Medical Infusion System

[0001] The present invention generally relates to a medical device implantable into the patient's body. The system relates to a device for a convection-enhanced delivery system, often referred to as high pressure micro perfusion, comprising at least one pump with a fluid reservoir, infusion system and infusion catheter. The infusion system includes at least a tube connecting the pump outlet to the infusion catheter. Also disclosed are methods of delivering drugs to a patient and implanting a device.

BACKGROUND OF THE INVENTION [0002] A major problem in the development of many pharmaceutically active drugs is to find a suitable delivery form for administering these drugs to a patient so as to obtain a therapeutic level at the site of action. In addition, if the target site of the drug is a specific organ or localized tumor, systemic administration may not be sufficient to obtain effective concentrations of the drug at the target site to achieve the desired therapeutic effect. For example, it turns out that many oligonucleotides or proteins, often with high molecular weights (e.g., antibodies, hormones, etc.), are effective in vitro drugs, but it is often problematic to obtain effective in vivo drug concentrations at their target sites. so as to bring about a therapeutic effect.

[0003] Another problem to overcome in administering drugs to a patient is to cross the blood-brain barrier. The blood-brain barrier is often impenetrable

An obstacle to the passage of substances even when the substances are administered intravenously. Difficulties in penetrating the blood-brain barrier can be attributed to many causes, including, for example, the characteristics of the chemical stability of a particular drug, its molecular weight, and / or its chemical charge and polarity, etc.

[0004] Other drugs have toxic effects and should therefore be administered only topically. In the same context, the most suitable way of administering, for example, imaging substances may be topical administration to minimize systemic toxic side effects and / or improve their performance.

[0005] In existing local drug delivery techniques, such as impregnated polymer discs or bolus, distribution of the agent is dependent on physical diffusion. Often, the distribution of large molecules is limited and the rate of distribution is inversely proportional to the dimensions of the agent and is slow relative to tissue clearance. However, even drugs with ideal diffusion characteristics often have unsatisfactory concentrations on the periphery of the tissue or tumor. In the case of lethal tumors, cell populations that are outside the drug delivery site avoid exposure to the drug due to the heterogeneous infusion determined by the concentration gradient that develops between the injection site and the advancing tumor periphery.

[0006] For the purpose of convectionally enhanced drug delivery to brain tissue, a highly sophisticated delivery system has been described, see, for example, International Patent Application Publication No. PCT No. WO 95/05864. The substances are administered at a specific flow rate into the tissue or tumor (for example, 0.5 to 15.0 μΙ / minute) and the drug concentration spreads uniformly around the infusion site. This convection enhanced delivery technique

EP 1 615 682 B1 is only feasible with huge and heavy syringe pumps, because the requirement for continuity of flow characteristics is very high. The described syringe pumps are connected directly to a catheter, which is located in the brain with the outer end protruding from the skull and uncovered outside the body surface. Portable pumps used for intravenous, interstitial or intrathecal administration are thought to have insufficient flow characteristics for this use. Also, the catheter having direct access to the target tissue can only be used during hospital treatment of the patient and must be replaced after some time (after a few hours or days, for example), as entry through the body surface can potentially become infected.

[0007] The need for enormous, non-portable syringe pumps and their direct connection of the external surface of the body with an implanted catheter into the brain limits the use of this delivery system only for hospital treatment of the patient. In particular, it is very inconvenient for the patient that the catheter is exposed or visible outside the body (e.g., the head) during outpatient treatment of the patient. In addition to this cosmetic inconvenience to the patient, the exposed catheter creates an additional risk of infection because the entry site can be easily manipulated due to mechanical stress. In addition, if repeated cycles are desired, it may be necessary to perform repeated surgical operations to implant a new catheter. These surgical operations are not only additional psychological obstacles, but carry a high risk of additional infection and further complications for the patient.

[0008] Drug delivery especially to the brain using permanently attached pumps has also been

EP 1 615 682 B1

US 5,735,814. is highly described in the context of treating locomotor disorders, see the exemplary patent Ser. Ahneryki nr

US 5,711,316, or the treatment of neurodegenerative disorders, see, for example, the US Patent No. Ser. Aheeryki nr

Although the technique using these devices is sophisticated, and also involves the use of a sensor, it does not meet the requirements for administration by convective enhanced delivery to the brain tumor. For example, these pumps have insufficient flow characteristics for use in this feeding method. In addition, when fluids are administered over a long period of time (e.g., days, weeks or months), electrically powered pumps will likely need to be recharged or replaced, leading to subsequent surgical intervention. In addition, in the case of intermittent treatment in combination with large volumes of solvents, the supply of these solvents must be extracorporeal or other, otherwise additional surgical operations may be necessary.

[0009] Also described is the periodic administration of a substance through an access port system that can be connected to an infusion catheter, see, for example, US Pat. Ser. U.S. Patent No. 5,897,528. Access port systems are generally access ports covered by a septum that allows multiple punctures with a needle. The access port is connected via an access port catheter and a connector to the infusion catheter. This system allows repeated administration of pharmaceutical fluids. However, the position of the catheter during periodic drug administration, as has been described so far, is limited to body fluids (e.g., blood vessels or interstitial fluids), because as a result of the implantation of the catheter into the tumor or tissue, the catheter holes are overgrown by cells, especially tumor cells when placed in it and thus clogging up when

EP 1 615 682 B1 is comfortable to wear to initiate action, no solvent is applied.

[0010] Therefore, there is still a need to administer a therapeutic agent to a patient with a continuous flow using convective enhanced delivery technique, during outpatient patient treatment that is suitable for intermittent therapy, minimizes the number of surgical operations needed for implantation and maintenance, and is convenient for operation and / or use. Faster improved side effects profile, enhanced stability, reduced dosing quantity and dosing frequency, option for a large number of cycles and improved patient compliance are also desirable when delivering therapeutic agents to a patient. In addition, it will be more desirable to have a system including a pump and a device permanently attached, such as a catheter, that can be intrathecal inserted. The discussion below discloses delivery systems, kits, and methods that help meet these needs.

SUMMARY OF THE INVENTION [0011] Effective administration of a liquid Oarmaceutical to a specific site within a patient is complicated by the complexity of the in vivo system and the physical and chemical properties of the agent. A device has been developed that effectively delivers a therapeutically effective amount of a liquid Oarmaceutical to a patient that allows the agent to be delivered to a specific site within the patient, for example, to a particular tissue or tumor. In one application of the present invention, the portable convection enhanced delivery system administers the Oarmaceutical in liquid form to a specific site within the patient. In yet another embodiment of the present invention, the system includes

A portable extracorporeal pump with a fluid reservoir that is connected via an infusion system to an infusion catheter implanted into a patient's tissue or tumor. The fluid, in one application of the present invention, is administered using high flow micro-perfusion. The system can be used to deliver a variety of therapeutic agents, such as, for example, drugs, proteins, protein toxins, imaging agents, antibodies for treatment or imaging, proteins in enzyme exchange therapy, growth factors, and / or viruses or oligonucleotides in gene therapy , etc. These delivery systems have been found to improve bioavailability and safety as well as improve the pharmacokinetic and pharmacodynamic properties of the delivered therapeutic agent. The present invention also allows for the first time out-of-hospital treatment of a patient using convective enhanced delivery technique using a portable pump.

BRIEF DESCRIPTION OF THE FIGURES FIGURES [0012] Other advantages of the present invention will be readily appreciated when they become better understood by reference to the following detailed description considered in conjunction with the accompanying drawings, where:

Fig. 1 shows a device comprising components such as a portable pump (2) with a solvent tank (1), infusion tube (3) with a filter (4), ancillary system (5) (here the access port needle) connecting the infusion tube with the access port chamber (6), the access port catheter (7) connected by means of a connector element (8) to one infusion catheter (9) which is placed with its perfusion holes at the target site (10), in the tissue or in the tumor. The part of the device on the left from the dashed line is extracorporeal,

EP 1 615 682 B1, on the other hand, is the part of the device to the right of the dashed line that is permanently attached.

Figures 2a and b show the flow characteristics of a syringe pump ("Graseby® 3200", Graseby Medical Limited, Watford, Herts, United Kingdom) often used in clinics for use in convection enhanced delivery. Figure 2a shows the flow characteristics at a set flow of 240 μΐ / hour. Fig. 2b illustrates the flow characteristics of this pump at a set flow of 480 μΐ / hour.

Figures 3a and 3b show the flow characteristics of a portable pump ("Pegasus Vario" from Pegasus GmbH, Kiel, Germany). Figure 3a shows the flow characteristics at a set flow of 240 μΐ / hour. Fig. 3b shows the flow characteristics at a set flow of 480 μΐ / hour.

Figures 4a and 4b show the distribution of Evans Blue dye on an 0.4% agarose gel isotropic, which proved to be a suitable model for simulating brain diffusion characteristics. The picture was taken after 0, 1, 3, 6, 12 and 24 hours of infusion duration, read from the left side of the first line to the right and then from the left side of the second line to the right. In fig. 4a shows the distribution of the dye using a rotating radial piston pump "Pegasus Vario from Pegasus GmbH, Kiel, Germany" at a flow of 480 μΐ / hour, while in Figure 4b the distribution of the dye using the highly sophisticated "Graseby® 3200 syringe pump, Graseby Medical Limited, Watford, Herts, United Kingdom ", until now used in convection enhanced delivery technology, at a flow of 480 μΐ / hour.

