WO2011046443A1

WO2011046443A1 - Ultrasound triggered controlled release drug delivery

Info

Publication number: WO2011046443A1
Application number: PCT/NO2010/000254
Authority: WO
Inventors: John Brungot; Sverre Holm; Lars Hoff; Ivar Wergeland; Arne RØNNEKLEIV; Øystein EVENSEN
Original assignee: Vivid As
Priority date: 2009-10-15
Filing date: 2010-06-30
Publication date: 2011-04-21

Abstract

A capsule for controlled release of a substance, such as a vaccine, into a subject, such as a fish. The capsule comprises a reservoir which contains the substance, and at least one membrane that closes the reservoir. The membrane is designed to burst by means of resonance under the influence of an acoustic signal emitted from a source outside the subject.

Description

ULTRASOUND TRIGGERED CONTROLLED RELEASE DRUG DELIVERY

Technical field

The invention relates to controlled release of a substance to a subject.

Specifically, the invention relates to a capsule, a method, a system and a use for controlled release of a substance to a subject.

Background of the invention

EP-548 236 relates to ultrasound-mediated administration of drugs into aquatic animals.

WO-01/64185 relates to a biologically implantable cell encapsulation device.

WO-03/046801 relates to an ultrasound-activated identification chip that can be implanted in a fish.

Summary of the invention

The invention is disclosed in the patent claims.

Brief description of the drawings

Figure 1 is a schematic block diagram showing an exemplary embodiment of a system for controlled release of a substance to a subject.

Figure 2 is a cross-sectional view which schematically illustrates an embodiment of a capsule for controlled release of a substance to a subject.

Figure 3 is a cross-sectional view which schematically illustrates an embodiment of a capsule for controlled release of a substance to a subject.

Figure 4 is a cross-sectional view which schematically illustrates an embodiment of a capsule for controlled release of a substance to a subject.

Figure 5 is a cross-sectional view which schematically illustrates an embodiment of a capsule for controlled release of a substance to a subject.

Figure 6 is a schematic flow chart illustrating a method for release of a substance to a subject.

Detailed description

The subject 130 may be a living organism such as an animal or a human.

Specifically, the subject may be an aquatic animal, for example, a fish such as a salmon. Alternatively, the subject may be a fish of another species, another aquatic animal or other animal, or a non-living subject. The subject 130 contains a capsule 100 for controlled release of the substance to the subject. The capsule comprises a reservoir 110 containing the substance, and at least one membrane 120 that closes the reservoir. In the illustrated embodiment, the reservoir 110 is cylindrical or tubular, and the lower end may be closed, for example, by a lower end piece of the same material as that of the reservoir 110. This embodiment comprises only one membrane. The membrane 120, in the illustrated embodiment, is shown as an upper end piece which closes the reservoir 110 at its upper end.

Alternatively, the capsule 100 may comprise two membranes, the reservoir 110 being closed by a first membrane at a first end and by a second membrane at a second end.

Alternatively or additionally, the capsule may also comprise an inner membrane, which separates two cavities in the capsule.

The membrane 120 is designed to burst or rupture under the influence of an acoustic signal emitted from an acoustic source 150. In an embodiment, the membrane 120 is designed to burst by means of resonance under the influence of the acoustic signal. The acoustic source 150 is located outside the subject 130, as shown. A medium having given acoustic properties may be disposed between the source 150 and the subject 130. The medium may, for example, comprise water, including salt water, fresh water and brackish water.

The capsule reservoir 110 may comprise a plastic material, e.g., a polymer such as polypropylene. The membrane 120 may comprise silicon or silicon nitride, or other material which advantageously has the property that the membrane bursts suddenly when subjected to sufficient mechanical strain.

In the case where the subject 130 is a fish, it is expedient that the reservoir 110 and the capsule 100 should consist of materials that are not harmful to a fish when ■ implanted in the fish.

In the case where the subject 130 is a fish that is intended for use as a foodstuff for humans, it is also expedient that the reservoir 110 and the capsule 100 should consist of materials that are not harmful if consumed by humans, and/or materials which can be easily removed when preparing or processing the fish, i.e., when using the fish as a foodstuff.

