WO2007042961A2

WO2007042961A2 - Device for controlled release of chemical molecules

Info

Publication number: WO2007042961A2
Application number: PCT/IB2006/053564
Authority: WO
Inventors: Mark Thomas Johnson; Ralph Kurt
Original assignee: Koninklijke Philips Electronics N.V.
Priority date: 2005-10-11
Filing date: 2006-09-29
Publication date: 2007-04-19
Also published as: WO2007042961A3

Abstract

The invention relates to a device allowing the controlled release of chemical molecules upon actuating pressure on a rupturable barrier of a reservoir in which the molecules are located.

Description

DEVICE FOR CONTROLLED RELEASE OF CHEMICAL MOLECULES

The present invention is directed to the field of miniaturized devices having reservoirs which contain small devices or device components and/or chemicals, especially drugs.

Microarray systems have been developed that analyze numerous compounds, such as for drug activity or hybridization analysis of nucleotide molecule sequences. For example, U.S. Pat. No. 5,843,767 (Beattie) discloses a micro -fabricated, flow-through biosensor for the discrete detection of binding reactions. The apparatus includes a nanoporous glass wafer having tapered wells in which nucleic acid recognition elements are immobilized.

U.S. Pat. No. 6,083,763 (Balch) discloses an apparatus for analyzing molecular structures within a sample substance using an array having a plurality of test sites upon which the sample substance is applied. The test sites typically are in microplate arrays, such as microtitre plates. These apparatuses, however, do not provide any means for sealing one or more of the wells or for selectively exposing one or more of the wells, for example, on demand or upon passive exposure to certain conditions. U.S. Pat. No. 5,797,898 and No. 6,123,861 (Santini, et al.) describe microchip devices that release drug molecules from reservoirs having reservoir caps that actively or passively disintegrate.

U.S. Pat. No. 5,252,294 (Kroy) discloses micromechanical structures having closed cavities for use in storage and handling of substances, for example, in research and testing of the substances. There is no disclosure, however, of selectively controlling exposure of individual cavities without microvalves, nor is there any disclosure of isolating individual sensing means.

US 2005/0124979 Al discloses a device for controlled release of chemical molecules comprising: a substrate; a plurality of discrete reservoirs located in the substrate, wherein the reservoirs each have at least one opening at a surface of the substrate; chemical molecules, for release, disposed in the reservoirs; a rupturable barrier layer closing the at least one opening; and a pressure generating material disposed in the reservoirs, the pressure generating material being selected from the group consisting of water- swellable materials, osmotic pressure generating materials; and combinations thereof, wherein the chemical molecules can be selectively released from each reservoir by rupturing the barrier layer, due to pressure generated by the pressure generating material.

However, this device has the undesired disadvantage, that the release of the chemical molecules can in most applications only be controlled inadequately and with a time delay.

It is therefore an object of the present invention to provide a device, which allows a better control of the release of the chemical molecules in the reservoirs.

This object is solved by a substrate material according to claim 1 of the present invention. Accordingly, a device for controlled release of chemical molecules is provided, comprising:

(a) a substrate;

(b) a plurality of discrete reservoirs associated with or built onto the substrate, wherein the reservoirs each have at least one opening at a surface of the substrate;

(c) chemical molecules, for release, disposed in the reservoirs;

(d) a rupturable barrier layer closing the at least one opening; wherein the rupturable barrier is adapted to be ruptured by applying a pressure > (greater than or equal to) 500Pa and ≤ (smaller than or equal to) 80OkPa on the rupturable barrier for selectively releasing the chemical molecules from the reservoirs by rupturing the barrier layer.

A device according to the present invention has for most applications one or more of the following advantages over the prior art:

Due to the minimum amount of pressure of >500Pa that it needs to rupture the barrier, the release of the chemical molecules can be controlled in most applications quite easily, effectively and time-efficiently. The minimum amount of pressure also ensures a robust operation of the device, i.e. it remains closed when e.g. implanted into the body of a patient until the pressure is applied by the device. It should only open on demand and not by accident due to other pressures.

In most applications a pressure above the maximum amount of pressure will damage either the dispensing device, damage the body of the patient and/or introduce an audible sound (i.e. for a fragrance dispensing device). Preferably the rupturable barrier is adapted to be ruptured by applying a pressure > IkPa and ≤ 50OkPa, more preferably > 1OkPa and ≤ 10OkPa, and most preferred > 2OkPa and ≤ 8OkPa on the rupturable barrier for selectively releasing the chemical molecules from each reservoir by rupturing the barrier layer.

