WO2009144625A1

WO2009144625A1 - Implantable drug delivery device with dosage control

Info

Publication number: WO2009144625A1
Application number: PCT/IB2009/052096
Authority: WO
Inventors: Ventzeslav P. Iordanov; Michel P. B. Van Bruggen; Hendrika C. Krijnsen; Fransciscus J. L. Everaerts
Original assignee: Koninklijke Philips Electronics N.V.
Priority date: 2008-05-28
Filing date: 2009-05-20
Publication date: 2009-12-03

Abstract

An implantable drug delivery device (10, 30) is provided, comprising a reservoir(14) for storing reservoirfluid and a plurality of capsules (20), the capsules (20) comprising medicine, the outer surface of the capsules (20) being made of a water degradable materialthat does not dissolve in the reservoirfluid. The device (10, 30) further comprises an actuator (13) for initiating release of a capsule (20) of the pluralityofcapsules (20) from the 5 device (10, 30), a valve (17) for controlling the release of the capsule (20) and processing electronics (12) being arranged for controlling the actuator (13) and the valve (17).

Description

Implantable drug delivery device with dosage control

FIELD OF THE INVENTION

This invention relates to an implantable drug delivery device comprising a reservoir for storing encapsulated medicine, an actuator for initiating release of the medicine and processing electronics for controlling the actuator.

BACKGROUND OF THE INVENTION

In recent years drug delivery systems have been developed to optimize the therapeutic properties of drug products and render them more safe, effective, and reliable. For pharmaceutical companies, novel drug delivery technologies provide a strategic tool for expanding their existing markets, e.g. by extending product life, improved performance and acceptability, increased efficacy and patient compliance. The ability to accurately deliver therapeutic agents has been a major goal in drug delivery research over the last two decades. Implantable drug delivery systems rely on a wide range of techniques, including osmotically driven pumps, diffusion or erosion rates, non-uniform drug loading profiles etc. These devices and delivery methods require that the drugs are carefully pre-mixed and stored in a liquid form. Many therapeutic proteins and other bio molecules are however marginally stable in aqueous solutions. It would therefore be preferable to store the medicine as dry solids.

An implantable drug delivery device with controlled drug release is described in US patent 6,458,118, which describes an implantable drug delivery device comprising drugs contained within capsules. Using capsules enables storing the drugs in solid form. The device further comprises a reservoir with a carrier fluid that will dissolve the drug when freed from the capsule, a drug releaser for freeing the microencapsulated drug from the capsule and an electromechanical pump to convey the dissolved drug to a catheter, through which the drug is delivered to a target site within a patient. This device has several disadvantages. First, in addition to an electromechanical pump for releasing the drug from the device, the device further comprises a drug releaser for releasing the drug from the capsule. This makes the construction of the device complex, more expensive and larger, while increasing the chance of operation failures. Furthermore, the use of drug capsules results in waste material accumulating in the device. A third problem is that it is not possible to accurately control the amount of drugs released from the capsules, dissolved in the carrier fluid and delivered by the device.

OBJECT OF THE INVENTION It is an object of the invention to provide an implantable drug delivery device enabling more accurate control of the drug dosage.

SUMMARY OF THE INVENTION

According to a first aspect of the invention, this object is achieved by providing an implantable drug delivery device comprising a reservoir for storing reservoir fluid and a plurality of capsules, the capsules comprising medicine, the outer surface of the capsules being made of a water degradable material that does not dissolve in the reservoir fluid. The device further comprises an actuator for initiating release of a capsule of the plurality of capsules from the device, a valve for controlling the release of the capsule and processing electronics being arranged for controlling the actuator and the valve.

According to the invention, the drug is not released from the capsule until the capsule is released from the device. The valve controls the release of the capsules. When the capsule enters the aqueous environment of the body fluid (e.g. blood, cerebrospinal fluid) outside the device, the capsule material dissolves in the body fluid and the medicine is set free from the capsule. Because the medicine is still in the capsule when the capsule leaves the device, the amount of medicine released is exactly the amount of medicine that was stored in the capsule. This makes it possible to regulate the amount of released drugs very accurately.