In the case where the subject 130 is a fish of a specific species, for example, a salmon, it is expedient that the reservoir 1 10 and the capsule 100 should consist of materials that are not harmful when implanted in a fish of this particular species. It is also expedient to use materials that do not cause fouling or encrustation in the capsule's intended environment. For this purpose, surface treatment with a suitable material may be used. The substance held within the reservoir 110 and which is to be released from the capsule 100 upon rupture of the membrane 120, may be a liquid. The liquid may be water or oil based. Alternatively, the substance may be a solid substance, for example in powder form. Alternatively, the substance may be in gaseous form. Alternatively, the substance may comprise both liquid and solids, or both liquid and gas, or both solids and gas, or a combination of all three, i.e., liquid, solids and gas.

The substance contained within the reservoir 110 and that is to be released from the capsule 100 upon rupture of the membrane 120, may be a therapeutic or

prophylactic substance.

In such an example, the substance comprises a vaccine. In the case where the subject 130 is a salmon, the vaccine may comprise a vaccine against bacterial diseases and/or a vaccine against viral diseases, including a vaccine against infectious pancreatic necrosis (IPN), pancreas disease (PD), ISA (infectious salmon anaemia), and/or HSMI (heart and skeletal muscle inflammation). The vaccine may be a type known as "living vaccine" or "dead vaccine".

Other examples of therapeutic or prophylactic substances may comprise medication used to treat chronic diseases, such as insulin in the case of diabetes, thyroxin in the case of hypothyreosis, etc. Administration of hormones can also be used to influence growth, sexual receptivity, sexual maturation, gender control (of hermaphrodite fish), mental status etc. Alternatively, the substance may comprise nutrients, including vitamins and/or minerals, or trace elements.

Other substances comprise materials for food make-up, including colorants to enhance fillet colour.

For illustrative purposes, the capsule 100 is shown in an upright position, with the membrane 120 directed upwards. It will be understood that the orientation of the capsule in space, and in particular its orientation in relation to the gravity field, need not necessarily be as illustrated.

If the capsule is to be implanted in a fish, it can be inserted manually or

mechanically/automatically into the fish's tissue, for example, into the fish's abdominal cavity using a cannula. It may be expedient to insert the capsule at a reasonable distance to the fish's bones/skeleton and to any swim bladder. The capsule may, for example, be placed under the fish's dorsal fin.

In an example, the capsule 100 exhibits a characteristic resonance frequency for acoustic signals. In an example, the characteristic frequency changes when the membrane 120 bursts.

This means that the capsule may have two distinct resonance frequencies, of which a first resonance frequency is associated with capsule 100 when the membrane 120 is in its intact form. The consequence of this is that the membrane 120 will burst when the capsule is subjected to an acoustic signal with this first resonance frequency, provided that the signal also has a certain signal energy, or a certain signal power and duration.

The capsule may also have a second resonance frequency, associated with capsule 100 with membrane 120 in its ruptured, non-intact form. The second resonance frequency can be used to detect that a rupture of the capsule membrane 120 has taken place. This can thus be used as an indication that the substance has been released to the subject 130, for example, that the vaccine has been released into the body tissues of the fish.

The membrane 120 may be designed to burst at resonance frequencies in an ultrasonic range. More specifically, it may be designed to rupture at resonance frequencies in the range of 20 kHz - 1000 Hz, or in the range of 40 kHz - 200 kHz, or in the range of about 100 kHz.

In an embodiment the membrane 120 is biased. The biasing can be selected as a function of, inter alia, desired ambient pressure for use.

The membrane 120 may be affixed to the reservoir 110 by welding, or alternatively by gluing or other methods of joining that result in a fluid sealing and sufficient pressure resistance as an appropriate function of the area of use and ambient conditions.

In an example, a periphery of the membrane 120 comprises a region with a weakness, for example, an inserted notch, which may contribute to a provoked fatigue failure at the periphery in response to the resonance.

In an example, a central region of the membrane is reinforced, for example, in that the membrane is provided with a boss of greater mass in the central region of the membrane. This may contribute to improved resonance effect.

It is also possible to cause the membrane 120 to rupture under the influence of the. acoustic signal in ways other than by resonance. For example, this can be

accomplished by subjecting the membrane to a low- frequency pulse with powerful negative pressure, so that the membrane is pulled outwards in order suddenly to be released, with destructive effect. In such a case, the capsule should contain some gas or air together with the substance that is released to the subject.

The membrane can alternatively rupture as a result of cavitation induced by the applied acoustic signal.

In an embodiment the reservoir further contains an acoustically responsive element that is released together with the substance when the membrane ruptures.

