Patent Application
20130253430
The present application relates to medical devices and methods of delivering at least two drug agents from separate reservoirs or containers. More specifically, the present invention is concerned with patch-like, wearable, self-contained substance infusion devices that can be used to deliver medicaments to a patient through a single dispense interface. The drug agents may be available in two or more reservoirs, containers, or packages, each containing independent (single drug compound) or pre-mixed (co-formulated multiple drug compounds) drug agents.
Certain disease states require treatment using one or more different medicaments. Some drug compounds need to be delivered in a specific relationship with each other in order to deliver the optimum therapeutic dose. This invention is of particular benefit where combination therapy is desirable, but not possible in a single formulation for reasons such as, but not limited to, stability, compromised therapeutic performance and toxicology.
For example, in some cases it might be beneficial to treat a diabetic with a long acting insulin and with a glucagon-like peptide-1 (GLP-1), which is derived from the transcription product of the proglucagon gene. GLP-1 is found in the body and is secreted by the intestinal L cell as a gut hormone. GLP-1 possesses several physiological properties that make it (and its analogs) a subject of intensive investigation as a potential treatment of diabetes mellitus.
There are a number of potential problems when delivering two medicaments or active agents simultaneously. The two active agents may interact with each other during the long-term, shelf life storage of the formulation. Therefore, it is advantageous to store the active components separately and only combine them at the point of delivery, e.g. injection, needle-less injection, pumps, or inhalation. However, the process for combining the two agents needs to be simple and convenient for the user to perform reliably, repeatedly and safely.
A further problem is that the quantities and/or proportions of each active agent making up the combination therapy may need to be varied for each user or at different stages of their therapy. For example one or more actives may require a titration period to gradually introduce a patient up to a “maintenance” dose. A further example would be if one active requires a non-adjustable fixed dose while the other is varied in response to a patient's symptoms or physical condition. This problem means that pre-mixed formulations of multiple active agents may not be suitable as these pre-mixed formulations would have a fixed ratio of the active components, which could not be varied by the healthcare professional or user.
Additional problems arise where a multi-drug compound therapy is required, because many users cannot cope with having to use more that one drug delivery system or make the necessary accurate calculation of the required dose combination. This is especially true for users with dexterity or computational difficulties. In some circumstances it is also necessary to perform a priming procedure of the device and/or needle cannulae before dispensing the medicaments. Likewise, in some situations, it may be necessary to bypass one drug compound and to dispense only a single medicament from a separate reservoir.
Accordingly, there exists a strong need to provide devices and methods for the delivery of two or more medicaments in a single injection or delivery step that is simple for the user to perform. Our invention overcomes the above-mentioned problems by providing separate storage containers for two or more active drug agents that are then only combined and/or delivered to the patient during a single delivery procedure. Preferably, but not necessarily, setting a dose of one medicament through adjustment of a flow rate will automatically fix or determine the dose of the second medicament (i.e. non-user settable). Our invention also gives the opportunity for varying the quantity of one or both medicaments. For example, one fluid quantity can be varied by changing the properties of the injection device (e.g. allowing the device to accept a bolus of a secondary medicament into the flow of the primary medicament).
The second fluid quantity can be changed by manufacturing a variety of secondary drug containing packages with each variant containing a different volume and/or concentration of the second active agent. The user or healthcare professional would then select the most appropriate secondary package or series or combination of series of different packages for a particular treatment regime. In other cases, the patch pump device of our invention may be programmed remotely such that two separate reservoirs of medicament are pumped or infused through a single dispense interface at different rates.
Our invention also provides a medicated module that can be removably engaged with an external port on the exterior of the patch pump housing to automatically cause a secondary medicament to be dispensed into a manifold that is in fluid communication with the primary medicament and are infused into a user through a single dispense interface, preferably a needle placed subcutaneously. Such a configuration eliminates the need for the user to manually set or adjust a flow of secondary medicament from a second reservoir contained within the patch pump.
These and other advantages will become evident from the following more detailed description of the invention.
Our invention allows complex combinations of multiple drug compounds within a single drug delivery system. The invention can allow the user to set a single dispense rate that will result in the delivery of a multi-drug compound through a single dispense interface. This single dose rate setter controls the mechanism of the device such that a predefined combination of the individual drug compounds is delivered when the primary rate is set and medicament delivered through the single dispense interface.
