Patent Grant
7922462
The present invention relates to actuators suitable for actuation of pumps for the delivery of fluids. In a specific aspect, the invention relates to an actuator system suitable for actuating a membrane pump arranged in a drug delivery device adapted to be carried by a person. However, the present invention may find broad application in any field in which a given member, component or structure is to be moved in a controlled manner.
In the disclosure of the present invention reference is mostly made to the treatment of diabetes by injection or infusion of insulin, however, this is only an exemplary use of the present invention.
Portable drug delivery devices for delivering a drug to a patient are well known and generally comprise a reservoir adapted to contain a liquid drug and having an outlet in fluid communication with a transcutaneous access device such as a hollow infusion needle or a cannula, as well as expelling means for expelling a drug out of the reservoir and through the skin of the subject via the access device. Such drug delivery devices are often termed infusion pumps.
Basically, infusion pumps can be divided into two classes. The first class comprises infusion pumps which are relatively expensive pumps intended for 3-4 years use, for which reason the initial cost for such a pump often is a barrier to this type of therapy. Although more complex than traditional syringes and pens, the pump offer the advantages of continuous infusion of insulin, precision in dosing and optionally programmable delivery profiles and user actuated bolus infusions in connections with meals.
Addressing the above problem, several attempts have been made to provide a second class of drug infusion devices that are low in cost and convenient to use. Some of these devices are intended to be partially or entirely disposable and may provide many of the advantages associated with an infusion pump without the attendant cost and inconveniencies, e.g. the pump may be prefilled thus avoiding the need for filling or refilling a drug reservoir. Examples of this type of infusion devices are known from U.S. Pat. Nos. 4,340,048 and 4,552,561 (based on osmotic pumps), U.S. Pat. No. 5,858,001 (based on a piston pump), U.S. Pat. No. 6,280,148 (based on a membrane pump), U.S. Pat. No. 5,957,895 (based on a flow restrictor pump (also known as a bleeding hole pump)), U.S. Pat. No. 5,527,288 (based on a gas generating pump), or U.S. Pat. No. 5,814,020 (based on a swellable gel) which all in the last decades have been proposed for use in inexpensive, primarily disposable drug infusion devices, the cited documents being incorporated by reference.
As the membrane pump can be used as a metering pump (i.e. each actuation (or stroke) of the pump results in movement of a specific amount of fluid being pumped from the pump inlet to the pump outlet side) a small membrane pump would be suitable for providing both a basal drug flow rate (i.e. providing a stroke at predetermined intervals) as well as a drug bolus infusion (i.e. a given number of strokes) in a drug delivery device of the above-described type.
More specifically, a metering membrane pump may function as follows. In an initial condition the pump membrane is located at an initial predefined position and the inlet and outlet valves are in their closed position. When the means for moving the membrane (i.e. the membrane actuator) is energized an increase of the pressure inside the pumping chamber occurs, which causes opening of the outlet valve. The fluid contained in the pumping chamber is then expelled through the outflow channel by the displacement of the pump membrane from its initial position towards a fully actuated position corresponding to the end position for the “out-stroke” or “expelling-stroke”. During this phase, the inlet valve is maintained closed by the pressure prevailing in the pumping chamber. When the pump membrane is returned to its initial position (either due to its elastic properties or by means of the membrane actuator) the pressure in the pumping chamber decreases. This causes closing of the outlet valve and opening of the inlet valve. The fluid is then sucked into the pumping chamber through the inflow channel, owing to the displacement of the pump membrane from the actuated position to the initial position corresponding to the end position for the “in-stroke” or “suction-stroke”. As normally passive valves are used, the actual design of the valve will determine the sensitivity to external conditions (e.g. back pressure) as well as the opening and closing characteristics thereof, typically resulting in a compromise between the desire to have a low opening pressure and a minimum of backflow. As also appears, a metering membrane functions as any conventional type of membrane pump, for example described for use as a fuel pump in U.S. Pat. No. 2,980,032.
As follows from the above, the precision of a metering pump is to a large degree determined by the pump membranes movement between its initial and actuated positions. These positions may be determined by the pump cavity in which the pump membrane is arranged, i.e. the membrane is moved between contact with two opposed surfaces, this allowing e.g. the pump to be driven by an expanding gas (see PCT/DK03/00628), or they may be determined by a membrane actuator member being moved between predefined positions. Indeed, to secure a high delivery precision it would be desirable to monitor that the pump membrane is actually moved between its two positions. Membrane movement may be measured using any convenient means such as electrical contacts or electrical impedance measurement (resistance or capacitance) between electrical contacts/elements arranged on opposed surfaces of the pump membrane and the pump housing.
Instead of, or in addition to, monitoring the pump per se it is also possible to positively detect the flow rate from any given type of pump by incorporating additional metering means, e.g. based on thermo-dilution as disclosed in EP 1 177 802.
To further monitor proper functioning of an actuated system such as a drug infusion pump, it would be desirable to provide means for detecting different operational conditions of the system, such as an occlusion condition downstream of a pump, e.g. full or partial occlusion of a transcutaneous access device. As the outlet conduit leading from the pump outlet to the distal outlet opening of a transcutaneous access device is relatively stiff, a given pressure rise in the outlet conduit during pump actuation can normally be taken as an indication for an occlusion condition and thus be utilized to detect the latter. For example, US 2003/167035 discloses a delivery device comprising pressure sensors being actuated by a resilient diaphragm arranged in flow communication with in the outlet conduit.
Having regard to the above-identified problems, it is an object of the present invention to provide an actuator system, or component thereof, suitable for driving an actuatable structure or component.
It is a further object to provide an actuator system which allows for detection of different operational conditions of the system, thereby ideally providing a system which can be actuated and controlled in a safe and efficient manner.
It is a further object to provide an actuator system which can be used in combination with a pump assembly arranged in a portable drug delivery device, system or a component therefore, thereby providing controlled infusion of a drug to a subject.
It is a further object to provide an actuator system which can be used in combination with a pump such as a membrane pump.
It is a further object of the invention to provide an actuator, or component thereof, which can be provided and applied in a cost-effective manner.
In the disclosure of the present invention, embodiments and aspects will be described which will address one or more of the above objects or which will address objects apparent from the below disclosure as well as from the description of exemplary embodiments.
