogel transmission layer;
Figure 2 is a graph of an oxygenation effect (compared to atmospheric oxygen at 100%)
versus time (in rnins) showmg oxygen production from a polymer film in accordance with the
invention in combination with a hydrogel layer; and
Figure 3 is a graph of H202 recovery from dry stored films, expressed as ug H202 recovered
per milligram of film, versus storage time (in days)

Figme 4 is a graph of current (in micro Amps) versus time (rn rams) showing iodine
production from a polymer film in accordance with the invention and from polymer films
comprising glucose and/or lactate ions
Example 1
Polyvinyl alcohol (PVA) (98-99% hydrolysed, 124,000-186,000 molecular weight, code
36,316-2 from Aldnch) was dissolved in de-ionised water to a fmal concentration of 5% w/w
The water was heated to boiling point, and the PVA granules were slowly added, with
constant agitation The water temperature was maintained at 80°C or above, until the PVA had
dissolved The PVA solution was allowed to cool to room temperature about (21°C) before
use
Urea-Hydrogen Peroxide (UHP) (containing 35% hydrogen peroxide, code U1753 from
Sigma) was added to the 5% PVA solution, to give 1.0% w/w. This gave a final PVA
concentration 4 95% w/w The UHP was readily soluble, and only slight agitation at RT
(21°C) was required to dissolve the powder
To form the dry films, constituting an upper component, a plastic container with a surface
area of 124cm2 was used Into this, either 10 or 20 grams of the UHP/PVA solution was
poured The UHP/PVA solutions were spread evenly over the entire surface, and placed at
40°C for 16-24 hours to dry After the films were dried, they were removed and kept in air
tight polythene bags, at RT (21°C) The films had a thickness of about 0 1mm or 0.2mm,
depending on the amount of UHP/PVA solution used
To assess the release of hydrogen peroxide (H2O2) from the UHP/PVA films, the production
of iodme and oxygen were measured from a secondary hydrated hydrogel usmg amperometric
electrochemistry.

A hydrated hydiogel layer, constituting a lower component, was formulated to include the
following ingredients by weight
Water (ex Fisher, distilled, de-ionised, analytical grade) 64 7%
Sodium AMPS (ex Lubrizol AMPS 2405 Monomer) 30 0%
Polyethylene glycol diacrylate (PEG400 diacrylate, ex UCB Chemicals, 0 19%
available as Ebecryl 11) (a cross-linker)
1-hydroxycyclohexyl phenyl ketone (ex Aldrich - 40,561-2) (a photormtiator) 0.01 %
Anhydrous glucose, (ex Fisher, analytical grade, code GO50061) 5 00%
Potassium iodide (ex Fisher, analyical grade, P584050) 0 05%
Zinc L-lactate hydrate (ex Aldrich) 0 10 %
The mixture was dispensed into casting trays containing a polyester scrrm (polyester ~non-
woven, open mesh support, available from HDK Industries Inc, Product Code 5722) of
dimensions 100mm. x 100mm, to a depth of about 1 5mm The hydrogel was then set, by
exposure to irradiation under a UV lamp for up to 60 seconds at a power rating of
approximately lOOmW/cm2, The hydrogel was then allowed to cool to 30°C or below.
Measurements were made using an Ezescan instrument and software supplied by
Whistoribrook Technologies, Luton, UK (Ezescan is a Trade Mark) Measurements were
made using a sensor comprising an alumina substrate screen printed with carbon paste
(ED5000 from Electa Ltd, UK) to produce 3 electrodes (working, reference and counter
electrodes) The reference electrode was further coated with Ag/AgCl paste. To measure
oxygen, and to prevent interference from the hydrogen peroxide, the oxygen sensor was
wrapped and sealed in a single layer of Teflon fluorocarbon 0.005 inches (0 013mm) thick
(Teflon is a Trade Mark) This formed a chamber into which electrode buffer could be
placed To measure iodine production, a potential of -lOOmV was applied over 16 hours, and
to measure oxygen production, a potential of -550mV was applied over 16 hours

