WO2021138710A1

WO2021138710A1 - Substrate for use in a transdermal patch or dressing

Info

Publication number: WO2021138710A1
Application number: PCT/AU2020/051440
Authority: WO
Inventors: Christophe Jean Alexandre BARBÉ; Aparajita KHATRI
Original assignee: Sg Ventures Pty Limited
Priority date: 2020-01-09
Filing date: 2020-12-24
Publication date: 2021-07-15

Abstract

The present invention relates to a substrate for use in a transdermal patch or 5 dressing, such as a wound dressing. The substrate includes an absorbent matrix loaded with ceramic particles that encapsulate a releasable dopant. Methods for loading such ceramic particles into substates and forming transdermal patches and dressings are also provided. The present invention relates to a substrate for use in a transdermal patch or dressing, such as a wound dressing. The substrate includes an absorbent matrix loaded with ceramic particles that encapsulate a releasable dopant. Methods for loading such ceramic particles into substates and forming transdermal patches and dressings are also provided.

Description

SUBSTRATE FOR USE IN A TRANSDERMAL PATCH OR DRESSING

FIELD OF INVENTION

The present invention relates to a substrate for use in a transdermal patch or dressing, such as a wound dressing. The substrate includes an absorbent matrix loaded with ceramic particles that encapsulate a releasable dopant. Methods for loading such ceramic particles into substates and forming transdermal patches and dressings are also provided.

BACKGROUND ART

Transdermal patches are known and generally take the form of a medicated adhesive patch that is placed on the skin of a person to be treated in order to deliver a desired dose of medication into the skin or through the skin and into the bloodstream. An advantage of a transdermal drug delivery route over other types of medication delivery such as oral, topical, intravenous, intramuscular, etc. is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. The main disadvantage to transdermal delivery systems stems from the fact that the skin is a very effective barrier; as a result, only medications whose molecules are small enough to penetrate the skin can be delivered by this method. A wide variety of pharmaceuticals are now available in transdermal patch form.

There are five main types of transdermal patches:

Single-layer Drug-in-Adhesive - The adhesive layer of this system also contains the drug. In this type of patch the adhesive layer not only serves to adhere the various layers together, along with the entire system to the skin, but is also responsible for release of the drug. The adhesive layer is surrounded by a temporary liner and a backing. Multi-layer Drug-in-Adhesive - The multi-layer drug-in-adhesive patch is similar to the single-layer system. The multi-layer system is different, however, in that it adds another layer of drug-in-adhesive, usually separated by a membrane, but not in all cases. One of the layers is for immediate release of the drug and the other layer is for control release of drug from the reservoir. This patch also has a temporary liner-layer and a permanent backing. The drug release from this depends on membrane permeability and diffusion of drug molecules. Reservoir - Unlike the single-layer and multi-layer drug-in-adhesive systems, the reservoir transdermal system has a separate drug layer. The drug layer is a liquid compartment containing a drug solution or suspension separated by the adhesive layer. The drug reservoir is totally encapsulated in a shallow compartment moulded from a drug-impermeable metallic plastic laminate, with a rate-controlling membrane made of a polymer like vinyl acetate on one surface. This patch is also backed by the backing layer. In this type of system the rate of release is zero order.

Matrix- The matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer, partially overlaying it. These types of patches are also known as a monolithic device.

Vapour Patch - In a vapour patch, the adhesive layer not only serves to adhere the various layers together but also to release vapour. Vapour patches release essential oils for up to 6 hours and are mainly used for decongestion. Other vapour patches on the market aim to improve quality of sleep or aid in smoking cessation. Dressing for medical purposes, such as wound dressings, are also known. A dressing may include only an absorbent matrix, for example for stemming bleeding and providing protection from infection in the case of wounds, or ease pain and minimise swelling in other circumstances where swelling may be present. Dressings may be passive, including no active or medicating component, or may be impregnated with an active component.

The present invention provides an alternative to these systems, including an absorbent matrix that is loaded with ceramic particles that encapsulate a dopant. Unlike previous systems, the ceramic particles are designed to provide desired release properties of the dopant from the ceramic particles, and therefore from the absorbent matrix. Specifically, it is considered that release of the dopant from the ceramic particles may be primarily due to interaction of bodily fluid, such as sweat and skin oils (i.e. skin surface film liquids), with the ceramic particles. As such, delivery of the dopant to the user is determined to a large extent by release properties of the ceramic particles, in addition to the rate of absorption of the dopant into and/or through the skin.

The subject matter claimed herein is not limited to embodiments that solve any disadvantages or that operate only in environments such as those described above. Rather, this background is only provided to illustrate exemplary technology areas where some embodiments described herein may be practiced.

Various aspects and embodiments of the invention will now be described.

SUMMARY OF INVENTION

As mentioned above, the present invention relates generally to a substrate for use in a transdermal patch or dressing, such as a wound dressing where the substrate includes an absorbent matrix loaded with ceramic particles that encapsulate a releasable dopant.

According to a first aspect of the invention there is provided a substrate for use in a transdermal patch or wound dressing, said substrate comprising an absorbent matrix impregnated with ceramic particles comprising a ceramic matrix and a dopant releasably encapsulated within said ceramic matrix. The absorbent matrix preferably comprises a non-woven fibrous matrix or a textile matrix. This may be natural or synthetic. For example, the absorbent matrix may be selected from one or more synthetic polymers selected from polyesters (e.g. polyethylene terephthalate, polylactic acid, polyglycolic acid, polycaprolactone), poly-ethers (e.g. polyethylene glycol (PEG/PEO), polyurethanes (e.g. polyether urethanes, polyester urethanes), polyethylenes (e.g. HDPE, LDPE), acrylic polymers (e.g. polymethyl methacrylate, polyethyl acrylate), polyamides (e.g. poly(imino carbonates)), cellulose and its derivatives (e.g. ethyl cellulose, hydroxypropyl methylcellulose), polyanhydrides, polycarbonates, polysulfones, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, and copolymers (e.g. PLGA, poly(L-lactide-co- caprolactone)); and/or one or more natural polymers selected from polysaccharides (e.g. cellulose, chitosan, starch) and proteins (e.g. silk fibroin, collagen).

In a preferred embodiment, the absorbent matrix comprises a non-woven cellulose matrix. The shape and thickness of the absorbent matrix in not particularly limited. For example, the absorbent matrix may be rectangular, square or circular, or any other shape.

The absorbent matrix is preferably impregnated with the ceramic particles by loading the absorbent matrix with a slurry of the ceramic particles. The slurry preferably has a solids content of from 5-60 wt.%, for example 10-50 wt.% or 20-40 wt.%.

The ceramic particles dispersed throughout the absorbent matrix comprise a dopant releasably held within a ceramic matrix. The particles may comprise solid, porous spheres.