According to a preferred embodiment of the present invention, the rupturable barrier is adapted to be ruptured by applying a pressure > 500Pa and ≤ 80OkPa for a time period > 10ns and ≤ 100s on the rupturable barrier for selectively releasing the chemical molecules from each reservoir by rupturing the barrier layer. By doing so, the control of the drug release can in most applications furthermore be improved. Preferably, the rupturable barrier is adapted to be ruptured by applying a pressure > 500Pa and ≤ 80OkPa for a time period > lμs and ≤ Is, and most preferred > 500Pa and ≤ 80OkPa for a time period > lOOμs and ≤ 100ms on the rupturable barrier for selectively releasing the chemical molecules from each reservoir by rupturing the barrier layer. Preferably, the rupturable barrier is adapted to be ruptured by applying a pressure > 1OkPa and ≤ lOOkPa for a time period > 10ns and ≤ 100s, more preferred > 1OkPa and ≤ lOOkPa for a time period > lμs and ≤ Is, and most preferred > 1OkPa and ≤ lOOkPa for a time period > lOOμs and ≤ 100ms on the rupturable barrier for selectively releasing the chemical molecules from each reservoir by rupturing the barrier layer.

Preferably, the rupturable barrier is adapted to be ruptured at a critical stress, also called breaking stress or strength > lOMPa and ≤ 500MPa, more preferably > 50MPa and ≤ lOOMPa selectively releasing the chemical molecules from each reservoir by rupturing the barrier layer.

In order to better understand the stress characteristics in most applications of the present invention, reference is made to some background theory as applicable for most of these applications:

The (uniaxial) stress σ_x is proportional to the applied pressure P divided by the bulge height ho:

P a¹ σ\ =

2 - h_n - t

Herein, a is the half width of the smallest side of the membrane and t its thickness. It has been proven that in most cases a parabola excellently approximates the shape of the deformed membrane (in steady state); hence the strain ε_x can be assumed to be proportional to the square of the bulge height:

3 - a^:

Using basic mechanical correlations the shape of the linear part of the stress- strain-characteristics can be calculated as follows:

σ_r = σ_n 0 + M ^■ £„ with M = _Λ l - v t

In these equations σo is the initial stress (also called pre-strain) in the sample, whereas M, E and v are its Elastic modulus, Young's modulus and Poisson's ratio.

The critical stress (= strength) = σ_c is the stress at which the material breaks.

For most applications it is advantageous to keep the critical stress within the margins given above.

According to a preferred embodiment of the present invention, the device furthermore includes pressure means for applying pressure on and/or towards the rupturable barrier.

According to a preferred embodiment of the present invention, the pressure means are adapted to apply pressure on the rupturable barrier with a pressure increase ≥ lPa/s and ≤ lTPa/s (TPa = Terra Pascal = 10¹² Pa).

By doing so, it is possible for most applications to more effectively ensure that the release of the chemical molecules occurs without an undesirably long time delay. Preferably, the pressure means are adapted to apply pressure on the rupturable barrier with a pressure increase ≥ lPa/s and ≤ lTPa/s, more preferably ≥ lkPa/s and ≤ lGPa/s, and most preferred ≥ lOkPa/s and ≤ lOOMPa/s.

According to a preferred embodiment of the present invention, the rupturable barrier has a thickness ≥ 50nm and ≤ lOμm, preferably ≥ lOOnm and ≤ 3μm, and most preferred ≥ 300nm and ≤ lμm.

According to a preferred embodiment of the present invention, the pressure means is electrically controlled. This ensures for most applications an even more time- efficient release of the drug. Preferably, the pressure means include an inkjet printer and/or hydraulic system (i.e. a fluid pressure system with controlled release valves). According to a preferred embodiment of the present invention, the pressure means include at least one electrical pressure generator. For some applications this has shown to be suitable in practice. Preferably, the electric pressure generator includes a piezo-electrical means, e.g. a piezoacuator and/or a loudspeaker. In the latter embodiment, the pressure generation is achieved electro-acoustically. According to a preferred embodiment of the present invention, the rupturable barrier includes at least two layers, and preferably the layer that is exposed to the chemical molecules in the reservoirs is made out of a material selected out of the group of organic materials, polymers, metals, noble metals, inorganic materials, insulators or mixtures thereof and whereby preferably the layer that is exposed to the outside is made out of a material selected out of the group of organic materials, polymers, metals, noble metals, inorganic materials, insulators or mixtures thereof.