Iodine Measurement
The open sensor was attached to the Ezescan instrument via a suitable connector block and
lead The block and sensor were contained inside a chamber, to minimise water loss through
evaporation 25pl of a 0 1M KC1 solution was added to the working electrode. A 5 x 5 x
0 1cm square of the secondary hydrogel was placed onto the KC1 and sensor, so that the
working electrode was under the centre of the hydrogel A 2 x 2 cm square of the UHP/PVA
film was placed onto the centre of the hydrogel, directly above the electrode The potential
was then applied, and the experiment carried out over 16 hours, at 25°C, reading the current
generated every minute.
As UHP is released, the peroxide oxidises iodide to iodine and diffuses throughout the
hydrogel The iodine can then be reduced at the electrode, and the current generated used as a
marker for the release of peroxide
The results are shown in Figure 1 The results show that (I) lodme was produced, and (li) the
different weight of the PVA/UHP film released an increased amount of UHP
Oxygen Measurement
The sensor was filled with 0 1M KC1, and soaked in this solution for 24 hours before use The
sensor was rmsed and refilled with fresh 0.1M KC1. The open end was sealed off, to prevent
fluid loss. The sensor was attached to the Ezescan instrument via a suitable connector block
and lead The block and sensor were contained in a chamber, to minimise water loss through
evaporation To the Teflon above the sensor, 25ul de-iomsed water was added, and a potential
of ~550mV then applied The current response was monitored until this formed a plateau at
approximately -2.5j.iA mdicatmg equilibration with atmospheric oxygen The water was then
removed and replaced with 25pl O.lmg/ml catalase in water (equivalent to 6 units of activity)

Onto this, a 5 x 5 cm squaie of the secondary hydiogel was placed, followed by a 2 x 2 cm
square of the UHP/PVA film The experiment was performed over 16 hours, at 25°C, reading
the current every minute The principle of the technique was identical to that of the
commercially available 'Clark oxygen sensors' If oxygen is produced by catalase- mediated
decomposition of hydrogen peroxide, it will diffuse through the Teflon layer into the electrode
electrolyte and equilibrate in the KCI, where it will be reduced at a working electrode poised
at -550 mV vs the Ag-AgCl reference electrode. The resultmg cathodic current is
proportional to concentration of dissolved oxygen
Results are shown in Figure 2, which is a graph of oxygen production expressed as a
percentage of atmospheric oxygen (taken as 100%) versus time. The Teflon coated sensor was
equilibrated with atmospheric oxygen (the plateau marked as 100%). At approximately 50mins
after the start of the run, catalase was applied to the Teflon surface, followed by the hydrogel
layer (the same composition as used for the lodme experiments), then the PVA/UHP film was
added uppermost
Figure 2 shows that (i) oxygen was produced and was measurable at the electrode, and (n) the
increased weight of the PVA/UHP films delivered different volumes of oxygen.
Example 2
5%w/w PVA solution was prepared as described in Example 1.
5%w/w PVP solution was prepared by dissolving 5g PVP (360,000 average molecular weight,
Sigma Code PVP360) in 95g DI water The PVP is cold water soluble and does not require
any further treatment
Using these stock solutions, the following were prepared"

Sample 1* to 5% PVP solution, water was added to give 0.5%w/w Final [PVP] =
4.92 %w/w
Sample 2 to 5% PVA solution, UHP was added to give 1 4%w/w Final [PVA] =
4.93 %w/w pH = 5 9
Sample 31 as sample 2, but pH adjusted with small volume of citric acid to give pH 4 3.
Sample 4 to 5% PVA solution, UHP was added to give 1 4%w/w, and PVP was added to
give l%w/w Final [PVA] =4.88% pH = 5 9
Sample 5. as sample 4, but pH adjusted with small volume of citric acid to give pH 4 3.
lOg of each sample was dispensed into an 8 4cm diameter petri dish, and dried at 40°C for
18hours Samples 2-5 were then stored in a desiccator at RT (about 21°C), while sample 1 was
stored undesiccated at RT (about 21°C)
Samples were tested for hydrogen peroxide, usmg the following method.
lOmg of each film was removed and placed mto a 7ml bijou container 1ml of DI water was
added, and the samples were soaked for 30mins to allow the hydrogen peroxide to diffuse out
To a 4ml cuvette, 2 2ml DI water, 0.5ml 0.1M Na phosphate pH 5 0 (with citric acid), 0 1ml
lmg/ml lactoperoxidase, 0 1ml 3mg/ml TMB (tetra methyl benzidine) in DMSO were added
0.5ml of the sample-soaked water was then added to the cuvette, mixed and allowed to stand
for 5mins for the colour to develop After 5mins, the colour was then read at 630nm The
quantity of hydrogen peroxide present was then estimated from a standard curve of hydrogen
peroxide in water, assayed usmg the same assay method
The results in Figure 3 demonstrate the hydrogen peroxide stability in PVP, PVA and
PVA+PVP films Within the testing period, stable hydrogen peroxide films were maintained.
The use of PVP would appear to aid hydrogen peroxide stability within the films This is
thought to be due to the known complexation between PVP and hydrogen peroxide

