WO2013054138A1

WO2013054138A1 - Heat patches

Info

Publication number: WO2013054138A1
Application number: PCT/GB2012/052545
Authority: WO
Inventors: Marc Barry Brown; Daniel Guy WOOD; Colin Martin BROWN
Original assignee: The Mentholatum Company Ltd
Priority date: 2011-10-12
Filing date: 2012-10-12
Publication date: 2013-04-18
Also published as: GB201117673D0

Abstract

A heat patch comprising iron, carbon, potassium chloride and water as active ingredients, has at least two of a heat storage agent, a humectant, and a plasticiser are dissolved in or compatible with the water, thereby allowing the patch to remain flexible during and after use.

Description

HEAT PATCHES

The present invention relates to patches for the delivery of heat to the skin, and having a reaction system comprising iron, carbon, potassium chloride, and water which is capable of generating heat on exposure to air.

Many heat patches are known, based on a reaction system comprising iron, carbon, vermiculite, potassium chloride, and water. The heat release from the inorganic oxidation of iron is initiated by exposure to oxygen, such as when the patch is removed from the plastic pouch. After initiation, the patch generates heat and reaches the maximum temperature of ca. 43 °C, usually within 30 minutes, and can continue to deliver heat for up to 8 hours.

The patch is generally hermetically sealed to prevent ingress of oxygen from the air. Removal of the seal exposes the contents to the atmosphere, thereby allowing an oxidative reaction to generate a level of heat, just above skin temperature, for a period of hours. WellPatch^ Deep Heat is an example of this type of patch, and is commonly used for pain relief. The reaction system is provided in an air permeable semi-synthetic pouch, hermetically sealed in a plastic pouch to prevent product activation (i.e. heat generation). The composition, and function of the components, of this type of patch is as follows:

While this type of patch has proven successful over the years, it would be desirable to extend the duration of heat delivery. The patches also become somewhat inflexible and solidify during use, and it would be desirable to provide a patch that retained flexibility during and after use. A heating pack based on the oxidation of iron was disclosed in US-A- 1,819,807, wherein the heat generating components consisted of crushed cast iron, crushed carbon steel, Epsom salt, sodium chloride, ammonium chloride and water, with the water being kept separate, prior to use.

US-A-3,976, 049 discloses an exothermic reaction as a result of combining iron powder, a chloride or sulphate of a metal, active carbon, and water, encased in bag manufactured from a cloth or film, or multiples thereof. The film or cloth must be permeable to air or aeration holes must be added to control the air permeation.

US-A-4,366,804 discloses a device wherein the exothermic components are contained within a durable inner pouch that is permeable to both air and water. A water carrying member resides on the outside of the inner bag and presents water to the other reaction components.

US-A-5,918,590 discloses a packaging and arrangement wherein small heat cells are produced within a film using methods such as thermoforming or a vacuum and have a maximal height of approximately 1.0 cm, a diameter of approximately 2-3 cm and at least one surface permeable to oxygen.

US 2002/0119186 discloses similar iron oxidation technology to that employed in earlier devices, but effectively incorporating a transdermal patch underneath the heat patch. It is suggested that heat generated from the patch will increase drug delivery to the skin.

US-A-7,878,187 discloses heat cells comprising exothermic compositions based on the exothermic oxidation of iron, with the addition of an absorbent gelling material.

It has now surprisingly been found that it is possible to replace vermiculite with a combination of water soluble components that reduce agglomeration during and after use, thereby allowing the patch to remain flexible, even after use. While flexibility is relative, the patches of the invention generally lose little flexibility during use, with spent patches more closely resembling the patch before use than conventional patches after use.

Thus, in a first aspect, the present invention provides a self heating device for warming the skin of a subject when in use, said device containing finely divided iron, finely divided carbon, and potassium chloride all in the presence of water, said device being sealed to prevent contact of the contents with air, removal or breaking of the seal allowing air to contact the contents, thereby permitting an oxidative reaction to occur, characterised in that at least two of a heat storage agent, a humectant, and a plasticiser are dissolved in, or compatible with, the water.

An advantage of the present invention is that the resulting device remains flexible when in a flexible container, such as a bag or sachet, even after use.

Devices of the present invention may be in any suitable format suitable for application to the skin or outer layer. It is preferred that heat be able to cross any outer layer to reach the skin. Outer layers may be clothing or, in the case of animals, fur, for example. Reference herein to skin includes reference to an outer layer as described above.

Typically, the device will be in the form of a flexible bag that may be applied to the skin and conform wholly or partially to the contours thereof. The bag, or patch, may be self adhesive, non-adhesive, or may be held in place by a dressing, such as a bandage. Where used, the nature of any adhesive will be readily apparent to one skilled in the art. The device may be solid, or may be refillable, although it will be appreciated that any refilling should be performed under an oxygen-free, or substantially oxygen-free, atmosphere, in order to prevent the exothermic reaction associated with the heating function of the patch.

Devices of the present invention may be referred to herein as 'patches', although it will be appreciated that such reference includes all other forms of such devices, unless otherwise apparent from the context.

Devices of the present invention may be sealed by any suitable means. A bag may be slit open or punctured, but this will usually result in leakage of the contents. More preferably, the patch comprises at least one panel of a semi-permeable material that permits the ingress of oxygen, while preventing the egress of the contents from the patch. A removable impermeable panel may be located over the semi-permeable panel, such as by adhesive, or the patch may be sealed within an impermeable pouch or bag, for example, such that oxygen can get to the contents when the pouch is opened.

In preparation of patches of the present invention, it is preferred to mix the water with the soluble components and then to introduce the aqueous preparation into the bag under an inert atmosphere, such as nitrogen. The insoluble solid components can be added together with, but preferably before or after, the aqueous preparation, and the bag sealed, still under the inert atmosphere. The iron and carbon are generally provided in quantities known in the art. These constituents are not soluble in the water, but it is preferred that they are combined with the water, preferably in a homogeneous manner. Preferred amounts of iron are between 30 and 70% w/w of the reactive contents of the patch, inclusive, preferably between 35% and 55% w/w, and more preferably between 45% and 55% w/w.

Carbon is preferably provided in an amount between 10% and 25% w/w, more preferably between about 12 and 18% w/w.

The iron and carbon are both finely divided, by which is meant that they are particulate solids in which the average size of the particles is vanishingly small to the naked eye. More particularly, the iron particles preferably have a diameter of no more than 0.06 mm, and more preferably no more than 0.05 mm. A useful maximum diameter for iron particles has been found to be 0,044 mm. Diameters below this are more preferred, with 0.01 mm and below particularly preferred, and 0.009 mm and below being a preferred embodiment.

Carbon particle diameters are preferred to be no more than 0.2 mm, and preferably less than or equal to 0.15 mm. Particle sizes of less than 0.15 mm are preferred, and a range of sizes of 0.4 mm - 0.15 mm is a preferred embodiment. More preferred is a range of sizes that does not have a specified lower limit, but with an upper limit of 0.15 mm. Average sizes of 0.1 mm or less are more preferred, and very fine sizes of 0.08 and less, and even 0.04 mm and less are particularly preferred.

It is preferred that the components of the reaction are selected such that the oxidative reaction does not heat the device to any more than 55°C at any time after exposure to air. It is preferred that the maximum temperature is 50°C, preferably 48°C, particularly 45°C, and more preferably 42 ±2 °C, particularly 42 ±1 °C.

It is preferred that the reaction components are selected such that the device heats to an initial minimum of 38°C. This may typically take between 15 minutes and 45 minutes, although it is possible for some patches to take 1 hour or more to heat up, but such long heating times are less preferred. After this time, the reaction usually emits less heat, and it is preferred that the device does not cool to below 32°C for at least 6 hours after commencement of the reaction. It is preferred that the components of the reaction are so selected as to prevent cooling to below 32°C, when in situ at RTP, for at least 8 hours. The heat storage/release agent, the humectant, and the plasticiser are selected in place of the vermiculite used in the art. The function of these components is to be water soluble or compatible, and to be able to do two or more of: present water to iron; insulate the reaction, preventing heat loss; control oxygen permeation; and form a film.

By compatible with water is meant that the substance is hydrophilic or otherwise interacts with water molecules through surface interactions, ionic interactions or Van der Waal's interactions. Particularly larger molecular substances do not dissolve in water from size considerations, but may otherwise strongly interact with water.

Suitable examples of heat storage release materials (HSRM's) include: gels, such as celluloses, carbomers, hyaluronic acid, sepineo P600, sepigel 305, polyethylene glycol (PEG), hydroxy ethyl cellulose, carboxymethyl cellulose, natural rubbers, and gums, such as xanthan gum. Preferred heat storage release materials include HEC 250 HX, xanthan gum, and polyethylene glycols, such as PEG1000/4000.

Suitable examples of humectants include: urea, cyclomethicone, glycerol, polydextrose, sodium lactate, propylene glycol, sorbitol, triacetin, triethanolamine, glycerol. Preferred humectants include urea, glycerol and propylene glycol. It will be appreciated that some HSRM's may also serve as humectants, such as the celluloses, carbomers, hyaluronic acid, PEG, and even the aerosils, as well as numerous others that will be apparent to those skilled in the art.

Suitable examples of plasticisers include Plasdones, especially Plasdone K-90, polyvinyl pyrrolidone (PVP), copovidone, ollicoat IR, gelatine, celluloses, polycarbophil, glycerol, oleic acid, citric acid, phosphate esters, fatty acid esters, glycol derivatives, hydrocarbons and hydrocarbon derivatives, adipic acid/butanediol polyesters, epoxidised soya oils, diethyl phthalate, dibutyl phthalate, citric acid esters such as triethyl citrate and the like, castor oil, triacetin, and chlorinated paraffins.

An exemplary table of humectants and HSRM's useful in the present invention is listed in the following table, along with sub-types of the HSRM's. Excipient Classification Sub classification

Aerosil OX50 Colloidal silica

Aerosil 90 Colloidal silica

Aerosil 200 Colloidal silica

Aerosil 380 Colloidal silica

Aerosil TT600 Colloidal silica

Bentonite Colloidal silica

Silica Colloidal silica

Zeolite Colloidal silica

HEC Natural polymer

Hyaluronan HSRM Natural polymer

Sodium CMC Natural polymer

Starch Natural polymer

Xanthan gum Natural polymer

Carbopol 974 Synthetic polymer

Carbopol Ultrez 10 Synthetic polymer

Kollidon VA64 Synthetic polymer

Kolliphor 407 Synthetic polymer

PEG-400 Synthetic polymer

Plasdone S630 Synthetic polymer

Glycerin

Hexylene glycol

Propylene glycol Humectant

Triacetin

Urea

The above table provides sub-classification of the HSRMs and lists a number of humectants suitable for use in the present invention.

The polymers were selected based on their ability to retain water, with colloidal silicas retaining water in a different way to natural/synthetic polymers. The amount of water that can be retained is dependent on the polymer's molecular weight and structure, and whether it is branched or linear, for example, as well as its chemical composition.

With natural polymers, the main advantages over synthetic polymers is that they are generally cheaper to produce, less toxic, biodegradable and generally have better swellability in an aqueous environment.

Synthetic polymers are generally less prone to microbial contamination in comparison to natural polymers, have better batch uniformity as a result of their production methods, including controlled environments, and generally have better aesthetics.

The colloidal silicas have a different method of water retention, with the silanol groups on the surface of the silicon dioxide being believed to interact with water molecules via electrostatic interactions. This is believed to result in a three dimensional network which can retain water. In addition, they are generally inert, and tend to have high compatibility with other excipients.

The amounts of each component of the heat storage/release agent, the humectant, and the plasticiser may generally be varied between about 0.1 and 10% w/w, each independently, preferably between 0.2 and 5% w/w, although final amounts will depend on the nature of the component selected and the temperature and duration desired, with amounts of 0.05% and up to 12% being included within the scope of the invention, according to the purpose they are intended to serve, and as readily discernible by one skilled in the art.

Suitable subjects are any animal for which it is desired to provide warmth to an external surface, but preferred animals are mammals, preferably large mammals able to wear a patch without excess discomfort. Preferred subjects are humans.

Potassium chloride may be used in 100% saturating amounts, which are generally in the region of 1.49% w/w of the aqueous solution. This may be achieved, if desired, by incorporating excess potassium chloride (KC1) during assembly or when dissolving the KC1 in water if performed as a separate step. The excess may be removed, or some, or all, allowed to remain in order to ensure saturation. This has the advantage that the solution can remain saturated, or reach saturation or close to saturation again, when the device is heated. In general, it is preferred to use an amount of between 80 and 100% of the saturating amount of C1 in the water used. Amounts of greater than 90% w/w are preferred, and saturating, or close to saturating amounts are also preferred, especially between 95 and 100% w/w. Amounts of between 25% and 90% are useful, and a particularly preferred amount is 75% saturation and up to 10% either side of this figure, preferably as much as 5% either side.

These amounts of potassium chloride are particularly effective with levels of water > 15% w/w, and especially >18% w/w. It is preferred that the amount of water is no greater than 30%, preferably no greater than 25% w/w, and preferably no greater than 22% w/w, as too much water can dampen the reaction.

The components of the device can cross react. Small two component interaction effects on DUR₃₂ were observed between carbon and potassium chloride, and carbon and water, larger effects on DUR32 were the two component interactions observed between HEC 250 HX and water, and potassium chloride and water. The interaction between HEC 250 HX and water can be described in a linear manner where increasing the amount of HEC 250 HX in the formulation from 0.02 g to 0.43 g, whilst keeping the water at a high level (6.41 g) resulted in an increased DUR32 from 139.3 min to 260.3 min. In contrast, when HEC 250 HX was increased from 0.02 g to 0.43 g whilst water remained at the low level (2.14 g) resulted in a decreased DUR₃₂. This may be because insufficient water is provided to the iron for oxidation as HEC 250 HX is not fully hydrated and absorbs the water from the reaction. When the content of potassium chloride in the formulation is increased from 0.15 g to 1.49 g and the level of water is low (2.14 g) DUR32 increased from 13.6 min to 141.0 min. In contrast, when the content of potassium chloride in the formulation is increased from 0.15 g to 1.49 g and the level of water is high (6.41 g), DUR32 increased from 47.5 min to 352.1 min. The results with low water and high KC1 may result in a potentially a high amount of solid particulates of potassium chloride being present. If these are not in solution, then it seems unlikely that they could influence the oxidation reaction, thereby resulting in a lower DUR₃₂.

In one embodiment, the preferred constituents are; iron, carbon, HEC 250 HX, urea, Plasdone .90, potassium chloride and water. HEC 250 HX, urea, and potassium chloride were all found to be useable at or close to their maximum compatibility in water as they had minimal effect on T_max in the 2 h preliminary thermogenic screening, although it was desirable to restrict the level of Plasdone 90 to 50 % of its maximum compatibility in water due to retardation of the thermogenic properties of the heat patch. A 20 % w/w variation in the level of iron, carbon and water from the original prototype formulation is individually acceptable. It is an advantage that the patches of the invention form less/fewer agglomerates in comparison to the WellPatch Deep Heat which results in improved patch flexibility.

The present invention will be further illustrated by reference to the accompanying Figures, in which:

Figure 1 shows an assessment of bespoke hotplate temperature measurement over a 6 h time period, n=l;

Figure 2 shows the reproducibility of the WellPatch^-¹ Deep Heat patch (square) vs. MENOlnv (diamond), each point refers to the mean temperature ± standard deviation, n=5; Figure 3 shows temperature profiles generated from iron oxidation formulations employing the heat storage material, HEC 250 HX, at two concentrations (2.14 % w/w - diamonds and 0.54 % w/w - squares) as an alternative for vermiculite, n=T;

Figure 4: Temperature profiles generated from iron oxidation formulations employing the heat storage material, xanthan gum, at two concentrations (2.00 % w/w - diamonds and 0.50 % w/w - squares) as an alternative for vermiculite, n=l ;

Figure 5 shows temperature profiles generated from iron oxidation formulations employing the humectant, glycerol, at two concentrations (12 % w/w - diamonds and 4 % w/w - squares) as an alternative for vermiculite, n=l ;

Figure 6 shows temperature profiles generated from iron oxidation formulations employing the humectant, urea, at two concentrations (12 % w/w - diamonds and 4 % w/w - squares) as an alternative for vermiculite, n=l;

Figure 7 shows temperature profiles generated from iron oxidation formulations employing the humectant, propylene glycol, at two concentrations (12 % w/w— diamonds and 4 % w/w - squares) as an alternative for vermiculite, n=l;

Figure 8 shows temperature profiles generated from iron oxidation formulations employing the plasticiser, Plasdone K-90, at two concentrations (5.00 % w/w - diamonds and 1.25 % w/w - squares) as an alternative for vermiculite, n=l ;

Figure 9 shows temperature profiles assessed over 3 h of formulations based on the MEN05 formulation containing a combined vermiculite alternative from each category; heat-storage material, humectant and plasticiser, n=l . The exact composition of each formulation are summarised in Table 2, below;

Figure 10 is a schematic representation of generated heat assessment. Step 1 is the preparation of prototype patches, step 2 is the positioning of data logger probe and step 3 is the positioning of patch onto mounts for monitoring temperature; Figure 11 shows heating profiles of the WellPatch^(R) Deep Heat patch and Prototype Formulation 1, n=3;

Figure 12 shows heating profiles of Prototype Formulation 2 with HEC 250 HX at a range of percentages of the maximum 'useable' level, n=l;

Figure 13 shows heating profiles of Prototype Formulation 2 with urea at a range of percentages of the maximum 'useable' level, n=l;

Figure 14 shows heating profiles of Prototype Formulation 2 with Plasdone K90 at a range of percentages of the maximum 'useable' level, n=l ;

Figure 15 shows heating profiles of Prototype Formulation 2 with potassium chloride at a range of percentages of the maximum 'useable' level, n=l;

Figure 1 shows heating profiles of formulations with a low (10.75 % w/w), medium (19.42 % w/w) and high (26.55 % w/w) water content, n~l;

Figure 17 shows a half normal plot illustrating the relative effect of each component and/or the component interactions have on the maximum temperature (Tmax);

Figure 18 shows a selection of the effect of each component on the outcome, maximum temperature (T_max); (a) the effect of carbon, (b) the effect of urea, (c) the effect of potassium chloride and (d) the effect of water;

Figure 19 shows the effect of the two component interaction between HEC 250 HX and water on the outcome, maximum temperature (T_max);

Figure 20 shows a half normal plot illustrating the relative effect of each component and/or the component interactions have on the time to maximum temperature (t_max);

Figure 21 shows a selection of the effect of each component on the outcome, time to maximum temperature (t_max); (a) the effect of carbon, (b) the effect of potassium chloride and (c) the effect of water;

Figure 22 shows examples of a selection of the effect of two component interactions on the outcome, time to maximum temperature (t_max); (a) the interaction between carbon and potassium chloride, (b) the interaction between carbon and water and (c) the interaction between potassium chloride and water;

Figure 23 shows a half normal plot illustrating the relative effect of each component and/or the component interactions have on the duration above 32 °C (DUR₃₂); Figure 24 shows a selection of the effect of each component on the outcome, duration above 32 °C (DUR₃₂); (a) the effect of carbon, (b) the effect of urea, (c) the effect of potassium chloride and (d) the effect of water;