More specifically, our invention relates to a patch pump designed to use an internal pump to dispense one or more medicaments directly to a user. The pump is intended to provide the user with a continuous dose of a primary drug via a dispense interface, such as a single needle cannula placed subcutaneously. The device also has the capability to dispense one or more secondary drugs via this same dispense interface. This provides flexibility of therapy where more than one medicament has been prescribed for the user or where a short-term additional medicament is required in combination with the longer term patch pump delivered medicament. A patch type pump is intended to form a self-contained unit containing the drive system, drug reservoir and dispense interface in a single device that may or may not also feature controls for operating the device either integrated or remotely. Preferably, the patch pump is designed to be worn or removably attached to a user's skin.
Examples of patch pump type devices that can incorporate our invention are described in issued patent U.S. Pat. No. 6,749,587. The '587 patent describes the structure and functionality of drive mechanisms, controllers, propulsion means, flow paths, needle assembles, and housing designs for pump patch type injection devices, specifically the interaction of electronic circuits, propulsion means and medicament reservoir during both dose setting and dose delivery. The full description of the patch pump type injection devices disclosed in U.S. Pat. No. 6,749,587 is incorporated herein by reference.
Although, the patch pump embodiments of our invention are similar to those used in the treatment of diabetes whereby the medicaments are infused as liquids subcutaneously through a needle and are left on the body whether controlled remotely or not, our invention could be employed by similar devices where another format of drug (gas, powder etc.) is supplied over time to a user or patient (intravenous, respiratory, oral etc.) through any form of shared dispense interface (needle, mask, tracheal tube etc.). Importantly, the secondary medicament as described in the embodiments herein need not be a different compound to the primary drug, for example, an insulin bolus (secondary) added to basal insulin flow (primary). It may even be appropriate that the second compound be a diluent or carrier compound for the primary drug. The use of such a carrier e.g. saline solution, may temporarily alter the combined therapeutic profile or therapeutic benefit where a deviation is required for a short period
Each of the embodiments of the present invention require at least two separate reservoirs, where at least one reservoir is contained within the pump patch housing and is designed to dispense a primary medicament through a manifold and out a single dispense interface, preferably a cannula that protrudes through the housing of the patch pump. The additional reservoirs can be inside the housing or removably attached to a port on the housing, as in the case of the medicated module embodiment. In the configurations where the secondary reservoir(s) are contained in the housing, the reservoir(s) could be pre-filled before delivery to the user (to improve usability or minimize filling errors) or filled by the user in the same manner as the primary reservoir in most current, conventional insulin pumps. In this case, the secondary drug reservoir can either be flushed by the flow of the primary drug (in-line placement) or actuated independently from the primary reservoir (parallel dispense) and combined with the primary drug during dispense to the user through the single dispense interface.
The additional reservoir can be inside the housing removably attached to a port, e.g. a loading port in the housing. The additional or second reservoir may have an inlet and an outlet and may be replaceable through a loading port in the housing, e.g. a pump patch housing where the second reservoir may be connected to a manifold such that primary medicament flowing from the first reservoir flows in the inlet and out the outlet of the secondary reservoir.
Alternatively, the secondary reservoir can be housed in an external device, e.g., a medicated module that is introduced to the primary device at such a time as the secondary drug is required. As used herein, the medicated module includes any type of standalone device comprising housing containing a cavity or reservoir of a single dose of medicament, where the housing is attachable to an external port on a patch pump. Through activation of medicated module when attached to the patch pump, the secondary medicament is caused to flow into the manifold of the patch pump and eventually delivered to a user through a single dispense interface, preferably a needle cannula. Again, this introduction can be in-line with the primary medicament or parallel and combined before dispense.
One embodiment for such an external device could be a modified single-use drug reservoir needle having a safety needle guard. Using such a device, the actuation of the needle guard being pressed against the patch pump port can drive the secondary medicament into the patch pump manifold system as and when the additional/secondary medicament is required. This system could be used where various secondary medicaments are required at varying time intervals compared with the constant primary medicament flow. The user or physician could then add the additional medicament(s) as and when required, using it as a form of injection port for additional injections, thereby reducing the discomfort and risk of infection associated with additional skin punctures.
In the case of in-line introduction of the secondary medicaments, the secondary medicament may be supplied as a capsule that is placed in series with delivery of the primary medicament, the delivery of which pushes or flushes this secondary medicament through (i.e., a single drive mechanism delivers both medicaments). In another embodiment the secondary medicament reservoir may comprise an inlet and an outlet and may be replaceable through a loading port in the housing, e.g. a housing of a patch pump device. The secondary medicament reservoir may be connected to a manifold such that primary medicament flowing from the first reservoir flows in the inlet and out the outlet of the secondary reservoir. In an additional embodiment, a bypass route may be incorporated into the device design to allow flow of only the primary drug to the user when the secondary drug is not required. The drug flow can then be rerouted via the secondary reservoir as and when needed by a linearly or rotationally actuated section of the flow channel. A simple system of one-way valves can be used to prevent back-flow, accidental mixing and leaking from the system.