Preferably one of the two layers is a polymer (such as PE, acrylate, PC, PET or the like) and the second layer is a metal layer. According to a preferred embodiment, the outer layer or the rupturable barrier as a whole is covered with a bio-compatible coating as known in the art. This may help to apply the invention for medicinal purposes.

According to a preferred embodiment the rupture barrier has a pre-strain σo in the range ≥ 0 and ≤ 50MPa. The term pre-strain includes and/or means especially a tensile stress in the material. With this pre-strain it is for most applications possible to fine-tune the robustness of the device (not to rupture unintentionally) and to lower the pressure threshold needed to open the barrier

Moreover we could modify the morphology of the barrier layer incorporating perforations like micro structures, which will improve rupturing and subsequent release of chemical molecules.

According to a preferred embodiment of the present invention at least one, preferably all of the reservoirs comprise a second layer through which pressure is applied towards the rupturable barrier. According to a preferred embodiment of the present invention, the second layer has a modulus of elasticity ≥ IMPa and ≤ 500MPa, preferably ≥ 10 MPa and ≤ 100MPa.

According to a preferred embodiment of the present invention, the second layer has a critical strain (percentage the material can be stretched without rupturing) in the range ≥ 0.5 % and ≤ 100 %, preferably ≥ 5 % and ≤ 50 %.

According to a preferred embodiment of the present invention, the chemical substances in the at least on reservoir are such that the reservoir(s) are substantially filled with an incompressible fluid. This has for most applications proven itself to be advantageous for the pressure transfer towards the rupturable barrier layer.

According to a preferred embodiment of the present invention, the pressure means are provided in such a way that a plurality of independently controllable pressure means is provided and that one of said independently controllable pressure means is associated with ≥ 1 and ≤ 9, preferably ≥ 3 and ≤ 5 of the reservoir(s). A device according to the present invention may be of use in a broad variety of systems and/or applications, amongst them one or more of the following:

- implantable drug delivery systems;

- transdermal drug delivery systems; - chronotherapy systems;

- implantable measuring and direct feedback systems;

- electronic pills;

- fragrance dispensers;

- electronic noses; - insulin delivery systems (for diabetics) preferably with closed feedback loop

(including sensors); anti smoking / nicotine delivery systems;

- implantable hormone delivery systems e.g. for preventing pregnancy;

- air or water purification devices (release chemical substances); - inhalation apparatuses for e.g. asthma treatment; diagnosis devices (e.g. microfluidic biosensors, where some components have to be added);

Accurate delivery of small, precise quantities of one or more chemicals into a carrier fluid are of great importance in many different fields of science and industry. Examples in medicine include the delivery of drugs to patients using intravenous methods, by pulmonary or inhalation methods or by the release of drugs from vascular stent devices.

Examples in diagnostics include releasing reactions into fluids to conduct DNA or genetic analysis, combinatorial chemistry, or the detection of a specific molecule in an environmental sample. Other applications involving the delivery of chemicals into a carrier fluid include the release of fragrances and therapeutic aromas from devices into air and the release of flavouring agents into a liquid to produce beverage products. The aforementioned components, as well as the claimed components and the components to be used in accordance with the invention in the described embodiments, are not subject to any special exceptions with respect to their size, shape, material selection and technical concept such that the selection criteria known in the pertinent field can be applied without limitations. Additional details, features, characteristics and advantages of the object of the invention are disclosed in the subclaims, the figures and the following description of the respective figures and examples, which -- in an exemplary fashion -- show several preferred embodiments of a substrate material as well as a device according to the invention.

Fig. 1 shows a very schematic cross- sectional view of a device according to a first embodiment of the present invention before rupture of the rupturable barrier;

Fig. 2 shows the device of Fig. 1 after rupture of the rupturable barrier; Fig. 3 shows a very schematic cross- sectional view of a device according to a second embodiment of the present invention before rupture of the rupturable barrier;

Fig. 4 shows a very schematic cross- sectional view of a device according to a third embodiment of the present invention having three reservoirs associated with one pressure means before rupture of the rupturable barriers;

Fig. 5 shows the device of Fig. 4 after rupture of one of the rupturable barriers; and

Fig. 6 shows the device of Fig. 4 and 5 after rupture of all of the rupturable barriers.

