Variable Dose Therapeutic Drug Dispenser

Abstract

A variable volume fluid dispenser (10) for use in medical treatment and diagnosis includes a tubular body (12) having a proximal end (16) and a distal end (14). Each end includes a fluid connector (18, 26), and the tubular body (12) defines an interior volume. A piston (30) is disposed within the interior volume and is configured to form a fluid and gas seal within the interior volume of the tubular body (12) and to move axially between the proximal end (16) and the distal end (14) under the action of a displacement fluid via the fluid connectors (18, 26). The position of the piston (30) relative to the tip determines the volume of fluid dispensed.

Description

[Technical field]

[0001] The present invention relates to medical devices, and more particularly to devices and associated methods for storing a defined volume of fluid, such as an infusate and / or therapeutic agent. [Background technology]

[0002] Medical procedures involve the injection of precise volumes of fluids into the body for both diagnostic and therapeutic purposes. Routes of administration include, but are not limited to, intravenous, intraarterial, intraperitoneal, intramuscular, intravitreal, intratumoral, intracystic, intrathecal, intraventricular, and into the brain parenchyma via a technique called convection-enhanced delivery (CED).

[0003] Fluids, including drugs injected for the diagnosis and monitoring of disease, delivered via these routes include, but are not limited to, radiopaque contrast agents for magnetic resonance imaging (MRI), X-ray, and X-ray computed tomography (CT), radioisotopes used in single photon emission computed tomography (SPECT) and positron emission tomography (PET), and dyes.

[0004] Fluids carrying therapeutic agents infused via these routes include, but are not limited to, chemotherapeutics, antibiotics, enzymes, neurotrophins, gene therapy agents, siRNA and antisense oligonucleotides, enzymes, immunomodulatory therapies (such as monoclonal antibodies and chimeric antigen receptor T cell (CAR-T) therapeutic agents), Auger electron emitters, immunotoxins, molecular targeted therapies, monoclonal antibodies, oncolytic viruses, nanoparticles, and botulinum toxins. Some of these therapeutic agents can be potentially dangerous to both the patient and the clinical staff involved in preparing the treatment. Furthermore, many of these therapeutic agents are very expensive.

[0005] A wide range of conditions can be treated by injecting these agents via one or more of the above routes of administration, including infectious, malignant, metabolic, autoimmune, rheumatic, enzyme deficiency and neurological conditions.

[0006] The success of treating neurological diseases has been compromised by the limited access of therapeutics to the central nervous system when administered systemically. This is due to the presence of the blood-brain barrier (BBB). Nonetheless, even if the BBB could be freely crossed by systemically delivered therapeutics, the ubiquitous effects of many potential therapeutics can cause significant toxicity. Thus, successful treatment of many neurological diseases requires a means to deliver an effective therapeutic dose of a drug that is limited to the pathological alterations of the central nervous system (CNS).

[0007] CED techniques can be used to achieve direct delivery of therapeutics to clinically relevant brain regions. With CED techniques, fluids containing therapeutics, such as drugs including viral vectors, proteins, or chemical therapeutics, are infused at carefully controlled flow rates through carefully placed microcannulas, allowing bulk flow to uniformly carry the therapeutic throughout a defined brain target. The therapeutic / infusate can travel through the extracellular space within the tissue, displacing the extracellular fluid. Since extracellular fluid constitutes approximately 20% of the brain volume, the volume of distribution per infusate can be approximately 5 / 1. The dose delivered by CED can be tightly controlled at the target volume, where the BBB acts to retain the therapeutic / infusate, providing a long exposure time and negligible, if any, systemic exposure.

[0008] Neurological disorders that can potentially be treated by direct injection of therapeutics / infusates into the brain parenchyma using CED techniques include neurodegenerative disorders, enzyme deficiency conditions, neuroinflammatory disorders, neuro-oncological disorders, and acquired neurological injuries. Depending on the particular pathology being treated, injections into multiple target regions within an individual's brain may be required. For example, when treating a Huntington's disease patient with a gene therapy drug, the patient's caudate nucleus and putamen volumes may be targeted. Typically, one cannula is delivered to each caudate nucleus, and two cannulas may be required to fill each putamen. Thus, a total of six cannulas may be required. The volume of gene therapy drug required to treat a Huntington's disease patient will vary from person to person depending on the size of each nucleus, which may further vary depending on the overall brain size and the degree of brain atrophy suffered. Thus, the injection volume of each cannula to meet the individual's specific targets must be calculated and prescribed.

[0009] Typical volumes injected into subcortical gray matter structures range from 200-800 μl per cannula, but can be significantly higher to cover the entire brain. These larger volumes may be necessary in cases of widespread brain disease or brain tumors, where 3-5 ml can be delivered per cannula.

[0010] As mentioned above, therapeutic drugs used for a wide range of medical conditions are often dangerous and / or expensive. Existing techniques for administering these drugs to patients often require a physician or other medical staff to draw the drug into a syringe and flush it through an infusion line before connecting it to a catheter or cannula placed in the patient's body. This is usually done in a ward, or in an associated clinical space such as an operating theatre. If the therapeutic drug / infusate is delivered by CED and the distribution of the infusate is monitored while the patient is in the MRI scanner, the infusion line needs to be 2-3 metres long as the associated pump needs to be away from the magnetic field. The syringe is loaded into a pump programmed to deliver a defined volume at an appropriate flow rate. Compliance of long infusion lines can cause unpredictable dosing as the initial flow of fluid in the line when the pump is switched on causes line expansion, i.e. an increase in the content of the line. Furthermore, when the pump is switched off, residual pressure in the line can cause the line to bleed out, which can continue for some time. After the injection is complete, the syringe and injection line are disconnected from the cannula or catheter and discarded in a hazardous waste container.

[0011] Risks associated with this procedure include staff and patient exposure to hazardous drugs and therapies, waste of expensive drugs and therapies in syringes and long infusion lines, dosing errors, etc. These risks are amplified by the complex dosing schedule described above for delivering therapy to the brain simultaneously through multiple cannulas, each of which may require a different volume to be infused.

[0012] WO 2013 / 117661 provides an example of a device for delivering therapeutic fluid to the brain. The device includes a cannula that is inserted into the brain and a percutaneous fluid access device that is secured directly to the patient's skull. The access device incorporates an external connector device that provides a fluid link between an external syringe pump that delivers the therapeutic agent and an internal system that incorporates the cannula.

[0013] The external system includes a fluid reservoir consisting of a flexible plastic tube sealed at both ends with a septum. The inside diameter (bore dimension and length) of the tube represents the internal volume and volume of infusate, i.e., the volume of therapeutic agent contained within the tube. Different lengths of tubing are considered so that different therapeutic doses, i.e., fixed volume sets, are available so that the appropriate tube can be selected when a specific therapeutic dose is required, i.e., the selected tube is filled with the required dose of infusate. When delivery of infusate is required, it can be connected proximally via an infusion line with a hollow needle connector to a syringe (pre-primed with an inert fluid) via appropriate tubing, and distally, a double-ended hollow needle connector may connect the fixed volume infusion line to a cannula that includes a proximal septum seal.