A drug delivery device according to the invention may further comprise a movable inner housing having two flow path positions. In one position, a first position, the second reservoir is placed in-line with the first reservoir. In another position, a second position, the second reservoir is placed out of line with the first reservoir. The housing may be slideable or rotatable. The drug delivery device may comprise a rotatable inner housing, wherein the inner housing may rotate about an axis to place the second reservoir in-line with a manifold such that the primary medicament will dispense, flush, or drive the secondary medicament from the second reservoir. The drug delivery device may comprise an inner housing further comprising a flow path. When the inner housing is in the second position the flow path may be placed in-line with manifold. This provides a benefit of allowing use of the drug delivery device in situations where delivery of the secondary medicament is not needed. However, the device may be configured to allow repositioning of the inner housing between the first position and the second position. The drug delivery device may comprise an opening or loading port in or on the housing and a movable inner housing. Positioning of the inner housing into the second position may allow for the replacement of second reservoir through the opening (not sown) in the housing of the drug delivery device. This provides the benefit of allowing replacement of the secondary reservoir while the medicament from the first reservoir is delivered.
In another embodiment relating to parallel dispense, the patch pump device can be supplied with several additional secondary medicaments loaded such that the user may decide when these are needed and dispense them into the manifold and flow of the primary medicament as required. As with other embodiments of this nature, a system of one-way valves can be used to prevent back-flow, accidental mixing and leaking from the system to permit efficient delivery of combined medicaments via the same dispense interface.
By defining the therapeutic relationship between the individual drug compounds our delivery device would help ensure that a patient/user receives the optimum therapeutic combination dose from a multi-drug compound device without the inherent risks associated with multiple inputs where the user has to calculate and set the correct dose combination every time they use the device. The medicaments can be fluids, defined herein as liquids, gases or powders that are capable of flowing and that change shape at a steady rate when acted upon by a force tending to change its shape. Alternatively, one of the medicaments may be a solid that is carried, solubilized or otherwise dispensed with another fluid medicament or carrier.
According to one specific aspect this invention is of particular benefit to users with dexterity or computational difficulties as the single input and associated predefined therapeutic profile removes the need for them to calculate their prescribed dose every time they use the device and the single input allows considerably easier setting and dispensing of the combined compounds.
In a preferred embodiment a master or primary drug compound, such as insulin, is contained within a multiple dose first reservoir connected to a miniaturized pump mechanism known to those skilled in the art of infusion devices that is capable of delivering a continuous dose of medicament and/or a pulse (bolus) of medicament. The pump mechanism preferably is battery operated and controlled through one or more electronic circuits that are manually and/or remotely operated and/or programmed. The pump mechanism is in fluid communication with a manifold and contained within a housing having a bottom surface configured to be removably attached to a user's skin, for example through an adhesive. Also in fluid communication with the manifold is a cannula having distal and proximal ends, where the distal end protrudes through the housing of the patch pump, preferably through an opening in the bottom surface. A preferred cannula is one where the distal end is sharpened like the distal end of an injection needle. Alternatively, the cannula may be of a flexible material for improved user comfort and may or may not be inserted by a separate needle (similar to an injection needle) that is retracted by the device after insertion of the cannula.
The first reservoir can be any type of container, such as a cartridge, and can be filled with primary medicament prior to delivery to the user or it can be filled by the user (or health care provider) immediately prior to use by using an external source, such as, a standard syringe through a port in the housing. The first reservoir can be re-usable, disposable, or non-replaceable. The second reservoir, when contained within the housing can be of the same design as the first reservoir, preferably a replaceable container, most preferably containing a single dose of a secondary medicament.
Although our invention specifically mentions insulin, insulin analogs or insulin derivatives, and GLP-1 or GLP-1 analogs as two possible drug combinations, other drugs or drug combinations, such as an analgesics, hormones, beta agonists or corticosteroids, or a combination of any of the above-mentioned drugs could be used with our invention.
For the purposes of our invention the term “insulin” shall mean Insulin, insulin analogs, insulin derivatives or mixtures thereof, including human insulin or a human insulin analogs or derivatives. Examples of insulin analogs are, without limitation, Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin or Des(B30) human insulin. Examples of insulin derivatives are, without limitation, B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.
As used herein the term “GLP-1” shall mean GLP-1, GLP-1 analogs, or mixtures thereof, including without limitation, exenatide (Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu- Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2), Exendin-3, Liraglutide, or AVE0010 (H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2).
