Drug delivery apparatus

Abstract

Percutaneous access apparatus is described that includes a percutaneous fluid access device having an extracorporeal portion, one or more ports accessible from the extracorporeal portion and a septum for sealing each port. A connector device having one or more hollow needles is attachable to the percutaneous fluid access device. The apparatus also includes an attachment mechanism for attaching the connector device to the extracorporeal portion and an actuation mechanism that, after the connector device has been attached to the extracorporeal portion, can be used to drive the one or more hollow needles through the septum to establish fluid communication between the one or more hollow needles and the one or more ports. The apparatus may be used for neurosurgery applications.

Claims

1. A percutaneous access apparatus comprising: a percutaneous fluid access device comprising an extracorporeal portion, one or more ports accessible from the extracorporeal portion and a septum for sealing each port, and a connector device comprising a body and a needle holder holding one or more hollow needles, the needle holder being moveable within the body, wherein the apparatus includes an attachment mechanism for attaching the connector device to the extracorporeal portion, and an actuation mechanism that, after the connector device has been attached to the extracorporeal portion, can be used to move the needle holder within the body to thereby drive the one or more hollow needles through the septum to establish fluid communication between the one or more hollow needles and the one or more ports.

2. An apparatus according to claim 1, wherein the attachment mechanism comprises a first set of features on the extracorporeal portion and a second set of features on the connector device, wherein the first and second sets of features provide, when engaged, accurate alignment of the connector device with the extracorporeal portion.

3. An apparatus according to claim 1, wherein the attachment mechanism provides a kinematic, or pseudo-kinematic, connection between the extracorporeal portion and the connector device.

4. An apparatus according to claim 1, wherein the one or more hollow needles comprise a plurality of hollow needles and the one or more ports comprise a plurality of ports, wherein the attachment mechanism allows repeatable alignment of each hollow needle with a predetermined respective one of the ports.

5. An apparatus according to claim 1, wherein the attachment mechanism comprises a locking device for releasably locking the connector device to the extracorporeal portion, the connector device comprising the locking device.

6. An apparatus according to claim 5, wherein the locking device comprises a screw and a hinged engagement member, wherein tightening the screw forces the hinged engagement member into contact with the extracorporeal portion thereby locking the connector device to the extracorporeal portion.

7. An apparatus according to claim 1, wherein the needle holder is retained within an axial alignment channel formed within the connector device.

8. An apparatus according to claim 7, wherein the actuation mechanism can be actuated to drive the needle holder back and forth along the alignment channel.

9. An apparatus according to claim 8, wherein the actuation mechanism comprises a threaded shaft and a rotatable knurled hub having a threaded channel, the needle holder being attached to a distal end of the threaded shaft and the threaded shaft being retained in the threaded channel of the rotatable knurled hub, wherein rotation of the knurled hub translates the needle holder back and forth along the alignment channel.

10. An apparatus according to claim 1, wherein the percutaneous fluid access device comprises a subcutaneous base portion through which the one or more ports extend, wherein the subcutaneous base portion comprises one or more port outlets for connection to one or more implanted catheters.

11. An apparatus according to claim 1, wherein the percutaneous fluid access device comprises a subcutaneous base portion, the subcutaneous base portion being at least partially insertable into a complementary recess formed in a bone, the subcutaneous base portion comprising one or more features for gripping an internal surface of the complementary recess thereby directly anchoring the subcutaneous base portion to the bone.

12. An apparatus according to claim 1, wherein the percutaneous fluid access device comprises printed titanium.

13. An apparatus according to claim 1, wherein the one or more ports comprise a plurality of ports and the septum is a single septum provided to cover each of the plurality of ports, wherein the single septum can be accessed and removed via the extracorporeal portion of the percutaneous fluid access device.