It is an advantage of the device according to the invention, that it does not need a separate drug releasing mechanism. Consequently, the device is less complex, more compact and functions more reliable than the drug delivery device of US patent 6,458,118. Furthermore, because the capsule material dissolves in the aqueous environment outside the device, no waste materials accumulate in the device or poison the human body.

In a preferred embodiment the device further comprises a dose control sensor for monitoring the release of the capsule. The processing electronics are further arranged for receiving release data concerning the release of the capsule from the dose control sensor and for controlling the actuator and the valve in dependence of the release data.

This makes it possible to count the capsules passing the valve. The drug dosage can very accurately be controlled by closing the valve as soon as the intended number of capsules has passed. The drug is thus released with a known and controllable number of discrete amounts.

These and other aspects of the invention are apparent from and will be elucidated with reference to the embodiments described hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS In the drawings:

Fig. 1 shows an embodiment of an implantable drug delivery device according to the invention, Fig. 2, shows a close up of the valve and the dosing channel of the device of

Fig. 1,

Fig. 3 shows a further embodiment of an implantable drug delivery device according to the invention, and

Figs. 4a, 4b, 4c, 5a, 5, b and 5c show examples of capsules for use in devices according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

Fig. 1 shows an embodiment of an implantable drug delivery device 10 according to the invention. The device 10 comprises a reservoir 14 filled with reservoir fluid and a plurality of capsules 20. The reservoir fluid is such that it does not dissolve the material of the capsules 20. For example, the reservoir fluid may be oil-based. For use in implantable devices, a bio-compatible oil is preferable. The reservoir fluid may be in a gel or pasta form. The capsules 20 comprise a certain amount of medicine. Preferably the medicine is in solid form, because many therapeutic proteins and other bio molecules are marginally stable in aqueous solutions. Therefore, such biologies are often handled and stored as dry solids ("dry" is defined as substantially free of residual moisture). Lyophilization (freeze-drying) is a known and useful way to long-term preserve a protein structure and its activity. Traditional freeze-drying methods involve the freezing of an aqueous solution containing various stabilizing agents, followed by application of a vacuum to remove the water by sublimation, producing a dry porous solid that is relatively stable and suitable for long-term storage.

The device 10 further comprises an actuator 13, some electronic circuitry 12 and a battery 11 for powering the actuator 13 and the electronic circuitry 12. The electronic circuitry 12 controls the actuator 13. The actuator 13 causes the capsules 20 to move to the dosing channel 15. For example, the actuator 13 may be a pump for creating a flow of reservoir liquid through the reservoir 14 or a vibrating element for enhancing the diffusive movements of the capsules 20 through the reservoir 14. Many kinds of known actuators may be used for this device 10. The actuator may, e.g., be based on electromagnetic, electrochemical, physical or pure mechanical principles. A valve 17, at the end of the dosing channel 15 separates the reservoir 14 from the surroundings of the device 10. When closed, the valve 17 keeps the reservoir fluid and the capsules 20 inside the reservoir 14 and protects the device 10 from back diffusion of body fluids into the device 10. The valve 17 may be used in combination with a flow restrictor for preventing water diffusion from the environment into the device 10. When opened, the valve 17 allows capsules 20 in the dosing channel 15 to leave the device 10 and enter the aqueous tissue in which the device 10 has been implanted. In this aqueous environment, these capsule 20 dissolve and the medicine is thereby released. The release of the medicine may be realized by means of a catheter port. More than one exit ports may be provided for delivering more than one type of medicine and/or delivering the medicine at different locations inside the user. Typical dimensions of the device 10 are 20 mm in diameter (if cylindrical) and

30 mm in length. Preferably, the device 10 has round edges to prevent tissue damage near the implanted device 10. This leads to approximately 9 mL internal volume of which about 50% is used for the drug reservoir 14. The size of the reservoir 14 may of course be larger or smaller when the treatment it provides requires so. Materials that may be used for the construction of the exterior and interior of the device 10 include metals, ceramics and polymers. Metals are preferable for the bulk parts of the implant structure while ceramics and polymers are typically used at interfaces and articulating surfaces. The polymers that may be used include polyethylene, PET (Polyethylene Terephthalate), PTFE (Polytetrafluoroethylene) and polyurethane due to the fact they are well tolerated in the human body.