Examples of beta agonists are, without limitation, salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, fenoterol, bitolterol mesylate, salmeterol, formoterol, bambuterol, clenbuterol, indacaterol.
Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.
In one embodiment of our invention there is provided a medicated module attachable to the patch pump drug delivery device that comprises an outer housing having a proximal end, a distal end, and an outer surface. There is a reservoir in the housing that contains a secondary medicament. The medicated module assembly of our invention contains a needle guard that can reduce the risk of accidental needle sticks before and after use as well as preventing a user from using the module a subsequent time when the secondary medicament has already been expelled. The movable needle guard or shield is configured to move axially in both the distal and proximal directions when pressed against and removed from a port in the patch pump housing. When the needle assembly is removed from the port, the guard is returned to post-use extended position to securely lock the guard from further substantial axial movement. By “substantial” movement we do not mean the typical amount of “play” in a system, but instead we mean that the guard and/or distal needle do not move axially a distance that exposes the distal end of the cannula once it is locked out.
Inside the medicated module housing there is a cavity that contains a capsule, which comprises a single dose of medicament in a reservoir. As the needle guard is retracted during an application to the port on the patch pump housing, a trigger button on the device is unlocked. Activation of this trigger button releases some form of stored internal energy (such as a compressed spring, pressurized gas or electric battery) that acts to force the capsule onto the distal cannula of the module and further to compress the capsule, thus decreasing its volume and dispensing its contents. This allows the seals of the capsule to be pierced by the needle cannula such that the medicament can be expelled from the reservoir and into the manifold within the patch pump housing. The medicated module of our invention is preferably designed in such a way as to limit its use to one exclusive patch pump device (or family of devices) through employment of dedicated/coded/exclusive features to prevent attachment of a non-appropriate medicated module to a non-matching device.
A particular benefit of our invention is that the medicated module makes it possible to tailor dose regimes when required, especially where a titration period is necessary for a particular drug. The medicated module could be supplied in a number of titration levels with obvious differentiation features such as, but not limited to, aesthetic design of features or graphics, numbering etc, so that a patient could be instructed to use the supplied medicated module in a specific order to facilitate titration. Alternatively, the prescribing physician may provide the patient with a number of “level one” titration medicated modules and then when these were finished, the physician could then prescribe the next level. A key advantage of this titration program is that the primary device remains constant throughout.
Should the patient attempt to reuse a previously used medicated module, our invention includes the locking needle guard that is activated after a first predefined travel/retraction of the guard/insertion of the needle. The locked needle guard would alert the patient to this situation and the inability to use the module for a second time. Visual warnings (e.g. change in color and/or warning text/indicia within an indication window on the module once insertion and/or fluid flow has occurred) can also be used. Additionally, tactile feedback (presence or absence of tactile features on the outer surface of the module hub following use) could be used as well.
These as well as other advantages of various aspects of the present invention will become apparent to those of ordinary skill in the art by reading the following detailed description, with appropriate reference to the accompanying drawings.
Exemplary embodiments are described herein with reference to the drawings, in which:
Referring first to
The device 10 has a housing 8 with a bottom surface 5. The device can comprise two or more assemblies that are assembled together for use, and wherein one of the assemblies is disposable and the other of the assemblies is reusable. The reusable assembly can be removably attachable to the disposable assembly, for example, where the reusable assembly may be designed to include the more costly components of fluid delivery device 10. Preferably the fluid delivery device 10, with assemblies attached, is small, with a cross-sectional area about the size of a credit card and a thickness less than one inch to facilitate wearability by the user. The bottom surface 5 of housing 8 preferably includes an exit port assembly 9 including a transcutaneous patient access tool, such as the rigid or flexible cannula 4 for penetrating the skin of a patient.
Although not shown, a processor or electronic microcontroller is connected to a power source and the propulsion means and can include a microprocessor, an electronic memory, an electronic clock oscillator, an analog to digital converter and a multiplexer.
The processor is programmed to cause a flow of one or more medicaments through manifold 3 to the exit port assembly 9 based on flow instructions from a separate, remote control device (not shown). The fluid delivery device 10 preferably further includes a wireless receiver connected to the processor for receiving the flow instructions from the separate, remote control device and delivering the flow instructions to the processor. Alternatively, the device could have a number of externally accessible user input features to allow the user or a health care provider to program the device.