The ceramic matrix may be a polymerisation and/or condensation and/or crosslinking product of a precursor material. It may be a hydrolysed silane, such as a hydrolysed organosilane. It may comprise an organically modified ceramic, such as an organically modified silica (organo-silica). It may be a ceramic having bound organic groups. The bound organic groups may be ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, isooctyl, decyl, dodecyl, cyclohexyl, cylcooctyl or cyclopentyl. These may be substituted (e.g. with functional groups, halogens, aryl groups, etc.) or may be unsubstituted. Other suitable organic groups include aryl groups, which may have between about 6 and 14 carbon atoms, and may have for example, 6, 8, 10, 12 or 14 or more than 14 carbon atoms. Examples include phenyl, biphenyl, naphthyl and anthracyl. These may each, optionally, be substituted by one or more alkyl groups (e.g. C1 to C6 straight chain or branched alkyl), halogens, functional groups or other substituents. The organic group may be an alkenyl or alkynyl or benzyl group. The alkenyl or alkynyl group may have between 2 and about 18 carbon atoms, and may be straight chain, branched or (if sufficient carbon atoms are present) cyclic. It may have 1 or more than 1 double bond, or 1 or more than 1 triple bond, and may have a mixture of double and triple bonds. If the group has more than one unsaturated group, the unsaturated groups may be conjugated or unconjugated.

The solid matrix may comprise chemical groups derived from a catalyst used in the formation of the ceramic particles, and the groups may be on the surface of the particles. If a surfactant used in the formation reaction is capable of combining chemically with the precursor material, the matrix may comprise chemical groups derived from the surfactant. For example, if the precursor material comprises an organotrialkoxysilane, and the catalyst comprises a trialkoxyaminoalkylsilane, then the matrix may comprise aminoalkylsilyl units. These may be distributed evenly or unevenly through the particle. They may be preferentially near the surface of the particle. They may provide some degree of hydrophilicity, e.g. due to amino functionality, to the particle surface. Additionally, the surfactant may be capable of combining chemically with the precursor material. For example if the precursor material comprises an organotrialkoxysilane, and the surfactant comprises trialkoxysilyl functionality, then the matrix may comprise surfactant derived units. The surfactant may be adsorbed on the surface of the particle. The dopant may be selected from the group consisting of hydrophobic and hydrophilic small molecule drugs such as antibiotics (e.g. chloramphenicol), analgesics, such as diclofenac, Procaine, Dimethocaine (synthetic derivative), Lidocaine, ibuprofen, dibucaine, bupivacaine, capsaicin, amitriptyline, glyceryl trinitrate, opioids (e.g. Fentanyl, Morphine, Buprenorphine, Oxycodon, Methadone, Tramadol, Hydrocodone), natural or synthetic cannabinoids (e.g. CBD (Cannabidiol), delta-9-tettrahydrocannabinol (THC), Cannabinol (CBN), Cannabigerols (CBG) Cannabichromenes (CBC), Cannabinodiol (CBDL), Cannabicyclol (CBL), Cannabielsoin (CBE) and Cannabitriol (CBT), Cannabidivarin (CBDV), and other analgesics such as menthol, pimecrolimus, and phenytoin) or anti-nausea scopolamine (or Hyoscine), proteins for therapeutic purposes e.g. antibodies, growth hormones (for wound healing), or steroids for the treatment of skin eczema, birth control, or for hormone replacement therapy (e.g. estrogen or testosterone), nitroglycerine, Vitamin B12, Folate, Iron, Vitamin D or Vitamin E or a fluorescent, radioactive or metal (e.g. gold) tracer.

The dopant, which may be a hydrophobic material, a hydrophilic material, an oligonucleotide or a polynucleotide (DNA & RNA), or a peptide or protein, etc., may represent between about 0.01 and 50% of the weight or the volume of the particle, or between about 0.01 and 10%, 0.01 and 1%, 0.01 and 0.5%, 0.01 and 0.1%, 0.01 and 0.05%, 0.1 and 30%, 1 and 30%, 5 and 30%, 10 and 30%, 0.1 and 10%, 0.1 and 1% or 1 and 10% of the weight or the volume of the particle, and may represent about 0.01 , 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or 30% of the weight or the volume of the particle.

In a particular embodiment of the invention, the dopant is lidocaine. For example, the absorbent matrix of about 10 cm² size, may be loaded with up to 50 mg of lidocaine, preferably from 5 to 35 mg of lidocaine.

The particle may have a diameter between about 1 nm and about 1000 nm. The particles may be spherical, oblate spherical or may be ovoid or ellipsoid. They may be regular or irregular shaped. They may be non-porous, or may be mesoporous or microporous. They may have a specific surface area of between about 2 and 400 m²/g, or between about 2 and 25, 2 and 20, 2 and 15, 2 and 10, 10 and 50, 10 and 25, 15 and 25 or 20 and 50 m²/g, and may have a specific surface area of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 1,3 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 28, 30, 35, 40, 45 or 50 m²/g.

The dopant is capable of being released from the particle, for example over a period of time. The release may be at a controlled or sustained rate. The particles may be capable of releasing the dopant over a period of between about 1 minute and 1 week, for example 72 hours, 48 hours, 24 hours, 12 hours, 6 hours, 4 hours or less than 2 hours. The rate of release of the dopant may be characterised by a half-release time, which is the time after which half of the original amount of hydrophobic material has been released. The particle(s) may have a half-release time of between about 1 minute and 96 hours. The particles may therefore be used in applications requiring sustained release over relatively short periods, for example between about 1 minute and about 1 hour, or they may be used in applications requiring sustained release over intermediate periods, for example between about 1 hour and about 1 day, or they may be used in applications requiring sustained release over relatively long periods, e.g. greater than 1 day.

In another aspect of the invention there is provided a transdermal patch comprising: an occlusive or non-occlusive dressing comprising a substrate according to the first aspect of the invention and as hereinbefore described in more detail, an adhesive portion adapted to adhere the dressing to the skin, and a backing laminate; and a protective liner.

The adhesive portion preferably comprises a pressure sensitive adhesive (PSA) encircling or laminated over the absorbent matrix. The PSA may, for example, be selected from polyacrylates, silicone based PSA, hybrid chemistry PSA (e.g. hybrid silicone-acrylate PSA), polyisobutylene, synthetic or natural rubber and thermoplastic elastomers. The adhesive may be applied to a foam material, for example a polyethylene foam.

The backing laminate is preferably chemically resistant and inert to other constituents in the delivery system. This may be selected from, for example, poly vinyl chloride film, polyethylene film, polyester films, polyisobutylene, silicone oil, aluminium film and polyolefin films. Preferably the backing layer comprises an aluminium laminate.

During storage, the patch is covered by a protective liner that is removed and discarded before the application of the patch to the skin. Because the liner is in intimate contact with the transdermal delivery system, the liner should be chemically inert. Typically, the protective liner is composed of a base layer and a release coating layer. For example, the base layer may comprise paper fabric (non-occlusive), polyethylene (occlusive), polyvinyl chloride (occlusive). The release coating layer may comprise highly crosslinked silicon polymer, fluoropolymers, e.g. polytetrafluoroethylene or PTFE (Teflon). Other materials that may be used for the protective liner are polyester foil and metalized laminates.

