GB2440679A

GB2440679A - Transdermal drug delivery device with temporal control

Info

Publication number: GB2440679A
Application number: GB0715120A
Authority: GB
Inventors: Dewan Fazlul Hoque Chowdhury
Original assignee: Individual
Current assignee: Individual
Priority date: 2006-08-03
Filing date: 2007-08-03
Publication date: 2008-02-06
Anticipated expiration: 2027-08-03
Also published as: GB2440679B; GB0715120D0; GB0615429D0

Abstract

The device comprises at least one micro-channel 23 providing fluid communication between one or more reservoirs 22 and a contact surface from which a drug formulation may diffuse through the skin of a patient. The device has an upper layer with the reservoirs 22, a rate controlling membrane layer 24 with multiple micro-channels 23 of sinuous form defining different transport times by their different lengths, widths or structures, so as to control the timing of drug delivery to the patient., and a lower layer with compartments 26 for receiving the drug formulation from the micro-channels 23. This layer has adhesive for attachment to the skin.

Description

TRANSDERMAL DRUG DELIVERY WITH TEMPORAL CONTROL

Technical field

The invention relates to patches or other devices for delivering drugs or other biologically active substances by diffusion through the skin of a human or animal patient.

Background of the invention

There has been enormous work in recent years to develop active transdermal drug delivery systems that offer enhanced penetration of drugs through the skin such that a broader range of drugs may be delivered and timed control over delivery can be built in. However at the same time there have been numerous attempts to develop chemical and pharmaceutical penetration enhancer' formulations to increase the range of drugs that can be delivered through the skin, and this has led to the possibility of delivering drugs through the skin that are as large as the Insulin molecule.

As a result of the advancements with the enhancer formulations one inherent problcm is the lack of control over the timing of drug delivery, since by virtue of the enhancement of drug delivery, the rate of absorption of the drug from any reservoir is rapid and therefore to attain a desirable pharmacokinetic profile, i.e., rapid absorption followed by a sustained plateau, actively controlled devices that are battery operated :. have been developed, and these include control of valves at the interface of a reservoir * *.

that isolate the drug from the skin until desired. ** , * ** * I I

* Numerous examples exist whereby rate controlling membranes have been developed for the control over the rate of delivery from a drug reservoir to the skin, via the : .* membrane. However two inherent problems of this mechanism are the requirement for compatible polymeric materials for the rate controlling membrane, and also the saturation of the rate controlling membrane to the extent that drug release profiles cannot be adequately predicted due to the effect on the skin over time of the drug and the formulation within which it is contained, and the saturation levels of the skin, and skins level of hydration, all of which affect the kinetics of drug diffusion through the skin and eventual uptake into the systemic circulation.

It follows therefore that it would be advantageous to be able to release drugs to the skin via passive yet controlled means which do not require polymeric rate controlling membranes and their innate compatibility and saturation issues. Furthermore it would be advantageous to be able to passively transfer the drug to a new' area of skin over a period of time to reach and sustain the plateau of blood drug concentration.

Summary of the invention

A transdermal drug delivery device providing at least some of these advantages is defined in claim 1. Preferred features of such a device are defined in the sub-claims.

A rate controlling membrane in accordance with the invention may be prepared from inert solid materials (as distinct from existing polymeric and semi solid rate controlling materials), e.g., inert metals or inert polymers such as PTFE (Teflon ) and polydimethyl siloxane (PDMS). Micro-channels are created in the rate controlling membrane, through which the drug formulation flows by capillary action. The rate of drug movement through the micro-channels is a function of their overall length, structure and diameter (and the drug formulation characteristics).

Such rate controlling membranes possessing different internal structures of micro-channels would have their own unique profile with respect to the time taken for the ::: drug to pass through the membrane. Reservoirs may be provided, each interfaced to * rate controlling membranes such that the rate of travel of drug from the reservoir to the skin via the rate controlling membrane is different for each reservoir/ membrane combination, such that a rapid plateau can be reached and sustained by way of in-tandem delivery of the drug from the reservoirs to the skin from where it will be : absorbed.

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Because the drug delivery mechanism relies on capillary action, movement of the drug through this rate controlling membrane is initiated when: i. One face of the membrane is brought into contact with the drug reservoir opening.

ii. Air in the micro-channels of the rate controlling membrane can be displaced.