[0014] The syringe is connected to an infusion pump, which moves an inert fluid through a fixed volume extension line to move a prescribed dose of therapeutic agent into the cannula for delivery to the brain tissue by convection, thereby flushing the cannula dead space of residual therapeutic agent. Summary of the Invention [Problem to be solved by the invention]

[0015] A drawback of this system is that the delivery of therapeutics to specific brain regions is highly variable and depends, as mentioned above, on the size of the individual's brain and, more specifically, on the size and shape of individual brain nuclei. Particularly for gene therapy drugs, very precise dosing may be required to prevent off-target transfection and the occurrence of long-term side effects. For example, a volume difference of ±20 μl may be desirable, and the number of fixed volume sets required to accommodate these volume differences (described in WO 2013 / 117661) makes the described method impractical.

[0016] The fixed volume extension line described in WO 2013 / 117661, when connected to an infusion line, results in mixing of the inert fluid and therapeutic agent at the proximal end. [Means for solving the problem]

[0017] The present invention provides a variable volume fluid dispenser for medical therapeutic and diagnostic applications, the variable volume fluid dispenser comprising: a tubular body having a proximal end and a distal end, the tubular body defining an interior volume between the proximal end and the distal end; a fluid connector at each of the proximal and distal ends; a piston located within the internal volume, the piston configured to move axially between the base end and the tip end under the action of fluid displacement through the fluid connector, the position of the piston relative to the tip defining a volume of fluid dispensed.

[0018] In use, when an amount of dispensing fluid less than the volume of the internal volume is contained within the dispenser, the piston can divide the internal volume into a tip volume and a base volume, such that the tip volume defines a dispensing chamber between the tip fluid connector and the distal face of the piston. In use, the fluid contained in the dispensing chamber defines a defined volume of fluid that can be stored within the variable volume fluid dispenser until delivery / dispensing, and the volume of the dispensing chamber, i.e., the tip volume, depends on the position of the piston relative to the proximal and distal ends.

[0019] Variable volume fluid dispensers address problems associated with the safe dispensing, safe storage, and precise delivery of defined volumes of fluids for the treatment, diagnosis, and monitoring of disease.

[0020] The variable volume aspect of the variable volume fluid dispenser is provided by movement of the piston to increase or decrease a tip volume, the tip volume being defined between the distal end of the tubular body and a distal face of the piston. It will be appreciated that the maximum volume of fluid contained in the variable volume fluid dispenser is when the piston abuts the proximal end. The proximal volume is defined between the proximal end of the tubular body and a proximal face of the piston.

[0021] The tubular body may be formed of a hard, pharmacologically inert material. For example, the tubular body may be made of glass or plastic. For example, the tubular body may be made of borosilicate glass (optionally type 1 borosilicate glass), such as Pyrex®. Alternatively, the tubular body may be made of laboratory grade polypropylene and / or polyethylene resin. The tubular body may be formed of a plastic, such as a cyclic olefin polymer (COP) or a cyclic olefin copolymer (COC).

[0022] One or both fluid connectors may comprise a hollow needle that makes the fluid connection by piercing a septum of a connection member of a device to which the dispenser is connected. Alternatively, one or both fluid connectors may be a seal pierceable by a hollow needle. For example, the seal may be a septum stopper pierceable by a hollow needle. Alternatively, one or both fluid connectors may be a split septum that can be opened. For example, a device such as a blunt cannula or male luer may penetrate the split septum to facilitate fluid flow through the split septum. Alternatively or additionally, one or both fluid connectors may comprise a valve that can be actuated / opened, for example, by connection to an actuation interconnection member. For example, the valve may be a mechanical valve, which requires physical actuation of the valve to allow fluid flow. Alternatively or additionally, the valve may be a pressure sensitive valve, which is operable to open when fluid flows (e.g., in response to a pressure gradient established across the valve) and close when fluid flow stops. The pressure sensitive valve may comprise a split seal or a split septum. Alternatively or additionally, one or both fluid connectors may comprise a needleless connector.

[0023] One or both fluid connectors may further comprise a removable cap, particularly if either fluid connector is a hollow needle, the fluid connector may further comprise a cap, such as a removable shipping cap that hermetically seals the needle.

[0024] The proximal fluid connector can be configured to connect the proximal end of the dispenser to an infusion line, for example from a syringe pump. The infusion line can include an interconnector to the proximal fluid connector. For example, the proximal fluid connector can include a septum and the interconnector can include a hollow needle configured to pass through the septum.

[0025] The distal fluid connector can be configured to connect the distal end of the dispenser to the proximal end of the cannula, which includes an interconnector to the distal fluid connector, or, for example, the distal fluid connector can include a hollow needle and the interconnector can include a pierceable septum seal, with the hollow needle configured to pierce the septum seal.

[0026] As previously mentioned, the piston may divide the internal volume into a proximal volume and a distal volume, both of which may be configured to hold a relatively incompressible fluid, particularly a liquid.

[0027] The proximal connecting member and / or the distal connecting member may be a luer fitting configured to connect with a reciprocal luer fitting. Advantageously, a hollow needle connector housed in a male luer fitting protects the user from needle injuries when handling the device.

[0028] In use, the double ended hollow needle connector can be used to connect the dispenser to a compatible member, for example a cannula or infusion line, with the dispenser fluid connector and the compatible member / device fluid connector each comprising a pierceable seal.

[0029] A variable volume fluid dispenser according to the present invention provides a device configured to contain a tailored volume of fluid for delivery to a patient for diagnostic or therapeutic purposes, which may include a therapeutic agent, such as a gene therapy agent, to be delivered to a specific brain target region.

[0030] As mentioned above, as an example, the treatment of Huntington's disease requires six cannulas to deliver to six targets, i.e., two cannulas for each putamen and one cannula for each caudate nucleus. It will be understood that the size of the nuclei varies between individuals and even between different sides of an individual's brain. Thus, the amount of therapeutic agent that needs to be delivered through each cannula is predetermined, and therefore each dispenser associated with each cannula needs to be filled with a corresponding defined amount of fluid, including the therapeutic agent, in order to safely and accurately deliver the therapeutic agent to the patient. A variable volume dispenser meets this requirement because each dispenser can be configured to contain a defined amount of fluid, including the therapeutic agent, in the tip volume, i.e., the dispensing chamber.

[0031] At least an axial portion of the tubular body may be transparent and include internal or external surface markings to indicate the position of the tip of the piston and thereby the flow rate of the fluid contained within the tubular body. The markings may include a calibrated scale including graduation marks.

[0032] The piston may include a circumferential seal member operable to form a fluid and gas seal within the interior volume of the tubular body. The circumferential seal member may include one or more contact surfaces. For example, the circumferential seal may include an O-ring type seal, a lip seal, an elongated sealing surface, and the like. One or more contact surfaces of the circumferential seal may be configured with low friction characteristics such that when a fluid acts on the distal or proximal surface of the piston, the piston is free to move with little or no resistance against the interior surface of the dispenser. For example, at least the outer surface of the circumferential seal may include glass or polytetrafluoroethylene (PTFE). A PTFE or alternative fluoropolymer coating on the distal surface of the piston provides a drug compatible surface. The tubular body portion may also be silicone coated or have a baked-on silicone coating to reduce friction of the interacting surfaces. Alternatively, the outer surface of the circumferential seal may include silicone.

[0033] A further aspect of the present invention provides a method of filling a dispense chamber of a variable volume fluid dispenser, the method comprising: degassing the internal volume, priming the internal volume with an inert fluid via the proximal fluid connector, and driving the piston axially with the inert fluid until the internal volume is filled with the inert fluid and the piston abuts the distal end; attaching a fluid container to the distal end and an extractor to the proximal end; filling the tip volume with a defined amount of fluid to be dispensed by simultaneously extracting inert fluid from the interior volume and drawing a predetermined amount of fluid from the container into the tip volume; Disconnecting the extractor and the container of fluid from the distal and proximal ends, respectively.