Figure 25 shows examples of a selection of the effect of two component interactions on the outcome, duration above 32 °C (DUR3₂); (a) the interaction between carbon and potassium chloride, (b) the interaction between carbon and water, (c) the interaction between HEC 250 HX and water and (d) the interaction between potassium chloride and water;

Figure 26 shows a half normal plot illustrating the relative effect of each component and/or the component interactions have on the duration, measure using the area under a curve with the baseline set at 32 °C (AUC32);

Figure 27 shows heating profiles of lead candidate prototype formulations from the statistical design that were close to the preferred product profile, n=l;

Figure 28 shows heating profiles of lead candidate prototype formulations from the statistical design that met the preferred product profile, n=l;

Figure 29 shows the mean thermogenic profile of heat patches comprised of seven different particle sizes of carbon (n > 2) ranging from < 0.1 mm (Carbon A) to 1.7 - 4.8 mm (Carbon G);

Figure 30 shows the mean thermogenic profile of heat patches comprised of seven different particle sizes of iron (n > 2) ranging from 0.006 - 0.009 mm (Iron A) to 1 - 2 mm (Iron G); lines relating to the thermogenic profiles of formulations containing Iron B and F have been smoothed;

Figure 31 shows maximum temperature of heat patches containing different levels of water from 0 - 50 % w/w; each value represents the mean ± range (n > 2);

Figure 32 shows temperature profiles generated from iron oxidation formulations employing bentonite, at two levels (MEN03, 11.90 % w/w and MEN04, 3.26 % w/w), n=l;

Figure 33 shows temperature profiles generated from iron oxidation formulations employing

Aerosil 200, at two levels (MEN03, 11.90 % w/w and MEN04, 3.26 % w/w), n=l ;

Figure 34 shows temperature profiles generated from iron oxidation formulations employing silica, at two levels (MEN03, 11.90 % w/w and MEN04, 3.26 % w/w), n=l;

Figure 35 shows temperature profiles generated from iron oxidation formulations employing triacetin, at two levels (MEN03, 11.90 % w/w and MEN04, 3.26 % w/w), n=l ; Figure 36 shows temperature profiles generated from iron oxidation formulations employing a combination of HEC and triacetin (1 : 1), at two levels (MEN03, 11.90 % w/w and MEN04, 3.26 % w/w), n=l;

Figure 37 shows mean temperature profiles generated from iron oxidation formulations containing the humectant, hexylene glycol at five different levels, n=l ;

Figure 38 shows mean temperature profiles generated from iron oxidation formulations containing the heat storage release material, Carbopol-974 at five different levels, n=T;

Figure 39 shows mean temperature profiles of iron, carbon and water, with potassium chloride at 5 different percentages of its maximal solubility in water, assessed in closed systems, n>2;

Figure 40 shows mean temperature profiles of iron, carbon and water, with magnesium chloride at 5 different percentages of its maximal solubility in water, assessed in closed systems, n>2; and

Figure 41 shows thermogenic profiles of key exemplar formulations that met or surpassed the Target properties; data are represented by the mean value (exemplar formulations, n=3 and WellPatch Deep Heat data as above, n=6).

The present invention will now be illustrated by reference to the following, non-limiting Examples.

EXAMPLES

Abbreviation Definition

ANOVA Analysis of variance

AUC₃₂ Area under the curve with a baseline set at 32 °C

AUC35 Area under the curve with a baseline set at 35 °C

DU 32 Duration above 32 °C

DUR35 Duration above 35 °C

HEC Hydroxyethyl cellulose

MEN Mentholatum

P probability

r² Linear regression

Tmax Maximum temperature

tmax. Time to maximum temperature EXAMPLE 1

1.1 Prototype formulation preparation and assessment

Due to immediate heat generation when the key components are combined in the presence of oxygen a method of formulation assembly had to be designed. The insoluble components (iron, carbon and vermiculite, when used) were measured into a crimp top glass vial. The glass vial was sealed and pierced with two hypodermic needles which provided an inlet and outlet for gas. Each vial was purged with gaseous nitrogen for approximately two min, following which both needles were removed. The soluble components (water, potassium chloride and the vermiculite replacements, when used) were mixed and allowed to hydrate, if necessary, prior to being added to the sealed vial containing the insoluble components using a hypodermic needle and a syringe. The prototype formulations were mixed using a vortex mixer for two min and allowed to stand for thirty min. To initiate the reaction the crimp top and septum were removed, the vial was then quickly transferred onto the bespoke hotplate (maintained at a surface temperature of ca. 32 °C, human skin surface temperature) and a probe connected to a temperature logger (UKAS calibrated, model HI141001, Hanna Instruments, UK) was inserted into the prototype formulation. Each prototype formulation was compared to the WellPatch^ Deep Heat (not in the original packaging). To ensure a direct comparison the same weight of excipients were transferred from the WellPatch^(R5 Deep Heat patch, placed into a glass vial and purged with nitrogen. To initiate the reaction, the lid was removed and a temperature logger was inserted. Upon completion, each heating profile was characterised and values for the maximum temperature (T_max), time to maximum temperature (t_max) and duration above 35 °C (DUR₃₅) were recorded, for preliminary assessment only T_max was used.

1.2 Preliminary assessment of vermiculite alternatives

Iron and carbon are essential to the reaction, so a replacement for vermiculite was sought.

Vermiculite alternatives were selected based on their properties; heat-storage release material, film/plasticiser and ability to act as humectants. A replacement for vermiculite should preferably have the following characteristics: " Ability to present water to iron

^B Insulation of the reaction, preventing heat loss (relatively high heat capacity) B Ability to control oxygen permeation ■ Ability to form a film B Be water soluble

After selection the thermogenic properties of each vermiculite alternative were assessed using the method described in 1.1 above. The formulations were prepared using the vermiculite alternatives at two different ratios (Table 1); first, the same % w/w used in the WellPatch^(R) Deep Heat patch (11.90 % w/w, MENOl, MEN - Mentholatum) and second, approximately a quarter of the current % w/w (3.26 w/w, MEN02). Due to the hygroscopic nature of several of the compounds tested (CMC sodium, Plasdone K-90, mannitol, hydroxy ethylcellulose (HEC) 250 HHX, HEC 250 HX, xanthan gum, Sepineo, Carbopol 947P and Sepigel 305), further water was required to produce useable liquid/semi-solids, such that the overall percentage of vermiculite alternative within these formulations was lower in the MENOl prototype formulations (1-5 %). The weights for the MEN02 prototype formulations were nevertheless based on 25 % of the weight used in the MENOl prototype formulations.

Table 1: Composition of prototype formulations.

^Percentage of CMC sodium, Plasdone K-90, mannitol, HEC 250 HHX, HEC 250 HX, xanthan gum, Sepineo, Carbopol 947P and Sepigel 305 was lower (1-5 %). 1.3 Investigation into combined vermiculite alternatives

Following preliminary screening of vermiculite alternatives, nine potential alternatives were shortlisted which was subsequently reduced to seven due to component similarity. Further investigation of HEC 250 HX, xanthan gum and PEG1000/4000 as potential heat storage release materials, urea, glycerol and propylene glycol as potential humectants and Plasdone K-90 as a plasticiser was conducted.

1.3, 1 Preliminary assessment of combined vermiculite alternatives

The thermogenic properties of eight prototype formulations were assessed over a period of 3 h. The eight formulations (Table 2) allowed the evaluation of each possible combination of vermiculite alternatives based on the levels used in the preliminary individual vermiculite alternative assessment.

Table 2: Preliminary assessment of combined vermiculite alternatives.

*HEC 250 HX was replaced with xanthan gum at the same % w/w in formulations marked with an asterisk.

RESULTS

1.4 Feasibility experiments

1.4.1 Experimental setup

Commercially available hotplates rely upon a temperature feedback system which may cause temperature fluctuations in the region of ± 5 °C of from the desired temperature. MedPharm modified a water based hotplate to evaluate the thermogenic properties of the exothermic systems based on iron oxidation. It was necessary to modify the hotplate, so water circulated at an adverse gradient through a series of channels, This ensured that a constant surface temperature of 32 °C (external surface temperature of human skin) was maintained throughout the experiments. A temperature fluctuation of less than ± 0.3 °C was observed over a 6 h period (Figure 1), thus the bespoke hotplate was deemed to be 'fit for purpose'.

1.4.2 Iron oxidation reproducib ility

A prototype formulation containing the essential components; iron, carbon, potassium chloride and water (excluding vermiculite) combined at the same ratio as the WellPatch^ Deep Heat patch is referred to as MENOlnv. The temperature profile of MENOlnv was assessed over a 30 minute period and compared to the WellPatch⁰^ Deep Heat patch at the same weight. The prototype formulation MENOlnv, which contained the same quantity of excipients, showed no statistical difference (p > 0.05) in heat generation over the thirty minute period (Figure 2). MENOlnv appeared to be cooling towards the end of the 30 minute experimental period, so a longer experimental period was implemented.

1.5 Preliminary screening of vermiculite alternatives

Tables 3 and 4 show the preliminary results obtained with various materials. We screened a selection of commonly used pharmaceutical excipients that were readily to hand. The excipients that were progressed were based on not only their heat storage release properties but also on how easily they would be to formulate. For example CMC did not appear to produce a useable gel under the test conditions and was not progressed on this occasion. The use of CMC as a heat storage agent, for example, is contemplated by the present invention, as are other agents that provided an acceptable T_max.

Table 3: Summary of preliminary results from high level vermiculite alternative formulations (MEN01).

Vermiculite alternative Tmax (°C) Category

Sodium CMC 49.5 Heat storage-release

Carbopol 974P 32.6 Heat storage-release

Croscarmellose sodium 0 Heat storage-release D(-)-Mannitol 32.1 Humectant

Glycerol 31.3 Humectant

Glycerol triacetate 31.8 Humectant

Hydroxyethylcellulose (250 HX) 39.2 Heat storage-release

Hydroxyethylcellulose (250HHX) 49.4 Heat storage-release

Hydroxypropylcellulose 0 Heat storage-release

Kollicot R 49.1 Heat storage-release

Liquid paraffin 0 Heat storage-release

PEG 400 31.7 Heat storage-release

PEGIOOO: PEG4000 (50: 50) 31 Heat storage-release

PEG400: PEG4000 (30: 70) 31.2 Heat storage-release

Plasdone -25 42.7 Plasticiser

Plasdone K-90 39.8 Plasticiser

Plasdone S-630 30.5 Plasticiser

Poloxamer 407 40.1 Heat storage-release

Polycarbophil 45.6 Heat storage-release

Propylene carbonate 31.6 Plasticiser

Heat storage-

Propylene glycol 31.8

release/Humectant

Sepigel 305 47.3 Heat storage-release

Sepineo P600 39.9 Heat storage-release

Sodum lactate, 50% 31.7 Humectant

Starch solution 31.3 Humectant

Urea 32.4 Humectant

Xantham Gum (Xantural 180) 50.1 Heat storage-release Table 4: Summary of preliminary results from low level vermiculite alternative formulations (MEN02).

Vermiculite alternative Tmax (°C) Category

Sodium CMC 47.5 Heat storage-release

Carbopol 974 P 41.8 Heat storage-release

D(-)-Mannitol 52.6 Humectant

Glycerol 46.1 Humectant

Glycerol triacetate 44.1 Humectant

HEC 250 HHX 52.2 Heat storage-release

HEC 250 HX 51.4 Heat storage-release

Kollicot R 40.5 Heat storage-release

Liquid paraffin 54.9 Heat storage-release

Liquid paraffin (0.38 g) 41.5 Heat storage-release

PEG 400 48.3 Heat storage-release

PEGIOOO: PEG4000 (50: 50) 47.1 Heat storage-release

PEG400: PEG4000 (30: 70) 43.6 Heat storage-release

Plasdone 25 52.9 Plasticiser

Plasdone K90 36.9 Plasticiser

Poloxomer 407 34.1 Heat storage-release

Polycarbophil 35.8 Heat storage-release

Propylene carbonate 44 Plasticiser

Propylene glycol 39.8 Humectant

Sepigel 305 38.5 Heat storage-release

Sepineo P600 32.2 Heat storage-release Sodum lactate, 50% 34 Humectant

Starch solution 50.2 Humectant

Urea 52.1 Humectant

Xantham Gum 52.5 Heat storage-release

1.5.1 Vermiculite alternative: Heat storage-release material

The maximum temperature generated from the formulations was lower when the amount of vermiculite alternative within the formulation was higher (as observed within the MEN01 prototype formulations). This is clearly demonstrated by the heat storage release material, HEC 250 HX (Figure 3). The formulation containing the low level (0.54 % w/w) of HEC 250 HX demonstrated a controlled heat generation for the first 5 min until approximately 50 °C was attained after which the temperature was maintained for the remainder of the 30 min experimental period. In contrast, the formulation that contained a higher level (2.14 % w/w) of HEC 250 HX demonstrated a slower rise to a lower maximum temperature and began to lose heat rapidly. A similar effect was observed with the formulations that contained xanthan gum (Figure 4). Although similar maximum temperatures were attained the formulation containing a higher level (2.0 % w/w) of xanthan gum lost heat at a faster rate in comparison to the formulation that contained a lower level (0.5 % w/w) of xanthan gum. It is postulated that the lower levels of heat storage release material the more accessible the water is for the reaction to proceed.

1.5.2 Verm iculite alternative : Humectants

The humectant category (including; glycerol, urea and propylene glycol) generally showed larger scale differences in heat generation at the two different levels, in comparison to the heat storage release materials. The formulations that contained lower levels (4.00 % w/w) of the vermiculite alternative were observed to generate heat, whilst formulations that contained higher levels (12.00 % w/w) predominantly prevented any heat generation. The formulations that had a low content (4.00 % w/w) of glycerol (Figure 5), urea (Figure 6) and propylene glycol (Figure 7) reached a maximum temperature of 46.1, 52.1 and 39.8 °C, respectively. However, the respective formulations with a higher content (12.00 % w/w) all showed a maximum temperature below 35 °C. It was postulated that the higher levels of humectant within the formulations proceeded to provide an excess of water to the reaction, which prevented heat generation. It is also plausible that the humectant coated the iron particles with an air impenetrable film which may prevent the exothermic reaction proceeding, resulting in no heat generation. The preliminary data suggests that urea acted as the best humectant as it reached the highest temperature and appeared to maintain the temperature for the duration of the experimental period, thus warranted further investigation.

7.5.5 Vermiculite alternative: Plasticiser

Although numerous plasticisers were tested, Plasdone K-90 (Figure 8) demonstrated prolonged steady heat generation when present in the formulation at low levels (1.25 % w/w). In contrast at higher levels (5.00 % w/w) the heating profile of the formulation appeared to peak at a maximum temperature of approximately 40 °C within 15 min and then began to cool to a temperature below the formulation with low (1.25%, w/w) Plasdone K-90 after approximately 24 min.

1.6 Combined vermiculite alternatives

1.6.1 Investigation into combined vermiculite alternatives

Following the preliminary screening of the individual components (Section 1.5) the combinations of the best performing vermiculite replacements were shortlisted, including;

- HEC 250 HHX

^■ HEC 250 HX

^■ xanthan gum

^■ urea

^■ glycerol

^■ PEG 1000 PEG 4000 0 propylene glycol ^■ Plasdone K-25 H Plasdone -90

Prior to investigation into the thermogenic properties the list was shortened to seven vermiculite alternatives. HEC 250 HHX and Plasdone IC-25 were removed from further assessment due to chemical similarities in comparison to HEC 250 HX and Plasdone K-90 respectively. Each formulation generated temperatures above the specified lower limit, 35 °C (Ref. 1) with exception of the MEN05-F8; the formulation that contained xanthan gum, PEG 4000/PEG 1000 and Plasdone K-90. Results are shown in Figure 9. The lack of heat generation may have been due to coating of the iron particles potentially preventing air permeation on the site of reaction, thus preventing heat generation. However, when xanthan gum was replaced with HEC 250 HX (MEN05-F4) heat generation was observed where a maximum temperature of 44.1 °C was reached within 15 min. Furthermore, the temperature remained above 35 °C for 160 min. It was noted from visual inspection that all of the formulations which contained xanthan gum were thicker and drier than the respective formulations with HEC 250 HX and as such a formulation based on xanthan gum may potentially present problems with future device selection. Despite this the most promising result from these prototype formulations was exhibited by, MEN05-F1, a formulation that contained HEC 250 HX, urea and Plasdone K-90 as the combined vermiculite alternatives. MEN05-F1 reached a maximum temperature of 43.1 °C in 14 min and remained within an acceptable range of 35-43 °C for a duration in excess of 180 min. As such it was thought the excipient combination in MEN05-F1 warranted further investigation.

It was decided to progress with HEC 250 HX, urea and Plasdone K-90.

EXAMPLE 2

The prototype formulation used in this Example was as developed in Example 1, and is shown in Table 5. Table 5: Composition of the prototype formulation from MENl 007-01 and the WelIPatch^(R) Deep Heat patch.

2 Preferred Profile

The aim of this Example was to provide:

A retention time of > 8 hours (assessed as the time at a temperature above skin surface temperature, i.e. > 32 °C);

A patch that remained flexible;

A patch that reached an initial operating temperature of 42 ± 1 °C; and

A patch that produced fewer/small agglomerates. Materials

3 METHODS

3.1 Preparation and assessment of prototype and commercial patches

3, 1.1 Preparation of prototype patches

Due to the requirement of the presence of oxygen for heat to be generated, the preparation of prototype formulations was performed in an inert atmosphere (nitrogen gas). The insoluble components (iron and carbon) were weighed into glass vials and sealed until required. The soluble components (HEC 250 HX, urea, Plasdone K90, potassium chloride and water) were weighed into a glass vial, mixed and allowed to hydrate prior to use. Following hydration, when required the soluble components were aliquoted into small glass vials. Under a nitrogen atmosphere the insoluble components were transferred into the glass vial that contained the soluble components and the two parts of the prototype formulation were manually mixed until the insoluble phase was uniformly distributed amongst the soluble phase. The resultant mixture was subsequently transferred into WellPatch Deep Heat packaging and sealed with tape. The patches were left in the nitrogen atmosphere for a maximum period of 5 min until required. Assessment of temperature generation was performed described below. The control WellPatch Deep Heat patch was treated in the same way as the prototype formulations - in a nitrogen atmosphere, the heat patch was opened carefully along one edge and the contents were transferred to a glass vial. Following manual mixing of the patch contents the mixture was transferred back into the heat patch and the patch was sealed with tape. The patches were left in the nitrogen atmosphere for a maximum period of 5 min until required. Assessment of temperature generation was performed as described below.

3.1.2 Temperature assessment of patches

Following assembly of the patch, the patches were stored under a nitrogen atmosphere (for a maximum of five min) prior to use. To initiate the reaction the patch was removed from the nitrogen atmosphere. A probe connected to a temperature logger (UKAS calibrated, model HI141001, Hanna Instruments, UK) was quickly attached to the centre of the patch and the patch was folded over (Figure 10, Step 2). Imminently after the probe had been attached to the patch it was positioned on two evenly spaced mounts in an attempt to ensure air circulated around on the entire patch (Figure 10, Step 3). Upon completion of the thermogenic assessment, each heating profile was characterised and values for the maximum temperature (T_max), time to maximum temperature (t_max) and duration above 32 °C (DUR₃₂) were recorded. For preliminary assessment the temperature profiles were only assessed for a 2 h period.