According to a first aspect of the invention, an actuator system is provided comprising an actuator lever, a supporting structure, a moveable structure moveable by actuation of the actuator lever, and an actuator for moving the actuator lever. A first stationary pivoting joint (in the following the term pivot joint may be used as an equivalent term) is formed between the actuator lever and the supporting structure, and a second floating pivoting joint is formed between the actuator lever and the moveable structure allowing the moveable structure to float relative to the actuator lever, the floating pivoting point providing a constant-length actuator arm defined between the first pivoting joint and the second pivoting joint. By this arrangement the lever is attached to the supporting structure, however, as the joint between the lever and the moveable structure is floating, the moveable structure is allowed (to a certain degree) to move relative to the supporting structure (and visa versa) yet still preserving the arm length and thus the ability to actuate a structure in a controlled and efficient manner.
In an embodiment thereof an actuator system is provided comprising an actuator lever, a supporting structure, a moveable structure being moveable by actuation of the actuator lever, and an actuator providing an actuation force at an actuator position on the actuator lever. A first stationary pivoting joint is formed between the actuator lever and the supporting structure, whereby a first actuator arm length is defined between the first pivoting joint and the actuator position. A second floating pivoting joint is formed between the actuator lever and the moveable structure allowing the moveable structure to float relative to the actuator lever, whereby the floating pivoting point provides a second constant-length actuator arm being defined between the first pivoting joint and the second pivoting joint.
In an alternative configuration an actuator system is provided comprising an actuator lever, a supporting structure, a moveable structure moveable by actuation of the actuator lever, and an actuator for moving the actuator lever. A first floating pivoting joint is formed between the actuator lever and the supporting structure allowing the actuator lever to float relative to the supporting structure, and a second floating pivoting joint is formed between the actuator lever and the moveable structure allowing the actuator lever to float relative to the moveable structure, the floating pivoting points providing a constant-length actuator arm being defined between the first pivoting joint and the second pivoting joint. By this arrangement the lever is allowed (to a certain degree) to move relative to the supporting structure as well as the actuated structure yet still preserving the arm lengths.
In an embodiment thereof an actuator system is provided comprising an actuator lever, a supporting structure, a moveable structure being moveable by actuation of the actuator lever, and an actuator providing an actuation force at a predefined actuator position on the actuator lever. A first floating pivoting joint is formed between the actuator lever and the supporting structure allowing the actuator lever to float relative to the supporting structure, whereby a first constant-length actuator arm is defined between the first pivoting joint and the actuator position. A second floating pivoting joint is formed between the actuator lever and the moveable structure allowing the actuator lever to float relative to the moveable structure, whereby the floating pivoting point provides a second constant-length actuator arm defined between the first pivoting joint and the second pivoting joint.
For both alternatives the second joint may be arranged between the first joint and the actuator position, or the first joint may be arranged between the second joint and the actuator position.
The floating joints are advantageously formed by a line bearing (e.g. formed by a knife-edge or rounded rod member) or point bearing (e.g. formed from a pointed member or a ball) formed on the actuator lever cooperating with a substantially planar surface allowing the knife-edge or ball bearing to float relative thereto. In the present context such a planar surface would also include a groove in which a point formed member would be allowed to float. By this arrangement the actual position of a floating joint will be determined by the position of the knife-edge or ball bearing and thus by the lever, the planar surface of the other structure being allowed to move without changing the length of the lever arms.
To hold the contact structures of the joints (especially the floating joints) in contact with each other, a biasing member may be provided. As an example, the actuator may be of the coil-magnet type, the coil and magnet(s) being arranged on the actuator lever respectively the supporting structure. As long as the magnetic relationship is substantially constant (e.g. the coil is positioned within a (near) constant magnet field, the force provided by the moving component (i.e. arranged on the lever) will substantially constant.
In an exemplary embodiment the actuator system is provided in combination with a pump for pumping a liquid between an inlet and an outlet thereof, the pump comprising a pump member performing a pump stroke when actuated by the actuator lever. The pump may comprise inlet and outlet valves associated with the pump inlet respectively the pump outlet, and a pump chamber in which the pump member is moved to perform a pump stroke respectively a suction stroke. The combination may further comprise a reservoir adapted to contain a fluid drug and comprising an outlet in fluid communication with or being adapted to be arranged in fluid communication with the pump inlet, and a transcutaneous access device comprising a distal end adapted to be inserted through the skin of a subject, the transcutaneous access device comprising an inlet in fluid communication with or being adapted to be arranged in fluid communication with the pump outlet, the combination thereby providing a drug delivery device. The reservoir may be any suitable structure adapted to hold an amount of a fluid drug, e.g. a hard reservoir, a flexible reservoir, a distensible or elastic reservoir. The reservoir may e.g. be prefilled, user fillable or in the form of a replaceable cartridge which again may be prefilled or fillable.
When actuating a given member, it would be desirable to provide an actuator system which allows for detection of different operational conditions of the system, thereby ideally providing a system which can be actuated and controlled in a safe and efficient manner.
Correspondingly, according to a further aspect of the invention, an actuator system is provided comprising an actuator member for moving a structure, the actuator member having a first position and a second position, and actuating means for moving the actuator member between the first and second positions. The system further comprises detection means for detecting the first respectively the second position and supplying signals indicative thereof (e.g. when a position was reached or left), and a controller for determining on the basis of the supplied signals the time lapsed when the actuator member is moved between the first and second positions in a given direction, e.g. T-in or T-out for a suction respectively an expelling pump stroke. The controller is provided with information representing at least one defined time range, each time range being associated with movement of the actuator member in a given direction between the first and second positions and a given actuation force, e.g. as determined by a supplied current, the controller being adapted to compare the determined time lapsed with the one or more defined time ranges and perform an action corresponding to the time range associated with the determined time lapsed.
The time range(s) may be predefined, selectable or they may be dynamically influenced by actuation history over a short or long period of time. The time range(s) may be closed, open or open-ended. The action may be in the form of a “positive” action, e.g. actuating an alarm, initiating a modified actuation pattern, or a “negative” action, e.g. no action. The motion provided by the actuator may be e.g. reciprocating, linear or rotational, which movement may then be transformed into the desired actuation pattern for a given structure to be moved. Correspondingly, the actuator means may be of any suitable type, e.g. a coil-magnet system, a shape memory alloy (SMA) actuator, a solenoid, a motor, a gas generator, a piezo actuator, a thermo-pneumatic actuator, or a pneumatic actuator.