[0034] The method further includes hermetically sealing the fluid contents of the variable volume fluid dispenser by attaching a shipping cap to one or both of the distal and proximal ends.

[0035] The step of extracting inert fluid from the internal volume while simultaneously drawing a defined amount of fluid into the tip volume can be performed by creating a pressure gradient in either direction: the pressure in the proximal volume can be lowered by pumping inert fluid through the proximal fluid connector, or the pressure in the tip volume can be increased by pumping fluid through the distal connector.

[0036] The inert fluid pumped into or extracted from the base volume acts on the piston to increase or decrease the volume of fluid in the tip volume, i.e., the dispensing chamber, which is a predetermined volume of fluid to be dispensed for treatment or diagnosis. [Brief description of the drawings]

[0037] Next, an embodiment of the present invention will be described with reference to the accompanying drawings.

[0038] [Figure 1] FIG. 1 illustrates a variable volume therapeutic agent dispenser. [Diagram 2] FIG. 2 shows a cross-sectional view of the dispenser of FIG. 1 containing a defined amount of therapeutic agent and an amount of inert fluid. [Diagram 3] FIG. 3 shows the dispenser of FIG. 1 being vented and filled with an inert fluid. [Figure 4] FIG. 4 illustrates the filling of the dispenser of FIG. 1 with a fluid containing a therapeutic agent. [Diagram 5] FIG. 5 shows an exploded view of an application of the dispenser of FIG. [Figure 6] FIG. 6 shows an exploded view of the septum seal connector at the proximal end of the cannula. [Figure 7] FIG. 7 shows a connecting member that includes a luer fitting configured to connect with a reciprocal luer fitting provided on an infusion line. [Figure 8] FIG. 8 illustrates an alternative design for a bulkhead seal connector. [Figure 9] FIG. 9 illustrates an exploded view of the bulkhead seal connector of FIG. [Figure 10] FIG. 10 shows a cross-sectional view of the bulkhead seal connector of FIGS. [Figure 11] FIG. 11 shows an enlarged view of the septum seal connector of FIG. 10 in use. [Figure 12] FIG. 12 shows a wearable article for holding a dispenser during use. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] An example of a variable volume fluid dispenser 10 is shown in Figures 1 and 2. Variable volume fluid dispenser 10 includes a tubular body 12 sealed at both ends, which will hereinafter be referred to as a distal end 14 and a proximal end 16 to distinguish one end of tubular body 12 from the other.

[0040] The distal end 14 and the proximal end 16 each include a fluid connector 18, 26 that facilitates sealing of the dispenser 10 when the tubular body contains an inert fluid or a dispensing fluid. One or both of the fluid connectors 18, 26 may include a hollow needle connector, a seal, e.g., a septum seal, pierceable by a hollow needle, a split septum that can be opened, e.g., by a blunt cannula or male luer that can penetrate the split septum to facilitate fluid flow. Alternatively, the fluid connectors 18, 26 may include a valve that can be actuated / opened by connecting to an actuation interconnect member. The valve may be a mechanical valve that requires physical actuation of the valve to allow fluid flow. Alternatively, the valve may be a pressure sensitive valve operable to open when fluid flows and close when fluid flow stops. Alternatively, one or both of the fluid connectors may include a needleless connector. Examples of needleless connectors are described in the article "Needleless Connectors: A Primer on Terminology" published in the Journal of InFusion NurSing, January 2010, Vol. 33, No. 1, p22-31. The fluid connectors 18, 26 can be attached to the tubular body 12 by any suitable means, such as, for example, using an adhesive. The fluid connectors 18, 26 can be attached to the tubular body using a crimp. To minimize the overall weight of the dispenser 10, the crimp is preferably made of a lightweight or low density material, such as, for example, aluminum.

[0041] In the illustrated embodiment, the tip 14 includes a fluid connector 18 incorporating a hollow needle 20 (see FIG. 2). To ensure that the dispenser 10 and its contents are sealed, in the illustrated embodiment, the tip 14 also includes a shipping cap 22 that includes a silicone stopper 24. The silicone stopper 24 is pierced by the tip of the hollow needle 20 when fastening the cap 22 to the fluid connector 18 to hermetically seal the dispenser 10. When applied to the dispenser 10, the cap 22 prevents ingress from the atmosphere and ensures safe shipping of the dispenser 10.

[0042] In the illustrated example, proximal end 16 includes a fluid connector 26. In this example, fluid connector 26 is a septum stopper that provides an airtight seal at proximal end 16, thereby preventing ingress from the atmosphere and ensuring safe and sterile transport of dispenser 10 when fluid is contained therein. It will be appreciated that septum stopper 26 is configured for use in the conventional manner and can be pierced with a hollow needle or cannula to allow the contained fluid to be dispensed.

[0043] It will be appreciated that instead of the hollow needle 20 and cap 22 arrangement as described above and shown in Figure 2, the tip 14 may include a septum stopper. In this regard, it will be appreciated that a double ended / tipped hollow needle (not shown) may be used to pierce the tip septum stopper in use and another septum seal connector (see Figure 5) which is typically attached to the cannula and which facilitates delivery of therapeutic fluid to the patient as the fluid is dispensed.

[0044] It will be appreciated that both the distal end 14 and the proximal end 16 may include caps (not shown) to ensure that each end and contents of the dispenser 10 remain sterile until needed for delivery / dispensing of the fluid contained therein.

[0045] The dispenser 10 includes an interior volume that can be divided into a distal volume 27 and a proximal volume 28 by a movable piston member 30. The movable piston member 30 is a short cylinder and is configured to move axially relative to an inner wall 31 of the tubular body 12. The movable piston member 30 forms an interfacial fluid and gas seal between an outer periphery / outer periphery surface 33 of an outer seal of the piston 30 and an inner periphery / inner wall 31 of the tubular body 12.

[0046] The piston 30 is preferably made of a rigid material, which allows for the dispensing and retrieval of fluid from the dispenser 10 with minimal compliance of the piston 30, thereby improving dosage accuracy and responsiveness during dispensing. In the illustrated example, the piston 30 is made of glass (e.g. borosilicate glass) or a plastic material (e.g. polytetrafluoroethylene, PTFE, or polyetheretherketone, PEEK) with a peripheral seal 33 that provides surface contact, thereby forming a fluid and gas seal within the interior volume of the dispenser body 12. At least the contact surfaces have low frictional resistance characteristics so that the action of fluid acting on the end surfaces, i.e. the distal end 37 or proximal end 35 of the piston 30, allows unhindered displacement of the piston 30.

[0047] The configuration of the circumferential seal 33 may include one or more seal contact surfaces. For example, the circumferential seal 33 may comprise one or more O-ring type seals disposed along the width of the periphery of the piston 30 to ensure a fluid and gas seal within the interior volume of the piston 10. Other seals, such as a lip seal formed around the periphery of the piston, may be used in place of an O-ring seal. However, it will be understood that the configuration of the periphery wall of the piston is such that a fluid and gas seal is formed to prevent ingress of fluid between the proximal volume 28 and the distal volume 27.