3.2 Restricting the limits for the statistical experimental design

3.2.1 Maximal compatibility of soluble excipients

The maximal compatibility of each soluble excipient (HEC 250 HX, Plasdone K90, Urea, Potassium chloride) in water was assessed independently. In order to establish a useable range for potassium chloride and urea, each component was weighed into a glass vial at; 0.10 ± 0.02 g₅ 0.25 ± 0.02 g, 0.50 ± 0.02 g, 1.0 ± 0.02 g and 2.0 ± 0.02 g. Water (1.0 ± 0.05 g) was subsequently added to each vial and the vial was stirred overnight. Once the maximal compatibility range had been established, further addition of the excipient was added to the vial that was just beneath optimal compatibility. The level of maximal compatibility for urea was determined at the level prior to precipitation. The maximal compatibilities for HEC 250 HX and Plasdone K90 were investigated using the same method as the other soluble excipients however the volume of water used was 5.0 ± 0.10 g and the excipients levels in the initial range were between 0.10 - 2.0 g for HEC 250 HX and 0.10 - 8,0 g for Plasdone K90. Maximal compatibility of HEC 250 HX and Plasdone K90 was determined as the point prior to complete hydration of the polymer. At maximal compatibility HEC 250 HX possessed poor gelation characteristics, as such HEC 250 HX was used at lower levels to avoid poor formulation homogeneity. Similarly, the physical properties restricted the use of Plasdone K90 as it was too tacky and viscous to produce a uniform formulation. Following identification of the maximal compatibility level, each excipient was assessed in terms of temperature generation when added independently to 'Prototype Formulation (Table 6) at a range of compatibility levels between 1 - 100 % of maximal compatibility (Table 7). Patches were constructed and the temperature was assessed for a period of 2 h as described above.

Table 6. Composition of 'Prototype Formulation 2' used to screen maximal compatibility of soluble excipients.

*Potassium chloride was only included at this level when assessing the impact of HEC 250 HX, urea and Plasdone K90 on temperature generation.

Table 7. Amount of the soluble excipient used at the percentage of their maximal compatibility level in water. Each excipient was assessed independently.

Excipient required (g / 4.27 g water)

% of maximal

compatibility in

Potassium water HEC 250 HX Urea Plasdone K90

chloride

100 % 0.43 2.18 3.03 1.49

75 % 0.33 1.64 2.27 1.12 50 % 0.22 1.09 1.51 0.74

25 % 0.11 0.55 0.76 0.37

5 % 0.02 0.11 0.15 0.07

1 % 0.004 0.022 0.030 0.015

3.2.2 Preliminary assessment of water content

Following the preliminary investigation into the 'useable' levels of soluble excipients, an acceptable level of water to be incorporated within the patch that had minimal effect on the thermogenic properties of a prototype formulation was investigated. Example 1 showed that the level of water was critical to heat generation. Accordingly, a 'useable' water content based on 'Prototype Formulation was investigated (Table 8). The patches were constructed and temperature was assessed for a period of 2 h as described above.

Table 8. Preliminary assessment of prototype formulation water content

Theoretical composition, % w/w

Component/Formulation High water Medium water Low water content content content

Iron 49.83 54.67 60.55

Insoluble

Carbon 14.75 16.18 17.92

HEC 250 HX 0.78 0.86 0.95

Urea 2.89 3.17 3.51

Soluble Plasdone K90 0.93 1.02 1.13

Potassium chloride 4.27 4.68 5.18

Water 26.55 19.42 10.75 3.3 Full factorial statistical experimental design

3.3. J Design of experiments

Upon evaluation of the limits for the statistical experimental design, a full 2⁷ factorial statistical design with five centre points was employed to investigate the level of each component required to produce prototype formulations that have properties in accordance with the preferred profile. The level of each soluble component and water to employ within the design was determined from the preliminary experiments described in 2.2 above. The level of insoluble components was set as a 20 % w/w variation of the iron and carbon levels used in 'Prototype Formulation Γ Section 1, Table 3. The levels used for the statistical design are detailed in Table 9.

Table 9. Formulation composition for full scale statistical design.

The patches were constructed and heating profiles assessed using the methods detailed in 2.1 above. The heating profiles of each formulation were assessed until the temperature had dropped below 30 °C. In addition to the usual characterisation of the heating profile (T_max, tmax and DUR32), AUC32 (area under the curve with a baseline set at 32 °C) was also recorded in an attempt to produce a more accurate representation of duration above the surface temperature of human skin. The composition and run order of the prototype formulations included are as shown in Table 10, below.

Table 10. Levels of components in each prototype formulation, H refers to high level, L refers to low level and C refers to centre level.

Composition

Prototype

HEC Plasdone Potassium formulation Iron Carbon Urea Water

250 HX 90 chloride

Runl-v22 H L H L H L L

Run2-v56 H H H L H H L

Run3-v88 H H H L H L H

Run4-v82 H L L L H L H

Run5-vl l l L H H H L H H

Run6-v60 H H L H H H L

Run7-vl33 C C C C C C C

Run8-v45 L L H H L H L

Run9-v50 H L L L H H L

Runl0-v47 L H H H L H L

Runl l-v71 L H H L L L H

Runl2-v29 L L H H H L L

Runl3-vl l L H L H L L L

Runl4-v21 L L H L H L L

Runl5-vl l0 H L H H L H H

Runl6-v83 L H L L H L H

Runl7-v54 H L H L H H L

Runl8-v67 L PI L L L L H

Runl9-v93 L L H H H L H

Run20-vl24 H H L H H H H Run21-v65 L L L L L L H

Run22-v36 H H L L L H L

Run23-vl3 L L H H L L L

Run24-vl25 L L H H H H H

Run25-vl5 L H H H L L L

Run26-v34 H L L L L H L

Run27-v59 L H L H H H L

Run28-v32 H H H H H L L

Run29-vl02 H L H L L H H

Run30-v27 L H L H H L L

Run31-vl20 H H H L H H H

Run32-v78 H L H H L L H

Run33-v89 L L L H H L H

Run34-v44 H H L H L H L

Run35-v24 H H H L H L L

Run36-v98 H L L L L H H

Run37-vl06 H L L H L H H

Run38-vl l9 L H H L H H H

Run39-vl4 H L H H L L L

Run40-v42 H L L H L H L

Run41-v39 L H H L L H L

R n42-vl23 L H L H H H H

Run43-vl30 C C C C C C C

Run44-v75 L H L H L L H

Run45-vl l7 L L H L H H H

Run46-vl l6 H H L L H H H

Run47-vl L L L L L L L

Run48-vl07 L H L H L H H

Run49-v74 H L L H L L H

Run50-v20 H H L L H L L

Run51-v43 L H L H L H L

Run52-vl31 C C C C C C C Run53-v96 H H H H H L H

Run54-vl6 H H H H L L L

Run55-v35 L H L L L H L

Run56-vl28 H H H H H H H

Run57-v38 H L H L L H L

Run58-vl22 H L L H H H H

Run59-v31 L H H H H L L

Run60-v49 L L L L H H L

Run61-v92 H H L H H L H

Run62-v87 L H H L H L H

Run63-v90 H L L H H L H

Run64-v66 H L L L L L H

Run65-v4 H H L L L L L

Run66-vl32 C C C C C C C

Run67-v84 H H L L H L H

Run68-v9 L L L H L L L

Run69-v3 L H L L L L L

Run70-v81 L L L L H L H

Run71-vl l3 L L L L H H H

Run72-v91 L H L H H L H

Run73-v55 L H H L H H L

Run74-v94 H L H H H L H

Run75-vl04 H H H L L H H

Run76-v30 H L H H H L L

Run77-vll8 H L H L H H H

Run78-v8 H H H L L L L

Run79-v97 L L L L L H H

Run80-vl7 L L L L H L L

Run81-v58 H L L H H H L

Run82-v41 L L L H L H L

Run83-v6 H L H L L L L

Run84-v64 H H H H H H L Run85-v69 L L H L L L H

Run86-v51 L H L L H H L

Run87-v5 L L H L L L L

Run88-v28 H H L H H L L

Run89-v2 H L L L L L L

Run90-vl l5 L H L L H H H

Run91-v40 H H H L L H L

Run92-vl27 L H H H H H H

Run93-v77 L L H H L L H

Run94-vl21 L L L H H H H

Run95-v72 H H H L L L H

Run96-vl26 H L H H H H H

Run97-vl l2 H H H H L H H

Run98-v25 L L L H H L L

Run99-vl03 L H H L L H H

Runl00-v26 H L L H H L L

Runl01-v7 L H H L L L L

Runl02-vl8 H L L L H L L

Runl03-v80 H H H H L L H

Runl04-v61 L L H H H H L

Runl05-v37 L L H L L H L

Runl06-v48 H H H H L H L

Runl07-v85 L L H L H L H

RunlO8-vl08 H H L H L H H

Runl09-v70 H L H L L L H

Runl l0-v73 L L L H L L H

Runl l l-v46 H L H H L H L

Runl l2-vl09 L L H H L H H

Runl l3-v63 L H H H H H L

Runl l4-v86 H L H L H L H

Runl l5-v79 L H H H L L H

Runl l6-vl29 C C C C C C C Runl l7-vl l4 H L L L H H H

Runl l8-v95 L H H H H L H

Runl l9-vl9 L H L L H L L

Runl20-vl2 H H L H L L L

Runl21-v68 H H L L L L H

Runl22-v99 L H L L L H H

Runl23-v53 L L H L H H L

Runl24-v33 L L L L L H L

Runl25-vl05 L L L H L H H

Runl26-v57 L L L H H H L

Runl27-v62 H L H H H H L

Runl28-v76 H H L H L L H

Runl29-vl01 L L H L L H H

Runl 30-52 H H L L H H L

Runl31-vl0 H L L H L L L

Runl32-vl00 H H L L L H H

Runl33-v23 L H H L H L L

3.4 Macroscopic evaluation

Visual observations of the formulations that satisfied the preferred profile were recorded prior to heat assessment, after mixing in the nitrogen atmosphere and 24 h post run. The appearance, particularly changes in the formation of agglomerates, was recorded using digital photography.

3.5 Statistical methods

The t-test was used to compare the T_max of the WellPatch Deep Heat and Prototype Formulation 1. Data were compared at the 95 % confidence level, p < 0.05. Statistical analysis could not be performed on the preliminary data due to the low number of replicates (n=l). 4 RESULTS AND DISCUSSION

4.1 Prototype and commercial patch assessment

A prototype formulation (Prototype Formulation 1) containing the components iron, carbon, HEC 250 HX, urea, Plasdone K90, potassium chloride and water was designed based on the lead formulation from the previous study MEN 1007-01. The formulation was adapted so it could be incorporated into a patch by reducing the water content. The prototype formulation was compared against the WellPatch^ Deep Heat patch in terms of heat generation for a period of 2 h (Figure 11). The T_max for the WellPatch^(R> Deep Heat patch was 36.8 ± 1.3 °C. The T_max for 'Prototype Formulation Γ was observed to be significantly higher at 45.0 ± 2.6 °C (t-test, p < 0.05).

4.2 Statistical experimental design component restriction

4.2.1 Maximal compatibility of soluble excipients

The maximal compatibility of each soluble component was evaluated to restrict the statistical experimental design in an attempt to increase the number of prototype formulations that met the preferred product profile. The visual maximal compatibility of each soluble component and 'useable' levels are listed in Table 1 1. Although HEC 250 HX hydrated at ca. 151 mg/g, it possessed poor gelation characteristics. Therefore, a lower, fully hydrated level (101.6 mg/g) was selected to investigate for the statistical design. Urea was soluble at levels ca. 1000 mg/g. However, precipitation was observed over a 24 h period therefore the amount selected to investigate for the statistical design was reduced to 511.3. Plasdone K90 was soluble at over 1000 mg/g. However, the mixture formed was observed to be highly viscous and sticky. Mixtures of this viscosity would not easily be mixed with the insoluble components to produce uniformly distributed prototype formulations, so the upper level to investigate was reduced to 708.7 mg/g. Potassium chloride was investigated at maximal optimal compatibility (348.0 mg/g), as it was observed to be physically stable over a 24 h period. Table 11. Maximal compatibility of each soluble component in water.

Following visual assessment of the soluble components in water the effect of each component on heat generation when formulated in 'Prototype Formulation 2' at different percentages of the maximal 'useable' level were assessed independently over a 2 h period. The assessment of the maximal 'useable' level of HEC 250 HX (Figure 12) highlighted a narrow range of temperatures at 2 h ranging from 36.6 °C at 50 % of the maximal 'useable' level to 39.0 °C at 25 % of the maximal 'useable' level. With the exception of HEC 250 HX at 5 % of the maximal 'useable' level the trend suggested that a higher content (> 75 % of the maximal 'useable' level) of HEC 250 HX resulted in a faster t_max. Without being bound by theory, it may be that, at the lower content (< 50 % of the maximal 'useable' level) of HEC 250 HX there was too much 'free water' (not trapped within the gel matrix) within the formulation that prevented the rapid rise in temperature to an apparent volume effect. Due to the narrow range of temperatures after the 2 h preliminary assessment the maximal 'useable' level the range to be employed for the statistical experimental design was set between 5-100 %.

The temperature profiles generated with different percentages of the maximal useable level of urea demonstrated no distinct differences in heat generation (Figure 13). After 2 h the temperature ranged from 36.4 °C at 100 % of the maximal 'useable' level of urea to 38.4 °C when urea was used at 25 % of the maximal 'useable' level, These preliminary results suggested that a maximal 'useable' level between 1 and 100 % would be suitable to investigate in the full scale statistical design. Plasdone K90 maximal 'useable' levels between 1-50 % highlighted no obvious difference in terms of temperature generated during the 2 h preliminary assessment (Figure 14). In contrast, a noticeable decrease in heat generated from the prototype formulation was observed when the maximal 'useable' level of Plasdone K90 was increased above 50 %. The temperatures at 2 h time point illustrated this with the temperature decreasing by 14 °C when the Plasdone level was increased from 5 % of the maximal useable level to 100 % of the maximal useable level. A relatively small decrease in temperature of less than 1 °C was noticed when the percentage of the maximal useable level of Plasdone 90 was increased from 5 % (39.1 °C) to 50 % (38.3 °C). Without being bound by theory, it may be that the high amount of Plasdone within the formulation may have coated the iron particles and, hence, reduced the oxidation rate. As a result, the maximal 'useable' level of Plasdone K90 was restricted to be between 5-50 % for the statistical experimental design.

The investigation into the effect of potassium chloride level on heat generation is illustrated in Figure 15. Increasing the content of potassium chloride in the formulation would appear to slow t_max and prolong the duration. The t_max for prototype formulations that contained potassium chloride at 25, 50 and 100 % of the maximal 'useable' level are 33, 46 and 101 min, respectively. Although the screening profile is only a 2 h duration, the heating curves suggested that the prototype formulations containing a lower content of potassium chloride, for example 1 % of the maximal 'useable' level did not reach the same T_max, and lost heat towards the end of the 2 h period in comparison to prototype formulations that contained a higher level of potassium chloride (i.e. 100 % of the maximal 'useable' level) that appeared to still be generating heat up to the 2 h period. Thus, it appears that potassium chloride acts primarily to sustain the reaction. This is in contrast to the previous teaching of the art, which holds that KC1 acts as a reaction catalyst.

4.2.2 Prelim inary assessment of water content

Following the preliminary investigation into the useable limits of the soluble components the effect of water on heat generation was assessed. Example 1 shows the importance of water within the formulation. Too high (ca. 38 % w/w) and too low (ca. 24 % w/w) water content lead to heat generation that did not fit the preferred profile when not present in a bag or sachet (data not shown). In the present Example, the heating profiles of the prototype formulations with a medium (19.42 % w/w) and high (26.55 % w/w) water content were almost identical with a T_max of 44.9 °C and 45.1 °C, respectively. A marginal increase in T_max was observed from the formulation with low water content (47.1 °C). Based on the preliminary results the level of water for the statistical design was selected to remain approximately between 10-27 % w/w. As such, it appears that less water is required for patch based systems, in comparison to the paste-like systems evaluated in Example 1, possibly because the water is 'trapped' within the patch system. The water in the paste like systems was potentially lost to the surroundings, as it was not contained within a patch, so that a higher amount of water was required within the formulation to reach the desired temperatures.

4.3 Statistical design

Following the determination of the useable levels of soluble components within the prototype formulations a full scale 2 factorial design was conducted to optimise the thermogenic properties of the formulation with the aim to develop formulations that would meet the preferred product profile. For ease of result interpretation each component within the statistical design was assigned a letter; iron (A), carbon (B), HEC 250 HX (C), urea (D) Plasdone K90 (E), potassium chloride (F) and water (G).

4.3.1 Maximum temperature (T_max)

The mathematical model generated by the statistical design was of above average fit to the experimental data for T_max once hierarchically corrected (r² > 0.63, ANOVA, p < 0.0001). The half normal plot, a graphical representation each parameter has on the outcome (Figure 17) illustrated that potassium chloride (F) had the greatest effect on T_max (shown by the furthest proximity to the linear plot), although several other independent components exerted an effect (carbon (B), urea (D) and water (G)). Upon hierarchical correction of the half normal plot further components were shown to exert an effect on T_max, however the effect was not of the same magnitude as observed with the previously listed components. Significant multi-component interactions were also highlighted by the half normal plot, with the two component interaction between HEC 250 HX and water exerting the greatest effect on T_max.

The key independent effects exerted on T_max by carbon, urea, potassium chloride and water are graphically represented in Figure 18. If there were no multi-component interactions, increasing the amount of carbon from the low amount (2.85 g) to the high amount (14.43 g) would increase T_max from 31.9 °C to 35.2 °C (Figure 18a). The porous nature of the carbon used within the formulation may absorb and retain water subsequently presenting the water to the iron at low levels in a thin film of water, which would be likely to mean that the oxygen absorbed within the water can reach the iron with greater ease than if there was a thicker film of water (either due to lower carbon content or higher water content). The thin film of water caused by the carbon content within the formulation would not absorb as much heat in comparison to a thicker film of water surrounding the iron, so that heat would be lost from the system and a higher temperature recorded. Increasing the content of urea in the formulation from the low level (0.02 g) to the high level (2.18 g) was shown to decrease T_max from 35.1 °C to 32.0 °C (Figure 18b). Urea is believed to act as a wetting agent within the formulation, and it is possible that a high level of urea would increase the level of water surrounding the iron particles, effectively forming a less air permeable film, hence decreasing the speed at which oxidation could occur.

