Drug cartridges, drug delivery devices and methods of making same - Patents.com

Abstract

In one aspect, a drug delivery device provided herein comprises a monolithic body having a plurality of fluid ducts and at least one outlet duct formed in the plurality of fluid ducts; a plurality of drug cartridges attached to the body, each of the plurality of drug cartridges having a reservoir for containing at least one drug, the plurality of fluid ducts configured to carry the drug from the plurality of drug cartridges to the at least one outlet duct; and a needle support positioned away from the body, the needle support comprising a needle configured for insertion into a patient's body for drug delivery, the needle support comprising an adhesive for removably fixing to the patient, the needle support connected to the body by a flexible tether through which passes at least one fluid passageway formed to carry the drug from the at least one outlet duct to the needle.

Description

[Technical field]

[0001] The present invention relates to a method of making a drug cartridge and a drug delivery device. [Background technology]

[0002] Sterilization techniques are well known in the medical field, especially for sterilizing drug cartridges and drug delivery devices intended for parenteral drug delivery. In the prior art, techniques have been developed that involve sterilization of drug delivery devices, such as syringes, at the manufacturing facility to maintain sterility until the time of use, and the sterilized devices are packaged, for example, in pouches. Separately, drugs are prepared and maintained in a sterile state and introduced into the drug delivery device at the time of use.

[0003] Prior art technology has also been developed for pre-filled drug delivery devices, which are filled with a drug at a manufacturing facility, sterilized, and packaged to maintain sterility at the time of use.

[0004] Also, from the standpoint of convenience, it would be desirable for a patient on combination drug therapy to be able to administer all of their prescribed medications from a single injection device. The present invention provides a device that can be loaded with one or more medications in the ratios prescribed for that particular patient, either in a ready-to-use liquid state or in a reconstituted dry state, that can reconstitute the dry medications, and that can automatically administer these medications in sequence to the patient. Summary of the Invention

[0005] In one aspect, a drug delivery device provided herein comprises a monolithic body having a plurality of fluid ducts and at least one outlet duct formed in the plurality of fluid ducts; a plurality of drug cartridges attached to the body, each of the plurality of drug cartridges having a reservoir for containing at least one drug, the plurality of fluid ducts configured to carry the drug from the plurality of drug cartridges to the at least one outlet duct; and a needle support positioned away from the body, the needle support comprising a needle configured for insertion into a patient's body for drug delivery, the needle support comprising an adhesive for removably fixing to the patient, the needle support connected to the body by a flexible tether through which passes at least one fluid passageway formed to carry the drug from the at least one outlet duct to the needle.

[0006] In another aspect, a drug delivery device provided herein comprises a monolithic body having a plurality of fluid ducts and at least one outlet duct formed in said plurality of fluid ducts; and a plurality of drug cartridges attached to said body, each of said plurality of drug cartridges having a reservoir for housing at least one drug, a first of said drug cartridges having a fluid outlet; A first of the fluid ducts is aligned to extend from the fluid outlet, a first opening is formed in a first face of the body, the first fluid duct extending to the first opening, a second of the fluid ducts extends from the first opening along the first face to be exposed along the first face, a second opening is formed in the first face of the body, the second fluid duct extending to the second opening, and the second opening is in fluid communication with the at least one outlet duct.

[0007] In yet another aspect, a drug delivery device provided herein comprises a body having a plurality of fluid ducts and at least one outlet duct formed in the plurality of fluid ducts; a plurality of drug cartridges attached to the body, each of the plurality of drug cartridges having a reservoir for containing at least one drug; and a displaceable actuator plate disposed adjacent to the body, a first of the drug cartridges having a fluid outlet, a first of the fluid ducts being aligned to extend from the fluid outlet, a displaceable seal selectively seals the fluid outlet between a first state in which the fluid outlet is sealed and a second state in which the fluid outlet is not sealed, and displacement of the actuator plate displaces the seal from the first state to the second state.

[0008] In yet another aspect provided herein is a method of reconstituting a drug in a drug delivery device, comprising the steps of: providing a reservoir for a drug in a dry state; introducing a diluent into the reservoir to interact with the drug and generate an intermediate mixture, wherein a pressure of the diluent is measured while the diluent is being introduced and the diluent is introduced into the reservoir until the pressure of the diluent reaches a predetermined pressure; withdrawing the intermediate mixture from the reservoir; conveying the intermediate mixture through a vent to expel entrained gases and generate an evacuated mixture; and introducing the evacuated mixture into the reservoir.

[0009] Advantageously, the present invention provides a drug delivery device that can be used for bulk drug delivery and / or combination drug delivery.

[0010] The present invention also advantageously provides a drug delivery device configured with multiple flow paths that can be controlled to direct flow for delivery, mixing, and reconstitution as needed.

[0011] As used herein, the terms "drug" or "drug component" can be used interchangeably and refer to any therapeutic agent in any physical state (e.g., solid, liquid, suspension) and / or any component in any physical state, intended to be mixed with or act in conjunction with any therapeutic agent (e.g., diluent) and / or any combination or mixture of therapeutic agents (e.g., a mixture of a diluent and one or more therapeutic agents). The drug may be prepared using any known technique, including, but not limited to, lyophilization, spray drying dispersion (SDD), spray freeze drying (SFD), and melt crystallization (e.g., to form a crystallized suspension).

[0012] As used herein, the term "ultraviolet radiation" shall mean electromagnetic radiation having wavelengths typically found in the ultraviolet portion of the light spectrum, including within the range of 100 nm to 315 nm, suitable for decontamination. Ultraviolet radiation includes electromagnetic radiation with wavelengths in the ultraviolet B (UVB) range (280 nm to 315 nm) and / or electromagnetic radiation with wavelengths in the ultraviolet C (UVC) range (100 nm to 280 nm).

[0013] As used herein, the term "electron beam" is intended to mean a focused stream of highly charged electrons suitable for decontamination. Electron beams may be characterized as "low energy", e.g., having a kinetic energy of 300 keV or less.

[0014] As used herein, the term "X-ray radiation" is intended to mean electromagnetic radiation having energies ranging up to 10 MeV, and in some cases up to 7.5 MeV. X-ray radiation may be characterized as being in the wavelength range of "soft" X-ray, "hard" X-ray, or gamma radiation. X-ray radiation may be administered up to a dose of 25 kGy. Alternatively, lower doses may be applied to achieve sufficient sterility assurance levels for the relevant bioburden.

[0015] Also, as used herein, the term "pulsed light" refers to repeated short bursts of electromagnetic radiation suitable for decontamination, including electromagnetic radiation in the visible and invisible portions of the light spectrum. Each burst of pulsed light may be characterized as "high energy," for example, on the order of 300 J, with a high power flash of, for example, on the order of 1 mW, delivered for a short period of time, such as 0.3 milliseconds. Pulsed light may include ultraviolet radiation, where the ultraviolet radiation is delivered in repeated short bursts, including ultraviolet radiation in the ultraviolet A (UVA) range (315 nm to 400 nm) in addition to the UVB and UVC ranges mentioned above. Additionally, pulsed light may include electromagnetic radiation effective for decontamination, including, but not limited to, x-ray radiation, light in the visible spectrum (400 nm to 770 nm), and / or infrared radiation in the infrared portion of the light spectrum (770 nm to 1100 nm). As will be appreciated by those skilled in the art, the pulses of pulsed light may include a mixture of different types of electromagnetic radiation, for example, a mixture of visible light and ultraviolet radiation (eg, UVC).

[0016] As used herein, the term "decontamination" and variations thereof are intended to mean the removal of pathogens, bacteria, or other living microorganisms. High levels of removal are achievable, including levels commensurate with sterilization.

[0017] These and other features of the present invention may be better understood with reference to the following detailed description and accompanying drawings. [Brief description of the drawings]