[0048] The piston 30 is configured to move as fluid is added to and dispensed from the dispenser 10 when the fluid connectors 18, 26 are open / actuated to permit fluid flow to and from the dispenser 10. In this regard, the circumferential seal of the piston 30 is configured with low friction characteristics such that the piston 30 is free to move with little or no resistance against the inner wall 31 of the dispenser 10 when fluid acts on the distal surface 37 or proximal surface 35 of the piston 30. For example, at least the outer surface of the circumferential seal can include a material such as glass, polytetrafluoroethylene (PTFE), silicone, or polyetheretherketone (PEEK).

[0049] Displacement of the piston 30 facilitates loading and dispensing of fluid, such as a fluid containing a therapeutic agent, into and out of the dispenser 10. Containment of the piston 30 within the interior volume allows for storage of a predetermined maximum volume of fluid, such as a fluid containing a therapeutic agent, but allows for variable volumes of fluid up to the maximum volume of the dispenser 10 contained within the tip volume 27. The position of the movable piston member 30 defines the volume of fluid that can be contained and dispensed relative to the tip 14 under the action of fluid displacement. The maximum interior volume of the dispenser 10 is defined between the tip 14 of the dispenser 10 and a distal face 37 of the piston 30 when the proximal end 35 of the piston 30 abuts the proximal end 16 of the dispenser 10.

[0050] When the tip volume 27 contains a quantity of fluid, the tip volume 27 becomes a dispensing chamber and is filled with a known volume of fluid, for example, a fluid containing a therapeutic agent. In the illustrated example (see Figs. 2, 4), the dispenser 10 contains a quantity of inert fluid 38 and a quantity of fluid containing a therapeutic agent 36. The inert fluid 38 is contained in the proximal volume 28, and the fluid containing the therapeutic agent 36 is contained in the tip volume 27. In this example, the dispenser 10 includes a dispensing chamber (tip volume 27) and an inert chamber (proximal volume 28). The process of preparing the dispenser 10 is described below with reference to Figs. 3 and 4.

[0051] In the illustrated example, the tubular body 12 is transparent and made of a rigid material such as glass, e.g., borosilicate glass (PyrEX®), or plastic, e.g., laboratory grade polypropylene and / or polyethylene resin. The tubular body may be formed from a plastic such as a cyclic olefin polymer (COP) or a cyclic olefin copolymer (COC).

[0052] The body 12 includes a calibrated scale 32 including graduation marks 34 so that the position of the piston 30 and the amount of fluid including therapeutic agent 36 contained within the dispensing chamber (tip volume 27) can be easily visually identified. It will be appreciated that only the axial portion of the body 12 can be transparent and include graduations calibrated to allow the position of the piston 30 and the amount of therapeutic fluid to be seen. Advantageously, the calibrated volume scale 32 on the dispenser 10 accurately indicates the true volume of fluid including therapeutic agent 36 contained within the dispenser 10 to be injected, making delivery of an accurate volume more certain. The tip 37 of the piston 30 indicates on the scale 32 whether or not there is fluid 36 remaining within the dispensing chamber, i.e., tip volume 27. Thus, when the fluid 36 has been fully dispensed, the tip 37 of the piston 30 abuts the tip 14 of the dispenser 10.

[0053] The variable volume fluid dispensers 10 may be provided in a range of sizes corresponding to predetermined maximum volumes, e.g., 0.5 ml, 1 ml, 2 ml, 3 ml, 4 ml, and 5 ml, each capable of containing a volume of fluid less than the maximum volume of the interior volume of the dispenser 10, as described above and below.

[0054] In the illustrated example, Figure 1 represents an empty dispenser 10, and Figure 2 represents the dispenser 10 containing a quantity of dispensed fluid, namely, therapeutic agent 36 and a quantity of inert fluid 38. The inert fluid 38 may be a fluid that has no biological or therapeutic effect when injected into the body, such as artificial cerebrospinal fluid (aCSF), saline, or Hartmann's fluid. In most cases, the inert fluid 38 functions purely as a hydraulic fluid and does not enter the body.

[0055] 3 shows the dispenser 10 being primed with aCSF. In this example, the interior volume of the dispenser 10 is degassed and primed with aCSF.

[0056] In the method shown in FIG. 3, the cap 22 is omitted from the distal end 14, and a hollow needle 40 of a syringe 42 containing an inert fluid, for example aCSF, penetrates the septum stopper 26 at the proximal end 16. Depression of the plunger 44 of the syringe 42 displaces the inert fluid 38 from the syringe 42 into the dispenser 10, i.e., the inert fluid 38 fills the proximal volume 28 and moves the piston 30 towards the distal end 14 of the dispenser 10. The action of the inert fluid 38 on the piston 30 also displaces gas from within the distal volume 27 through the hollow needle 20 at the distal end 14 of the dispenser 10. The process of filling the dispenser 10 with the inert fluid involves axially moving the piston 30 until the distal end 37 of the piston 30 abuts the distal end 14 of the dispenser 10, causing the interior volume of the dispenser to be completely filled with the inert fluid 38.

[0057] After the dispenser 10 has been evacuated and filled with the inert fluid 38, the fluid containing the therapeutic agent 36 can be loaded into the dispensing chamber, or tip volume 27. This process is illustrated in FIG.

[0058] Figure 4 illustrates the creation of the therapeutic dispenser 10 shown in Figure 2, i.e., the interior volume of the dispenser 10 includes a predetermined / defined volume (the distal volume 27) and a volume (the proximal volume) of fluid containing the therapeutic agent 36 for dispensing. In Figure 4, a vial (container) 46 of fluid containing the therapeutic agent 36 is attached to the distal end 14 of the dispenser 10, and an empty syringe (extractor) 48 is attached to the proximal end 16 of the dispenser 10.

[0059] In the illustrated embodiment, the tip 14 of the dispenser 10 includes a hollow needle 20 that pierces an illustrated septum stopper 50 on a vial 46 of therapeutic fluid 36 .

[0060] By withdrawing the plunger 44 of the syringe 42, the syringe 42 facilitates extracting the inert fluid 38 from the interior volume of the dispenser 10 via the proximal end 16 and simultaneously drawing the fluid containing the therapeutic agent 36 into the dispenser 10 via the distal end 14. The act of extracting the inert fluid 38 acts on the piston 30 to draw in the fluid containing the therapeutic agent 36, forming a dispensing chamber where the volume of the fluid containing the therapeutic agent 36 replaces an equal volume of the inert fluid 38.

[0061] The step of extracting inert fluid from the internal volume while simultaneously drawing a predetermined amount of fluid into the distal volume can be performed by creating a pressure gradient in either direction: the pressure in the proximal volume can be lowered by pumping inert fluid through the proximal fluid connector (as shown in FIG. 4), or the pressure in the distal volume can be increased by pumping fluid through the distal connector.

[0062] The volume of fluid, including therapeutic agent 36, that is drawn into dispenser 10 is indicated by the position of the tip of piston 30 in alignment with calibrated graduations 32 on the wall of tubular body 12.

[0063] When the dispenser 10 contains the required amount, i.e., a defined amount of fluid including the therapeutic agent 36, the syringe 42 (extractor) and vial (container) 46 can be removed from the dispenser 10. In the illustrated example, the tip 14 of the dispenser 10 includes a hollow needle as a fluid connector 18. Therefore, for safety and to ensure that the contents of the dispenser 10 are sterile and uncontaminated, a shipping cap 20 is provided that includes an internal cap 22, which includes an internal seal / stopper 24, e.g., a silicone seal, attached to the tip 14. In the illustrated example, the tip of the hollow needle 20 penetrates partway through the seal 24 provided as part of the shipping cap 22. In this configuration, the dispenser 10 is sealed and can be safely shipped.