The acoustically responsive element can in this case exhibit a resonance property that is essentially different from a resonance property of the capsule 100 as a whole, that is to say, essentially different from the capsule in its intact form. For example, the acoustically responsive element may comprise an additional, for example, gas-filled, capsule, wherein a gas-filled cavity in the additional capsule is sealingly surrounded by a plastic material, e.g., a polymer.

A technical consequence of such an additional responsive element is that the release of the element from the capsule 100 can be detected, for example, by acoustic detection means. This detection can be used as an indication that the element, and thus also the substance, has been released to the subject,

The acoustic source 150 shown in Figure 1 is designed to emit an acoustic transmission signal in an area in which the subject 130 is located.

The system, as illustrated, further comprises an acoustic receiver 160, arranged for receiving an acoustic receiving signal in the area in which the subject 130 is located, and a control unit 140. The control unit 140 may be designed to control properties of the signal emitted by the acoustic source 150 as a function of properties of the received acoustic signal at the receiver 160. For this purpose, the control unit 140 may comprise a processor 143 for processing data. The control unit 140 may further comprise an I/O-adapter 146 connected to adapter circuits, illustrated as an amplifier 148, for delivering an electric, analogue signal that is fed to the acoustic source 150. Properties of the electric signal determine corresponding properties of the acoustic signal emitted by the acoustic source 150, and such properties may include frequency and power, and time sequences for them. The properties may also, or alternatively, include discrete or continuous frequency spectrum, wave form, signal energy etc.

The electric signal that is delivered to the acoustic source 150 can be generated by a signal generator (which is not shown, but which may be a part of the I/O-adapter), or alternatively by the processor 143, controlled by suitable program

instructions/software.

The adapter circuits of the I/O-adapter 146, illustrated as amplifiers 147, 148, also comprise a circuit 147 adapted to amplify and/or adapt the signal emitted by the acoustic receiver 160, such that it is given a form, preferably a digital form, which is suitable for inputting into and processing by the processor.

It will therefore be understood that either the adapter circuit 147 or the I/O-adapter 146 may comprise a discretising (sample) circuit and an A/D transformer, in order to provide a time-discrete, digital representation of the received acoustic signal at the receiver 160. Similarly, it will be understood that either the adapter circuit 148 or the I/O adapter 146 may comprise a D/A transformer and a filter, in order to provide an analogue representation of the digital signal emitted by the bus 142 and the processor 143.

The control unit 140 further comprises memory circuits, for example, a first memory 144 for data and a second memory 145 for program instructions. The processor 143, the memory circuits 144, 145, the I/O adapter 146 and any additional (non-illustrated) circuits, for example, for external communication, such as network communication, user interface, etc., are connected together by a internal bus 142 in control unit 140.

In an embodiment, the control unit 140 may be configured to analyse the received acoustic signal, and to recognise a transient, acoustic pulse which is generated when the membrane ruptures. Such recognition can be achieved by comparing the received acoustic signal with a pre-stored signal or pre-stored signal properties. The comparison may take place in the frequency plane, the time sequences for the spectra of the signals being compared. The comparison may alternatively take place in the time plane. The pre-stored signal or the pre-stored signal properties may be provided experimentally by analysing the acoustic pulse that is generated as the membrane ruptures in a test situation. The pre-stored signal or parameters which indicate the pre-stored signal properties can, for example, be stored in the first memory 144.

In the case where the capsule 100 that is contained within the subject, in addition to the substance also contains an acoustically responsive element that is released when the membrane 120 ruptures, and which exhibits a resonance property which is essentially different from a resonance property of the capsule in its intact form, the control unit 140 can expediently be designed to detect the resonance property of the acoustically responsive element.

This may, for example, be achieved by subjecting the subject 130 to a wide- spectrum acoustic signal with the aid of the acoustic source 150, and detecting frequency ranges in which resonance occurs with the aid of the acoustic receiver 160. Alternatively, if the resonance property of the acoustically responsive element is known in advance, the resonance property can be detected by subjecting the subject to an acoustic signal which has the known resonance property, receiving the acoustic response, and on the basis of the response, determining whether the subject exhibits such resonance property.

Implementation of such detection can easily be done by creating program

instructions that can be stored in the program memory, and executed by the processor.

Such detection can indicate whether the capsule content has been released to the subject.