14. A connector device for attachment to a percutaneous fluid access device having one or more ports and a septum for sealing each port, the connector device comprising: a body and a needle holder holding one or more hollow needles, the needle holder comprising a threaded shaft and being moveable within the body, an attachment mechanism for attaching the body of the connector device to an extracorporeal portion of the associated percutaneous fluid access device, and an actuation mechanism comprising an internally threaded portion that engages the threaded shaft and drives the one or more hollow needles towards the septum of the associated percutaneous fluid access device when the threaded portion is rotated to thereby provide fluid communication between the one or more hollow needles and the one or more ports of the associated percutaneous fluid access device.

15. A connector device according to claim 14, wherein the needle holder surrounds at least a portion of an outer surface of at least one of the one or more hollow needles.

Description

(1) The invention will now be described, by way of example only, with reference to the accompanying drawings in which;

(2) FIG. 1 shows a drug delivery system of the present invention,

(3) FIGS. 2a and 2b show in more detail the implanted catheters and guide tubes of FIG. 1,

(4) FIGS. 3a, 3b and 3c show the percutaneous port and the connector device respectively of the percutaneous access apparatus shown in FIG. 1,

(5) FIGS. 4a and 4b show in more detail the guide member of the connector device of FIG. 3b,

(6) FIG. 5 shows in more detail the needle holding member of the connector device of FIG. 3b,

(7) FIGS. 6a to 6d show how the connector device is secured to the percutaneous port,

(8) FIGS. 7a and 7b illustrate how turning the knurled ring of the connector device forces the needles of the needle holding member through the septa of the percutaneous port,

(9) FIGS. 8a and 8b are cross-sectional views of the illustrations of FIGS. 7a and 7b respectively,

(10) FIG. 9 illustrate a drug storage tube,

(11) FIGS. 10a and 10b show modified Luer connectors,

(12) FIG. 11 shows the Luer connectors of FIGS. 10a and 10b aligned relative to one another,

(13) FIG. 12 shows the Luer connectors of FIGS. 10a and 10b connected to one another, and

(14) FIG. 13 shows an alternative embodiment of the connector device.

(15) Referring to FIG. 1, an overview of the apparatus for delivering fluid to the brain is illustrated when implanted in a subject.

(16) The apparatus comprises four fine catheters 2, each catheter being inserted into the brain via a previously implanted guide tube 4 (although it should be noted that only two of these are shown in FIG. 1). Suitable stereotactic insertion apparatus and methods have been described elsewhere previously, for example see U.S. Pat. No. 7,329,262 for details of a stereoguide based catheter insertion procedure. Supply tubing 6 runs from each catheter 2 to a hub 8. The hub 8 is connected by a length of multi-lumen tubing 10 to percutaneous access apparatus 12. The catheters 2, guide tubes 4, supply tubing 6, hub 8 and multi-lumen tubing 10 are all subcutaneously implantable (i.e. buried beneath the skin of the patient).

(17) The percutaneous access apparatus 12 comprises a percutaneous fluid access device that is anchored directly to the skull of the patient. The percutaneous fluid access device comprises an extracorporeal portion to which an associated connector device is releasably attached. The percutaneous access apparatus 12 thus enables a fluidic link to the implanted catheters 2 to be established when required. In particular, the arrangement provides a separate, isolated, fluidic pathway to each catheter 2. More details about the percutaneous access apparatus 12 are provided below.

(18) Outside of the body, the connector device of the percutaneous access apparatus 12 is linked to four external supply tubes 14. Each supply tube 14 includes an in-line bacterial and/or air filter 16. A four channel syringe pump 18 (which may comprise four separate single channel syringe pumps) is also provided. An outlet tube 20 from each channel of the syringe pump 18 is linked to one of the external supply tubes 14 via a drug storage tube 22. As will be explained in more detail below, each drug storage tube 22 is preloaded with a desired volume of therapeutic agent allowing the syringe pump 18 to be loaded with an inert solution (e.g. saline or artificial CSF). Fluidic connections between the drug storage tube 22 and the outlet tubes 20 and supply tubes 14 are made using low dead volume Luer lock connectors 24 of the type described in more detail below.

