WO2010150154A1

WO2010150154A1 - Detecting a temporal alteration of an optical property of a subcutaneous layer for drug delivery

Info

Publication number: WO2010150154A1
Application number: PCT/IB2010/052741
Authority: WO
Inventors: Giovanni Nisato; Roelf Kassies
Original assignee: Koninklijke Philips Electronics N.V.
Priority date: 2009-06-25
Filing date: 2010-06-17
Publication date: 2010-12-29

Abstract

Arrangement for detecting a temporal alteration of an optical property of a subcutaneous layer in vivo, drug delivery device (400) comprising the arrangement and method for drug delivery are described. For an optimized control of drug delivery by a transdermal drug delivery device an optical feedback control is described, which allows to detect the alteration of an optical property of a subcutaneous layer caused by an injected fluid from a fluid jet; and to control an actuator of the micro- jet pump in response to the fluid administered under the skin of a subject. If no drug is delivered transdermally the injection speed may be increased and the frequency as well as the injection speed may be controlled in dependence of each other following lookup tables that are generated during calibration of the device. A drug delivery device and a method for drug delivery make use of the optical detection for in situ and real time monitoring of injected substances.

Description

Detecting a temporal alteration of an optical property of a subcutaneous layer for drug delivery

FIELD OF THE INVENTION

The present invention generally relates to the field of needle-less drug injections, devices therefor and to the control of such injections.

BACKGROUND OF THE INVENTION

With continuing progress made in health care and the development of drugs serving all different purposes, transdermal drug delivery, i.e. drug delivery directly through the skin is becoming increasingly important to be used for controlled and/or continuous delivery of drugs. WO 2008/142640 Al discloses a variable drug delivery device comprising a tubular reservoir connected to a high speed jet pump for transdermal needle-less micro-jet drug delivery. In this document a schematic drawing of a high-speed piezo jet pump is shown, as well as an embodiment of a filling system and a venting valve.

The drug delivery device disclosed in WO 2008/142640 Al relies on pre-trials in order to adjust the correct parameters to be able to administer a given amount of a drug transdermally.

SUMMARY OF THE INVENTION

It is an object of the present invention to improve the control in transdermal delivery systems, devices and/or methods.

This object is achieved by an arrangement, system or device for detecting an alteration of an optical property of a subcutaneous layer, to a drug delivery device comprising the arrangement and to a method for drug delivery.

In particular the present invention relates to an arrangement for detecting an alteration of an optical property of a subcutaneous layer in vivo, i.e. in situ and in real time comprising a first light source to illuminate the subcutaneous layer, a first light detector to detect a first intensity of light reflected by the subcutaneous layer from the first light source, and first means for detecting a temporal change in the first light intensity as an alteration of the optical property of the subcutaneous layer. The arrangement according to the present invention presents the significant advantage, that the effect of a drug delivery on a sub- dermal layer of the skin of a treatment subject can be directly observed and in real time, by detecting a temporal alteration of an optical property of a subcutaneous layer with a minimum amount of devices on the basis of the scattered light intensity of a light source which is detected. This avoids the need to prepare specimens of skin samples to determine if the drug has been delivered correctly. Both transitory and / or permanent optical changes can be used for control purposes.

The arrangement may comprise a second light source to illuminate the subcutaneous layer. Expediently according to a further development of the embodiment of the present invention the second light source may be used to provide a reference path for light scattering in an unaltered area of the subcutaneous layer. By providing a reference path, the sensitivity of the arrangement can be improved and differential measurements can be taken. Differential measurements also provide the advantage of quantitative and not just qualitative or relative measurements. Light from the second light source may be detected with the first light detector. In such a case where the second light acts as a reference it is preferred if the light from the second source is the same or similar to the light from the first source. To distinguish between the two, the first and second light sources may be switched on and off alternatively, e.g. in a time multiplex manner. Alternatively, in order to be able to monitor another aspect of the subcutaneous layer, the second light source may be different from the first light source, e.g. it can operate at a different frequency or be modulated with a modulation which allows light from the first light source to be distinguished from the second light source when it is detected by a single detector. Detecting different optical aspects of the subcutaneous layer using two light sources allows a differentiated detection strategy such as to be able to detect and control different or alternative aspects of the delivery.

In embodiments of the present invention the substance such as a drug that is to be administered may have or may be modified to have an optical property that can be used to distinguish light reflected or scattered by the drug from light reflected or scattered by the subcutaneous layer. Such a modification to the substance may be for example the addition of a biodegradable non- harmful fluorescing material and the light source used for the second light may for example be chosen such as to cause the substance to fluoresce.