In the context of the present application and as used in the specification and claims, the term controller covers any combination of electronic circuitry suitable for providing the specified functionality, e.g. processing data and controlling memory as well as all connected input and output devices. The controller may comprise one or more processors or CPUs which may be supplemented by additional devices for support or control functions. For example, the detection means, a transmitter, or a receiver may be fully or partly integrated with the controller, or may be provided by individual units. Each of the components making up the controller circuitry may be special purpose or general purpose devices. The detection means may comprise a “sensor” per se, e.g. in the form of an electrical contact, or an optical or magnetic sensor capable of being influenced by the position of the actuator member, in combination with circuitry supplying time signals indicative of when a position was reached or left. Such circuitry may be formed fully or partly integrally with the controller. For example, both may rely on a common clock circuit. As appears, the distinction between the detection means and the controller may be more functional rather than structural.
As appears, for each direction and each force a number of defined time ranges may be provided, however, in the simplest form only a single time range associated with movement of the actuator in one direction is provided. For example, a determined time lapsed within such a single time range may indicate an alarm or malfunctioning condition whereas lapsed times outside this range would be considered within normal operation. In a more advanced form a number of time ranges is provided for each direction. The time ranges may be “closed” (e.g. 50-100 ms) or “open” (e.g. >50 ms or <100 ms).
As appears, it is important that a determined lapsed time is correctly correlated with a given actuator movement. Thus, in an exemplary embodiment the controller is adapted to control the actuating means for moving the actuator between the first and second positions in a given direction, and determine a lapsed time corresponding to a given actuation of the actuator member between the first and second positions in a given direction. However, a given actuator movement may also be “passive”, i.e. provided by forces not “actively” generated by actuator means. For example, an actuated movement may be followed immediately by a passive movement (e.g. provided by an elastic member deformed during the active movement, the elastic member then serving as an actuator) which could then be correlated to the former.
To further control the relation between movement and time, the controller may be adapted to determine on the basis of signals supplied by the detection means that the actuator is correctly positioned in either the first or the second position corresponding to the given direction of actuation, and provide a signal (e.g. error or alarm signal) in case the actuator member is not correctly positioned corresponding to the given direction of actuation.
To provide time signals well correlated to the first and second positions, an exemplary embodiment of the system comprises first and second stop means adapted to engage the actuator member in the first respectively the second position, whereby engagement between the actuator member and the first respectively the second stop means allows the detection means to detect that the actuator member is in the first respectively the second position. It should be emphasized that the term “actuator member” in this context may be a structure of the actuator member per se (e.g. an actuator lever) or a component functionally and motionally coupled to the actuator member (e.g. a component moved by the actuator such as a piston or a pump membrane) such that the first and second positions for such a component correspond to the first and second positions for the actuator member per se. Detection of the “stop” positions may be by any suitable detection means, e.g. comprising electrical contacts, optical or magnetic sensors.
As stated above, the time range(s) may be predefined, selectable or they may be dynamically determined. For example, upon initial use of a given actuated system, the system may be actuated a number of times (e.g. when priming a pump), and the lapsed times detected during these actuations be used to determine a value which is unique for the actual system, which value may then be used to calculate one or more defined ranges to be used for the subsequent determination of different conditions for the system. As a safety feature, the actuator system may be provided with preset values or ranges within which the dynamically determined ranges should fall, this to prevent that a dynamic range is determined for a defective system.
As stated in the introductory portion, the actuator system of the present invention may find broad application in any field in which a given member, component or structure is to be moved in a controlled manner. In an exemplary embodiment the actuator system is provided in combination with a pump for pumping a liquid between an inlet and an outlet thereof, the pump comprising a pump member performing a pump action when actuated by the actuator member moved between the first and second positions. The pump may be of any desired type, e.g. a membrane pump, a piston-cylinder pump or a roller-tube pump. The actuator system of the present invention may be used to monitor and detect normal operations of the system as well as operations associated with a malfunctioning of the system or the application in which a given pump is used.
For example, the pump outlet of a drug delivery device may be in fluid communication with a hydraulically rigid outlet conduit, such that a partial or full occlusion of the outlet conduit (e.g. corresponding to a distal outlet opening of conduit such as a distal opening of a cannula or a hollow needle) will result in a substantially unrestricted pressure rise in the outlet conduit, whereby for a predetermined actuation force applied to the pump member from the actuation member the duration of the pump stroke will be extended. To detect such a condition the controller is provided with information representing a defined time range indicative of an occlusion condition in the outlet conduit, the controller being adapted to produce an alarm signal in case the determined lapsed time of a pump stroke is within the occlusion condition time range. The alarm signal may be used to activate an associated user alarm such as an audible, visual or tactile alarm, or it may be used to initially try to overcome the occlusion by modifying pump operation.
The pump may comprise inlet and outlet valves associated with the pump inlet respectively the pump outlet, and a pump chamber in which the pump member is moved to perform a pump stroke respectively a suction stroke, the suction stroke being associated with the actuator member being moved between the second and first positions. For such a combination the controller may comprise information representing one or more of the following defined time ranges for a given actuation force and/or direction: (a) a time range associated with normal pump operation during a pump stroke, (b) a time range associated with a shortened pump stroke, (c) a time range associated with a prolonged pump stroke, (d) a time range associated with normal pump operation during a suction stroke, (e) a time range associated with a shortened suction stroke, and (f) a time range associated with a prolonged suction stroke, where the controller being adapted to compare the determined time lapsed with the defined time range(s) and perform an action corresponding to the time range associated with the determined time lapsed. Depending on the state of the pump a given time range may define different conditions, e.g. during priming of the pump and during normal operation of the pump, a given range may correlate to different situations. Further time ranges may be defined based upon the above time ranges, e.g. for each time range a lower and an upper time range may be defined, or the different time ranges may be used to calculate combined time ranges, e.g. a sum or difference of two ranges or an average of two ranges.
Such a combination may further comprise a reservoir adapted to contain a fluid drug, the reservoir comprising an outlet in fluid communication with, or being adapted to be arranged in fluid communication with, the pump inlet. The combination may further comprise a transcutaneous access device comprising a pointed end adapted to penetrate the skin of a subject, the access device comprising an inlet in fluid communication with, or being adapted to be arranged in fluid communication with, the pump outlet. For such a device the different time ranges (a)-(f) may be used to detect different conditions during operation of the pump. For example, (a) may be used to indicate normal pump operation, (b) to indicate that air is pumped instead of liquid, e.g. during priming of the pump or when the pump is sucking air due to a leak, or that the inlet valve is malfunctioning (c) to indicate a further occlusion situation, e.g. more severe, (d) to indicate normal pump chamber filling during operation, (e) to indicate inlet valve malfunctioning, and (f) to indicate that a non-vented reservoir is close to empty. As indicated, the time ranges are associated with a given actuation force, such that it may be necessary to have two or more sets of ranges if it is desirable to operate the actuation means at different levels. For example, a coil-magnet actuator may be operated at different current levels, e.g. 1V, 2V and 3V dependent upon the operational requirements. The actuator may start operate e.g. a pump at 1V and if an occlusion situation is detected, the current may be raised to overcome the obstruction. Indeed, for such a higher current a different set of time ranges will be relevant.