(19) In use, the catheters 2, guide tubes 4, supply tubing 6, hub 8 and multi-lumen tubing 10 are all subcutaneously implanted in the subject (i.e. the skin flap 23 showed in a raised position in FIG. 1 is folded down and sutured in place). The percutaneous fluid access device of the percutaneous access apparatus 12 is also secured in place (e.g. attached to the skull and left protruding through the scalp) thereby providing the required fluid connection as and when required. These components are preferably suitable for long term implantation within a subject. For example, they may be designed to remain implanted for months or years.

(20) When delivery of therapeutic agent is required, the connector device is attached to the percutaneous fluid access device. The supply tubes 14 (pre-primed with inert fluid) are then connected to the syringe pump via drug storage tubes 22 that contain the required dosage of therapeutic agent that is to be delivered. Each channel of the syringe pump is arranged to expel inert fluid (saline, artificial CSF etc) thereby pushing the therapeutic agent through the apparatus and expelling it from the tips of each catheter 2. The rate of fluid flow can be precisely controlled using the syringe pump 18 and the amount of therapeutic agent can be precisely set by defining the volume of the drug storage tubes 22. It is possible for fluid delivery to be continuous or intermittent. Fluid may also be delivered through all, or just some, of the catheters in parallel and/or it may be delivered sequentially through a sub-set of one or more catheters in turn. The precise delivery protocol can be set by a clinician.

(21) Turning to FIGS. 2a and 2b, the fine catheter 2 and guide tube 4 of the apparatus described with reference to FIG. 1 are illustrated in more detail.

(22) The guide tube 4 comprises an elongate tube 62 having a head 64 at its proximal end. The head 64 has a screw thread formation 66 on its outer surface that allows it to be secured to a burr hole formed in the skull by a press-fit action. The catheter 2 comprises a length of fine tubing for insertion into the lumen of the guide tube. The distal end or tip of the fine tubing of the catheter 2 extends beyond the distal end of the elongate tube 62 when inserted therein and comprises a hole for dispensing fluid. A hub 56 is provided at the proximal end of the fine tubing of the catheter 2. Further details of such a guide tube and catheter combination are outlined in WO2003/077785.

(23) Referring to FIGS. 3A, 3B and 3C, the percutaneous access apparatus 12 of FIG. 1 is illustrated. FIGS. 3A and 3B illustrate the percutaneous fluid access device 100 that is implanted in the subject and FIG. 3C shows the external connector device 130 that attaches to the percutaneous fluid access device 100 whenever fluid delivery is required.

(24) Referring to FIGS. 3A and 3B, the percutaneous fluid access device 100 comprises a subcutaneous portion 102, a percutaneous portion 104 and an extracorporeal portion 106.

(25) The subcutaneous portion 102 is substantially cylindrical with protruding ribs 108 that enable secure attachment of the device to a hole formed in the skull via an interference or press fit. The external surface of the subcutaneous portion 102 is also roughened to promote osseointegration after implantation. The ribs 108 have an inclined surface that is at an angle of between 15 and 35 degrees to the longitudinal axis; this helps retain the device securely in place after implantation.

(26) The percutaneous portion 104 (which can also be termed a transcutaneous portion) is the part of the device that passes through the skin. The surface of the percutaneous portion 104 is also roughened to promote skin in-growth after implantation thereby reducing the risk of infection. The percutaneous portion 104 is conical (i.e. it increases in diameter from skin surface) with an angle from the vertical of between 5 and 40 degrees.

(27) The extracorporeal portion 106 is the part of the device that protrudes above the outer surface of the dermis. The extracorporeal portion 106 thus has a smooth surface to prevent tissue in-growth; such a smooth surface also allows it to be easily cleaned thereby reducing the chance of bacterial retention.