A second light detector may be provided to detect a second light intensity of light reflected from the subcutaneous layer from one light source. Advantageously according to a further development of the embodiment of the present invention the second light detector can be provided independently of, or in addition to the second light source, e.g. in order to further improve provision of a reference measurement path in an unaltered area of the subcutaneous layer. Measurements via an unaltered are of the subcutaneous layer also provide the advantage of quantitative and not just qualitative or relative measurements. The second light detector may be used to detect light originating from the first light source and/or it can be used to detect light from the second light source. If the second detector detects light from both the first and second light sources the two light sources may differ from each other, e.g. in wavelength, or the first and second light sources may be modulated differently and the second light detector may be adapted to distinguish between light from the first and second light sources. Use of a second detector allows additional control of the delivery.

Preferably a second means is provided for comparing the first light intensity and the second light intensity to thereby detect any change in the first light intensity.

Beneficially according to a further development of an embodiment of the present invention the second means for comparing the light intensity of the two light detectors are provided, in order to allow for an easy implementation of differential measurements and to provide a basic value for the light scattering in an unaltered subcutaneous layer with a constant optical property. Differential measurements also provide the advantage of quantitative and not just qualitative or relative measurements.

In embodiments of the present invention where the substance such as a drug that is to be administered have, or have been modified to have, an optical property that can be used to distinguish light reflected or scattered by the drug from light reflected or scattered by the subcutaneous layer, the second detector may be adapted to detect this optical property of the substance. Where the modification to the substance is for example the addition of a biodegradable non-harmful fluorescing material, then the second detector may be adapted such as to detect the fluorescence. This has the advantage that the administration of the drug can be detected directly, e.g. in addition to detecting optical properties of the subcutaneous layer.

Third means may be provided to generate a first control signal in response to a change detected in the first light intensity. Advantageously according to a further development of the embodiment of the present invention the third means are provided for generating a control signal in response to a change detected in the light intensity. Beneficially, temporal changes are detected by periodically sensing the intensity. This allows improved control of the delivery. The third means can be adapted to generate the control signal proportional to the change in the first light intensity.

Expediently according to a further development of an embodiment of the present invention the control signal is generated that is proportional to the change in the light intensity. Proportional control can allow for a graded reaction to changes in the optical signals such that stronger signals result in a stronger control of the injection speed of a pump. Accordingly, such a signal can beneficially be provided to control electronics, in order to control the electro-mechanical operator of the micro-jet pump and execute appropriate control in order to adapt the admission of a drug in the proper manner. Optionally, a support structure having a planar surface is provided, there being a first light path or opening in the planar surface in communication with a light detector, and a second light path or opening in the planar surface in communication with one light source, and a third opening in the planar surface to accommodate a nozzle.

Advantageously, a further embodiment of the arrangement of the present invention comprises the planar support structure with the first light path, e.g. an opening communicating with the light detector, the second light path, e.g. an opening communicating with the light source, and the third opening allowing the accommodation of micro-jet nozzle so that a minimum structure is provided for standardized use in measurement and control of sub-dermal drug delivery. The support preferably already has a shape, which can be easily brought into contact with the skin surface of a treatment subject, e.g. by bringing the planar surface of the support structure in contact with the skin surface of the treatment subject both facing each other.

The object is also achieved by a delivery device comprising a pump for transdermal needle-less micro-jet delivery into a subcutaneous layer, the above arrangement for detecting a temporal alteration of an optical property of a subcutaneous layer. The detecting can be done in vivo, i.e. in situ and in real time. The pump can have a micro-jet nozzle. The pump is preferably capable of generating a jet that penetrates a patient's skin. The delivery can be of a drug. The drug delivery device is preferably a hand-held device. A hand-held device is on whose weight and size is such that it can be manipulated by a single hand of an adult person under normal circumstances.

The drug delivery device according to the present invention presents the significant advantage, that it immediately allows to control whether the jet, e.g. micro-jet generated by the pump, e.g. micro-jet pump penetrates the skin interface and to execute appropriate feedback control, in order to allow for an increased or decreased jet injection speed and the associated volume control, of the substance, e.g. drug to be submitted at the same time, by applying for instance a different voltage and a different frequency to a piezo actuator of the pump, e.g. micro-jet pump. Embodiments of the present invention also provide the advantage of quantitative and not just qualitative or relative measurements. The object is also achieved by a method for monitoring transdermal drug entry using a pump, wherein the temporal alteration of an optical property of a subcutaneous layer is monitored when the pump is active, e.g. monitored in vivo, i.e. in situ and in real time.

