GB2485637A

GB2485637A - Multi-layered Transdermal Patch activated upon removal of an impermeable inner liner

Info

Publication number: GB2485637A
Application number: GB1115920.9A
Authority: GB
Inventors: Dewan Fazlul Hoque Chowdhury
Original assignee: Individual
Current assignee: Individual
Priority date: 2010-11-22
Filing date: 2011-09-14
Publication date: 2012-05-23
Also published as: GB201019761D0; GB201115920D0; GB201101526D0; WO2012069820A1; GB201103750D0

Abstract

A transdermal patch for delivering an active agent to the skin of a patient comprises an upper layer 1 containing the active agent; a lower layer 2 for adhesion to the skin of the patient and permeable to the active agent; and an impermeable release liner 3 disposed between the upper and lower layers and removable so as to permit the diffusion of the active agent from the upper layer through the lower layer to the skin of the patient. Preferably the transdermal patch includes a tab 4 facilitating the removal of release liner 3. Tab and release liner may be two parts of a single sheet folded (Figure 9) optionally in a concertina fold (Figure 10). The patch may be contained in a packaging within which the tab is affixed or which comprises means to retain the upper and lower layers as the release liner is removed. The upper layer may contain rivastigmine with a silicone adhesive or a copolymer of methyl methacrylate and butyl methacrylate, and the lower layer a penetration enhancer and/or an anaesthetic.

Description

Multi-layered Transdermal Patch

Technical field

The invention relates to transdermal patches for delivering active agents to the skin of a patient. It has particular application to the use of such patches for delivering active agents that suffer problems of instability during long-term storage and for delivering multiple active agents in combination therapies.

The patient may be human or animal. The active agents are delivered to the surface of the skin, typically in order to permeate the skin and have a physical or chemical effect on the body of the patient. The active agents may be delivered for therapeutic, cosmetic or experimental purposes but are generically referred to in this specification as "drugs".

The invention is also relevant to the delivery of active agents into the body through other surfaces, for example mucosal membranes, inside the mouth and during the treatment of wounds. The use in this specification of the terms "transdermal" and "skin" are not intended to exclude such other routes of delivery.

Background

Transdermal patches are widely used for delivering pharmaceutical and chemical agents through the skin. Some of the most common forms of transdermal patches are reservoir patches, matrix patches and drug in adhesive patches. The components that make up the patches, which are in direct contact with the skin and in direct contact with the drug, generally require a vast number of safety studies prior to their approval for use as drug delivery patches. As a result there are a limited number of polymeric systems that are available on the market and approved for use in transdermal systems.

It follows that the ability to deliver a drug transdermally may be restricted by virtue of the availability of a compatible polymer matrix or adhesive. In many cases incompatibilities do not pose short term stability issues, and are generally an issue for achieving long term stability, which is a requirement of regulatory agencies for the purpose of granting drug approval, with an average requirement of 2 year shelf life on the product.

With respect to other formulation types such as liquids and suspensions, a method of overcoming the stability and compatibility issues has been to make extemporaneous preparations, and to reconstitute formulations immediately prior to use, e.g., by mixing a powder formulation with an aqueous solution to produce a suspension that would then be given a shelf life of several days, whereas the individual components separately would have a shelf life of 2 years or more in most cases. A specific example of a drug that would benefit from this type of reconstitution' at the point of applicationluse is rivastigmine, which is conventionally supplied in a transdermal patch format. As discussed below a wide range of other materials may suffer medium-long term incompatibility issues. It is critical for regulatory issues governing the use of reconstituted' formulations that it should be possible to reproducibly and consistently reconstitute the formulation in an essentially operator-independent manner. It would therefore be beneficial to provide a transdermal patch format that permits such drugs to be reconstituted immediately prior to use.

It would also be beneficial to provide a transdermal patch format that can be used to deliver combination therapies, in which one active agent is reliably delivered to the skin, followed by a second active agent. For example, capsaicin is highly irritant and can only be delivered to the skin at effective levels if preceded by the application of a local anaesthetic.

GB 2440679 describes a transdermal drug delivery patch with temporal control.

Multiple channelled layers are described that will control the entry of drug from one layer to another with the objective of controlling the rate of introduction of active agent to the skin via a patch construction. The emphasis is placed on the rate controlling membrane, with several layers already sandwiched together with seals that would need to be broken in order to induce the flow of active agent from one layer to another. The patent focuses on the flow of liquids through micro-channels. In this patent we describe a system whereby the diffusion of drug molecules through solid to semi solid matrices is controlled which does not rely on micro-channels or the mass flow of bulk material and rather relies on the thermodynamics of molecular diffusion through matrices.