Example 3:
5 %w/w PVA solution was prepared as described in Example 1
PVP (360,000 average molecular weight, Sigma Code PVP360) and H202 (30%w/w, Sigma
Code H1009) were added to the 5 % PVA solution to give final concentrations of 1 % and
0.5% respectively PVA final concentration was 4 85% 20g of this mix was poured into a
10cm2 dish and dried at 40°C for 16 hours
Secondary hydrogel layers were prepared using the following formulations
Reagent Gel 1 Gel 2 Gel 3 Gel 4
Water (ex Fisher, distilled, de-ionised, analytical grade) 64 7% 67 8% 69 7% 69 8%
Sodium AMPS (ex Lubrizol AMPS 2405 Monomer) 30 0% 30 0% 30 0% 30 0%
Polyethylene glycol diacrylate (PEG700 diacrylate, ex 0 19% 0 19% 0 19% 0 19%
Aldnch - 455008) (a cross-linker)
l-hy&oxycydohexyl phenyl ketone (ex Aldnch - 40,561-2) 0 01% 0 01% 0 01% 0 01%
(a photornrhator)
Anhydrous glucose, (ex Fisher, analytical grade, code 5 00% 5 00% 0% 0%
GO50061)
Potassium iodide (ex Fisher, analyical grade, P584050) 0 05% 0 05% 0 05% 0.05%
ZincL-lactate hydrate (ex Aldnch) 010% 0% 0 10% 0%
50g of each of the formulations was poured into a 10cm2 dish and polymerised under lOOmW/
cm2 UV radiation, for 25seconds The gels were removed and stored at 4°C before use
The effect of glucose and lactate in the secondary hydrogels was examined using iodine as a
marker for H202 release The open sensor was attached to the Ezescan mstrument via a
suitable connector block and lead The block and sensor were contained inside a chamber, to
minimise water loss through evaporation 30j.il of a 0 1M KC1 solution was added to the
working electrode. A 5 x 5cm square of the secondary hydrogel was placed onto the KC1 and

sensor, so that the working electrode was under the centre of the hydrogel A 2 x 2 cm square
of the H202/PVA firm was placed onto the centre of the hydrogel, directly above the
electrode The potential was then applied, and the experiment carried out over 16 hours, at
25°C, reading the current generated every minute
As H202 is released, the peroxide oxidises iodide to iodme and diffuses throughout the
hydrogel The iodme can then be reduced at the electrode, and the current generated used as a
marker for the release of peroxide
Discussion*
Referring to Example 1 and Figures 1 and 2, iodme and oxygen production were a direct
consequence of peroxide release When the dried PVA/UHP layer was placed onto the
hydrogel, the PVA film hydrated sufficiently to allow the release of the UHP The PVA film
remained intact and could be removed complete Because the hydrogel contamed iodide ions,
the peroxide reacted with these to form iodine, following the equation.
H202 + 2 T + 2H+ ► I2 + 2H20
The iodme would then diffuse through the gel and to the sensor electrode. As Figure 1 shows,
the response was UHP volume dependant, with the heavier weight of PVA film delivering a
larger iodine response When the iodide was exhausted, the iodme graphs declined This was
due to the iodme in the hydrogel vaponsmg from the surface, thus driving the iodme
concentration in the hydrogel down
The oxygenation graph of Figure 2 also demonstrated the release of UHP from the PVA film,
after hydration in contact with the hydrogel The sensor was equilibrated with ambient air, to
gain a stabilised graph This was taken as 100% A decrease from this point would indicate
that the oxygen concentration at the sensor was being lowered, while any mcrease would show