[0064] From the above, it will be appreciated that filling of dispenser 10 with a defined / predetermined volume of fluid containing therapeutic agent 36 can be performed by a trained pharmacist using aseptic technique prior to delivery. It will be appreciated that liquids containing therapeutic agents, such as gene therapy agents, require preparation in a Class II biological safety cabinet.

[0065] FIG. 5 shows an example of the equipment 60 required to dispense / deliver a volume of fluid 36 from dispenser 10 using aseptic technique.

[0066] In the illustrated example, the proximal end 16 of the dispenser 10 is connected to a first end 62 of an infusion line 64 that includes a hollow needle connector 66 that pierces the septum stopper connector 26 at the proximal end 16 of the dispenser 10. A second end 67 of the infusion line 64 connects to a pump 68, such as a syringe pump.

[0067] If the tip 14 includes a delivery cap 22, the cap 22 is removed to expose the hollow needle 20 so that it can be connected to a means for delivering a fluid containing therapeutic agent 36 to a patient. In the illustrated example, the delivery means is a cannula 70 extending from a septum seal connector 72.

[0068] Cannula 70 may be an intracranial cannula that facilitates infusion of fluid 36 directly into the brain.

[0069] After ensuring that the cannula's septum seal connector 72 is clean / sterile, the distal end 14 of the dispenser 10 can be connected to the cannula 70 via the hollow needle connector 20. Once a fluid connection has been established at both the proximal end 16 and the distal end 14 of the dispenser 10, the pump 68 can be activated.

[0070] In the illustrated example, the septum seal connector 72 that facilitates connection of the dispenser 10 to the cannula 70 includes an air bubble vent 74. The configuration and components of the air bubble vent 74 are described below and shown in FIG. 6. In summary, the air bubble vent 74 reduces the risk of air bubbles entering the brain if air bubbles emerge from the solution being infused or become entrained in the infusate during connection and / or disconnection of the variable volume fluid dispenser 10 or the infusion line 64 to the cannula 70. It will be appreciated that air bubbles injected into brain tissue can tear the tissue and disrupt the dispensing of the therapeutic fluid / infusate.

[0071] A septum seal connector 72 is preferably provided at the proximal end of the cannula 70. The septum seal connector 72 may be permanently joined to and / or integrally formed with the cannula 70, which further reduces the possibility of introducing air bubbles during connection of the cannula 70 to the distal fluid connector 20. The septum seal connector 72 may further be configured to prevent pathogens (e.g., microorganisms such as bacteria) from entering the cannula 70, thereby reducing the risk of treatment-induced intracranial infection.

[0072] 6 shows an exploded view of a cannula 70 and a septum seal connector 72 configured to attach to the tip fluid connector 20. The septum seal connector 72 includes a perforated filter guard 80, a filter 82, retaining rings 83A, 83B, a retaining cap 84, a septum stopper 86, and a septum cap 88.

[0073] In the illustrated example, filter 82 is a low volume air bubble filter made of expanded polytetrafluoroethylene (ePTFE) and has a superhydrophobic, gas permeable, microporous structure configured to remove air bubbles from the flowing treatment fluid. In the illustrated example, filter 82 is effective at removing air bubbles at flow rates of 30 μl / min or less. Filter 82 is housed within perforated filter guard 80, in the illustrated example, filter 82 is received on hollow post 85 and retained therein by retaining ring 83A, hollow post 85 being concentrically disposed within filter guard 80.

[0074] In the illustrated example, the filter guard 80 is a hollow shell with a plurality of perforations (small holes) 87 distributed around the periphery of the septum. The perforations 87 facilitate degassing of the fluid as it flows through the filter 82 from the dispenser 10 to the cannula 70. The filter guard 80, as the name suggests, protects / guards the filter 82 from damage.

[0075] The combination of filter 82 and filter guard 80 aids in the dispersion of entrained air / bubbles from the dispenser fluid stream before the fluid enters cannula 70 .

[0076] The septum seal connector 72 also includes a retaining cap 84 which connects to the filter guard 80 to complete assembly of the seal connector and contains the filter 82 within the assembly. The retaining cap 84 includes hollow retention posts 89 and a retaining ring 83B which engage the filter 82 to ensure that the filter 82 is properly positioned and retained within the filter guard 80 and ensure efficient functioning of the filter 82 during use.

[0077] In the illustrated example, the retention cap 84 includes a septum stopper 86 that provides a sealing unit until the septum 86 is pierced by a hollow needle, thereby fluidly connecting the connector 72 to the cannula 70 .

[0078] The septum stopper 86 is held in compression by a septum cap 88 .

[0079] In the illustrated example, the retaining cap 84 and the filter guard 80 are joined by a snap fit connection, although they may be joined using alternative configurations such as threaded, welded or adhesive connections.

[0080] The septum seal connector 72 incorporating the low volume air bubble filter 82 reduces the risk of air being delivered, for example to the brain, along with the fluid containing the therapeutic agent / infusate. It will be appreciated that fluid containing air / bubbles will occupy space and may stretch or tear brain tissue while also interfering with the delivery / dispensing of the therapeutic agent / infusate. The septum seal connector 72 may also function to filter pathogens, including bacteria and other microorganisms, from the fluid.

[0081] Figures 8-11 show an alternative design of septum seal connector 174. Figure 8 shows septum seal connector 174 in an assembled, ready-to-use state. Similar to septum seal connector 72, septum seal connector 174 includes a retaining cap 84. Retaining cap 84 includes a proximal connector 176, e.g., a threaded connector, for connecting to a fluid connector of a delivery system.

[0082] FIG. 9 shows an exploded view of septum seal connector 174, and FIG. 10 shows a cross-sectional view. Proximal connector 176 may include a septum 86 for sealing proximal connector 176 until septum 86 is pierced by, for example, a hollow needle. Septum seal connector 174 includes a fluid passageway 140 that fluidly connects proximal connector 176 and cannula 70. In this design, septum seal connector 174 includes a first membrane 150 and a second membrane 152. First membrane 150 and second membrane 152 are disposed between a distal end of fluid passageway 140 and a proximal end of cannula 70. First membrane 150 and second membrane 152 may be substantially parallel to each other or substantially perpendicular to the axis of fluid passageway 140. The first membrane 150 is positioned closer to the tip of the fluid passageway 140 than the second membrane 152 so that fluid entering the septum seal connector 174 through the septum 86 reaches the first membrane 150 before the second membrane 152. An annular washer 153 may be positioned between the first membrane 150 and the second membrane 152 to form a peripheral fluid seal between the membranes and the housing of the connector 174, separating the membranes in the middle to form a cylindrical gap between them. The cylindrical gap may have a diameter between 2 mm and 6 mm, and most preferably 4 mm. The gap may separate the membranes 150, 152 by 0.05 mm to 0.2 mm, and most preferably 0.1 mm. The first membrane 150 and the second membrane 152 may be connected to other components of the septum seal connector 174 via a connecting surface 180. The connecting surface 180 may be bonded by any suitable method, such as, for example, by ultrasonic welding or using an adhesive layer. The septum seal connector 174 may include a support member 184 to support a distal surface of the second membrane 152 and allow fluid that has passed through the second membrane 152 to more easily reach the cannula 70 .