The object is also achieved by a method of control of transdermal needle-less micro-jet delivery using a pump, wherein the temporal alteration of an optical property of a subcutaneous layer is detected, e.g. detected in vivo, i.e. in situ and in real time wherein the injection speed of the pump is controlled in dependence of the alteration of the optical property.

The object is also achieved by a method for delivery with a pump having an injection speed and being capable of generating a jet that penetrates a patient's skin, for transdermal needle-less micro-jet delivery, wherein the temporal alteration of an optical property of a subcutaneous layer is detected, e.g. detected in vivo, i.e. in situ and in real time, an wherein the injection speed of the pump is controlled in dependence of the alteration of the optical property.

The method for delivery of a substance, e.g. for drug delivery according to the present invention presents the significant advantage, that it allows for an optical detection, if a substance, e.g. drug administered needle-less by a micro-jet pump is successfully performed, and at the same time for control of the injection speed in dependence of the alteration of the optical property of the subcutaneous layer. This allows for a feedback control solution suitable for a pump such as a micro-jet pump, a high speed pump or a high pressure pump to administer substances transdermally such as drugs transdermally.

A high speed pump may be applied, however, a high pressure pump could be applied as well in order to guarantee a forcible entry of a substance such as medication. The pump can have a micro-jet nozzle. The delivery can be of a drug. The present invention includes both therapeutic and non-therapeutic methods. An example of non-therapeutic use is the delivery of cosmetic or recreational drugs. An example of a cosmetic application of the present invention is the injection of Botox Cosmetic or Vistabel which are trade names and are here not used generically to describe the neurotoxins produced by C. Botulinum. Advantageous further embodiments of the invention are given in the dependent claims. For example, expediently according to further development of an embodiment of the delivery device according to the present invention, the light detector, the light source and the injection nozzle of the pump, e.g. micro-jet pump are arranged in a geometrical relationship that allows an easy detection of an alteration of an optical property of a subcutaneous layer, caused by the entry of the micro-jet in the epidermis or dermis of a subject whereto a substance such as a drug is administered. This is preferably done in close proximity to the exit hole of the micro-jet in the proximity of the jet injection axis of the micro-jet at a similar distance therefrom. By close proximity can be understood, e.g. within 5mm, within 10 mm within 15 mm or within 20 mm or within 25 mm of the jet injection axis. The jet axis itself may be excluded from observation.

Further advantageously according to another development of the embodiment of the delivery device, e.g. drug delivery device of the present invention, a fourth means to control the actuator of the pump, e.g. a micro-jet pump or a high speed or high pressure pump is provided, wherein a fourth means is adapted to receive the first control signal and to control the actuator in correspondence to the first control signal.

Expediently according to a further development of the delivery device, e.g. drug delivery device according to an embodiment of the present invention, light guide means, to at least guide the light from the light source to a dermal interface and from the dermal interface to a light detector are provided. Such an arrangement is preferably suitable for disposal, whereas the active components can remain in place, and only the components contacting the surface of the skin are removable and replaceable.

Expediently according to a further development of an embodiment of the method according to the present invention, in case no alteration of the optical property is detected the injection speed is increased. This method advantageously allows it to adjust the injection speed to a level until the jet penetrates the skin automatically.

Further advantageously, a further development of an embodiment of the method according to the present invention allows it to calculate the amount of substance to be delivered, e.g. the drug delivery administered by micro-jet transdermal delivery, to be controlled by volume and frequency according to an equation that can be implemented in the control circuitry for the micro-jet pump.

The present invention also provides a delivery device for delivery of a substance subcutaneously, e.g. in vivo, comprising: a pump, and an arrangement for detecting a temporal alteration of an optical property of a subcutaneous layer, e.g. in situ and in real time comprising: a first light source to illuminate the subcutaneous layer, a first light detector to detect a first light intensity reflected by the subcutaneous layer from the first light source, the first light detector being adapted for detecting a temporal change in the first light intensity as an alteration of the optical property of the subcutaneous layer.

The pump can have a micro-jet nozzle for transdermal needle-less micro-jet drug delivery in a subcutaneous layer.