In another aspect of the invention there is provided a dressing, such as a wound dressing, comprising a substrate according to the first aspect of the invention and as hereinbefore described in more detail.

According to one another aspect of the invention there is provided a method of preparing a substrate for use in a transdermal patch or dressing, the method comprising impregnating an absorbent matrix with a slurry of ceramic particles, the ceramic particles comprising a ceramic matrix and a dopant releasably encapsulated within the ceramic matrix.

While it is considered that satisfactory results may be achieved using a wet matrix, it has been found that particularly good results are achieved with a dry or partially dried matrix. As such, the method preferably further comprises drying or partially drying the impregnated absorbent matrix.

Various embodiments of the invention may be gleaned from the description of the substrate and transdermal patch above. For completeness, various embodiments will be described hereafter.

While various other materials are suitable, as described above, the absorbent matrix preferably comprises a cellulose matrix, preferably in the form of a non- woven cellulose matrix.

In the case of transdermal patches, the adhesive portion more preferably comprises a foam tape that is applied to the absorbent matrix such that it encircles the absorbent matrix or is laminated over the absorbent matrix. In one embodiment the foam tape comprises a polyethylene foam coated with an acrylate adhesive. On forming the occlusive dressing the backing laminate may be laminated to the adhesive portion and absorbent matrix to form the occlusive dressing. The backing laminate may comprise an aluminium laminate. Likewise, the protective liner may comprise an aluminium laminate.

It is envisaged that in certain embodiments the occlusive dressing may be provided complete and the absorbent matrix impregnated with the slurry of ceramic particles and subsequently dried. In either case, as previously described, the slurry preferably has a solids content of from 5-60 wt.%, more preferably 10-50 wt.% or 20-40 wt.%..

The ceramic particles may comprise solid, porous spheres. The ceramic matrix may be a polymerisation and/or condensation and/or crosslinking product of a precursor material. It may comprise a hydrolysed silane, such as a hydrolysed organosilane. It may comprise an organically modified ceramic, such as an organically modified silica (organo-silica). The ceramic matrix may comprise bound organic groups, such as ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, isooctyl, decyl, dodecyl, cyclohexyl, cylcooctyl and cyclopentyl groups. The bound organic groups may be substituted (e.g. with functional groups, halogens, aryl groups, etc.) or may be unsubstituted. The precursor material may comprise an organotrialkoxysilane, and the ceramic matrix may be formed in the presence of a trialkoxyaminoalkylsilane catalyst.

The dopant may be selected from the group consisting of hydrophobic and hydrophilic small molecule drugs such as antibiotics (e.g. chloramphenicol), analgesics, such as diclofenac, Procaine, Dimethocaine (synthetic derivative), Lidocaine, ibuprofen, dibucaine, bupivacaine, capsaicin, amitriptyline, glyceryl trinitrate, opioids (e.g. Fentanyl, Morphine, Buprenorphine, Oxycodon, Methadone, Tramadol, Hydrocodone), natural or synthetic cannabinoids (e.g. CBD (Cannabidiol), delta-9-tettrahydrocannabinol (THC), Cannabinol (CBN), Cannabigerols (CBG) Cannabichromenes (CBC), Cannabinodiol (CBDL), Cannabicyclol (CBL), Cannabielsoin (CBE) and Cannabitriol (CBT), Cannabidivarin (CBDV), and other analgesics such as menthol, pimecrolimus, and phenytoin) or anti-nausea scopolamine (or Hyoscine), proteins for therapeutic purposes e.g. antibodies, growth hormones (for wound healing), or steroids for the treatment of skin eczema, birth control, or for hormone replacement therapy (e.g. estrogen or testosterone), nitroglycerine, Vitamin B12, Folate, Iron, Vitamin D or Vitamin E or a fluorescent, radioactive or metal (e.g. gold) tracer. The dopant may represent between about 0.01 and 50% of the weight or the volume of the particle, or between about 0.01 and 10%, 0.01 and 1%, 0.01 and 0.5%, 0.01 and 0.1%, 0.01 and 0.05%, 0.1 and 30%, 1 and 30%, 5 and 30%, 10 and 30%, 0.1 and 10%, 0.1 and 1% or 1 and 10% of the weight or the volume of the particle.

In a particular embodiment the dopant is lidocaine. The absorbent matrix may be loaded with up to 50 mg of lidocaine, preferably from 5 to 35 mg of lidocaine for a 10cm² absorbent matrix.

The ceramic particles have a diameter between about 1 nm and about 1000 nm. They may have a specific surface area of between about 2 and 400 m²/g. The dopant may be capable of being released from the ceramic particles over a period of between about 1 minute and 1 week, for example over 72 hours, 48 hours, 24 hours, 12 hours, 6 hours, 4 hours or less than 2 hours.

BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

To further clarify various aspects of some embodiments of the present invention, a more particular description of the invention will be rendered by references to specific embodiments thereof, which are illustrated in the appended drawings. It should be appreciated that these drawings depict only typical embodiments of the invention and are therefore not to be considered limiting on its scope. The invention will be described and explained with additional specificity and detail through the accompanying drawings in which:

FIG. 1 illustrates a TEM (19000x, 100 kV) of silica nanoparticles with encapsulated lidocaine, the nanoparticles having an average particle size of ~ 60 nm.

FIGS. 2 illustrates a particle patch with cellulose disc (10 cm²) for loading with lidocaine particles.

FIG. 3 illustrates SEM images for an empty cellulose matrix, and cellulose matrix loaded with, 25 mg, 35 mg and 50 mg of lidocaine that is encapsulated in ceramic matrix.

FIG. 4 illustrates a graph of Lidocaine extracted from 10 cm² EMLA, Versatis and particle patches.

FIGS. 5A and 5B illustrate graphs of cumulative quantity of lidocaine permeated (through the membrane into the buffer) from 1.54 cm² cores of various patches at different times. FIGS. 6A and 6B illustrate graphs of efficiency of lidocaine permeation (% of total lidocaine) into the buffer from 1.54 cm² patch sections of various types of patches. FIGS. 7A and 7B illustrate graphs of the release of lidocaine in the membrane from 1.54 cm² patch sections of various types of patches over time.

FIG. 8 illustrates a graph of percentage of total lidocaine released (efficiency) from the patches into the buffer and the membrane after 24 hours.

FIG. 9A illustrates a graph of cumulative quantity of lidocaine released into the buffer from 1.54 cm² patch sections at different doses over 72 hours.

FIG. 9B illustrates a graph of levels of lidocaine permeated in the membrane from 1.54 cm² patch sections at different doses over 72 hours.

FIG. 9C illustrates efficiency of total lidocaine release (i.e. percentage of total lidocaine released) from 1.54 cm² patch sections at different doses into the membrane and the buffer after 72 hours.

FIG. 10 illustrates a TEM of silica nanoparticles with encapsulated fentanyl, the nanoparticles having an average particle size of ~ 50-60 nm.