The present invention also provides a method for operating a pump having a moveable pump member, comprising the steps of (i) actuating the pump member between first and second positions, (ii) determining the time lapsed when the pump member is moved between the first and second positions in a given direction and under given conditions, (iii) comparing the determined time lapsed with one or more defined time ranges, and (iv) performing an action corresponding to the time range associated with the determined time lapsed. One or more time ranges may either be predetermined or calculated on basis of previously determined times lapsed. The pump may comprise an inlet in fluid communication with a liquid filled reservoir, and an outlet in fluid communication with a transcutaneous access device, wherein the defined time range(s) is/are associated with one or more of the following conditions, an empty or near-empty reservoir, pumping of air, pumping of liquid, obstruction of the inlet, obstruction of the outlet, obstruction of the transcutaneous access device, and pump malfunctioning.
The invention also provides a method of controlling an actuator member, comprising the steps of (i) providing an actuator member suitable for moving a structure, the actuator member having a first position and a second position, (ii) providing an actuator for moving the actuator member between the first and second positions, (iii) providing a detector for detecting the first respectively the second position and supplying time signals indicative thereof, (iv) providing a controller comprising information representing at least one defined time range, each time range being associated with movement of the actuator member in a given direction between the first and second positions and a given actuation force, (v) actuating the actuator to thereby move the actuation member, (vi) supplying time signals to the controller, (vii) determining on the basis of supplied time signals the time lapsed when the actuator member is moved between the first and second positions in a given direction, (viii) comparing the determined time lapsed with one or more defined time ranges, and (ix) performing a control action corresponding to the time range associated with the determined time lapsed.
For many mechanical systems static frictional forces will be relevant. If this is the case in a given system operated by the above-described actuator system, it may be desirable to “ramp up” the actuation force to thereby prevent “overshoot” and thereby too fast movement between the two positions which would render it more difficult to discriminate between different conditions.
A further strategy to detect an occlusion situation for a pump is based on the principle of detecting the force (or a value representative thereof) necessary to move the pump actuator away from the first (i.e. initial) position. By slowly ramping up the force (e.g. current through a coil) it will be possible to detect the force necessary to overcome a static friction force as well as the pressure in the system. In this way the current may be utilized to detect an occlusion situation. Further, when an initially empty pump is primed, air is pumped having a very low viscosity which can be used to detect properties of the pump system, e.g. static friction and elastic properties of a pump membrane. For example, when the pump is primed the energy necessary for driving the pump membrane between its initial and actuated positions can be determined. When subsequently the energy necessary for driving the pump membrane between its initial and actuated positions when liquid is pumped is determined, the difference between the energies can be used to calculate the energy used for the pump work and thus the pressure in the pump system. When liquid is pumped under normal operation conditions, pump actuation may be controlled to achieve pump time cycles under which the pump operates most efficiently, e.g. to ensure that the valves operate efficiently with minimum back-flow.
As used herein, the term “drug” is meant to encompass any drug-containing flowable medicine capable of being passed through a delivery means such as a hollow needle in a controlled manner, such as a liquid, solution, gel or fine suspension. Representative drugs include pharmaceuticals (including peptides, proteins, and hormones), biologically derived or active agents, hormonal and gene based agents, nutritional formulas and other substances in both solid (dispensed) and liquid form. In the description of the exemplary embodiments reference will be made to the use of insulin. Correspondingly, the term “subcutaneous” infusion is meant to encompass any method of parenteral delivery to a subject.
In the following the invention will be further described with references to the drawings, wherein
In the figures like reference numerals are used to mainly denote like or similar structures.
When in the following terms as “upper” and “lower”, “right” and “left”, “horizontal” and “vertical” or similar relative expressions are used, these only refer to the appended figures and not to an actual situation of use. The shown figures are schematic representations for which reason the configuration of the different structures as well as their relative dimensions are intended to serve illustrative purposes only.
More specifically, a pump actuator 1 comprises an upper housing member 10 and a lower housing member 20, both comprising a distal main portion 11, 21 and a therefrom extending proximal arm portion 12, 22. On an upper surface of the lower main portion a pair of opposed walls 23, 24 are arranged and at the proximal end of the lower arm a post member 25 and a knife-edge member 26 are arranged perpendicularly to the general plane of the lower arm. In an assembled state the two main portions form a housing in which a pair of magnets 40, 41 is arranged on the opposed upper and lower inner surfaces of the main portions. The pump actuator further comprises a lever 30 having a proximal end 31 comprising first and second longitudinally offset and opposed joint structures in the form of a groove 33 and a knife-edge 34 arranged perpendicular to a longitudinal axis of the lever, and a distal end 32 with a pair of gripping arms 35 for holding a coil member 36 wound from a conductor. A membrane pump is arranged in a pump housing 50 having a bore in which an actuation/piston rod 51 is arranged, the rod serving to actuate the pump membrane of the membrane pump (see below for a more detailed description of the membrane pump). The outer free end of the rod is configured as a substantially planar surface 52. In an assembled state the lever is arranged inside the housing with the coil positioned between the two magnets, and the housing is attached to the pump housing with the knife-edge of the knife-edge member 26 nested in the lever groove 33 and the knife-edge of the lever is positioned on the planar rod end surface, this arrangement providing first and second pivoting joints. As the actuating rod is biased outwardly by the elastic pump membrane the lever is held in place by the two joints and the housing in combination, the lever only being allowed to pivot relative to the first joint (see also below). Due to this arrangement a gearing of the force provided from the coil-magnet actuator to the actuation rod is realized, the gearing being determined by the distance between the two pivoting joints (i.e. a first actuator arm) and the distance between the first/proximal pivoting joint and the “effective” position of the coil on the lever (i.e. a second actuator arm). By the term “effective”, the issue is addressed that the force generated by the coil actuator may vary as a function of the rotational position of the lever, this being due to the fact that the coil is moved between stationary magnets, which may result in a varying magnetic field for the coil as it is moved. The actuator further comprises a pair of contact members 28, 29 adapted to cooperate with a contact rod 37 mounted in the housing and which will be described with reference to
In the
In
With reference to
In an assembled state as shown in
In the cross-sectional view of
In order to provide electrical connections between the electrical components of the actuator, i.e. the contact members and the coil, and controller circuitry (see
As appears from the above, the two contact/stop members serve to control the stroke volume of the pump, however, they may also be used to control operation and performance of the actuated component (e.g. a pump) and the system/device in which it is embedded. More specifically, such information can be retrieved by detecting the time lapsed for moving the lever between its initial and actuated position. In the following this principle will be illustrated by means of a skin-mountable drug delivery device comprising a drug-filled reservoir, a pump and a transcutaneous access device. Before turning to the control system, an illustrative drug delivery device will be described in detail.