A second light source can also be provided to illuminate the subcutaneous layer. A second light detector can be provided to detect a second light intensity of light reflected from the subcutaneous layer from one light source. The second light detector can be adapted to compare the first light intensity and the second light intensity for detecting a change in the first light intensity. A comparator can be provided to generate a first control signal in response to a change detected in the first light intensity. The comparator can be adapted to generate the first control signal proportional to the change in the first light intensity. This can allow a quantitative measurement and not just a qualitative or relative measurement. The delivery device can comprise a support structure having a planar surface, a first light path in the planar surface being in communication with a light detector, a second light path in the planar surface being in communication with a light source, and a third opening in the planar surface to accommodate a nozzle.

The first light source, the nozzle, e.g. micro-jet nozzle, and the first light detector can be arranged in such a manner that the nozzle is located between the first light source and the first light detector.

The first light source and the first light detector can be arranged in the neighborhood of where the micro-jet leaves the micro-jet nozzle. By neighborhood can be understood, e.g. within 5mm, within 10 mm within 15 mm or within 20 mm or within 25 mm of the jet injection exit.

The delivery device can be provide with an actuator to actuate the pump, and a controller to control the actuator, wherein the controller is adapted to receive the first control signal and to control the actuator in correspondence to the first control signal.

The delivery device may also comprise light paths to guide the light from at least the first light source to a dermal interface, and/or to guide light to the first light detector from a dermal interface, wherein the light paths and the nozzle are arranged in a separate disposable subunit of the delivery device. SHORT DESCRIPTION OF THE FIGURES

Below advantageous further developments of the invention will be further explained on the basis of examples and embodiments in drawings wherein:

Fig. 1 shows a cross-section through a micro-injection profile, Fig. 2 schematically shows a path of light through a subcutaneous layer having an unaltered optical property,

Fig. 3 shows a light path through a subcutaneous layer having an altered optical property,

Fig. 4 shows a drug delivery device according to an embodiment of the present invention comprising a disposable arrangement,

Fig. 5 shows a block chart of a configuration of a drug delivery device according to an embodiment of the present invention and

Fig. 6 shows a flow-chart of a method according to an embodiment of the present invention. Fig. 7 shows another drug delivery device according to another embodiment of the present invention.

The present invention will be described with respect to particular embodiments and with reference to certain drawings but the invention is not limited thereto but only by the claims. The drawings described are only schematic and are non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn on scale for illustrative purposes. Where the term "comprising" is used in the present description and claims, it does not exclude other elements or steps. Where an indefinite or definite article is used when referring to a singular noun e.g. "a" or "an", "the", this includes a plural of that noun unless something else is specifically stated.

The term "comprising", used in the claims, should not be interpreted as being restricted to the means listed thereafter; it does not exclude other elements or steps. Thus, the scope of the expression "a device comprising means A and B" should not be limited to devices consisting only of components A and B. It means that with respect to the present invention, the only relevant components of the device are A and B.

Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.

Moreover, the terms top, bottom, over, under and the like in the description and the claims are used for descriptive purposes and not necessarily for describing relative positions. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other orientations than described or illustrated herein.

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more embodiments.

Similarly it should be appreciated that in the description of exemplary embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects. This method of disclosure, however, is not to be interpreted as reflecting an intention that the claimed invention requires more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed embodiment. Thus, the claims following the detailed description are hereby expressly incorporated into this detailed description, with each claim standing on its own as a separate embodiment of this invention.

Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the following claims, any of the claimed embodiments can be used in any combination.

Furthermore, some of the embodiments are described herein as a method or combination of elements of a method that can be implemented by a processor of a computer system or by other means of carrying out the function. Thus, a processor with the necessary instructions for carrying out such a method or element of a method forms a means for carrying out the method or element of a method. Furthermore, an element described herein of an apparatus embodiment is an example of a means for carrying out the function performed by the element for the purpose of carrying out the invention.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Figure 1 depicts a cross-section of a micro-injection profile, showing the structure of a mammal's skin. The Stratum corneum SC performs as the interface with the outside world. Underneath the stratum corneum SC, a plurality of layers is comprised. In order of increasing depth with regard to the stratum corneum SC these layers are the epidermis ED, the dermis D and the hypodermis HD, also referred to as subcutaneous fat.

Furthermore, an entering light beam LS and an exiting light beam LD are shown. In between them a light path propagates through the skin tissue. Above that a nozzle such as a jet nozzle JN is shown that ejects a fluid jet FJ. Further an injection zone IZ can be observed in the inner part of the tissue, indicated by way of a darkened area. By observing the drawing one can contemplate, that when building up a fluid reservoir that contains a substance, e.g. a drug to be administered in the inner part of the skin tissue, the optical property of a subcutaneous layer of the skin tissue will be affected; and accordingly light propagation along a light path LP in the tissue will be different as without the forming of an injection zone IZ. Such an alteration, for example, results in the variation of a scattering of the light and thus in the total amount of light that is scattered and detectable as the outcoming light beam LD.