Potassium chloride was found to exert the largest independent effect on T_max, whereby increasing the amount from the low level (0.15 g) to the high level (1.49 g) would result in an increased T_max of 7.3 °C to 37.2 °C (Figure 18c). Potassium chloride has previously been thought to catalyse this reaction. In this Example, the increased T_max with a high level of potassium chloride appeared to be due to the change in pH of the water within the formulation, thereby favouring one stage of the multi-step redox reaction of iron to iron oxide. Similar to potassium chloride, the higher the water content within the patch, the higher the maximum temperature. When the water content was increased from the low level (2.14 g) to the high level (6.41 g), this increased T_max from 32.2 °C to 34.9 °C (Figure 18d). This outcome contradicts the expected effect of water on T_max, where a higher content of water might have been expected to result in decreased T_max due to a combination of volume effect and the heat capacity of water. The effect observed here may be because the water content threshold was not reached and the high amount of water required to lower the T_max in the reaction was not included in the experimental design. It is possible for a volume effect could be observed with excess of any component within the formulation and is not only observed with water.

The two component interaction between HEC 250 HX and water was observed to have the greatest impact on T_max (Figure 19). This can be described in a linear manner where changing the level of HEC 250 HX from 0.02 g to 0.43 g at a high level of water (6.41 g) resulted in an increased T_max from 32.2 °C to 37.6 °C. In contrast when a formulation had a low level of water (2.14 g) changing the level of HEC 250 HX from 0.02 g to 0.43 g resulted in a decreased T_max from 34.3 °C to 30.1 °C. This reason for this was thought to that a fully hydrated HEC 250 HX was present at high HEC 250 HX and high water content resulting in controlled presentation of water to the reaction but at a low level of water the HEC 250 HX may not have been completely hydrated so when moisture was released as a result of a temperature rise from the reaction the 'free water' was potentially absorbed and retained by the partially hydrated HEC 250 HX.

4.3,2 Time to maximum temperature (t_max)

Despite the relative problems in recording an accurate point for t_raax and numerous multi- component interactions a relatively good correction between the experimental data and the mathematical model was observed after hierarchal correction (r > 0.74, ANOVA, p < 0.0001). The half normal plot illustrated that carbon (B), potassium chloride (F) and water (G) all exerted an effect on t_max, with potassium chloride exerting the largest effect (Figure 20). Several multi -component interactions were also observed, the interaction between carbon and potassium chloride, carbon and water and potassium chloride and water were shown to be of importance.

The key single component effects exerted on t_max by carbon potassium chloride and water are illustrated in Figure 21. If there were no multi-component interactions present, increasing the level of carbon from 2.85 g to 4.27 g would increase t_max from 19.7 min to 35.1 min (Figure 21a). The independent effect that had the greatest impact on t_max was the level of potassium chloride. Increasing the level of potassium chloride from the low level (0.15 g) to the high level (1.49 g) increased t_max by 28.5 min to 41.7 min (Figure 21b). It is possible that potassium chloride changes the pH of the solution to a less favourable pH for one of the steps in this multi-step oxidation reaction which resulted in a slower t_max. The level of water had the second largest independent effect on t_max where increasing water content from the low level (2.14 g) to the high level (6.41 g) increased the t_max from 17.7 min to 37.1 min (Figure 21c). It was postulated that the longer t_max with increased water content was a result of a 'volume effect' where the higher volume of water would take longer to reach an elevated temperature in comparison to a small volume of water. A selection of two component interactions that exerted an effect on t_max are graphically represented in Figure 22. Small but noticeable effects on t_max of two component interactions were noted between carbon and water (Figure 22b) and potassium chloride and water (Figure 22c). However, the two component interaction that had the greatest effect on t_max was the interaction between carbon and potassium chloride (Figure 22a). When increasing the level of carbon from 2.85 g to 4.27 g with a low level of potassium chloride (0.15 g) t_max decreased by 0.4 min to 13.0 min. In contrast when the formulation had a high level of potassium chloride (1.49 g) changing the carbon level from 2.85 g to 4.27 g increased t_max from 26.0 min to 57.31 min.

4.3.3 Duration above 32 °C (DUR₃₂ andAUC₃₂)

In an enclosed system that generates heat via the oxidation of iron determination of the duration above 32 °C can be evaluated with a relatively high amount of accuracy as the component levels remain the same throughout the experiment, i.e. water is not lost during heat generation because of evaporation as the patch is sealed. Duration above 32 °C was determined using the time taken for the temperature to drop beneath 32 °C (DUR₃₂) and in an attempt to distinguish between prototype formulations that generated heat marginally above 32 °C for prolonged durations and prototype formulations that generated more heat over a shorter duration area under the curve (AUC₃₂) was also used to interpret the data.

DUR₃₂ was shown to be a relatively good fit to the mathematical model upon hierarchal correction (r² > 0.66, ANOVA, p < 0.0001), illustrated by Figure 23. A multi -component interaction between HEC 250 HX (C), potassium chloride (F) and water (G) was observed to influence DUR₃₂. It appeared that the saturation level of potassium chloride in the water was sufficiently high to prolong the reaction but in combination with HEC 250 HX at close to maximal hydration presented water to the iron in a cycled manner controlling the reaction, i.e. as the iron generated heat, water evaporated and was reabsorbed by HEC 250 HX then presented to the iron again. The half normal plot highlighted that potassium chloride (F) had the greatest independent effect on DUR₃₂ (Figure 23). Water (G), carbon (B) and urea (D) were also observed to influence independent effects on DUR₃₂.

Providing there are no multi-component interactions increasing the amount of carbon from 2.85 g to 4.27 g would increase DUR₃₂ from 89.2 min to 187.9 min (Figure 24a). Increasing the level of carbon may allow better circulation of air around the reaction components improving the available surface area for the redox reaction to occur. Increasing the amount of urea from 0.02 g to 2.18 g in the formulation was found to decrease DUR32 from 178.7 min to 98.4 min. The decrease in duration with a higher amount of urea in the formulation was thought to be due to urea acting as a 'wetting agent' resulting in a similar effect on duration that would be expected with a high quantity of water (Figure 24b). The most significant independent effect on DUR32 was the effect of potassium chloride (Figure 24c). Raising the level of potassium chloride in the formulation from 0.15 g to 1.49 g increased DUR₃₂ by 206 min from 30.5 min to 246.5 min. This data is contradictory to what is commonly thought, and supports the proposition that potassium chloride may sustain the reaction rather than act as a catalyst. Water was also observed to contribute significantly to increased duration of the reaction (Figure 24d). When the water level was increased from 2.14 g to 6.41 g DUR32 increased from 77.3 min to 199.8 min. As the oxidation reaction occurs within a thin film of water surrounding the iron particles a higher amount of water should decrease the heating duration however, it was thought that the level of water used within the restricted range of the patch was below the threshold of water required to reduce the temperature produced.

The key multi-component effects on DUR32 are illustrated in Figure 25. Although small two component interaction effects on DUR₃₂ were observed between carbon and potassium chloride (Figure 25a) and carbon and water (Figure 25b), the most significant effects on DUR₃₂ were the two component interactions observed between HEC 250 HX and water (Figure 25c) and potassium chloride and water (Figure 25d). The interaction between HEC 250 HX and water can be described in a linear manner where increasing the amount of HEC 250 HX in the formulation from 0.02 g to 0.43 g whilst keeping the water at a high level (6.41 g) resulted in an increased DUR₃₂ from 139.3 min to 260.3 min. In contrast, when HEC 250 HX was increased from 0.02 g to 0.43 g whilst water remained at the low level (2.14 g) resulted in a decreased DUR₃₂ (Figure 25c). It was postulated that the effect observed was due to insufficient water provided to the iron for oxidation as HEC 250 HX is not fully hydrated and absorbs the water from the reaction. The interaction between potassium chloride and water is illustrated in Figure 25d. When the content of potassium chloride in the formulation is increased from 0.15 g to 1.49 g and the level of water is low (2.14 g) DUR32 increased from 13.6 min to 141.0 min, In contrast, when the content of potassium chloride in the formulation is increased from 0.15 g to 1.49 g and the level of water is high (6.41 g) DUR32 increased from 47.5 min to 352.1 min. This could be due to the fact that with a low amount of water and high amount of potassium chloride there are potentially a high amount of solid particulates of potassium chloride present. As these were not in solution it was thought that the potassium chloride would not influence the oxidation reaction resulting in a lower DUR₃₂.

AUC32 was used in addition to DUR₃₂ to provide an alternative analysis of the effect of each component on the duration of the experiment. The same key independent and multi- component interactions were identified, although a marginally improved correlation to the mathematical model upon hierarchal correction (r > 0.69, ANOVA, p < 0.0001), illustrated by Figure 26, was observed. AUC32 confirmed that the most profound effect on duration could be attributed to the potassium chloride level within the formulation.

4.3.4 Summary of the statistical design

Following interpretation of the statistical design, ten lead prototype formulations that accorded closely with the preferred profile, were identified and considered in greater detail. Prototype formulations that did not reach the minimum required temperature (32 °C) or significantly exceeded the maximum temperature were dismissed as potential formulations. The thermogenic properties of each of the 128 prototype formulations and 5 centre points are summarised in Table 12, below.

Table 12. Summarised results from the prototype formulations from the statistical design,

Prototype Tma tmax DUR₃₂ AUC₃₂ formulation (°C) (min) (min) (min.degree)

Runl-v22 23.9 3 0 X

Run2-v56 33.6 87 111 97.1

Run3-v88 36.4 26 42 122.1

Run4-v82 27.2 16 0 x

Run5-vl l l 39.3 34 524 2441.9

Run6-v60 45 22 78 601.1

Run7-vl33 47.9 193 445 4919.1

Run8-v45 35.9 16 25 59.8 Run9-v50 48.5 35 453 3658.2

Rutil0-v47 30.6 14 0 X

Runl l~v71 40.9 25 73 432.6

Runl2-v29 24.1 2 0 5609.0

Runl3-vll 33.5 8 10 9.4

Runl4-v21 24.5 4 0 X

Runl5-vl l0 46.3 70 713 5609.0

Runl6-v83 41.6 17 61 304.4

Runl7-v54 29.2 13 0 X

Runl8-v67 45.1 25 283 2299.0

Runl9-v93 31.9 15 0

Run20-vl24 42.5 98 614 3483.8

Run21-v65 35 27 111 202.7

Run22-v36 45.1 23 343 3063.4

Run23-vl3 25 9 0 X

Run24-vl25 45.8 44 194 1407.4

Run25-vl5 24.1 10 0 X

Run26-v34 48.9 37 281 3732.8

Rim27-v59 33 15 14 9.1

Run28-v32 26 4 0 X

Run29-vl02 45.2 56 259 1889.6

Run30-v27 24.2 6 0 X

Run31-vl20 42.1 32 800 3910.5

Run32-v78 37.8 22 38 135.5

Run33-v89 24.6 2 0 X

Run34-v44 47.7 64 223 2257.7

Run35-v24 23.7 5 0 X

Run36-v98 36.2 52 315 724.8

Run37-vl06 24.4 3 0 X

Run38-vl l9 46.4 102 516 5134.9

Run39-vl4 47.5 43 205 2165.2

Run40-v42 29.8 11 0 X Run41-v39 41.1 62 275 1427.9

Run42-vl23 43.3 59 209 1433.5

Run43-vl30 46.6 145 395 4194.1

Run44-v75 26.7 3 0 X

Run45-vl l7 44.3 19 356 1920.3

Run46-vl l6 44.5 183 662 5387.5

Run47-vl 34 8 16 19.3

Run48-vl07 46.4 161 548 4972.2

Run49-v74 22.6 3 0 X

Run50-v20 24.5 12 0 X

Run51-v43 32.5 11 7 1.2

Run52-vl 1 41.1 99 443 2866.8

Run53-v96 26.1 4 0 X

Run54-vl6 30.8 12 0 X

Run55-v35 42.3 26 403 2813.1

Run56-vl28 43.2 94 481 3288.7

Run57-v38 44.4 75 244 2264.0

Run58-vl22 25.8 2 0 X

Run59~v31 26.8 9 0 X

Run60-v49 43.6 36 304 2332.6

Run61-v92 27.8 4 0 X

Run62-v87 41.8 28 159 957.1

Run63-v90 23.5 2 0 X

Run64-v66 40 24 187 945.0

Run65-v4 35.9 14 41 110.9

Run66-vl32 47.7 136 429 4977.7

Run67-v84 39.7 21 393 1128.5

Run68-v9 35.2 11 20 40.3

Run69-v3 36.3 27 57 184.5

Run70-v81 24.5 2 0 X

Run71-vl l3 24.5 3 0 X

Run72-v91 26 4 0 X Run73-v55 44.4 56 232 1705.5

Run74-v94 25.3 66 0 X

Run75-vl04 42.7 89 943 4832.7

Run76-v30 27.8 10 0 X

Run77-vl l8 43.3 34 677 3281.6

Run78-v8 25.6 10 0 X

Run79-v97 24.4 3 0 X

Run80-vl7 31.5 19 0 X

Run81-v58 40.8 28 236 819.8

Run82-v41 39.8 12 277 984.5

Run83-v6 28.8 9 0 X

Run84-v64 44.4 28 92 699.1

Run85-v69 27.6 27 0 X

Run86-v51 38.1 25 423 1307.5

Run87-v5 31.6 11 0 X

Run88-v28 34.6 12 19 31.1

Run89-v2 36.8 13 67 211.3

Run90-vll5 42.7 58 596 4048.2

Run91-v40 42.6 26 490 3274.4

Run92~vl27 44.4 63 552 4831.8

Run93-v77 25 11 0 X

Run94-vl21 25.2 2 0 X

Run95-v72 37.1 20 76 306.5

Run96-vl26 47.3 106 363 4053.3

Run97-vl l2 45.3 172 660 7170.5

Run98-v25 26.4 11 0 X

Run99-vl03 45.7 28 545 3088.2

Runl00-v26 25.3 7 0 X

Runl01-v7 24.5 2 0 X

Runl02-vl8 24.1 3 0 X

Runl03-v80 32.1 14 4 0.1

Runl04-v61 25.2 16 0 X Runl05-v37 28.8 12 0 X

Runl06-v48 26.3 10 0 X

Runl07-v85 32.8 21 17 8.3

Runl08-vl08 29 11 0 X

Runl09-v70 23.5 2 0 X

Runl l0-v73 28.4 8 0 X

Runl l l-v46 24.3 3 0 X

Runl l2-vl09 37.8 37 189 597.4

Runl 13-v63 24.9 0 0 X

Runl l4-v86 25.7 16 0 X

Runl l5-v79 31.6 24 0 X

Runll6-vl29 25 489 4223.5 unl l7-vl l4 32.1 27 11 0.2

Runl l8-v95 25.8 7 0 X

Runl l9-vl9 25.4 9 0 X

Runl20-vl2 28.7 6 0 X

Runl21-v68 33.5 37 76 62.3

Runl22-v99 35.4 155 390 819.5

Runl23-v53 24.6 13 0 X

Runl24-v33 28.9 10 0 X

Runl25-vl05 27.1 5 0 X

Runl26-v57 26 10 0 X

Runl27-v62 23.4 7 0 X

Runl28-v76 28.1 8 0 X

Runl29-vl01 43.1 36 150 938.1

Runl30-52 27.8 18 0 X

Runl31-vl0 23.6 2 0 X

Runl32-vl00 32 8 0 X

Runl33-v23 23.8 2 0 X Five of the lead prototype formulations that narrowly exceeded or missed T_max were still included in the selection of leads, as they satisfied a prolonged duration of over 6 h due to the thermogenic assessment of each formulation only once. These prototypes, Run5-vl l l, RunlS-vl lO, Run46-vl l6, Run77-vl l8 and Run92-vl27 are illustrated in Figure 27, and their thermogenic properties are summarised in Table 13.

Five of the lead prototype formulations (Run20-vl24, Run31-vl20, Run75-vl04, Run90- vl l5 and Run 91-v40) met the preferred product profile in terms of heat generation. The heating profiles of these formulations are summarised in Table 10 and represented graphically in Figure 28.

Table 13. Summary of thermogenic properties of lead candidate prototype formulations, n=l .

Prototype Tmax DUR₃₂ AUC32 formulation (°C) (min) (min) (min. degree)

Run5-vl l l 39.3 34 524 2441.9

Runl5-vll0 46.3 70 713 5609.0

Run20-vl24 42.5 98 614 3483.8

Run31-vl20 42.1 32 800 3910.5

Run46-vl l6 44.5 183 662 5387.5

Run75-vl04 42.7 89 943 4832.7

Run77-vl l8 43.3 34 677 3281.6

Run90-vl l5 42.7 58 596 4048.2

Run91-v40 42.6 26 490 3274.4

Run92-vl27 44.4 63 552 4831.8 The three lead prototype formulations that were identified as front runners were Run46-vl 16, Run75-vl04 and Run92-vl27. The DUR₃₂ for the lead prototype formulations were 662 min, 552 min and 943 min respectively. Although t_max may appear long this is due to minor fluctuations in the heating profiles once at maximum temperature.

4.4 Macroscopic evaluation of lead prototype formulations

The visual appearance of the lead prototype formulation were assessed prior to addition to the packaging and after a 24 h period and compared to the WeilPatch Deep Heat patch. The lead prototype formulation pre-run was a dry black powder with a uniformly distributed small particle size (not shown). Post-run (24 h after initiation) the appearance had not change significantly, it was still dark black in colour, presumably indication an excess of carbon, with slightly larger aggregates than the pre-run formulation (not shown). Prior to disassembling the patch there was still good flexibility. The good flexibility could be attributed to the small particle size of iron and carbon employed in the formulation. The pre- run appearance of the WeilPatch Deep Heat patch was a compacted black/brown powder, with a larger particle size than the lead prototype formulation (not shown). The post run appearance had changes significantly with the formation of large solid aggregates which would lead to poor patch flexibility (not shown).

4.5 Comparison of lead prototype formulations

Following identification of ten lead prototype formulations that generated temperature profiles close to the preferred profile and assessment of their macroscopic appearance their characteristics were compared against the WeilPatch Deep Heat and the preferred product profile. The preferred product has a retention time in excess of 8 h above 32 °C (human skin surface temperature) and a maximum operating temperature of 42 ± 1°C (temperature measured underneath the adhesive of the patch through the packaging not directly into the exothermic formulation). In addition, improved flexibility due to minimal product agglomeration is preferred. The ten lead prototype formulations identified from the statistical design which fit the preferred product profile are summarised in Table 14. Table 14. Comparison of lead prototype formulation to the preferred product profile.

Prototype Heat Maximal operating Smaller/Fewer aggregates than formulation generation temperature WellPatch Deep Heat 24 h post run

(>8h) (41-43 °C)

Run5-vlll X

Runl5-vll0 X X

Run20-vl24 ✓ X

Run31-vl20 ✓ X

Run46-vll6 X V

Run75-vl04

Run77-vll8 X ·

Run90-vll5 X

Run91-v40 ✓ ·

Run92-vl27 X

EXAMPLE 3 DEFINITIONS AND ABBREVIATIONS

Table 15: List of definitions and abbreviations used in the following Examples.

In this Example, the effects of iron and carbon particle size and water content thermogenic properties of patches of the invention were assessed.

Alternatives for vermiculite were assessed at different concentrations.

In addition, alternative metal salts to potassium chloride were evaluated.