The battery 11 has to be well insulated. For this purpose it may be placed inside a laser welded metal case, from which one or two sheathed wires extend. As an insulation material on the wires polyurethane may be used due to the ability to create smaller diameter leads and its improved biocompatibility. Titanium may be used for the casing due to its biocompatibility while platinum and platinum- iridium electrodes may be used for their biocompatibility and resistance to galvanic corrosion. Ultra High Molecular Weight Polyethylene (UHMWPE) is used for the load-bearing surface due to its good wear resistance and low friction. Viton polymets may be used as sealing rings. Fig. 2, shows a close up of the valve 17 and the dosing channel 15 of the device 10 of Fig. 1. Close to the valve 17, the reservoir 14 narrows into the dosing channel 15 such that only one or a few capsules 20 can pass the dosing channel simultaneously. Preferably, the dosing channel 15 comprises a dose control sensor 16 for monitoring the release of the capsules 20. The dose control sensor 16 may monitor the capsule 20 release by, e.g. continuously measuring the electrical conductance in the dosing channel 15. If the dose control sensor 16 is not capable of detecting individual ones of the capsules 20 passing, it may derive an estimate of the number of capsules 20 passing from such measurements of the electrical conductance. Preferably, the dose control sensor 16 is used for counting the number of individual capsules 20 passing the channel while the valve 17 is open. Release data is communicated from the dose control sensor 16 to the processing electronics 12 and comprises, e.g., the electrical conductance in the dosing channel 15, a counted number of passing capsules 20 or just some trigger signal each time a capsule 20 passes.

Drug delivery is initiated by the processing electronics 12. The processing electronics 12 activate the actuator 11 and open the valve 17. When processing of the release data indicates that the planned amount of medicine has been released, the valve 17 is closed and the actuator may be deactivated.

Fig. 3 shows a further embodiment of an implantable drug delivery device 30 according to the invention. Most elements are the same as in the embodiment of Fig. 1. However, this embodiment comprises some additional features. The device 30 comprises internal and/or external sensor(s) 32 for detection of operation control signals and/or biological/physiological parameters. The sensor readings are processed by the processing electronics 12 for, e.g., triggering the delivery or interruption of the delivery. Wireless communication means 33 are provided for communicating sensor readings or operational information to the outside. Such operational information may comprise a device identification number, sensor data, remaining drug quantity, remaining battery power and/or error messages. Drug delivery profiles may be stored in a memory of the device 30 prior to implementation or via the wireless link 33. The system can be programmed to work in several modes like single shot delivery (possibly externally triggered), continuous flow delivery, complex profiled delivery or sensor triggered delivery.

Furthermore, the device 30 may be equipped with a septum 34, allowing drug reservoir's 14 refill. The reservoir may be refilled with capsules 20 for extending the period during which the device 30 can be used. The reservoir may also be refilled with reservoir fluid for compensating for pressure changes resulting from the release of drugs from the device 30. The device 30 may also comprise multiple reservoirs and a pressure regulating mechanism. Pressure compensation may, for example, be realized by providing a gas compartment 31 with pressurized or liquidified gas. Another way of providing pressure compensating may be to provide an opening in the device for allowing environmental matter to be sucked in when the pressure within the device decreases.

Figs. 4a, 4b, 4c, 5a, 5, b and 5c show examples of capsules for use in devices 10, 30 according to the invention. The capsules comprise water-soluble or water degradable polymeric or inorganic matrix in which the therapeutic molecules can be appropriately stabilized. Such materials systems can rely on the ingredients that are also applied in depot formulations known in the art. Although the following paragraphs mainly mention the use of microspheres composed of a polymeric matrix comprising appropriately stabilized therapeutic molecules, all other suspensions and emulsions that contain therapeutic molecules may be used in the device 10, 30 according to the invention.