More specifically,
The patch unit comprises first and second openings 415, 416 which may be open or covered by needle penetratable membranes allowing the transcutaneous access device to be provided in a sterile unit inside a sealed patch unit. The transcutaneous access device is in the form of a hollow needle comprising a first needle portion 413 having a first pointed end adapted to penetrate the skin of the subject, the first needle portion extending generally perpendicular to the mounting surface, and a second needle portion 414 in fluid communication with the first needle portion via an intermediate needle portion 415 and having a second pointed end, the second needle portion being arranged substantially in parallel with the mounting surface. The needle is connected to the housing by a mounting means allowing the needle to pivot corresponding to an axis defined by the second needle portion, whereby the needle is moveable between an initial sterile position in which the first needle portion is retracted relative to the mounting surface, and a second position in which the pointed end of the first needle portion projects through the second opening. Alternatively, a soft cannula with an insertion needle may be used in place of the hollow needle, see for example U.S. application 60/635,088 which is hereby incorporated by reference.
The housing further comprises actuation means (not shown) for moving the needle between a retracted and an extended state, and retraction means (not shown) for moving the needle between the extended and a retracted position. The actuation and retraction means are actuated by gripable first and second strip members 421, 422 connected to the respective means through slot-formed openings in the housing, of which the slot 423 for the first strip can be seen. The second strip is further connected to the patch member 432. Arranged on the housing is user-actuatable male coupling means 440 in the form of a pair of resiliently arranged hook members adapted to cooperate with corresponding female coupling means 455 on the pump unit. The housing further comprises an actuator 425 for establishing fluid communication between the pump assembly and the reservoir (see below), and mechanical communication means 426 for activating and de-activating the expelling means.
The pump unit 450 comprises a housing 451 in which a reservoir and expelling means are arranged, the expelling means comprising a pump and actuator assembly 470 of the type described with reference to
The control and pump/actuation means, which may be arranged on a PCB or flex-print, comprises in addition to the pump and actuator assembly 470, a microprocessor 483 for controlling, among other, the pump actuation, a contact switch 484 cooperating with the communication means 426 on the patch unit, signal generating means 485 for generating an audible and/or tactile signal, and an energy source 486.
The controller comprises a PCB or flex-print to which are connected a microprocessor 583 for controlling, among other, the pump actuation, contacts 588, 589 cooperating with corresponding contact actuators on the patch unit or the remote unit (see below), position detectors in the actuator, signal generating means 585 for generating an audible and/or tactile signal, a display (if provided), a memory, a transmitter and a receiver allowing the pump unit to communicate with an wireless remote control unit. An energy source 586 provides energy. The contacts may be protected by membranes which may be formed by flexible portions of the housing.
With reference to
With reference to
In
The pump further comprises a fluid connector in the form of hollow connection needle 350 slidably positioned in a needle chamber 360 arranged behind the connection opening, see
The above-described pump assembly may be provided in a drug delivery device of the types shown in
As appears, when the two units are disconnected, the proximal end 532 of the infusion needle is withdrawn from the pump outlet whereas the connection needle permanently provides fluid communication between the pump and the reservoir.
Turning to the above-mentioned operation and performance control by means of elapsed time detection for actuator lever movement between an initial and an actuated position or vice versa,
Turning to “normal” operation conditions, the lapsed time for movement between the initial and the actuated position (or between the actuated and the initial position) is calculated and compared with set time value ranges (e.g. pre-set or calculated ranges). Depending on the relation between the time lapsed and the set time value ranges a given pre-defined signal (or non-signal) is output from the processor which may then be utilized to perform a given action relevant for the device or system in which the actuator and control system is implemented.
Whereas a general example of an actuator operation and performance control principle has been described above, a more specific implementation of the principle will be described with reference to a drug delivery device of the type described above.
During operation of the pump after priming of an initially empty pump, liquid drug is sucked from the flexible reservoir into the pump chamber as the piston/actuator returns from an actuated to an initial position, whereas liquid drug is pumped from the pump chamber out through the transcutaneous access device as the piston/actuator is moved from the initial to the actuated position. During normal operation of the pump the time used for both of these pump strokes can be assumed to be near-constant as the conditions remain substantially unchanged. However, during operation of the pump certain conditions may arise which will influence operation of the pump and thereby potentially also of the amount of drug delivered. A major concern associated with infusion of drugs is occlusion of the access device.
A problem with existing drug delivery pumps is their ability to detect occlusions, especially when the pump is used for low flow applications. The problem is caused by the combination of low flow and compliance of the pump as it can take several hours for a blocked pump to build up enough pressure before the occlusion detector gives an alarm. Many traditional delivery pumps are compliant because the reservoir is part of the pump mechanism and/or because the fluid passage from the pump to the point of delivery (e.g. the distal end of an infusion needle) is compliant.
Using a membrane pump as a suction pump in a drug delivery device, a hydraulically much stiffer system can be achieved as the reservoir is “behind” the pump. Correspondingly, by also paying attention to the compliance of the outlet portion of the system a very stiff system may be provided such that an eventual occlusion will give an instant pressure increase, making it possible to alarm the user of an occlusion significantly faster than with traditional pumps. However, instead of providing an additional pressure sensor, the present invention can utilize that occlusion downstream of the pump will result in longer pump cycles for the outlet stroke given the same force is applied from the pump membrane actuator.
A further condition that would be desirable to detect would be under-dosing due to backflow of drug to the reservoir during the expelling stroke in case of malfunctioning of the inlet valve, e.g. when drug particles are captured in the valve. For such a condition it can be expected that the outlet stroke cycle will be shorter as a portion of the drug in the pump chamber is pumped backwards through the open inlet valve. In addition, this situation may also result in a shortened suction stroke as flow resistance through the open inlet valve may be reduced. On the other hand, in case of (partial) inlet valve occlusion, the suction stroke will result in longer cycle times. A longer suction stroke time may also be indicative of the reservoir being (close to) empty.
As the pump unit of
The processor should be adapted for compensating for “normal” bounce of the sensors/switches, however, excessive bouncing may be registered as a malfunctioning condition. Further, registering passive movement of the actuator during non-actuated periods may also be utilized to register a malfunctioning condition.