Fig. 1 shows a very schematic cross-sectional view of a device 1 according to a first embodiment of the present invention before rupture of the rupturable barrier. This device comprises a substrate 10 and a pressure means 20. The substrate 10 comprises a plurality of reservoirs 40 (only one is shown in the fig.), in which chemical molecules, such as drugs are provided for controlled release. The reservoirs 40 are laterally separated from each other via solid walls 60, towards the outside via a rupturable barrier layer 30 and towards the pressure means 20 via a second layer 50, which is partly elastic as described above.

The pressure means 20 is derived from an ink-jet printing device. A fluid 70 is used to controllably provide pressure towards the second layer 50 of the substrate 10. An Activation of a nozzle of the inkjet head releases a drop of this fluid 70 (either liquid or gas), which induces a build up of pressure below the reservoir 40. Since the second layer 50 of the reservoir 40 is flexible and the drug inside the capsule relatively incompressible, this pressure increase will be transferred to the rupturable barrier 30, which will result in rupture of the membrane and release of the drug.

Fig. 2 shows the device after the appliance of pressure; the chemical molecules are then leaving the device somewhat in direction of the arrow A. It should be noted that an open and a closed configuration of the inkjet pressure actuator is possible. In the open configuration the droplets directly hit the lower membrane of the device and have to be removed afterwards anyhow. That can be done by pumping the small volumes away or to let the liquid evaporate e.g. by using the body heat. After all the drug has been delivered, the entire device is disposed. Fig. 3 shows a very schematic cross- sectional view of a device 1' according to a second embodiment of the present invention before rupture of the rupturable barrier. This embodiment differs from the device shown in Fig. 2 in that the pressure means 20' comprise also a layer 80 which is partly elastic. This latter configuration makes it easier to separate the substrate 10 and the pressure means 20' in the form of the inkjet head and replace the substrate 10 with a new capsule to proceed with a new treatment. In this model, the pressure means 20' may be considered as a reusable device, whilst the substrate 10 is replaceable.

Fig. 4 shows a very schematic cross- sectional view of a device 1" according to a third embodiment of the present invention having three reservoirs associated with one pressure means before rupture of the rupturable barriers, Fig. 5 shows the device of Fig. 4 after rupture of one of the rupturable barriers and Fig. 6 shows the device of Fig. 4 and 5 after rupture of all of the rupturable barriers.

In the embodiment of Fig. 4 to 6, there is one pressure means 20" associated with three reservoirs 40a, 40b. The reservoir 40a is - similar to the devices of Figs. 1 to 3 - located in the direct vicinity of the nozzle of the pressure means 20" . In case pressure is applied via the pressure means, the chemical molecules located in this reservoir will be set free at first, as can be seen in Fig.5. As more liquid drops are delivered, the pressure will start to increase further from the nozzle, rupturing also the rupturable barriers of the reservoirs 40b. In this manner, a progressively increasing dosage can be realised by defining the number of drops delivered by the inkjet head. Note: in this case the release barrier needs to be "weaker" than the elastic membrane. If not, the membrane in the already opened capsule will just swell further and the other capsules will not open. It is also possible to use this single pressure means to sequentially deliver repeated dosages of the drug, by increasing the pressure level in a step-wise manner (by sequentially releasing one, or more than one liquid drops). In this mode of operation, it will be necessary to keep track of how many capsules above the nozzle have already been ruptured, which can easily be realised by incorporating a small memory into the device.

In further embodiments, the capsules do not all need to be the same size (which allows for e.g. different rate of drug dosing) and need not be situated adjacent to each other (i.e. could be arranged in concentric circles/hexagons etc.). It should be noted that whilst the above embodiments are focussed on the use of a single inkjet head as a pressure means, it is apparent that a preferred embodiment of the device will comprise a multiplicity of such pressure means and reservoirs. This enables the device to become more flexible (delivering a variety of different drugs, or delivering drugs with increased accuracy by using several smaller capsules) and/or to increase the lifetime of the device (more capsules contain in total more drug).

This may be realised, for example, by providing the device with an array of pressure means, each of which is associated with one (or more) reservoirs, as described before. Indeed, the nozzles of commercially available ink jet heads are typically arranged in several (1-10) parallel rows (~ 1 mm distance) and in each row a few hundred nozzles are placed next to each other, a few hundred μm distance in between, hence forming the desired array. It is therefore proposed to incorporate such arrays of inkjet pressure actuators in a device further comprising an array of capsules.