WO 2005/025549 describes a multilayered transdermal drug delivery device whereby separate layers are created as individual patches. At the time of administration the separate layers are combined to form a dual layered patch.

WO 9 1/03998 discloses a transdermal drug delivery system comprising two layers comprising active agents that are contacted at use.

WO 0 1/26705 discloses dual adhesive transdermal drug delivery system comprising two layers with active agents.

Although the latter three prior patent applications disclose the use of multilayered patches that are contacted/combined together on use, a key consideration is the ability to meet the regulatory requirement of robustness and reproducibility of joining the layers together at the point of use to ensure the patient does not miss a dose of medication due to inadequate assembly of the multipart patch system.

Summary of the invention

The invention provides a transdermal patch for delivering an active agent to the skin of a patient, the transdermal patch comprising: an upper layer containing the active agent; a lower layer for adhesion to the skin of the patient, the lower layer being permeable to the active agent; an impermeable release liner disposed between the upper layer and the lower layer to prevent diffusion of the active agent from the upper layer to the lower layer, the release liner being capable of removal from between the upper layer and the lower layer to permit the active agent to diffuse from the upper layer, through the lower layer to the skin of the patient.

The invention thus permits the separation of the drug and other components of the patch such as penetration enhancing agents, adhesive component and polymer matrix component into two or more individual layers based on their relative compatibilities.

The invention also permits the lower layer to contain a second active agent that is prevented from mixing with the first active agent contained in the upper layer during storage of the patch, and that will contact the skin of the patient before the first active agent, which is useful for combination therapies.

It should be noted that "upper" and "lower" are used in this specification as convenient labels for the layers, based on the orientation of the patch shown in the drawings. Of course, the patch may be made, stored and used in any orientation.

The release liner is preferably capable of removal from between the upper layer and the lower layer in a direction generally parallel to the plane of the release liner. The transdermal patch may further comprise a tab that is attached to a first edge of the release liner and extends across the release liner to protrude beyond a second, opposite edge of the release liner.

The release liner can thus be readily removed at the point of use in a way that ensures accurate joining of the multiple layers in an operator-independent way to ensure consistency, robustness and reproducibility.

The transdermal patch may be supplied in packaging, wherein the packaging has an opening through which the transdermal patch can be removed in a direction generally parallel to the plane of the release liner, and wherein the tab is affixed to the packaging. Thus the removal of the patch from its packaging conveniently also ensures correct removal of the release liner from the patch so that it is ready for use.

The benefit of this invention in enabling the separating of the drug from the other components based on their relative compatibilities is demonstrated using the following experimental data generated for Rivastigmine (free base), as follows: Table 1: Formulation compatibility ofRivastigmine free base Component % degradation after 4 weeks at 75°C 10mg Rivastigmine (base) + 50mg Plastoid B, >5% Eudragit E100, Durotak (387-2051, 2052, 2353) 10mg Rivastigmine (base) + 50mg Silicone adhesive <2% (Bio-PSA Q7-4302) 50mg Rivastigmine free base up to 5% The results indicated that the drug alone is prone to degradation (through oxidation).

The oxidation is believed to be a product of the elevated temperature and atmospheric oxygen present in the sample chamber. The results further indicate silicone adhesive provides some protection from oxidation (in the presence of atmospheric oxygen).

One would expect the polymer matrix materials to be similar in their protective capacity (by virtue of physical shielding from the atmosphere), however there is an element of drug degradation observed in all cases with the exception of silicone adhesive. Bio-PSA Q7-4302 are pressure sensitive silicone adhesives designed to adhere transdermal drug delivery systems to the skin and show enhanced chemical stability in the presence of amine-functional drugs, excipients and enhancers.

A further study investigated the stability of Rivastigmine over a period of 3 weeks when combined in approximately a 1:1 ratio with Plastoid B alone. (Plastoid B is a neutral copolymer of butyl methacrylate and methyl methacrylate, obtainable from Degussa.) This combination was found to lead to up to a five-fold reduction in one of the key impurities that arise from degradation of the drug, when compared with the formulation set out in the first row of Table 1.