Consequently the detection of the outgoing light beam LD, and its total intensity in dependency of the incoming light beam LS will result in a measure of the success of transdermal delivery, e.g. drug delivery, as well as its temporal increase being able to give a measure for determining the amount of a substance, e.g. a drug that is administered. The present invention includes both medical and non-medical methods of delivery subcutaneously.

Generally no standard parameters for transdermal delivery, e.g. drug delivery can be used, as the morphological and mechanical properties, such as thickness and tension of the tissue vary from subject to subject; and further also depend on an anatomical location as to where the fluid jet is applied.

A delivery device, e.g. a drug delivery device, may be for instance used to apply insulin or to provide a vaccination. In adapting the penetration depth of the fluid jet a pain sensation can be reduced and a corresponding uptake of the injected substance, e.g. drug uptake can be optimized. In particular in a commercial unit, a combination of a durable unit containing a power supply and a driving electronics, as well as the mechanical actuation of the pump, e.g. micro-jet pump and a disposable substance containing cartridge such as a disposable drug containing cartridge in contact with the skin may be provided.

As Fig. 2 shows, according to an aspect of the present invention, light is emitted from a light source 210 passing through the stratum corneum SC and is scattered in the skin in layers underneath the stratum corneum SC, with unaltered optical properties along a scattering path 225 exiting again through the skin interface 215 and arriving at a light collection and detection unit 220 with a measurable light output intensity. Advantageously, the light source 210 and the light collection and detection unit 220 are arranged in the area of a jet injection axis 315. The best geometrical relationship between the light source and the light collection and detection unit with respect to the jet injection axis 315 may be found on the basis of pre-trial experiments. For instance, they need not to be symmetrical as shown in Fig. 2, but can have any suitable geometrical configuration that allows for a good detection of the scattered light 225. "In the area of a jet injection axis 315" can be understood to be, e.g. within 5mm, within 10 mm within 15 mm or within 20 mm or within 25 mm of the jet injection axis.

As Fig. 3 shows, an injection region 310 alters the path of scattered light 325 through the stratum corneum SC and the skin tissue underneath it, and thus a different light output intensity will be measured by the light collection and detection unit as a consequence of the building up of the injection region, which building up deforms the skin area.

As Fig. 4 shows, an embodiment of a delivery device, e.g. a drug delivery device 400 according to the present invention. The delivery can be of a drug. The drug delivery device is preferably a hand-held device. A hand-held device is one whose weight and size is such that it can be manipulated by a single hand of an adult person under normal circumstances.

The delivery device, e.g. a drug delivery device 400 may comprise a power supply 410, which may be a stationary power supply in form of a cable connected to a wall outlet, or may be a battery. Furthermore a drive electronics 415 are provided, in order to supply an electromechanical actuator 420 of a pump such as a micro-jet pump having a plunger 437, a membrane 430 and a nozzle 435, with corresponding control signals, in order to form an appropriate fluid jet, e.g. micro-jet, injecting from the nozzle 435 for transdermal delivery of a substance, e.g. drug delivery. Furthermore, one or more optical detectors 457 are provided to supply a measured light intensity value of light received from the subcutaneous layer, to the driver electronics 415. Preferably, appropriate control parameters for actuation of the electromechanical actuator 420 in dependency of the received light intensity are calculated. Furthermore, one or more light sources 425 are shown. Above that light guide means 460 providing light along a light path to a planar surface 490 of the delivery device, e.g. drug delivery device, and a light guide means 455 providing light along a light path from a planar surface of the drug delivery device to the optical detection unit 457 are depicted. Light guide means 455 and/or 460 (that provide a light path) may be a simple opening or hole, may include lenses, mirrors, prisms, light guides, optical fibers etc. As can be seen, from the dark color, a support structure 480 is provided in the delivery device, e.g. drug delivery device containing the light guide means 455 and 460 as well as the nozzle 435 and the membrane 430. This support structure, as also shown by reference numeral 450, is optionally disposable and may be separable from the delivery device, e.g. drug delivery device by appropriate fixing means, whereas the parts of the delivery device, e.g. drug delivery device encompassed by bracket 440 are durable. In this manner a simple construction compatible with disposable cartridges is provided that allows for real-time monitoring and at the same time fulfils hygienic standards, in decoupling the light source and detection optics from the skin tissue. Expediently according to further development of an embodiment of the delivery device according to the present invention, the light detector, the light source and the injection nozzle of the pump, e.g. micro-jet pump are arranged in a geometrical relationship that allows an easy detection of an alteration of an optical property of a subcutaneous layer, caused by the entry of the micro-jet in the epidermis or dermis of a subject whereto a substance such as a drug is administered. This is preferably done in close proximity to the exit hole of the micro-jet in the proximity of the jet injection axis of the micro-jet at a similar distance therefrom. The area of illumination by the light source can be within 5mm or 10 mm radius of the injection site, whereby the injection site itself is preferably masked out. Alternatively the area of illumination may be within 5mm, within 10 mm within 15 mm or within 20 mm or within 25 mm of the jet injection axis.