Fig. 4a shows a water-soluble polymeric microsphere 40 filled with medicine 21. Preferably, the medicine is in a dry and solid form. In Fig. 4b, the medicine 21 is incorporated in the outer shell 41 of the microsphere. The inner core 42 may be hollow or filled with some liquid or solid material that can be dissolved in the human body without causing any physical problems.

Fig. 4c shows a dendrimer 43. Dendrimer molecules are symmetric macro molecules built around a small molecule or in a linear polymer core using connectors and branching units. Dendrimers are synthetic, highly branched, mono-disperse macro molecules of nanometer dimensions. The medicine 22 may be attached to the end points of the outer branches of the dendrimer 43 or may be incorporated in the dendrimer structure. The dendrimer 43 is water-soluble or water degradable, causing the medicine 22 to be released when entering the aqueous environment outside the drug delivery device 10, 30. Fig. 5a shows an example of a microsphere 51 incorporating the medicine 24 in its outer surface. In Fig. 5b, the medicine 25 is attached to the outer surface of the microsphere 52. In Fig. 5c, the medicine 26 is coupled to the microsphere 53 via a ligand 26. It should be noted that the above-mentioned embodiments illustrate rather than limit the invention, and that those skilled in the art will be able to design many alternative embodiments without departing from the scope of the appended claims. In the claims, any reference signs placed between parentheses shall not be construed as limiting the claim. Use of the verb "comprise" and its conjugations does not exclude the presence of elements or steps other than those stated in a claim. The article "a" or "an" preceding an element does not exclude the presence of a plurality of such elements. The invention may be implemented by means of hardware comprising several distinct elements, and by means of a suitably programmed computer. In the device claim enumerating several means, several of these means may be embodied by one and the same item of hardware. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

Claims

CLAIMS:

1. An implantable drug delivery device (10, 30) comprising: a reservoir (14) for storing reservoir fluid and a plurality of capsules (20), the capsules (20) comprising medicine, the outer surface of the capsules (20) being made of a water degradable material that does not dissolve in the reservoir fluid - an actuator (13) for initiating release of a capsule (20) of the plurality of capsules (20) from the device (10, 30), a valve (17) for controlling the release of the capsule (20), and processing electronics (12) being arranged for controlling the actuator (13) and the valve (17).

2. An implantable drug delivery device (10, 30) as claimed in claim 1, further comprising a dose control sensor (16) for monitoring the release of the capsule (20), the processing electronics (12) further being arranged for receiving release data concerning the release of the capsule (20) from the dose control sensor (16) and for controlling the actuator (13) and the valve (17) in dependence of the release data.

3. An implantable drug delivery device (10, 30) as claimed in claim 2, wherein the dose control sensor (16) is arranged for detecting individual ones of the capsules (20) passing the valve (17).

4. An implantable drug delivery device (10, 30) as claimed in claim 1, further comprising a memory, coupled to the processing electronics (12), for storing a dosage program, the processing electronics (12) being arranged for controlling the actuator (13) and the valve (17) in accordance with the dosage program.

5. An implantable drug delivery device (30) as claimed in claim 4, further comprising communication means (33) for receiving the dosage program.

6. An implantable drug delivery device (30) as claimed in claim 1, further comprising a body sensor (32) for monitoring a physiological parameter of a user of the implantable drug delivery device (30).

7. An implantable drug delivery device (30) as claimed in claim 6, further comprising communication means (33) for communicating the monitored physiological parameter to the user.

8. An implantable drug delivery device (30) as claimed in claim 6, wherein the body sensor (32) is coupled to the processing electronics (12) and wherein the processing electronics (12) are arranged for controlling the actuator (13) and the valve (17) in dependence of the monitored physiological parameter.

9. An implantable drug delivery device (30) as claimed in claim 1, further comprising a pressure compensating means (31) for compensating pressure variations.