[0083] The first membrane 150 is hydrophobic and gas permeable. Where the fluid passageway 140 contacts the first membrane 150, a hole 154 is provided in the first membrane 150 to allow fluid from the fluid passageway 140 to pass through the first membrane 150 via the hole 154. The septum seal connector 174 may include a support member for supporting the proximal surface of the first membrane 150 and an annular connecting surface for attaching the membrane around its periphery and around its central hole 154 (not shown in FIG. 9). The second membrane 152 is fluid permeable and preferably hydrophilic. It is not essential that the second membrane 152 be hydrophilic, but venting works most efficiently using a combination of hydrophobic and hydrophilic membranes. If the hydrophobic first membrane 150 is used alone, air may be drawn from the atmosphere through the first membrane 150 into the infusate if the pressure in the line falls below atmospheric pressure. This may occur if the connector is more than 10-25 cm above the head (depending on intracranial pressure). The second membrane 152, being hydrophilic, prevents air from entering the brain in such circumstances. The second membrane 152 is impermeable to gases and bacteria. The second membrane 152 is unpermeable to gases and bacteria, such that fluid from the fluid passageway 140 must pass through the material of the second membrane 152 to reach the cannula 70. At least one vent hole 160 (e.g., two, three, four, or more than three vent holes) is provided in the septum seal connector 174 proximal to the first membrane 150. The first membrane 150 is unperforated where the vent hole 160 meets the first membrane 150, such that fluid from the fluid passageway 140 must pass through the material of the first membrane 150 to reach the vent hole 160.

[0084] The operation of the septum seal connector 174 is explained in the enlarged view of FIG. 11. A mixture of fluid and gas (e.g., infusate delivered to the patient's brain through the cannula 70 with some entrapped air bubbles) enters the septum seal connector 174 through the septum 86 and the fluid passageway 140. The mixture passes through the first membrane 150 through the hole 154. The fluid is attracted to the hydrophilic second membrane 152 and permeates through the second membrane 152 (which is fluid permeable) into the cannula 70. The layer of fluid and the second membrane 152 form a barrier that prevents gas from entering the cannula 70. The gas passes along the gap between the first membrane 150 and the second membrane 152 and can escape through the gas permeable first membrane 150 at one of the vent holes 160. The hydrophobic nature of the first membrane 150 repels fluids and prevents the fluid from forming a similar barrier as on the second membrane 152, thereby allowing gas to escape through the vent hole 160 and out of the septum seal connector 174.

[0085] Advantageously, the tubular body 12 of the dispenser 10 is rigid, which means that the configuration of the dispenser 10 is non-compliant / low compliance to pressure increases, i.e., the tubular body 12 does not expand due to an increase in pressure. Thus, when the system 60 has delivered a measured volume of fluid containing the therapeutic agent 36, as shown in FIG. 5, further movement of the piston 30 is prevented by the tip 14 of the dispenser 10. The rigidity characteristic of the tubular body 12 is such that a sudden increase in pressure occurs within the internal volume of the dispenser 10 and the infusion line 64. The device 60 is typically configured such that an increase in pressure will trigger a responsive alarm in the pump 68 as an indication that the therapeutic agent 36 has been fully dispensed, and an automatic shutoff function of the pump 68 will be activated.

[0086] It will be appreciated that the alarm also indicates completion of delivery of therapeutic agent 36 to the therapist. Once therapeutic agent 36 has been fully administered, the therapist may disconnect dispenser 10 from the catheter septum seal connector 72 and infusion line 64. Advantageously, once infusion is complete, dispenser 10 is free of therapeutic agent 36. Thus, once disconnected, the depleted dispenser 10 may be safely disposed of in an appropriate waste container, such as, for example, a chemical / sharps bin.

[0087] To complete the process, the fluid containing the therapeutic agent may be flushed from the dead space within the cannula 70. To do so, the infusion line 64 can be connected directly to the septum seal connector 72 of the cannula via the hollow needle connector 66A of the infusion line 64, and the pump 68 can be operated to flush the therapeutic agent 36 from the dead space with an inert fluid, for example aCSF.

[0088] The above description with reference to Figures 3, 4 and 5 demonstrates that the procedure for preparing and using the dispenser 10 is safe, with simple, logical steps and minimal handling of the dispenser 10.

[0089] From the above, it will be appreciated that the dispenser 10 contains a predetermined amount of therapeutic agent 36, thereby avoiding overdosing due to incorrect programming of the infusion pump 68.

[0090] As discussed above, the proximal fluid connector includes the septum connector 26. FIG. 7 shows an example of a connecting member 100 configured to connect the proximal end 16 of the dispenser 10 to the infusion line 64 from the syringe pump 68 (see FIG. 5) and which is a female Luer fitting. The Luer fitting 100 is an interconnector that includes a hollow needle 110 that passes through the septum 26. In the example shown, the Luer fitting 100 includes a hollow bullet tip needle 110 made of an MRI compatible material, such as PEEK or titanium. The Luer fitting 100 can retain and conceal the hollow needle 110, reducing the risk of injury when handling the Luer fitting 100.

[0091] The distal fluid connector may include a luer fitting as shown in FIG. 7, where luer fitting 100 includes a hollow needle 110 configured to connect to a reciprocal luer fitting, such as connector 72 (see FIG. 5), and includes a septum stopper at the proximal end of catheter or cannula 70.

[0092] As will be appreciated from the above, in addition to the dispenser 10 being made from a rigid / non-compliant material, the system would also benefit from the infusion line 64 being made from a non-compliant / low compliance material, i.e., a material that is resistant to expansion under pressure. For example, the infusion line may be an elongated tube made from a material such as polyetheretherketone (PEEK). In one example, the infusion line has an outer diameter of 0.5 mm and an inner diameter in the range of 0.1 mm to 0.3 mm, but preferably in the range of 0.1 mm to 0.2 mm.

[0093] The combination of a rigid tubular body 12 (as described above) and a non-compliant infusion line reduces the risk of potential dosing inaccuracies.

[0094] The resulting hydraulic system incorporating the dispenser 10 described above is therefore very sensitive to changes in pump pressure and flow rate. This is an important safety feature because if the cannula 70 becomes occluded, the resulting sudden rise in pressure will activate the pump alarm and switch off the pump 68. In contrast, if the infusion line is compliant, i.e., expands under pressure, the pressure rise will be more gradual / slow and a significant amount of fluid may accumulate in the expanding infusion line. Thus, if a cannula occlusion is overcome, for example as a cored tissue pellet is expelled, the resulting jet of fluid may cause localized brain damage.

[0095] The example shown in Figure 5 represents a dispenser 10 used to deliver a fluid containing a therapeutic agent 36 to a patient's brain. However, it should be understood that such a dispenser 10 can be used for the controlled injection of discrete amounts of agents used in the diagnosis, monitoring and treatment of diseases in humans and animals. The device can be used to inject diagnostic and therapeutic agents into the body via one of a number of routes, including intravenous, intraarterial, intraperitoneal, intramuscular, intravitreal, intraventricular, intrathecal, intraparenchymal, and intratumoral or cystic cavities.

[0096] Fluids, including drugs, that may be delivered via these pathways using the variable volume dispenser 10 and injected for diagnosis and monitoring of disease include, but are not limited to, radiopaque contrast agents for magnetic resonance imaging (MRI), X-ray and X-ray computed tomography, radioisotopes used in single photon emission computed tomography (SPECT) and positron emission tomography (PET), and dyes.