Fig. 5 gives a general example of a block diagram of an embodiment of a delivery device, e.g. a drug delivery device 500 according to the present invention. The drug delivery device is preferably a hand-held device. A hand-held device is one whose weight and size is such that it can be manipulated by a single hand of an adult person under normal circumstances. In the device one or more optical sources 510 are connected to driver electronics 530 as is one or more optical detection units 550, and a power supply 520. The driver electronics 530 processes the signals from the one or more optical detection units and controls an actuator such as a micro-jet actuator 560 appropriately, i.e. to control operation of a pump. Hence, the drive electronics 530 also act as a controller and the controller may control various functions as detailed below. The driver electronics 530 may also operate the one or more optical sources in response to the light intensity detected by the one or more optical detection units 550 and increase (or decrease) the light intensity emitted by the one or more optical sources 510 or operate the one or more optical sources at a light emitting frequency.

In particular the driver electronics 530 may operate as a controller and control the volume injected by the micro-jet pump by operating the micro-jet actuator 560 in a suitable way. In this case a volume injected in form of a pulsing micro-jet can be delivered as a function of the injection speed. For instance, by increasing the injection speed as may be required to pierce the epidermis, a total delivered dose per shot, respectively micro-jet will also increase. Consequently the light detected by the one or more optical detection units and the subsequent processing of the light intensity in the driver electronics 530 is not only important to determine the success of the skin injection process but also for performing the appropriate injection frequency, respectively the number of micro-jets per time unit to achieve the desired drug influx. The flux follows the following equation:

Flux (ml/s) = Vjet (single jet volume) [ml] x f (injection repeat frequency) [1/s].

Accordingly the repeat frequency of the injection needs to be appropriately adjusted by the driver electronics that may be embodied in form of a microcontroller, in case the injection speed is modified. The dependency of such a modification in absolute values may be provided in form of a lookup table, which may relate a voltage applied to the piezoelectric actuator of the micro-jet pump, which in Fig. 4 was marked by reference sign 420 and jet volumes and speed.

For instance, such a lookup table may be provided as a result of a calibration procedure for a respective device, as it may depend on the specific characteristics of a piezoelectric element driving the micro-jet formation and thus may be individual to each respective device. A corresponding calibration table listing the respective parameters voltage, jet volume, and speed may be stored in a suitable memory of the driver electronics 530.

As Fig. 7 shows in a top view, another embodiment of a delivery device, e.g. a drug delivery device 700 according to the present invention may comprise a power supply 710, which may be a stationary power supply in form of a cable connected to a wall outlet, or may be a battery. The drug delivery device is preferably a hand-held device. A hand-held device is one whose weight and size is such that it can be manipulated by a single hand of an adult person under normal circumstances. Furthermore drive electronics 715 are provided, in order to supply an electromechanical actuator 720 of a pump such as a micro-jet pump having a plunger, a membrane and a nozzle, with corresponding control signals, in order to form an appropriate fluid jet, e.g. micro-jet, injecting from the nozzle for transdermal delivery of a substance, e.g. drug delivery. Furthermore, a first optical detector 757 is provided to supply a first measured light intensity value of light received from the subcutaneous layer, to the driver electronics 715. Preferably, appropriate control parameters for actuation of the electromechanical actuator 720 in dependency of the received light intensity are calculated. Furthermore, a first light source 725 is shown. Above that a first light guide means provides light along a first light path to a planar surface of the delivery device, e.g. drug delivery device, and a second light guide means provides light along a second light path from a planar surface of the drug delivery device to the first optical detection unit 757. Furthermore, a second light source 726 is shown. In addition, a third light guide means provides light along a third light path to a planar surface of the delivery device, e.g. drug delivery device, and a fourth light guide means provides light along a fourth light path from a planar surface of the drug delivery device to a second optical detection unit 758. Any of the above light guide means (that provide a light path) may be a simple opening or hole, may include lenses, mirrors, prisms, light guides, optical fibers etc. The support structure 780 of the delivery device, e.g. drug delivery device contains the light guide means as well as the nozzle and the membrane. This support structure is also optionally disposable and may be separable from the delivery device, e.g. drug delivery device by appropriate fixing means, whereas parts of the delivery device, e.g. drug delivery device are durable. In this manner a simple construction compatible with disposable cartridges is provided that allows for real- time monitoring and at the same time fulfils hygienic standards, in decoupling the light source and detection optics from the skin tissue.