(28) The extracorporeal portion 106 has a substantially cylindrical outer surface with a conical recess 109 and two v-shaped grooves 110 spaced apart around its circumference. A macro-alignment feature 112 is also provided. The conical recess 109 and grooves 110 act as very precise (kinematic) location features for the associated connector device, whilst the macro-alignment feature 112 ensures the connector device is in the approximately correctly orientation prior to attachment. Further details of the connector device are provided below.

(29) As shown in the cross-sectional views of FIG. 3B, the percutaneous fluid access device 100 comprises four ports 120. Each port 120 is in fluid communication with a lumen of the multi-lumen supply tube 6. The supply tube 6 exits the subcutaneous portion 102 from its side and, when implanted, runs a short distance in a channel formed in the bone. The four ports 120 are accessible from the extracorporeal portion via a septum 122. In particular, each port 120 comprises an elongate channel having an axis substantially parallel to the longitudinal axis of the device. A single septum 122 that is accessible from the extracorporeal portion seals the end of the channel of all four ports. During fluid delivery, hollow needles of the connector device pierce the septum, enter the channels and thereby provide the required fluid communication with each port. In the absence of an attached connector device, the septum seal provides a fluid seal for all ports that prevents leakage of fluid or ingress of unwanted material (e.g. bacteria etc). FIG. 3B also shows in dashed outline the location of the dermal layer 121 and underlying bone 123 when the device is implanted.

(30) FIG. 3C shows the connector device 130 for attachment to the percutaneous fluid access device 100. The connector device 130 comprises a connector base 131 having an attachment mechanism for securing the connector device 130 to the percutaneous fluid access device 100 in a precisely define relative position. The connector device 130 also includes a needle holder 134 attached to the end of a shaft 136. The shaft 136 has an external thread that engages a corresponding internal thread of a knurled portion 138. The needle holder 134 is located within a guide channel inside the connector base 131 and rotation of the knurled portion 138 relative to the connector base 131 drives the needle holder 134 back and forth along the channel. After the connector base 131 has been attached to the percutaneous fluid access device 100 by the attachment mechanism 132, the knurled portion 138 can be rotated to drive the hollow needles held by the needle holder 134 through the septum of the percutaneous fluid access device 100 thereby establishing the required fluid communication. The supply tubes 16 connected to the needles of the needle holder 134 are also shown. More details of the various components of the percutaneous fluid access apparatus are provided below.

(31) Referring to FIGS. 4a and 4b, the attachment mechanism of the connector base 131 mentioned with reference to FIG. 3c is illustrated.

(32) FIG. 4A shows a top-down view of the connector base 131 of the connector device 130. As explained above, the connector base 131 is configured to be releaseably attachable to the percutaneous fluid access device 100. The connector base 131 has a generally cylindrical outermost surface with a fluted slot 146 formed along one side and an internal lip 148 at the lower end. The inner walls of the connector base 131 are generally cylindrical and define a guide channel 154 along which an associated needle holder 134 (not shown) can slide. The connector base 131 also includes an attachment mechanism 132 that comprises two fixed balls 150 and 152. A floating ball member 154 comprising a third ball 155 is carried by a hinge 156 (not shown in FIG. 4A). A macro-alignment feature in the form of a v-shaped slot 158 is formed in the internal lip 148.

(33) FIG. 4B is a sectional view of the connector base 131 along the line A-A shown in FIG. 4A. The hinge 156 carrying the floating ball member 154 is shown. An elongate aperture 160 having an internal screw thread is also provided adjacent the hinge 156 and ball member 154. The elongate aperture 160 is arranged so that the tip of a screw (not shown) inserted through the aperture will protrude from the aperture and engage the floating ball member 154. Tightening the screw thus deflects the floating ball member 154 (i.e. it pivots at the hinge 156) thereby moving the ball toward the centre of the connector base. This allows the connector base 131 to be locked onto the percutaneous fluid access device 100 when required. The floating ball member 154 springs back when the screw is removed, thereby allowing the connector base 131 to be removed from the percutaneous fluid access device 100.