Commercial inkjet heads are usually prepared from CMOS Si technology, and have a size of a few square millimetres. It is known how to fabricate inkjet printer heads using the poly-Si on glass technology which is known from the production of e.g. active matrix LCDs and other flat panel displays. As the poly-Si technology is a lower cost technology, it is more suitable for larger sized drug delivery devices (where e.g. several different drugs must be delivered), or for disposable applications. Whilst it is possible to activate the multiplicity of pressure actuators by directly driving each of the actuators using a direct electrical connection from a dedicated driving IC, in a preferred embodiment (not shown in the figs), it is proposed to configure the pressure actuators in the form of an active matrix array, whereby the number of actuators can be greatly increased without using a large number of drivers. Whilst the invention has been described in terms of an inkjet printer based pressure generating means, it is apparent that the invention may be embodied by any of the well known pressure generation means such as a hydraulic system (fluid under pressure and controlled valves), piezo based materials or foils, thermal expansion materials (bimetallic strips etc), loudspeakers etc.

The particular combinations of elements and features in the above detailed embodiments are exemplary only; the interchanging and substitution of these teachings with other teachings in this and the patents/applications incorporated by reference are also expressly contemplated. As those skilled in the art will recognize, variations, modifications, and other implementations of what is described herein can occur to those of ordinary skill in the art without departing from the spirit and the scope of the invention as claimed. Accordingly, the foregoing description is by way of example only and is not intended as limiting. The invention's scope is defined in the following claims and the equivalents thereto. Furthermore, reference signs used in the description and claims do not limit the scope of the invention as claimed.

Claims

1. A device for controlled release of chemical molecules comprising:

(a) a substrate;

(b) a plurality of discrete reservoirs associated with or built onto the substrate, wherein the reservoirs each have at least one opening at a surface of the substrate; (c) chemical molecules, for release, disposed in the reservoirs; (d) a rupturable barrier layer closing the at least one opening; wherein the rupturable barrier is adapted to be ruptured by applying a pressure greater than or equal to 500 Pa and smaller than or equal to 800 kPa on the rupturable barrier for selectively releasing the chemical molecules from the reservoirs by rupturing the barrier layer.

2. The device according to claim 1, wherein the rupturable barrier is adapted to be ruptured by applying a pressure greater than or equal to 500 Pa and smaller than or equal to 800 kPa for a time period greater than or equal to 10ns and smaller than or equal to 100s on the rupturable barrier for selectively releasing the chemical molecules from the reservoirs by rupturing the barrier layer.

3. The device according to claim 1 or 2, furthermore including pressure means for applying pressure on and/or towards the rupturable barrier.

4. The device according to claim 3, wherein the pressure means are adapted to apply pressure on the rupturable barrier with a pressure increase greater than or equal to 1 Pa/s and smaller than or equal to 1 TPa/s.

5. The device according to any of the claims 1 to 4, wherein the rupturable barrier includes at least two layers, and whereby preferably the layer that is exposed to the chemical molecules in the reservoirs is made out of a material selected out of the group of organic materials, polymers, metals, noble metals, inorganic materials, insulators or mixtures thereof and whereby preferably the layer that is exposed to the outside is made out of a material selected out of the group of organic materials, polymers, metals, noble metals, inorganic materials, insulators or mixtures thereof.

6. The device according to any of the claims 1 to 5, wherein at least one, preferably all of the reservoirs comprise a second layer through which pressure is applied towards the rupturable barrier.

7. The device according to any of the claims 1 to 6, wherein the second layer has an modulus of elasticity greater than or equal to 1 MPa and smaller than or equal to 500 MPa.

8. The device according to any of the claims 1 to 7, wherein the second layer has a critical strain in the range greater than or equal to 0.5 % and smaller than or equal to 100 %.

9. The device according to any of the claims 1 to 8, wherein the pressure means are provided in such a way that a plurality of independently controllable pressure means is provided and that one of said independently controllable pressure means is associated with 1 or more and 9 or less of the at least one reservoirs.

10. A system incorporating a device according to any of the claims 1 to 9, said system being adapted to be used in one or more of the following applications:

- implantable drug delivery systems;

- transdermal drug delivery systems; - chronotherapy systems;

- implantable measuring and direct feedback systems;

- electronic pills;

- fragrance dispensers; - electronic noses;

- insulin delivery systems for diabetics with closed feedback loop, including sensors; anti smoking / nicotine delivery systems;

- implantable hormone delivery systems for preventing pregnancy; - release of chemical substances in air or water purification devices;

- inhalation apparatuses for e.g. asthma treatment

- diagnosis devices e.g. microfluidic biosensors.