A practical effect of this is that the dosage of acoustic energy applied to the subject can be stopped in response to the detection of the release of the capsule content to the subject. This will thus limit the total dosage of acoustic energy applied to the subject and prevent overdosage of acoustic energy to the subject. Figures 2, 3, 4 and 5 indicate additional features of possible embodiments of the capsule 100. It will be understood that individual elements explained for each embodiment are not necessarily limited to that embodiment, but that different elements can be also be combined between embodiments. It should also be understood that the illustrated embodiments are only shown by way of example, and that many other possibilities will be recognised by those of skill in the art.

Everything that is disclosed with reference to capsule 100 in the description above, with reference to Figure 1, should be regarded as a description of each and every exemplary embodiment in Figures 2, 3, 4 and 5. It should be understood that the figures are not necessarily shown to scale.

Figure 2 is a cross-sectional view which schematically further illustrates an embodiment of a capsule for controlled release of a substance to a subject.

The capsule 200 comprises a reservoir 210 containing the substance 240. On the upper side of the substance 240 there is illustrated a gas or vacuum pocket 230. The pocket 230 may be filled with a compressible gas, for example, air or nitrogen. Other possible examples comprise sulphur hexafluoride and fluorinated

hydrocarbons. Alternatively, the pocket 230 may contain a suspension of gas bubbles and liquid. The pressure in the pocket 230 may be in the range of zero to several tens of atmospheres, e.g., zero to 40 atmospheres. In the detailed design process, weight may be given, inter alia, to obtaining a stable structure at the relevant external pressure of use.

The reservoir 210 may be cylindrical or tubular. The horizontal section is not illustrated here, but it may be circular or have another suitable form. The lower end of the reservoir 210 is closed. A membrane 220 is configured as an upper end piece which closes the reservoir 210 at its upper end.

The membrane 220 is designed to burst under the influence of an acoustic signal emitted from an acoustic source 150, as described for the membrane 120 with reference to Fig. 1.

Figure 3 is a cross-sectional view which schematically further illustrates an embodiment of a capsule for controlled release of a substance to a subject.

The capsule 300 comprises a reservoir 310 which contains the substance 340. On the upper side of the substance 340 there is illustrated a gas or vacuum pocket 330. What has been stated above with regard to the pocket 230 applies also to the pocket 230.

On the underside of the substance 340 there is illustrated an additional gas pocket 360, also containing a compressible gas.

The reservoir 310 may be cylindrical or tubular. The horizontal section is not illustrated here, but it may be circular or have another suitable form. A membrane 320 is configured as an upper end piece which closes the reservoir 310 at its upper end.

A further membrane 350 is configured as an upper end piece which closes the reservoir 310 at its lower end.

The membranes 320 and 350 are designed to burst under the influence of an acoustic signal emitted from an acoustic source 150, as described for the membrane 120 with reference to Fig. 1. In an aspect, the membranes 320 and 350 have almost the same properties, such that they both will "compete" to rupture first when subjected to the acoustic signal. One of the membranes can thus act as a back-up element for the other, the capsule thus exhibiting redundant/fail-safe properties. If both membranes rupture, there is the advantage that the substance will more easily exit the capsule.

Figure 4 is a cross-sectional view which schematically illustrates an embodiment of a capsule 400 for controlled release of a substance to a subject.

This embodiment corresponds essentially to what has been illustrated and explained with reference to Figure 2, the capsule 400 comprising a reservoir 410 containing the substance 440. On the upper side of the substance 440 there is illustrated a gas or vacuum pocket 430, corresponding to the pocket 230 in Figure 2. The reservoir 410 corresponds to the reservoir 210 in Figure 2, and is closed at its lower end. A membrane 420, corresponding to the membrane 220 in Figure 2, is configured as an upper end piece that closes the reservoir 410 at its upper end. The embodiment in Figure 4 differs from the embodiment in Figure 2 by the addition of an additional gas pocket 460 on the underside of the substance 440 and on the upper side of the closed bottom part of the reservoir 410. The gas pocket 460 may be described in the same way as the gas pocket 360 in Figure 3.

Figure 5 is a cross-sectional view which schematically illustrated an embodiment of a capsule for controlled release of a substance to a subject.