[0097] Fluids containing therapeutic agents that may be delivered via these pathways using the variable volume dispenser 10 include, but are not limited to, chemotherapeutics, antibiotics, enzymes, neurotrophins, gene therapy agents, siRNA and antisense oligonucleotides, enzymes, immunomodulatory therapies (such as monoclonal antibodies and chimeric antigen receptor T cell (CAR-T) therapies), immunotoxins, botulinum toxins, molecular targeted therapies, monoclonal antibodies, oncolytic viruses, nanoparticles, and therapeutic radionuclides including boron and Auger electron emitters.

[0098] The variable volume therapeutic agent dispenser 10 illustrated in Figures 1 to 5 and described above has a number of safety features which are advantageous over existing methods of delivering potentially hazardous diagnostic and therapeutic agents / drugs such as gene therapeutic agents, chemical therapeutic agents, and radioisotopes. For example, the dispenser 10 can be filled with a prescribed amount of therapeutic or diagnostic agent 36 in the controlled environment of a pharmacy by a trained pharmacist, in a biological and / or radiation safety cabinet as required. As described above, after the dispenser 10 has been filled, it can be hermetically sealed by applying a transport cap 22 to the hollow needle connector 18 at its tip. The dispenser can be labeled and safely transported to a location where it can deliver fluids containing the diagnostic or therapeutic agent 36, for example a hospital ward or an MRI suite. On receipt of the labeled contents of the dispenser and checking against the patient's details and prescription, the fluid connector of the patient's cannula or catheter is cleaned, the cap 22 is removed, and the hollow needle connector 18 at the tip 14 of the dispenser 10 connects to the septum seal connector of the cannula or catheter. An infusion line, primed with an inert fluid and connected to an infusion pump, is connected through its distal connector 62 to the fluid connector 26 at the proximal end of the dispenser and the pump is switched on.

[0099] The described method has clear safety advantages over a physician drawing up the biohazardous material from a vial into a syringe on the ward, removing any air bubbles from the syringe, then priming and connecting the infusion line to the patient's catheter or cannula, loading the syringe into the pump, and programming the pump to deliver the prescribed volume at the appropriate flow rate. Risks include human error when dispensing prescriptions in stressful clinical environments such as wards, needlestick injuries, contamination of the clinical environment due to spillage during dispensing, and exposure of staff and patients to biohazardous materials. In situations where the prescribed treatment is dispensed by a pharmacist into a syringe and then transported to the ward, there may be the possibility of accidental spillage during priming and degassing of the infusion line, or accidentally depressing the syringe plunger when loading the syringe pump.

[0100] The use of the variable volume fluid dispenser 10 is particularly advantageous in minimizing dead space within the infusion system. Typically, the device is connected directly to a cannula or catheter, so the distance to the target is relatively short, and the diagnostic or therapeutic agent is separated from the infusion pump and potentially long infusion lines by a piston. This minimizes the loss of potentially valuable therapeutic agent in the dead space of the infusion line and syringe, and the loss of therapeutic agent that may adhere to the material of the infusion line. For viral vectors, this loss can be more than 10% of the dose. A rigid, variable volume fluid dispenser, e.g., glass, with very low viral vector binding, combined with a relatively short cannula, can minimize this loss. Variable volume fluid dispensers are offered in a variety of sizes, e.g., 0.5 ml, 1.0 ml, 2.0 ml, 3 ml, 4 ml, 5 ml, etc., allowing the size of the device to be tailored to the therapeutic agent being delivered, minimizing waste. This is in contrast to clinically available infusion pumps that typically accommodate a limited range and variety of compliant plastics rather than 2ml, 5ml, 10ml, 20ml, 50ml, etc. glass syringes. Nevertheless, therapeutic agents can be delivered by glass variable volume dispenser 10 when connected to a standard infusion pump driving a standard plastic syringe. As an example, a typical volume of gene therapy agent delivered from a CED cannula to a brain target would be 300 μl. This can be loaded into the distal dispensing end of a 0.5ml rigid / non-compliant variable volume fluid dispenser 10 and connected to the CED cannula. The proximal end of dispenser 10 can then be connected to a 2ml plastic syringe filled with an inert fluid and an extension line, which can then be connected to a standard medical syringe pump (see FIG. 5) used to deliver the therapeutic agent.

[0101] As mentioned above, the dispenser 10 is rigid and made of glass or plastic, which makes the dispenser 10 MRI compatible. Thus, the dispenser 10 can be safely and securely placed within an MRI coil, such as a head coil. Additionally, using a low compliance material for the infusion line 64, where possible, means that the infusion line can be as long as necessary to ensure that the infusion pump 68 is placed at a safe distance from the magnetic field. Using a low compliance infusion line between the syringe in the infusion pump and the variable volume fluid dispenser 10, for example using PEEK tubing with an internal diameter of 0.1 mm to 0.2 mm, has the advantage of creating a more responsive hydraulic system to drive the delivery of the therapeutic agent. This can improve the accuracy of delivery, as variable volumes of infused therapeutic agent can be lost in the dead space of a compliant line that stretches when pressurized. Additionally, the system can be safer, as the pump will alarm and switch off if pressure in a non-compliant line increases too quickly due to a clogged cannula.

[0102] The dispenser 10 is particularly suited for complex dosing regimens, for example, to deliver different volumes of fluid containing a therapeutic agent through multiple cannulas simultaneously into the brain of a patient. Some therapeutic agents may need to be delivered through six or eight cannulas. In this case, a corresponding number of variable-volume fluid dispensers 10 containing defined volumes of therapeutic agent may be connected to their assigned cannulas, and each may be connected to a separate infusion line and syringe pump. If all pumps are set to a predetermined flow rate, the clinician overseeing the treatment may operate them randomly, and when the defined volume is delivered to any dispenser 10, the piston 30 engages the tip 14 of the dispenser 10 and stops, which causes a pressure rise in the proximal chamber 28 and infusion line, which causes the pumps to alarm and switch off. When all pumps have alarmed and switched off, the treatment is complete. This can be verified by the clinician inspecting the position of the piston 30 relative to the marked graduations 32 of each dispenser 10. Once free of fluid, each dispenser 10 can be removed from its respective cannula and discarded in an appropriate clinical waste container. This process greatly simplifies the delivery method, increases safety and reduces the chance of human error.

[0103] Since some treatments may take hours to administer, it is preferable that the dispenser 10 be held securely and conveniently during the treatment. This is especially true when multiple dispensers 10 are used simultaneously. Holding the dispensers 10 in this manner reduces the chance of damage to the dispensers 10 and increases patient comfort. To this end, a wearable article 200 may be provided that is configured to hold one or more dispensers 10. FIG. 12 shows an example of a wearable article 200. Preferably, the wearable article 200 can hold multiple dispensers 10, e.g., two, four, six, eight, or more than eight dispensers 10. The wearable article 200 may be configured to be worn around the patient's head, arm, or chest. The wearable article 200 may be provided in the form of a small garment, e.g., a headband, belt, or sash, that can be worn in addition to the patient's regular clothing. For example, the wearable article 200 shown in FIG. 12 is in the form of a band that is worn around the patient's arm. Alternatively, wearable article 200 may be provided as a larger garment, such as a jacket, coat, shirt, hat, etc.