FIG. 11 illustrates a graph of release of fentanyl from the nanoparticles compared with a commercial patch.

FIG. 12 illustrates a TEM of silica nanoparticles with encapsulated cannabidiol CBD), the nanoparticles having an average particle size of ~ 75-200 nm. FIG. 13 illustrates a graph of release of CBD-loaded patches after 24 hours. FIG. 14 illustrates SEM images of the top, middle and bottom of dried patches showing penetration of the CBD nanoparticles through the whole matrix (water only).

FIG. 15 illustrates SEM images of the top, middle and bottom of dried patches showing penetration of the CBD nanoparticles through the whole matrix (water and Tween 20).

FIGS. 16 and 17 illustrate graphs providing a comparison of the 72h release of CBD from CBD particles loaded onto the cellulose matrix with or without the presence of Tween 20.

FIGS 18 and 19 illustrate SEM images of submicron protein loaded particles in cellulose matrix, the particles having an average particle size of ~ 300-500 nm.

FIG 20 illustrates SEM images of submicron Praziquantal loaded Ethylsiloxane particles in cellulose matrix, the particles having an average particle size of ~ 1 micron.

EXAMPLES

The following are provided for exemplification only and should not be construed as limiting on the invention in any way.

EXAMPLE 1

Background

The overarching aim of the experimental strategy was to evaluate the performance of empty cellulose patches after loading with lidocaine containing silica nanoparticles prepared according to International Publication No. WO 2006/133519, the content of which is incorporated herein in its entirety. The particle loaded patches were assessed for their permeation and efficiency using the Franz cell diffusion apparatus.

The examples present data pertaining to optimisation of homogeneous patch loading, and the release profile of lidocaine from the patches through and into the synthetic skin (STRAT-M) over time. For comparison, commercial EMLA patches (prilocaine/lidocaine patches from ASPEN) and commercial Versatis lidocaine patches (from Grunenthal GMBH) were also tested.

Production of Particle Patches

Lidocaine containing silica nanoparticles were prepared according to the methodology described in International Publication No. WO 2006/133519. The particles were characterised for size using the Malvern Mastersizer, for morphology and size by Transmission Electron Microscopy (TEM) and for lidocaine loading by reverse phase HPLC. Lidocaine particles used in these experiments were spherical particles having a particle size of about 60 nm. The particles contained from 15.2-15.5 wt.% lidocaine. The particles were produced as a slurry with from 33-37 wt.% solid content. Figure 1 illustrates a TEM (19000x, 100 kV) of silica nanoparticles with encapsulated lidocaine, the nanoparticles having an average particle size of ~ 60 nm.

The concept was to load the lidocaine particle slurry containing the required amount of lidocaine into the cellulose matrix. An example of a patch with cellulose disc (10 cm²) for loading with lidocaine particles are illustrated in Figures 2. The base consists of an occlusive dressing (user part) and a protective liner (closure part). The occlusive dressing includes an aluminium backing laminate, an absorbent cellulose disc and a foam tape ring. The foam tape is a polyethylene foam coated with acrylate adhesive. The protective liner is an aluminium laminate. A peel off seal between the aluminium backing laminate and the protective liner encloses the cellulose disc which is to be impregnated with lidocaine particles. Optimisation of particle loading in Cellulose matrix

Loading of the patches having a standard thickness cellulose disc was optimised using a lidocaine particle slurry diluted in water to 15 wt.% of solids (from 33-37 wt.% in the original slurry). The aim was to assess the maximum loading capacity of the cellulose disc of the empty patches without adversely affecting the smoothness of the patch. It was noted that 25 mg and 35 mg of lidocaine could be loaded with no significant loss of feel. However, loading 50 mg of lidocaine led to deposits on top of the patch indicating saturation of the matrix. This was further confirmed by high resolution SEM imaging that showed that while the lidocaine particles were located below the surface of cellulose matrix for 25 and 35 mg lidocaine, when 50 mg lidocaine was loaded, the particle residues were caked on top of the surface. Reference is made to Figure 3 which illustrates SEM images for an empty cellulose matrix, and cellulose matrix loaded with, 25 mg, 35 mg and 50 mg of lidocaine. Overall, the best results in terms of feel and loading were obtained when 25 mg worth of lidocaine were loaded into the cellulose matrix.

To increase the capacity of the patches to 50 mg of lidocaine, patches having a cellulose disc with double the thickness of the original cellulose disc were prepared and tested. To estimate the best viscosity for uniform loading, lidocaine particle slurries at 5, 10 and 15 wt.% content were prepared. It was found that loading was optimal at a lidocaine particle content of 5 wt.% of the solution. This content resulted the most even distribution of the lidocaine particle slurry and loading to the greatest depth into the cellulose disc. The feel of the patch after loading and drying (40°C overnight) was smooth.

Homogeneity of Loading

Three standard thickness patches were loaded with particles to give 25 mg of lidocaine and were analysed for homogeneity of loading between the patches. The commercial patches were also tested to validate the analytical techniques and processes used.

The following patches were assessed:

1) Particle Patch: patches loaded with lidocaine particles in water and then dried overnight at 40°C.

2) Commercial EMLA

3) Commercial Versatis The results of HPLC based determination of lidocaine loadings in these patches is provided in Table 1, below, and illustrated graphically in Figure 4.

Table 1: Homogeneity of lidocaine loading in different patches

The results illustrate consistency of loading between the lidocaine particle patches with a % error at ~ 2%. The commercial patches (n=3) showed loadings close to expected with no more than 2% error. Thus, these data not only validated the analytical process used, but also confirmed the consistency of the process of loading of particles onto the cellulose discs in the lidocaine particle patches.

Performance of the Particle Patches

(i) Permeation through the skin

The particle patches loaded with 25 mg of lidocaine encapsulated in ceramic particles were either used wet or dried overnight at 40°C to assess their lidocaine release profile using a Franz cell-based diffusion assay. All patches were cut as 1.54 cm² discs using a coring device and were assessed for lidocaine release through the synthetic membrane (STRAT-M). For dried patches, 150 pi of PBS was placed onto the membrane prior to their placement on the membrane to allow a good initial patch contact with the membrane. Given their inherently moist nature, the commercial patches and the wet particle patches were placed without addition of PBS onto the membrane. Additional water here would have impacted on the contact efficiency for the moist patches.

EM LA contains 25 mg of lidocaine /10 cm² and Versatis contains 50 mg/10 cm². The lidocaine permeated through the skin into receptor PBS buffer was measured at different times during the experiment for up to 24 h.

Graphical representations of the cumulative quantity of lidocaine permeated (buffer) from the 1.54 cm² patches at different times are provided in Figures 5A and 5B. Graphical representations of the efficiency of lidocaine permeation from the 1.54 cm² patches are illustrated in Figures 6A and 6B. The permeation data clearly demonstrates the superior release profile of the dry particle patches in comparison with the commercial and wet patches at all times.