With reference to
In order to get very tight valves the surfaces of the valve seats as well as the rubber membranes are polished. This leads to sticking between the valve seat and the membrane. This phenomenon was reflected on the pump stroke duration measurements as shown in
Dependent upon the actual design of a given pump, it may be found that there is only minimal variation between the pumps and that substantially the same time values are detected when pumping e.g. dry or wet. For such a pump design it may be desirable to use pre-set time ranges. However, for a different pump design there may be some variation between the individual pumps for which reason it may be desirable to calculate a set of time ranges for the individual pump based on well-defined pump conditions. For example, if the pump characteristics are different for a dry and a wet pump as shown in
In the above embodiments the time lapsed between two end positions is measured, however, one or more additional contacts may be provided to provide further information in respect of actuator movement during an actuator stroke and thereby allowing the system to detect a further number of conditions. The additional contacts may be without mechanical contact (e.g. optical or magnetic) in order not to impair free movement of the actuator. Thus, for any additional contact one or more additional sets of defined time ranges may be defined, each time range being associated with movement of the actuator member in a given direction between two given positions and a given actuation force. For example, a near-initial switch could be used to continuously estimate characteristics which are more related to pump/membrane properties than pump resistance, e.g. altering of the pump membrane properties due to prolonged contact with a given drug. In this it will be possible to adapt the pump actuation to the new pump properties.
In the above examples the relation between pump actuation and pump member movement has been discussed, however, during normal operation of an infusion pump the user will normally not relate to the actual pump stroke pattern as dispensing of drug may be based on volume, e.g. an amount measured in ml or a rate measured in ml per hour, or it may be based on units of active drug in a given formulation, e.g. a bolus of insulin measured in units, or an infusion rate of insulin measured in units per hour, which is then used to calculate the corresponding number and the pattern for actuation of the coil.
In addition to the above principles for detection of pump/actuator conditions, by measuring the delivered energy to empty the pump chamber it is possible to calculate the relative counter pressure in the pump. This energy can be measured by obtaining the integral of current*voltage by time for the movement or it can be calculated by counting the number of necessary current pulses or the number of timeslots necessary to move the piston from top to bottom or simply as the time duration if DC current and DC voltage are applied. Indeed, in order to determine pressure based on e.g. P*V the energy consumed by e.g. friction and initial pump stretching should be deducted. The calculated counter pressure or a specific limit for delivered energy to empty the pump chamber can be used as an indication of occlusion and used as a trigger for an occlusion alarm signal. The calculated counter pressure can also be used to compensate for mechanical counter pressure sensitivity in the volumetric accuracy of the pump system by changing the pump frequency depending on the counter pressure or the time duration to the next pump stroke. As for the expelling-stroke energy also the energy for the suction-stroke can be measured in case the pump is actuated correspondingly. This can also be used to indicate abnormal behaviour in the pump system including the valves. The calculated counter pressure can be used to decide and optimise the control of the next piston movement during the stroke assuming a slow counter pressure variation by time, e.g. size of current or slope in current ramp or duty cycle in pulse width modulation of current.
Instead of extra contacts/switches for initial, actuated and in-between positions, the system can be designed to monitor the driving power of the piston excitation system during the movement of the piston, e.g. timely monitoring of the current and/or the voltage or a special electrical measuring signal (e.g. AC signal) can be superposed on the driving signal and the corresponding signals generated can be picked up by an additional coil.
When the pump described with reference to
Referring to
Although a linear voltage-time relationship is shown in
In the above description of the exemplary embodiments, the different structures providing the described functionality for the different components have been described to a degree to which the concepts of the present invention will be apparent to the skilled reader. The detailed construction and specification for the different structures are considered the object of a normal design procedure performed by the skilled person along the lines set out in the present specification. For example, the individual components for the disclosed embodiments may be manufactured using materials suitable for medical use and mass production, e.g. suitable polymeric materials, and assembled using cost-effective techniques such as bonding, welding, adhesives and mechanical interconnections.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2004 00507 | Mar 2004 | DK | national |