(34) Moreover, the relative positions of the connector base 131 and percutaneous fluid access device 100 are defined by the engagement of the three ball of the connector base (i.e. the two fixed balls 150 and 152 and the third ball 155) with the grooves 110 of the percutaneous fluid access device 100. This arrangement, which is typically called a kinematic connection or kinematic joint, provides a highly repeatable mechanical linkage in which the six points of contact between the balls and grooves constrain the six degrees of freedom of movement between the connector base 131 and percutaneous fluid access device 100. This precise alignment ensures the hollow needles of the needle holder 134 (not shown) are correctly positioned relative to the ports of the percutaneous fluid access device 100.

(35) It should be noted that, instead of the hinge 156 and floating ball member 154 arrangement shown in FIGS. 4A and 4A, various alternative arrangements could be implemented. For example, the tip of the screw could comprise a ball that directly engages a feature (e.g. groove) of the percutaneous fluid access device. A cam and lever arrangement could also be used instead of a screw to bias the floating ball member into contact with the percutaneous fluid access device.

(36) Referring to FIG. 5, there is provided an exploded view of the connector device 130. The connector base 131 is arranged to receive a needle holder 134. The needle holder 134 comprises a substantially flat, keyhole shaped, supporting member 180. Four hollow needles 182 project perpendicularly from the flat surface of the supporting member. The four hollows needles 182 are spaced apart in a configuration that matches the arrangement of the ports of the percutaneous fluid access device 100. The needle holder 134 is also shaped to fit within, and slide along, the guide channel 154 of the connector base 131 that is described above. The needle holder 134 also includes four internal channels that provide separate fluidic channels between the lumens of the four hollow needles 182 and the four supply tubes 14. The screw threaded shaft 136 attached to the needle holder 134 is held by the threaded inner surface of the knurled portion 138. A lip 183 protruding from the connector base 131 secured the knurled portion 138 to the base 131.

(37) Referring to FIGS. 6a to 6d, the procedure for locking the connector device 130 to the percutaneous fluid access device 100 is illustrated.

(38) FIG. 6a shows the connector device 130, a screw 190 and a percutaneous fluid access device 100. FIGS. 6b and 6c show how the connector base 131 of the connector device 130 can be located on the percutaneous fluid access device 100. FIG. 6d shows the screw 190 inserted into the elongate aperture 160 of the connector base 131 and tightened so that the three ball of the connector base (i.e. the two fixed balls 150 and 152 and the third ball 155 shown in FIGS. 4a and 4b) firmly engage the recess 109 and grooves 110 of the percutaneous fluid access device 100. The connector device 130 is thus locked to the percutaneous fluid access device 100 (although no fluid linkage has yet been established).

(39) Referring to FIGS. 7A, 7B, 8A and 8B, the procedure for establishing a fluid connection is illustrated. FIGS. 7A and 8A show the configuration of the connector device 130 after it has been locked to the percutaneous fluid access device 100. The hollow needles 182 of the needle holder 134 are positioned above the septum 122 in alignment with the respective channels of the ports 120. The connector base 131 is held in one hand whilst the other hand rotates the knurled portion 138 of the connector device 130 in an anticlockwise direction thereby driving the shaft 136 and needle holder 134 along the guide channel inside the connector base 131. As shown in FIG. 7B and 8B this translational motion of the needle holder along the guide channel causes the four hollow needles 182 to pierce the septum 122 and enter the four ports 120. Holding the connector base 131 ensures no torque is applied to the device-bone connection. In this manner, the four separate fluid pathways through the percutaneous access apparatus 12 are established.

(40) Once the required fluid delivery has occurred, the knurled portion 138 can be rotated in a clockwise direction to withdraw the four hollow needles 182 back through the septum 122. The connector device 130 can then be unlocked from the percutaneous fluid access device 100 by removing the screw 190.