Referring to Figures 5A and 5B, initially (up to 6 h), the quantity of permeated lidocaine for both dry and wet particle patches was more than that for the commercial patches, with Versatis displaying the lowest permeated quantities. However, at 24 h, though the dry particle patches continued to permeate significantly higher quantities than the other patches, the wet particle patch performance was equivalent to that for the EMLA patch. The Versatis patch continued to display much lower permeation than all of the other patches.

Referring to Figures 6A and 6B, the efficiency of the patches defined by the percentage of lidocaine permeated in comparison to the amount of lidocaine loaded into the patches was also established. This showed the superior efficiency of the dry particle patches at all times, reaching 51 % at 24 h. The wet particle patch and the EMLA patch were comparable (11% at 24 h), while the Versatis patch displayed much lower efficiencies than the particle patches (2% at 24 h).

(ii) Lidocaine Release in the Membrane

The main purpose of transdermal lidocaine patches is to provide localised pain relief. As such, the membrane release profile over time for the patches was determined. The membranes were harvested at different times and the quantity of lidocaine was assessed by HPLC. This was a single study with no replicates.

Referring to Figures 7 A and 7B, the release profiles of the patches is graphically illustrated. This demonstrates a constant release of active from the particle patches characterised by stabilised membrane levels from 4 h onwards. The dry particle patches showed superior or comparable levels to the EM LA patch at early and late time points respectively.

While no lidocaine had permeated through to the buffer at 0.5 h (Figure 7A), the levels of lidocaine in the membrane at 0.5 h were noticeable for all types of patches (Figure 7B). Dry particle patches released the highest quantities (0.42 mg), followed by EMLA (0.32 mg) and Versatis (0.2 mg). Wet particle patches also released lower levels of lidocaine in the membrane (0.08 mg). EMLA showed the highest levels at 4 h and diminished at later times, while Versatis showed the highest levels at 12 h, stabilising at that level for up to 24 h.

Efficiency of release in the membrane for the dry patches was the highest, releasing -18% at 0.5 h and stabilising at -11% from then on. Wet patches stabilised at (3-6%) in the membrane from 4 h onwards. Versatis displayed the lowest efficiency (2-5%) and EMLA patch efficiency ranged from 13% (at 4 h) to 5% by 24 h. Overall, dry particle patches displayed a superior release profile, with higher early release in the membrane and sustained release at a significant level for at least 24 h. It is not clear why the wet particle patches released a lower quantity of lidocaine in comparison to the dry particle patches. (iii) Efficiency of Lidocaine released at 24 h

A comparison of the efficiency of the different patches, defined by % of total (loaded) lidocaine that is released from the patches (i.e. buffer + membrane), is illustrated in Figure 8. This shows superior efficiencies of the dry particle patches, releasing >65% of the payload by 24 h, in comparison to only 7% from the Versatis patch and 22% released from EM LA. Wet particle patches were comparable to the EMLA patch.

This is a surprising result as one would generally have expected the lidocaine particle patch of the invention to release less than the EMLA patch. As the EMLA patch is basically an adsorbed emulsion of lidocaine on the patch (loading of Lidocaine on the patch are the same i.e. 25mg), one would have expected the release curve for the particle patch of the invention to be lower than that for the EMLA patch. However, the experimental results contradict these expected results.

Dose response: Effect of different particle loadings on the permeation profiles

Given the high efficiency of the dry particle patches, tests were conducted to determine the lowest dose of lidocaine in the dry particle patches to achieve an effect comparable to that provided by the commercial patches. The patches were loaded with lidocaine particles containing 25 mg, 10 mg, 5 mg and 1 mg of lidocaine and dried overnight at 40°C. Permeation from the patches was measured over 72 h. The results are illustrated in Figures 9A-9C. A clear correlation of lidocaine release with the loaded dose was noted. At all times, the trend was 25 mg > 10 mg > 5 mg > 1 mg. This indicated that levels of drug administered can be controlled by controlling the drug loading in the dry particle patches. When compared with the commercial patches, notably, the 25 mg particle patches showed the highest levels of permeation at all times (Note: EMLA = 25 mg of lidocaine; Versatis = 50 mg of lidocaine. Further, 10 mg particle patches showed greater permeation than Versatis while 5 mg particle patches showed comparable permeation. Not surprisingly, the lowest dose 1 mg particle patch displayed the lowest levels of lidocaine release at all times.

These experiments also showed higher early release (up to 5 h) by the 25 mg particle patch compared to commercial patches but importantly, the lower dose, 10 mg and 5 mg particle patches, showed a comparable release to EMLA and Versatis.

The levels in of lidocaine in the membrane were not estimated at all times for this experiment, however at 72 h, though not significant, the trend showed dose dependency. Versatis showed maximum levels, 25 mg and 10 mg particle patches showed similar levels to EMLA, while 5mg and 1 mg particle patches showed lower levels.

In terms of efficiencies, all particle patches showed >90% load release by 72 h, while Versatis released 14% and EMLA released 26% of its payload by 72 h. This suggested a more efficient mechanism of lidocaine release in particle patches especially when comparing the 25 mg particle patch to EMLA patch with similar loading.

Again, this is a surprising result as one would generally expect the release of the particle patch of the invention to be less than that of the EMLA patch.

Summary and Conclusions

In this study, the lidocaine loaded particle patches were assessed for their performance and also compared with the commercial EMLA and Versatis Lidocaine patches. The concept of loading a cellulose matrix with ceramic particles loaded with lidocaine was successful. The particle patches could be produced consistently with minimal error in the loadings. When tested for performance, dry particle patches outperformed all patches, demonstrating the highest efficiencies at all times. At early times, (up to 5-6 h), the release was higher than the commercial patches. Release then stabilised to a constant value suggesting a continuous and controlled release over time.

Though permeation and efficiency of the wet patches (particles in water) was comparable to the EMLA patch, lower levels of lidocaine were released into the membrane in comparison to the commercial and dry particle patches. It is not known if these levels are adequate for therapeutic effect.

Overall, the efficiencies of the particle patches was either comparable or superior to the commercial patches. Particle patches loaded at 10 mg and 5 mg of lidocaine were found to be comparable in permeation to EMLA up to 5 h and either superior or comparable to Versatis for up to 48 h, suggesting a suitable dosing to achieve comparable performance to the commercial patches.

In conclusion, the dry particle patches loaded at up to 10-fold lower dose than Versatis display comparable performance in these experiments.

It is to be noted that in these studies, the release from Versatis patch was significantly higher (7-14%) than that noted in previous studies at similar times (~1-2%). Hence, though the data is an indicator of relative performances, the comparison between commercial patches and the particle patches of the invention is not absolute and may not represent the actual differences in their profiles. It is possible that this is a STRAT-M specific effect as these high levels of release have not been seen with human skin or in in vivo studies in piglets. Importantly, when used in humans no more than 2-3% release is seen. Therefore, while relative trends can be elucidated between systems, comparisons between the patches with similar mode of delivery would be more reliable using the STRAT-M membrane based system. EXAMPLE 2

In order to confirm the above findings for other active dopants, fentanyl loaded particles were prepared with a fentanyl loading of 9.2% (by HPLC) and a size range by TEM of 50-60nm. A TEM image of the produced particles is provided in Figure 10.