4.6 Materials

Table 16: List of materials used in the study.

Material Grade Supplier

Activated carbon, Darco 12-20 mesh, granular

Reagent Sigma, UK (242241)

Activated carbon, Darco 4-12 mesh, granular

Reagent Sigma, UK (242233)

Activated charcoal (242276) Reagent Sigma, UK Activated charcoal (329428) Reagent Sigma, UK

Activated charcoal (C3014) Reagent Sigma, UK

Activated charcoal (C3345) Reagent Sigma, UK

Aerosil 200 Reagent Evonik, Germany

Aerosil 380 Reagent Evonik, Germany

Aerosil 90 Reagent Evonik, Germany

Aerosil OX50 Reagent Evonik, Germany

Bentonite Reagent Sigma, UK

Calcium chloride Reagent Sigma, UK

Carbon (242268) Reagent Sigma, UK

Carbopol 974 Ph. Eur. Lubrizol, USA

Carbopol Ultrez 10 Reagent Lubrizol, USA

Glycerol Ph. Eur. VWR, UK

Hexylene glycol Reagent Sigma, UK

Pentapharm,

Hyaluronic acid PC

Switzerland

Pharmaceutical

Hydroxyethyl cellulose 250 HX Ashland, USA grade

Iron (12310) Reagent Aldrich, UK

Iron (209309) Reagent Aldrich, UK

Iron (44890) Reagent Aldrich, UK

Iron granules Reagent Alfa Aesar, UK

Iron powder Reagent Alfa Aesar, UK

Iron sponge Reagent Alfa Aesar, UK

Kollidon VA-64 Reagent BASF, Germany

Magnesium chloride Reagent Sigma, UK

PEG-400 Ph. Eur. VWR, UK

Plasdone S-630 Reagent ISP, UK

Potassium chloride Ph. Eur. VWR, UK

Potassium nitrate Reagent Sigma, UK

Potassium sulphate Reagent Sigma, UK Propylene glycol Ph. Eur. VWR, UK

Silica Ph. Eur. BUFA, Germany

Sodium chloride Ph. Eur. VWR, UK

Sodium CMC Reagent Sigma, UK

Triacetin Ph. Eur. VWR, UK

Water for injection BP Fresenius Kabi, UK

Zeolite Reagent Sigma, UK

Zinc chloride Ph. Eur. VWR, UK

METHODS

Effect of iron and carbon particle size on the thermogenic properties of a heat patch

Heat patches of the composition outlined in Table 17 were prepared using the following procedure. Seven different sizes of iron and carbon were investigated and are detailed in Table 18.

(i) Potassium chloride was weighed into suitably sized glass vials.

(ii) Water was weighed into the vial from Step (i) and the excipients were stirred until fully dissolved (observed visually).

(lit) The insoluble components; iron and carbon were weighed into a separate suitably sized glass vial and vortexed to ensure they were mixed.

(iv) The vials were placed inside a nitrogen atmosphere until required.

(v) The packaging of a WellPatch Deep Heat patch was carefully cut along the top and the contents were discarded.

(vi) In a nitrogen atmosphere, the insoluble phase from Step (iii) was added to the soluble phase from Step (ii) and thoroughly mixed until the mixture appeared visually homogeneous.

(vii) The mixture from Step (vi) was transferred into WellPatch Deep Heat packaging and sealed using a heat sealer.

(viii) The patch was agitated to ensure the contents were evenly distributed within the packaging. The patch was removed from the nitrogen atmosphere and the probe from the Hanna Instruments temperature logger was positioned in the centre of the patch and data was acquired.

Following assessment each formulation was characterised in terms of (where applicable);

• Time to maximum temperature (t_max)

• Maximum temperature (T_max)

• Duration above 32 °C (DUR₃₂)

• Area under the curve 32 °C (AUC₃₂)

Table 17. Function of excipients and composition of prototype formulation MENOl .

Table 18. Particle size of iron and carbon investigated within the heat patches.

Letter assignment Carbon particle size Iron particle size

A -100 mesh (< 0.15 mm) 6-9 μηι (0.006 - 0.009 mm)

B 100-400 mesh (0.04 - 0.15 mm) -325 mesh (< 0.044 mm)

C 20-60 mesh (0.3 - 0.8 mm) ca. 0.05 mm

D 20-40 mesh (0.4 - 0.8 mm) 200 mesh (ca. 0.074 mm)

E ca. 20 mesh (ca. 0.8mm) 100 mesh (ca. 0.15 mm)

F 12-20 mesh (0.8 - 1.7 mm) 20 mesh (ca. 0.8 mm)

G 4-12 mesh (1.7 - 4.8 mm) 1-2 mm The effect of water content on thermogenic properties of a heat patch

The level of water within the patch was investigated by changing the water content within the patch in 5 % w/w increments from 0 % up to 50 %. The compositions (% w/w) of the heat patches assessed are outlined in Table 19. The patches were prepared using the following procedure;

(i) Potassium chloride was weighed into suitably sized glass vials as before.

(ii) Water, at increasing levels, was weighed into the vial from Step (i) and the excipients were stirred until fully dissolved.

(iii) The insoluble components; iron and carbon were weighed into a separate suitably sized glass vial and vortexed to ensure they were mixed.

(iv) The vials were placed inside a nitrogen atmosphere until required.

(vi) In the nitrogen atmosphere, the insoluble phase from Step (iii) was added to the soluble phase from Step (ii) and thoroughly mixed until the mixture appeared visually homogeneous.

(vii) The mixture from Step (vi) was transferred into a WellPatch Deep Heat patch packaging. Where possible (up to 30 % w/w water) the patch was agitated to ensure the contents were evenly distributed. Above 30 % w/w water the contents of the patch were distributed using a spatula.

(viii) The patch from Step (vii) was sealed using a heat sealer, removed from the nitrogen atmosphere and the probe from the Hanna Instruments temperature logger was positioned in the centre of the patch and data was acquired.

(ix) Following assessment each formulation was characterised in terms of; Time to maximum temperature (t_max) Maximum temperature (T_max) Duration above 32 °C (DUR₃₂) Area under the curve 32 °C (AUC₃₂)

Table 1 . Composition (% w/w) of prototype formulation MEN02 used to investigate the effect of water level on the thermogenic properties of the heat patch.

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Identification of heat storage release materials, humectants and plasticisers

Identification and assessment of alternative heat storage release materials, humectants and plasticisers

Alternative excipients for use as heat storage release materials / humectants / plasticisers were selected, in order to assess the effect on the heating profile when combined with excipients involved in the exothermic oxidation of iron. The selected alternative excipients were screened at two levels (% w/w), using the following procedure:

(i) The insoluble components (iron, carbon and water insoluble alternative excipient, where applicable) were weighed into a crimp top glass vial.

(ii) The glass vial from Step (i) was sealed with a rubber septum which was pierced with two hypodermic needles to provide an inlet and outlet for gas.

(iii) The vial from Step (ii) was purged with nitrogen gas for approximately two minutes following which both needles were removed, re-sealing the vial and preventing the loss of nitrogen gas.

(iv) The soluble components (water, potassium chloride and heat storage release material / humectant / plasticiser, when used) were mixed in a glass bijou and allowed to hydrate, if required.

(v) The soluble components were transferred to the vial from Step (ii) using a hypodermic needle and a syringe.

(vi) The prototype formulation from Step (v) was mixed using a vortex mixer for two minutes

(vii) To initiate the iron oxidation reaction the crimp top and septum were removed, the vial from Step (vi) was transferred onto the bespoke hotplate (maintained at a surface temperature of ca. 32 °C, human skin surface temperature) and a probe from the Hanna Instruments temperature logger was positioned directly into the formulation.

(viii) The effect of each excipient on temperature generation was assessed over a 2 h period at two initial levels (n=T) to screen alternative excipients suitable for full assessment, as detailed below. The two levels of additional excipient and formulation compositions are outlined in Table 20.

Following assessment each formulation was characterised in terms of;

® Time to maximum temperature (t_max)

• Maximum temperature (T_max)

* DUR₃₂ (2 h)

Table 20. Composition of prototype formulations used to screen additional excipients.

Assessment of thermogenic properties of selected alternative heat storage release materials, humectants and plasticisers in closed systems

Following excipient screening, a selection of the alternative excipients that generated a maximum temperature above 32 °C were selected for further investigation at up to five different levels (% w/w).

(i) The basic composition of the heat patch employed is outlined in Table 21 and was prepared as detailed above.

(ii) Each excipient was added at up to 5 different levels (% w/w) and tested as defined above. Each measurement was performed in triplicate (n=3).

(iii) Following assessment each formulation was characterised in terms of;

• Time to maximum temperature (t_max) • Maximum temperature (T_max)

• Duration above 32 °C (DUR₃₂)

• Area under the curve 32 °C (AUC₃₂)

Table 21. Formulation composition of MEN05 used to screen potential heat storage release materials, humectants and plasticisers in closed systems.

Identification and investigation into metal salts that promote heat generation for the iron oxidation reaction

Alternative metal salts were selected for investigation. The solubility of each metal salt in water was investigated to determine levels to be incorporated within the iron oxidation formulations and the effect of the metal salts on temperature generation was investigated at a selection of different levels (% w/w) of the maximal solubility of the metal salt within water.

Solubility assessment of metal salts in water

The maximum solubility of each metal salt in water was assessed using the following procedure: (i) Accurately 0.10 ± 0.02 g, 0.25 ± 0.02 g, 0.50 ± 0.02 g, 1.0 ± 0.02 g and 2.0 ± 0.02 g of the selected metal salt was weighed into separate vials.

(ii) Water (1.00 ± 0.05 g) was added into each vial and the vial was stirred for 2 h.

(iii) The visual appearances of the solutions prepared were recorded. The approximate solubility range was established between the solutions where the metal salt was observed to dissolve and where the metal salt did not fully dissolve.

(iv) The narrowed down range was then used as a starting point and the metal salt was added gradually until the system was at the saturation point (observed visually).

Temperature assessment

The effect of each metal salt on heat generation was assessed at 5 different levels (% w/w).

(i) The composition of the heat patches are outlined in Table 22 and were prepared as outlined above. Each metal salt was included in the formulation at 5, 25, 50, 75 and 100 % of its maximal solubility in water.

(ii) Each formulation was tested as defined above, and the thermogenic properties of each formulation were assessed in triplicate (n=3).

(iii) Following assessment each formulation was characterised in terms of;

• Time to maximum temperature (t_max)

• Maximum temperature (T_{mi [})

• Duration above 32 °C (DUR₃₂)

• Area under the curve 32 °C (AUC₃₂) Table 22. Formulation composition of MEN06 to investigate the effect of different metal salts on the thermogenic properties of a heat patch.

*The level of the metal salt determined following solubility assessment

RESULTS AND DISCUSSION

Effect of iron and carbon particle size on thermogenic properties heat patches of the invention

The composition of a WellPatch Deep Heat patch (excluding vermiculite) was used to assess the effect of iron and carbon particle size on the thermogenic properties of the patch. To assess the effect of carbon size independently the level of water, potassium chloride and iron were maintained constant within the patch as was the particle size of the latter (iron). When the effect of iron particle size was assessed, the carbon particle size was kept constant. Seven different particle sizes of carbon were assessed, ranging from <0.15 mm (carbon A) to 1.7-4.8 mm (carbon G). The patches that contained the smallest particles sizes of carbon, carbon A (<0.15 mm, which includes particle sizes less than 0.04 mm) and carbon B (0.04 - 0.15 mm) were observed to generate temperatures above 32 °C, surface temperature of human skin (Figure 29). Patches that contained carbon with particle sizes above 0.3 mm (carbon C - G) were observed not to reach 32 °C.

The highest mean T_max, 41.5 °C was observed from patches containing carbon A (Table 23). Carbon A (<0.15 mm) was also observed to exhibit the shortest t_max at 45 min in comparison to the other patches containing carbon at particles sizes that generated over 32 °C. The longest DUR3₂ was also observed when the patch contained carbon A. Patches containing carbon A (<0.15 mm) and carbon B (0.04 - 0.15 mm) both generated temperatures above 40 °C, however the mean AUC32 was significantly longer when carbon A (5570.1 min.degree) was used in comparison to carbon B (1804.7 min.degree). It is assumed that surface area was a significant factor and, as such, carbon having larger particle size may be equally effective where it is porous or otherwise offers greater surface area. A higher level of variation in AUC32 was observed when the particle size was larger (carbon B, 0.04 - 0.15 mm) where AUC₃₂ ranged from 1298.9 - 2730.6 min.degree in comparison to carbon A (<0.15 mm) where the AUC₃₂ ranged from 4729.0 - 6411.3 min.degree. It is plausible that the reason for the differences observed are due to the contact between the iron and carbon, where a smaller particle size of carbon would be able to surround the iron particle with greater ease presenting a larger surface for the oxidation reaction to occur. Without being restricted by theory, it is thought that the porous carbon may absorb water and subsequently present a thin layer of water to the iron particle, which can facilitate the transfer of oxygen and promote the oxidation of iron. The effect of increased DUR₃₂ can be explained by the increase in surface area when a smaller particle size is employed. This may allow for a greater area for the redox reaction to occur and hence a sustained production of heat. Although the particle size of carbon A and B are similar, the particle sizes are described by the unit, mesh, which refers to the ability of a particle to fit within the gap on a sieve. The particle size of carbon A is -100 mesh (< 0.15 mm), the minus term prior to the number indicates that all particles pass through the sieve with a pore size of 100 mesh. Carbon B is defined as 100 - 400 mesh meaning over 90 % of particles fall within this size (0.04 - 0.15 mm). The difference in thermogenic properties observed would suggest that carbon A contains a greater number of smaller particles in comparison to carbon B resulting in a larger surface area and subsequently a higher T_max despite the suggested overlap in particle size. A T_max less than 32 °C was observed for carbon particle sizes C G inclusive, with the largest particle size (carbon G, 1.7 - 4.8 mm) producing the lowest T_max (mean T_max 22.0 °C), as such it is postulated that this may be a result of the poor contact between the iron and carbon resulting in a smaller reaction area as particle size increased, hence production of less heat as observed in Figure 29. Table 23. Summary of the thermogenic properties of heat patches containing seven different particle sizes of carbon (n>2). The numbers represent the mean with the range in brackets.

Assigned Particle size

Excipient Tmax ( C) (min) DUR32 (min) AUC32 (min. degree) letter (mm)

41.5 45.0 824.0 5570.1

A <0.15

(41.3-41.6) (38.0-52.0) (797.0-851.0) (4729.0-6411.3)

40.2 55.8 353.0 1804.7

B 0.04-0.15

(38.4-42.0) (19.0-138.0) (295.0-415.0) (1298.9-2730.6)

28.4 754.7

C 0.3 - 0.8 0 0

(24.7-29.0) (457.0- 1327.0)

23.6 136.8

Carbon D 0.4-0.8 0 0

(22.3 - 24.6) (3.0- 271.0)

23.3 10.8

E ca.0.8 0 0

(22.6 - 24.3) (2.0- 24.0)

23.2 4.0

F 0.8-1.7 0 0

(22.0-24.0) (2.0 - 5.0)

26.8

G 1.7-4.8 0 0

(22.0 ~~ 22.8) (2.0-116.0)

The effect of iron particle size was assessed in the same way as carbon and similar trends were observed. Seven iron particle sizes between 0.006-0.009 mm (iron A) to 1-2 mm (iron G) were investigated. All patches constructed using iron with a particle size less than 0.8 mm (iron A - F) generated temperatures above 32 °C (Figure 30). When the particle size of iron was greater than 1 mm (Iron G), the mean T_max obtained was 31.0 °C (Table 24). The highest mean T_masof 42.8 °C was obtained when using iron B (particle size 0.044 mm), however iron A (particle size 0.006-0.009 mm) was also observed to produce a T_max of 41.5 °C, exhibited a shorter t_max (45.0 min) and had a longer, less variable duration (mean DUR₃₂, 824.0 min) and was therefore selected for use within later formulations. Similarities in reported particle size between iron B (< 0.044 mm) and C (ca. 0.05 mm) would lead to the expectation that the thermogenic properties using these two different irons would be similar. However, this was not observed. The lower T_max observed for iron C would suggest that the average particle size of iron was larger than that of iron B, resulting in a smaller surface area for the reaction to occur and subsequently a lower T_max. Data presented in Figures 29 and 30 would suggest that the particle size of iron had less of an effect on the thermogenic properties in comparison to the particle size of carbon as the times remaining above 32 °C (DUR₃₂) were observed to be less variable.

Table 24. Summary of the thermogenic properties of heat patches containing seven different particle sizes of iron (n>2). The numbers represent the mean with the range in brackets.

Assigned Particle size

Excipient Tmax ( C) (min) DUR.32 (min) AUC3₂ (min. degree)

Letter (mm)

41.5 45.0 824.0 5570.1

A. 0.006 - 0.009

(41.3-41.6) (38.0-52.0) (797.0-851.0) (4729.0-6411.3)

42.8 317.3 781.7 4781.0

B 0.044

(42.2-43.2) (307.0-333.0) (774.0 - 795.0) (3505.7-6817.2)

38.5 112.5 731.3 2501.8

C ca.0.05

(36.6-40.1) (13.0-299.0) (647.0-858.0) (931.6 -3866.2)

35.4 406.3 690.7 897.5

Iron D ca.0.074

(31.5-38.1) (20.0-1159.0) (0.0-1217.0) (0.0-2588.7)

38.2 40.0 813.0 2528.8

E ca.0.15

(38.1 -38.2) (39.0-41.0) (772.0 - 854.0) (2468.8 -2588.7)

40.9 214.0 607.0 3531.1

F ca.0.8

(40.5-41.2) (214.0-214.0) (599.0-615.0) (3509.2-3552.9)

31.0 382.0

G 1-2 0 0

(30.9-31.0) (349.0-415.0)

The effect of water content on thermogenic properties of a heat patch

Suitable levels of water that could be incorporated within a heat patch were assessed. The thermogenic properties of patches containing the same amount of iron (iron A, 0.006-0.009 mm), carbon (carbon A, <0.15 mm) and potassium chloride but increasing levels of water from 0 - 50 % w/w are summarised in Table 25. The T_raax was observed to increase within increasing levels of water from 0 - 25 % w/w (Figure 31). The highest mean T_max was 43.2 °C which was observed with 25 % w/w water within the formulation. Addition of further water to the formulation (i.e. > 25 % w/w) resulted in a decrease in T_max obtained. The dotted line plotted on Figure 31 illustrates the trend in the data, highlighting that it appears that the effective water content within the formulation lies between ca. 3 to 29 % w/w, wherein effective is defined as the generation of temperature above 32 °C, the surface temperature of human skin. It was also observed that increasing the water content of the formulation increased the duration of the heat (Table 25). For example, when the patch contained 5 % w/w water within the formulation the mean DUR₃₂ was observed to be 360.7 min in comparison to 788.7 min where the formulation contained 25 % w/w water. Above 30 % w/w water content the formulations were observed not to generate sufficient heat (i.e. temperature greater than skin surface temperature, 32 °C). This is likely to be a result of a volume effect i.e. the volume of water within the formulation effectively saturates the formulation with liquid to a level where the volume of liquid increases the time required for oxygen to travel between iron and carbon and as a result the temperature the system can attain is reduced.