The above are components that are utilised, for example, in the commercial Exelon® patch containing Rivastigmine. (Exelon® is a registered trade mark of Novartis AG.) Antioxidant is incorporated into the formulation of that patch in order to slow down the long term oxidative degradation of the drug caused by ingredients other than the silicone adhesive component. It can be seen from this how, in accordance with the present invention, the patch may also be constructed in the absence of any antioxidant by producing a version that allows the drug or drug/silicone adhesive component to be produced and stored as a separate layer to the rate controlling matrix (in contact with which the drug would otherwise be prone to oxidation, in the absence of antioxidant), and the two layers brought into to contact to reconstitute' the formulation immediately prior to use.

It is also widely accepted that many transdermal formulations containing permeation enhancers, in particular surfactant based permeation enhancers, as well as organic solvents for enhancing permeation, are not all compatible with drugs over prolonged periods. A patch device that separates the two will therefore provide a means of producing a commercially viable product that perhaps would otherwise not be possible due to incompatibility issues. In such systems where the drug is kept as a separate layer, the drug will diffuse into the matrix layer immediately upon coming into direct contact with it. Generally speaking the rate of diffusion into the polymer matrix will be several fold higher than diffusion through the skin (though the polymer matrix may be a rate limiting membrane whereby the composition of the matrix is modulated to reduce drug diffusion through the matrix at a rate that is in sync with the rate of permeation through the skin, or perhaps even less than the rate of diffusion through the skin). Thus the drug will very rapidly permeate into the matrix layer and saturate it, followed by absorption through the skin, without any significant lag period being noticed. This has been determined to be the case for Rivastigmine base permeation through the skin, whereby the skin permeation is up to 40 times slower than the diffusion of the drug through the polymer membrane. It follows from this that in cases like the Exelon® patch where the drug permeation through the skin is significantly lower than the drug permeation through the polymer matrix, the drug will evenly diffuse into the polymer matrix virtually independent of the area of patch that contains the drug, relative to the overall area of patch with the matrix that will come into contact with the skin, i.e., the portion of patch containing drug may be smaller/more concentrated than the overall matrix patch surface area with which it is combined.

In the case of a Rivastigmine patch being constructed in accordance with the invention, there will essentially be a bottom layer that is in contact with the skin which is a placebo' patch, i.e., the Exelon® patch without any active drug and without its impermeable backing liner. A second layer would be silicone adhesive impregnated with the drug. A study has been carried out in which different levels of silicone have been loaded to produce a patch that contains the same surface area and drug loading as the Exelon® patch (since it is a regulatory requirement that similar drug release kinetics and permeation kinetics are achieved for a generic equivalent, as well as ensuring that the surface area and drug loading remains the same).

Table 2 Rivastigmine base-silicone adhesive compositions Rivastigmine base concentration (%w/w) in 10 square em patch Sampleno. 1 2 3 4 5 6 7 8 Actual weight of 18 18 18 18 18 18 18 18 Rivastigmine (mg) %w/wRivastigmine 14.3 20 25 28 30.5 32 35 40 Actual weight of Silicone adhesive Bio-PSA Q7-4302 108 72 54 46.29 41.03 38.25 33.43 27 (mg) %w/w Bio-PSA Q7-4302 85.7 80 75 72 69.5 68 65 60 Sample S is the equivalent of the ratio of silicone adhesive and drug in the Exelon® patch. It was determined from the above study that samples 1-4 provide a system of adequate tackiness to allow the two layers of the patch to be combined where a single layer was produced containing just drug/Rivastigmine base and silicone adhesive.

Samples 6-8 did not provide sufficient tackiness. Furthermore it was demonstrated that samples 1-5 show the same drug release kinetics as the Exelon® patch as shown in the graph in Figure 11. Note: in Figure lithe "Nemaura Patch" is where silicone adhesive layers prepared according to the sample compositions indicated in samples i-S above were combined with a laboratory prepared placebo' Exelon® patch, and release kinetics monitored (with the mean of the data of the Nemaura patch being presented here). The concentration in the receiver compartment of the Franz cell was determine by a HPLC method published by Dr Reddy's Laboratories.