The second light source 726 may be used to provide a reference path for light scattering in an unaltered area of the subcutaneous layer. For this reason the area of the skin illuminated by the second light source may be different from the area illuminated by the first light source, e.g. it can illuminate and are more than 5 mm from the injection site, more than 10 mm and optionally less than 20 mm from the site. By providing a reference path, the sensitivity of the arrangement can be improved and differential measurements can be taken. Light from the second light source 726 may be detected with the first light detector 757. In such a case where the second light acts as a reference it is preferred if the light from the second source 726 is the same or similar to the light from the first source 725. To distinguish between the two, the first and second light sources may be switched on and off alternatively, e.g. in a time multiplex manner. Alternatively, in order to be able to monitor another aspect of the subcutaneous layer, the second light source 726 may be different from the first light source 725, e.g. it can operate at a different frequency or be modulated with a modulation which allows light from the first light source 725 to be distinguished from the second light source 726 when it is detected by a single detector. Detecting different optical aspects of the subcutaneous layer using two light sources allows a differentiated detection strategy such as to be able to detect and control different or alternative aspects of the delivery. A second light detector 758 may be provided to detect a second light intensity of light reflected from the subcutaneous layer from one light source. Advantageously according to a further development of the embodiment of the present invention the second light detector 758 can be provided independently of, or in addition to the second light source 726, e.g. in order to further improve provision of a reference measurement path in an unaltered area of the subcutaneous layer. The second light detector 758 may be used to detect light originating from the first light source 725 and/or it can be used to detect light from the second light source 726. If the second detector 758 detects light from both the first and second light sources 725, 726 the two light sources may differ from each other, e.g. in wavelength, or the first and second light sources may be modulated differently and the second light detector may be adapted to distinguish between light from the first and second light sources. Use of a second detector allows additional control of the delivery. Preferably the drive electronics 715 has a comparator for comparing the first light intensity signal from the first detector and the second light intensity signal from the second light detector to thereby detect any change in the first light intensity. Beneficially the comparator is adapted for comparing the light intensity of the two light detectors, to thereby allow differential measurements and to provide a basic value for the light scattering in an unaltered subcutaneous layer with a constant optical property. This can allow quantitative measurements instead of only qualitative or relative measurements. The drive electronics 715 may be adapted to generate a control signal in response to a change detected in the light intensity returned from the subcutaneous layer. Beneficially, temporal changes are detected by periodically sensing the intensity. This allows improved control of the delivery. The drive electronics can be adapted to generate the control signal proportional to the change in the first light intensity. Proportional control can allow for a graded reaction to changes in the optical signals such that stronger signals result in a stronger control of the injection speed of a pump. Accordingly, such a signal can beneficially be provided to the control electronics 715, in order to control the electro-mechanical operator of the micro-jet pump and execute appropriate control in order to adapt the admission of a drug in the proper manner.

In further embodiments of the present invention the substance such as a drug that is to be administered can have, or can be modified to have, an optical property that can be used to distinguish light reflected or scattered by the drug from light reflected or scattered by the subcutaneous layer. For example, the second detector may be adapted to detect this optical property of the substance. Where the modification to the substance is for example the addition of a biodegradable non-harmful fluorescing material, then the second detector may be adapted such as to detect the fluorescence. This has the advantage that the administration of the drug can be detected directly, e.g. in addition to detecting optical properties of the subcutaneous layer.