Table 25. Summary of the thermogenic properties of heat patches containing different % w/w water within the formulation (n>2). The numbers represent the mean with the range in brackets.

Water (% w/w) Tmax ( C) tmax (min) DUR32 (min) AUC32 (min.degree)

0 21.6(21.3-22.1) 29.3 (1.0-86.0) 0 0

5 37.7 (35.5-41.7) 255.3 (151.0-433.0) 360.7 (161.0-731.0) 2072.5 (75.3-5847.3)

10 39.1 (38.3 -39.7) 255.3 (222.0-289.0) 324.0 (290.0 - 346.0) 784.4(714.3-885.2)

15 39.2 (38.1 -40.2) 51.0(20.0-81.0) 592.5 (570.0-615.0) 1626.6 (1499.5- 1753.8)

20 38.3 (37.6-39.0) 66.5 (30.0- 103.0) 909.5 (816.0-1003.0) 2738.1 (2049.4-3426.9)

25 43.2 (41.9-43.8) 172.7 (38.0-254.0) 788.7 (736.0 - 842.0) 5826.3 (5757.9-5921.2)

30 27.1 (26.4-27.2) 54.7(1.0-101.0) 0 0

35 24.7(22.9-27.7) 5.7(1.0-13.0) 0 0

40 22.3 (21.8-22.8) 1.7(1.0-2.0) 0 0

45 21.7(21.1-21.9) 2.3 (2.0 - 3.0) 0 0

50 20.7 (20.6-20.9) 32.3 (2.0-92.0) 0 0

Identification of heat storage release materials, humectants and plasticisers

Vermiculite is believed to retain heat and act as a humectant and complete removal from the formulation of the art potentially reduces the heat retention of the patch. As such, in order to explore alternative excipients, additional excipients to replace vermiculite as a heat storage release material and humectant were investigated over a 2 h period and their T_max, t_max and DU ₃₂ (2 h) was recorded. The classification of each excipient as either a HSRM or humectant is detailed in Tables Al and A2 below.

It was generally observed that formulations containing the higher level (11.90 % w/w) of the alternative excipients had a lower T_max. Given the large number of excipients investigated, the thermogenic properties of each formulation is summarised in Tables Al and A2, and only a selected range of exemplar formulations that illustrated the trends observed in the two classifications of alternative excipients (HSRM and humectants) are highlighted in Figures 32 - 36.

Bentonite is an absorbent aluminium phyllo silicate, similar to vermiculite. Bentonite is an impure clay that is currently used in several medical products. Both levels of bentonite were observed to reach their T_max within 20 min. Upon reaching maximum temperature, the formulations began to cool steadily over the 2 h experimental period but remained above 40 °C (Figure 32). There was little difference between the T_max which was 57.1 °C for MEN03 (11.90 % w/w bentonite) and 59.6 °C for MEN04 (3.26 % w/w bentonite). It is anticipated that bentonite would have a greater effect on the thermogenic properties of formulations that contained higher amounts of water, as it is highly absorbent material in comparison to its weight. For example, a high level of water in the formulation without bentonite e.g. > 30 % w/w would potentially prevent a high T_max (as observed above) however if the water level was high, but the water retained and released steadily by the bentonite the patch would appear dry and would generate a higher than expected T_max.

A series of hydrophilic fumed silica (Aerosil) excipients were investigated as potential heat storage release materials as they are hydrophilic and to an extent can retain water. In this Example, five different Aerosils were investigated with different surface areas. The number following Aerosil refers to the specific surface area, i.e. 200 is 200 m²/g, with the exception of TT600 which has a specific surface area of 200 m²/g. Aerosil 90, 200, 380, TT600 and OX50 were all selected for investigation to study the effect of specific surface area of the heat storage release materials on the thermogenic properties of the patch. It was noted that the smaller bead size which results in a larger specific surface area increased T_maX} for example, the T_max at the higher % w/w level (MEN03) of Aerosil 380 was 57.0 °C, which was higher in comparison to Aerosil 200 (51.4 °C) and Aerosil 90 (49.3 °C), which is consistent with the results obtained whilst investigating the particle size of iron and carbon {supra . These observations were thought to be attributable to the behaviour of Aerosil with water. When combined with water the silanol groups on the surface of the silicone dioxide are believed to interact with the water via electrostatic interactions (e.g. hydrogen bonding and Van der Waals interactions) resulting in a three dimensional network which can retain water. These interactions, although relatively weak, may present water to the iron and carbon in controlled manner. The smaller the bead size (larger the specific surface area) would have a higher number of interactions due to more accessible silanol groups which results in a slower more controlled presentation of water and resultantly, a higher T_max.

The formulation containing the low level of Aerosil 200 (MEN04, 3.26 % w/w) demonstrated controlled heat generation for the first 16 min until a T_mas of 54.0 °C was attained after which the temperature was maintained above 45 °C for the remainder of the 2 h experimental period. In contrast the formulation with the higher level of Aerosil 200 (MEN03, 11.90 %) demonstrated a similar thermogenic profile, although the T_mas attained was 51 A °C. The higher T_max observed with the formulation containing the lower level of Aerosil 200 may have been due to better 'air flow' properties within the patch due to less excipient (Figure 33).

Silica was also investigated as a potential heat-storage release material/humectant as it was thought that the gel -like properties of silica could present water to the reaction in a controlled manner as the water is effectively trapped within the polymer and not 'free' within the patch. The two levels of silica produced almost identical heating profiles, with both MEN03 (11.90 % w/w silica) and MEN04 (3.26 % w/w silica) reaching T_max within 20 min and gradually cooling at comparable rates for the remainder of the experimental period to approximately 40 °C (Figure 34). The T_max obtained for MEN03 and MEN04 were 54.9 °C and 56.4 °C, respectively. The small difference in T_max between MEN03 and MEN04 would suggest that the two levels of alternative excipient investigated would were too close to observe the effect on heat generation from the iron oxidation reaction. It is possible a lower level of silica would result in a higher T_max as water may be released and reabsorbed by the silica at a rate that would allow efficient contact between the iron and carbon for the redox reaction to occur.

In addition to heat storage release materials, the effect of humectants on the thermogenic properties of the iron oxidation formulations were also investigated. In these examples, triacetin, a commonly used pharmaceutical humectant and a cellulose gel (HEC) were selected as they provided a good representation of the thermogenic properties exhibited by humectants (controlling the water presentation to the iron oxidation reaction, resulting in a longer t_max) and heat storage release materials (retaining heat resulting in a longer DUR₃₂). The addition of triacetin (glycerin triacetate) to the iron oxidation formulation, MEN03 at 11.90 % w/w was observed to retard heat generation, illustrated by a T_max of 34.0 °C and no noticeable temperature increases during the 2 h experimental duration (Figure 35). The addition of triacetin to the iron oxidation formulation, MEN04 at a low level, 3.26 % w/w resulted in a T_max of 46.6 °C and was also observed to increase the t_max to 40 min in comparison to the alternative excipients classified as heat storage release materials. The reason for the lack of heat generation when 11.90 % of the humectants was incorporated into the formulation (MEN03) may be attributable to the porous carbon either absorbing the humectant or being coated with the humectant and therefore potentially preventing the redox reaction occurring within a layer of water between iron and carbon hence preventing heat generation.

Upon combination of the humectant, Triacetin, with a HSRM, HEC, the temperature profiles generated for the iron oxidation formulations containing the alternative excipient at 11.90 % w/w (MEN03) and 3.26 % w/w (MEN04) were observed to change compared to the humectant alone. The triacetin and HEC were combined in a 1 :1 ratio so the total weight was equal to either 11.90 % w/w (MEN03) or 3.26 % (MEN04). The T_max for the iron oxidation formulation containing the triacetin and HEC in a 1 :1 ratio at 11.90 % w/w (MEN03) was 32.5 °C which was reached within 20 minutes, after which the temperature was maintained for the duration of the study (Figure 36). The iron oxidation formulation containing the triacetin and HEC in a 1 :1 ratio at 3.26 % w/w (MEN04) had a t_max of ca. 20 min and a higher max (51.1 °C) in comparison to triacetin alone (46.6 °C). It is postulated that the FIEC within the iron oxidation formulation that also contained triacetin, retained water within its polymer structure of HEC, reducing the level of water involved within the reaction and hence the heat capacity, which resulted in the generation of a higher T_max,

Following identification of alternative HSRM and humectants, alternative excipients that generated temperatures in excess of 38 °C or demonstrated desirable heat retention properties (i.e. long DUR ₂ (2h)) were identified for further investigation. The thermogenic properties of the alternative excipients / excipient combinations investigated are summarised in Table 26. Two representative excipients were selected, the humectant, hexylene glycol and the heat storage release material, Carbopol-974 as they illustrated the trends in heating profiles exhibited by the two groups of alternative excipients (humectants and HSRM).

When the iron oxidation formulation contained a low level (LI) of hexylene glycol a higher max and longer DUR32 were observed in comparison to when a high level of hexylene glycol was present within the formulation (L5, Figure 37). The mean T_max was observed to decrease from 38.0 °C at LI (the lowest content of hexylene glycol) to 24.2 °C at L5 (highest level of hexylene glycol). It is thought that this is a result of the humectant coating the iron carbon particles and preventing air flow for the oxidation reaction to occur.

Similarly, as the level of the HSRM, Carbopol-974, was increased from the lowest level (LI) to the highest level (L5) within the iron oxidation formulation the T_max was observed to decrease from 38.3 °C to 34.1 °C (Figure 38). The DUR₃2 of the formulations was also observed to decrease over the experimental period from 1119 min at LI to 707 min at L5. It is believed that this observation can be attributed to the water retention properties of the polymer, whereas, as the amount of polymer within the formulation is increased, water has a greater chance of remaining trapped within the polymer matrix. In contrast, when Aerosil (all varieties investigated) was incorporated into formulations in a closed system, different behaviour in comparison to Carbopol-974 was observed, i.e. when the level of Aerosil was increased T_max was also observed to increase (Table 26). It is postulated that this was a result of their different methods of water retention. Carbopol, when dry, is comprised of tightly coiled acidic polymer molecules that uncoil and cross link as they hydrate. This cross linked structure may retain water more effectively, in comparison to Aerosil, which retains water in a three dimensional network formed via electrostatic interactions (e.g. hydrogen bonding and Van der Waals interactions) of the silanol with the water resulting in a lower T_max with higher Carbopol content within the formulation as water cannot be presented to the iron and carbon for the oxidation reaction to occur.

Table 26. Thermogenic properties of selected potential heat storage release materials and humectants with iron, carbon, potassium chloride and water in closed systems at five different levels, n=l.

Excipient T ¹ max tmax DUR32 AUC32

Level

(classification) (°C) (min) (min) (min.degree)

1 32.7 72 571 28.3

2 33.5 312 468 64.7

Aerosil 90

3 37.0 450 120 1455.2 (HSRM)

4 38.3 16 907 1840.9

5 43.8 155 416 3611.1

1 34.7 301 1044 283.4

2 36.0 263 932 1513.8

Aerosil 200

3 36.7 51 187 2206.2 (HSRM)

4 42.9 670 790 5269.2

5 59.1 269 376 4499.0

Table 26 continued. Thermogenic properties of selected potential heat storage release materials and humectants with iron, carbon, potassium chloride and water in closed systems at five different levels, n=l .

Excipient Tmax tmax DUR₃₂ AUC32

Level

(classification) (°C) (min) (min) (min. degree)

1 33.6 169 212 162.2

2 36.8 164 964 3577.382

Aerosil 380

3 39.3 534 997 4558.4 (HSRM)

4 48.4 472 580 7153.7

5 58.4 231 464 7231.8

1 32.8 37 789 32.8

2 33.6 308 228 425.8

Aerosil OX50

3 36.2 189 483 1618.7 (HSRM)

4 36.7 621 781 2728.8

5 38.5 359 791 3558.2

1 35.2 306 728 832.0

2 36.8 299 538 2124.5

Aerosil TT600

3 39.6 56 901 3786.8 (HSRM)

4 40.5 239 819 2972.6

5 43.6 526 693 5506.0

1 44.3 206 537 4636.5

2 44.9 64 365 3724.0

Bentonite

3 44.4 174 479 4185.4 (HSRM)

4 41.6 39 1122 4829.6

5 44.2 43 417 2567.6

1 38.3 25 1119 1840.6

2 38.0 27 846 1364.0

Carbopol 974

3 35.7 445 947 602.4 (HSRM)

4 35.0 101 448 1433.0

5 34.1 93 707 1225.5 Table 26 continued. Thermogenic properties of selected potential heat storage release materials and humectants with iron, carbon, potassium chloride and water in closed systems at five different levels, n=l.

Excipient Tmax ax DUR₃₂ AUC₃₂

Level

(classification) (°C) (min) (min) (min. degree)

1 34.8 1080 1327 102.2

1:1, Hexylene glycol/ 2 37.0 23 868 1195.4 propylene glycol 3 31.5 77 0 0

(humectants) 4 24.0 137 0 0

5 24.5 1 0 0

1 35.6 137 630 1054.6

2 34.2 135 739 739.6

PEG-400

3 33.8 332 202 164.1

(HSRM)

4 25.3 2 0 0

5 25.5 1 0 0

1 35.1 148 1206 1690.4

2 35.5 1064 1050 956.5

Carbopol Ultrez 10

3 36.8 803 941 2901.7 (HSRM)

4 42.9 12 1255 5662.4

5 63.7 63 884 4587.3

1 33.6 77 353 240.6

2 35.8 105 950 1753.2

Glycerol

3 34.7 306 464 653.6 (Humectant)

4 25.2 4 0 0

5 23.8 2 0 0

1 38.0 36 4 2435.6

2 36.3 59 1332 1044.4

Hexylene glycol

3 32.0 66 706 0 (Humectant)

4 24.2 2 0 0

5 24.2 2 0 0 Table 26 continued. Thermogenic properties of selected potential heat storage release materials and humectants with iron, carbon, potassium chloride and water in closed systems at five different levels, n=l.

Excipient T ¹ max tmax DUR32 AUC32

Level

(classification) (°C) (min) (min) (min. degree)

1 34.0 300 539 534.1

2 35.6 284 953 1987.4

Propylene glycol

3 33.5 283 296 297.4 (Humectant)

4 25.6 2 0 0

5 24.2 1 0 0

1 29.0 135 0 0

2 31.8 214 0 0

Silica

3 37.8 643 658 3724.8 (HSRM)

4 43.3 244 1047 3651.4

5 44.1 55 626 6090.4

1 36.1 311 901 2159.2

2 36.1 328 731 2000.9

Sodium CMC

3 36.1 14 239 437.0

(HSRM)

4 34.4 60 127 384.8

5 32.8 54 268 53.7

1 33.4 23 84 99.7

1 :1 Sodium CMC/ 2 33.9 21 108 88.5 hexylene glycol 3 37.1 276 1028 3261.2

(HSRM humectant) 4 34.8 131 300 598.1

5 32.7 14 22 10.1

1 33.4 1199 1194 440.4

1:1 Sodium CMC/ 2 33.6 210 645 681.8 triacetin 3 40.3 431 677 3424.8

(HSRM/humectant) 4 35.6 146 320 775.9

5 35.1 85 105 207.2 Table 26 continued. Thermogenic properties of selected potential heat storage release materials and humectants with iron, carbon, potassium chloride and water in closed systems at five different levels, n=l.

The thermogenic properties of formulations containing potassium chloride or one of five alternative metal salts, i.e. calcium chloride, magnesium chloride, zinc chloride, potassium nitrate and potassium sulphate, were investigated using the level of iron, carbon and water of the WellPatch Deep Heat patch of the art.

Prior to thermogenic assessment, the maximal solubility of each metal salt in water was assessed. The visual maximal solubility of each metal salt is listed in Table 27. The maximum solubility ranged from ca. 113.3 mg of potassium sulphate per g of water to ca. 3594.9 mg of zinc chloride per g of water. Table 27. Maximal solubility of metal salts in water.

Following identification of the solubility limit, each metal salt was prepared at 5, 25, 50, 75 and 100 % of their maximal solubility in water and combined with iron and carbon at the same level as the WellPatch Deep Heat patch of the art, and their thermogenic properties were assessed. The thermogenic properties of each metal salt at the five levels are summarised in Table 28. It was observed that a change of the counterion of the metal salt from chloride to either a nitrate or sulphate had a negative effect on the thermogenic properties in comparison to potassium chloride. A change in the metal but keeping the counterion as chloride was observed to change the thermogenic properties resulting in different heating profiles such as prolonging the t_max but still producing iron oxidation formulations that generated temperatures over 32 °C.

The investigation into the effect of potassium chloride level on heat generation is illustrated in Figure 39. As previously observed, increasing the content of potassium chloride in the formulation would appear to slow t_max. For example the mean t_max for formulations that contained potassium chloride at 5, 75 and 100 % of the maximal solubility are 70.0, 120.3 and 173.3 min, respectively. The mean DUR₃₂ appeared to decrease as the level of potassium chloride increased. For example, DUR32 decreased from 957.7 min at 25 % of the maximal solubility to 596.0 min at 100 % of the maximal solubility of potassium chloride in water. It would appear that a level of potassium chloride between 25 and 75 % of the maximal solubility in water has little effect on the DU 32 and AUC32. A level of 75% was selected for further investigations.

An opposite trend was observed when magnesium chloride was added to the formulation in place of potassium chloride. When magnesium chloride was added at 5 % of its maximum solubility in water, the mean T_max obtained was 35.3 °C, in comparison to 24,4 °C when magnesium chloride was incorporated at 100 % of its maximum solubility in water (Figure 40). The DUR₃₂ was also observed to decrease as the level of magnesium chloride was increased in the iron oxidation formulations.

Table 28. Mean thermogenic properties of iron, carbon and water, with metal salts at 5 different percentages of their maximal solubility in water, assessed in closed systems, n>2

% of maximum T ¹ max tmax DUR₃₂ AUC₃₂

Metal Salt Level

solubility (°C) (min) (min) (min.degree)

1 5 33.5 214.3 400.0 435.2

2 25 34.2 120.7 381.3 481.7

Calcium

3 50 33.5 204.0 318.3 272.6 chloride

4 75 25.2 0 0 0

5 100 24.7 0 0 0

1 5 39.8 50.0 270.0 1359.8

2 25 40.7 401.3 957.7 3536.9

Potassium

3 50 37.8 182.3 763.7 2745.2 chloride

4 75 41.9 120.3 702.3 4377.7

5 100 39 173.3 596.0 2327.2

1 5 24.4 2.0 0 0

2 25 24.6 2.0 0 0

Potassium

3 50 22.8 177.0 0 0 nitrate

4 75 24.6 1.7 0 0

5 100 24.9 1.7 0 0

Potassium 1 5 35.1 28.0 199.7 384.2 sulphate 2 25 25.7 2.7 0 0

3 50 23.8 71.3 0 0 4 75 23.0 46 0 0

5 100 22.7 111.3 0 0

1 5 35.3 354.3 710.0 1011.0

2 25 32.8 374.0 60.0 49.9

Magnesium

3 50 34.1 154.0 588.0 656.7 chloride

4 75 32.5 351.3 289.5 71.9

5 100 24.4 1.0 0 0

1 5 30.9 14.7 0 0

2 25 28.4 204.3 0 0

Zinc

3 50 25.3 1.7 0 0 chloride

4 75 22.6 112.3 0 0

5 100 24.1 2.3 0 0

CONCLUSIONS

Seven different particle sizes of iron and carbon were assessed. It was identified that the smaller particle size of both iron and carbon resulted in the most desirable thermogenic properties with higher T_max and longer durations. Following the assessment of particle size, the effect of water was also assessed. The thermogenic properties of patches containing the same amount of iron, carbon and potassium chloride but increasing levels of water from 0 - 50 % w/w were investigated. The T_ma was observed to increase within increasing levels of water up to -30% w/w. Addition of further water to the formulation (i.e. > 25 % w/w) resulted in a retardation of the thermogenic properties of the patch.