Furthermore, given that the concentration of drug for the given amount of adhesive in samples 1-4 is smaller than the concentration of drug in silicone in the Exelon® patch (although the absolute amount is the same), this further provides a stable composition, whereas there would be a likelihood of drug precipitation or crystallisation if the concentration of drug relative to the silicone adhesive were to increase. However the use of lower amounts of silicone adhesive for a given amount of drug need not be ruled out, since despite the absence of adequate tackiness it will be readily appreciated how this drug-adhesive' layer can be combined to an impermeable backing liner on the one side and to the polymer matrix on the other side using an additional layer of silicone adhesive on either side of the drug-adhesive layer.

The impermeable backing liner must be both one that is impermeable to the drug (for example polyester) and one to which the composition of the drug-adhesive layer will reliably adhere. If both properties cannot be found in a single material then the backing liner can combine two layers that have the respective properties bonded together.

Different types of polymers, solvents, adhesives, and permeation enhancers are not discussed here as they are widely published in literature. The individual patch components/layers described in this invention may consist of one or more of the following: -drug alone -drug and one or more compatible vehicle (which may be polymer, adhesive, oil, gelling agent, viscosity modifying agent, stabilising agent, inert bulking agent) -polymer matrix -adhesive -permeation enhancing agent (surfactant and/or organic solvent, or other permeation enhancing agent, with appropriate visco-elastic properties to form a patch layer) -stabilising agent (such as anti-oxidant).

Each patch layer will have the requisite physicochemical and mechanical properties that allow the component to be formed as a solid, semi solid or liquid layer, which also allows two or more layers to then be joined in a manner that allows the active components to diffuse evenly throughout the combined patch. The active components are described as being a component that must diffuse evenly throughout the patch to achieve its desired function, which may include drug, antioxidant, permeation enhancer etc. It may be preferable to increase the amount of permeation enhancer in direct contact with the skin, prior to the contact of drug with the skin, since the drug can potentially make up to 30% (in some cases higher percentages) of the total matrix. It follows that a means of achieving this would be with a device that has two discrete layers, one containing the drug and the other containing the matrix and permeation enhancer.

When the two are brought into contact with each other, the layer in contact with the skin containing the permeation enhancer will start modulating the stratum comeum prior to the drug arriving at the skin interface, thus providing a means of enhanced diffusion, since 100% of the skin will initially be covered with the permeation enhancer layer, without being impeded by the physical presence of the drug. It follows that the same argument may also be applied to any other type of skin permeation enhancer in a patch. Diffusion of drug from the second layer to the first layer in contact with the skin may be controlled so as to prolong the contact period of the permeation enhancer with the skin prior to arrival of drug at the patch-skin interface. Furthermore the rate of skin permeation can potentially be increased by modulating the rate of drug permeation from the drug reservoir matrix layer into the underlying rate controlling/permeation enhancing layer such that they are close to being in sync with each other, thus maintaining the high surface area of contact between the skin and the permeation enhancing layer, as drug will not have the opportunity to accumulate at the interface between the permeation enhancing layer and the skin, and would instead diffuse directly from the drug reservoir layer through the permeation enhancing layer, into the skin.

-10 -A further example is given whereby perhaps a first active agent must be applied to prepare the skin to reduce the irritation that may otherwise be unbearable from a second active agent. An example being Capsaicin, whereby above a few percentages the level of irritation is not acceptable thus a local anaesthetic is currently applied to the skin before the patch. However in accordance with the present invention a local anaesthetic could be applied as a separate patch layer, thus maximising the effect of the anaesthetic prior to the effect of the drug.

A further example of drugs that would benefit from this type of patch construction are the prostaglandins such as Alprostadil which are generally highly unstable in the liquid or semi-solid form. Alprostadil is used in erectile dysfunction treatment, and is supplied as a dry powder which is reconstituted prior to use. Use of a transdermal patch applied locally would allow for localised delivery as well as cessation of the effects of the drug by removal of the patch, whereas currently a defined dose is administered. The dry powder or lyophilised form of the drug may be stored in one layer of the patch, if required in a mesh-like membrane which allows the drug to be securely held, and furthermore in light of the high potency of the drug it may be combined with an inert bulking agent to facilitate the manufacturing process for this layer, as well as to ensure the adequate and consistent distribution of the drug on that layer. This layer would then be brought into contact with an adhesive or matrix or reservoir type layer comprising a liquid or semi-solid (e.g. a gel) as described above at the point of use, immediately prior to administration.