Control of fluid flow can be through the use of actuators such as solenoids, piezo actuators, magnetic actuators, thermal generators or other mechanisms to generate, direct or redirect a force, temperature gradient, electromagnetic field or other medium for controlling flow of one or more medicaments between the reservoirs and the exit port assembly. If the reservoirs are maintained at ambient pressure, metering of the flow can include a rotary peristaltic head, linear peristaltic mechanism, electromagnetic fluid propulsion, a displacement pump, or other means for moving fluid from the reservoirs to the exit port assembly. A rotary peristaltic head that is driven by a motor drive may accomplish such propulsion means. If the reservoir is pressurized, one or more valves may simply control flow, and not to propel the fluid. The reservoirs may be included in a sealed compartment, and pressurized gas provide the driving force, or the reservoirs may be in contact with a force generating member such as a spring, a separate elastomeric structure, or a cantilever beam attached to the housing of the device.
As shown in the figures, housing 8 is free of user input components, such as electromechanical switches or buttons or interfaces otherwise accessible to a user to adjust the programmed flow rate through the processor, for providing flow instructions to the device. The lack of user input components allows the size, complexity and costs of the device 10 to be substantially reduced so that the device 10 lends itself to being small and either partially or fully disposable in nature. The bottom surface 5 of housing 8 can contain an adhesive layer (not shown) comprising a standard biocompatible glue such as those used in common adhesive bandages, and may include a protective covering to avoid the adhesive sticking to unwanted objects prior to attachment to the skin of the patient. The skin penetrating cannula 4 can be introduced through the patient's skin prior to attachment of the device to the patient's skin, at the same time as it is attached to the patient's skin, or after it is attached to the patient's skin. Simultaneous puncturing of the patient's skin by the penetrating cannula 4 and attachment of the device may be preferred to simplify attachment and reduce pain of transcutaneous puncturing. The sub-assembly comprising the cannula and adhesive patch may be designed to be detachable from the housing 8 so as to permit reusability of the main body of the device while allowing for disposal of components in contact with the patient.
Each of the above described embodiments require that all the reservoirs are located within housing 8 during dispense.
Once module 60 is connected to port 61 the user can activate module 60 by pressing button or trigger 63 to cause the secondary medicament to be dispensed into manifold 3 where it is carried out through cannula 4 by the flow of the primary medicament from reservoir 1. This secondary compound can either be dispensed into a live flow such that the module would remain attached until the dose was delivered or, it could dispense into the manifold 3 and be gradually dispensed into the user by the flow of primary medicament. The module 60 and port 61 can have matching dedicated connectors to prevent the module from connecting to a non-authorized device. Any known attachment means can be used to attach the medicated module to device 10, including all types of permanent and removable connection means, such as threads, snap locks, snap fits, luer locks, bayonet, snap rings, keyed slots, and combinations of such connections. A guard 64 can also be used to protect the dispense interface of the module and/or the user prior to attachment to device 10. Once the secondary medicament is dispensed and the module is disconnected from port 61, the guard 64 will lock into place and prevent re-attachment to the device.
Materials of construction for the medicated module and device 10 include, but are not limited to, COC (an amorphous polymer based on ethylene and norbonene, also referred to as cyclic olefin copolymer, ethylene copolymer, cyclic olefin polymer, or ethylene-norbornene copolymer); LCP (a liquid crystal polymer having an aramid chemical structure that includes linearly substituted aromatic rings linked by amide groups, and further can include partially crystalline aromatic polyesters based on p-hydroxybenzoic acid and related monomers and also highly aromatic polyesters); PBT (polybutylene terephthalate thermoplastic crystalline polymer or polyester); COP (a cyclic olefin polymer based on ring-opening polymerization of norbornene or norbornene-derivatives); HDPE (high density polyethylene); and SMMA (styrene methyl methacrylate copolymer based on methyl methacrylate and styrene). The needle pierceable septa, bungs, and/or seals that are used with both the module and device 10 can be manufactured using TPE (thermo plastic elastomer); LSR (liquid silicone rubber); LDPE (low density polyethylene); and/or any kind of medical grade rubber, natural or synthetic.
Exemplary embodiments of the present invention have been described. Those skilled in the art will understand, however, that changes and modifications may be made to these embodiments without departing from the true scope and spirit of the present invention, which is defined by the claims.
The present application is a U.S. National Phase Application pursuant to 35 U.S.C. §371 of International Application No. PCT/EP2011/071131 filed Nov. 28, 2011, which claims priority to European Patent Application No. 10192989.1 filed Nov. 29, 2010 and U.S. Provisional Patent Application No. 61/433,800 filed Jan. 18, 2011. The entire disclosure contents of these applications are herewith incorporated by reference into the present application.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2011/071131 | 11/28/2011 | WO | 00 | 5/29/2013 |
| Number | Date | Country | |
|---|---|---|---|
| 61433800 | Jan 2011 | US |