Alternative excipients to replace vermiculite and act as heat storage release materials/plasticiser and humectants were investigated. It was generally observed that formulations containing the higher level (11.90 % w/w) of the alternative excipients had a lower T_max. However, formulations containing a low level of alternative excipients (3.26 % w/w) generated required temperatures (i.e. greater T_max than 32 °C) and as such were identified for inclusion in the patent and were investigated at further levels within the iron oxidation formulations.

The thermogenic properties of formulations containing potassium chloride or one of five other potential metal salts were investigated. It was identified that salts containing chloride ions appeared to result in the most beneficial thermogenic properties for a heat patch, generating a T_max above 32 °C. In addition, it was observed that there was little variation in thermogenic properties of the iron oxidation formulations when potassium chloride was incorporated into the formulation between 25 - 75 % of its maximal solubility in water.

Table Al - Thermogenic properties of MEN03 formulations containing various excipients (n=l).

Excipient Classification Tmax ( C) (min) DUR.32 (2 h)

Aerosil OX50 55.7 19 118

Aerosil 90 49.3 29 119

Aerosil 200 51.4 36 118

Aerosil 380 57.0 13 118

Aerosil TT600 56.0 14 118

Bentonite 57.1 13 119

Carbopol 974 36.7 12 117

Carbopol Ultrez 10 41.9 14 117

HSRM

HEC 60.5 19 118

Hyaluronan 58.3 21 118

Kollidon VA64 40.7 15 118

Kolliphor 407 47.2 7 112

PEG-400 34.6 16 117

Plasdone S630 40.1 37 117

Silica 54.9 16 118

Sodium CMC 55.2 18 118

Zeolite 62.7 13 119

Glycerin 36.7 83 115

Hexylene glycol 33.1 9 118

Humectant

Propylene glycol 33.1 119 107

Triacetin 34.0 93 111

1 :1, HEC HG HSRM / 40.2 14 116

1 :1, HEC/Triacetin humectant 32.5 22 72 l :l, PEG-400/

36.7 112 112 Glycerol

1:1, PG/HG Humectants 36.4 60 113

1: 1, Zeolite/

HSRMs 56.3 28 119 Bentonite

Table A2. Thermogenic properties of MEN04 formulations containing various excipients

(n=l).

Excipient Classification Tmax ( C) (min) DUR₃₂ (2 h)

Aerosil OX50 54.3 13 118

Aerosil 90 47.1 24 118

Aerosil 200 54.0 16 119

Aerosil 380 56.1 25 119

Aerosil TT600 56.2 14 118

Bentonite 59.6 16 119

Carbopol 974 63.5 31 119

Carbopol Ultrez 10 50.9 31 119

HEC IISRM 63.0 10 119

Hyaluronan 48.5 14 118

Kollidon VA64 48.3 11 118

Kolliphor 407 47.9 40 118

PEG-400 49.1 11 119

Plasdone S630 44.9 16 118

Silica 56.4 15 119

Sodium CMC 47.9 43 82

Zeolite 60.4 13 118

Glycerin 41.3 36 117

Hexylene glycol 48.8 20 119

Humectant

Propylene glycol 43.4 48 116

Triacetin 46.6 37 118

1:1, HEC/HG HSRM / 36.2 94 116 1:1, HEC/Triacetin humectant 51.1 19 119 l :l, PEG-400/

51.7 18 118 Glycerol

1 :I, PG/HG Humectants 40.4 5 67

1 :1, Zeolite/

HSRMs 64.9 20 118 Bentonite

EXAMPLE 4

Fortythree exemplar formulations were screened and separated into three groups for ease of data interpretation; Group 1 contained twelve formulations that achieved a T_max below 40 °C, Group 2 contained 27 formulations that had a T_raax of 42 ± 2 °C, and Group 3 contained four formulations that had a T_max of greater than 44 °C. This was for convenience only, as the formulations of Group 1 were not significantly below 40 °C, while those above 44 °C could also be optimised to provide a lower T_max.

The majority of the exemplar formulations developed and screened resided in Group 2, many containing a hydrophilic polymer as the HSRM, for example, hydroxyethyl cellulose and sodium carboxymethyl cellulose. These hydrophilic polymers were investigated further as potential heat-storage release materials as it was thought possible that, with the hydration of the polymer during preparation of the soluble phase (water and metal salt) of the patch upon exposure to the reactants, then water would be presented to the reaction in a controlled manner, as the water is likely effectively to be trapped within the cross-linked polymer matrix, rather than 'free' within the patch to saturate the reactants (iron and carbon). This results were consistent with this hypothesis, although the present invention is not bound thereby.

The four humectants investigated; urea, hexylene glycol, propylene glycol and triacetin, when incorporated within the exemplar formulations were all observed to prolong the DUR32.

Target properties for a patch were as follows:

Heat retention, 8 hours (480 min) above 32 °C;

Heating effect, initial operating temperature of 42 ± 2 °C; Minimum temperature, 38 °C; and

Maximum temperature, 55 °C.

Materials

Table 29: List of materials used in the study.

Material Grade Supplier

Activated carbon Reagent Sigma, UK

Aerosil 200 Reagent Evonik, Germany

Aerosil 380 Reagent Evonik, Germany

Aerosil 90 Reagent Evonik, Germany

Aerosil TT600 Reagent Evonik, Germany

Bentonite Reagent Sigma, UK

Carbopol 974 Ph. Eur. Lubrizol, USA

Carbopol Ultrez 10 Reagent Lubrizol, USA

Glycerol Ph. Eur. VWR, UK

Hexylene glycol Reagent Sigma, UK

Hydroxyethyl Pharmaceutical

Ashland, USA cellulose 250 HX grade

Iron (44890) Reagent Aldrich, UK

Magnesium chloride Reagent Sigma, UK

PEG-400 Ph. Eur. VWR, UK

PEG-4000 Ph. Eur. Fagron, UK

Potassium chloride Ph. Eur. VWR, UK

Propylene glycol Ph. Eur. VWR, UK

Sodium CMC Reagent Sigma, UK

Triacetin Ph. Eur. VWR, UK

Water for injection BP Fresenius Kabi, UK

Xanthan gum USP-NF, Ph. Eur. CP Kelco, USA

Zeolite Reagent Sigma, UK METHODS

The exemplar formulations were prepared and their thermogenic properties assessed as detailed in the previous Example.

Preparation and testing of exemplar formulations

Heat patches of the composition outlined in the accompanying composition tables (below) were prepared using the following procedure:

(i) Potassium chloride was weighed into suitably sized glass vials.

(iii) Additional soluble excipients, where applicable, were added to the vial, mixed and allowed to hydrate overnight if required.

(iv) The insoluble components; iron and carbon (and additional insoluble excipients, where applicable) were weighed into a separate suitably sized glass vial and vortexed for approximately 2 minutes to ensure they were mixed.

(v) The vials were placed inside a nitrogen atmosphere until required.

(vi) The packaging of a WellPatch Deep Heat patch was carefully cut along the top and the contents were discarded.

(vii) In a nitrogen atmosphere, the insoluble phase from Step (iv) was added to the soluble phase from Step (iii) and thoroughly mixed until the mixture appeared visually homogeneous,

(viii) The mixture from Step (vii) was transferred into the patch of the art (WellPatch Deep Heat) packaging and sealed using a heat sealer (Figure 10, Step 1).

(ix) The patch was agitated to ensure the contents were distributed within the packaging.

(x) The patch remained within the nitrogen atmosphere for a maximum period of 5 minutes until it was removed for assessment.

(xi) The prototype patch was removed from the nitrogen atmosphere and the probe from the data logger was positioned in the centre of the patch. (xii) The patch was folded onto itself and secured in position (Figure 10, Step 2).

(xiii) The patch was positioned on a set of mounts to allow the air to circulate around the whole external surface of the patch that would not be in contact with the skin (Figure 10, Step 3).

Assessment of exemplar formulations

Preliminary screening of potential formulations

To screen the thermogenic properties of the exemplar formulations, one patch was assembled in the packaging for each exemplar formulation as described above. Each patch was screened over a period of approximately 12 h. The thermogenic properties of the patch were assessed for a period of approximately 12 h and the resultant thermogenic properties were characterised in terms of t_max, T_max and DUR₃₂.

Performance testing of exemplar formulations

Based on the outcome from the studies described above, if a formulation met the 'Target Properties' listed above, then it was selected for further investigation at n=3 replicates. Each exemplar formulation was screened over a maximum period of 24 h and the thermogenic properties were characterised in terms of t_max, T_max, DUR₃₂ and AUC32.

RESULTS AND DISCUSSION

Screening of exemplar formulations

The thermogenic properties of the exemplar formulations screened are characterised in terms of T_raax, t_max and DUR₃₂ in Table 30. The composition of each formulation is given as a rough guide in Table 30. The definitive formulations are given in the accompanying composition tables below, and this series of formulations is MEN07.

As noted above, 43 exemplar formulations were screened and based on the results separated into three groups, designated as 1, 2, and 3, according to their T_max (<40 °C, 40 - 44 °C, and > 44 °C).

Starch and Xanthan Gum did not perform especially well, and have use in formulations to bring down T_max. Starch is commonly used in pocket handwarmers. Poor heat generation from formulations containing either starch or xanthan gum may be as a result of these polymers interacting or retaining the water, making it less accessible than that of other HSRMs, such as the celluloses (HEC and CMC), inhibiting its reaction with the iron and carbon, thereby preventing the generation of a high T_mas and long DUR ₂. This is not confirmed, and does not bind the present invention.

Hydrophilic polymers as the HSRM, for example; hydroxyethyl cellulose and sodium carboxymethyl cellulose were present in many Group 2 formulations.

Other formulations that met the 'Target Properties' criteria contained the HSRM Aerosil (silicon dioxide) in various forms, and often in combination with HEC. The sustained temperature profiles obtained from these formulations may be attributable to the method in which water is presented to the reactants (iron and carbon). The silanol groups on the surface of the silicon dioxide may interact with the water via electrostatic interactions (e.g. hydrogen bonding and Van der Waals interactions), resulting in a three dimensional network which can retain water. As the reaction progresses, and the system becomes warmer, the attraction of water to the silicon dioxide is likely to be reduced, and the water becomes more accessible, resulting in the reaction being sustained.

The four humectants investigated; urea, hexylene glycol, propylene glycol and triacetin, when incorporated within the exemplar formulations, were all observed to prolong the DUR₃ . The effect of each humectant was observed to be dependent on the other alternative excipients within the formulation. For example, comparison of the formulations containing HEC would rank the humectants (most effective to least effective) in the following order; triacetin (MEN07-HXTR, 1144 min) > urea (MEN07-HXU, 1072 min) > propylene glycol (MEN07- HXPG, 951 min) > hexylene glycol (MEN07-HGHEC , 576 min). The same trend was observed when xanthan gum was combined with the same humectants. When urea was incorporated within the formulation (MEN07-EDUXG) the DUR₃₂ was 1144 min in comparison to the same formulation containing propylene glycol (MEN07-EDPGXG) where the DUR₃₂ was almost 200 minutes less (974 min). Similarly, when urea (MEN07-XGU) was compared to the same formulation with triacetin (MEN07-XGGT) the DUR₃₂ were 510 and 634 min, respectively. In contrast, when the humectants were incorporated in formulations containing CMC the humectant propylene glycol (MEN07-CMCPG, 593 min) prolonged DUR₃₂ by over 50 minutes in comparison to triacetin (MEN07-CMCTR, 554 min). A small number of formulations, Group 3, generated temperatures in excess of 44 °C, with the formulation containing xanthan gum and urea achieving the maximum value T_max of 49.7 °C in the initial screen. The formulation containing the two metal salts (potassium chloride and magnesium chloride in a 1 :4 ratio) had the longest DUR₃₂ (876 min) of the formulations in Group 3.

Table 30. Summary of thermogenic properties of the screened exemplar formulations, n=l. Group classification refers to; Group 1 formulations with a Tmax of < 40 °C, Group 2 formulations with a T_max of 42 ± 2 °C and Group 3 formulations with a T_max of > 44 °C.

Common constituents: Fe 52±2%, H₂0 25±5%, C 15%±1.5%, KCI Tmax DUR₃₂

Formulation Group classification

4.5+1% (unless otherwise stated) (°C) (min) (min)

MEN07-CMCT Na CMC 1.6%, Triacetin 1.6% 39.2 235 438 1

MEN07-BZ-1 Bentonite 1.6%, Zeolite 1.6% 37.1 35 508 1

MEN07-HGHEC Hexylene Glycol 0.1%, HEC 250 HX 0.5% 38.5 45 576

MEN07-BHEC Bentonite 1.6%, HEC 250 HX 1.6% 38.0 5 660 1

MEN07-BZ-2 Bentonite 0.8%, Zeolite 0.8% 39.4 304 698

MEN07-RUN7M Urea 5%, HEC 250 HX 1% 38.3 349 823 1

MEN07-ZU Zeolite 0.8%, Urea 0.1% 37.8 292 841 1

MEN07-STU Starch 3.7%, Urea 0.1% 39.2 269 927

MEN07-EDPGXG Propylene Glycol 2%, Xanthan Gum 0.5%, KCI 2.9% 38.5 408 928

MEN07-RU 26M Urea 0.1%, HEC 250 HX 1.7%, C 11.5%, KCI 6% 38.4 433 934

MEN07-EDUXG Urea 2%, Xanthan Gum 0.5%, KCI 2.9% 39.2 246 937

MEN07-R2EDUXPG Urea 2%, Xanthan Gum 0.5%, Propylene Glycol 0.6%, KCI 2.9% 39.9 425 954 1

MEN07-RUN9M Urea 0.1%, HEC 250 HX 0.1%, Fe 68.8%, ¾0 10.2%, KCI 7.1% 43.2 301 358 2

MEN07-CMCPEG Na CMC 1.6%, PEG-400 0.07% 40.2 194 604 2

MEN07-HECTR75 HEC 250 HX 0.1%, Triacetin 0.5% 40.4 299 624 2

MEN07-XGGT Xanthan Gum 0.26%, Triacetin 0.1% 41.3 561 634 2

MEN07-HECHGR75 HEC 250 HX 0.1%, Hexylene Glycol 0.5% 41.9 310 645 2

MEN07-A200HX Aerosil 200 2.1%, HEC 250 HX 2.1%, 40.3 258 677 2

MEN07-XGPEG Xanthan Gum 0.26%, PEG-400 0.1% 40.0 240 680 2

MEN07-HGCU Hexylene Glycol 0.1%, Carbopol Ultrez 10 11.9% 42.2 6 680 2

MEN07-RUN97M Urea 7.5%, HEC 250 HX 1.5% 41.4 258 687 2

MEN07-A90HX Aerosil 90 2.1%, HEC 250 HX 2.1% 42.2 318 739 2

MEN07-PG4000 PEG-4000 3.7%, Urea 0.1% 41.9 257 748 2

MEN07-TT600HX Aerosil TT600 2.1%, HEC 250 HX 2.1% 42.2 395 756 2

MEN07-BU Bentonite 0.8%, Urea 0.1% 40.0 298 767 2

MEN07-HXTR HEC 250 HX 1.6%, Triacetin 0.07% 41.2 685 810 2

MEN07-1M:2K HEC 250 HX 1.6%, Urea 0.07%, MgCl 1.8% 43.2 178 834 2

MEN07-CMC974 Na CMC 2.1%, Carbopol 974 2.1% 42.3 357 874 2

MEN07-CMCUR75 Na CMC 1.6%, Urea 0.07% 40.6 538 901 2

MEN07-HXPG HEC 250 HX 1.6%, Propylene Glycol 0.07% 41.1 194 901 2

MEN07-1M:1K HEC 250 HX 1.6%, Urea 0.07%, MgCl 2.75%, KCl 2.75% 43.4 303 904 2

MEN07-HXU HEC 250 HX 1.6%, Urea 0.07% 42.5 667 905 2

MEN07-R2ED Urea 2%, HEC 250 HX 0.5%, Plasdone K90 0.6%, KCL 2.9% 40.4 219 924 2

MEN07-A380HX Aerosil 380 2.1%, HEC 250 HX 2.1% 40.6 256 933 2

MEN07-R2EDV2 Urea 2%, HEC 250 HX 0.5%, KC1 3% 42.1 431 947 2

MEN07-HXPEG HEC 250 HX 2%, PEG-400 0.07% 43.8 490 985

MEN07-C974U-1 Carbopol 974 2.1%, Urea 0.5% 40.1 24 1004 2

MEN07-1M:4K HEC 250 HX 2%, Urea 0.07%, MgCl 1.1% 41.5 352 1067 2

MEN07-2M:1K HEC 250 HX 1.6%, Urea 0.07%, MgCl 3.7%, KC1 1.83% 41.5 310 1182 2

MEN07-XGU Xanthan Gum 0.26%, Urea 0.1% 49.7 426 510 3

MEN07-CMCTR Na CMC 1.6%, Triacetin 0.07% 48.7 519 554 3

MEN07-CMCPG Na CMC 1.6%, Propylene Glycol 0.07% 46.1 521 593 3

MEN07-4M:1K HEC 250 HX 1.6%, Urea 0.07%, KC1 1.10%, MgCl 4.4% 44.1 282 876 3

From the above table, it can be seen that poloxamers, when combined with a humectant, can provide very low t_max in the region of just a few minutes. In this table, triacetin at levels of less than 1.6% is desirable for formulations intended to reach at least 40° C. Propylene glycol can be seen to be a preferable humectant, and is preferably combined with hydroxyethyl cellulose as an HSRM. Plasdone is a useful plasticiser, and is capable of reducing t_max by 50%. HEC 250 HX can be seen to be a preferable HSRM, and provides preferred combinations with an aerosol. Urea can be seen to be a preferred humectant, working across the range tested, as does polyethylene glycol. Aerosil is a preferred family of HSRM.- always used in 2.1% and all formulations are a 2

Performance testing of exemplar formulations

Based on the outcome of the provisional screening in the previous section, 20 formulations that met or exceeded the 'Target properties' were selected for performance testing with a higher number of replicates (n=3).