The air in the micro-channels can be displaced as follows: i. A valve on one of the lower edges of the rate controlling membrane.

ii. Reduction of air pressure at the lower face of the rate controlling membrane.

If the rate controlling membrane is in direct contact with the reservoir then drug may begin to saturate the part of the upper layers of the channels and there could potentially be blockages due to precipitation at the mouth of the channels. This can be avoided by ensuring the reservoir and the rate controlling membrane do not come into contact until the point of administration.

In this specification, the biologically active substance to be delivered through the skin of the patient is referred to as a drug, although the invention is equally applicable to non-pharmaceutical substances, e.g. skin permeation enhancers such as alcohols and oil-based permeation enhancers such as cardamom.

The drawings Figure 1 is a schematic illustration of a transdermal drug delivery device according to the invention.

Figure 2 is a schematic perspective view of an upper surface of a further embodiment :. of transdermal drug delivery device according to the invention.

Figure 3 is a schematic perspective view of a structured layer of the transdermal drug delivery device of Figure 2.

*:*::* Figure 4 is a schematic plan view of a lower layer of the transdermal drug delivery ** device of Figure 2.

Figure 5 is a vertical section through the transdermal drug delivery device of : Figures2to4.

0 Figure 6 is a schematic plan view of a further, folding embodiment of transdermal drug delivery device according to the inventioit

Detailed description

In the schematic illustration in Fig. 1, a reservoir body 21 contains multiple reservoirs 22 for holding the drug for delivery to a patient, in an appropriate formulation. A layer below the reservoir body (i.e. closer to the skin of the patient when the device is in use) provides a rate controlling membrane body 24 formed with micro-channels 23 therethrough. A resilient membrane 28 between the reservoir body 21 and the rate controlling membrane 24 is pierced by pores (not shown in Figure 1) to provide fluid communication between the micro-channels 23 and the reservoirs 22.

Each of the channels 23 in the rate controlling membrane 24 is micro-engineered to have a precise structure, length and diameter. The micro-channels 23 leading from each reservoir 22 to the skin may be engineered to have different structures such that the channels 23 in each membrane section will provide a different temporal drug transport profile. In Figure 1, the channel shown on the left is longer than that on the right, so the drug transported through it may be expected to take longer to reach the patient's skin. The diameter or other properties of the channel 23 may be varied to change the rate of transport of the drug formulation along it. As shown at the top of the left channel, there may be multiple connections from one reservoir 22 to a channel 23.

A layer below the rate controlling membrane body 24 contains compartments 26 to :. function as collection chambers for accumulation of drug from the reservoirs 22 following transport through the channels 23 and prior to diffusion through the skin.

The same layer may also contain valves 25 either to allow displacement of air as the drug formulation enters the micro-channels 23 or, using self-sealing valves, for * drawing a vacuum at point of use to create a negative pressure within the micro-channels 23, thus enhancing capillary diffusion of the drug formulation through the channels 23.

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An adhesive layer 27 is provided at the base of the device for skin attachment. The adhesive layer 27 may cover the entire bottom surface -in which case it must be permeable to the drug formulation -or be excluded from the openings (not shown) of the drug accumulation compartments 26.

The reservoir body 21, resilient membrane 28 and rate controlling membrane 24 are attached to each other by means of a suitable adhesive, which is omitted from the diagram.

The rate-controlling membrane 24 could be manufactured using any of the following techniques: Manufacturing Process Technology Nano-structuring processes -Mould replication for polymeric materials -Lithography (including PTFE and solid -Micro-imprinting polymers) Nano-structuring processes -Photolithographic fabrication for siliconlinert metals X-ray lithography Electron beam lithography - Chemical etching -Physical and chemical vapour deposition * S Lithography is essentially a process for printing features on a planar surface. *

Lithography tools, commonly referred to as soft lithography, allow precisely defined * :* : :* features to be produced on a substrate, which can be removed from the substrate as * free-standing 3-dimensional nano objects. There are a number of techniques that fall within the field of soft lithography, primarily for construction of micrometer sized objects. These include: I..... * S