Patch tests 10 cm² empty cellulose patches were loaded with ~4.1 g of silica encapsulated fentanyl suspended in Dl water. The loaded patches were dried overnight at 40°C prior to use. For comparison a commercial Matrix Patch : Duragesic (25pg/hr) containing ~4.4mg Fentanyl in 10cm² patch was used. Method

1.54 cm² cored samples from both were estimated for fentanyl release through a synthetic membrane (STRAT-M) over a period of 72h. The receiving buffer was a phosphate buffer at pH 5.6 and a temperature of 32°C. Samples (1 mL) were collected at indicated times over a period of time. Results are illustrated graphically in Figure 11.

As shown in Figure 11, the release of fentanyl from the nanoparticle fibrous patches was at least 2-3 fold higher than that of the commercial patch for the first 48 hours. By 72 hours both patches appeared to be releasing similar quantities.

EXAMPLE 3 In order to consider larger particles, cannabidiol (CBD) loaded particles were prepared with a CBD loading of 16.4% and a size range by TEM of 75-200nm. A TEM image of the produced particles is provided in Figure 12. Patch tests

10 cm² empty cellulose patches were loaded with ~18mg of silica encapsulated Cannabidiol suspended in distilled water and, in addition, 10 cm² empty cellulose patches were loaded with ~14mg of free Cannabidiol (99.9% purity) suspended in Ethanol. Both were dried overnight at 40°C prior to use.

Method:

1.54 cm² cored samples from both were estimated for CBD release through a synthetic membrane (STRAT-M) over a period of 24h. The receiving buffer was 10% Ethanol, 1% Tween 20 in PBS; and the temperature 32°C.

100 pl_ of simulated skin surface fluids was placed between the patches and the membrane to mimic skin surface. The Simulated Skin Surface Fluid was produced by mixing a solution of 0.5% NaCI and 0.1% urea (pH adjusted to 6.6 with HCI) with Canola Oil at 50:50 ratio.

The release was calculated as the % of input dose of CBD measured (by HPLC) in the receiving buffer as well as in the membrane at 24h.

Results are illustrated graphically in Figure 13. It was found that the patches could be efficiently loaded with CBD particle without any loss of feel. The release of CBD into the membrane and the receiving buffer was similar for the free CBD and the CBD-loaded particles.

Figures 14 and 15 illustrate SEMs that show effective loading of CBD nanoparticles in the non-woven cellulose matrix with or without Tween 20. The SEM images are taken of the top, middle and bottom of the dried patches showing penetration of the CBD nanoparticles through the whole matrix. Specifically, the images of Figure 14 show particles loaded in the cellulose matrix in Dl water only at ~147mg of particles (25 mg CBD). The images of Figure 15 show particles loaded in the cellulose matrix in Dl water with 15% Tween 20 at ~173mg of particles (25 mg CBD).

A comparison of the 72h release of CBD from CBD particles loaded onto the cellulose matrix with or without the presence of Tween 20 is provided in Figures 16 and 17.

Method 10 cm² cellulose discs were loaded with ~25 mg CBD (in particles) in Dl water or in Dl water+15% Tween 20. Release was estimated over a period of 72 h by the Franz cell system and Strat-M membrane to assess if the presence of the surfactant assists CBD release into and/or through the membrane. The release of CBD from the cellulose matrix was detected (HPLC) earlier (12h) and was greater than that noted from CBD particles in the presence of Tween 20.

It is considered that further experimentation may be desirable to compare loading and release against commercially available CBD patches and to compare permeation using Human skin.

EXAMPLE 4 In order to determine loading ability using larger particles further testing was conducted. Results are illustrated in Figures 18-20.

Figure 18 illustrates effective loading of submicron protein particles in a non- woven cellulose matrix in presence of 4% Tween 20 in Dl water. The images show cellulose matrix (10 cm²) loaded with RITC labelled (fluorescent) submicron ovalbumin particles (~12.4mg; 300-500nm). The top panel in Figure 18 is an image of a particle-loaded cellulose matrix after drying overnight at 40°C. The lower panel includes SEM images of sections from the top, middle and bottom of the dried patches showing penetration of the submicron particles through the whole matrix.

Figure 19 illustrates effective loading of submicron protein particles in a non- woven cellulose matrix in Dl water. The images show cellulose matrix (10 cm²) loaded with submicron ovalbumin particles (~60mg; 300-500nm). The top panel in Figure 19 is an image of a particle-loaded cellulose matrix after drying overnight at 40°C. The lower panel includes SEM images of sections from the top, middle and bottom of the dried patches showing penetration of the submicron particles through the whole matrix.

Figure 20 illustrates effective loading of Micron sized Ethylsiloxane Matrix particles in a non-woven cellulose matrix. The images show cellulose matrix (10 cm²) loaded with Micron Praziquantal (drug) Ethylsiloxane particles (-150 mg; 1 Micron). The top panel in Figure 20 is an image of a particle-loaded cellulose matrix after drying overnight at 40°C. The lower panel includes SEM images of sections from the top, middle and bottom of the dried patches showing penetration of the Micron sized Ethylsiloxane particles through the whole matrix.

SUMMARY

In summary, the examples show effective loading of nano-, submicron- and micron- sized silica particles at different concentrations in the non-woven cellulose matrix. As such, it is considered that the methodology and resultant substrates may effectively be loaded with a range of different sized particles with a reasonable expectation of success.

The examples illustrate that it is possible to successfully produce substrates loaded with lidocaine, fentanyl, CBD, protein (Ovalbumin) and other drugs (Praziquantal). It is considered therefore that it is reasonable to expect that a wide variety of dopants, such as those described herein, may be encapsulated as described. It is further considered that one could reasonably expect loading and release of such dopants, including those as described herein, to be similar to those exemplified. As such, it is considered the scope of the invention extends well beyond the exemplified dopants, at least to include those described earlier.

From the examples it is considered that the loading efficiency is not impacted by the presence of the surfactant Tween 20. However, it is observed that the process of loading is smoother in the presence of the surfactant, i.e. , Tween 20.

The release of fentanyl particles in the cellulose matrix was far superior than that noted for the commercial patch with equivalent loading, i.e., earlier release at 2-3 fold greater rate up to 48 h. The release of CBD from the cellulose matrix was comparable to that noted for free CBD and was found to be superior when particles were loaded in the absence of Tween 20.

While cellulose matrixes are exemplified as the absorbent matrix, it should be understood that the absorbent matrix is explicitly not so limited. It is considered that one could reasonably expect satisfactory results from other absorbent matrixes, such as those described earlier.

Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers, but not the exclusion of any other step or element or integer or group of steps, elements or integers. Thus, in the context of this specification, the term “comprising” is used in an inclusive sense and thus should be understood as meaning “including principally, but not necessarily solely”.