This application is a continuation of international application no. PCT/DK2005/000185 filed Mar. 18, 2005 and claims priority of Danish application no. PA 2004 00507 filed Mar. 30, 2004 and U.S. provisional application Ser. No. 60/564,164 filed Apr. 21, 2004 all of which are hereby incorporated by reference.
| Number | Name | Date | Kind |
|---|---|---|---|
| 2605765 | Kollsman | Aug 1952 | A |
| 2960097 | Dessau | Jan 1957 | A |
| 2980032 | Schneider | Feb 1959 | A |
| 3705601 | Arisland | Dec 1972 | A |
| 4016879 | Mellor | Apr 1977 | A |
| 4077405 | Haerten et al. | Mar 1978 | A |
| 4137020 | Ito et al. | Jan 1979 | A |
| 4245634 | Albisser et al. | Jan 1981 | A |
| 4262824 | Hrynewycz | Apr 1981 | A |
| 4340048 | Eckenhoff | Jul 1982 | A |
| 4370305 | Affonso | Jan 1983 | A |
| 4378015 | Wardlaw | Mar 1983 | A |
| 4399824 | Davidson | Aug 1983 | A |
| 4402407 | Maly | Sep 1983 | A |
| 4519792 | Dawe | May 1985 | A |
| 4529401 | Leslie et al. | Jul 1985 | A |
| 4544369 | Skakoon et al. | Oct 1985 | A |
| 4552561 | Eckenhoff et al. | Nov 1985 | A |
| 4645491 | Evans | Feb 1987 | A |
| 4657490 | Abbott | Apr 1987 | A |
| 4710170 | Haber et al. | Dec 1987 | A |
| 4734092 | Millerd | Mar 1988 | A |
| 4753651 | Eckenhoff | Jun 1988 | A |
| 4755173 | Konopka et al. | Jul 1988 | A |
| 4788556 | Hoisington et al. | Nov 1988 | A |
| 4871351 | Feingold | Oct 1989 | A |
| 4877034 | Atkins et al. | Oct 1989 | A |
| 4886499 | Cirelli et al. | Dec 1989 | A |
| 4894054 | Miskinyar | Jan 1990 | A |
| 4928528 | Marques | May 1990 | A |
| 4994078 | Jarvik | Feb 1991 | A |
| 5008110 | Benecke et al. | Apr 1991 | A |
| 5049146 | Bringham et al. | Sep 1991 | A |
| 5076890 | Balembois | Dec 1991 | A |
| 5122116 | Kriesel et al. | Jun 1992 | A |
| 5122201 | Frazier et al. | Jun 1992 | A |
| 5149340 | Waycuilis | Sep 1992 | A |
| 5169390 | Athayde et al. | Dec 1992 | A |
| 5211201 | Kamen et al. | May 1993 | A |
| 5224843 | van Lintel | Jul 1993 | A |
| 5256157 | Samiotes et al. | Oct 1993 | A |
| 5336052 | Zollner et al. | Aug 1994 | A |
| 5390671 | Lord et al. | Feb 1995 | A |
| 5391950 | Krawczak | Feb 1995 | A |
| 5482473 | Lord et al. | Jan 1996 | A |
| 5485917 | Early | Jan 1996 | A |
| 5494415 | Morita | Feb 1996 | A |
| 5514095 | Brightbill et al. | May 1996 | A |
| 5527287 | Miskinyar | Jun 1996 | A |
| 5527288 | Gross et al. | Jun 1996 | A |
| 5568806 | Cheney, II et al. | Oct 1996 | A |
| 5584808 | Healy | Dec 1996 | A |
| 5584813 | Livingston et al. | Dec 1996 | A |
| 5586085 | Lichte | Dec 1996 | A |
| 5609572 | Lang | Mar 1997 | A |
| 5647853 | Feldmann et al. | Jul 1997 | A |
| 5720391 | Dohm et al. | Feb 1998 | A |
| 5776109 | Urrutia | Jul 1998 | A |
| 5814020 | Gross | Sep 1998 | A |
| 5851197 | Marano et al. | Dec 1998 | A |
| 5858001 | Tsals et al. | Jan 1999 | A |
| 5860952 | Quinn | Jan 1999 | A |
| 5913856 | Chia et al. | Jun 1999 | A |
| 5925017 | Kriesel et al. | Jul 1999 | A |
| 5928194 | Maget | Jul 1999 | A |
| 5931814 | Alex et al. | Aug 1999 | A |
| 5941611 | Trzmiel et al. | Aug 1999 | A |
| 5954643 | VanAntwerp et al. | Sep 1999 | A |
| 5957895 | Sage et al. | Sep 1999 | A |
| 5968011 | Larsen et al. | Oct 1999 | A |
| 5997501 | Gross et al. | Dec 1999 | A |
| 6045534 | Jacobsen et al. | Apr 2000 | A |
| 6060319 | Deetz et al. | May 2000 | A |
| 6074369 | Sage et al. | Jun 2000 | A |
| 6083196 | Trautman et al. | Jul 2000 | A |
| 6088619 | Hein et al. | Jul 2000 | A |
| 6099512 | Urrutia | Aug 2000 | A |
| 6120492 | Finch et al. | Sep 2000 | A |
| 6123519 | Kato et al. | Sep 2000 | A |
| 6126637 | Kriesel et al. | Oct 2000 | A |
| 6132755 | Eicher et al. | Oct 2000 | A |
| 6165155 | Jacobsen et al. | Dec 2000 | A |
| 6241704 | Peterson et al. | Jun 2001 | B1 |
| 6270478 | Mernøe | Aug 2001 | B1 |
| 6280148 | Zengerle et al. | Aug 2001 | B1 |
| 6293925 | Safabash et al. | Sep 2001 | B1 |
| 6302866 | Marggi | Oct 2001 | B1 |
| 6302869 | Klitgaard | Oct 2001 | B1 |
| 6358731 | Hsu | Mar 2002 | B1 |
| 6364865 | Lavi et al. | Apr 2002 | B1 |
| 6485461 | Mason et al. | Nov 2002 | B1 |
| 6500150 | Gross et al. | Dec 2002 | B1 |
| 6551276 | Mann et al. | Apr 2003 | B1 |
| 6554791 | Cartledge et al. | Apr 2003 | B1 |
| 6555986 | Moberg | Apr 2003 | B2 |
| 6558351 | Steil et al. | May 2003 | B1 |
| 6589229 | Connelly et al. | Jul 2003 | B1 |
| 6613015 | Sandstrom et al. | Sep 2003 | B2 |
| 6622037 | Kasano | Sep 2003 | B2 |
| 6656159 | Flaherty | Dec 2003 | B2 |
| 6716192 | Orosz | Apr 2004 | B1 |
| 6740059 | Flaherty | May 2004 | B2 |
| 6749587 | Flaherty | Jun 2004 | B2 |
| 6808691 | Herve et al. | Oct 2004 | B1 |
| 6818178 | Kohl et al. | Nov 2004 | B2 |
| 6878136 | Fleury et al. | Apr 2005 | B2 |
| 6949084 | Marggi et al. | Sep 2005 | B2 |
| 6960192 | Flaherty et al. | Nov 2005 | B1 |
| 7052483 | Wojcik | May 2006 | B2 |
| 7070580 | Nielsen | Jul 2006 | B2 |
| 7097631 | Trautman et al. | Aug 2006 | B2 |
| 7097690 | Usher et al. | Aug 2006 | B2 |
| 7141023 | Diermann et al. | Nov 2006 | B2 |
| 7144384 | Gorman et al. | Dec 2006 | B2 |