Figures 5a and 5b show an auxiliary system including the access port needle (5a) bent at an angle of 90 °, and

EP 1 615 682 B1 a transparent cap (5b) which is covered by a ring of soft material (5c). Fig. 5a is a cross-sectional view and Fig. 5b is a bottom view.

Fig. 6 is a cross-sectional view of an access port comprising one chamber with a cover (6a), a partition at the distal end (6b) and an outlet at the proximal end (6c).

Figure 7 is a schematic side view of the infusion catheter (9) with its end at the proximal end (9a), the entrance from the distal end (9c) and the area (9b) in which the perfusion holes are arranged.

Figure 8 is a cross-sectional view of an access port comprising two port chambers with a shield (6a), two partitions at the distal end of each chamber (6b) and two outlets (6c), one for each chamber, and the needle shielding covering of one of the chambers ( 6d).

DETAILED DESCRIPTION OF THE INVENTION [0013] With reference to the figures, the delivery system according to the present invention makes it possible to administer a dispersed or dissolved substance, for example, in aqueous media, even in large volumes, for many hours, days, weeks, months, or years of treatment. , into a tissue or tumor using convection enhanced delivery techniques.

[0014] At the beginning with reference to Fig. 1, one embodiment of the device according to the present invention is illustrated. This particular implementation includes components such as a portable pump (2) with a solvent tank (1), infusion tube (3) with a filter (4), ancillary system (5) (access port needle) connecting the infusion tube with an access port ( 6), the access port catheter (7) connected with the use of a connector element (8) to one infusion catheter (9), which is placed with its perfusion holes in place

EP 1 615 682 B1 in the tissue or tumor. The parts of the device on the left from the dashed line are extracorporeal, while the parts of the device on the right from the dashed line are permanently attached.

[0015] With reference to Figs. 5a and 5b, one embodiment of an auxiliary system is illustrated, comprising an access port needle (5a) bent at an angle of 90 °, and a transparent cap (5b) which is covered by a ring of soft material (5c). The range of the upper surface as well as the angle may differ from those illustrated. Fig. 5a is a cross-sectional view, while Fig. 5b is a bottom view. Dashed lines refer to hidden parts of the device.

[0016] Referring to Fig. 6, a cross-sectional view of one embodiment of an access port is illustrated that includes one chamber with a shield (6a), a partition at the distal end (6b), and an outlet at the proximal end (6c).

[0017] With reference to Fig. 7, there is schematically illustrated a view of one embodiment of an infusion catheter (9) with its end located at the proximal end (9a), the entrance from the distal end (9c) and the area (9b) in which there are perfusion holes.

[0018] Referring to Fig. 8, a cross sectional view of one access port implementation comprising two port chambers within one shell (6a), two baffles at the distal end of each chamber (6b), and two outlets (6c), one for each chamber are illustrated , and a needle shielding covering of one of the chambers (6d).

[0019] The portability of the pump system allows saturation of the target site (for example, tissue or tumor) with soluble or suspended drug without limitation regarding hospital treatment of the patient.

[0020] In one embodiment, the delivery system is configured for use in outpatient treatment

EP 1 615 682 B1.

[0021] The portable delivery system further allows flushing of the implanted catheter using physiological fluid to prevent it from clogging as a result of cellular growth while no drugs are being administered. In this way, intermittent therapies become possible, without repeated surgery to implant a new infusion catheter.

[0022] In addition, the pump in connection with the access port system allows an easy procedure for removing the pump for additional procedures, such as maintaining or replacing the pump and / or infiltration tube, recharging the accumulator batteries, refilling the reservoir and / or replacing the infiltration fluid, which may be useful for long-term and intermittent administration and was usually not possible without additional surgery, when an implanted pump is used.

[0023] Systems for use for convection enhanced delivery according to prior art include and a heavy non-portable pump implementing the present invention, the device uses a light portable pump in connection with an additional access port system. In a further application of the present invention, the infusion catheter, connector piece, access port catheter and access port are completely fixed. In another embodiment of the present invention, the infusion catheter, connector piece and access port with the access port catheter are completely permanently attached. In one embodiment, entry into the body is reduced to a small needle that is covered by a transparent cap with a soft liner. Such a device reduces the risk of contamination and infection from the puncture site. When replacing components of the device, for example, a reservoir for only a syringe infusion catheter. In j ednj

Fluid, the access port needle can be replaced with a sterile needle.

[0024] The use of an access port system in conjunction with an infusion catheter to administer a substance dispersed or dissolved in cancer or tissue fluids opens the common advantages of access port systems also for an area, for example, convection enhanced use

Thus, entry into the body of the access port. In one delivery, in which access port systems have not been used so far. In one embodiment of the present invention, the infusion catheter is in fluid communication with the access port catheter and the access port is surgically implanted in such a way that both of these elements can be permanently fixed, is reduced to the site of implementation, access to the access port is marked also as an auxiliary system is a small access port needle, which is covered by a transparent cap with a soft lining.

[0025] In yet another use of the present invention, the infusion catheter is in fluid communication with an access port that is surgically implanted in such a way that the infusion catheter and access port are permanently fixed. In one implementation, the access port access, also referred to as the auxiliary system, is a small access port needle, which is covered by a transparent cap with a soft lining.

[0026] In addition, the access port system may be located at any suitable location that is advantageous for positioning the portable pump, and / or for patient convenience, and / or for the mechanical stability of the access port system (e.g., above the rib).

[0027] By using an access port system in conjunction with an infusion catheter, it allows accurate placement of the infusion catheter in one stage of a surgical procedure in the middle of a tissue or tumor. In the next step, the access port may be placed in a suitable way (e.g., above

The access port catheter may then be tunneled and inserted loosely towards the infusion catheter entrance. In the next step, two implanted catheters may be substantially permanently attached using a suitable connector element. This not only prevents the need for additional surgery, but can also take into account the effect of mechanical stress on the position of the infusion catheter. The position of the infusion catheter may be positioned to minimize such mechanical stress.

[0028] By using the access port system in conjunction with the infusion catheter of the present invention to administer the substance dispersed or dissolved in fluids for rapidly growing tumors or tissues, it enables the use of the commonly used advantages of access port systems in areas including, for example, convective enhanced delivery have not been previously described in the field.

[0029] In contrast to regular diffusion (e.g. regular infusion technique used), a pressure gradient-dependent technique of convective enhanced delivery of therapeutic agents allows the production of current convective flow that has the potential to uniformly disperse even large molecules over much larger distances through the tissue or cancer.

[0030] Applicants have unexpectedly found that portable pumps, which until now have not been accepted as useful in reinforced convection techniques due to their discontinuous flow characteristics, may unexpectedly be used in convective enhanced delivery technique in combination with at least one infusion catheter according to the present invention. The portable pump allows for the first time out-of-hospital patient treatment using convective enhanced delivery technology. In addition, using

An access port system, including an access port with an access port catheter and an infusion tube with an access port needle, the advantages and benefits of using access port system technology are additionally available to the delivery device through convection enhanced delivery.

[0031] Prior to the present invention, clinically useful constant flow rates used together with convective enhanced delivery could only be achieved using syringe pumps such as, for example, Graseby® 3200 (Graseby Medical Limited, Watford, Herts, United Kingdom) or Harvard® 2100 (Harvard Apparatus, Inc., Holliston, Ma., USA). These syringe pumps are typically connected directly to the infusion catheter or are connected via an infusion tube implanted into a tissue, such as brain tissue, as described in published international patent application WO 95/05864. The maximum fluctuation of these syringe pumps, when used in conjunction with the infusion tube, access port system and filter, was as low as about 0.05 ml / hour and the fluctuation frequency was about 0.7 sec^-1 at a set flow rate of 0.48 ml / hour as shown in Fig. 2b.

[0032] Various portable pumps have demonstrated stepped flow delivery characteristics, where the degrees were from about 0.05 ml to about 0.1 ml, even in the so-called continuous flow mode, thereby causing high real flow fluctuations. Such a high fluctuation value is not optimal for use with convective enhanced delivery to many tissues, especially, for example, to brain tissue, where flow rate constants of 0.1 μΐ / minute to 15.0 μΐ / minute are desired. One device was tested, which was to be characterized by delivery at minimum stages of 0.4 μΐ in continuous flow mode. Because it is known that pipes and other devices can smooth the characteristics

In this case, the infusion tubing, access port system and another infusion catheter were connected to the pump, and the smoothing flow characteristics were recorded. Despite the impact of the device, the portable pumps showed a flow characteristic with a 20-fold higher fluctuation than the flow characteristics of the comparative syringe pumps (Figures 2a and 2b) in the same test setting.

[0033] The flow characteristics of the tested 'Pegasus Vario portable pump from Pegasus GmbH, Kiel, Germany) at a set flow of 480 μΙ / hour, showing a fluctuation of up to 1 ml / hour with a frequency of 0.3 sec is shown in Figure 3b. Flow characteristics were recorded using a specific fluid flow measurement system at the Institut fur Mikro- und Informationstechnik, Villingen Schwenningen, Germany. The measurement compares the flow of the tested system with the reference flow using calibrated sensors from Bronkhorst, using hydrostatic techniques (SP45, type: 300x600tp45). Details of the experiment are described in Example 3.