Unless the context requires otherwise or specifically stated to the contrary, integers, steps or elements of the invention recited herein as singular integers, steps or elements clearly encompass both singular and plural forms of the recited integers, steps or elements. It will be appreciated that the foregoing description has been given by way of illustrative example of the invention and that all such modifications and variations thereto as would be apparent to persons of skill in the art are deemed to fall within the broad scope and ambit of the invention as herein set forth.

Claims

1. A substrate for use in a transdermal patch or dressing, said substrate comprising an absorbent matrix impregnated with ceramic particles comprising a ceramic matrix and a dopant releasably encapsulated within said ceramic matrix.

2. A substrate according to claim 1, wherein said absorbent matrix comprises a non-woven fibrous matrix or a textile matrix.

3. A substrate according to claim 2, wherein said non-woven fibrous matrix or textile matrix is fabricated from one or more synthetic polymers selected from polyesters (e.g. polyethylene terephthalate, polylactic acid, polyglycolic acid, polycaprolactone), poly-ethers (e.g. polyethylene glycol (PEG/PEO), polyurethanes (e.g. polyether urethanes, polyester urethanes), polyethylenes (e.g. HDPE, LDPE), acrylic polymers (e.g. polymethyl methacrylate, polyethyl acrylate), polyamides (e.g. poly(imino carbonates)), cellulose and its derivatives (e.g. ethyl cellulose, hydroxypropyl methylcellulose), polyanhydrides, polycarbonates, polysulfones, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, and copolymers (e.g. PLGA, poly(L-lactide-co- caprolactone)); and/or one or more natural polymers selected from polysaccharides (e.g. cellulose, chitosan, starch) and proteins (e.g. silk fibroin, collagen).

4. A substrate according to any one of the preceding claims, wherein said absorbent matrix is impregnated with said ceramic particles by loading said absorbent matrix with a slurry of said ceramic particles.

5. A substrate according to claim 4, wherein said slurry has a solids content of from 5-60 wt.%, preferably 10-50 wt.% or 20-40 wt.%.

6. A substrate according to any one of the preceding claims, wherein said ceramic particles comprise solid, porous spheres.

7. A substrate according to any one of the preceding claims, wherein the ceramic matrix is a polymerisation and/or condensation and/or crosslinking product of a precursor material.

8. A substrate according to claim 7, wherein the ceramic matrix comprises a hydrolysed silane, such as a hydrolysed organosilane.

9. A substrate according to claim 7, wherein the ceramic matrix comprises an organically modified ceramic, such as an organically modified silica (organo- silica).

10. A substrate according to claim 7, wherein the ceramic matrix comprises bound organic groups.

11. A substrate according to claim 10, wherein the bound organic groups are selected from ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, isooctyl, decyl, dodecyl, cyclohexyl, cylcooctyl or cyclopentyl.

12. A substrate according to claim 11 , wherein the bound organic groups are substituted (e.g. with functional groups, halogens, aryl groups, etc.) or are unsubstituted.

13. A substrate according to claim 7, wherein the precursor material comprises an organotrialkoxysilane, and the ceramic matrix is formed in the presence of a trialkoxyaminoalkylsilane catalyst.

14. A substrate according to any one of the preceding claims, wherein the dopant is selected from the group consisting of hydrophobic and hydrophilic small molecule drugs such as antibiotics (e.g. chloramphenicol), analgesics, such as diclofenac, Procaine, Dimethocaine (synthetic derivative), Lidocaine, ibuprofen, dibucaine, bupivacaine, capsaicin, amitriptyline, glyceryl trinitrate, opioids (e.g. Fentanyl, Morphine, Buprenorphine, Oxycodon, Methadone, Tramadol, Hydrocodone), natural or synthetic cannabinoids (e.g. CBD (Cannabidiol), delta-9-tettrahydrocannabinol (THC), Cannabinol (CBN), Cannabigerols (CBG) Cannabichromenes (CBC), Cannabinodiol (CBDL), Cannabicyclol (CBL), Cannabielsoin (CBE) and Cannabitriol (CBT), Cannabidivarin (CBDV), and other analgesics such as menthol, pimecrolimus, and phenytoin) or anti-nausea scopolamine (or Hyoscine), proteins for therapeutic purposes e.g. antibodies, growth hormones (for wound healing), or steroids for the treatment of skin eczema, birth control, or for hormone replacement therapy (e.g. estrogen or testosterone), nitroglycerine, Vitamin B12, Folate, Iron, Vitamin D or Vitamin E or a fluorescent, radioactive or metal (e.g. gold) tracer.

15. A substrate according to any one of the preceding claims, wherein the dopant represents between about 0.01 and 50% of the weight or the volume of the particle, or between about 0.01 and 10%, 0.01 and 1%, 0.01 and 0.5%, 0.01 and 0.1%, 0.01 and 0.05%, 0.1 and 30%, 1 and 30%, 5 and 30%, 10 and 30%, 0.1 and 10%, 0.1 and 1% or 1 and 10% of the weight or the volume of the particle.

16. A substrate according to any one of the preceding claims, wherein the dopant is Lidocaine.

17. A substrate according to claim 22, wherein said absorbent matrix is loaded with up to 50 mg of lidocaine, preferably from 5 to 35 mg of lidocaine.

18. A substrate according to any one of the preceding claims, wherein the ceramic particles have a diameter between about 1 nm and about 1000 nm.

19. A substrate according to any one of the preceding claims, wherein the ceramic particles have a specific surface area of between about 2 and 400 m²/g.

20. A substrate according to any one of the preceding claims, wherein the dopant is capable of being released from the ceramic particles over a period of between about 1 minute and 1 week, for example over 72 hours, 48 hours, 24 hours, 12 hours, 6 hours, 4 hours or less than 2 hours.

21. A transdermal patch comprising: an occlusive or non-occlusive dressing comprising a substrate according to any one of claims 1 to 20, an adhesive portion adapted to adhere the dressing to the skin, and a backing laminate; and a protective liner.

22. A transdermal patch according to claim 21, wherein said adhesive portion comprises a pressure sensitive adhesive (PSA) encircling or laminated over the absorbent matrix, the PSA preferably selected from polyacrylates, silicone based PSA, hybrid chemistry PSA (e.g. hybrid silicone-acrylate PSA), polyisobutylene, synthetic or natural rubber and thermoplastic elastomers.

23. A transdermal patch according to claim 22, wherein the PSA is applied to a foam material, for example a polyethylene foam.

24. A transdermal patch according to any one of claims 21 to 23, wherein said backing laminate is selected from poly vinyl chloride film, polyethylene film, polyester films, polyisobutylene, silicone oil, aluminium film and polyolefin films, preferably an aluminium laminate.

25. A transdermal patch according to any one of claims 21 to 24, wherein said protective liner comprises a base layer and a release coating layer.

26. A transdermal patch according to claim 25, wherein the base layer comprises paper fabric, polyethylene, polyvinyl chloride.

27. A transdermal patch according to claim 25 or 26, wherein the release coating layer comprises highly crosslinked silicon polymer, fluoropolymers, e.g. polytetrafluoroethylene or PTFE (Teflon).