[0018] [Figure 1] FIG. 1 is a schematic diagram showing the structure, container communication and functional elements of a drug delivery device according to the present invention. [Diagram 2] FIG. 1 is a perspective view of a drug delivery device according to the present invention with the upper housing removed. [Diagram 3] FIG. 3 is a perspective view showing, in hidden lines, the arrangement of components within the drug delivery device of FIG. 2. [Figure 4]FIG. 4 is a perspective view of the drug delivery device of FIG. 3 with the barrier removed to show the body. [Diagram 5] FIG. 5 is a perspective view of the drug delivery device of FIG. 4 with the diluent pack removed to show the drug cartridge. [Figure 6] FIG. 6 is an enlarged view of the drug cartridge and body of FIG. 5. [Figure 6A] FIG. 13 is a schematic diagram of an assembly configuration in which three sets of three drug containers are connected to the main body. [Figure 6B] FIG. 13 is a schematic diagram of an assembly configuration in which one group of five drug containers and two groups of two drug containers are connected to a main body. [Figure 6C] FIG. 13 is a schematic diagram of an assembly configuration in which one group of five drug containers, one group of three drug containers, and a separate single drug container are connected to the main body. [Figure 6D] FIG. 6C is a schematic diagram of an assembled configuration in which the multiple drug containers that make up each group of FIG. 6B are replaced with a single larger drug container. [Figure 7] FIG. 1 is a cross-sectional view of a drug cartridge according to the present invention, in an assembled state, including a reservoir and a plug adapter. [Figure 8] 1 is a cross-sectional view of a reservoir of a drug cartridge according to the present invention. [Figure 8A] 9 shows the components of the reservoir of FIG. 8 in a partially collapsed and deformed state. [Figure 9] 1 is a cross-sectional view of components of a plug adapter of a drug cartridge according to the present invention. [Figure 10] FIG. 2 is a cross-sectional view of a drug cartridge according to the present invention showing a radial seal closure. [Figure 11] FIG. 11 is a cross-sectional view of the drug cartridge of FIG. 10 with the lower portion of the hard shell removed. [Figure 12] 1 shows a vented drug cartridge according to the present invention. [Figure 13] FIG. 2 is a detailed view of a plug adapter that can be used with the radial seal according to the present invention. [Figure 14] FIG. 14 is a cross-sectional view of the plug adapter of FIG. 13. [Figure 15] FIG. 1 is a perspective view of a reservoir that can be used in a radial seal according to the present invention. [Figure 16] FIG. 16 is another view of the reservoir of FIG. 15 showing a retention mechanism for a radial seal closure. [Figure 17A] 1 shows a reservoir oriented for filling according to the present invention. [Figure 17B] 17B shows the reservoir of FIG. 17A with the plug adapter in a venting position. [Figure 17C] 17B shows the plug adapter fully installed in the reservoir of FIG. 17A. [Figure 18] FIG. 1 is a cross-sectional view of a medication cartridge according to the present invention showing a face seal with an internal retention feature. [Figure 19] FIG. 2 is a cross-sectional view of a drug cartridge according to the present invention showing the internal flow paths. [Figure 20A] 1 shows a reservoir oriented for filling according to the present invention. [Figure 20B] 20B shows the reservoir of FIG. 20A with the plug adapter in a venting position. [Figure 20C] 20B shows the plug adapter fully installed in the reservoir of FIG. 20A. [Figure 21] 1 shows a drug cartridge according to the present invention with a hard shell that allows for full expansion of the reservoir. [Figure 22] 1 shows a drug cartridge according to the present invention with a hard shell that inhibits reservoir expansion. [Figure 23] 1 shows a plug adapter usable with the present invention utilizing a face seal and inward detents. [Figure 24] 24 shows a cross-sectional view of the plug adapter of FIG. 23 with the seal in place. [Diagram 25] 24 shows a cross-sectional view of the plug adapter of FIG. 23 without the seal in place. [Figure 26] 24 shows a reservoir that can be assembled to the face seal type plug adapter of FIG. 23. [Figure 27] FIG. 27 is a cross-sectional view of a drug cartridge utilizing the face seal reservoir of FIG. 26 and the plug adapter of FIG. 23. [Figure 28] FIG. 28 is a perspective view of the drug cartridge of FIG. 27. [Figure 29] FIG. 1 is a cross-sectional view of a drug cartridge utilizing a face-sealed reservoir with a tapered neck and a plug adapter with a vent passage along the neck. [Diagram 30] FIG. 30 is a cross-sectional view of the drug cartridge of FIG. 29 in a sealed position. [Figure 31A] FIG. 30 is a perspective view of a sealing element of the drug cartridge of FIG. 29. [Figure 31B] FIG. 31B is a cross-sectional view of the sealing element of FIG. 31A. [Figure 32A] FIG. 13 is a perspective view of a drug cartridge utilizing a latching mechanism between a plug adapter and a reservoir. [Figure 32B] FIG. 32B is an exploded perspective view of the drug cartridge of FIG. 32A. [Figure 32C] 32B shows the plug adapter of FIG. 32A in a vented position. [Fig. 32D] 32B shows the plug adapter of FIG. 32A in a sealed position. [Figure 32E] FIG. 32E is a cross-sectional view of the drug cartridge of FIG. 32D with the plug adapter in a sealed position. [Figure 33A] 31B shows the sealing element of FIG. 31A in a vented position with the cut surface positioned so that the protruding bead is visible. [Figure 33B] 31B shows the sealing element of FIG. 31A in a venting position for freeze-drying. [Figure 33C] 31B shows the sealing element of FIG. 31A in a sealed position. [Figure 34A] 2 is a cross-sectional view of a plug adapter in a sealed position according to the present invention; [Figure 34B] FIG. 1 is a perspective view of a valve usable with a plug adapter in accordance with the present invention; [Figure 34C] FIG. 34C is a cross-sectional view of a plug adapter using the valve of FIG. 34B in a sealed position. [Figure 35A] FIG. 34B is a cross-sectional view of the plug adapter of FIG. 34A in an open position. [Figure 35B] FIG. 34C is a cross-sectional view of a plug adapter using the valve of FIG. 34B in an open position. [Figure 36A] 1 illustrates a method of accessing a drug cartridge by displacing a plug according to the present invention. [Figure 36B] 13 illustrates a method of accessing the drug cartridge by sliding the seal away from the outlet according to the present invention. [Figure 36C] 1 illustrates a method of accessing a drug cartridge by moving a lid according to the present invention. [Figure 36D] 1 illustrates a method of accessing a drug cartridge by opening a latch according to the present invention. [Figure 36E] 13 illustrates a method of accessing a drug cartridge by displacing a plug using an internal spring according to the present invention. [Figure 37A] 1 illustrates a method of accessing a drug cartridge by peeling back a film in accordance with the present invention. [Figure 37B] 1 illustrates a method of accessing a drug cartridge by rupturing a film with electromotive force, in accordance with the present invention. [Figure 37C] 13 illustrates a method of accessing a drug cartridge by breaking a film using a spring force in accordance with the present invention. [Figure 37D] 13 illustrates a method of accessing a drug cartridge by cutting a film using a rotational motion in accordance with the present invention. [Figure 38A] 13 illustrates a method of accessing the drug cartridge by cutting along a perforation line according to the present invention. [Figure 38B] 13 illustrates a method of accessing a drug cartridge by shearing along a tear line according to the present invention. [Figure 39A]1 illustrates a method of accessing a drug cartridge by engaging two ends of a film covering a flow channel, in accordance with the present invention, in which the film is attached to a flat surface. [Figure 39B] 13 illustrates a method of accessing a drug cartridge by engaging two ends of a film covering a flow channel, in which the film is attached to a cylindrical surface, according to the present invention. [Figure 39C] 13 illustrates a method of accessing a drug cartridge by peeling a film via relative rotation of internal components in accordance with the present invention. [Figure 39D] 13 illustrates a method of accessing the drug cartridge by peeling a film through a ball valve type element according to the present invention. [Figure 40A-1] 1 illustrates an initial seal state of a system for accessing a drug cartridge by moving two seals according to the present invention. [Figure 40A-2] FIG. 40A-1 shows the final open state of the system. [Figure 40B] 1 illustrates a method of decontaminating a fluid pathway using a disinfectant reservoir and a slidable piston according to the present invention. [Figure 40C] 1 illustrates a method of accessing a drug cartridge using a removable lateral seal and clamping mechanism according to the present invention. [Figure 41A] 1 illustrates a method of decontaminating a fluid pathway using a cannulated disinfectant reservoir according to the present invention. [Figure 41B] 1 illustrates a method of accessing a drug cartridge using a single-ended sheathed needle and septum in accordance with the present invention. [Figure 41C] 41C shows the system of FIG. 41B in use. [Figure 41D] 1 illustrates a method of accessing a drug cartridge using a double-ended sheathed needle and septum in accordance with the present invention. [Figure 41E]1 illustrates a method of accessing a drug cartridge using a spring-loaded needle that is preloaded within the outlet of the drug cartridge according to the present invention. [Fig.41F] 1 illustrates a method of accessing a drug cartridge using a spring-loaded needle in an extended state within the outlet of the drug cartridge according to the present invention. [Diagram 42] 1 is a cross-sectional view of a drug delivery device showing possible fluid pathways according to the present invention. [Diagram 43] FIG. 43 is a detailed view of a portion of FIG. 42. [Diagram 44] FIG. 2 is a perspective view of a main body usable in the present invention. [Diagram 45] The main body of FIG. 44 is shown together with the barrier. [Figure 46] FIG. 1 is a cross-sectional view showing potential non-sterile areas of a drug delivery device requiring sterilization. [Figure 47] FIG. 1 is a perspective view showing potential non-sterile areas of a drug delivery device requiring sterilization. [Figure 48] FIG. 1 is a cross-sectional view showing areas of a drug delivery device that should be sterilized by ultraviolet light, pulsed light, or electron beam and areas that should not be sterilized. [Figure 49] 1 illustrates locations where additives can be utilized within a drug delivery device to block the transmission of ultraviolet or pulsed light. [Figure 49A] 1 illustrates locations where additives can be utilized within a drug delivery device to block the transmission of ultraviolet or pulsed light. [Figure 49B] 1 illustrates locations where additives can be utilized within a drug delivery device to block the transmission of ultraviolet or pulsed light. [Figure 49C] 1 illustrates locations where additives can be utilized within a drug delivery device to block the transmission of ultraviolet or pulsed light. [Figure 50] In addition to the locations shown in FIG. 49, further locations are shown where additives can be used to block the transmission of ultraviolet or pulsed light. [Figure 51] FIG. 51 is a full cross-sectional view of a drug delivery device showing the blocking component shown in FIG. 50. [Figure 52] FIG. 1 is a cross-sectional view of a drug delivery device showing a shield for blocking ultraviolet light, pulsed light, or electron beam radiation. [Figure 52A] FIG. 13 is a cross-sectional view of a drug delivery device showing an alternative shield for blocking ultraviolet light, pulsed light, or electron beam radiation. [Figure 52B] FIG. 52B is a top view of the shield shown in FIG. 52A. [Diagram 53] 1 is a cross-sectional view of a drug delivery device showing flow paths and valve configurations according to the present invention. [Figure 54] FIG. 54 is a detailed view of a portion of FIG. 53, focusing on the body of the drug delivery device. [Figure 55] 1 shows a drug cartridge attached to the body of a drug delivery device having a valve in a closed state according to the present invention. [Figure 56] 56 shows the drug cartridge of FIG. 55 with the valve open to define a flow path. [Figure 57] FIG. 57 is a detailed view of a portion of FIG. 56. [Figure 58] 1 shows a drug cartridge with a reservoir support usable with a dry product according to the present invention. [Figure 59] 59 shows the reservoir support of FIG. 58 in use. [Figure 60] 1 shows a drug cartridge with an alternative reservoir support that can be used for dry products according to the present invention. [Figure 61] 61 shows the reservoir support of FIG. 60 in use. [Figure 62] 1 shows a drug cartridge with a reservoir support fixture according to the present invention. [Figure 63] 63 shows the reservoir support fixture of FIG. 62 in use. [Fig. 64A] 1 shows a jig that can be used in the present invention. [Figure 64B] 1 shows an open fixture that can be used with the present invention. [Fig. 64C] 1 shows a tray that can be used in the present invention. [Fig.64D] 64D shows the tray of FIG. 64C loaded with drug cartridges. [Figure 64E] Shows the load of FIG. 64D placed in the tab. [Figure 65] 1 shows a drug delivery device with a drug cartridge in a barrel configuration according to the present invention. [Figure 66] FIG. 66 is a cross-sectional view of the drug delivery device of FIG. [Figure 67A] 1 shows a drug cartridge in a sealed barrel configuration according to the present invention. [Figure 67B] 67B shows the drug cartridge of FIG. 67A in an actuated state. [Figure 68] 13A-13C show various configurations of a barrel-configured drug cartridge with a bypass channel. [Figure 69] 66 illustrates sterilization of a portion of the drug delivery device of FIG. 65. [Figure 70] 1 illustrates a drug delivery device with a drug cartridge in an alternative barrel configuration according to the present invention. [Figure 71] FIG. 71 is a perspective view of the drug delivery device of FIG. [Figure 72] FIG. 71 is a cross-sectional view of the drug delivery device of FIG. [Figure 73A] 13A and 13B show schematic diagrams of the position of the drug delivery device on the body relative to UV irradiation. [Figure 73B] The UV threshold dose achieved after 3 seconds of UV exposure is shown. [Figure 73C] The UV threshold dose achieved after 30 seconds of UV exposure is shown. [Figure 74] 13 shows a drug delivery device with a drug cartridge in yet another barrel configuration according to the present invention. [Figure 75] 75 illustrates actuation of the plunger in the drug delivery device of FIG. 74. [Figure 76] 76 illustrates actuation of the plunger in the opposite direction following the action shown in FIG. 75. [Figure 77] 77 shows the rotation of the plunger into another barrel following the action shown in FIG. 76. [Figure 78] 78 shows the actuation of the plunger following the action shown in FIG. 77. [Figure 79A] 1 shows a drug delivery device according to the present invention, which is attached via a clip onto a patient's clothing. [Figure 79B] FIG. 79B is a side view of the drug delivery device of FIG. 79A. [Figure 80A] 1 shows a drug delivery device according to the present invention attached to the patient's abdomen via an adhesive. [Figure 80B] FIG. 80B is a side view of the drug delivery device of FIG. 80A. [Figure 81A] 1 shows a drug delivery device according to the present invention, which is attached to a patient's waist via a strap or belt. [Fig. 81B] FIG. 81B is a side view of the drug delivery device of FIG. 81A. [Fig. 82A] FIG. 13 is a top view of an alternative plug adapter usable with the present invention. [Fig. 82B] FIG. 82B is a cross-sectional view of the plug adapter of FIG. 82A. [Figure 83A] FIG. 82B is a top view of a drug cartridge with the plug adapter of FIG. 82A. [Figure 83B] FIG. 83B is a cross-sectional view of the drug cartridge of FIG. 83A prior to assembly with a ferrule. [Fig. 84A] FIG. 83B is a top view of the drug cartridge of FIG. 83A with the ferrule attached. [Fig. 84B] FIG. 84B is a cross-sectional view of the drug cartridge of FIG. 84A. [Figure 85] FIG. 1 is a perspective view of a drug cartridge with a ferrule attached in accordance with the present invention. [Figure 86] FIG. 86 is a cross-sectional view of the drug cartridge of FIG. 85. [Figure 87A] FIG. 13 is a side view of an alternative plug adapter usable with the present invention. [Fig. 87B] FIG. 87B is a cross-sectional view of the plug adapter of FIG. 87A. [Fig. 88A] FIG. 87B is a top view of a drug cartridge with the plug adapter of FIG. 87A. [Fig. 88B] FIG. 88B is a cross-sectional view of the drug cartridge of FIG. 88A prior to assembly with a ferrule. [Figure 89A]FIG. 88B is a top view of the drug cartridge of FIG. 88A with the ferrule attached. [Fig. 89B] FIG. 89B is a cross-sectional view of the drug cartridge of FIG. 89A. [Figure 90] 1A-1C are schematic diagrams showing examples of fluid configurations that can be used in the present invention. [Figure 91] 1A-1C are schematic diagrams showing examples of fluid configurations that can be used in the present invention. [Figure 92] 1A-1C are schematic diagrams showing examples of fluid configurations that can be used in the present invention. [Figure 93] 1A-1C are schematic diagrams showing examples of fluid configurations that can be used in the present invention. [Figure 94A] 1A-1C are schematic diagrams showing examples of fluid configurations that can be used in the present invention. [Figure 94B] 1A-1C are schematic diagrams showing examples of fluid configurations that can be used in the present invention. [Figure 95] 1 is a cross-sectional view of a displaceable actuator plate that can be used in the present invention. [Figure 96A] FIG. 13 is a cross-sectional view of an actuator plate mounted on a gear plate. [Figure 96B] FIG. 96B is a cross-sectional view similar to FIG. 96A showing the gear plate rotating and lifting the actuator plate. [Figure 96C] FIG. 96B is a top view of the gear plate of FIG. 96A. [Figure 96D] FIG. 96B is a side view of FIG. 96A. [Figure 96E] FIG. 96C is a side view of FIG. 96B. [Figure 97A] FIG. 13 is a side view of the actuator plate in a lowered position. [Figure 97B] FIG. 97B is a side view showing the actuator plate being lifted from the position of FIG. 97A to displace the valve. [Figure 98] FIG. 11 is a cross-sectional view of a biasing means configured to bias a valve to an open state. [Figure 99] FIG. 2 is a top view of a vibrating plate usable in the present invention. [Figure 100] FIG. 1 is a top view of a rotating or vibrating turntable usable with the present invention. [Figure 101] FIG. 1 is a top view of an integrated accelerometer usable in the present invention. [Figure 102] FIG. 1 is a top view of an internal piezoelectric actuator usable in the present invention. [Figure 103] 1 shows a magnetic stirrer that can be used in the present invention. [Figure 104] 1 shows a low profile, collapsible and deformable reservoir that can be placed under a drug cartridge in a drug delivery device that can be used in the present invention. [Figure 105A] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 105B] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 105C] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Fig. 105D] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 106A] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 106B] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 106C] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 106D] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 106E] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Fig. 106F] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 107A] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 107B] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 107C] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Fig. 107D] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 107E] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Fig. 107F] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 107G] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Fig. 107H] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Fig. 107I] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Fig. 107J] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 107K] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Fig. 107L] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 107M] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Fig. 107N] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Fig. 107O] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 107P] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 108] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Fig. 109] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 110] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 111] 1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 112]1 shows an example of a configuration for circulation of the mixture during reconstitution that can be used in the present invention. [Figure 113] FIG. 1 is a top perspective view of a vent usable in the present invention. [Fig. 114] 1A and 1B are top and side views of a vent that can be used with the present invention. [Figure 115] FIG. 13 is a top view of a base plate of a vent with straight channels formed therein that can be used with the present invention. [Fig. 116] FIG. 13 is a top view of a base plate of a vent having channels formed therein that define a tortuous path that can be used with the present invention. [Fig. 116A] 13 illustrates an alternative embodiment of a vent with a serpentine path that makes a vertical turn. [Fig. 116B] 13 illustrates an alternative embodiment of a vent with a serpentine path that makes a vertical turn. [Figure 116C] 13 illustrates an alternative embodiment of a vent with a serpentine path that makes a vertical turn. [Figure 117] FIG. 13 is a top view of a base plate of a channeled vent with an extension that can be used in the present invention. [Fig. 117A] 1 shows a vent having an expansion portion having a diverging portion and a tapered portion. [Fig. 117B] 1 shows a vent having an expansion portion having a diverging portion and a tapered portion. [Fig. 118A] FIG. 2 is a top view of a valve module usable in the present invention. [Fig. 118B] 13A-13C are top views of alternative configurations of actuator gears and worm gears usable with the present invention. [Figure 119] FIG. 118B is a top perspective view of the valve module of FIG. 118A with the actuator gear removed. [Figure 120] FIG. 120 is a top view of the valve module of FIG. 119. [Fig. 121A] FIG. 120 is a top view of a portion of the valve module of FIG. 119 with the leaf spring removed. [Fig. 121B]FIG. 119 is a top view of a portion of the valve module of FIG. 118 with the leaf spring and actuator gear removed. [Fig. 122A] FIG. 121C is a top perspective view of the partial valve module of FIG. 121B with the flexible body of the valve removed. [Fig. 122B] FIG. 121B is an enlarged view of a portion of the partial valve module of FIG. 121A with the flexible body of the valve removed. [Fig. 123A] FIG. 121B is a top view of the partial valve module of FIG. 121A with the flexible body of the valve removed. [Fig. 123B] FIG. 122B is a top view of FIG. 122A with the valve superimposed on the flow path. [Figure 124] FIG. 123B is a top perspective view of the partial valve module of FIG. 123A with the top layer removed. [Fig. 125] FIG. 125 is a top perspective view of a second intermediate layer usable in the partial valve module of FIG. 124. [Fig. 126A] FIG. 125 is a side view of the partial valve module of FIG. 124. [Fig. 126B] FIG. 125 is a side view of the partial valve module of FIG. 124. [Figure 126C] FIG. 125 is a side view of the partial valve module of FIG. 124. [Fig. 126D] FIG. 125 is a side view of the partial valve module of FIG. 124. [Figure 127] FIG. 126B is an enlarged portion of FIG. 126A. [Figure 128] FIG. 126 is a top perspective view of the second intermediate layer of FIG. 125. [Figure 129] FIG. 126 is a top view of the second intermediate layer of FIG. 125. [Fig. 130] FIG. 126 is a bottom view of the second intermediate layer of FIG. 125. [Fig. 131] FIG. 118B is a cross-sectional view of the valve module of FIG. 118A. [Fig. 132] FIG. 13 is a top perspective view showing the configuration of a leaf spring of an actuator gear that can be used in the present invention. [Fig. 133]FIG. 133 is a top perspective view of the configuration of FIG. 132 with the actuator gear shown through. [Fig. 134] FIG. 133 is a top perspective view of the configuration of FIG. 132 with the leaf spring removed. [Fig. 135] 131 showing the valve in an unenergized state. FIG. [Fig. 136] 136 shows the valve of FIG. 135 in a deflected state. [Fig. 137] FIG. 132 is a top perspective view of FIG. 131 with the actuator gear removed. [Fig. 138] FIG. 137 is a side view of FIG. [Fig. 139A] 1 illustrates diagrammatically one set of valve and actuator gear configurations that can be used in the present invention. [Fig. 139B] 139B shows a schematic diagram of the valve of FIG. 139A and a mechanism of a drug delivery device to which the valve can be fluidly coupled. [Figure 139C] FIG. 124 is a view similar to FIG. 124 showing the arrangement of the valves shown in FIGS. 139A and 140A. [Fig. 139D] FIG. 129 is a view similar to FIG. 129 showing a fluid connection between a valve and a mechanism of a drug delivery device to which the valve can be fluidly coupled. [Figure 139E] A view similar to FIG. 130 showing a fluid connection between a valve and a mechanism of a drug delivery device to which the valve can be fluidly coupled. [Fig. 140A] 10A-10C show schematic diagrams of alternative configurations of valve sets and actuator gear that can be used in the present invention; [Fig. 140B] 140B shows a schematic diagram of the valve of FIG. 140A and a mechanism of a drug delivery device to which the valve can be fluidly coupled. [Fig. 141] 1 shows a top perspective view of a drug delivery device according to the present invention. [Fig. 142] FIG. 142 is a top perspective view of the drug delivery device of FIG. 141 with the reservoir removed. [Fig. 143] FIG. 142 is a top perspective view of the drug delivery device of FIG. 141 with the reservoir and barrier removed. [Fig. 144] FIG. 143 is shown in perspective to show the internal passages. [Fig. 145] FIG. 13 is a top perspective view of an alternative valve module usable with the present invention. [Fig. 146] FIG. 145 is an enlarged view of FIG. 145, with certain portions shown in transparent form. [Fig. 147] FIG. 146 is a side view showing the arrangement of the actuator gear of the valve module of FIG. 145. [Fig. 148A] 148A and 148B illustrate schematic diagrams of a valve configured to be deflected in a downward (inward) direction from an unbiased state (FIG. 148A) to a deflected state (FIG. 148B). [Fig. 148B] 148A and 148B show schematic diagrams of a valve configured to be deflectable in a downward (inward) direction from an unbiased state (FIG. 148A) to a deflected state (FIG. 148B). [Figure 149] FIG. 13 is a top perspective view of an alternative valve module usable with the present invention. [Fig. 150] 149, but showing certain parts in transparent form. [Fig. 151] FIG. 150 is a bottom perspective view of the valve module of FIG. 149. [Fig. 152] FIG. 141 is a top view of the valve module of FIG. 140 showing the internal passages. [Fig. 153] FIG. 153 is an enlarged view of a portion of FIG. 152. [Fig. 154] FIG. 154 is a top perspective view of the enlarged portion shown in FIG. 153. [Fig. 155] FIG. 150 is a side view of a portion of the valve module of FIG. 149 showing tubes defining one or more fluid ducts. [Fig. 156] 1 illustrates an exemplary fluid flow of a drug delivery device under negative and positive pressure according to the present invention. [Fig. 157] 1 illustrates an exemplary fluid flow of a drug delivery device under negative and positive pressure according to the present invention. [Fig. 158] 1 illustrates an exemplary fluid flow of a drug delivery device under negative and positive pressure according to the present invention. [Fig. 159] 1 illustrates an exemplary fluid flow of a drug delivery device under negative and positive pressure according to the present invention. [Fig. 160] 1 illustrates an exemplary fluid flow of a drug delivery device under negative and positive pressure according to the present invention. [Fig. 161] 1 illustrates an exemplary fluid flow of a drug delivery device under negative and positive pressure according to the present invention. [Fig. 162] 1 illustrates an exemplary fluid flow of a drug delivery device under negative and positive pressure according to the present invention. [Fig. 163] 1 illustrates an exemplary fluid flow of a drug delivery device under negative and positive pressure according to the present invention. [Fig. 164] 1 illustrates an exemplary fluid flow of a drug delivery device under negative and positive pressure according to the present invention. [Fig. 165] 1 illustrates an exemplary fluid flow of a drug delivery device under negative and positive pressure according to the present invention. [Fig. 166] 1 illustrates an exemplary fluid flow of a drug delivery device under negative and positive pressure according to the present invention. [Fig. 167] 1 illustrates an exemplary fluid flow of a drug delivery device under negative and positive pressure according to the present invention. [Fig. 168] 1 illustrates an exemplary complete flow diagram of a drug delivery device utilizing negative and positive pressure according to the present invention. [Fig. 169] 1 illustrates an exemplary complete flow diagram of a drug delivery device utilizing negative and positive pressure according to the present invention. [Fig. 170] 1 illustrates an exemplary complete flow diagram of a drug delivery device utilizing negative and positive pressure according to the present invention. [Fig. 171] 1 illustrates an exemplary complete flow diagram of a drug delivery device utilizing negative and positive pressure according to the present invention. [Fig. 172] 1 illustrates an exemplary complete flow diagram of a drug delivery device utilizing negative and positive pressure according to the present invention. [Fig. 173] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Fig. 174] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Fig. 175] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Fig. 176] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Fig. 177] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Fig. 178] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Fig. 179] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Fig. 180] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Fig. 181] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Fig. 182] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Fig. 183] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Fig. 184] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Fig. 185] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Fig. 186] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Fig. 187] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Fig. 188] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Fig. 189] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Fig. 190] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Fig. 191] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Fig. 192] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Fig. 193] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Fig. 194] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Fig. 195] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Fig. 196] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Figure 197] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Figure 198] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Figure 199] 19 shows an actuator for opening the seal shown in FIGS. 187-198 according to the present invention. [Figure 200] 19 shows an actuator for opening the seal shown in FIGS. 187-198 according to the present invention. [Figure 201] 19 shows an actuator for opening the seal shown in FIGS. 187-198 according to the present invention. [Fig. 202] 19 shows an actuator for opening the seal shown in FIGS. 187-198 according to the present invention. [Fig. 203] 19 shows an actuator for opening the seal shown in FIGS. 187-198 according to the present invention. [Fig. 204] 19 shows an actuator for opening the seal shown in FIGS. 187-198 according to the present invention. [Fig. 205] 19 shows an actuator for opening the seal shown in FIGS. 187-198 according to the present invention. [Fig. 206] 19 shows an actuator for opening the seal shown in FIGS. 187-198 according to the present invention. [Fig. 207] 19 shows an actuator for opening the seal shown in FIGS. 187-198 according to the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] In one aspect, the present invention is directed to a method of making a drug cartridge and a method of making a drug delivery device. Referring to the drawings, an exemplary drug delivery device is shown at 10. As will be appreciated by those skilled in the art, a variety of drug delivery devices can be made by the method of the present invention. The configuration and assembly of the components of the drug delivery device can be varied as appropriate and are within the scope of the present invention.