[0034] It has surprisingly been found that this uneven flow characteristic of a portable pump (Pegasus Vario, Pegasus GmbH, Kiel, Germany) was still suitable for convectionally enhanced delivery when used in conjunction with the present invention. The total experiment carried out to demonstrate the suitability of the convection-enhanced delivery technique for pumps exhibiting flow characteristics is described in Example 1.

[0035] In one application of the present invention, the device induces a continuous flow greater than about 0.001 ml / hour and on average less than about 0.5 ml / hour, which is suitable for convective enhanced delivery to brain tissue when the total volume flow in one period of fluctuation

EP 1 615 682 B1 is less than about 0.5 μΐ and the oscillation amplitude is from about 0.1 ml / hour to about 0.8 ml / hour.

[0036] In yet another application of the present invention, the device induces a continuous flow greater than about 0.001 ml / hour and on average less than about 1 ml / hour, which is suitable for convective enhanced delivery to brain tissue when the total volume of flow in one fluctuation period it is less than about 0.5 μΐ and the fluctuation amplitude is from about 0.1 ml / hour to about 1 ml / hour.

[0037] In yet other applications of the present invention, the device induces a continuous flow greater than about 0.001 ml / hour and on average less than about 1 liter / hour, 0.5 liter / hour, 0.1 liter / hour, 0.05 liter / hour, 10 ml / hour, 5 ml / hour, 1 ml / hour, 0.5 ml / hour, 0.1 ml / hour, 0.05 ml / hour or 0.01 ml / hour. The skilled person knows which flow is suitable for different tissues: body cavities or tumors. The total flow volume in one fluctuation period in these embodiments is less than about 0.5 μΐ and the fluctuation amplitude is from about 0.1 ml / hour to about 1 ml / hour.

[0038] In still other applications of the present invention, the device induces a continuous flow greater than about 0.001 ml / hour and on average less than about 1 liter / hour, 0.5 liter / hour, 0.1 liter / hour, 0.05 liter / hour, 10 ml / hour, 5 ml / hour, 1 ml / hour, 0.5 ml / hour 0.1 ml / hour, 0.05 ml / hour or 0.01 ml / hour. The skilled person knows which flow is suitable for different tissues: body cavities or tumors. The total flow volume in one fluctuation period in these embodiments is less than about 5 μl and the fluctuation amplitude is from about 0.1 ml / hour to about 10 ml / hour.

[0039] In other applications, the flow fluctuations of the present invention may be even smaller than those indicated above. These devices are still within the scope of this

EP 1 615 682 B1 of the invention.

[0040] In other applications, even higher flows than those described herein can be used when the solvent is introduced into a tumor or highly circulatory tissue into a body cavity or vessel, respectively.

[0041] For patient compliance, the cosmetic advantage of the described infusion system is also desirable, especially in cases where the target site of administration of the substance is behind the visible part of the body (for example, brain tissue), where in the prior art convective reinforced delivery systems, the catheter infusion dangled from the patient's head at the place of placement.

[0042]

Flushing the perfusion holes of the catheter implanted into the tissue or tumor using a constant flow as well as intermittent flow prevents cells from overgrowing the perfusion holes of the infusion catheter, especially from, for example, rapidly growing tumor cells when the infusion catheter is placed in the tumor or tissue . It is believed that the build-up occurs quickly as soon as the solvent supply is stopped for a period of several hours to days, which results in blockage of the device. In this way, the administration of the substance directly into the tissue (outside body fluids or body cavities) with repeated cycles with no treatment intervals, as well as during long-term administration, becomes possible by using the device according to the present invention. Repeated surgical operations are also prevented to re-implant a new infusion catheter for each cycle, which are necessary using devices according to the prior art and are associated with the danger of contamination and the resulting infection. General risks associated with any surgical procedure are also avoided. The flows necessary to keep open

Perfusion wells are dependent on many factors, such as, for example, the number of perfusion wells, their diameter, and the rate of tumor cell growth. In one embodiment, the flow that prevents such build-up is from about 0.001 ml / hour to about 1 ml / hour of final flow in the infusion catheter.

[0043] Liquid pharmaceutical agents suitable for use in the present invention include any agent suitable for delivery in a solvent system, or, for example, an agent formulated for delivery in an aqueous solution, such as for subcutaneous injection. Such pharmaceutical agents include, for example, agents such as analgesics, wound care agents, analeptics, anesthetics, anthelmintics, anticoagulants, anti-rheumatic agents, anti-arrhythmics, antibiotics, dementia, anti-diabetic agents, antidotes, anti-epileptics. antihemorrhagics, antihypertensives, anti-migraine preparations, anti-cancer agents, parkinson's agents, anti-inflammatory, antiallergic agents, anti-hypnotic, anti-fungal, anti-oligonucleotide disease treatments, anti-tuberculosis drugs, antiatherosclerotic agents, biological materials, blood flow stimulants, choleretic agents, corticosteroids, cytokines, cytostatic agents, diagnostic agents, fibrotics, diagnostic agents geriatric agents, gonadotropins, agents for the treatment of the liver, hormones and their inhibitors, sleeping pills, immunglobulins, immunomodulators, immunotherapeutic agents, organ perfusion solvents, proteins, toxins, protein agents, protective agents, sedatives, cardiac drugs, sedatives and stimulants, minerals, muscle relaxants, neurotropic agents, oligonucleotides, ophthalmic agents, osteoporotic agents, oto1ogiczne, medicines

EP 1 615 682 B1 psychopharmaceuticals, sera, the formulations of thyroid vaccine agents, antispasmodic agents, urologic, vitamins, drugs, proteins, protein toxins, antibodies or parts of them for treatment, proteins in enzyme replacement therapy, growth factors, vectors, viruses in the treatment of gene and / or diagnostic agents as agents or antibodies or parts thereof for imaging, x-ray contrast agents, oiigonucleotides that inhibit expression, for example TGF-β, MIA, c-erbB-2 / HER-2, jun, fos, VEGF or IL-10, including their subtypes, such as, for example, TGF-β 1, TGF-β 2, TGF-β 3, etc., appropriate receptors, on example of TGF-β RI, TGF-β RII, TGF-β RIII, etc. and / or combinations thereof. The pharmaceutical agent may be dissolved or suspended in a physiological solvent or in any other suitable solvent. The above agents may be in the form of the free base, or salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of these compounds. (Partly based on the list provided in The Merck Index, Merck & Co. Rahway, NJ (2001)). The above-mentioned agents, as well as combinations thereof, can be used in the devices, methods, kits, combinations and compositions described herein.

[0044] In one embodiment of the present invention, the surface of the device in contact with the therapeutic agent can be coated in a suitable manner. By way of illustration, the coating may be made of anti-infective, anti-viral, fungicidal, or x-ray absorbing material. In addition, the surface can be modified using surface-modifying groups in such a way that blood compatibility, abrasion resistance, appropriate friction coefficient and degradation resistance are assured, or molecular adhesion is reduced.

[0045] In one embodiment, the flexible tubes are connected by a tube or tube with an outer and inner diameter,

Wherein the outer diameter is slightly larger than the inner diameter of the tube that is connected through this tube, preventing solvent from leaking from the tube. In yet another embodiment, the outer diameter of the pipe or tube includes a radial countersink or elevation to improve the seating of the tube on the pipe or tube. Pressing the tube from the outside into the pipe connecting the seated tube can further improve the connection.

[0046] The components of the device of the present invention may be made of a number of materials including, for example, metal, polymer and / or composite materials, including materials such as titanium, high-grade steel, aluminum, alloys, polymer foams, plastics, stainless steel and / or metal, and combinations, mixtures and modifications thereof. Materials intended for implantation into the patient's body can be made of biocompatible materials, such as, for example, polymers, polymer segments of polystyrene, polyolefins, polyamides, or polyurethanes, and metals. The choice of such materials depends on many factors including the desired mechanical properties as well as porosity, surface properties, and material toxicity. By way of illustration, the component of the present invention may be made of a material such as titanium, alloy, stainless steel, ceramic, silicone, Teflon®, polypropylene, polyethylene, polystyrene, polyolefins, polyimide, ^poliami^dy, poMurehn ^ P^ET P^ETG^{, PETE}, ^PE, P^TG^, HDP^E, PC^,PVC, nylon, urethane, and / or copolymer, for example, and may be laminated with a layer of gold, silver and / or aluminum or may have such layer introduced by another method (to minimize gas and liquid permeability) by sputtering or deposition in another way or incorporation in this material. Some commercially available products useful in making the present invention include, for example, BioSpan® segmented polyurethane ureas,

EP 1 615 682 B1

Bionate® polycarbonate urethanes, Elasthane ™, and Elasthane ™ polyether urethanes, which can be used in medical devices implanted for a long period of time. Elasthane ™ has a chemical structure and properties similar to Pellethane® 2363. Thermoplastic silicone urethane copolymers such as PurSil ™ silicone polyether urethane and CarboSil ™ silicone polycarbonate urethane can also be used in the present invention.

[0047] In yet another embodiment, the connecting device is a screw connection. By way of illustration, the thread on one port is matched to the nut on the other port, so that seamless communication is possible. The ports have a self-sealing, one implementation, between two seals, which is of a type to prevent leakage of solvent. In yet another embodiment, the nut of one port includes a locking system. By way of illustration, the locking system is an eye attached to the nut and several eyelets located on the corresponding port, which allow easy fastening of the screw connection using wire, nail, screw, seam, etc. In yet another embodiment, the connecting system is a bayonet connector comprising two corresponding ports. The ports can be self-sealing. The bayonet coupling includes integrated locking systems. Many other techniques known in the art can be used to connect ports according to the present invention.