The two or more layers' of the patch may be brought into contact by a number of means. The simplest means is where the layers are packed separately and the user is required to then remove each from its respective packaging and then physically place one on to the other. The other extreme is some automated way of dispensing the layers from a purpose built dispenser that opens each layer and joins them together appropriately and then dispenses them as a single patch, with the objective of course being that a single final patch is dispensed that can be simply adhered to the skin of the patient. Alternatively it may be a combination of the above methods, and such techniques will be known to those skilled in the art of tape conversion' whereby various layers are laminated using complex equipment and processes.

Tdeally however one would wish to refrain from the additional cost of a dispensing system, whilst at the same time avoiding the precarious regulatory position of a multi-layer system that must be manually assembled. From this point of view it would be preferable if the process of removing the patch from the pouchllaminated sachet in which it is stored results in the automatic joining of the layers.

One such example (where there are two layers for example) is where the individual layers are cast onto two halves of a strip of backing membrane. The two halves are then folded inwards with a connection means in the form of a disposable strip or other that is present joining the two separate layers from the centre. An important consideration here is that the walls of the sachet will need to be made rigid or have structural elements that prevent it from collapsing when the patch is being removed from the sachet whilst simultaneously joining the two layers, thus also at the same time removing them from the backing liner. Upon opening the sachet the end of the strip is gently pulled outward, and this action directly leads to the two patches being peeled off the backing layer and being joined together such that at the end of the strip a single patch emerges from the sachet where the two layers are now joined as a single patch. The rigidity of the walls prevents the sachet from collapsing during this procedure, and it also prevents the mouth of the sachet from expanding beyond a defined distance which is sufficient to allow the patch to be exited from the sachet whilst the walls exert the requisite pressure to combine the two layers together.

Alternatively or in conjunction with this the backing liner may be restrained within the sachet using a physical interlock such as adhesive, or a mechanical interlocking means, to securely hold the backing liner inside the package whilst the two halves of the patch are brought into contact and exited from the pack as a single patch.

Although the backing liner by definition allows adhesive layers to be reversibly attached to it, the removal of an adhesive layer requires a peeling action/motion, lifting the adhesive layer at a vertical angle; thus an adhesive element may be used by ensuring vertical lifting of the adhesive away from the backing liner is not possible, thus securing the backing liner inside the package. This may also be achieved by virtue of some rigid restraining element which prevents the sachet/packaging from -12 -collapsing or from opening up beyond a defined distance, that distance being sufficient to allow the layers of the patches to be combined and exited from the package as a single patch, whilst preventing the backing liner from being released from inside the package.

A further backing layer from the portion intended to be in contact with the skin would be present which would then be removed together with the strip used to pull the sachet from the patch, and the patch adhered directly to the skin. One mechanism for using this packaging method for multiple layers would be to have one of the layers with discrete regions, each containing different formulation components, all of which then directly come into contact with the opposite layer. Alternatively means may be engineered whereby an elongated package is used such that the above step occurs multiple times in series to adhere multiple layers prior to the final patch exiting the sachet/packaging.

It will also be appreciated how altemative mechanical arrangements may be used to achieve the same outcome. One example of this is where the two patch layers are constmcted whereby they are in a layered matrix, whereby the layers are separated by an impermeable membrane preventing the diffusion of the active components from one layer to another. A removable tab may be present which removes a portion of the impermeable membrane thus bringing portions of the various layers into direct contact, allowing the diffusion of the active agent to take place. From a practical perspective in both embodiments of the invention it may be preferable to have a highly permeable membrane separating the layers in the regions where direct contact between layers is intended at the point of use. This is to facilitate the process of combining the layers, since the layers may otherwise present highly tacky adhesive surfaces, depending upon their composition, which could potentially interfere with the process of the two halves being combined by virtue of their tackiness. This will ease the process of bringing the layers into contact, whilst not impeding the diffusion of active agents between layers once they have been joined as a single patch.

A further embodiment of the above system that would be deemed to be within the broad description provided above, i.e., that of a multilayered patch being stored as -13 -discrete layers within a package, with the layers being combined as part of the process of removal of the patch from its packaging (such as, though not restricted to, an aluminium heat sealed sachet), but is worthy of further elaboration here for purpose of avoidance of any ambiguity, would be one where the process described above will lead to removal of the combined patch from the package whereby the backing liner separating the multiple patch layers is drawn away from the package which leads to the exposure of the tacky/adhesive' sides of the layers facing each other, thus leading them to be attracted to each other and combined as a single unit. In this case the layers of the patch would be combined without being peeled off the backing liner, and instead the backing liner separating the layers would be peeled off leading the patch layers to combine.