This embodiment corresponds in a number of features to what has been illustrated and explained with reference to Figures 2, 3 and 4 above, the capsule 500 comprising a reservoir 510 that contains the substance 540. On the upper side of the substance 540 there is illustrated a gas or vacuum pocket 530, corresponding to the pocket 230 in Figure 2. The reservoir 510 corresponds to the reservoir 210 in Figure 2, and is closed at its lower end, but may have a greater height. A membrane 520, corresponding to the membrane 220 in Figure 2, is configured as an upper end piece that closes the reservoir 510 at its upper end. Like the embodiment in Figure 4, the capsule 500 comprises an additional gas pocket 570 on the upper side of the closed bottom part of the reservoir 510. The gas pocket 570 can be described in the same way as the gas pocket 460 in Figure 4. The embodiment in Figure 5 differs from the embodiment in Figure 4 by an additional membrane 550 disposed on the underside of the substance 540 and on the upper side of gas pocket 570. The additional membrane 550 may have other resonance properties, and in particular another resonance frequency, than the upper membrane 520. The additional membrane 550 can thus serve as a signature that is acoustically observable only when the membrane 520 has been opened. The identification of a resonance caused by the additional membrane 550 can thus serve as an indication that the upper membrane 520 has undergone rupture, and thus that the substance 540 has been released.

As an alternative to the illustrated embodiments in Figures 2-5 it is also possible to configure a multi-chamber solution, where one and the same capsule comprises two or more parallel reservoirs, closed by their respective membrane. In such a case, the different reservoirs in the capsule may contain different substances that can be released in a controlled manner independent of each other.

The illustrated method starts in step 600. First, in step 610, the method comprises introducing a capsule as disclosed in the present patent specification into the subject. Next, in step 620, the subject is subjected to an acoustic signal, emitted from a source outside the subject. As a consequence thereof, the at least one membrane closing the reservoir bursts, illustrated in step 630. This in turn means that the substance is released into the subject, illustrated in step 650. The subject may be a living organism, such as an animal or a human. In particular, the subject may be a fish, for example, a salmon.

The invention relates also to the use of a capsule as disclosed in the present patent specification, for controlled release of a substance to a subject. Figure 6 may also be regarded as an example of such a use.

A possible advantage of the invention is that the capsule can be deposited in the subject a long time, for example, several months, before it is activated and the substance is released to the subject.

Additional possible features or aspects of the invention can be seen from the additional elements below. What follows relates in particular to the cases and embodiments where the subject is a fish, for example, a salmon, and in the cases and embodiments where the substance released from the capsule is a vaccine. It will be understood that many of the additional features can also be used with other embodiments of the invention.

In the case where the subject is a fish, the released substance can have both a systemic effect, i.e., an effect on the whole organism, or a separate or reinforced effect in the region of the organism in which the capsule has been deposited. Embodiments of the system can be designed to function under very varying pressure conditions. The capsule may then be so constructed that it withstands the pressures to which fish, and in particular salmon, are normally subjected, but the capsule must nevertheless be capable of being opened by realistic sound pressures. To this end, the capsule, or the membrane in the capsule, is resonant with a relatively high Q value. The sound pressure in this range may be 10 to 100 times greater than the sound pressure otherwise in the beam. This means that the area of the capsule that is to be ruptured by the sound pressure, i.e., the membrane(s), is small compared to (e.g., less than half of) the wave length at the resonance frequency of the capsule. The resonant mechanism makes it possible to obtain sufficiently large mechanical impact for the membrane and thus sufficiently high stress on the membrane. It also follows that the fish are to a small extent subjected to the high sound frequencies that cause the capsule to rupture.

For the acoustic signal that is to open (burst, rupture) the capsule, it is expedient to have good syntonisation between beam width and beam intensity. Large beam width gives a greater chance of striking the capsule quickly, but at the same time spreads the sound intensity so that there may be problems in obtaining sufficiently high sound pressure.

A factor that is utilised in some embodiments is material fatigue in the membrane material. With resonance frequencies around 100 kHz, we can easily subject the membrane to loading and unloading in the magnitude 10⁶ (fluctuations/cycles) in order to open it, whilst extreme pressures/tensions to which the membrane is otherwise subjected relate to events that occur once or several times a day. This will give loading and unloading in the magnitude of 1000 through a life cycle of the chip.

To prevent the pressure-sensitive membrane from lying in the acoustic shadow from the rest of the capsule, it is expedient that the capsule should be considerably smaller in extent than the acoustic wavelength in water at the resonance frequency. For example, the diameter of the membrane may be smaller than half the wavelength. In some applications, the swim bladder of the fish can cause shadow effects of significance for the opening of the capsule. If the capsule lies freely in the abdominal cavity of the fish, it will sink towards the bottom of the abdominal cavity, and therefore lie below the swim bladder. This problem can be solved by sending the acoustic signals towards the fish from the side or from below, not from straight above.