[0020] With reference to FIG. 1, a drug delivery device 10 may comprise a body 12 to which one or more drug cartridges 14 are attached. The drug delivery device 10 is shown as a wearable patch-type drug delivery device having a needle support 16, a pump 18, and a control unit 20. The control unit 20 may include a computer processor or logic controller. The control unit 20 may be configured to control the pump 18 to control the flow of drug from the drug cartridge 14 to a needle 15 attached to the needle support 16 for injection into a patient. The needle 15 may be a standard hypodermic needle or cannula, or a soft cannula housed within a rigid sheath. The drug 13 may be made to flow from one drug cartridge 14 to another drug cartridge 14, for example, to deliver a diluent from one drug cartridge 14 to another drug cartridge 14. The pump 18 may be used to draw the drug from the drug cartridge 14, pump the drug to another drug cartridge 14, and further pump the drug through a predetermined fluid duct or fluid pathway to the needle 15 for delivery from the needle 15 into the patient's body. The pump 18 may also be configured to be bidirectionally reversible, thereby circulating the drug in and out of the drug cartridge 14, for example to facilitate reconstitution. The control unit 20 may be configured to cause the insertion and / or withdrawal of the needle 15 into and from the patient during preparation for drug administration and after drug delivery. Any known configuration may be utilized for these processes. In addition, various other components (e.g., valves, bubble traps, motors, etc.) may also be provided in the drug delivery device 10, as shown diagrammatically in FIG. 1. An optional power source (e.g., a storage power source such as a battery) may be provided to provide power for the operation of the needle 15, the pump 18, the control unit 20, and the valve adjustments (as described below). One or more motors may be provided to control the pump 18 and the valves. The motor is preferably an electric motor, such as a stepper motor.

[0021] 2-6, the drug cartridge 14 may be attached to the body 12 in various configurations, including along the periphery of the body 12. The body 12 may be disk-shaped, allowing the drug cartridge 14 to be attached around the body 12. To facilitate the flow of the drug, the body 12 may be formed with a plurality of fluid ducts 22 arranged to extend from the drug cartridge 14 to one or more outlet ducts 25. The fluid ducts 22 may be arranged in any manner, for example, a single passageway from the drug cartridge 14 to one or more outlet ducts 25. Alternatively, the fluid ducts 22 may be branched to combine the multiple fluid ducts 22 in various combinations, and in some cases, all of the multiple fluid ducts 22 are combined as a single fluid flow that is ultimately directed to one or more outlet ducts 25. As shown in FIGS. 6A-6D, the drug cartridges 14 may be combined in various combinations. FIG. 6A shows three groups 1, 2, 3 of drug cartridges 14, each of which contains three drug cartridges 14 and feeds one outlet duct 25. This allows mixing of the drug cartridges 14 within a group (e.g., the drug cartridges 14 in group 1 can be changed to allow different combinations) and the resulting combinations can be further mixed downstream of the outlet duct 25. FIG. 6B shows three groupings, but not evenly grouped, with group 1 containing five drug cartridges 14 and groups 2 and 3 containing two drug cartridges 14 each. By varying the size of the groups, the amount and concentration of the resulting drug combination can be controlled. Another embodiment of varying the size of the groups is shown in FIG. 6C. FIG. 6D shows the use of drug cartridges 14 of various sizes corresponding to the groups, with the different size cartridges varying the amount and / or concentration of the individual components. For example, the drug cartridges 14 of group 1 may be formed to extend along a longer arc around the body 12 than either of the corresponding drug cartridges 14 of groups 2 and 3.As will be understood by those skilled in the art, one or more groups may be combined to lead to a common outlet duct 25 (i.e., the number of valves in the outlet duct 25 can be varied as appropriate and is not limited to a one-to-one correspondence with the groups of drug cartridges 14).

[0022] 65-69, the drug cartridge 14 may be mounted on one side of the body 12 so as to extend generally perpendicularly from the side. In this way, the drug cartridge 14 may be generally within the footprint of the body 12. When mounted circumferentially as described above, the drug cartridge 14 may radiate outward from the periphery of the body 12. The drug cartridge 14 disposed circumferentially around the body 12 may be connected to the fluid duct 22 along the periphery of the body 12 (e.g., as shown in FIG. 6) and / or at multiple locations on one side of the body (e.g., as shown in FIG. 173-174). When mounted on one side as shown in FIG. 65, the drug cartridge 14 may extend axially from the body 12, for example, within the footprint of the body. When mounted circumferentially, the axial profile of the drug delivery device 10 may be minimized, whereas when mounted on one side, the radial profile of the drug delivery device 10 may be minimized.

[0023] The body 12 may be formed in any manner. By way of non-limiting example, the body 12 may be a single monolithic body with the fluid ducts 22 etched, milled, molded, and / or otherwise formed within the body 12. The fluid ducts 22 may be formed along an exterior surface of the body 12 and / or embedded within the body 12. The body 12 may be formed of a polymeric material.

[0024] At least a portion of the fluid duct 22 may be open to exposure along the first surface 24 of the body 12. This allows a fluid pathway for the drug to be exposed along the first surface 24.

[0025] As shown in Figures 2-4, the body 12 may be connected to the needle support 16 by a flexible tether 11. The tether 11 is threaded with at least one fluid passage 13 formed to carry a drug from one or more outlet ducts 25 to the needle 15 for delivery to the patient. The tether 11 may be formed by any flexible material, such as a polymeric or elastomeric material. In this manner, the body 12 and the needle support 16 may be fixed to the patient's body, with the tether 11 providing a flexible connection between the body 12 and the needle support 16. Preferably, the tether 11 is not directly fixed to the patient's body (e.g., the tether 11 is not adhered to the patient's body).

[0026] One or more electrical conductors may also be threaded through the tether 11 to electrically connect the body 12 and the needle support 16. This allows for the transfer of signals and power between the body 12 and the needle support 16. Alternatively, a wireless receiver and / or wireless transmitter may be provided on the body 12 and the needle support 16 to allow wireless signal transmission between the body 12 and the needle support 16.

[0027] The drug delivery device 10 may be formed in multiple bodies, including one body portion corresponding to the body 12 and another body portion corresponding to the needle support 16. Moreover, the drug delivery device 10 is particularly well suited for attachment to the patient's physical anatomy for injection. This allows for injection into the body, particularly for delivery of medication over a long period of time. The patient can attach the drug delivery device 10 on the skin or to clothing (e.g., clipped to a belt) during injection, which allows other activities such as reading, watching entertainment, etc. As shown in Figures 79A-81B, the drug delivery device 10 is preferably for one-time use and is temporarily attached to the patient's body. As shown in Figures 80A-80B, a releasable adhesive 19, such as a pressure-sensitive adhesive, may be provided on the drug delivery device 10 in the portions corresponding to the body 12 and the needle support 16 in order to securely attach the drug delivery device 10 to the patient's body. Additionally or alternatively, as shown in Figs. 81A-81B, the drug delivery device 10 may be provided with a belt or strap 21 for securing a part of the patient's body, such as the waist, when the drug delivery device 10 is attached to the patient's body. To minimize inadvertent withdrawal of the needle 15 from the patient during drug delivery, the drug delivery device 10 is preferably attached securely. The belt or strap 21 may be provided with a pocket 23 for receiving all or a part of the drug delivery device 10, for example, a part corresponding to the body 12 of the drug delivery device 10. The needle support 16 may be attached to the patient using an adhesive 19, with the body 12 part of the drug delivery device 10 in the pocket 23 supported by the belt or strap 21. Furthermore, as shown in Figs. 79A-79B, the drug delivery device 10 may be provided with a clip 17 for attachment to a waistband or other part of the patient's clothing. The needle support 16 may be attached to the patient using an adhesive 19, with the body 12 supported by the clip 17. Clip 17 may be secured to body 12 using any known connection method, including fusion, adhesive, and the like.The clip 17 may be used in conjunction with a belt or strap 21 to act as a spacer within the product (pocket) 23 to better ensure that the body 12 is stably supported. The clip 17 may also be removable, providing the patient with the option of using the clip 17 as a clip or removing the clip 17 and using the adhesive 19 when attaching to the body.

[0028] 3, the drug delivery device 10 may comprise a housing 9 covering the body 12. The housing 9 may also house the pump 18 and the control unit 20. One or more outlet ducts 25 may extend through a portion of the housing 9, for example to communicate with at least one fluid passageway 13 located in the tether 11. Channels may be formed in the housing 9, tubing or the like may be provided to form portions of the one or more outlet ducts 25 extending through the housing 9.

[0029] In a further aspect of the present invention, a method of making a drug cartridge 14 is provided. With reference to Figures 7-36 and 175-186, the drug cartridge 14 may be initially provided separate from the body 12, particularly so that the body 12 may be pre-loaded with a drug. As will be appreciated by those skilled in the art, the drug cartridge 14 may be formed in a variety of ways consistent with the disclosure herein. As shown in Figure 12, each drug cartridge 14 may be formed to include a reservoir 26 and a cartridge support 28. The cartridge support 28 includes a fluid outlet 34 and a lumen 36 for carrying the drug from the reservoir 26 to the fluid outlet 34.

[0030] To avoid the need for venting the reservoir during drug delivery, the reservoir 26 may be formed to be collapsible during drug removal. As shown in FIG. 10, the cartridge support 28 may include a rigid shell 30 surrounding the reservoir 26. The rigid shell 30 defines an interior volume 32. As shown in FIG. 8A, the rigid shell 30 maintains its shape even when the reservoir 26 is collapsed during use. The rigid shell 30 may be formed of an upper portion 30A and a lower portion 30B. The upper portion 30A may be joined to the lower portion 30B by, for example, gluing, fusing, welding, snap engagement, heat sealing, etc. Such a two-part configuration allows the upper portion 30A and the lower portion 30B to be positioned around the reservoir 26 during assembly. As shown in FIG. 19, one or more channels 211 may be formed inside the shell 30 (e.g., upper portion 30A) to provide one or more surface breaks around the reservoir 26. For example, as shown in FIG. 29, the channels 211 may be disposed around the periphery of the shell 30. The channels 211 may be formed as through holes in the shell 30 to provide ventilation to the interior volume 32, particularly during expansion and collapse (contraction) of the reservoir 26. The surface breaks may minimize adhesion of the reservoir 26 to the shell 30 during use, which may facilitate filling and emptying the reservoir 26. Additionally, as shown in FIGS. 21 and 22, the upper and lower portions 30A and 30B may be formed with concave or convex surfaces to demarcate reservoirs of different sizes.

[0031] Reservoir 26 may be an elastomeric or thermoformed membrane formed as a pouch element or a bonded element (e.g., heat sealed, laser welded, fused, glued, etc.). Compatibility with the contained drug component and resistance to permeation of contaminants are important for reservoir 26. As shown in FIG. 11, reservoir 26 may include a flange 27 located between upper 30A and lower 30B portions of rigid shell 30. In FIG. 11, lower portion 30B is shown removed to best show flange 27.

[0032] In one embodiment, the drug cartridge 14 may be modular to facilitate pre-filling with a drug, with the cartridge support 28 divided into multiple parts. As shown in FIG. 8, the reservoir section 14A of the drug cartridge 14 may include a reservoir 26, a rigid shell 30, and a fill port 38 that defines an open passageway to the reservoir 26. As shown by arrow 40 in FIG. 8, after sterilization of the reservoir section 14A, the drug may be introduced into the reservoir 26 through the fill port 38. The drug may be a combination of one or more drug components in various physical states, for example, two different drugs. As discussed below, the drug may include solid components that can be reconstituted by the drug delivery device 10 to make it ready for use.

[0033] 9, the plug adapter 14B of the drug cartridge 14 may be provided separately so as to be attachable to the reservoir section 14A. The plug adapter 14B may include a fluid outlet 34 and an internal lumen 36.

[0034] Separate from filling the reservoir 26, the lumen 36 of the plug adapter 14B may be sterilized. This sterilization may be accomplished by at least one lumen seal formed on the plug adapter 14B over the entire sterile lumen 36 to limit the ingress of contaminants. The at least one lumen seal may isolate the fluid outlet 34 from the sterile lumen 36 or may be located outside the fluid outlet 34. Details of the seal formation will be described later. As will be appreciated by those skilled in the art, the entire lumen 36 need not be sealed. For example, a portion of the lumen 36 adjacent to the fluid outlet 34 may be outside the lumen seal, along with the fluid outlet 34.

[0035] 7 and 10, with the reservoir 26 filled and the lumen 36 sterilized, the plug adapter 14B may be assembled to the reservoir section 14A to form the drug cartridge 14. The plug adapter 14B may function to block the fill port 38. When assembled, a portion of the lumen 36 extends through the fill port 38 and communicates with the reservoir 26. This configuration defines a fluid pathway from the reservoir 26 to the fluid outlet 34.

[0036] The reservoir section 14A and plug adapter 14B may be manufactured, sealed, sterilized, and assembled in separate processes, allowing for bulk processing. Once sterilized, the packaged components may be maintained in a clean environment pending use, as described herein. The sterilized components may be handled and assembled in a clean, controlled environment (e.g., under a clean, environmentally controlled hood and / or in a clean, environmentally controlled enclosure or room, etc.).