that the oxygen concentration was being raised above that of the ambient an Figure 2 clearly
showed that an increase in the oxygen concentration relative to that of an was taking place
Again, the weight of the PVA film gave a different oxygen response, indicating that the
increased PVA film thickness was able to deliver more IMP into the hydrogel below Also,
the hydrogel formulation was the same as that used with the iodine experiments, i.e. the
hydrogel contamed iodide, and so was producing iodine during the oxygenation experiment.
This showed that UHP was in excess, and was able to drive both the iodine and oxygen
production.
Further, the graph presented in Figure 3 clearly demonstrates that hydrogen peroxide can be
formulated as stable, dry films Hydrogen peroxide was formulated into PVA-only films,
PVA + PVP films, and a PVP-only film PVP is known to form complexes with hydrogen
peroxide, and it is therefore assumed that the PVP present in the formulations aided hydrogen
peroxide stability during drying and storage The graph showed that as the %PVP was
increased (from 0% to 1 % to 5%), the recoverable hydrogen peroxide also mcreased. The use
of PVP in the formulation is therefore advantageous as an hydrogen peroxide stabiliser, but it
is not essential smce PVA-only films also provide a stable hydrogen peroxide recovery, albeit
at a lower level
Figure 4 shows iodine production in the presence or absence of glucose and lactate within the
hydrogel. Generally, the graphs show that there is no gross effect on the production of iodine,
although there are small differences. The most likely cause of these differences is the variation in thickness of the PVA/PVP/H202 films, caused by the drying process, which would yield
different doses of H202 into the iodide containing hydrogel But overall, the graph shows that
iodine production is not hindered by the absence of glucose, lactate or both, i.e lodme
production using H202 is not dependant on the presence of glucose and/or lactate in the
hydrogel layer.

WE CLAIM:
1 A hydrogen peroxide delivery system in the form of a skin dressing,
comprising an upper component having hydrogen peroxide, and a lower component in
hydrated condition, such that when the upper and lower components are placed in
contact with each other, hydrogen peroxide migrates towards the lower component,
wherein the delivery system is free of a source of lactate ions and a supply of glucose
2 A hydrogen peroxide delivery system as claimed in claim 1, wherein the upper
component in dry condition prior to use
3 A delivery system as claimed in any one of the preceding claims, wherein the
upper and lower components are dressing components
4 A delivery system as claimed in any one of the preceding claims, wherein the
upper component comprises a polymer material
5 A delivery system as claimed in claim 4, wherein the polymer material
comprises polyvinyl alcohol
6 A delivery system as claimed in any one of the preceding claims, wherein the
upper component is in the form of a sheet, layer or film
7 A delivery system as claimed in any one of the preceding claims, wherein the
hydrogen peroxide is in the form of a hydrogen peroxide urea complex.
8 A delivery system as claimed in any one of the preceding claims, wherein the
lower component comprises a hydrated hydrogel
9 A delivery system as claimed in any one of the preceding claims, wherein the
lower component comprises iodide ions

10 A delivery system as claimed in any one of the preceding claims, wherein the
lower component is in the form of a sheet, layer or film
11 A delivery system as claimed in any one of claims 1 to 9, wherein the lower
component is in the form of an amorphous gel or lotion
12 A delivery system as claimed in any one of the preceding claims, which
optionally comprises zinc ions
13 A delivery system as claimed in any one of the preceding claims, wherein the
upper and lower components are separately packaged prior to use

ABSTRACT

HYDROGEN PEROXIDE DELIVERY SYSTEM IN FORM OF A SKIN
DRESSING
A hydrogen peroxide delivery system in the form of a skin dressing, comprising an
upper component comprising hydrogen peroxide, and a lower component in hydrated
condition, such that when the upper and lower components are placed in contact with
each other, hydrogen peroxide migrates towards the lower component, wherein the
delivery system is free of a source of lactate ions and a supply of glucose The present
invention also related to a hydrogen peroxide delivery system in the form of a skin
dressing, comprising an upper component in dry condition comprising hydrogen
peroxide, and a lower component in hydrated condition, such that when the upper and
lower components are placed in contact with each other, hydrogen peroxide migrates
towards the lower component