(41) If required, the various components of the fluid delivery system can be MRI compatible.

(42) Referring to FIG. 9, a drug storage tube 22 of the type described above is illustrated. The function of each drug storage tube 22 is to store the required volume of therapeutic agent that is to be dispensed through the associated catheter.

(43) The drug storage tube 22 comprises a length of single lumen tubing 248 having a first end that terminates at a first fluid connector portion 250 and second end that terminates at a second fluid connector portion 252. The first and second fluid connector portions 250 and 252 are self-sealing connector portions that can mate with a complementary connector portion to establish a fluid link. For example, the first and second fluid connector portions 250 and 252 may be provided by a modified male Luer lock based connector portion of the type described in more detail below with reference to FIG. 10B.

(44) The volume of the drug storage tube 22, including the dead volume of the first and second connector portions, is pre-selected to match the desired volume of fluid that is to be dispensed. In particular, the length of the single lumen tubing is pre-selected so that the internal volume of the drug storage tube 22 (including the dead volume of the connector portions) equals a desired value. In one example, the drug storage tube 22 may be pre-loaded with the desired volume (e.g. 300 l 6 l) of GDNF. Once connected to an apparatus as shown in FIG. 1, the therapeutic agent can be pushed through the drug storage tube 22 by the flow of inert liquid from the pump and delivered to the patient.

(45) A kit of drug storage tubes may also be provided. Each drug storage tube may comprise a certain, different, pre-defined volume. The required drug storage tube may then be selected and loaded with the appropriate drug as required. The procedure of loading the drug storage tube may be performed, for example, by a pharmacist.

(46) FIGS. 10A and 10B illustrate a pair of mating Luer lock connectors that have been modified so as to have a low dead volume. Such connectors are suitable for applications, such as dispensing fluid to the brain, where low dead volumes are required due to the relatively low volumes of fluid being delivered. Preferably, the fluid path through the pair of connectors has a small and/or substantially invariant cross-sectional area. For example, the diameter of the fluid path may be about 0.7 mm. FIG. 10A shows a female Luer connector 300 in which a hollow needle 302 has been attached to the end of the lumen 304. The hollow needle 302 has a sharp tip 306 and a fluid aperture 308.

(47) FIG. 10B shows a male Luer connector 310 in which a septum 312 has been inserted near the end of the lumen 314. The inclusion of the septum 312 in the male Luer connector 310 provides a fluid seal in the absence of an associated female Luer and also minimises the dead volume of the male Luer connector 310.

(48) FIG. 11 shows the female Luer connector 300 aligned with the male Luer connector 310 prior to connection. FIG. 12 shows the male and female Luer connectors after engagement by a twisting action. In particular, the septum 312 of the male Luer connector 310 is pierced by the needle 302 of the female Luer connector 300 thereby providing a fluidic connection. The aperture 308 of the needle 302 is located a small distance d from the septum.

(49) FIG. 13 shows an alternative connector device 430 suitable for attachment to the percutaneous fluid access device 100. The connector device 430 includes a connector base 432 that can be locked to the percutaneous fluid access device 100 in the manner described with reference to FIGS. 4a and 4b above. An additional guide device 434 is provided that can be secured to the connector base 432 after the base has been locked to the percutaneous fluid access device 100. A needle holder 436 is attached to the end of an elongate shaft 438 by a screw thread. The needle holder 436 and elongate shaft 438 may then be inserted into the channel of the additional guide device 434 and pushed along the channel until the hollow needles 440 of the needle holder engage and pierce the septum of the attached percutaneous fluid access device 100. The additional guide device thus ensures the needles are guided into contact with the septum from the required direction thereby reducing the risk of the septum being damaged. The additional guide device 434 may be detached from the connector base 432 after the fluidic connection has been established.

(50) It should be remembered that the above are merely examples of the various aspects of the present invention.