28. A transdermal patch according to any one of claims 21 to 24, wherein the protective liner comprises polyester foil or metalized laminate.

29. A dressing, such as a wound dressing, comprising a substrate according to any one of claims 1 to 20.

30. A method of preparing a substrate for use in a transdermal patch or dressing, said method comprising impregnating an absorbent matrix with a slurry of ceramic particles, said ceramic particles comprising a ceramic matrix and a dopant releasably encapsulated within said ceramic matrix.

31. A method according to claim 30 further comprising the step of drying or partially drying the impregnated absorbent matrix.

32. A method according to claim 30 or 31, wherein said absorbent matrix is a non-woven fibrous matrix or textile matrix, preferably fabricated from one or more synthetic polymers selected from polyesters (e.g. polyethylene terephthalate, polylactic acid, polyglycolic acid, polycaprolactone), poly-ethers (e.g. polyethylene glycol (PEG/PEO), polyurethanes (e.g. polyether urethanes, polyester urethanes), polyethylenes (e.g. HDPE, LDPE), acrylic polymers (e.g. polymethyl methacrylate, polyethyl acrylate), polyamides (e.g. poly(imino carbonates)), cellulose and its derivatives (e.g. ethyl cellulose, hydroxypropyl methylcellulose), polyanhydrides, polycarbonates, polysulfones, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, and copolymers (e.g. PLGA, poly(L-lactide-co-caprolactone)); and/or one or more natural polymers selected from polysaccharides (e.g. cellulose, chitosan, starch) and proteins (e.g. silk fibroin, collagen).

33. A method according to any one of claims 30 to 32, wherein said slurry has a solids content of from 5-60% wt.%, preferably 10-50 wt.% or 20-40 wt.%.

34. A method according to any one of claims 30 to 33, wherein said ceramic particles comprise solid, porous spheres.

35. A method according to any one of claims 30 to 34, wherein the ceramic matrix is a polymerisation and/or condensation and/or crosslinking product of a precursor material.

36. A method according to claim 35, wherein the ceramic matrix comprises a hydrolysed silane, such as a hydrolysed organosilane.

37. A method according to claim 35, wherein the ceramic matrix comprises an organically modified ceramic, such as an organically modified silica (organo- silica).

38. A method according to claim 35, wherein the ceramic matrix comprises bound organic groups.

39. A method according to claim 38, wherein the bound organic groups are selected from ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, isooctyl, decyl, dodecyl, cyclohexyl, cylcooctyl or cyclopentyl.

40. A method according to claim 39, wherein the bound organic groups are substituted (e.g. with functional groups, halogens, aryl groups, etc.) or are unsubstituted.

41. A method according to claim 35, wherein the precursor material comprises an organotrialkoxysilane, and the ceramic matrix is formed in the presence of a trialkoxyaminoalkylsilane catalyst.

42. A method according to any one of claims 30 to 41 , wherein the dopant is selected from the group consisting of hydrophobic and hydrophilic small molecule drugs such as antibiotics (e.g. chloramphenicol), analgesics, such as diclofenac, Procaine, Dimethocaine (synthetic derivative), Lidocaine, ibuprofen, dibucaine, bupivacaine, capsaicin, amitriptyline, glyceryl trinitrate, opioids (e.g. Fentanyl, Morphine, Buprenorphine, Oxycodon, Methadone, Tramadol, Hydrocodone), natural or synthetic cannabinoids (e.g. CBD (Cannabidiol), delta-9-tettrahydrocannabinol (THC), Cannabinol (CBN), Cannabigerols (CBG) Cannabichromenes (CBC), Cannabinodiol (CBDL), Cannabicyclol (CBL), Cannabielsoin (CBE) and Cannabitriol (CBT), Cannabidivarin (CBDV), and other analgesics such as menthol, pimecrolimus, and phenytoin) or anti-nausea scopolamine (or Hyoscine), proteins for therapeutic purposes e.g. antibodies, growth hormones (for wound healing), or steroids for the treatment of skin eczema, birth control, or for hormone replacement therapy (e.g. estrogen or testosterone), nitroglycerine, Vitamin B12, Folate, Iron, Vitamin D or Vitamin E or a fluorescent, radioactive or metal (e.g. gold) tracer.

43. A method according to any one of claims 30 to 42, wherein the dopant represents between about 0.01 and 50% of the weight or the volume of the particle, or between about 0.01 and 10%, 0.01 and 1%, 0.01 and 0.5%, 0.01 and 0.1%, 0.01 and 0.05%, 0.1 and 30%, 1 and 30%, 5 and 30%, 10 and 30%, 0.1 and 10%, 0.1 and 1% or 1 and 10% of the weight or the volume of the particle.

44. A method according to any one of claims 30 to 43, wherein the dopant is lidocaine.

45. A method according to claim 44, wherein said absorbent matrix is loaded with up to 50 mg of lidocaine, preferably from 5 to 35 mg of lidocaine.

46. A method according to any one of claims 30 to 45, wherein the ceramic particles have a diameter between about 1 nm and about 1000 nm.

47. A method according to any one of claims 30 to 46, wherein the ceramic particles have a specific surface area of between about 2 and 400 m²/g.

48. A method according to any one of claims 30 to 47, wherein the dopant is capable of being released from the ceramic particles over a period of between about 1 minute and 1 week, for example over 72 hours, 48 hours, 24 hours, 12 hours, 6 hours, 4 hours or less than 2 hours.

49. A method according to any one of claims 30 to 48, wherein the substrate is used in a transdermal patch, the method further comprising: forming an occlusive or non-occlusive dressing comprising the substrate, an adhesive portion adapted to adhere the occlusive dressing to the skin, and a backing laminate; and applying a protective liner to the occlusive or non-occlusive dressing.

50. A method according to claim 49, wherein said adhesive portion comprises a pressure sensitive adhesive (PSA) encircling the absorbent matrix, the PSA preferably selected from polyacrylates, silicone based PSA, hybrid chemistry PSA (e.g. hybrid silicone-acrylate PSA), polyisobutylene, synthetic or natural rubber and thermoplastic elastomers.

51. A method according to claim 50, wherein the PSA is applied to a foam material, for example a polyethylene foam.

52. A method according to any one of claims 49 to 51 , wherein said backing laminate is selected from poly vinyl chloride film, polyethylene film, polyester films, polyisobutylene, silicone oil, aluminium film and polyolefin films, preferably an aluminium laminate.

53. A method according to any one of claims 49 to 52, wherein said protective liner comprises a base layer and a release coating layer.

54. A method according to claim 53, wherein the base layer comprises paper fabric, polyethylene, polyvinyl chloride.

55. A method according to claim 53 or 54, wherein the release coating layer comprises highly crosslinked silicon polymer, fluoropolymers, e.g. polytetrafluoroethylene or PTFE (Teflon).

56. A method according to any one of claims 49 to 52, wherein the protective liner comprises polyester foil or metalized laminate.