[0037] Alternatively, the drug cartridge 14 may be formed as a single component without the need for separate reservoir section 14A and plug adapter 14B. As shown in Figs. 175-178, a fill port 38 may be provided in the upper portion 30A. Note that in Fig. 177, the upper portion 30A is shown in a lower position, but the upper portion 30A and the lower portion 30B are considered to be first and second portions independent of the direction of gravity. The flange 27 of the upper portion 30A may be extended to have wings 27A. The wings 27A are disposed at an angle to a plane defined by the interface between the upper portion 30A and the lower portion 30B. The wings 27A also extend outwardly away from the reservoir 26 to form a free end 27B. A fluid outlet 34 may be formed in the wings 27A near the free end 27B. The lumen 36 extends from the reservoir 26 to the fluid outlet 34 and defines a flow path from the reservoir 26 to the fluid outlet 34. As shown in FIG. 173, the wings 27A with the fluid outlet 34 defined therein allow the drug cartridge 14 to be mounted on one side of the body 12 with the reservoir 26 radiating outward from the periphery of the body 12. This allows the footprint of the drug delivery device 10 to be reduced. The wings 27A of the reservoir section 14A may be tessellated such that there are substantially no gaps between the reservoir section 14A and the body 12 when mounted to the body 12.

[0038] In the configuration of Figs. 175-186, the fill port 38 and the lumen 36 are provided separately. In this manner, the reservoir 26 may be filled through the fill port 38, which is then sealed, for example, with an elastomeric plug and / or a crimp cap. To minimize disturbance of the lumen 36 during filling, the lumen 36 is preferably located in the vicinity of the fill port 38. This allows the lumen 36 to be positioned above most of the reservoir 26 when the drug cartridge 14 is in an upright position for filling. This is preferable for lyophilization.

[0039] As described above, the upper portion 30A may be formed to be rigid (hard) and to surround the storage portion 26. Alternatively, as shown in Figs. 175 to 186, the storage portion 26 may be formed integrally with the upper portion 30A and the lower portion 30B. For example, the flange 27 may be rigid (hard) and may indicate the boundary between the upper portion 30A and the lower portion 30B. Flexible storage portion walls 26R, 26S may be provided on the upper portion 30A and the lower portion 30B, respectively, and edges of the storage portion walls 26R, 26S may be attached to the flange 27. The flexible storage portion walls 26R, 26S, together with the flange 27, cooperatively define the storage portion 26. The flexible reservoir walls 26R, 26S may be formed of any elastomeric or thermoformable film, such as a film of cyclic olefin copolymer (COC), and may optionally include a layer of polychlorotrifluoroethylene (PCTFE). The flexible reservoir walls 26R, 26S are configured to respond to filling of the reservoir 26 and removal of the drug from the reservoir 26. The flexible reservoir walls 26R, 26S may fold (collapse, shrink) when the drug is removed from the reservoir 26 while the reservoir 26 is not vented.

[0040] As part of the filling of the reservoir 26, the drug cartridge 14 may be utilized for lyophilization of the drug, where the drug is initially introduced into the reservoir 26 in a liquid state. The plug adapter 14B may have an adjustable vent from an open to a closed state. Once filled and assembled, the drug cartridge 14 with the vent open may be exposed to lyophilization conditions (low temperature and vacuum to extract moisture), which allows the drug in the reservoir 26 to be lyophilized. The vent of the plug adapter 14B may then be adjusted to a closed state. Similarly, as shown in FIG. 179, the filling port 38 may be provided with an adjustable vent plug 38A to facilitate lyophilization of the drug in the reservoir 26.

[0041] Alternatively, a dry form of the drug may be introduced into the reservoir 26 first, and then a diluent may be introduced to reconstitute the drug into a liquid form when the drug delivery device is in use. To limit the "dead space" in the reservoir 26 when loading the dry form of the drug, a reservoir support 300 may be used, as shown in Figs. 58-64E. By minimizing the "dead space", the empty volume in the reservoir 26 is limited. As shown in Figs. 58-59, the reservoir section 14A, particularly the lower portion 30B of the rigid shell 30, may be formed with an opening 301 formed to receive the reservoir support 300 in the interior volume 32 adjacent the reservoir 26. The reservoir support 300 has a front surface 302 for limiting the expansion of the reservoir 26. The front surface 302 may be contoured to provide the reservoir 26 with a larger volume away from the fill port 38. In this way, as shown in FIG. 59, when the drug D1 in dry form is introduced into the reservoir 26, the front surface 302 limits the expansion of the reservoir 26. In the filled state, the reservoir 26 may be spherical. Once the reservoir 26 is filled with the drug D1 in dry form, the plug adapter 14B or vent plug 38A is attached to the reservoir section 14A (top 30A) and then the reservoir support 300 is removed. Drug in the form of diluent D2 may then be added during reconstitution, with the reservoir 26 in an expanded state. To determine the fill level, the back pressure may be measured (monitored) when filling the drug in the form of diluent D2. By minimizing the "dead space", pockets of compressible gas are minimized, which allows for a more accurate pressure measurement of the actual fill level. Furthermore, the concentration of the resulting liquid drug may be better controlled.

[0042] As shown in a comparison of Figures 60 and 61, reservoir support 300 having front surface 302 may have different configurations corresponding to different volumes of drug. The configuration of Figure 61 is for a smaller amount of drug than the configuration shown in Figure 59, requiring less volume in reservoir 26. Thus, reservoir support 300 is provided with an additional length that extends deeper into interior volume 32, with front surface 302 positioned to provide a greater restriction to expansion of reservoir 26 than that shown in Figure 59.

[0043] The opening 301 is shaped to snugly receive the reservoir support 300 and allow the reservoir support 300 to be removably mounted therein (e.g., by a friction or interference fit). To facilitate handling of the reservoir support 300, and in particular removal from the opening 301, a radially outwardly extending tab 303 may be provided, as shown in FIGS. 58 and 60. Alternatively, as shown in FIGS. 62 and 63, the reservoir support 300 may be provided as a separate tool or fixture that can be inserted into the opening 301 formed in the rigid shell 30. This allows the front surface 302 to be positioned at various positions within the reservoir 26 depending on the extent to which the reservoir support 300 is inserted into the rigid shell 30. The opening 301 may include a cross shape that matches the contour of the reservoir support 300 and act as a guide for the reservoir support 300. In this configuration, as shown in FIGS. 62-63, a support portion 304 may be provided on the reservoir support 300.

[0044] FIG. 64A shows a cup-shaped fixture 305 with a slot 306 formed therein for receiving the reservoir section 14A attached to the reservoir support 300. The slot 306 may be formed to be slightly larger than the thickness of the edge of the reservoir support 300 so as to fit snugly within the reservoir support 300. The fixture 305 may be used to hold the combination of the reservoir section 14A and the reservoir support 300 during any of the filling processes described above in connection with FIG. 59, FIG. 61, or FIG. 63. Additionally, the fixture 305 may have an internal contour to match the external contour of the reservoir section 14A and the reservoir support 300 to maximize the contact area. Advantageously, the fixture 305 can hold the reservoir section 14A and the reservoir support 300 during freeze-drying. By matching the internal contour of the fixture 305 to the external contour of the reservoir section 14A and the reservoir support 300, heat transfer between the components may be maximized. The material of fixture 305 may be selected to have high thermal conductivity to facilitate heat transfer during freeze-drying (eg, anodized aluminum).

[0045] An alternative open fixture 307 is shown in Figure 64B. Fixture 307 is formed with slots 306 for receiving reservoir section 14A attached to reservoir support 300. Fixture 307 leaves a major portion of reservoir section 14A exposed to promote radiative and convective heat transfer during freeze-drying. This allows for more uniform heat transfer across the entire surface of reservoir section 14A compared to cup-shaped fixture 305 described above (which relies on conduction through the matching interior contours of fixture 305), as well as radiation and convection on the top of reservoir section 14A.

[0046] Any of the fixtures 305, 307 may be arranged in various quantities within a support structure (e.g., a tray or tub, etc.) to allow for batch freeze-drying and transport. Alternatively, as shown in Figs. 64C-64E, a tray 308 may be provided having a plurality of wells 310 formed therein, each of which may be configured to receive a reservoir section 14A having a reservoir support 300 attached thereto. The tray 308 has a support panel 312 with openings 314 for the wells 310. Each of the openings 314 has a contour to allow passage of the reservoir section 14A having the reservoir support 300 attached thereto. For example, as shown in Fig. 64C, each of the openings 314 may have a contour with an enlarged central region (e.g., a generally elliptical region) with laterally extending wings (e.g., rectangular wings). Each of the wells 310 has a pair of legs 316 extending downwardly from the support panel 312. Each of the legs 316 is open to define a slot 306 for receiving the storage section 14A. A bottom 318 is provided on each of the legs 316 to limit downward movement of the storage section 14A within the slot 306.

[0047] As shown in FIG. 64D, the tray 308 allows multiple assembled reservoir sections 14A and reservoir supports 300 assemblies to be accommodated within the wells 310. The wells 310 may be arranged in various arrangements to allow efficient filling. As shown in FIG. 64E, once loaded, the tray 308 may be placed within a tub 320 for subsequent processing and transport. The support panel 312 preferably has an extension that extends beyond the wells 310. The extension of the wells 310 allows the support panel 312 to be supported at its ends by the tub 320. When the tray 308 is placed within the tub 320, the legs 316 preferably do not contact the tub 320 (i.e., there is a gap between the legs 316 and the sidewalls of the tub 320). Additionally, the tab 320 is preferably provided with a depth sufficient to avoid contact between the tab 320 and the reservoir section 14A when the tray 308 is placed within the tab 320 (i.e., there is a gap between the bottom 318 and the base of the tab 320). The tray 308 may be formed from a polymeric material and may be formed by molding.

[0048] As will be appreciated by those skilled in the art, the plug adapter 14B can be substituted for the vent plug 38A in each of the embodiments of Figures 58-64E.

[0049] Because the drug cartridge 14 is pre-filled, it functions as a drug container during shipping and storage prior to use. The materials of the drug cartridge 14 must be compatible with the corresponding drug. Additionally, the drug cartridge 14 must be provided with a seal that is sufficiently strong to withstand the ingress of contaminants over the expected duration of use.

[0050] The plug adapter 14B may be formed for assembly to the reservoir section 14A in a variety of ways in forming the drug cartridge 14. As shown in FIGS. 13 and 14, a portion of the lumen 36 may be defined in the plug adapter 14B and in an elongated neck 42 terminating in a neck end 43. The neck 42 is formed for stretchable reception within the fill port 38. One or more seals 44 may be provided between an outer surface 46 of the neck 42 and an inner surface 48 of the fill port 38. The seals 44 (e.g., O-rings) are preferably secured to the outer surface 46, for example, by being received within a seal channel 50. Alternatively, as shown in FIGS. 23-25, the outer surface 46 of the neck 42 may be formed smoothly or, optionally, tapered, for example, converging toward the neck end 43. This allows the neck 42 to form a face seal through tight face-to-face interengagement with the inner surface 48 of the fill port 38, as shown in FIG. 27.

[0051] A cooperating locking member may be provided between the reservoir section 14A and the plug adapter 14B to allow for locking between the reservoir section 14A and the plug adapter 14B upon assembly. As shown in FIG. 26, the fill port 38 may terminate in a locking rib 52 that is configured to snap-engage into a locking channel 54 formed in the plug adapter 14B as shown in FIGS. 29 and 30. An inwardly facing detent 56 may be provided along the locking channel 54 to limit reverse movement of the fill port 38 away from the plug adapter 14B.

[0052] To enhance the integrity of the connection, a flexible seal 200 may be disposed within the locking channel 54, as shown in Figures 23-28, to allow the locking rib 52 to be pressure-engaged with the plug adapter 14B attached to the storage section 14A. The locking rib 52 may be flange-like. Preferably, there is a surface-to-surface engagement between the outer surface 51 of the locking rib 52 and the flexible seal 200.

[0053] The flexible seal 200 is preferably formed of a resilient material suitable for sealing, such as an elastomeric material, foam, thermoplastic, metal, etc. If the plug adapter 14B is formed of a thermoplastic material, the flexible seal 200 must be assembled to achieve a two-material construction. To facilitate assembly, the neck 42 may be formed as a two-piece component with a base stem 42A to which a sleeve 42B is attached. A portion of the bore 36 passes through both the base stem 42A and the sleeve 42B. The seal 200 may be annular in shape and may be inserted into the locking channel 54, surrounding the base stem 42A and positioned against the outer surface 202. The sleeve 42B may then be attached to the base stem 42A so as to overlap an inner portion of the seal 200. The sleeve 42B may be provided with a mounting channel 42C formed to telescopically receive the base stem 42A. The sleeve 42B may be secured to the base stem 42A using any known technique, including, but not limited to, adhesive bonding, fusion, friction fit, interference fit, shrink fit, and the like.

[0054] As shown in FIGS. 82A-84B, the sleeve 42B may be tapered along the fill port 38 to provide a form-fitting fit between the sleeve 42B and the fill port 38. Additionally or alternatively, the base stem 42A and the sleeve 42B may be modified to define a portion of the lumen 36, particularly the first lumen 36A. As shown in FIGS. 86-89, the sleeve 42B is formed to overlap the end of the base stem 42A, which partially surrounds the first lumen 36A. This allows for defining at least one turn in the lumen 36, particularly adjacent the reservoir 26. Advantageously, as discussed below, one or more modifications made to the reservoir 26 limit the momentum of the liquid introduced into the reservoir for reconstitution, thereby minimizing foaming and splashing. In particular, a third lumen 36C may be defined transversely relative to the first lumen 36A, thereby defining a turn in lumen 36. Additionally, a fourth lumen 36D may be defined in communication between the third lumen 36C and the reservoir 26 and may be disposed transversely relative to the third lumen 36C, thereby providing a secondary turn within lumen 36.

[0055] 18, the locking rib 52 may be formed to extend radially inwardly of the fill port 38, and a locking collar 58 extending radially outwardly from the outer surface 46 of the neck 42 may be formed to snap-engage an inner shoulder defined by the inner portion 31 of the locking rib 52. This configuration similarly prevents separation of the fill port 38 from the plug adapter 14B.

[0056] Additionally, as shown in Figures 13-16, a locking ring 64 may be provided around the neck portion 42. The locking ring 64 has locking tabs 66 configured to snap into locking openings 68 formed in the reservoir section 14A. A seal may be provided if desired. Additionally, the outer surface 202 of the plug adapter 14B may act as a stop to define the proper position between the reservoir section 14A and the plug adapter 14B. As will be appreciated by those skilled in the art, other locking configurations may be utilized.

[0057] Additionally or alternatively, as shown in FIGS. 82-89B, a ferrule 63 may be used to maintain the plug adapter 14B attached to the reservoir section 14A. The sleeve 42B may be provided with a locking flange 33, and the plug adapter 14B may have a stop flange 201 on which the outer surface 202 is disposed. The ferrule 63 may be formed of a crimpable material, including a metal or polymer that is sufficiently malleable to be crimped (with or without heat or other external factors). As shown in FIGS. 82A-83B and 87A-88B, the ferrule 63 may be initially provided as a blank having a tubular body with a diameter and length sufficient to enclose the stop flange 201, the locking flange 33, and the locking rib 52. As shown in Figures 84A-86 and 89A-89B, the crimping causes the ferrule 63 to be configured to tightly engage the stop flange 201, the locking flange 33, and the locking rib 52, which press the locking flange 33 radially inward to form a mechanical lock therebetween. The ferrule 63 is preferably formed to a length sufficient to be bent to cover face portions of the stop flange 201 and the locking rib 52. As will be appreciated by those skilled in the art, the ferrule 63 may be formed as a heat shrinkable, weldable, or adhesive sleeve to fit snugly over the stop flange 201, the locking flange 33, and the locking rib 52. The ferrule 63 must have sufficient stability once installed to avoid creep and to avoid undesirable loosening.

[0058] As a further alternative, as shown in FIGS. 32A-32E, the plug adapter 14B may be latched to the reservoir section 14A to form a connection between the plug adapter 14B and the reservoir section 14A. Here, the locking rib 52 may be configured as a flange around the inner surface 48 of the fill port 38. A pair of upright walls 57 may be provided on either side of the outer surface 51 of the locking rib 52 to form a yoke shape. The upright walls 57 may be formed with locking recesses 54A. The locking recesses 54A are formed to receive, by a snap fit, the locking detents 52A formed on either side of the plug adapter 14B. The upright walls 57 must have some flexibility to allow for outward flexing to allow the locking detents 52A to be inserted into the locking recesses 54A. To enhance the integrity of the seal between the plug adapter 14B and the reservoir section 14A, a flexible seal 200 may be provided in the form of a gasket configured to rest on the outer surface 51 with a central opening providing access to the interior of the fill port 38.

[0059] It should be noted that the interengagement of the locking detents 52A and the locking recesses 54A may be used to assemble the plug adapter 14B with the reservoir section 14A and to couple elements having a portion of the upstanding wall 57 joined to the plug adapter 14B using, for example, one or more of adhesive, fusion, welding, etc. Additionally or alternatively, the locking detents 52A may be joined to the locking recesses 54A using one or more of the techniques previously described.