It will be readily appreciated by the person skilled in the art that a number of different ways of combining the patch layers may be achieved, with the appropriate reinforcement of the packaging/sachet to cause multi-layers of a patch to be combined through the process of the patch being removed from its packaging, such that a single patch with the layers combined emerges from the packaging.

Description of Figures

Figure 1: Cross section of a patch according to a first embodiment of the invention in an open configuration.

Figure 2: Cross section of the patch of Figure 1 showing the two halves folded inwards.

Figure 3: Cross section of the patch of Figure 1 showing the two halves restrained by a rigid restraint layer.

Figure 4: Cross section of patch of Figure 1 showing the two layers in the process of being joined to form a combined layer.

Figure 5: Cross section of a patch according to a second embodiment of invention.

-14 -Figure 6: Cross section of a patch according to a third embodiment of the invention in an open configuration.

Figure 7: Cross section of the patch of Figure 6 in the folded position.

Figure 8: Cross section showing the patch of Figure 6 as a single unit following removal of the release liner.

Figure 9: An exploded cross-section of a patch according to a fourth embodiment of the invention, having a folded release liner.

Figure 10: An exploded cross-section of a patch according to a fifth embodiment of the invention, similar to Figure 9 but having a double folded release liner.

Figure 11: Graph of drug-release kinetics for a Rivastigmine patch in accordance with the invention compared to a prior art Exelon® patch.

Figure 1 shows a cross section of a patch showing backing liner 3, on which are formed a patch layer 1 and a second patch layer 2 joined together by a joining strip 5, which is in turn attached to a pull tag/strip 4. By pulling on the pull tag 4 the two halves are folded inwards as shown in Figure 2. The pull tag 4 is shown as protruding between the ends of the patch sections. This may be a narrow strip or may cover the entire surface of the patch, sufficient to provide robustness in the process of bringing the sides together. The folded patch is then ready to be inserted into suitable packaging for storage and distribution.

When, at the time of use, the pull tag 4 is pulled the restraining elements on the outer packaging 6 (Figure 3), which are designed to keep the packaging rigid, allow the tag 4 to be pulled out of the packaging whilst peeling the layers 1 and 2 off their backing layer 3, and into direct contact with each other. This is shown in Figure 4 (noting that the layers 1 and 2 are out of proportion here for clarity, as these layers would usually be up to several hundred micrometres in thickness), whereby the combined layers 7 are shown as they are pulled out of the packaging using the pull -15 -tag 4. It is emphasised that although the restraining layer in this example is shown as two rigid sides to the patch package, it may also be any other physical or mechanical system that restrains the patch liner 3 whilst the two patch layers are brought into contact with each other. These may for example be an adhesive or mechanical interlock to hold the backing liner 3 within the package whilst the patch layers 1, 2 are gradually adhered together and removed from the liner 3 and removed from the package. Altematively it may be a combination of these. The mouth of the packaging 6 through which the pull tag 4 and the layers 1,2 are withdrawn is preferably narrow enough and either rigid or resilient enough to ensure that the layers 1,2 are pressed together as they pass through it and so adhere to one another without the formation of air bubbles between them.

Figure 5 shows a cross section of a second embodiment of the invention showing patch layers 9 and 11 separated by an impermeable membrane 13, an impermeable backing membrane 8 on the top of the patch above the first layer 9, and a release liner 12. A removable tab 10 is present between patch layers 9 and 11, upon removal of which the active component is able to diffuse freely between the layers, optionally through a highly permeable membrane 14.

It will be appreciated that the two layers after being joined to form a single patch will consist of an upper side that contains a backing membrane 8 that will remain exposed when the combined patch 7 is applied to the skin, and a lower side which will act as a release liner 12, from which the combined patch 7 will be removed prior to application to the skin, and which protects the skin contact face. These have not been shown in Figures 1 to 4 as they are deemed to be well known features of such patches.

It follows that patch layers 1 and 2 in the first embodiment, following removal from the packaging, will each have a surface in contact with either a backing membrane or a release liner (depending on the function of each).