[0048] In one embodiment of the present invention, the device comprises a splitter, which in one embodiment may be a device comprising a plurality of proximal ports in an amount corresponding to the number of infusion catheters to be connected, the distal port, and the lumen through. By way of illustration, the distributor is permanently attached and is made of a solid material, such as, for example, polymeric material, plastic, and / or metal. In one

In an embodiment, the distributor includes appropriate connector elements and locking systems for establishing continuous fluid communication with the access port catheter or with the access port and infusion catheters. In one embodiment, the distal port diameter and access clearance are large enough to hold all proximal ports with their access clearance with equivalent solvent flow. In one embodiment of the present invention, the equivalent diameters of the proximal ports are smaller than the diameter of the distal port. In yet another embodiment, the diameters of different proximal ports differ from each other, correlating with the type of infusion catheter connected to it (internal diameter of the infusion catheter, number of infusion holes, diameter of these holes, etc.).

[0049] Inside the connection between the infusion catheter and injection elements, a filtration system can be integrated into the device at any suitable place. By way of illustration, the filtration system includes a sterile filter for removing pathogens; biological filter for biological materials such as proteins and / or antibodies; particle filter for removing solid particles; chemical filter for removing chemical products; and / or a filter to remove air or gases from the solvent. In one implementation, each filter includes a distal port and a proximal port, and a lumen through. Inside the lumen of each filter is a membrane or any other suitable device for removing air, particles, chemicals, and / or biological materials, such as, for example, pathogens including bacteria, fungi, and / or viruses. Various types of filters are known to those skilled in the art that may include separate covers or common covers. In one embodiment, a filter for removing air is placed outside the body. In yet another embodiment, the particle removal filter is located on the upstream side relative to the sterile filter.

EP 1 615 682 B1

A sterile filter typically has a pore diameter of about 0.45 pm or less, or about 0.22 pm or less, or about 0.1 pm or less. The particle filter has a pore diameter greater than about 0.45 pm, greater than about 0.22 pm, or greater than about 0.1 pm. In yet another embodiment, the filters are arranged on the inlet and outlet side in the following order: air filter, particle filter and sterile filter. In yet another embodiment of the present invention, the filters are located outside the body and have a flat profile so that they can be easily attached to the skin. In yet another embodiment, all filters are located outside the body, making them easy to maintain and replace. One device may use one or more filters from the same or different categories.

[0050] In one embodiment, the infusion catheter has an elongated body with a proximal port (see, for example, Figures 7, 9a), a distal port (see, for example, Figures 7, 9c), and an internal lumen and holes perfusion. The lumen of the infusion catheter may be divided into several lumens.

[0051] In yet another embodiment of the present invention, the perfusion holes are in an area near the proximal end of the infusion catheter or are located at the proximal end. By way of illustration, the material of the infusion catheter may be an inert material, a flexible material, and / or a biocompatible polymer, such as, for example, a polymer material, plastic, and / or metal, including polypropylene, polyethylene, polyimide, polyamide, polyurethane, and / or silicone.

[0052] In another embodiment of the present invention, the infusion catheter may be wire stabilized, or may be impregnated with detectable material to facilitate detection or act as a detectable tracer that allows monitoring

Location of the infusion catheter (e.g., barium compound in the case of X-ray monitoring). The detectable mark may be limited to the proximal end of the infusion catheter, and / or may have graduation marks spaced at regular intervals on the catheter and / or scattered along the entire length of the infusion catheter.

[0053] By way of illustration, the lumen of the catheter may be cylindrical, oval or angular and may include one, two, three or four or more lumens. The catheter may contain perfusion holes of any suitable shape, number, diameter and location, depending on the tissue or tumor to be infiltrated. Perfusion holes may be located in the opposite direction, opposite, radially, spirally, symmetrically and / or asymmetrically around the axis of the infusion catheter. The proximal end of the infusion catheter may be sharp, blunt, or rounded depending on the density of the tissue into which the infusion catheter is to be implanted. In yet another embodiment of the present invention, the perfusion hole can be formed by simply cutting off the proximal end of the catheter.

[0054] The catheter may be stabilized using a removable tube made of any suitable material (e.g., polymer material, plastic, and / or metal) sufficiently durable to place the infusion catheter in the tissue or tumor and removed after the catheter has been embedded in suitable place inside the tissue or tumor.

[0055] In a further embodiment, the infusion catheter comprises an additional device for securing it to the disk eye and / or seam edge. In one embodiment, the fastener has a hole in the catheter diameter and one or more additional holes of the appropriate diameter that allow the catheter to be attached using a nail, screw, suture, etc. to solid tissue or bone through this fastener.

EP 1 615 682 B1

In yet another embodiment, the infusion catheter comprises retaining balls in any suitable area.

[0056] In order to establish smooth communication between the corresponding ports according to the embodiments described herein (for example, between a reservoir, pump, access port, access port catheter, auxiliary system, divider, and / or infusion tube), the device may be integrated with the tube with two ports of any length containing the proximal and distal ports. The diameter of such a tube must be appropriate given the flow and volume of solvent that must be injected. The tube may have a length of up to about 1.5 m and a diameter of from about 0.1 mm to about 5 mm. In one embodiment, the material of which the tube is made may be a flexible polymer. The infusion tube has a proximal port and a distal port, and a lumen through.

[0057] In one application of the present invention, one or more of the permanently attached parts and / or one or more of the parts to be in contact with the liquid pharmaceutical agent and / or with the physiological solution are made of materials that are physiologically compatible, and include, for example, titanium, high-grade steel, surface-modified aluminum and their alloys, ceramics, polymers such as polypropylene, polyurethane, polyethylene, polyimide, polyamide, silicone, Teflon®, and combinations, mixtures and modifications thereof.

[0058] In one embodiment of the present invention, the solvent injection means comprise a proximal port and a distal port or distal end and lumen. Injection elements include, for example, syringes, balloons, pumps or other devices suitable for single or multiple infusions of a given amount of solvents with a constant, increasing and / or decreasing flow, as well as combinations thereof.

[0059] In one embodiment of the present invention, the one-way valve includes a distal port and a proximal port and a through clearance. The one-way valve includes a device that allows the solvent to flow only in one direction. If the flow is in a different direction, the valve is in the closed position. The one-way valve mechanism of operation may be any mechanism known to those skilled in the art, and may be based, for example, on balls, membranes, plate structures, etc. The valves are integrated with devices at any suitable place to provide the desired functionality. By way of illustration, one-way valves include connecting and / or blocking devices at their distal and proximal ports.

[0060] In one embodiment of the present invention, the portable pump is a pump, such as a gas pressure gauge pump, piston pump, rotary piston pump, diaphragm pump, syringe pump, centrifugal pump, suction pump, or a pump based on any other induction mechanism flow characteristics according to the present invention. In yet another embodiment of the present invention, the pump flow characteristics are improved by increasing the volume using an element that is in fluid communication with the port clearance and is in line with the flow downstream of the pumping mechanism. In one embodiment, the volume-increasing element is a soft tube with a closed distal end and an open proximal end, and a lumen through. This tube is in fluid communication with the solvent coming out of the pump. The volume is increased as the pump supplies solvent and the clearance is narrowed over a period of time when the pump does not supply solvent, thereby smoothing the flow peaks.

[0061] In one embodiment of the present invention, the access port system comprises an auxiliary system, an access port

EP 1 615 682 B1 and access port catheter. The access port includes the distal end and proximal port and the clearance through. The access port catheter also includes a distal and proximal end, and lumen clearance. The access port system may be any commercially available access port system derived from a rigid biocompatible material, including, for example, metal, polymer, and / or composite materials. In one implementation, the access port cover includes suitable devices for securing it, such as eyelets for the nails, seams, screws or hooks, etc. By way of illustration, the access port has one or more chambers.

[0062] In another embodiment of the present invention, the proximal port of the access port chamber is in fluid communication with the distal port of the access port catheter. As illustrated in Fig. 6, the outlet of the access port chamber is a pipe (see Figures 6, 6c). In yet another embodiment, this tube includes at least one step or dredge that improves, in combination with a suitable blocking system, the connection between the access port and the access port catheter.

[0063] The access port catheter is made of any flexible biocompatible material, including, for example, metal, polymer, and / or composite materials. The access port catheter may be stabilized using wire or any comparable technique to improve implantation. The wire can be removable. The catheter may be impregnated or may contain a detectable marker that allows monitoring of the position of the catheter (for example, barium compounds in the case of X-ray monitoring).

[0064] In another embodiment of the present invention, the access port catheter may be wire stabilized, or it may be impregnated with detectable material to facilitate detection or act as a detectable marker that allows monitoring of the position of the access port catheter (e.g., barium compound in

EP 1 615 682 B1 monitoring using X-rays). The detectable tag may be restricted to one end of the access port catheter, and / or may have scale lines spaced at regular intervals on the catheter and / or scattered along the entire length of the catheter.

[0065] By way of illustration, the lumen of the catheter may be cylindrical, oval or angular and may include one, two, three or four or more lumens. The proximal end of the access port catheter may be rectangular, sharp, blunt, or rounded, depending on the density of tissue into which the access port catheter is to be inserted.