-Replica moulding -Micromoulding in capillaries (MIMIC) -Microtransfer moulding -Solvent assisted microcontact moulding (SAMIM) -Microcontact printing It is primarily these latter lithographic techniques that would be employed to produce a complex 3D matrix that would aid in the passive control over drug movement from the reservoirs 22 to the skin. This can be achieved by patterning the desired structure in two dimensions on to a suitable substrate, such as PTFE, a solid polymeric material impermeable to the drug, or inert metal. The depth of the structure would form the channel cavity, and this would be enclosed by attachment of a thin layer of the same or different, non-patterned substrate to the upper surface. Addition of multiple layers, with interconnections between each layer to maintain fluid communication between the layers, would lead to a 3D construct of channels of almost any desired structure and diameter, yet maintaining minimal thickness of the rate controlling membrane by virtue of a horizontal orientation, as shown in Figure 3. The channels may range from nanometres to millimetres in width, though the preferred range of width is likely to be in the tens to hundreds of microns.

Overall control over the flow of the drug (formulation) from the reservoirs 22 to the skin will be dependent on and can be controlled through control of various parameters including the following: * Micro-engineered channel diameter.

* Structure and complexity of the channels.

* Channel length, i.e., distance of travel of the drug formulation. (It is *:*: conceivable that working with precision engineered micron sized channels we * could have channel lengths ranging from the thickness of the rate controlling r membrane, through to tens of metres).

* * Pressure differential, i.e., the degree of negative pressure applied downstream **.e** * of the reservoir.

* Drug formulation viscosity and surface tension.

Unlike the schematic illustration of Figure 1, the channels would preferably take a horizontal rather than vertical conformation within the patch, both for ease of manufacture and also to reduce the overall thickness of the patch, as shown in Figures 2 to S below.

Figure 3 shows a composite structure of a rate limiting membrane. This is indicated schematically as a square structure, but of course may be circular or any other shape deemed suitable, and appropriate for the drug formulation type. The channels 5 formed in the membrane body 4 are also indicated as being generally rectangular in cross section, but of course these too may have any suitable cross section, for example circular with a flat top to interface with a flat top layer (as shown in Figure 2). The channel 5 has a fluid entry point 1 and a fluid exit point 3. The entry point 1 would be in direct fluid communication with the drug reservoir 7, either at point of manufacture or immediately prior to use. The exit point 3 may be to a drug collection chamber 10 providing a large area of fluid communication with the skin surface (as shown in Figure 5).

Alternatively, the rate controlling membrane may comprise multiple structured layers of the kind shown in Figure 3. In this arrangement, the exit point 3 of the channel 5 in one layer is interfaced with the entry point I of the next layer downstream to maintain fluid communication through each layer of the rate controlling membrane between the drug reservoirs 7 and the collection chambers 10 in contact with the skin. The number of layers making up the rate controlling membrane is dependent on the maximum time lag required for drug travel from the reservoirs 7 to the skin. The thickness of *::, each layer will be in the region of tens to hundreds of micrometres, or sufficient to * ensure rigidity of the channels 5 within each layer such that if negative pressure is applied it does not cause either collapse or puncture of any of the side walls of the : micro-engineered channels.

****** * * Figure 2 shows an upper surface 2 of the rate controlling layer. This is required to enclose the micro-engineered channels 5 of the structured layer below (Figure 3) and preferably to provide a liquid-and gas-tight seal. The thickness of this layer 2 would range from tens to hundreds of micrometres. Its composition would be either the same as that of the structured layer 4 in which the micro-engineered channels 5 are created, or another compatible material that may be polymeric or metallic. This layer 2 would preferably be impermeable to gases and liquids and sufficiently robust to withstand negative pressure without caving in. Adhesion to the channelled layer 4 would be using suitable pharmaceutical adhesive, or alternatively it could potentially be attached through thermal compression. In the case of multiple channelled layers 4 being interfaced, a seal similar to the upper surface shown in Figure 2 may be placed between successive layers to seal between the respective channels 5 except at the interface point between the exit 3 of one layer and the entry 1 of the next layer.

Alternatively, if the channel 5 is formed in just one surface of each structured layer 4 without piercing the opposite surface (except at the interface point), then the structured surface of one layer 4 can seal the channel 5 of the adjacent layer 4 without the need for an intermediate sealing layer.