Figure 6 is a cross section showing a pull tab 4, connected to a release liner 3 positioned over patch layers 1 and 2, with patch layer 1 having an impermeable backing membrane 8 and patch layer 2 seated on a rigid release liner 12. Figure 7 is a cross section of Figure 6 in the folded position showing the positioning of patch -16 -layer 1 above layer 2, separated by the impermeable release liner 3 which doubles up on itself, with a release tab 4 attached to it shown towards the centre of the liner, with the square section depicting the area of grip of the release tab. The patch may be supplied in packaging in this folded state.

Figure 8 is a cross section showing the release tab 4 of Figure 7 having been pulled out with a left to right motion, which will come out of the packaging as a separate unit consisting of the release liner 3 and release tab 4. The release tab is shown connected to the central portion of the release liner 3. The patch has now become a single unit with layer 1 covered by a backing membrane 8, and layer 2 adhered to the release liner 12 from which it may be released and the single patch unit adhered to the skin as per standard patches. The release tab 4 and liner 3 may be connected to the discrete patch unit to assist removal of the patch from the package (not shown here), or alternatively release liners 12 and 3 may be the same release liner folded over itself However in practice release liner 3 will be more flexible than release liner 12. Release liner 12 will be sufficiently rigid to prevent the two layers from warping during the process of removal of release liner 3. Release liner 12 may also be suitably elongated towards the rear of the patch such that it provides a region for gripping on to the patch to prevent the entire patch from leaving the packaging prior to be combined as a single patch. This latter function may also be achieved by virtue of the restraint means discussed in earlier figures. Alternatively, the release tab 4 may be attached to the interior of the packaging so that the removal of the patch from the packaging (through a mouth at the left side as viewed in Figure 7) and the unpeeling of the release liner 3 from the layers 1,2 is carried out in a single operation. As previously described, if the packaging passage is provided with a narrow mouth, this can help to press the layers 1,2 into close contact as they pass through it.

Figure 9 is an exploded cross-section of another embodiment of the patch showing two layers 1 and 2, with the lower layer 2 being seated on a release liner 12, and there being a small section of an impermeable backing liner 13 adhered directly to layer 2.

The function of this liner is to act as a point onto which the upper layer 1 can be permanently secured during production, without creating any routes for molecular diffusion or mass transfer between the layers. It should be noted that whilst the -17 -impermeable liner 13 is shown as a section at one end of the patch, it could also form a peripheral ring around the edges of the patch if required which will provide some tolerance with respect to the combining of the two layers; i.e., the top layer 1 could be slightly smaller in dimensions than the bottom layer 2, and seat above the peripheral liner when the two layers combine (from its anchor point which would be the slightly wider strip of impermeable backing liner at the end at which the two layers are permanently fixed).

A flexible release liner 15 is present which is doubled up whereby one end of the liner is elongated and hinged/secured by some securing means to the packaging/sachet in which the patch is contained; for example the end of the liner may be heat sealed during the formation of the sachet into the joint of the distal side of the sachet (i.e., the end opposite to the open end from which the patch is drawn out). The configuration of the release liner 15 shown in figure 9 is applicable where the upper surface of the lower layer 2 is non-tacky, while the lower surface of the upper layer 1 would be tacky/have adhesive properties. The release liner 15 is shown as being anchored at point at 16 such the upper part of the release liner 15 will gently roll/unpeel away from the adhesive lower side of layer 1 when the region 17 is gripped by the user to pull the patch away from the sachet.

In the event that both the upper surface of layer 2 and lower surface of layer 1 are both tacky/have adhesive properties then the flexible backing liner 15 would be arranged as indicated in Figures 6-8 or Figure 10, i.e., a concertina style such that the liner would release/peel away from both layers simultaneously, whereby the patch is drawn out of the sachet as a single unit with both layers combined. This construction can also be repeated for the self-assembly of multiple layers during the process of removing the patch from the sachet by combining the layers in multiples of the configuration indicated in Figure 9 or 10.

This patent describes: -formulations for enhanced permeation consisting of high proportions of organic solvents.