[0066] The catheter may be stabilized using a removable tube made of any suitable material (e.g., polymeric material, plastic, and / or metal) that is sufficiently durable when introducing the access port catheter through tissue or cavity or body cavities relative to the infusion catheter and is removed when the catheter is placed in its appropriate location within the tissue.

[0067] The access port and access port catheter are implanted subcutaneously. The auxiliary system is any device that extracorporeal allows for smooth communication between the infusion tube and / or injection elements and the subcutaneous implanted access port.

[0068] In one embodiment, in which the access port needle is used as an auxiliary system, the distal end of the access port chamber is covered by a septum made of resilient and flexible material, such as silicone rubber, which is a self-sealing material, even when the septum is repeatedly pierced by a needle. Any other technique that allows multiple injections into the access port chamber may be used in the auxiliary system.

[0069] In yet another embodiment, the access port comprises two or more of the access port chambers mentioned above. IN

In one embodiment, these two access port chambers are integrated in one shell next to each other and have the same structure as described for the access port system with a single access port chamber. One access port compartment is optionally covered with a needle cover. In yet another embodiment, the two access port chambers are separated from each other. Both access port chambers may also contain a partition. The proximal access port chamber has a smaller septum integrated into the bottom of the distal chamber and additionally covered with a needle guard, as shown in Figure 8, for example. Each access port chamber has its own proximal port in fluid communication with the distal port of the access port catheter , infusion catheter, any other tubing or device.

[0070] In one embodiment of the present invention, the access port needle includes a distal port and a proximal port and a lumen. The access port needle in one embodiment is durable and long enough to connect the proximal infusion tube port to the distal end of the access port chamber after subcutaneous implantation of the access port. In one embodiment, the needle tip is beveled to prevent the silicone septum of the access port from breaking. By way of illustration, the needle is straight or bent at an angle of about 1 ° to about 180 °, or at an angle of about 1 °, or about 15 °, or about 30 °, or about 45 °, or about 60 °, ^lat^b about^kabout^Labout ⁹⁰% ^lat^b about^kabout^Labout ¹²⁰Ν ^lat^b about^kabout^Labout ¹⁵⁰% ^lat^b about^kabout^Lby 180 °. In another embodiment, the needle is covered with a transparent plug lined with a soft, non-irritating material that prevents contamination of the injection site surroundings, as shown in, for example, Fig. 5a and Fig. 5b.

[0071] The solvent tank is any device having a proximal port and distal port or distal end, and a lumen. In one implementation according to

In the present invention, the clearance is large enough to withstand pumping for many days at a flow rate resulting in a final flow in the infusion catheter of about 0.001 μΙ / hour to about 1 ml / hour. In one embodiment, the reservoir comprises two transparent adjacent foils matched at their periphery, forming a receiver with a flexible clearance. A tube is integrated into one corner of the receiver, which contains a proximal port, a distal port and a lumen through. The clearance of this tube is in fluid communication with the receiving lumen.

[0072] In one embodiment of the present invention, the reservoir is integrated with the cover of the portable pump. In yet another embodiment, the size of the portable pump including the integrated reservoir is no greater than about 125 cm³, 250 cm^{3 500} cm & lt; ⁷⁵⁰ cm & lt; ¹⁰⁰⁰ cm & lt; ¹²⁵⁰ cm & lt; ¹⁵⁰⁰ cm & lt; ^lat^b3000 stamen. By way of illustration, the tank has no larger dimensions than about 10 cm x 15 cm x 5 cm.

[0073] The materials and / or design of all tubes, tanks, catheters, access ports, filters and pumps, respectively, can be selected so that the flow characteristics are not adversely affected by movements, such as those described in the definition of "portable pump" and typical of operations associated with such devices.

[0074] All implanted devices, as well as devices in contact with the solvent intended for infusion, may be manufactured from materials compatible with sterilization, including, for example, chemical, steam, and / or radiation sterilization, and may be sterile prior to use .

[0075] By way of illustration, the device of the present invention may be implanted into a tumor for which it is desirable to include a solvent to provide the anti-cancer agent. These tumors include, for example, cancers such as duct cancer

EP 1 615 682 B1, cholangiocarcinoma, bladder cancer, bone cancer, bone marrow cancer, brain tumor, breast cancer, bronchiolar carcinoma, cervical cancer, malignant chorionic epithelium, cystic adenocarcinoma, cervical cancer, colon cancer, colorectal cancer and rectal cancer, embryonic cancer, endometrial cancer, epithelial cancer, esophageal cancer, gallbladder cancer, stomach cancer, head and neck cancer, heart cancer, hepatocellular carcinoma, intraperitoneal cancer, intestinal cancer, kidney cancer, liver cancer, lung cancer, medullary cancer, non-small cell bronchial / lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, papillary cancer, papillary adenocarcinoma, prostate cancer, rectal cancer, kidney adenocarcinoma, renal duct cancer, sebaceous gland cancer, skin cancer, small cell bronchial / lung cancer, small intestine cancer, soft tissue cancer, spleen cancer, squamous cell carcinoma, stomach cancer, nuclear cancer, testicular cancer, thymoma, thyroid carcinoma, endometrial cancer; astrocytoma, neuromas of the auditory nerve, blastoma, fibrosarcoma, trachoma, and pyogenic granulomas; malignant neoplasms, blastoma, malignant bone tumor, craniopharynx, ependymoma, glioblastoma, brain tumor formed by angioblasts, Hodgkin's lymphoma, leukemia, neuroblastoma, melanoma, meningioma, mesothelioma, hepatoma, fibroma, fibrosis, fibrosis eutrophic capillary, malignant, sarcoma (such as chondrosarcoma, Kaposi's sarcoma, fibrosarcoma, gliosarcoma, leiomyosarcoma, liposarcoma, lymphosarcoma from endothelial cells, malignant lymphangioma, myosarcoma, osteosarcoma, osteosarcoma), seminoma, trachoma, Willms tumor.

[0076] The target tissue may include any tissue of a patient for which treatment with a solvent providing a therapeutic agent is indicated. Such tissues include arteries, ducts

Bile, colon, bile, bladder, bones, bone marrow, brain, breast, uterine mucosa, epithelium, bile, pouch head, intraperitoneal space, intestine, heart, joints, kidney, liver, lung, neck, esophagus , ovaries, pancreas, prostate, kidney canals, skin and layers, spleen, stomach, testicles, thymus, thyroid, uterus or veins.

[0077] In addition to being useful in the treatment of humans, the present invention is also useful in the treatment of other patients including veterinary animals, reptiles, birds, exotic animals and farm animals, including mammals, rodents, and the like. Mammals include horses, dogs, pigs, cats, or primates (for example, monkeys, chimpanzees, or lemurs). Rodents include rats, mice, squirrels, or guinea pigs.

[0078] One embodiment of the solvent supply device for a tissue or tumor of the present invention includes solvent injection means comprising a proximal port in fluid communication with the distal port of at least one infusion catheter that is surgically implanted with its proximal end into the tissue or tumor. In one implementation, the two ports are secured using a connecting and / or blocking device.

[0079] In a further embodiment, the device may further include an infusion tube for fluid communication between the proximal port of the solvent injection elements and the distal port of the infusion catheter. In yet another embodiment, the device may further include an integrated filtration system, one-way valves inhibiting proximal outflow and / or additional tubes.

[0080] Still another embodiment of the solvent supply device for a tissue or tumor of the present invention includes two or more infusion catheters that are suitable for placement in different tissue and / or tumor target areas to

Improving the penetration of solvent into tissue and / or cancer.

[0081] In one embodiment, the device may further include a splitter with a plurality of proximal ports, in an amount corresponding to the number of infusion catheters, and a distal port and lumen through.

[0082] The apparatus of the present invention may further comprise an integrated filtration system, one-way valves and / or additional tubes.

[0083] In yet another embodiment of the solvent or tissue delivery devices of the present invention, solvent injection means include a portable pump. The proximal pump port is in fluid communication with the distal port of at least one infusion catheter. The distal port of the portable pump is in fluid communication with the proximal solvent tank port. In one embodiment, the device may further include an additional infusion tube for fluid communication between the proximal port of the portable pump and the distal port of the infusion catheter.

[0084] In yet another embodiment of the present invention, the solvent supply device for a tissue or tumor includes means for injecting solvent with a proximal port in fluid communication with the distal port of the infusion tube. The nearer port of the infusion tube is in fluid communication with the distal part of the access port chamber yet using an auxiliary system. In implementation, the proximal port of the solvent injection components is directly connected to the distal port of the auxiliary system. The access port is preferably implanted subcutaneously, e.g., above the rib. The proximal access port port is in fluid communication with the distal access port catheter port and the proximal access port catheter port is in fluid communication with the distal port of the at least one infusion catheter. In yet another

In an embodiment, the proximal access port is in fluid communication with the distal infusion catheter port. Several catheters may be in fluid communication with the proximal port of the access port catheter or directly with the proximal port of the inlet port using an additional splitter. The proximal end of the infusion catheter is surgically implanted into the target tissue or tumor. In yet another embodiment of the present invention, the solvent injection means and infusion tube are outside the body. All ports can be connected with appropriate connecting and blocking devices.

infusion.

combined [0085] In one embodiment, the access port system and / or infusion catheter are permanently attached.

[0086] In yet another embodiment, the pump with reservoir and infusion tube is located outside the body.