[0060] As shown in FIG. 32B, the plug adapter 14B may have a two-piece construction in which the sleeve 42B is attached to the base stem 42A to form a neck, as described above. Additionally, the sleeve 42B may have a polygonal profile with one or more tapered sides. The fill port 38 may have a similarly shaped cross-section that converges in a direction toward the reservoir 26 to provide a form-fitting fit with the sleeve 42B. In this configuration, the plug adapter 14B may be partially inserted into the fill port 38 to allow venting of the reservoir 26, as shown in FIG. 32C. To maintain the plug adapter 14B in a vented state, the leading edge 59 of the upstanding wall 57 may be positioned to act as a stop against the locking detent 52A. The leading edge 59 is positioned to space the sleeve 42B from the inner surface 48 of the fill port 38. As shown in Figure 32D, when locking detent 52A is biased over leading edge 59 into snap-fit ​​engagement with locking recess 54A, sleeve 42B is biased into sealing contact with inner surface 48. Figure 32E shows a cross-sectional view of plug adapter 14B in a sealed condition.

[0061] To construct a drug cartridge 14 with an adjustable vent for, for example, lyophilization as described above, at least one vent passage 72 may be formed in the mouth 62 of the fill port 38 as shown in FIGS. 20A-20C. The vent passage 72 may be defined as a recessed channel in the inner surface 48 of the fill port 38 with one or more vent protrusions 60 separating the vent passages 72. The vent protrusions 60 are preferably discontinuous around the inner circumference of the mouth 62. As shown in FIG. 20B, to allow venting, the neck 42 is inserted into the fill port 38 up to the length of the vent protrusions 60 to maintain one or more seals 44 over the ends of the vent passage 72. This allows the vent passage 72 to be in open communication with the reservoir 26 in an open vent state. As shown in FIG. 20C, the vent may be adjusted to a closed state by inserting the neck portion 42 further into the fill port 38, such that one or more seals 44 are disposed between the vent passage 72 and the reservoir 26, blocking communication therebetween.

[0062] In the embodiment of Figures 20A-20C, the vented gas escapes by bypassing portions of the plug adapter 14B. Alternatively, as shown in Figure 16, the vent passage 72 may be formed as a through hole through the fill port 38, allowing unrestricted venting directly to the outside atmosphere. As shown in Figures 17A-17C, venting is accomplished in the same manner as described above in the vent open state shown in Figure 17B and the vent closed state shown in Figure 17C, and the seal or seals 44 are adjusted in the same manner.

[0063] 31A-31B, the inner surface 48 of the fill port 38 may have a tapered section 49 adjacent the reservoir 26, the tapered section 49 tapering to converge in a direction toward the reservoir 26 to form a reduced diameter opening 53. A plurality of protruding beads 55 may be formed on the outer surface 46 of the neck 42, with a vent passage 72 formed between the plurality of protruding beads 55. The protruding beads 55 are configured to be pressurized engageable with the fill port 38. At least one seal 44 is disposed on the outer surface 46 of the neck 42 between the protruding beads 55 and the neck end 43. As shown in FIGS. 33A-33B, to achieve a vent open state, the neck 42 is inserted into the fill port 38 with the neck end 43 not in contact with the tapered section 49. As shown in FIG. 33C, when neck portion 42 is further inserted into fill port 38, the vent is closed with neck end 43 received within opening 53 and at least one of seals 44 sealingly engages tapered portion 49 of inner surface 48 to block communication between vent passage 72 and reservoir 26.

[0064] Alternatively, as shown in Figs. 182-184, the outer surface 46 of the vent plug 38A may be provided with a protruding bead 55. The vent plug 38A may have a hollow portion 38B on its upper surface, which is engageable by a pick-and-place machine or other tool for insertion into the fill port 38. To make the drug cartridge 14, the drug (medicine) is introduced into the reservoir 26 through the fill port 38 after sterilization. Thereafter, as shown in Fig. 180, the vent plug 38A (after sterilization) may be partially inserted into the fill port 38 to be in a vent-open state, with a vent passage 72 formed between the outer surface 46 of the vent plug 38A and the fill port 38. Preferably, to achieve the vented state, the vent plug 38A is inserted into the fill port 38 with the protruding bead 55 in contact with the tapered portion 49 and with the portion of the outer surface 46 located around the protruding bead 55 spaced from the fill port 38. The protruding bead 55 resiliently engages the fill port 38 to provide a retention force for the vent plug 38A in a vented state. The drug cartridge 14 may then be subjected to lyophilization conditions (low temperature and vacuum to extract moisture), which allows the drug in the reservoir 26 to be lyophilized. During lyophilization, the vent plug 38A functions to retain the drug in the reservoir 26 while allowing air to vent around the vent plug 38A. Once lyophilization is complete, as shown in FIG. 181, the vent plug 38A may be further inserted into the fill port 38 until it is in a closed state, whereby the outer surface 46 makes face-to-face contact with the fill port 38 to form a seal therebetween. A crimp cap 38C may be provided to secure the vent plug 38A to the fill port 38, as shown in FIG. 185.

[0065] Vent plug 38A may be formed of a sterilizable elastomeric material. Vent plug 38A is preferably large relative to fill port 38 and has sufficient elasticity to compress when urged to a closed state.

[0066] To best ensure stability of the vent plug 38A within the fill port 38, the fill port 38 preferably has a generally D-shaped cross-section (FIG. 177) and the vent stem 38D of the vent plug 38A preferably has a matching D-shaped cross-section configured to mate with the D-shaped fill port 38. When the vent plug 38A is inserted into the fill port 38, the interengagement of the curved portion of the vent stem 38D with the curved portion of the fill port 38 provides multi-axial stability to the vent plug 38A relative to the fill port 38. Additionally, the inner surface 38E of the vent stem 38D, inside the curved profile of the vent stem 38D, may also define a vent passageway 72 when the vent plug 38A is in the open vented state.

[0067] It should be noted that while lumen 36 may be shown open in certain figures in connection with the venting mechanism, lumen 36 may also be sealed, particularly in portions of plug adapter 14B not shown, and thus may not provide for venting.

[0068] The lumen 36 may be sterilized using any technique. The seal may also be formed using any technique. As a non-limiting example, as shown in FIG. 34A, the lumen 36 may be provided with a first lumen 36A extending from the reservoir 26, for example through the neck 42. The second lumen 36B may be disposed transversely to the first lumen 36A. The second lumen 36B terminates at a first end 74 with a valve seat 76 located at the interface between the fluid outlet 34 and the lumen 36. A second end 78 of the second lumen 36B may be open. A valve 80 may be disposed within the second lumen 36B. The valve 80 may be spool-shaped having a first enlarged land 82 and a second enlarged land 84 connected by an elongated core 86. To form a seal, the first enlarged land 82 is received in the valve seat 76. This seals off contaminants from the portion of bore 36 inside first enlarged land 82. To release the seal, valve 80 may be moved within second bore 36B so as to separate it from valve seat 76, as shown in FIG.

[0069] The second end 78 of the second lumen 36B may be formed closed or sealed with a plug or other element. The second end 78 may be provided open so that a control element can extend into the second lumen 36B to engage the valve 80 as it is moved. With the second end 78 open, the second enlarged land 84 is positioned between the second end 78 and the first lumen 36A to seal the lumen 36. In this manner, sterility may be maintained, particularly along the first lumen 36A and the portion of the second lumen 36B toward the fluid outlet 34. The valve 80 is formed such that the second enlarged land 84 remains continuously between the first lumen 36A and the second end 78 during movement of the valve 80.

[0070] Valve 80 may include elastomeric and / or non-elastomeric materials. Valve 80 requires sufficient internal resilience to maintain the formed seal. Additionally, as described below, valve 80 may be exposed to ultraviolet light, x-rays, pulsed light, or electron beam treatment. Appropriate material selection is required.

[0071] As will be appreciated by those skilled in the art, valve 80 provides a seal inside lumen 36, thereby leaving fluid outlet 34 open and exposed. This configuration maintains sterility from lumen 36 to reservoir 26, and the sterility of reservoir 26. However, for practical use, fluid outlet 34, for example, may need to be further sterilized.

[0072] As shown in Figures 34B and 34C, the valve 80 may include a plurality of spaced apart positioning ribs 85 extending longitudinally along the elongated core 86 from the first enlarged land 82. Preferably, the positioning ribs 85 are spaced apart from the second enlarged land 84 to define an open ring 87 between the positioning ribs 85 and the second enlarged land 84 around the elongated core 86. The positioning ribs 85 cooperate to define an outer diameter that is greater than the diameter of the valve seat 76. Thus, as shown in Figure 35B, the positioning ribs 85 engage the valve seat 76 to center the valve 80 within the valve seat 76, providing stability to the valve 80 in an unsealed position. A channel 89 is defined between the positioning ribs 85 to allow flow therethrough when the valve 80 is unsealed (when the positioning ribs 85 engage the valve seat 76). Preferably, the positioning ribs 85 are parallel, forming parallel channels 89 .

[0073] As shown in FIG. 178, the lumen 36 may be formed in a manner similar to that described above in relation to the fluid duct 22. In particular, a first lumen 36A may be formed along a first surface 27C of the wing 27A so as to be exposed for sterilization. A second lumen 36B may provide a change of direction so that a third lumen 36C is formed along a second surface 27D of the wing 27A. The first lumen 36A and the third lumen 36C are open channels so that sterilization is possible, including the second lumen 36B. A barrier 102 (described below) may be provided on each of the first surface 27C and the second surface 27D to seal the first lumen 36A and the third lumen 36C. Alternatively, flexible reservoir walls 26R, 26S may extend through flange 27 on either side of wing 27A such that barrier 102 seals first lumen 36A and third lumen 36C. As will be appreciated by those skilled in the art, lumen 36 may be provided in a variety of configurations having different exposed or recessed portions along wing 27A. In these configurations, the exposed portions of lumen 36 are covered to provide a closed flow path.

[0074] As an alternative to the valve 80, a seal may be provided along the lumen 36 upstream of the fluid outlet 34. As shown in Figs. 187-198, a well 1900 may be formed in the wing 27A along the lumen 36. A movable seal element 1902 is provided housed within the well 1900. The well 1900 is formed along the lumen 36 to block a fluid path therethrough to the fluid outlet 34. As shown in Fig. 190, the movable seal element 1902 protrudes from the first surface 27C of the wing 27A in the closed state. As shown in Figs. 191 and 193, when the movable seal element 1902 is in the closed state, a seal surface 1904 located around the periphery of the well 1900 is joined with a seal seat 1906 across the well 1900 to define at least one seal 1908 along the lumen 36 that is impermeable to the flow of fluids or liquids. The seal sheet 1906 is also secured to the movable seal element 1902 such that forcing the movable seal element 1902 into the well 1900 to an open state peels the seal sheet 1906 away from the sealing surface 1904, releasing the seal 1908 and opening the lumen 36 across the well 1900. As shown in FIGS. 195-197, the movable seal element 1902 has an open passageway 1910 that is aligned with the lumen 36 when the movable well 1900 is in an open state. The open passageway 1910 is provided at multiple radial positions to ensure flow through the movable seal element 1902 regardless of its radial orientation within the well 1900. As shown in FIG. 198, when the movable seal element 1902 is in an open state, the lumen 36 is open and has an unobstructed flow path to the fluid outlet 34.

[0075] As will be appreciated by those skilled in the art, any pressing means, including a manual or automatic press, may be utilized to urge the movable seal element 1902 into the open position. For example, as shown in FIGS. 191-192, a drive actuator 1912 may be utilized to apply pressure to the movable seal element 1902 causing its displacement.

[0076] The portion of the lumen 36 adjacent the well 1900 may be enlarged. In particular, the lumen 36 may have a diverging portion 36E leading into the well 1900 and a converging portion 36F leading out of the well 1900. The sealing surface 1904 may be disposed within the diverging portion 36E and within the converging portion 36F. Additionally, the sealing surface 1904 may be raised around the periphery of the well 1900 in the closed state with the movable sealing element 1902 nested within the sealing surface 1904.

[0077] The sealing sheet 1906 may be any material that can be sufficiently secured to the sealing surface 1904 to form the seal 1908 and subsequently non-destructively separated from the sealing surface 1904. The sealing sheet 1906 forms part of the lumen 36 in the open state and requires structural integrity after delamination. As a non-limiting example, the sealing sheet 1906 may be a thermoformable film with a sealing surface that is thermoplastic (e.g., cyclic olefin copolymer). The sealing sheet 1906 may be an extension of one of the barrier 102, including an extension of one of the flexible reservoir walls 26R, 26S. For example, the flexible reservoir wall 26R may extend through the flange 27 to cover the opening of the lumen 36, thereby functioning as the sealing sheet 1906.

[0078] Similar to valve 80, sealing seat 1906 provides a seal inside lumen 36 and spaced from fluid outlet 34, thereby leaving fluid outlet 34 exposed. This configuration maintains sterility from lumen 36 to reservoir 26, and the sterility of reservoir 26. However, for practical use, fluid outlet 34 must still be sterilized.

[0079] The cross-section of the fluid outlet 34 and / or lumen 36 (e.g., second lumen 36B) may be altered to minimize volume loss and minimize its diameter. For example, as shown in FIG. 82A, the fluid outlet 34 may be formed with a non-circular cross-section, such as an elliptical cross-section. Additionally, one or more sides of the cross section may be truncated. If the second lumen 36B has a non-circular cross section, the valve 80 may be formed to match the cross section of the second lumen 36B.

[0080] As shown in Figs. 65-72, as an alternative to the configuration of the drug cartridge 14 described above, the drug cartridge 14 may be configured to include a barrel 400. The barrel 400 includes a piston 402 configured to slide within the barrel 400 in some manner of fluid-tight contact, such as in a syringe. Here, the reservoir 26 is defined by the barrel 400 distal to the piston 402, such that distal advancement of the piston 402 contracts the reservoir 26 and causes the drug (medicine) to be expelled from the reservoir 26 via the outlet 404. As shown in Fig. 69, the outlet 404 may be formed in the body 12 and communicate with a fluid duct 22 leading to one or more outlet ducts 25. The fluid ducts 22 may be arranged in parallel and / or in series between the outlets 404 such that flow is conveyed through one or more of the outlets 404 to one or more of the outlet ducts 25.

[0081] The outlets 404 may each be sealed to maintain sterility of the reservoir 26 prior to use. With reference to FIGS. 66, 67A, and 67B, each of the barrels 400 may be provided with a delivery cannula 406 movably disposed within a hub 408 that is held by a collar 410 relative to a neck 412 of the barrel 400. As shown in FIG. 67A, in a pre-use state, a distal end 414 of the delivery cannula 406 may be received within an open channel 416 of a securing member 418. The securing member 418 functions to hold the distal end 414 of the delivery cannula 406 in a fixed position. The securing member 418 may include a radially projecting guide collar 420 configured to slide along an inner surface 422 of a guide ring 424, formed on the hub 408 to project distally from the collar 410. The guide collar 420 may also function to hold the securing member 418 in a fixed position relative to the guide ring 424.

[0082] A distal seal 426 may be provided to seal over the entire distal end 428 of the open channel 416. The distal seal 426 may be formed in a cup shape such that a portion of the fixation member 418 fits within the distal seal 426. The distal seal 426 may include an outer flange in sliding contact with the inner surface 422 of the guide ring 424. A cup-shaped pushing member 430 may be mounted on the distal seal 426 with a needle opening 432 axially aligned with the distal end 414 of the delivery cannula 406. The pushing member 430 is formed to slide within the guide ring 424.

[0083] 67A, in a pre-use state, a proximal end 434 of delivery cannula 406 may be received in a hub channel 436. A proximal seal 438 may be provided to seal across a proximal end 440 of hub channel 436.

[0084] The securing member 418 may be formed of an elastomeric material and the open channel 416 may be formed to snugly receive the distal end 414 of the delivery cannula 406. This configuration provides a retaining force to maintain the delivery cannula 406 in the position shown in FIG. 67A. Prior to use, it is particularly desirable to maintain a spacing between the distal end 414 of the delivery cannula 406 and the distal seal 426, and between the proximal end 434 of the delivery cannula 406 and the proximal seal 438. A positioning ring 442 may be provided about the delivery cannula 406 and may be spaced apart from the hub 408 prior to use. The hub 408 may be formed with a hollow 444 distal to the hub channel 436 to accommodate the positioning ring 442. A stop shoulder 446 may be formed about the hub channel 436 at the proximal end of the hollow 444.

[0085] Distal seal 426 and proximal seal 438 may each be formed from an elastomeric material that is pierceable (penetrable) and capable of providing an antimicrobial seal.