The drug delivery device according to embodiments of the present invention may be suitable for a wide variety of applications of which the following are only a few: delivering insulin, delivering dopamine receptor agonists, delivering interferon beta, as well as opiates, cannabinoids in injectable solutions; and furthermore in oncology the present invention may be used to deliver monoclonal antibodies as therapeutic agents. The drug delivery device according to embodiments of the present invention may be suitable for delivering non-therapeutic drugs such as recreational drugs or for cosmetic applications. A cosmetic application is for example the injection of Botox Cosmetic or Vistabel which include neurotoxins produced by C. Botulinum available for cosmetic treatment. The terms Botox Cosmetic, or Vistabel are here not used generically to describe the neurotoxins produced by C. Botulinum.

As Fig. 6 shows, a method for delivery especially drug delivery according to the present invention starts at 600 and continues to where a substance such as a drug is injected by needle-less fluid jet pulses, further continuing to a step 620, where the alteration of an optical property of a subcutaneous layer is detected, and accordingly at 630 a speed of the injection is controlled in dependency of the detection of the alteration of the optical property. The method ends at 640. It is to be understood that although preferred embodiments, specific constructions and configurations, as well as materials, have been discussed herein for devices according to the present invention, various changes or modifications in form and detail may be made without departing from the scope of this invention as defined by the appended claims.

Claims

CLAIMS:

1. Delivery device for in- vivo monitoring of a delivery of a substance subcutaneously, comprising a pump (420, 435) configured for delivering a substance subcutaneously, and an arrangement within the housing for detecting an alteration of an optical property of a subcutaneous layer in real time on delivery of a substance subcutaneously comprising: a first light source (210) to illuminate the subcutaneous layer, a first light detector (220) to detect a first light intensity (225) reflected by the subcutaneous layer from the first light source, and first means (415) for detecting a change in the first light intensity as an alteration of the optical property of the subcutaneous layer.

2. The delivery device of claim 1, wherein the pump has a micro-jet nozzle (435) for transdermal needle-less micro-jet drug delivery in a subcutaneous layer.

3. Delivery device according to claim 1, further comprising a second light source to illuminate the subcutaneous layer.

4. Delivery device according to claim 1 further comprising a second light detector to detect a second light intensity of light reflected from the subcutaneous layer from one light source.

5. Delivery device according to claim 4 further comprising second means for comparing the first light intensity and the second light intensity for detecting a change in the first light intensity.

6. Delivery device according to claim 1 further comprising third means to generate a first control signal in response to a change detected in the first light intensity.

7. Delivery device according to claim 6, wherein the third means is adapted to generate the first control signal proportional to the change in the first light intensity.

8. Delivery device according to claim 1 further comprising: - a support structure having a planar surface (490), a first light path in the planar surface being in communication with a light detector, a second light path in the planar surface being in communication with a light source, and - a third opening in the planar surface to accommodate a nozzle.

9. Delivery device according to claim 2, wherein the first light source (210), the micro-jet nozzle (435), and the first light detector (220) are arranged in such a manner that the nozzle is located between the first light source and the first light detector.

10. Delivery device according to claim 9, wherein the first light source (210) and the first light detector (220) are arranged in the neighborhood of where the micro-jet (320) leaves the micro -jet nozzle.

11. Delivery device according to claim 9, further comprising: an actuator (420) to actuate the pump, and a fourth means (415) to control the actuator, wherein the fourth means is adapted to receive the first control signal and to control the actuator in correspondence to the first control signal.

12. Delivery device according to claim 2, further comprising light guide means (455, 460) to guide the light from at least the first light source to a dermal interface (215), and/or to guide light to the first light detector from a dermal interface (215), wherein the light guide means and the nozzle are arranged in a separate disposable subunit (450) of the delivery device.

13. Method of control of in vivo transdermal needle-less micro-jet delivery using a pump (420, 435) having an injection speed, wherein the temporal alteration of an optical property of a subcutaneous layer is detected in real time at the delivery, and wherein the injection speed of the pump is controlled in dependence of the alteration of the optical property.

14. Method according to claim 13, wherein, if no alteration of the optical property is detected, the injection speed is increased.

15. Method according to claim 13, wherein in case a first amount of a substance is to be delivered, the amount of substance delivery is calculated according to the following equation: Flux [ml/s] = Vjet [ml] x f [ 1/s] , wherein: flux: substance influx,

Vjet: single jet volume,

F: injection repeat frequency.

16. Method of in vivo monitoring of transdermal needle-less micro-jet drug delivery using a pump (420, 435) having an injection speed, wherein the temporal alteration of an optical property of a subcutaneous layer is detected in real time at the delivery, and wherein the injection speed of the pump is controlled in dependence of the alteration of the optical property.