[0087] Still other embodiments of devices for supplying solvent to tissue or cancer include a pump or portable pump for injecting solvent that is connected to its distal port with a reservoir or syringe pump filled with the appropriate amount of solvent for infusing the target tissue or tumor for several minutes, hours, days or weeks. The proximal pump port is in fluid connection with the distal tube port. The proximal infusion tube port is in fluid with the distal part of the access port chamber using the auxiliary system. In yet another embodiment, the proximal pump port is in direct fluid communication with the distal port of the auxiliary system, with an integrated filtration system, tube or other device, respectively. The proximal port of the access port chamber is in fluid communication with the access port catheter and the proximal port of the access port catheter is in fluid communication with the distal port of at least one infusion catheter. Also, several catheters may be in fluid communication with the proximal port

EP 1 615 682 B1 access port catheter using an additional splitter. In another implementation, the proximal port of the access port is in fluid communication with the distal port of the splitter or infusion catheter, either directly or using additional tubing or other device. The proximal end of the infusion catheter is surgically implanted into the target tissue or tumor. All ports can be connected to the appropriate connecting and blocking device.

[0088] It is possible that the devices additionally include brain ventricular drainage. Drainage of the ventricle of the brain may include a tube of appropriate diameter containing the proximal end that is surgically implanted into the intraspinal or cerebrospinal fluid and the distal port and lumen through. The distal port of this drainage is in fluid communication with the body cavity, for example, with the vein, with the intraperitoneal space, or with the proximal port of the access port system. In yet another embodiment, the drainage of the brain ventricle includes at least one catheter with its openings that terminates in the intraspinal or cerebrospinal fluid and the distal port and lumen through. This catheter can be extended through additional tubes, and can also include integrated one-way valves. All parts can be connected by a suitable connecting and / or locking device.

[0089] In yet another embodiment, the proximal access catheter port is in fluid communication with the distal port of the splitter. The distal ports of two or more infusion catheters are in fluid communication with the equivalent many proximal splitter ports. In one embodiment, the brain ventricular drainage may additionally comprise one or more integrated one-way valves, an additional tube, and may be connected by a suitable connecting and blocking device.

[0090] In yet another application of the present invention, the device includes two access ports. Closer

The port of one of the permanently fixed access ports is in fluid communication via an access port catheter and appropriate connector elements and blocking systems with a distal port of at least one infusion catheter surgically implanted in the tumor or tissue. The distal port of this access port is in fluid communication with the liquid solvent injection means. Additional infusion tubes, filtration systems, auxiliary systems, etc. can be integrated with such devices as described in the above implementations. The proximal port of the second access port chamber may be in fluid communication with the distal port of the second access port catheter. In one embodiment, the proximal access catheter port is in fluid communication with the ventricular drainage. In yet another embodiment, the distal end of the second access port chamber is covered by a septum allowing multiple puncturing using the access port needle and withdrawing intraspinal or cerebrospinal fluid for diagnostic and / or therapeutic purposes using solvent removal means.

[0091] The means for removing the solvent may be any device, such as, for example, a solvent tank, syringe or balloon. Additional tubes, valves or flow regulators can be integrated into the device. In one embodiment, the distal port needle of the access port is in fluid communication with the tube containing the distal port and the proximal port and the lumen through. The distal port of the tube is in fluid communication with the proximal port of the portable pump to remove fluid from the intrathecal lumen. In one embodiment, the flow of removed intrathecal fluid approximately corresponds to the flow of a liquid pharmaceutical agent or physiological solvent that is administered to the tissue or tumor.

[0092] The diameters and lengths of all tubes, catheters, connector elements and device ports described in

The present application may have a suitable range corresponding to the flow rate.

[0093] Yet another embodiment of the present invention includes one of the embodiments described above in which at least one of the lumens in contact with the solvent and / or wherein at least one of the permanently attached parts is sterile.

[0094] Yet another embodiment of the present invention includes any of the embodiments described above comprising a solvent that is selected from physiological solvent and / or a liquid pharmaceutical agent.

[0095] It is possible to use one of the devices described herein for administering the solvent to the target tissue or tumor using convective enhanced delivery, which is also referred to as high pressure micro perfusion. Generally, this means that solvent delivery induces a current convective flow in the target tissue or tumor that has the potential to uniformly disperse even large molecules through the tissue or tumor. The solvent flow depends on the specific tissue or tumor to which the liquid pharmaceutical agent is administered and in some cases may be even greater than the ranges given herein.

[0096] In inducing current convective flow in brain tissue, in one embodiment of the present invention, the continuous flow of infused liquid pharmaceutical agent is about 0.001 ml / hour to about 1 ml / hour, or about 0.1 ml / hour to about 0, 8 ml / hour, or about 0.2 ml / hour, ^lat^b about 0.5 ml / hour.

[0097] ^IN In yet another use of the present invention, the pump-induced flow meets at least one of the following flow characteristics in at least one of the infusion catheters: average flow

EP 1 615 682 B1 is between about 0.001 ml / hour and on average below about 1.0 ml / hour; the total flow volume over one period of any fluctuation is less than about

0.5 μΐ; and / or the amplitude of the fluctuation is between about

0.1 ml / hour and about 1 ml / hour.

[0098] In yet other applications of the present invention, the pump-induced flow meets at least one of the following characteristics in at least one of the infusion catheters: the average flow is between about 0.001 mL / hour and on average below about 1 L / hour, 0 , 5 l / hour, 0.1 l / hour, 0.05 l / hour, 10 ml / hour, 5 ml / hour, 1 ml / hour, 0.5 ml / hour, 0.1 ml / hour, 0 , 05 ml / hour or 0.01 ml / hour; a person skilled in the art knows which flow is suitable for different tissues, body cavities or tumors; the total flow volume in one oscillation period is less than about 0.5 μΐ and the oscillation amplitude is from about 0.1 ml / hour to about 1 ml / hour.

[0099] In yet other applications of the present invention, the pump-induced flow meets at least one of the following characteristics in at least one of the infusion catheters: the average flow is between about 0.001 ml / hour and on average below about 1 liter / hour, 0 , 5 l / hour, 0.1 l / hour, 0.05 l / hour, 10 ml / hour, 5 ml / hour, 1 ml / hour, 0.5 ml / hour, 0.1 ml / hour, 0 , 05 ml / hour or 0.01 ml / hour; a person skilled in the art knows which flow is suitable for different tissues, body cavities or tumors; the total flow volume in one oscillation period is less than about 5 μΐ and the oscillation amplitude is from about 0.1 ml / hour to about 10 ml / hour.

[0100] In other applications, the flow or fluctuation may even be smaller than the values ​​indicated above. These devices are still within the scope of the present invention.

[0101] In other embodiments may be used yet

Higher flows than those described herein, in the case where the solvent is introduced into the tumor or tissue with high circulation, respectively into the body cavity or vessel.

[0102] In yet another embodiment of the present invention, a device that induces flow in an infusion catheter, as described herein, uses constant average flows, increasing or decreasing flows, as well as combinations thereof.

[0103] In yet another use of the present invention, the device is used for intermittent therapy, which means that the liquid pharmaceutical agent is administered alternately with another liquid pharmaceutical agent and / or a physiological solvent. The flow of physiological solvent at a time when no other liquid pharmaceutical agent is administered depends on many factors including, for example, the target tissue. By way of illustration, in the case of convective enhanced delivery to brain tissue, the flow may vary between about 0.001 ml / hour to about 1 ml / hour, or between about 0.01 ml / hour to about 0.4 ml / hour, or between about 0.05 ml to about 0.3 ml / hour in each infusion catheter. In one embodiment, the pump also operates periodically, using increasing or decreasing flows, as well as their combinations.

[0104] In yet another application, the infusion catheter is surgically implanted so that its perfusion holes terminate in the tumor or tissue into which the liquid pharmaceutical agent is to be administered. The access port connected to the access port catheter is implanted anywhere. In one embodiment, the access port catheter is inserted toward the open end of the infusion catheter. The access port catheter, as well as the catheter shortened to the appropriate length, they are arranged loosely enough, the infusion may be taking into account that in order to follow body movements without affecting the exact position

EP 1 615 682 B1 neither infusion catheter nor access port. Finally, an access port catheter connected to the infusion catheter using a suitable adapter. In yet another embodiment, the implanted device is filled with a physiological solution with which a liquid pharmaceutical agent is to be introduced.

[0105] Although the specification focuses on tumors and tissues, the method of the present invention can also be applied to body cavities, veins and arteries.

[0106] In yet another embodiment, the pump is portable and includes a fluid reservoir that is large enough to withstand convective enhanced delivery for many days at a flow rate that leads to a final flow in the infusion catheter between 0.1 and 15 μΙ / minute, or between 2 and 12 μΙ / minute, or between 3 and 10 μΙ / minute.

[0107] Until now, only syringe pumps, such as the widely used "Graseby® 3200" syringe pump (Graseby Medical Limited, Watford, Herts, United Kingdom), have been clinically used to treat convection-enhanced reinforced characteristics to achieve a consistent flow. their constant delivery due to flow. In one embodiment, the maximum swing of such a syringe in combination with the infusion tube, access port, access port catheter and filter is as small as 0.1 ml / hour in one second at an average flow rate of 480 μΙ / minute as shown in fig 2b.