[0086] To prepare for use, a force is applied to move the push member 430 proximally relative to the barrel 400. This results in proximal displacement of the fixation member 418 relative to the hub 408 along with proximal movement of the delivery cannula 406 relative to the hub 408, as shown in FIG. 67B. With sufficient proximal displacement, the proximal end 434 of the delivery cannula 406 breaks the proximal seal and comes into communication with the reservoir 26. Additionally, the positioning ring 442 contacts the stop shoulder 446 to limit further proximal movement of the delivery cannula 406. As the fixation member 418 is further displaced proximally relative to the barrel 400 under the force of movement by the push member 430, with the delivery cannula 406 held by the stop shoulder 446, the distal end 414 of the delivery cannula 406 breaks the distal seal 426 and extends through the needle opening 432. This allows communication with one or more fluid ducts 22 via the outlet 404 .

[0087] 66, the pushing member 430 may be received in a recess 448 formed in the body 12 such that the pushing member 430 is immovably fixed relative to the body 12. The barrel 400 is displaced distally relative to the body 12, which allows the pushing member 430 to move proximally relative to the barrel 400, as described above. This allows a flow path to be formed between the reservoir 26 of the barrel and the fluid duct 22.

[0088] As shown in FIG. 65, the drug delivery device 10 may also have multiple plungers 450. Each plunger 450 is aligned with the barrel 400 so as to extend into the barrel 400 and cause distal displacement of the corresponding piston 402. The end of the barrel 400 is open (at the proximal end) to allow the plunger 450 to enter the barrel 400 upon engaging the piston 402. It should be noted that with the barrel 400 sealed as described above and the reservoir 26 containing a drug in a non-compressible form (solid or liquid), distal pushing of the piston 402 by the plunger 450 results in distal displacement of the barrel 400. Sufficient distal displacement may achieve proximal movement of the pushing member 430 relative to the barrel 400 as described above.

[0089] When the drug cartridge 14 is configured to have a barrel 400, any barrel configuration may be utilized. For example, as shown in FIG. 67A, FIG. 67B, and FIG. 68, one or more barrels 400 may be provided with a bypass channel 452. As will be appreciated by those skilled in the art, the bypass channel 452 allows mixing of two or more portions within the barrel 400. The piston 402 of the barrel 400 is initially positioned to separate the reservoir 26 into two portions, each portion containing another component (a liquid-liquid combination or a liquid-dry combination). As the piston 402 advances distally, the multiple components (said other components) are brought together while mixing and / or reconstitution occurs. FIG. 68 illustrates various possible configurations for mixing or reconstitution of multiple components.

[0090] Further, as shown in Figs. 70-72 and 74-78, the barrels 400 may be disposed around the body 12. Referring to Figs. 74-78, one of the plungers 450 rotatable relative to the body 12 may be utilized to selectively align with the barrels 400. The plunger 450 may be rotatable in both directions to allow rapid sequential alignment with multiple barrels 400 as needed. Furthermore, the barrels 400 may house two or more drug components separated by a piston 402. Each piston 402 is configured to slide sealingly along the inside of one of the barrels 400. For example, a first drug component 456 may be provided in one or more barrels 400 separated from a second drug component 457 by the piston 402. Barrel / movable piston configurations that allow for reconstitution and / or mixing are known in the art. For example, as known in the art, each of the barrels 400 may be provided with a bypass channel 452 that allows the first drug component 456 and the second drug component 457 to mix upon sufficient displacement of the piston 402. The second drug component 457 may be in liquid form and may be incompressible. This allows a force of movement to be transmitted from the plunger 450 to the piston 402 via the second drug component 457. The end of the barrel 400 may be open to receive the plunger 450 with the outlet 404 of the barrel 400 facing radially outward from the body 12. Auxiliary pistons 461 may be provided to seal the second drug component 457 within the barrel 400. For each of the barrels 400, the plunger 450 may be pressurized into engagement with the auxiliary piston 461 as it displaces the auxiliary piston 461. This results in a displacement of the piston 402, the force of movement being transmitted via the second drug component. When the piston 402 is sufficiently displaced, the piston 402 overlaps the bypass channel 452 , thereby creating a fluid pathway across the piston 402 between the first drug component 456 and the second drug component 457 .Further displacement of auxiliary piston 461 urges second drug component 457 through bypass channel 452 to mix with first drug component 456. Further displacement causes auxiliary piston 461 to engage piston 402. Further displacement causes auxiliary piston 461 and piston 402 to displace collectively (integrally) and the mixed first drug component 456 and second drug component 457 are released from outlet 404, as shown in FIGS. 75-78.

[0091] Additionally, as shown in FIGS. 70-72, the barrel 400 may be configured to accommodate a first drug component 456. The first drug component 456 may be in a dry or liquid state and is mixed with at least one additional liquid component and introduced into the barrel 400 via the body 12. In this manner, the first drug component 456 may be reconstituted and / or mixed with one or more other drug components provided from outside the respective barrel 400. The piston 402 may be used to contour a reduced volume within each barrel 400 for the first drug component 456 prior to use. This allows for defining a pocket of limited volume to accommodate the first drug component 456 in a compressed state. The piston 402 may be displaced (e.g., radially outward) as a diluent or other liquid is pumped into the barrel 400. This increases the volume within the barrel 400 around the first drug component 456 as it is reconstituted and / or as it forms a mixture with the first drug component 456. Once prepared, the resulting reconstituted drug or drug mixture may be drawn from the barrel 400 through the body 12, for example, by negative pressure generated by the pump 18. The ends of the barrels 400 in this configuration may be closed, such as by a rear seal 454 sealing its proximal end to define a sterile envelope inside each barrel 400. The rear seals 454 may be vented to allow for displacement and pressure equilibration of the piston 402. For example, the rear seals 454 may each include a fine filtration element (e.g., a 0.2 micron filtration element) to provide a sterile vent, allowing air to be vented from the barrel 400 while preventing the ingress of microorganisms into the barrel 400. Additionally, one or more spacers 458 may be provided behind the piston 402 to limit the movement of the piston 402. The spacers 458 may be used to control (adjust) the allowable displacement of the piston 402, thereby controlling (adjusting) the allowable volume of the drug component 456 and any other components that are introduced, thereby allowing for control (adjustment) of the volume and concentration of the resulting reconstituted drug or mixture.The spacer 458 may be porous or have openings to allow the free movement of air therethrough as the piston 402 is displaced.

[0092] In addition to the valve 80 and the sealing seat 1906, various configurations may be utilized to form a seal on the drug cartridge 14, for example, a seal may be formed on the plug adapter 14B across the sterile lumen 36. These configurations provide a seal that does not require additional sterilization, similar to configurations utilizing the valve 80 or the sealing seat 1906. This category of seals shall be referred to as "non-sterile connection seal configurations." Additionally, seal configurations may be provided that provide a sterile connection to the body 12 of the drug delivery device 10, thereby eliminating the need to subsequently sterilize the drug cartridge 14, including the fluid outlet 34. This category of seals shall be referred to as "sterile connection seal configurations." It should be noted that in certain configurations the seal may be located within the lumen 36, and in certain configurations the seal is located outside the fluid outlet 34.

[0093] 36A-38B show different non-sterile connection seal configurations that can be used in the present invention as an alternative to the valve 80 or delivery cannula 406. Referring to FIGS. 36A-36E, a removable cap or plug 88 may be provided. The removable cap or plug 88 may be formed to resiliently engage a portion of the fluid outlet 34 and / or lumen 36 (see FIGS. 36A and 36E). As shown in FIGS. 36B-36D, the cap or plug 88 may be removably attached to a portion of the plug adapter 14B around the fluid outlet 34 and / or lumen 36. As shown in FIGS. 36D and 36E, a spring 90 or other biasing mechanism may be provided to aid in removal of the cap or plug 88. A latch 92 may be provided to resist the biasing force of the spring 90 in maintaining the cap or plug 88 in place until the appropriate time for removal.

[0094] Alternatively, as shown in Figures 37A-37D, a film 94 may be applied over a portion of the plug adapter 14B to cover and seal the fluid outlet 34 and the lumen 36. As shown in Figure 37A, the film 94 may be peelable. As shown in Figures 37B-37D, the film 94 may be breakable, for example, using electromotive force (Figure 37B), spring force (Figure 37C), and / or mechanical force (Figure 37D).

[0095] Additionally, as shown in Figures 38A-B, a portion of the plug adapter 14B may be heat sealed or otherwise joined to form a continuous seal across the fluid outlet 34 and the lumen 36. As shown in Figure 38A, this seal may be cut or broken to open the seal and expose the fluid outlet 34. Alternatively, as shown in Figure 38B, one or more tear lines 96 may be provided to form a line of weakness that allows removal of a portion of the seal to expose the fluid outlet 34.

[0096] 39A-41D show various sterile connection seal configurations that can be used with the present invention. For example, as shown in FIGS. 39A-39D, a "rolling diaphragm" configuration may be utilized in which a sterile barrier 97 having an outwardly extending edge 98 is provided on the plug adapter 14B. The sterile barrier 97 seals the lumen 36. When the plug adapter 14B is attached to the body 12, the outwardly extending edge 98 may capture a portion of the body 12 and roll back to expose the lumen 36. As shown in FIGS. 39A-39C, the plug adapter 14B and the body 12 may be formed with various cooperating surfaces to facilitate removal of the sterile barrier 97. Examples of cooperating surfaces include matching tapered surfaces (see FIG. 39A) and matching cylindrical surfaces (see FIG. 39B for removal on insertion and FIG. 39C for removal on rotation after insertion). 39D illustrates the use of a ball valve type element 99 to connect lumen 36 to body 12. Adjusting ball valve type element 99 removes sterile barrier 97, allowing communication between lumen 36 and body 12.

[0097] 40A-40C show various shift seal configurations that allow drug flow by adjusting the seal. For example, in FIG. 40A, a plug seal 320 may be provided in a first channel 323 in the body 12. A second channel 322 may be formed in the plug adapter 14B around the lumen 36. The fluid outlet 34 may be formed with a side port 34A and a closed end 34B. An annular ring seal 321 is initially positioned around the fluid outlet 34 to seal the side port 34A. As shown in FIG. 40A-1, when the fluid outlet 34 is inserted into the body 12, the plug seal 320 moves into the first channel 323 and the ring seal 321 moves into the second channel 322. This exposes the side port 34A, allowing communication between the lumen 36 and the body 12, as shown in FIG. 40A-2. One or more vent openings 326 may be provided in the first channel 323 to allow air to escape as the plug seal 320 moves into the first channel 323 .

[0098] Referring to FIG. 40B, the plug seal 320 may include a disinfectant reservoir 350 in the first channel 323. The fluid outlet 34 with the annular wiper 311 may be provided with a slidable piston 309. A disinfectant channel 313 is formed in the piston 309 to convey the disinfectant to the wiper 311. To form a connection between the lumen 36 and the body 12, pressure is applied to the (generally incompressible) liquid drug, which causes the piston 309 to move forward. Disinfectant released from the disinfectant reservoir 350 is conveyed through the disinfectant channel 313 to the wiper 311, and the movement of the piston 309 disinfects the inner surface of the fluid outlet 34. Upon sufficient movement, the piston 309 engages the plug seal 320, causing it to move into the first channel 323. Upon further sufficient movement, the piston 309 bypasses at least one fluid duct in the body, allowing an open communication with the lumen 36. The first channel 323 may be vented by one or more vent openings 326 .

[0099] Referring to FIG. 40C, a transverse seal 273 formed by multiple film layers 276, 277 may be provided to have a certain level of stiffness. The transverse seal 273 may be disposed through a slit 279 across the fluid outlet 34 and / or the lumen 36 to provide a seal therefor. A flange 278 may be formed around a portion of the slit 279. A clamping element 275 acts on the flange 278 to maintain the slit 279 in intimate sealing contact with the transverse seal 273 and hold it in place. The transverse seal 273 is removable through the slit 279 to allow open communication with the lumen 36, and the slit 279 is self-sealing. Sufficient elasticity must be provided in the material around the slit 279 to allow proper sealing and subsequent self-sealing against the transverse seal 273.

[0100] 41A-41F, the cannula 250 may include a lumen 36 configured to penetrate a septum 252 disposed on the body 12. The cannula 250 may be supported by a septum or plug disposed in the fluid outlet 34. As shown in FIG. 41A, the cannula 250 may be housed within a sealed septum 254. The septum 254 includes a disinfecting wiper 256 disposed on its exterior. The cannula 250 is maintained in a sterile condition within the sealed septum 254. During use, the cannula 250 penetrates the sealed septum 254, passes the wiper 256, and penetrates the septum 252. This allows for open communication between the lumen 36 and the body 12. 41B and 41C show a cannula 250 housed within a sheath 251 (e.g., an elastomeric sheath) and having a closed end 258 with a side port 260, where open communication is provided via the side port 260 when the cannula 250 penetrates a septum 252. As shown in FIG. 41B, a collapsible wall 259 (e.g., having bellows or pleats) may be provided around the cannula 250 sealed by a septum 254. The wall 259 may be formed such that the septum 254 collapses upon itself by pushing against the septum 252. When advanced sufficiently, the cannula 250 penetrates the septum 254. Upon puncturing the septum 252, the cannula 250 advances through the septum 254 and the sheath 251 is restricted by engagement with the septum 254. This allows the cannula 250 to advance further through the septum 252 to be exposed and to allow communication between the lumen 36 and the body 12 via the side port 260. Cooperating annular ribs 253, 255 may be formed on the septum 252, 254. The annular ribs 253, 255 are concentrically aligned with the septum 252, 254 in pressing engagement. The annular ribs 253, 255 cooperate to maintain alignment between the septum 252, 254. FIG. 41C illustrates that a pierceable (penetrable) backing 257 may be provided behind the septum 252 to provide rigidity and support to the septum 252.A central open passage 261 may be provided in the backing material 257 leading to a thin web 262 aligned to be punctured by the cannula 250. A spring 264 may be provided to advance the cannula 250 as shown in Figs. 41E and 41F. A locking ring 266 may be utilized to hold the cannula 250 in an initial position as shown in Fig. 41E. The locking ring 266 may be displaced or broken to allow the spring 264 to advance the cannula 250 as it punctures the septum 252. A sealing collar 268 may be provided around the cannula 250 to be advanceable with the cannula 250, thereby providing a seal around the cannula 250.

[0101] 41D provides the cannula 250 as double-ended with two closed ends 258A, 258B and two pairs of side ports 260A, 260B, where a secondary septum 263 is provided located inside the cannula 250. The cannula 250 may be held in place partially embedded in the secondary septum 263. In use, the cannula 250 penetrates the septum 252, the sealed septum 254, and the secondary septum 263 to allow open communication between the lumen 36 and the body 12 via the two pairs of side ports 260A, 260B.

[0102] In any of the embodiments of Figures 41A-41F, any of the septa 252, 254, and / or secondary septum 263 may include a biocidal material (including, but not limited to, antimicrobial silver) to promote sterility.

[0103] Once the reservoir section 14A of the drug cartridge 14 has been sterilized and aseptically filled and sealed with the plug adapter 14B, the drug cartridge 14 may be stored and transported as needed. The exterior portion of the drug cartridge 14, including the fluid outlet 34, may be open to the atmosphere during storage and assembly into the body of the device and is therefore not sterile.

[0104] As shown in Figs. 42 to 56, the drug cartridge 14 may be attached to the body 12 in any manner. For example, the plug adapter 14B and a portion of the body 12 may be joined by laser welding, adhesive, fusion, or the like. The drug cartridge 14 is assembled to the body 12 such that the fluid outlet 34 is aligned with the first fluid duct 22A to define a continuous flow path of the drug (medicine) from the reservoir 26. The first fluid duct 22A extends from the fluid outlet 34 to a first opening 100A formed in the first surface 24 of the body 12. The second fluid duct 22B may extend from the first opening 100A and communicate with the first fluid duct 22A. The second fluid duct 22B continues the flow path from the fluid outlet 34. The second fluid duct 22B is open along the first surface 24. As shown in Figures 173-174, the drug cartridge 14 may be attached to the second surface 24A of the body 12, and the first fluid duct 22A may extend from the fluid outlet 34 through the thickness of the body 12 to the second fluid duct 22B.

[0105] The barrier 102 may be provided across the first surface 24 to cover at least the first opening 100A. The barrier 102 closes the open side of the first opening 100A to contain the fluid duct 22A and the flow path within the first opening 100A. The barrier 102 is also selected to allow the passage of ultraviolet light, x-rays, pulsed light or electron beams, depending on the decontamination process selected. The barrier 102 may be transparent to the corresponding radiation, but need not be transparent. The barrier 102 need only be effectively transparent to the corresponding radiation, and need not be 100% transparent.