| 7303073 | Raynal-Olive et al. | Dec 2007 | B2 |
| 7744570 | Fangrow | Jun 2010 | B2 |
| 20010025168 | Gross et al. | Sep 2001 | A1 |
| 20020040083 | Kuwaki et al. | Apr 2002 | A1 |
| 20020040208 | Flaherty et al. | Apr 2002 | A1 |
| 20020055711 | Lavi et al. | May 2002 | A1 |
| 20020064468 | Wade | May 2002 | A1 |
| 20020123740 | Flaherty et al. | Sep 2002 | A1 |
| 20020161332 | Ramey | Oct 2002 | A1 |
| 20020169416 | Gonnelli et al. | Nov 2002 | A1 |
| 20030009131 | Van Antwerp et al. | Jan 2003 | A1 |
| 20030009133 | Ramey | Jan 2003 | A1 |
| 20030029501 | Williamson et al. | Feb 2003 | A1 |
| 20030060781 | Mogensen et al. | Mar 2003 | A1 |
| 20030065308 | Lebel et al. | Apr 2003 | A1 |
| 20030069546 | Sandstrom et al. | Apr 2003 | A1 |
| 20030073952 | Flaherty et al. | Apr 2003 | A1 |
| 20030088238 | Poulsen et al. | May 2003 | A1 |
| 20030114797 | Vaillancourt et al. | Jun 2003 | A1 |
| 20030135159 | Daily et al. | Jul 2003 | A1 |
| 20030167035 | Flaherty et al. | Sep 2003 | A1 |
| 20030187395 | Gabel et al. | Oct 2003 | A1 |
| 20030194328 | Bryant et al. | Oct 2003 | A1 |
| 20030199823 | Bobroff et al. | Oct 2003 | A1 |
| 20030216686 | Lynch et al. | Nov 2003 | A1 |
| 20030236498 | Gross et al. | Dec 2003 | A1 |
| 20040051674 | Mahringer | Mar 2004 | A1 |
| 20040087240 | Chen et al. | May 2004 | A1 |
| 20040098068 | Carbunaru et al. | May 2004 | A1 |
| 20040115068 | Hansen et al. | Jun 2004 | A1 |
| 20040116905 | Pedersen et al. | Jun 2004 | A1 |
| 20040127844 | Flaherty | Jul 2004 | A1 |
| 20040158207 | Hunn et al. | Aug 2004 | A1 |
| 20040162521 | Bengtsson | Aug 2004 | A1 |
| 20040171403 | Mikkola | Sep 2004 | A1 |
| 20040199123 | Nielsen | Oct 2004 | A1 |
| 20040204673 | Flaherty et al. | Oct 2004 | A1 |
| 20040220497 | Findlay et al. | Nov 2004 | A1 |
| 20040220536 | VanTassel et al. | Nov 2004 | A1 |
| 20040260233 | Garibotto et al. | Dec 2004 | A1 |
| 20050006309 | Effenhauser et al. | Jan 2005 | A1 |
| 20050022274 | Campbell et al. | Jan 2005 | A1 |
| 20050077225 | Usher et al. | Apr 2005 | A1 |
| 20050101933 | Marrs et al. | May 2005 | A1 |
| 20050171513 | Mann et al. | Aug 2005 | A1 |
| 20050203461 | Flaherty et al. | Sep 2005 | A1 |
| 20050240154 | Mogensen et al. | Oct 2005 | A1 |
| 20060015063 | Butikofer et al. | Jan 2006 | A1 |
| 20060017576 | Gordon et al. | Jan 2006 | A1 |
| 20060020300 | Nghiem et al. | Jan 2006 | A1 |
| 20060142698 | Ethelfeld | Jun 2006 | A1 |
| 20060200073 | Radmer et al. | Sep 2006 | A1 |
| 20060264835 | Nielsen et al. | Nov 2006 | A1 |
| 20070021733 | Hansen et al. | Jan 2007 | A1 |
| 20070073228 | Mernoe et al. | Mar 2007 | A1 |
| 20070104596 | Preuthun et al. | May 2007 | A1 |
| 20070112301 | Preuthun et al. | May 2007 | A1 |
| 20080009805 | Ethelfeld | Jan 2008 | A1 |
| 20090163874 | Krag et al. | Jun 2009 | A1 |
| Number | Date | Country |
|---|---|---|
| 2239457 | Dec 1999 | CA |
| 1612758 | May 2005 | CN |
| 2552446 | May 1977 | DE |
| 10255817 | Jun 2004 | DE |
| PA 2003 00696 | May 2003 | DK |
| PA 2003 00697 | May 2003 | DK |
| 568176 | Nov 1993 | EP |
| 398583 | Apr 1994 | EP |
| 937475 | Aug 1999 | EP |
| 1177802 | Jul 2000 | EP |
| 1256356 | Nov 2002 | EP |
| 1329233 | Jul 2003 | EP |
| 1475113 | Nov 2004 | EP |
| 1527792 | May 2005 | EP |
| 2020735 | May 1978 | GB |
| 2212387 | Jul 1989 | GB |
| 2000-104659 | Apr 2000 | JP |
| 2000-513259 | Oct 2000 | JP |
| 2000-515394 | Nov 2000 | JP |
| 2002-505601 | Feb 2002 | JP |
| WO 9007942 | Jul 1990 | WO |
| WO 9607397 | Mar 1996 | WO |
| WO 9630679 | Oct 1996 | WO |
| WO 9721457 | Jun 1997 | WO |
| WO 9857683 | Dec 1998 | WO |
| WO 9962576 | Dec 1999 | WO |
| WO 0202165 | Jan 2002 | WO |
| WO 0204048 | Jan 2002 | WO |
| WO 0205889 | Jan 2002 | WO |
| WO 0215889 | Feb 2002 | WO |
| WO 0215965 | Feb 2002 | WO |
| WO 0240083 | May 2002 | WO |
| WO 0245574 | Jun 2002 | WO |
| WO 0247746 | Jun 2002 | WO |
| WO 02055132 | Jul 2002 | WO |
| WO 02070024 | Sep 2002 | WO |
| WO 02081012 | Oct 2002 | WO |
| WO 02100457 | Dec 2002 | WO |
| WO 03026726 | Apr 2003 | WO |
| WO 03026728 | Apr 2003 | WO |
| WO 03080169 | Oct 2003 | WO |
| WO 03089028 | Oct 2003 | WO |
| WO 03090509 | Nov 2003 | WO |
| WO 03099358 | Dec 2003 | WO |
| WO 2004009160 | Jan 2004 | WO |
| WO 2004009160 | Jan 2004 | WO |
| 2004029457 | Apr 2004 | WO |
| WO 2004030728 | Apr 2004 | WO |
| WO 2004098682 | Nov 2004 | WO |
| WO 2004098683 | Nov 2004 | WO |
| WO 2004098684 | Nov 2004 | WO |
| WO 2004101071 | Nov 2004 | WO |
| WO 2005002649 | Jan 2005 | WO |
| WO 2005011779 | Feb 2005 | WO |
| WO 2005025652 | Mar 2005 | WO |
| WO 2005037185 | Apr 2005 | WO |
| WO 2005037350 | Apr 2005 | WO |
| WO 2005039673 | May 2005 | WO |
| WO 2005094919 | Oct 2005 | WO |
| WO 2005123186 | Dec 2005 | WO |
| WO 2005123189 | Dec 2005 | WO |
| WO 2006060277 | Jun 2006 | WO |
| WO 2006067217 | Jun 2006 | WO |
| WO 2006077263 | Jul 2006 | WO |
| WO 2006089958 | Aug 2006 | WO |
| WO 2006120253 | Nov 2006 | WO |
| WO 2006123329 | Nov 2006 | WO |
| WO 2007122207 | Nov 2007 | WO |
| WO 2009021950 | Feb 2009 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20070104596 A1 | May 2007 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60564164 | Apr 2004 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/DK2005/000185 | Mar 2005 | US |
| Child | 11541348 | US |