-18 -methods for drug administration using a transdermat patch whereby different components of the drug are separated in different layers and combined only at the point of use, preferably via an operator-independent mode of assembling the various layers, and preferably where the action of removing the patch from its primary packaging/sachet/pouch leads to the layers being automatically combined.

methods of enhancing drug permeation by separating the drug from the permeation enhancing layer such that a large area of the permeation enhancing layer is in continuous contact with the skin, and this area is not impeded or reduced by the presence of drug accumulating within the permeation enhancing layer in contact with the skin.

drug delivery patches in which a first layer contains a first active agent and a second layer contains a second active agent, the second active agent being irritant to the skin and the first active agent being first applied to the skin to prepare the skin to reduce the irritation.

drug delivery patches in which a first layer contains a first agent and a second layer contains a second agent, the second agent being a drug, e.g. a prostaglandin, in dry powder or lyophilised form that is suitable for storage, and the first agent being a liquid, gel or polymer matrix, in which the second agent can dissolve or through which the second agent can diffuse towards the skin.

devices for assembling multilayered patches that allow the storage of multilayered patches in a single primary package such as a foil sachet or pouch, such that the process of removal of the patch from the pouch leads to the automatic assembly or combining of the various layers.

Claims

-19 -CLAIMS1. A transdermal patch for delivering an active agent to the skin of a patient, the transdermal patch comprising: an upper layer containing the active agent; a lower layer for adhesion to the skin of the patient, the lower layer being permeable to the active agent; an impermeable release liner disposed between the upper layer and the lower layer to prevent diffUsion of the active agent from the upper layer to the lower layer, the release liner being capable of removal from between the upper layer and the lower layer to permit the active agent to diffuse from the upper layer, through the lower layer to the skin of the patient.
2. A transdermal patch according to claim 1, wherein the release liner is capable of removal from between the upper layer and the lower layer in a direction generally parallel to the plane of the release liner.
3. A transdermal patch according to claim 2, further comprising a tab that extends from a first edge of the release liner across the release liner to protrude beyond a second, opposite edge of the release liner.
4. A transdermal patch according to claim 3, wherein the release liner and the tab are two parts of a single sheet that is folded along the first edge.
5. A transdermal patch according to claim 3, wherein the release liner and the tab are parts of a single sheet that is concertina folded along three generally parallel folds, the part of the sheet between the two outer folds forming the tab and the remaining parts of the sheet being adhered respectively to the upper layer and the lower layer to form the release liner.
6. A transdermal patch according to any of claims 3 to S in combination with packaging in which the transdermal patch is contained, wherein the packaging has an -20 -opening through which the transdermal patch can be removed in a direction generally parallel to the plane of the release liner.
7. A transdermal patch according to claim 6, wherein the tab is affixed to the interior of the packaging.
8. A transdermal patch according to claim 6, wherein the packaging further comprises restraint means for retaining the upper and lower layers inside the packaging as the release liner is removed.
9. A transdermal patch according to any of claims 6 to 8, wherein the opening of the packaging is sufficiently narrow to press the upper and lower layers together as the patch is removed.
10. A transdermal patch according to any of claims 1 to 9, wherein the release liner is adhered to at least one of the upper layer and the lower layer, and wherein the removal of the release liner involves unpeeling the release liner from the layer or layers to which it is adhered.
11. A transdermal patch according to any preceding claim, further comprising an impermeable bond between a region of the upper layer and a region of the lower layer.
12. A transdermal patch according to claim 11, wherein the impermeable bond is formed by the said region of the upper layer and the said region of the lower layer both being adhered to a piece of impermeable membrane.
13. A transdermal patch according to claim 12, wherein the removable release liner overlaps the piece of impermeable membrane.
14. A transdermal patch according to any of claims 11 to 13, wherein the impermeable bond is formed between a region at an edge of the upper layer and a region at an edge of the lower layer. -21 -
15. A transdermal patch according to any preceding claim, further comprising a permeable membrane between the upper layer and the lower, which remains in place after the impermeable release liner has been removed.
16. A transdermal patch according to any of claims 1 to 9, wherein each of the upper layer and the lower layer is adhered to a backing liner, and wherein the removal of the release liner involves unpeeling each of the upper and lower layers from its backing liner.
17. A transdermal patch according to any preceding claim, wherein the lower layer contains a penetration enhancer.
18. A transdermal patch according to any preceding claim, wherein the lower layer contains an anaesthetic.
19. A transdermal patch according to any preceding claim, wherein the lower layer contains a polymer matrix that would cause instability of the active agent if stored for long periods in contact with the active agent.
20. A transdermal patch according to any preceding claim, wherein the active agent is rivastigmine.
21. A transdermal patch according to any preceding claim, wherein the upper layer comprises a silicone adhesive or a copolymer of methyl methacrylate and butyl methacrylate.
22. A transdermal patch substantially as described herein with reference to the drawings.