[0106] The ultraviolet radiation, X-ray radiation, pulsed light, or electron beam may be emitted from one or more radiation sources mounted on a fixed or movable fixture. The body 12 may be stationary or moving when exposed to the ultraviolet radiation, X-ray radiation, pulsed light, or electron beam. The body 12 must be positioned relative to the source of ultraviolet radiation, X-ray radiation, pulsed light, or electron beam to ensure sufficient exposure for the required level of decontamination. As a non-limiting example, the source or sources of ultraviolet radiation, X-ray radiation, pulsed light, or electron beam may be positioned in a tunnel above a moving belt carrying the body 12. The speed of the belt movement may be manipulated to control the rate of exposure of the body 12. Additionally, multiple sources of ultraviolet radiation, X-ray radiation, pulsed light, or electron beam may be utilized in the tunnel spaced radially along the circumference of the moving belt to provide hemispherical coverage of the body 12. Alternatively, one or more sources of ultraviolet radiation, x-ray radiation, pulsed light or electron beam may be mounted on a rigid fixture, movable arm or the like to cover the stationary body 12. Relative movement between the body 12 and the source of ultraviolet radiation, x-ray radiation, pulsed light or electron beam may be provided by movement of one or both elements. All elements may be statically mounted (disposed) in fixed, stationary positions without relative movement between them.

[0107] The barrier 102 may be a monolayer or multilayer polymer film including one or more of fluoropolymers, fluoropolymer copolymers, polyimides, polymethylpentenes, silicones, cyclic olefin copolymers, cyclic olefin polymers. Alternatively, the barrier 102 may be molded, extruded, laminated, and / or thermoformed from one or more of the above listed materials. Additionally, as shown in FIG. 57, the barrier 102 may conform to the topography of the first surface 24, including extending into one or more of the fluid ducts 22. This reduces the open volume in the fluid ducts 22.

[0108] The barrier 102 may be secured to the first surface 24 in any manner, including, but not limited to, heat sealing, gluing, fusing, and the like.

[0109] As shown in Figures 46 and 47, when the drug cartridge 14 is fixed to the body 12, certain parts of the flow path may be non-sterile, and such non-sterile parts are illustrated with an asterisk. This configuration may be applied when the drug cartridge 14 has a non-sterile connection seal configuration, such as the use of a valve 80. That is, some of the fluid outlet 34 may be non-sterile. Similarly, some parts of the body 12, such as the first fluid duct 22A, the second fluid duct 22B, and the opening 100A, may be non-sterile.

[0110] The barrier 102 allows for decontamination, including sterilization, of the flow path along the first surface 24. In this way, the drug cartridge 14 may be prepared separately and assembled to the body 12 with the fluid duct 22 and the fluid outlet 34 decontaminated. With the fluid duct 22 open along the first surface 24 and the fluid outlet 34 exposed, the first surface 24 may be exposed to ultraviolet light, x-ray radiation, pulsed light, or an electron beam, as shown in Figures 48-52 and 69. This allows the ultraviolet light, x-ray radiation, pulsed light, or electron beam to pass through the barrier 102 to decontaminate the exposed surfaces of the fluid ducts 22A, 22B and the fluid outlet 34. A sterilization pathway may be provided, which allows the seal to be opened to allow liquid flow (see Figures 55-56). A negative pressure may be applied to the fluid duct 22 to simultaneously or sequentially (in various combinations) withdraw drugs (medicines) from the reservoir 26 of the drug cartridge 14. Additionally, diluent may be pumped (pumped) through the fluid duct 22, if necessary, to reconstitute the dry drug components (pharmaceutical components) in one or more drug cartridges 14 and then extract the reconstituted liquid drug (liquid drug) using negative pressure.

[0111] As illustrated by the "X" in FIG. 48, it is preferred that certain portions of the drug cartridge 14 be protected from exposure to ultraviolet light, x-ray radiation, pulsed light or electron beam. These areas may be sensitive to such exposure, which may result in harm to the contained drug ingredients. As shown in FIGS. 52-53, to protect sensitive areas of the drug cartridge 14, including the reservoir 26, from the harmful effects of exposure to ultraviolet light, x-ray radiation, pulsed light or electron beam, one or more shields 104 may be provided that block ultraviolet light, x-rays, pulsed light or electron beam depending on which is used. The shields 104 may be planar (as shown in FIG. 52) or tubular (as shown in FIGS. 52A-52B). The sensitive areas may include biocidal materials, including but not limited to antimicrobial silver, to promote sterility. Additionally or alternatively, when ultraviolet and / or x-ray radiation is utilized, an ultraviolet and / or x-ray blocking additive may be added to a predetermined portion (shown as a shaded portion) 210 of the drug cartridge 14, as shown in FIG. 49-FIG. 51. The ultraviolet and / or x-ray blocking additive may be any known additive that effectively blocks the passage of ultraviolet or x-ray radiation. Non-limiting examples of known additives include inorganic materials such as oxides (e.g., titanium oxide, zinc oxide), as well as organic materials such as amine light stabilizers (e.g., those commercially available under the trade names "HALS Chimassorb 2020"), ultraviolet absorbers (e.g., those commercially available under the trade names "Tinuvin 326" and "Uvinul 3034" by BASF), and carbon black. The ultraviolet and / or x-ray blocking additive may be used in the pulsed light depending on the composition of the electromagnetic radiation contained in the pulsed light.

[0112] As shown above, the surfaces that need to be decontaminated are exposed and generally face the source of ultraviolet, x-ray, pulsed light, or electron beam radiation. Once through the barrier 102, these surfaces can receive the radiation unshielded. It should be noted that ultraviolet, x-ray, pulsed light, and electron beam radiation are effective to a certain depth in the material. Thus, as shown in FIG. 54, one or more ducts 22 may be provided to be housed within the body 12 as a containment duct 203. Any of the containment ducts 203 must be sufficiently close to the first surface 24 to be adequately decontaminated by exposure to ultraviolet, x-ray, pulsed light, or electron beam radiation. When a containment duct 203 is used, as shown in FIG. 54, the barrier 102 cannot be omitted or applied only where the duct 22 is exposed.

[0113] If the drug cartridge 14 is provided with wings 27A, the UV and / or X-ray blocking additive may be provided across the wings 27A across the well 1900. The additive is positioned between the fluid outlet 34 and the portion of the lumen 36 upstream of the seal 1908, as shown by the shaded portion 210 in FIGS. 49A-C. In this manner, the fluid outlet may be sterilized without adversely affecting the drug (medicine) contained within the lumen 36. Additionally, as shown in FIG. 52A, the tubular shield 104 may have a shape that overlaps the shaded portion 210, thereby providing UV / X-ray blocking in both radial and vertical directions.

[0114] FIG. 73A shows a body 12 that may be decontaminated using ultraviolet light. FIGS. 73B-73C show the amount of ultraviolet light received at the surface of the body 12 after a certain time interval. In FIGS. 73B-73C, the surface depicted in black is at a value considered to be a threshold dose (10 mJ / cm2). 2 ) in the UV radiation measurements. Surfaces depicted in white have a UV radiation measurement of at least 10 mJ / cm 2, i.e., a UV radiation measurement of at least a threshold dose. FIG. 73B is an image captured of body 12 exposed to UV radiation for 3 seconds, and FIG. 73C is an image captured of body 12 exposed to UV radiation for 30 seconds. As can be seen in FIG. 73C, good distribution of UV radiation can be achieved on surfaces oriented in various directions. FIG. 73C shows that body 12 can be sterilized by exposing it to UV radiation. Similar results are expected for x-ray radiation, pulsed light, and electron beam radiation.

[0115] As will be appreciated by those skilled in the art, additional sterilization techniques may be used to complement the application of ultraviolet radiation, x-ray radiation, pulsed light, and / or electron beam radiation, such as ultraviolet radiation, x-ray radiation, pulsed light, and / or heat and gas sterilization (e.g., ethylene oxide (EtO)). Furthermore, these sterilization techniques may be used in place of ultraviolet radiation, x-ray radiation, pulsed light, and / or electron beam radiation, for example, when a barrier 102 is not provided or is not transparent to such radiation. Decontamination techniques utilizing various combinations of ultraviolet radiation, x-ray radiation, pulsed light, and / or electron beam radiation may also be used.

[0116] As will be appreciated by those skilled in the art, the decontamination methods described herein can be used with a variety of drug delivery devices, including those that include a drug reservoir, i.e., where a drug reservoir is not provided separately. Additionally, the decontamination methods can be used to sterilize associated fluid pathways prior to loading with a drug (medication) to sterilize the associated fluid pathways. In accordance with the present invention, open fluid ducts within the body of the drug delivery device can be covered by a barrier and decontaminated by exposure to ultraviolet light, x-rays, pulsed light or electron beams passing through the barrier.

[0117] The drug delivery device 10 may be provided with various fluid configurations that allow for delivery of the drug from the reservoir 26 of the drug cartridge 14. Additionally, the fluid configurations may be configured to facilitate reconstitution and / or mixing, for example, by allowing the introduction of a diluent or other liquid component into one or more reservoirs 26. For example, in one configuration, at least one drug cartridge 14 may be provided with a diluent, and the pump 18 may be configured to be bidirectional, allowing for the withdrawal of the diluent from the drug cartridge 14 holding the diluent, pumping the diluent into at least one target drug cartridge 14 to allow for reconstitution and / or mixing, and then withdrawing the resulting liquid drug from the target drug cartridge 14 for transport to the needle 15 for delivery to the patient.

[0118] 90-94B are schematic diagrams illustrating various fluidic configurations that can be used with the drug delivery device 10. Referring to FIG. 90, a fluidic configuration for delivering drugs from multiple reservoirs 26 (reservoirs 26a-26i) to the needle 15 is shown. Valves may be provided to selectively control which reservoir 26 the drug is taken from. This allows different combinations of drugs to be drawn from the drug cartridge 14 in series and / or parallel to provide a combination drug therapy. Additionally, drugs may be provided in different forms (e.g., dry, liquid) in different drug cartridges 14. The different forms may be combined. For example, a dry drug may be reconstituted and then combined with a liquid drug. Additionally, the same drug may be drawn from multiple reservoirs 26, allowing for larger doses of a single drug.

[0119] Each of the reservoirs 26 may be disposed on the drug cartridge 14 as shown diagrammatically by dashed lines. As mentioned above, a valve 80, a sealing seat 1906, or other seals, including those mentioned above, may be provided on the drug cartridge 14 to selectively provide access to the drug contained therein. The valve 80, the sealing seat 1906, or other seal may be disposed on the body 12 and function to selectively seal the corresponding reservoir 26. The valve 80, the sealing seat 1906, or other seal sealing the reservoir 26 may be considered as a primary valve PV (primary valves PVa to PVi) configured to selectively allow flow to or from the reservoir 26. The primary valve PV may be a two-position type valve or seal (positions A, B) that selectively provides an open or closed state. A plurality of reservoirs 26, or a subset thereof, may be manifolded (connected) to a common fluid duct 22 and then regulated by a secondary valve SV (secondary valves SVa to SVc). The secondary valve SV may be a two-position valve (positions A and B) that selectively provides an open or closed state to allow or block flow through the secondary valve SV. The secondary valve SV allows flow to or from a desired subset of the reservoirs 26. FIG. 53 illustrates an example configuration of the primary valve PV and secondary valve SV. The secondary valve SV may be configured as valve 80 or sealing seat 1906 as described above.

[0120] Additionally, a fluid duct 22 may be provided between the secondary valve SV and the pump 18, forming a fluid path. At least one control valve CV may be provided between the secondary valve SV and the pump 18 to allow selective communication with a particular group of reservoirs 26. The control valve CV may be positionable in multiple positions (e.g., positions including a number of open positions equal to the number of secondary valves SV and an additional closed position). For example, in FIG. 90, the control valve CV has four positions (positions A, B, C, D) including three open positions (corresponding to each of the three control valves CVa-CVc) and one closed position.

[0121] In use, the primary valve PV, secondary valve SV, and control valve CV are adjustable to selectively define an open fluid path between the reservoir 26 and the pump 18. For example, to define an open fluid path from the pump 18 to the reservoir 26i, (1) the control valve CV may be adjusted to position A, (2) the secondary valve SVc may be adjusted to position A, and (3) the primary valve PVi may be adjusted to position A. This allows drug to be drawn from the reservoir 26i by the pump 18. Once the reservoir 26i is empty, the primary valve PVi may be closed by adjusting to position B, and the next reservoir (e.g., reservoir 26h) may be opened by adjusting the primary valve PVh to position A. The primary valve PV and secondary valve SV are preferably in a closed state with no flow intended therethrough. This allows maximum negative pressure (suction) to be applied by the pump 18 to the target reservoir 26.

[0122] To allow ventilation and smoother flow along either the fluid duct 22 and / or the outlet duct 25, the flow path may have a vent V, a check valve CKV (e.g., one-way check valve), and a flow restrictor FR (e.g., a Venturi tube). The check valve CKV, particularly as a one-way check valve, prevents backflow from non-sterile areas or from outside the drug delivery device 10 to best maintain the sterility of the active flow path. To further protect the sterility of the active flow path, at least two check valves CKV may be provided in series and in opposite directions in one or more couplings C1 to limit backflow in both directions across the coupling C1. A number of pressure sensors PS may be provided to measure (monitor) the flow pressure along various parts of the flow path.

[0123] The pump 18 may be motorized, in particular by an electric motor (e.g., a DC-powered electric motor) that may be housed within the housing 9. The pump 18 may be a positive displacement pump or a peristaltic pump. The pump 18 is preferably bidirectional. With reference to FIG. 90, a fluid path (flow path) is configured with the pump 18 drawing the drug from the reservoir 26. The pump 18 is thus arranged to have an outlet (pressure side) disposed towards the needle 15 and an inlet (suction side) disposed towards the reservoir 26. As will be explained further below, the pump 18 may be utilized to mix and / or reconstitute the drug by causing both flow to and from the reservoir 26. Here, the pump 18 is bidirectional allowing for reverse operation to switch between the pressure and suction sides of the pump 18. To facilitate this function, the pump 18 is preferably configured to allow for bidirectional operation. This is achievable with positive displacement pumps and peristaltic pumps.

[0124] The primary valve PV, the secondary valve SV, and the control valve CV may be adjusted by any known means (e.g., actuatable solenoids, valve actuators, etc.). With reference to Figs. 95-97B, a displaceable actuator plate 500 may be provided that defines one or more inclined cam surfaces 502. The inclined cam surfaces 502 are arranged to displace the primary valve PV, the secondary valve SV, and / or the control valve CV by displacement of the actuator plate 500. As a non-limiting example, the actuator plate 500 may be provided as a disk that is liftable relative to the body 12, and the inclined cam surfaces 502 may be defined along a limited arc of the actuator plate 500. The primary valve PV and the secondary valve SV may each be configured as a valve 80. As shown in Figs. 34-35B, the valve 80 may be opened by displacing it upward. As shown in Figs. 95-96B, a plurality of control elements 504 may project upward from the actuator plate 500 and be arranged to axially align with the primary valve PV and the secondary valve SV.

[0125] The actuator plate 500 may be non-rotatably attached to the gear plate 510 (FIG. 96B). As shown in FIG. 96C, the gear plate 510 may include an opening 511 to allow attachment to the body 12, and the gear plate 510 may be rotatable. A series of gear teeth 512 may be provided along the periphery of the gear plate 510. The gear teeth 512 may be meshingly engaged with one or more motor-driven drive gears or pinions (not shown) to rotate the gear plate 510. The same motor used to power the pump 18 may be used to drive the gear plate 510. The motor may include one or more drive shafts and may include a clutch for selectively engaging a driven element, such as the pump 18 or a pinion, to drive the actuator plate 500. It is also preferred that the motor is reversible to allow bidirectional movement of the actuator plate 500.

[0126] The gear plate 510 has a plurality of secondary inclined cam surfaces 503. As shown in FIG. 96A, the inclined cam surfaces 502 are hollow to allow the secondary inclined cam surfaces 503 to be inserted into the inclined cam surfaces 502. This allows the actuator plate 500 to rest on the gear plate 510. When the control element 504 is received in the bore 36 (e.g., the second bore 36B), the actuator plate 500 is restricted from rotating relative to the body 12. As shown in FIG. 96B, as the gear plate 510 rotates, the secondary inclined cam surfaces 503 rotate relative to the inclined cam surfaces 502, which causes the actuator plate 500 to rise (compare FIG. 96D with FIG. 96E and FIG. 97A with FIG. 97B). As the actuator plate 500 rises, the control element 504 displaces the valve 80 upward. As shown in Figures 97A and 97B, when the primary valve PV and secondary valve SV are displaced upwards, they are separated from their respective valve seats 76. As shown in Figure 98, biasing means 508 (e.g., a spring) may be provided for biasing the primary valve PV and secondary valve SV to an open state. This may help to open the primary valve PV and secondary valve SV. The biasing means 508 may be a coil spring that defines an open passage through which the control element 504 can pass.