Figure 4 shows the lower layer 12 of the patch, comprising drug reservoirs or accumulation chambers 10 that provide an interfacc to the surface of the skin. The layer may be formed from a rigid or flexible polymer film that is not permeable to the drug. The base of this layer may be lined with a resilient membrane (not shown) containing large pores of the order of millimetre diameter to provide obstruction-free communication for the drug between the chambers 10 and the skin surface. The chambers 10 are connected via conduits 14 to a single valve 9 such that if negative pressure is desired in the chambers 10 and throughout the rate controlling membrane, then this can be applied from a single point. Alternatively, negative pressure could be **... applied independently and selectively to each chamber 10 as shown in Figure 5.

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** *. In the vertical cross section of Figure 5, there may also be seen the adhesive layer 11 as previously described in relation to Figure 1.

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If the rate controlling membrane 8 is in direct contact with the reservoirs 7 then the drug may begin to saturate the upper parts of the channels 5 and there could potentially be blockages due to precipitation at the mouths of the channels 5. This can be avoided by ensuring the reservoirs 7 and the rate controlling membrane S do not come into contact until point of administration, as illustrated in Figure 6. Figure 6 shows the upper layer 2 of the rate controlling membrane, behind which (not visible in the drawing is the reservoir layer. Connected to the upper layer 2 by a hinge 13 is the rate controlling layer 4, behind which (not visible in the drawing) is the lower layer. Pores 15 that allow the drug formulation to flow from the reservoirs into the channels are visible in the drawing, which in fact shows different numbers of pores for different reservoirs. By folding the device along the hinge 13, the pores 15 can be brought into fluid communication with the entry ports 3 of the rate controlling membrane and the drug formulation can flow into from the reservoirs into the.

channels. Thus, during transport and storage of the patch, the drug does not enter the mouths of the channels and the problem of blocking does not occur. The pores 15 and entry ports 3 may be sealed by, for example, an adhesive cover sheet. When the patch is ready for use, the cover sheet is removed, the patch is folded along the hinge, and the timed transport of the drug through the channels to the patient begins.

It is possible to envisage means other than a hinge for allowing relative movement between the reservoir layer and the rate controlling layer, whereby the reservoirs and the micro-channels can be brought into fluid communication. For example, sliding movement in the plane of the layers could achieve that end, as could pushing the layers together in a generally perpendicular direction, which might involve rupturing a seal in the process. * S **** * S. * S S * S. *

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Claims

CLAIMS

1. A transdermal drug delivery device comprising: at least one reservoir 7 for containing a drug formulation capable of diffusion through the skin of a patient; a contact surface permeable to the drug formulation; and at least one micro-channel 5 providing fluid communication between the reservoir 7 and the contact surface.

2. A transdermal drug delivery device according to claim I, wherein the maximum width of the micro-channels 5 is less than one millimetre.

3. A transdermal drug delivery device according to claim I or claim 2, comprising a plurality of micro-channels 5 defining different transport times for the drug formulation along the length of different micro-channels 5.

4. A transdermal drug delivery device according to claim 3, wherein the different micro-channels 5 are of different lengths.

5. A transdermal drug delivery device according to claim 3 or claim 4, wherein the different micro-channels 5 are of different widths.

6. A transdermal drug delivery device according to any preceding claim, comprising: S...

S... an upper layer 6 that contains the reservoirs 7; a middle layer 8 in which the micro-channels 5 are formed; and a lower layer 12 that defines the contact surface.

7. A transdermal drug delivery device according to claim 6, wherein at least some of the micro-channels 5 follow a convoluted path through the middle layer 8.

8. A transderrnal drug delivery device according to claim 7, wherein the middle layer 8 comprises a first layer 4 having a surface in which the convoluted path is formed as an open channel 5 and a second layer 2 that lies against the surface to close the channel 5 over a majority of its length.

9. A transdermal drug delivery device according to any of claims 6 to 8, wherein the lower layer 12 further comprises chambers 10 in which the drug formulation can collect after emerging from the micro-channels 5 and before diffusing into the skin of the patient.

10. A transdermal drug delivery device according to any of claims 6 to 9, wherein the lower layer 12 further comprises at least one valve 9 through which air can be displaced or withdrawn from the micro-channels 5.

11. A transdermal drug delivery device according to any of claims 6 to 10, further comprising means to allow relative movement between the upper layer 6 and the middle layer 8, by which the reservoirs 7 can be brought into fluid communication with the micro-channels 5.

12. A transdermal drug delivery device according to claim 11, in which the means to allow relative movement is a hinge 13. S. * . * S.. S... * . * S* * . . * S.

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