[0108] In the characteristics of one embodiment, a pump having a flow whose fluctuation is 1 ml / hour or more per second in combination with a catheter is suitable for convective enhanced delivery technique.

[0109] In one use of the present invention, the compounds administered to a patient are formulated for injection, and include, for example,

An aqueous solution or suspension of compounds suitable for intravenous administration. When preparing injectable compositions, particularly for intravenous administration, by way of illustration, the dispersion phase comprises an aqueous solution of tonicity modifiers, buffered to a pH of about 7 to about 7.5, in yet another embodiment buffered to a pH of about 7 , 3 to about 7.5, or to a value from about 7.2 to about 7.4, in yet other embodiments, the solution is buffered to a pH of, for example, below 7, or, for example, below 6. Solution tonicity modifiers include, for example, substances such as sodium chloride, glucose, mannitol, trehalose, glycerol, or other pharmaceutical agents that make the osmotic pressure of the formulation isotonic with blood. Alternatively, when a larger amount of the tonicity modifier is used in the formulation, it may be diluted prior to injection using a pharmaceutically acceptable diluent to make the mixture isotonic with blood.

[0110] In a further application of the present invention, a preservative is added to the formulation. By way of illustration, the preservative includes substances such as benzalkonium chloride, propylparabe, butylparaben, chlorobutanol, benzyl alcohol, phenol, sodium benzoate, or EDTA.

[0111] The compositions of the present invention may further comprise a pharmaceutically acceptable carrier. Carrier materials that can be used in preparing the compositions of the present invention include any of the excipients typically used in pharmaceutical compositions and should be selected based on compatibility with the pharmaceutical agent and the release profile properties of the desired dosage form. By way of illustration, below are selected examples of pharmaceutical excipients except active

EP 1 615 682 B1 drugs:

(a) Binders, such as acacia, alginic acid and its salts, cellulose derivatives, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, magnesium aluminum silicate, polyethylene glycol, gums, polysaccharide acids, bentonites, hydroxypropyl methylcellulidinylcelliolin, polyethylene glycol , crospovidone, pivipone, polymethacrylates, hydroxypropyl methylcellulose, hydroxypropyl cellulose, starch, pregelatinized starch, ethyl cellulose, tragacanth, dextrin, microcrystalline cellulose, sucrose, or glucose, and the like.

(b) Disintegrants, such as starches, pregelatinized corn starch, pregelatinized starch, celluloses, cross-linked carboxymethylcellulose, sodium starch glycolate, crospovidone, cross-linked polyvinylpyrrolidone, croscarmellose sodium, calcium, alginate, alginate, sodium alginate sodium glycolate, and any disintegrants used to make tablets.

(c) Filling agents such as lactose, calcium carbonate, calcium phosphate, calcium dihydrogen phosphate, microcrystalline cellulose, calcium, dextran, cellulose starch, powdered, dextrose, dextrans, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

(d) Surfactants such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glycerin monostearate, Pluronic ™ line (BASF), and the like.

(E) A solubilizer such as citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate and sodium carbonate and the like.

(f) Stabilizers, such as any antioxidant agents, buffers, or acids, and the like, may also be used.

(g) Lubricants such as magnesium stearate, calcium hydroxide, talc, sodium stearyl fumarate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, magnesium, calcium and sodium stearates, stearic acid, talc, waxes, stearovet, boric acid, sodium benzoate , sodium acetate, sodium chloride, DL-leucine, polyethylene glycols, sodium oleate, or sodium lauryl sulfate, and the like.

(h) Wetting agents such as oleic acid, glycerin monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, or sodium lauryl sulfate.

(i) Diluents such as lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, calcium dihydrogen phosphate, diluents based on sucrose, powdered sugar, calcium hydrogen sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrans , inositol, solid cereal hydrolysates, amylose, powdered cellulose, calcium carbonate, glycine, or bentonite, and the like.

(j) Anti-caking agents or glidants,

Such as talc, corn starch, DL-leucine, sodium and magnesium lauryl sulfate, calcium or sodium stearates, and the like.

(k) A pharmaceutically compatible carrier includes substances such as acacia, gelatin, colloidal silica, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, calcium triphosphate, dipotassium phosphate, sodium stearyl lactate carrageenan, monoglyceride, diglyceride, or pregelatinized starch, and the like.

[0112] In addition, drug formulations are discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975. Further discussion of drug formulations can be found in Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New Yori NY, ¹⁹80.

[0113] It is obvious to those skilled in the art that two or more devices described herein can be used in parallel or in combination with each other.

[0114] As used herein, the term "auxiliary system" refers to a device enabling smooth access to an access port.

[0115] The term "access port" as used herein refers to a device, preferably permanently attached, into which fluid may be injected using an auxiliary system.

[0116] As used herein, the term "access port catheter" refers to a tube that can be connected to the exit port of an access port. The access port catheter includes a distal port and a proximal port and a lumen. The access port catheter allows seamless communication between the access port and, for example, a splitter, infusion catheter, or any other tubing or device.

[0117] As used herein, the term "access port system" preferably refers to a device that is permanently attached

EP 1 615 682 B1 and includes an access port.

[0118] As used herein, the term "connector element" refers to the device used to connect tubes, catheters, tanks, pumps, access ports that are in a fluid connection in such a way as to ensure smooth communication and prevent disconnection of fluid communication due to mechanical stress .

[0119] The term "convection enhanced delivery (CED)" as used herein refers to the delivery of a solvent that induces a current convective flow to a target tissue or tumor that has the potential to uniformly disperse even large molecules over large distances through the tissue or tumor. This method is also known as high pressure micro perfusion.

[0120] As used herein, the term "distal" refers to that portion of the device that is in the inlet side relative to the flow direction, viewed from the tumor or tissue side into which the infusion catheter has been implanted.

[0121] The term "volume increasing element" as used herein refers to any flexible device or device downstream of the pump that is further integrated into the tubing to smooth the peak flow induced by this pump. Therefore, the sheath of the volumizing element must be flexible enough to compensate for the flow peak / pressure peak, respectively. The clearance of the volume-expanding element is widened as the pump supplies solvent and the clearance is narrowed over a period of time when the pump does not supply solvent, thereby smoothing the peak flow values ​​downstream of the device in the direction of flow.

[0122] The means for increasing the volume may be, for example, a balloon, a membrane, a soft tube, etc.

[0123] The term "fluid medium" as used herein

"Pharmaceutical" refers to a fluid containing a pharmaceutical substance in dispersed or dissolved form.

[0124] The term "intermittent therapy" as used herein refers to the administration of a liquid pharmaceutical agent at least once over a specified period of time, for example, within minutes, hours, days, or weeks, alternating with at least one other liquid pharmaceutical agent and / or solvent physiological.

[0125] As used herein, the terms "injection components", "injection components", etc., refer to a device that can induce flow or a single large dose of solvent, and includes, for example, a pump, syringe, balloon, plunger, etc.

[0126] The term "needle guard" as used herein refers to a device that prevents penetration of an access port needle of some form or diameter through another access port needle of similar or different form or diameter. The needle shield can be made of any suitable material known in the art, such as, for example, a netting material with a suitable mesh diameter, or a foil with perforations of a certain diameter or form, etc.

[0127] As used herein, the term "one-way valve" refers to a device, such as a valve, for example, that allows smooth flow in substantially only one direction.

[0128] As used herein, the term "fluctuation" refers to any regular or irregular change in the solvent flow induced by a pump or other injection means.

[0129] As used herein, the term "physiological solvent" refers to a fluid that is administered to a patient and is used with or without a liquid pharmaceutical agent. A physiological solvent typically has a composition that is physiologically compatible with the patient's body, and typically has substantially similar pH and salt concentration as the target tissue or tumor. By way of illustration, a physiological solvent is a solution

0.9% aqueous sodium chloride with a pH from about 6 to about

[0130] As used herein, the term "portable pump" refers to a pump of such a mass and configuration that allows the patient to easily transport the pump while maintaining fluid flow rate characteristics that can be used with the device described herein. For example, in the case of an adult human, the maximum weight of a portable pump ranges, for example, from less than about 1 kg to less than about 0.05 kg, or less than about 0.75 kg, or less than about 0.5 kg, or less than about 0.25 kg, or less than about 0.1 kg, when unfilled. Such portable pumps can be worn close to the body in a manner that allows the patient's hands to be kept free, and can be attached to the body, for example, using a leather pouch attached to the belt. By way of illustration, a device such as a movable tripod, for example, is not needed when the patient is moving, thus ensuring complete mobility during the course of treatment. In addition, in one embodiment of the present invention, the pump is easy to maintain but sufficiently robust to ensure steady flow when the patient is moving, in an appropriate manner during treatment (e.g., walking, sitting, and / or lying down). In addition, in a further implementation, the portable pump is configured (for example, using secured buttons and programs) so that the risk of inadvertent changes in the pump function during daily activities does not exist at all or is essentially small. To facilitate treatment and use by the patient, refilling the solvent tank and reprogramming the pump should be simple and easy to understand without the need for any additional complicated devices, which is typical for out-of-hospital setting.

[0131] As used herein, the term "proximal" refers to this part

The device is located in the downstream direction when viewed from the tumor or tissue side into which the infusion catheter is implanted.

[0132] As used herein, the term "septum" refers to a material covering the distal portion of the access port enabling the needle to be inserted through the material without losing its sealing properties around the needle or losing its sealing properties when the needle is withdrawn. In one embodiment, the septum is flexible and able to hold the seal when the needle is inserted and withdrawn on one or more occasions.