The capsules can be manufactured, for example, by injection moulding or

thermoforming processes. The manufacturing process can be adapted for the production of suitably thin walls by using so-called "variotherm processing" or "melt compression/expansion" (comprising "plastification", "compression" and "expansion/injection"), or by so-called "injection-compression moulding". If an end piece ("cap") of the reservoir (i.e., the capsule apart from the membrane) is to consist of the material of the reservoir, a structural solution may include, inter alia, manufacturing this end piece as a hinged "cap" that can be welded after the cylindrical form of the reservoir has been provided. The membrane may

subsequently be welded onto the reservoir.

The capsules can in different embodiments be made with a volume in the range of 4-400 microlitres, or in the range of 10-100 microlitres, or in the range of 40-60 microlitres.

The capsules can in different embodiments be made with a diameter in the range of 1 - 10 mm, or in the range of 2 - 6 mm, or in the range of 2 - 5 mm.

The scope of the invention is not limited by the examples given in the detailed portion of the description, but by the claims.

Claims

PATENT CLAIMS

1. A capsule for controlled release of a substance to a subject, comprising a reservoir containing the substance; and

at least one membrane closing the reservoir, designed to burst under the influence of an acoustic signal emitted from a source outside the subject.

2. A capsule according to claim 1,

wherein the membrane is designed to burst by means of resonance under the influence of the acoustic signal.

3. A capsule according to one of claims 1-2,

wherein the membrane comprises silicon or silicon nitride.

4. A capsule according to one of claims 1-3,

wherein the subject is a human or an animal, including a fish.

5. A capsule according to one of claims 1-4,

wherein the substance is a therapeutic or prophylactic substance, including a vaccine.

6. A capsule according to one of claims 1-5,

wherein the capsule exhibits a characteristic resonance frequency for acoustic signals, and wherein the characteristic resonance frequency changes when the membrane bursts.

7. A capsule according to one of claims 1-6,

wherein the membrane is designed to burst at resonance frequencies in the range of 50 kHz - 200 kHz, or in the range of 80 kHz-150 kHz, or in the range of 90 kHz-120 kHz, or in the range of about 100k Hz.

8. A capsule according to one of claims 1-7,

wherein a periphery of the membrane comprises a region having a weakness.

9. A capsule according to one of claims 1-8,

wherein a central region of the membrane is reinforced.

10. A capsule according to one of claims 1-9, comprising one membrane, wherein the reservoir is closed by an end surface of the reservoir material at a first end of the reservoir and by the membrane at a second end of the reservoir.

11. A capsule according to one of claims 1-10, comprising two membranes, wherein the reservoir is closed by a first membrane at a first end and by a second membrane at a second end.

12. A capsule according to one of claims 1-11, further comprising an internal membrane that separates two cavities in the capsule.

13. A capsule according to one of claims 1-12,

wherein the reservoir further comprises an acoustically responsive element that is released or activated when the membrane bursts, the acoustically responsive element exhibiting a resonance property that is essentially different from a resonance property of the capsule.

14. A system for controlled release of a substance to a subject, comprising an acoustic source, designed to emit an acoustic transmission signal in an area in which the subject is located,

the subject comprising a capsule as disclosed in one of claims 1-13.

15. A system according to claim 14, further comprising

an acoustic receiver for receiving an acoustic receiving signal in an area in which the subject is located; and

a control unit, designed to control properties of the signal that is emitted by the acoustic source as a function of properties of the received acoustic signal.

16. A system according to claim 15,

wherein the capsule contains an acoustically responsive element that is released when the membrane bursts, and which exhibits a resonance property that is essentially different from a resonance property of the capsule; and

wherein the control unit is designed to detect the resonance property of the acoustically responsive element,

which detection indicates that the content of the capsule has been released to the subject.

17. A method for release of a substance to a subject, comprising

introducing a capsule as disclosed in one of claims 1-13 into the subject, and subjecting the subject to an acoustic signal emitted from a source outside the subject, with the consequence that the at least one membrane that closes the reservoir bursts, thereby releasing the substance into the subject.

18. The use of a capsule according to one of claims 1-13 for controlled release of a substance to a subject.