The thermogenic properties of the 20 selected exemplar formulations were characterised in terms of T_max, t_max, DUR32 and AUC₃₂ (Table 31). The thermogenic properties obtained from the initial screen of the exemplar formulations in the previous section were observed to be comparable to the performance testing with the exception of exemplar formulations; MEN07- XGU, MEN07-CMCPG, MEN07-HXTR, and MEN07-CMCTR, that had a marginally lower T_max and longer DUR32, and MEN07-C974U, which had a higher T_max and longer DUR₃₂. A selection is represented graphically in comparison to the existing product, WellPatch Deep Heat, in Figure 41.

Exemplar formulation A90FIX (Figure 41a) contained the excipients Aerosil 90 (silicon dioxide with a surface area of 90 m²/g) and HEC 250 HX in addition to iron, carbon, potassium chloride and water. The average T_max for A90HX was 42.5° C which showed no difference to WellPatch Deep Heat (T_max 41.9 °C). The DUR₃₂ of A90HX was almost 42 % longer at 845.0 min in comparison to 595.7 min for WellPatch Deep Heat. Similarly, AUC32 of A90HX was observed to be 78 % (6124.0 min.degree) higher in comparison to WellPatch Deep Heat (3441.5 min.degree). Aerosil retains water via weak electrostatic forces to the silicon dioxide. In contrast, water is retained in the cross-linked polymer matrix of the HEC. It is possible that the two different methods of retaining and presenting water to the iron and carbon for the reaction by of these excipients, Aerosil 90 and HEC 250 HX, may be complimentary forming an equilibrium between 'free' and 'bound' water so the reaction is sustained.

A further exemplar formulation, HXPG (Figure 41b) contained the HSRM, HEC 250 HX and the humectant, propylene glycol. The average T_max of HXPG was 41.8 °C in comparison to the T_max of WellPatch Deep Heat which was 41.9 °C. However, the DUR₃₂ was almost 60 % longer from HXPG (951.0 min) in comparison to WellPatch Deep Heat (595.7 min). Furthermore, the AUC₃₂ was over 100 % greater from HXPG (7171.9 min.degree) in comparison to WellPatch Deep Heat (3441.5 min.degree). The propylene glycol within the formulation may affect the thermogenic properties of the formulation by two mechanisms of action; first, acting as a humectant and controlling the water contact to the iron and carbon, thus controlling the reaction rate and second by acting as a HSRM retaining any heat produced. Similar thermogenic properties to the exemplar formulation HXPG were obtained when the humectant, propylene glycol was replaced with the HSRM, PEG-400, with increases in DUR32 and AUC32 by 61 % and 145 %, respectively (Table 31).

The exemplar formulation CMCTR (Figure 41c), contained the excipients CMC as the HSRM and triacetin as the humectant in addition to iron, carbon, potassium chloride and water. CMCTR generated a higher average T_ma (44.5 °C) in comparison to WellPatch Deep Heat (41.9 °C). The DUR₃₂ was observed to be 22 % longer than WellPatch Deep Heat, however the AUC32 of CMCTR was over 110 % greater (7371.3 min.degree) than WellPatch Deep Heat (3441.5 min.degree). Triacetin is likely to reduce the surface tension of the water within the system, promoting a thinner layer of water on the surface of the iron particles in comparison to formulations where no humectant is used, thus allowing for a more effective layer (i.e. thinner) for gas exchange involved in the redox reaction to occur. The sustained duration observed from CMCTR may then be attributed to the controlled release of water from the partially hydrated CMC within the formulation combined with the 'wetting' of the triacetin.

An exemplar formulation that combined two different hydrophilic polymers; sodium CMC and Carbopol 974 in addition to iron, carbon, potassium chloride and water, CMC974 (Figure 4 Id) was investigated due to the two different potential methods of retaining water. CMC as described previously can retain water within the voids in the polymer matrix, whereas Carbopol, when dry, is comprised of tightly coiled acidic polymer molecules that uncoil and cross link as they hydrate. This cross linked structure of the Carbopol may retain water more effectively than the cellulose polymers. The T_max of CMC974 was 41.5° C which was comparable to WellPatch Deep Heat, however the DUR32 was markedly prolonged by 38 % along with the AUC32 which increased by 85 %. Table 31. Thermogenic properties of the exemplar formulations that met the Target properties. Data is represented by the mean value with the range in brackets, n>3. Values refer to the mean ± SD, n=6.

42.8 5201.3

252.7 609.3

MEN07-C974HG (42.3 - (4719.2- (124.0-335.0) (579.0-657.0)

43.4) 5871.9)

38.4 1144.0 4652.1

283.7

MEN07-HXTR (37.6 - (1048.0- (3877.2- (204.0 - 369.0)

39.1) 1197.0) 5062.9)

41.8 7171.9

383.0 951.0

MEN07-HXPG (41.2- (6470.1- (333.0-439.0) (908.0- 1003.0)

42.4) 8273.2)

41.1 5519.6

327.7 750.0

MEN07-C974U (40.5 - (5002.0 - (315.0-338.0) (685.0-834.0)

41.8) 6012.1)

44.5 7371.3

392.0 727.3

MEN07-CMCTR (43.3 - (6848.3 - (283.0-485.0) (696.0-784.0)

46.2) 8357.2)

44.9 3174.7

262.7 374.3

MEN07-Run9M (42.7 - (2705.9- (182.0-303.0) (328.0-458.0)

47.1) 3432.5)

42.2 5465.3

390.7 715.0

MEN07-Run97M (41.5- (5231.5- (305.0-465.0) (661.0-819.0)

42.7) 5612.3)

40.9 6054.8

MEN07- 497.3 952.3

(40.0 - (5768.2- CMCUR75 (364.0 - 579.0) (827.0- 1106.0)

41.4) 6288.9)

41.6 4738.3

MEN07- 359.0 657.7

(39.0- (3557.3 - HECHGR75 (316.0-416.0) (630.0-700.0)

43.4) 5854.4)

40.9 5679.6

255.0 885.0

MEN07-R2ED* (40.4 - (5661.9- (219.0-291.0) (853.0-924.0)

41.4) 5697.4) 40.5 6424.7

231.3 1096.5

MEN07-R2EDV2 (38.4- (5265.0-

(67.0-431.0) (931.0- 1321.0)

42.1) 7585.0)

37.8 1144.0 4012.0

432.7

MEN07-EDUXG (37.0- (1009.0- (3289.8-

(366.0-541.0)

38.9) 1306.0) 5400.1)

37.1 3339.6

MEN07- 366.7 974.0

(35.7- (2094.8 -

EDPGXG (352.0-376.0) (813.0- 1094.0)

38.5) 4783.0)

40.4 6171.9

157.7 1072.0

MEN07-HXU (38.3- (5114.8-

(59.0-234.0) (964.0- 1273.0)

42.1) 7844.1)

*n=2 replicates

FORMULATION COMPOSITIONS

MEN07-CMCT

Component

% w/w

Iron 52.05

Carbon 15.59

Sodium CMC 1.63

Triacetin 1.63

Potassium chloride 4.50

Water 24.60

TOTAL 100.00

MEN07-BHEC

Component

% w/w

Iron 52.05

Carbon 15.59

Bentonite 1.63

HEC 250 HX 1.63

Potassium chloride 4.50

Water 24.60

TOTAL 100.00

EN07-HGHEC

Component

% w/w

Iron 53.47

Carbon 16.02

Hexylene glycol 0.12

HEC 250 HX 0.49

Potassium chloride 4.63

Water 25.27

TOTAL 100.00

MEN07-HGCU

Component

% w/w

Iron 47.35

Carbon 14.18

Hexylene glycol 0.11

Carbopol Ultrez 10 11.89

Potassium chloride 4.10

Water 22.37

TOTAL 100.00

MEN07-BZ-2

Component

% w/w

Iron 52.91

Carbon 15.85

Bentonite 0.83

Zeolite 0.83

Potassium chloride 4.58

Water 25.00

TOTAL 100.00

MEN07-CMCUR75

Component

% w/w

Iron 53.35

Carbon 15.79

Sodium CMC 1.59

Urea 0.07

Potassium chloride 5.51

Water 23.69

TOTAL 100.00

MEN07-HECHGR75

Component

% w/w

Iron 53.47

Carbon 16.02

HEC 250 HX 0.12

Hexylene glycol 0.49

Potassium chloride 4.63

Water 25.27

TOTAL 100.00

MEN07-HECTR75

Component

% w/w

Iron 53.47

Carbon 16.02

HEC 250 HX 0.12

Triacetin 0.49

Potassium chloride 4.63

Water 25.27

TOTAL 100.00

MEN07-BU

Component

% w/w

Iron 53.30

Carbon 15.97

Bentonite 0.83

Urea 0.10

Potassium chloride 4.61

Water 25.19

TOTAL 100.00

MEN07-A200HX

Component

% w/w

Iron 51.52

Carbon 15.43

Aerosil 200 2.12

HEC 250 HX 2.12

Potassium chloride 4.46

Water 24.35

TOTAL 100.00

MEN07-A90HX

Component

% w/w

Iron 51.52

Carbon 15.43

Aerosil 90 2.12

HEC 250 HX 2.12

Potassium chloride 4.46

Water 24.35

TOTAL 100.00

MEN07-A380HX

Component

% w/w

Iron 51.52

Carbon 15.43

Aerosil 380 2.12

HEC 250 HX 2.12

Potassium chloride 4.46

Water 24.35

TOTAL 100.00

MEN07-TT600HX

Component

% w/w

Iron 51.52

Carbon 15.43

Aerosil TT600 2.12

HEC 250 HX 2.12

Potassium chloride 4.46

Water 24.35

TOTAL 100.00

MEN07-ZU

Component

% w/w

Iron 53.30

Carbon 15.97

Zeolite 0.83

Urea 0.10

Potassium chloride 4.61

Water 25.19

TOTAL 100.00

MEN07-C974U-1

Component

% w/w

Iron 52.37

Carbon 15.69

Carbopol 974 2.16

Urea 0.50

Potassium chloride 4.53

Water 24.75

TOTAL 100.00

MEN07-1M:1K

Component

% w/w

Iron 53.35

Carbon 15.79

HEC 250 HX 1.59

Urea 0.07

Potassium chloride 2.75

Magnesium cliloride 2.75

Water 23.70

TOTAL 100.00

MEN07-1M_4K

Component

% w/w

Iron 53.35

Carbon 15.79

HEC 250 HX 1.59

Urea 0.07

Potassium chloride 4.40

Magnesium chloride 1.10

Water 23.70

TOTAL 100.00

MEN07-4M:1K

Component

% w/w

Iron 53.35

Carbon 15.79

HEC 250 HX 1.59

Urea 0.07

Potassium chloride 1.10

Magnesium chloride 4.40

Water 23.70

TOTAL 100.00

MEN07-2M:1K

Component

% w/w

Iron 53.35

Carbon 15.79

IIEC 250 HX 1.59

Urea 0.07

Potassium chloride 1.83

Magnesium chloride 3.67

Water 23.70

TOTAL 100.00

MEN07-1M:2K

Component

% w/w

Iron 53.35

Carbon 15.79

HEC 250 HX 1.59

Urea 0.07

Potassium chloride 3.67

Magnesium chloride 1.83

Water 23.70

TOTAL 100.00

MEN07-STU

Component

% w/w

Iron 51.75

Carbon 15.50

Starch 3.72

Urea 0.10

Potassium chloride 4.48

Water 24.45

TOTAL 100.00

MEN07-PG4000

Component

% w/w

Iron 51.75

Carbon 15.50

PEG-4000 3.72

Urea 0.10

Potassium chloride 4.48

Water 24.45

TOTAL 100.00

MEN07-XGU

Component

% w/w

Iron 53.61

Carbon 16.06

Xanthan gum 0.26

Urea 0.10

Potassium chloride 4.64

Water 25.33

TOTAL 100.00

MEN07-XGGT

Component

% w/w

Iron 53.61

Carbon 16.06

Xanthan gum 0.26

Triacetin 0.10

Potassium chloride 4.64

Water 25.33

TOTAL 100.00

MEN07-XGPEG

Component

% w/w

Iron 53.61

Carbon 16.06

Xanthan gum 0.26

PEG-400 0.10

Potassium chloride 4.64

Water 25.33

TOTAL 100.00

MEN07-Run7M

Component

% w/w

Iron 54.63

Carbon 16.17

Urea 5.00

HEC 250 HX 1.02

Potassium chloride 3.73

Water 19.45

TOTAL 100.00

MEN07-Run9M

Component

% w/w

Iron 68.88

Carbon 13.60

Urea 0.10

HEC 250 HX 0.10

Potassium chloride 7.11

Water 10.21

TOTAL 100.00

MEN07-Run26M

Component

% w/w

Iron 58.37

Carbon 11.53

Urea 0.08

HEC 250 HX 1.74

Potassium chloride 6.03

Water 22.25

TOTAL 100.00

MEN07-Run97M

Component

% w/w

Iron 49.40

Carbon 14.62

Urea 7.46

HEC 250 HX 1.47

Potassium chloride 5.10

Water 21.95

TOTAL 100.00

MEN07-CMCPEG

Component

% w/w

Iron 53.35

Carbon 15.79

Sodium CMC 1.59

PEG-400 0.07

Potassium chloride 5.51

Water 23.69

TOTAL 100.00

MEN07-CMCPG

Component

% w/w

Iron 53.35

Carbon 15.79

Sodium CMC 1.59

Propylene glycol 0.07

Potassium chloride 5.51

Water 23.69

TOTAL 100.00

MEN07-CMCTR

Component

% w/w

Iron 53.35

Carbon 15.79

Sodium CMC 1.59

Triacetin 0.07

Potassium chloride 5.51

Water 23.69

TOTAL 100.00

MEN07-HXPEG

Component

% w/w

Iron 53.35

Carbon 15.79

HEC 250 HX 1.59

PEG-400 0.07

Potassium chloride 5.51

Water 23.69

TOTAL 100.00

MEN07-HXPG

Component

% w/w

Iron 53.35

Carbon 15.79

HEC 250 HX 1.59

Propylene glycol 0.07

Potassium chloride 5.51

Water 23.69

TOTAL 100.00

MEN07-HXTR

Component

% w/w

Iron 53.35

Carbon 15.79

HEC 250 HX 1.59

Triacetin 0.07

Potassium chloride 5.51

Water 23.69

TOTAL 100.00

MEN07-EDPGXG

Component

% w/w

Iron 54.18

Carbon 16.03

Propylene glycol 1.99

Xanthan gum 0.54

Potassium chloride 2.93

Water 24.33

TOTAL 100.00

MEN07-EDUXG

Component

% w/w

Iron 54.18

Carbon 16.03

Urea 1.99

Xanthan gum 0.54

Potassium chloride 2.93

Water 24.33

TOTAL 100.00

MEN07-R2EDUXPG

Component

% w/w

Iron 53.84

Carbon 15.93

Urea 1.97

Xanthan gum 0.54

Propylene glycol 0.63

Potassium chloride 2.91

Water 24.18

TOTAL 100.00

MEN07-HXU

Component

% w/w

Iron 53.35

Carbon 15.79

HEC 250 HX 1.59

Urea 0.07

Potassium chloride 5.51

Water 23.69

TOTAL 100.00

MEN07-R2ED

Component

% w/w

Iron 53.84

Carbon 15.93

Urea 1.97

HEC 250 HX 0.54

Plasdone K90 0.63

Potassium chloride 2.91

Water 24.18

TOTAL 100.00

MEN07-R2EDv2

Component

% w/w

Iron 54.18

Carbon 16.03

Urea 1.99

HEC 250 HX 0.54

Potassium chloride 2.93

Water 24.33

TOTAL 100.00

MEN07-CMC974

Component

% w/w

Iron 51.52

Carbon 15.43

Sodium CMC 2.12

Carbopol 974 2.12

Potassium chloride 4.46

Water 24.35

TOTAL 100.00

MEN07-C974HG

Component

% w/w

Iron 52.37

Carbon 15.69

Carbopol 974 2.16

Hexylene glycol 0.50

Potassium chloride 4.53

Water 24.75

TOTAL 100.00

Claims

Claims:

1. A self heating device for warming the skin of a subject when in use, said device containing finely divided iron, finely divided carbon, and potassium chloride all in the presence of water, said device being sealed to prevent contact of the contents with air, removal or breaking of the seal allowing air to contact the contents, thereby permitting an oxidative reaction to occur, characterised in that at least two of a heat storage agent, a humectant, and a plasticiser are dissolved in the water.

2. A device according to claim 1, comprising at least one panel of a semi-permeable material, said panel being sealed prior to use.

3. A device according to claim 1 or 2, wherein the finely divided iron is a particulate solid having an average particle size of no more than 0.06 mm, preferably no more than 0.05 mm, more preferably 0.01 mm and below.

4. A device according to claim 1 or 2, wherein the finely divided carbon is a particulate solid having an average particle size of no more than 0.2 mm, preferably less than or equal to 0.15 mm, more preferably wherein the particle sizes are a range having a maximum diameter of 0.15 mm, but having no specified lower limit.

5. A device according to any preceding claim, wherein the components of the reaction are selected snch that the oxidative reaction does not heat the device to any more than 55°C at any time after exposure to air, preferably no more than 48°C, more preferably 45°C, and which preferably heats the patch to an initial temperature of 42 + 2 °C, preferably 42 ± 1 °C.

6. A device according to any preceding claim, wherein the reaction components are selected such that the device heats to an initial minimum of 38°C.

7. A device according to any preceding claim, wherein the reaction components are selected such that the device does not cool to below 32°C for at least 6 hours after commencement of the reaction.

8. A device according to any preceding claim, wherein the reaction components are selected such as to prevent the device cooling to below 32°C, when m situ at standard RTP, for at least 8 hours.

9. A device according to any preceding claim, wherein the heat storage/release agent, the humectant, and the plasticiser are selected to be water soluble or water compatible and to be able to do two or more of: present water to iron; insulate the reaction, preventing heat loss; control oxygen permeation; and form a film.

10. A device according to any preceding claim, wherein each of the heat storage/release agent, the humectant, and the plasticiser is provided separately.

11. A device according to any preceding claim, wherein the heat storage release material is HEC 250 HX, xanthan gum, PEG1000, or PEG4000, preferably HEC 250 HX.

12. A device according to any preceding claim, wherein the humectant is urea, glycerol or propylene glycol, preferably urea.

13. A device according to any preceding claim, wherein the plasticer is Plasdone K-90.

14. A device according to any preceding claim, comprising potassium chloride in an amount of between 80 and 100% w/w of the aqueous solution.

15. A device according to any claim 14, wherein the level of water > 15% w/w, and especially >18% w/w.

16. A device according to any claim 14 or 15, wherein the level of water is no greater than 30%, preferably no greater than 25% w/w, and more preferably no greater than 22% w/w.

17. A device according to any preceding claim, comprising; iron, carbon, HEC 250 HX, urea, Plasdone K90, potassium chloride and water.

18. A device according to any preceding claim, wherein the at least two of a heat storage agent, a humectant, and a plasticiser are two heat storage agents, at least one said agent having humectant properties, optionally further comprising an additional humectant or plasticiser, or both.

19. A device according to any preceding claim, wherein one or more of the at least two of a heat storage agent, a humectant, and a plasticiser is in suspension in the water.