[0133] As used herein, the term "solvent" refers to a solvent such as a physiological fluid or fluid pharmaceutical agent that can be infused using the device of the present invention.

[0134] The term "brain ventricular drainage" as used herein refers to fluid communication between the cerebrospinal fluid of the brain or intramedullary light and a body cavity, such as, for example, a vein or intraperitoneal space, or an external solvent reservoir. Smooth communication of the brain ventricular drain to the external solvent reservoir can be provided by an additional access port system as described herein.

[0135] The present invention is further illustrated by the following examples, which should not be considered as limiting the scope of the invention in any way.

EXAMPLES

Example 1 [0136] In this example, an isotropic 0.4% agarose gel model was used. (Chen ZJ, 2002). This gel was placed in a transparent acrylic cube with an edge length of 7 cm, up to a total volume of w

Approximately 340 ml. Then, under strictly controlled conditions in the laboratory, the gel was poured with blue dye

Evans, with a molecular weight of 960.8 for a period of hours and photographs of the resulting infusion standard were taken.

Photographs were taken at 0, 1, 3, 6, 12 and 24 hours during the infusion time. The experiment compared a syringe pump used for hospital treatment of a patient, Graseby 3200, (Graseby Medical Limited, Watford, Herts, United Kingdom) with rotating radial pistons Pegasus Vario with a pump with (Pegasus GmbH, Kiel, Germany) catheters. First, a polyimide tube with an internal diameter of 0.02 mm and an external diameter of 0.85 mm was used to use two different infiltration solvents (Graseby 3200 United Kingdom). Secondly, a ventricular catheter with a large number of lateral holes (4 rows of 8 holes, a total of 32 holes, from Medtronic Neurosurgery, Goleta, CA, USA) was used for infiltration.

[0137] Different flows were used in the experiment. Fig. 4b shows the distribution at a flow rate of 0.48 ml / hour using a "Pegasus Vario" rotating radial piston pump under test conditions. Figure 4b shows the corresponding distribution using a "Graseby 3200" syringe pump (Graseby Medical Limited, Watford, Herts, United Kingdom) at the same flow rate of 0.48 ml / hour.

[0138] Unexpectedly, the "Pegasus Vario" pump with rotating radial pistons, which until now was not accepted for convection enhanced delivery, showed such good distribution patterns over time (Fig. 4b) as the approved syringe pump (Graseby Medical approved) Limited, Watford, Herts, Fig. 4a).

[0139] An experiment was also carried out using an average flow rate of 240 Pΐ / hour in which comparable results were obtained.

EP 1 615 682 B1 for the treatment of glioma rotating pistons reservoir bag from

Example 2 [0140] A portable radial pump and infusion tube i were used for the delivery system

LogoMed GmbH, Windhagen, Germany. The type of portable pump used was the "Pegasus Vario" pump containing a polyurethane tank with a capacity of 50 ml. The infusion tube was 100 cm long and included an integrated flat sterile filter (pore diameter - 0.22 pm). Gripper® (22G) needles with lengths 16, 19, 25 and 32 mm from Deltec were used as infusion needles. Inc. St. Paul, Mnnesob, EU> A. Harbor^dost^ępu ^pABOUT^RT^-AND^-CAT^H, with a small profrtu, made of titanium, as well as an access port catheter, was purchased from Deltec. Inc. St. Paul, Minnesota, USA. The access port catheter was made of silicone and was impregnated with x-ray absorbing material and was connected to one infusion catheter (tumor catheter) using a CSF catheter connector made of nylon from Medtronic Neurosurgery, Goleta, CA, USA.

[0141] As shown in Figure 1, the infusion catheter was surgically implanted with its perfusion holes ending in the brain in the middle of the tumor (glioma), and was attached to the skull. The access port was connected to the access port catheter and was implanted on the patient's rib, while the access port catheter was located toward the open end of the infusion catheter, which was positioned in the cervical orientation. The overlapping end of the access port catheter has been shortened so that it is loose enough and can follow body movements without affecting the exact position of the infusion catheter during connection, and was then connected using a connector with the infusion catheter. All implanted devices were filled with physiological solution before

EP 1 615 682 B1 by implantation.

[0142] The reservoir, pump head, infusion tubing and access port needle were filled with the infusion solution, and the reservoir pump was positioned on a suitable body part using, for example, a belt around the waist. The access port needle was then inserted through the skin, adipose tissue and septum into the subcutaneous access port, followed by infusion.

[0143] The flow during the administration of the pharmaceutically active substance AP 12009 varied between 0.2 ml / hour and 0.5 ml / hour for 4-7 days.

[0144] During 7 days, when no liquid pharmaceutical agent was administered, the system was flushed with isotonic sodium chloride solution at a rate of 0.06 ml / hour. These cycles were repeated 6-13 times, giving a total treatment time of about half a year.

Example 3 [0145] This experiment was conducted to compare convective enhanced delivery flow characteristics using the approved Graseby® 3200 syringe pump (Graseby Medical Limited, Watford, Herts, United Kingdom) with the portable pump Pegasus Vario. The measurement was carried out at the "Institut fur Mikround Informationstechnik der Hahn-Schickard-Gesellschafte.^V>”, ^Wilhelm^-sc^hic^kard^-S^trasse ^{10, 78052 V}illin^genSchwenningen, Germany.

[0146] Measurements were carried out at the "Fluid flow" measurement site at this institute.

[0147] To exclude external influences, all measurements were carried out on a vibration damping table.

[0148] In a first step, the calibration curve of the sensor used in this experiment was calibrated, based on the principle of hydrostatics, with

By means of which flow is induced by connecting two tanks of different levels using pipes. The sensor used was the SP45 sensor, type 300 x 600 tp 45, channel 0.8 mm x 0.4 mm, with a heating power of 20 mW (20 V).

[0149] Pump performance was measured in conjunction with the devices that were used in Example 1. Briefly, the pump with reservoir was connected using an infusion tube with a filter and access port needle, access port, access port catheter, connector piece, and infusion catheter. In order to allow proper connection with the device under test, the infusion catheter was shortened in length just behind the perfusion holes, viewed from the tip. The fluid used in the tested system was water.

[0150] The results of the flows measured in this experiment are shown in Figs. 2a and 2b for the "Graseby® 3200" syringe pump and in Figs. 3a and 3b for the "Pegasus Vario" pump.

[0151] For all formulations used herein, dosages can be formulated by methods known in the art.

[0152] The invention has been described in an illustrative manner, and it should be understood that the terminology used is intended to describe the invention rather than to limit its scope. All patent documents and other references cited herein are hereby incorporated in their entirety by reference. In the light of the information given above, many modifications, equivalent solutions, and variations of the present invention are possible, therefore it should be understood that the invention falling within the scope of the appended claims may be implemented otherwise than as specifically described.

Example 4 [0153] The clinical study presented here was essentially designed as a safety study and was approved by local ethics committees and

EP 1 615 682 B1 carried out in accordance with current international

The Helsinki Declaration on medical tests performed on humans and with the guidelines of current Good Clinical Practice (GCP).

Patients were selected according to the following criteria.

[0154] Patients with anaplastic astrocytoma (AA), WHO grade 3, or malignant glioma (GBM), grade 4 WHO, refractory to treatment or recurrent after standard therapy (surgery, radiation, and in most cases various therapies) with the use of anti-cancer substances).

[0155] Patients were between 18 and 75 years old. Karnofsky's level of efficiency (KPS) was at least 70%. Patients with clinically significant acute infections, cardiovascular abnormalities or poorly controlled seizures, as well as pregnant and lactating women were excluded from the studies.

[0156] Surgical planning was based on computed tomography or magnetic resonance imaging. The perforated part of the catheter was placed in the solid, strengthened area of ​​the tumor. Ventricles, cysts, resection cavities resulting from previous surgical interventions, blood vessels and speech areas of the brain had to be bypassed by the catheter track. The catheter was introduced through a standard drilled hole in the skull in the center of the target tumor. The distal end of the catheter was inserted subcutaneously and filled with isotonic saline. The TGF-beta 2 specific antisense oligonucleotide was administered to the tumor using continuous high flow micro-perfusion (also referred to as convective enhanced delivery, CED) using an external portable pump system. The port system and pump were arranged according to fig. 1.

[0157] Case report: A 45-year-old man was diagnosed with anaplastic astrocytoma (AA) (grade III

WHO). After the initial diagnosis, surgery and radiation therapy were performed without success. The patient was enrolled in the study using treatment with the specific TGF-beta 2 antisense oiggonulleotide administered using the delivery system described in the present invention. Ten cycles of administration of the specific TGF-beta2 antisense oligonucleotide were performed at a flow rate of 8 μΙ / minute for several days at weekly intervals through a catheter placed inside the tumor.

[0158] Magnetic resonance imaging (MRI) images were used to monitor tumor size based on monthly control. 19.4 months after starting treatment with antisense oligonucleotides, the tumor size was reduced to 83% (partial response) and confirmed using a central MRI reading. A very long survival was obtained; the patient was still alive at the time of writing this report (i.e. 89 weeks after starting AP12009 and 160 weeks after initial diagnosis).

[0159] This clinical example proves that the delivery system of the present invention effectively allows CED-based drug to be administered topically to, for example, malignant brain glioma.