[0104] The wearable article 200 may be adjustable to provide a secure fit on the patient regardless of the patient's size. The wearable article 200 is preferably configured to hold the dispenser 10 in a position that is unlikely to impede patient movement and / or to interfere with diagnostic procedures that may be performed on the patient during the administration procedure, such as an X-ray or magnetic resonance imaging scan. For example, the wearable article 200 may be configured to hold the dispenser on the patient's upper chest or upper arm, or on the patient's forehead. The wearable article 200 may also include one or more straps or closures for holding the infusion line 64 and / or cannula 70 connected to the dispenser 10.

[0105] The wearable article 200 can include one or more dispenser holders 210, each configured to hold one dispenser 10. The dispenser holder 210 can include a compartment or a holding loop in which the dispenser 10 can be placed. The dispenser holder 210 can be adjustable to allow the dispenser 10 to be easily inserted and securely held. The wearable article 200 and / or the dispenser holder 210 can be adjustable by use of any suitable means, such as, for example, one or more elastics, adjustable fasteners such as belts, buckles, straps, or hook-and-loop fasteners. Alternatively or additionally, the dispenser holder 210 can be configured to open and close, for example, using a flap or lid. If the dispenser holder 210 includes a compartment, the dispenser holder 210 is configured to allow the infusion line 64 and the cannula 70 to exit the compartment even when the compartment is closed.

[0106] The dispenser holders 210 may be individually labeled with a unique identifier, such as a number, letter, or color, that distinguishes each dispenser holder 210 from other dispenser holders 210. This allows for easy and quick identification of the dispenser 10 during a dosing procedure, for example when the dispenser 10 becomes emptied and needs to be replaced with a new dispenser 10 filled with the same therapeutic agent.

[0107] If multiple cannulas are implanted and connected to the dispenser 10, management of the tubing between the head and the dispenser holder 210 may be aided by providing cable ties, straps, or spiral wraps.

[0108] In summary, many diagnostic and therapeutic drugs that require injection into the body for various medical conditions are often dangerous and / or expensive. Thus, as described above with reference to Figures 1-7, the use of dispenser 10, method and system 60 reduces staff and / or patient exposure to dangerous drugs or medications, reduces waste of expensive drugs or medications in syringes and long injection lines, reduces the risk of dosage errors as dispenser 10 is configured to contain a precise dose, and eliminates the guesswork by ensuring that the correct dose of therapeutic has been administered when dispenser 10 runs out of fluid.

[0109] Although particular embodiments of the invention have been described above, it will be understood that departures from the described embodiments will still fall within the scope of the claims.

Claims

1. A variable volume fluid dispenser for medical treatment and diagnosis, comprising: A tubular body having a proximal end and a distal end, the tubular body defining an internal volume between the proximal end and the distal end; Fluid connectors respectively provided at the proximal end and the distal end; A piston positioned within the internal volume, the piston being configured to move axially between the proximal end and the distal end under the action of fluid displacement through the fluid connectors; The piston is operable to divide the internal volume into a proximal volume and a distal volume, the distal volume being configured to contain a volume of fluid containing a therapeutic agent, the volume of fluid containing the therapeutic agent being less than the internal volume; The position of the piston relative to the distal end defines the volume of fluid to be dispensed containing the therapeutic agent; At least an axial portion of the tubular body is transparent and includes a calibrated scale including a plurality of internal or external markings for indicating the position of the tip of the piston, thereby indicating the volume of fluid containing the therapeutic agent included in the distal volume; The piston is configured such that when the fluid containing the therapeutic agent is completely dispensed, the tip of the piston abuts against the distal end of the dispenser. A variable volume fluid dispenser.

2. The tubular body is formed from a rigid pharmacologically inert material; Optionally, the tubular body is made of glass, or borosilicate glass, or plastic, or a resin of laboratory grade polypropylene and / or polyethylene. The dispenser according to claim 1.

3. One or both of the fluid connectors include one or both of a) a hollow needle and b) a seal pierceable by the hollow needle. The dispenser according to claim 1.

4. One or both of the fluid connectors include a split seal that can be opened to facilitate fluid flow. The dispenser according to claim 1.

5. One or both of the fluid connectors include a valve, the valve being opened / operated by connection to an actuating interconnecting member. The dispenser according to claim 1.

6. The valve is one of a) a mechanical valve that requires physical actuation to allow fluid flow and b) a pressure sensitive valve that is operable to open when fluid flows and close when fluid flow stops. The dispenser according to claim 5.

7. The dispenser according to claim 1, wherein one or both of the fluid connectors comprises at least one of: a) a needleless connector; b) a removable cap.

8. The dispenser according to claim 1, wherein the fluid connector at the proximal end comprises a septum stopper that can be pierced by a hollow needle.

9. The dispenser according to claim 1, wherein the fluid connector at the distal end comprises a connecting member incorporating a hollow needle, and the hollow needle is configured to pierce a pierceable interconnecting member provided on a device to which the dispenser is connected.

10. The dispenser according to claim 1, wherein at least one of the connecting member at the proximal end and the connecting member at the distal end is a luer fitting, and the luer fitting is configured to connect with a mating luer fitting.

11. The dispenser according to claim 1, wherein the plurality of markings includes a plurality of scale marks.

12. The dispenser according to claim 1, wherein the piston includes an outer peripheral seal member operable to form a seal for fluid and gas within the internal volume of the tubular body.

13. The dispenser according to claim 12, wherein the outer peripheral seal member includes one or more contact surfaces.

14. The dispenser according to claim 12, wherein the outer peripheral seal member is configured to have low friction characteristics such that when fluid acts on the distal or proximal end face of the piston, the movement of the piston relative to the inner surface of the dispenser is free with low resistance.

15. The dispenser according to claim 12, wherein at least the outer surface of the outer peripheral seal member includes glass, or polytetrafluoroethylene (PTFE), or silicon, or polyetheretherketone (PEEK).

16. An apparatus comprising the dispenser according to claim 1, further comprising a cannula for connection to the fluid connector at the distal end.

17. The apparatus according to claim 16, wherein the cannula comprises a septum seal connector configured to prevent gas and / or microorganisms from entering the cannula.

18. The apparatus according to claim 17, wherein the septum seal connector comprises a first membrane and a second membrane separated by an air gap, the first membrane being hydrophobic and the second membrane being hydrophilic.

19. A method of filling a dispensing chamber of a variable volume fluid dispenser, The dispenser of the variable volume fluid is a tubular body having a proximal end and a distal end, the tubular body defining an internal volume between the proximal end and the distal end, and a piston positioned within the internal volume, wherein the position of the piston relative to the distal end defines the volume of the fluid to be dispensed containing the therapeutic agent, at least an axial portion of the tubular body is transparent and includes a calibrated scale including a plurality of internal or external markings for indicating the position of the tip of the piston, thereby indicating the volume of the fluid containing the therapeutic agent included in the tip volume, The method is degassing the internal volume, priming the internal volume with an inert fluid, and axially driving the piston with the inert fluid until the internal volume is filled with the inert fluid and the piston abuts the distal end; attaching a fluid container to the distal end and an extractor to the proximal end; extracting the inert fluid from the internal volume while drawing a predetermined amount of fluid containing the therapeutic agent from the container into the internal volume, the extraction being performed by extracting the inert fluid until the position of the tip of the piston aligns with the marking of the calibrated scale corresponding to the predetermined amount; detaching the extractor and the fluid container from the proximal end and the distal end, respectively. **Claim 20** The method according to claim 19, further comprising hermetically sealing the fluid content of the dispenser of the variable volume fluid by attaching a transport cap to one or both of the distal end and the proximal end.

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