[0127] Referring to FIG. 199, an actuator 1001 for opening a sealing seat 1906 used as either a primary valve PV or a secondary valve SV is shown. As shown in FIG. 200, a plurality of wells 1900 may be arranged in a circle (concentrically) at the same radius around the body 12. This allows sequential opening of the movable sealing elements 1902, which all project upwardly against the first surface 24 of the body 12. The actuator 1001 includes an actuator plate 1002 having a downward detent 1004. The actuator 1001 includes a housing 1006 fixed to the body 12, the actuator plate 1002 being rotatable about the body 12. A rotation source 1008 (e.g., a spring drive (e.g., a clock spring or torsion spring), a motor drive, etc.) is provided between the housing 1006 and the actuator plate 1002 for rotating the actuator plate 1002. The rotation source 1008 may be maintained in a fixed, pre-use state using any known configuration. The rotation source 1008 may also be triggered to rotate using any known configuration (e.g., manual release, electrical release, frangible release, etc.). The detents 1004 are positioned to coincide with the radial alignment of the multiple wells 1900. Additionally, the actuator plate 1002 is restricted from moving away from the wells 1900. As shown in Figs. 203-204, rotation of the actuator plate 1002 causes the detents 1004 to move across each of the movable seal elements 1902 in turn, forcing each seal element 1902 into the corresponding well 1900. This results in delamination of the corresponding seal sheet 1906. To best ensure that the movable seal elements 1902 do not inadvertently return to a closed state, it is preferred that the actuator plate 1002 be held in a lowered position flush with the first surface 24. This may be achieved by applying pressure to the actuator plate 1002. Additionally, the rotational force of the rotation source 1008 may be utilized by providing cooperating tilting elements 1110 on the housing 1006 and on the actuator plate 1002 to convert the rotational force into a downward vertical force (see FIG. 206).Alternatively, the drive plate (housing) 1006 may be placed on the actuator plate 1002 (with the tilting elements 1110 stacked) with the housing 1006 engaged against the actuator plate 1002 (see FIG. 205). To allow the actuator plate 1002 to be maximally pressed in face engagement with the first surface 24, recesses 1112 may be formed in the first surface 24 into which the detents 1004 fit after adjusting all of the moveable seal elements 1902 (see FIG. 207). Advantageously, one rotation of the actuator plate 1002 may be utilized to adjust all of the moveable seal elements 1902.

[0128] As shown in Figures 91-94B, the drug delivery device 10 may be configured for mixing and / or reconstitution of drugs. With reference to Figure 91, one of the reservoirs 26 may be provided as a diluent reservoir 26j for containing a drug (medicine) as a diluent. A primary valve PVj may be provided to regulate the inflow into or outflow from the diluent reservoir 26j. Optionally, a secondary valve SCd may also be provided to regulate the inflow into or outflow from the diluent reservoir 26j. The primary valve PVj and the secondary valve SVd may be provided as valves having two positions (positions A, B) that allow or block the passage of flow, and may selectively provide an open or closed state.

[0129] If the pump 18 is bidirectional, it may be configured such that suction is directed to the fluid duct 22 that communicates with the reservoir 26j. When the secondary valve SCd and the primary valve PVj are both in an open state (position A), negative pressure from the pump 18 reaches the reservoir 26j and the diluent is withdrawn from the reservoir 26j. The diluent may be pushed (under positive pressure) into one or more target reservoirs 26 using valve operation as described above. For example, the target reservoir 26 may contain a drug in a dry or semi-liquid (slurry) state. The diluent may reformulate this drug to a fully liquid state suitable for injection into a patient. Alternatively, the diluent may be a component for a mixture of two or more parts that mixes with the drug in the target reservoir 26. Once the diluent has been delivered to the target reservoir 26, the pump 18 may be reversed to withdraw the mixed / reformulated drug for delivery through the needle 15. One or more pressure sensors PS may be used to measure the pressure of the diluent flow. As the reservoir 26 fills with diluent, the pressure in the reservoir 26 increases. By measuring the pressure, the fill volume and / or concentration may be monitored. For example, when a threshold pressure is detected, the target reservoir 26 may be shut off from further delivery of diluent.

[0130] One or more heaters H (e.g., resistive heaters) may be positioned along the diluent flow path to increase the temperature of the diluent. Heating the diluent may facilitate mixing and / or reconstitution.

[0131] To aid in mixing or reconstitution, the drug delivery device 10 may be stirred after delivery of the diluent to the target reservoir 26. This may be done manually. Alternatively, as shown in Figs. 99-100, the drug delivery device 10 may be placed on a vibration plate 600 or a rotating or vibrating turntable 602. Additionally or alternatively, the drug delivery device 10 may be provided with one or more on-board stirring mechanisms. The stirring mechanisms may be, for example, an accelerometer 604 (see Fig. 101) that may cause reciprocating motion of the drug delivery device 10, a piezoelectric actuator 606 (see Fig. 102) that may cause vibrations in the drug delivery device 10, and a magnetic stirrer 608 (see Fig. 103) located in the reservoir 26 to cause movement, such as rotation, by an adjacent moving magnet 610. The movable magnet 610 may be provided on the drug delivery device 10 or may be provided separately (eg, the magnet 610 may be provided on a rotating disk attached to the body 12).

[0132] It should also be noted that the diluent reservoir 26j may be configured as one of the drug cartridges 14 described above. As will be appreciated by those skilled in the art, the reservoir 26j may be configured in a variety of ways. For example, as shown in FIG. 104, the reservoir 26j may be provided as a low-profile, foldable reservoir formed generally within the contour of the body 12. In this manner, the reservoir 26j may be provided below the drug cartridge 14. As the area occupied by the reservoir 26j increases, the height of the reservoir 26j may be kept to a minimum.

[0133] Other fluid configurations of the drug delivery device 10 are possible. FIG. 92 shows a modified version of FIG. 91, in which parallel flow lines FL1, FL2 are provided from the pump 18 and controlled by a second control valve CV2. The second control valve CV2 may be a two-position valve (positions A, B) that allows selective opening of the parallel flow lines FL1, FL2. Flow line FL1 is an uninterrupted flow line between the pump 18 and the second control valve CV2. Flow line FL2 is configured for unidirectional flow from the pump 18 towards the control valve CV by a check valve CKV2. Additionally, a vent V and / or a flow restrictor FR may be provided along flow line FL2. Flow line FL2 may be used for delivery of diluent to the target reservoir 26, and flow line FL1 may be used for withdrawing mixed or reconstituted drug from the target reservoir 26.

[0134] 93, a flow path FL2 may be provided extending across the pump 18. A third control valve CV3 may be provided to regulate flow between the pump 18, the diluent reservoir 26j, and the target reservoir 26. The third control valve CV3 may be a two-position valve (positions A, B) that selectively allows flow between the pump 18 and the diluent reservoir 26j and between the pump 18 and the target reservoir 26.

[0135] As shown in Fig. 94A, a mixing container MC may be provided in flow path FL2, for example to allow the drug to be withdrawn from and re-delivered to reservoir 26 for ease of reconstitution. One or more static mixers SC may be provided along flow path FL2. A third flow path (flow line) FL3 may be provided extending across one-way pump 18 to provide communication to target reservoir 26. With the addition of third flow path FL3, second control valve CV2 and third control valve CV3 may be configured as three-position valves (positions A, B, C) selectively communicating with their respective flow paths.

[0136] The fluid configuration of the drug delivery device 10 may be configured to allow for the reconstitution of a drug in one or more target reservoirs 26 using the circulation of the mixture. For example, the configuration of FIG. 94B may be used to withdraw a mixture of diluent and drug from the target reservoir 26 and direct the mixture to the diluent reservoir 26j, and then withdraw the mixture from the diluent reservoir 26j and reintroduce the mixture to the target reservoir 26. As shown in FIG. 94B, a flow path FL4 may be provided to extend across the one-way pump 18 to provide communication with the diluent reservoir 26j. In this case, the control valve CV2 may be a two-position valve. This same circulation may be achieved using the configuration of FIG. 94A, but the mixture is directed to a mixing container MC for temporary containment during circulation.

[0137] As shown in Figures 105A-112, circulation of the mixture can improve the reconstitution process. For example, as shown in Figure 105A, in a first state, the diluent is contained in the diluent reservoir 26j and the drug intended to be reconstituted is contained in the target reservoir 26t. As shown in Figure 105A, when the pump 18 is in an off state, the target reservoir 26t is at a certain initial pressure. As shown in Figure 105B, the pump 18 is actuated to draw diluent from the diluent reservoir 26j and pump the diluent into the target reservoir 26t, which increases the pressure in the target reservoir 26t. The pressure in the target reservoir 26t may be monitored, and pumping of the diluent is stopped when a predetermined pressure is detected. Subsequently, as shown in FIG. 105C, the pump 18 is reversed to extract the diluent and drug mixture (which may be an intermediate mixture) from the target reservoir 26t and pump the intermediate mixture into the diluent reservoir 26j. This creates a negative pressure in the target reservoir 26t. As shown in FIG. 105C, some of the drug may not be completely mixed with the diluent, and therefore some of the drug remains in the target reservoir 26t. Advantageously, when the target reservoir 26t is emptied under the suction of the pump 18, the target reservoir 26t folds and deforms (collapses). The folded portion of the target reservoir 26t may press into engagement with the residual drug. The pressure from the folded portion of the target reservoir 26t may cause the residual drug to spread throughout the target reservoir 26t. This creates a "deflocculation" effect, increasing the surface area of ​​the residual drug throughout which the diluent can penetrate. When the intermediate mixture is reintroduced (pump 18 is reversed again) as shown in Figure 105D, it can better mix with the spread residual drug and enhance its reconstitution function.

[0138] As will be appreciated by those skilled in the art, beyond the step of FIG. 105D, further circulations involving further movement of the intermediate mixture back and forth between the diluent reservoir 26j and the target reservoir 26t may be utilized. Furthermore, as shown in FIG. 106A-106F, subsequent circulations may introduce only a portion of the intermediate mixture. As shown in FIG. 106A-106C, the same initial steps as shown in FIG. 105A-105C may be used. As shown in FIG. 106D, a portion of the intermediate mixture is returned to the target reservoir 26t, followed by a complete emptying of the target reservoir (see FIG. 106E) and a complete introduction of the intermediate mixture into the target reservoir 26t (see FIG. 106F). Partial circulation may also improve the wettability of the drug, which may also facilitate reconstitution of the drug. Once the final mixture is achieved, it may be withdrawn from the target reservoir 26t and directed to the needle 15 for delivery to the patient.

[0139] It should be noted that the fluid configurations of FIGS. 105A-106F may be based on the fluid configuration described above in connection with FIG. 94B.

[0140] Additionally, reservoir support 300 may be utilized to limit expansion of target reservoir 26t, thereby providing a physical stop that defines the fill level. Pressure measurement may be utilized, but is not necessary when using reservoir support 300.

[0141] As will be appreciated by those skilled in the art, a mixing container MC may be utilized in addition to or instead of the diluent reservoir 26j to temporarily contain the intermediate mixture, as shown in Figures 107A-107P. Figures 107A-107P show a similar process to Figures 106A-106F, but a mixing container MC is utilized to collect and hold the intermediate mixture removed in providing the final mixture for delivery to the patient. Advantageously, the mixing container MC may be connected in a manner that facilitates continuous reconstitution of the reservoirs 26t of multiple groups of targets, as shown in Figures 107A-107P. As will be appreciated by those skilled in the art, the diluent reservoir 26j may be located at various locations in the system. Depending on the location of the diluent reservoir 26j, one or more additional reservoirs 26d may be located at the location of the diluent reservoir 26j in Figures 105A-105D and Figures 106A-106F.

[0142] It should be noted that the fluid configurations of FIGS. 107A-107P may be based on the fluid configuration described above in connection with FIG. 94A.

[0143] Entrapped gas in the drug or diluent may affect reconstitution by forming undesired compressible pockets. To allow removal of entrapped gas, one or more vents V may be arranged in series in the flow path between the diluent reservoir 26j and the target reservoir 26t. FIGS. 113-117 show an embodiment of a vent V that can be used in the present invention. The vent V may have a base plate 700 in which a channel 702 is formed that extends between a first opening 704 and a second opening 706. As shown in FIG. 115, the channel 702 may be substantially straight between the first opening 704 and the second opening 706. Alternatively, as shown in FIGS. 116 and 117, the channel 702 may define a tortuous path between the first opening 704 and the second opening 706, and the path may include a plurality of bends 708 joined by connecting sections 710. As shown in FIGS. 116A-C, the plurality of bends 708 may be arranged to create vertical turns at the plurality of connecting sections 710. The plurality of connecting sections 710 are arranged along a common longitudinal axis (in a plan view) but are arranged in a plurality of vertically spaced apart planes. A first set of connecting sections 710 may be aligned in a collinear manner with a second set of connecting sections 710. The second set of connecting sections 710 are aligned in a collinear manner but spaced apart from the linear axis of the first set. Additionally, as shown in Figure 117, the channel 702 may have one or more enlargements 714, particularly along the straight connecting section 710, which may provide an area for gas to meet and merge. As shown in Figures 117A-B, the enlargements 714 may be diamond shaped with a diverging portion 714A that receives the flow and a converging portion 714B that directs the flow. Any amount of enlargements 714 may be utilized.

[0144] A gas permeable layer 712 is attached to the base plate 700 over the channels 702, which are in direct contact with the gas permeable layer 712. Gas may permeate from the channels 702 through the gas permeable layer 712. The channels 702 preferably act as a restriction. For example, the channels 702 may be narrow, thereby acting to push gas out of the channels 702. Tortuous paths and widening may further enhance this effect. It should also be noted that the vent structure is equally effective for flow in either direction, and thus venting is provided for flow in either direction between the first opening 704 and the second opening 706.

[0145] 105C and 106C, the drug cartridge 14 may have a reservoir 26t supported by a radially outwardly recessed concave portion of the rigid shell 30. The concave portion of the shell 30 has a radially outwardly curved surface over which the drug may spread. The fill port 38 is preferably positioned to form a flow path that impinges on the concave portion of the shell 30. This allows the diluent flow to force the drug against the surface of the concave portion of the shell 30, causing compression of the drug and thus increasing "deagglomeration" and wetting of the drug. As shown in FIG. 107C, the rigid shell 30 may be provided with an inwardly convex portion instead of a concave portion. The same considerations apply to this convex portion, and it may provide a larger surface for the drug to spread over.

[0146] Fig. 108 shows multiple target reservoirs 26t manifolded for simultaneous circulation, allowing mixing of drugs from the various target reservoirs 26t and diluent reservoirs 26j in the manifold fluid duct 22, in addition to reconstitution. The pressure of each target reservoir 26t can be monitored to determine its fill level.

[0147] As shown in FIG. 109, each of the reservoirs 26, including the target reservoir 26t, may be provided with a static mixer 800 adjacent to the corresponding reservoir 26, for example at the fill port 38, to improve mixing during withdrawal of the drug from each reservoir 26. Additionally, a filter 802 may be provided, for example along the fill port 38, to capture overly large solid particles, if desired. Additionally, optionally, a reservoir pressure sensor 804 may be provided on the rigid shell 30 to detect the pressure of each reservoir 26. The reservoir pressure sensor 804 is positioned to be pressed by the corresponding reservoir 26 during filling.

[0148] As shown in Figures 110-112, a reservoir pressure sensor 804 may be utilized to compare the pressure in the pump 18 and the corresponding reservoir 26 to determine the difference between these pressures. This may be utilized to identify clogs or blockages caused by solid particles of drug blocking a portion of the flow path. As shown in Figure 110, detection of the pressure difference may cause the flow to be reversed to loosen an obstruction, particularly when withdrawing the mixture from the target reservoir 26t (see Figure 111). Once the obstruction is removed, the pressure difference may dissipate (see Figure 112).

[0149] During use, the drug delivery device 10 may be activated for use in various ways. For example, before the patient wears the drug delivery device 10, the drug delivery device 10 may be pre-activated before use to allow reconditioning. Additionally, one or more skin sensors (e.g., capacitive skin sensors) may be provided on the drug delivery device 10 as a safeguard to detect proper attachment prior to activation and drug delivery. Upon activation, the needle 15 may be inserted into the patient and the pump 18 may be activated to deliver the drug. Flow pressure and timing may be measured (monitored) to assess the status of drug delivery. Status indicators, such as lights, may be provided on the drug delivery device 10 to provide the patient with the status of drug delivery. A dose may be considered the amount at which all of the drug cartridge 14 is depleted. Once drug delivery is complete, the drug delivery device 10 may be removed from the patient and disposed of in accordance with applicable regulations.

[0150] 118A-148B, by way of non-limiting example, as described above, a network of reversible valves may be used to selectively direct flow across various flow paths, for example, as shown in FIGS. 90-94B. As shown in FIGS. 131 and 135, a plurality of flexible valves 900 may be provided. Each flexible valve 900 has a flexible body 902 supported by its edge 904. Preferably, the edge 904 has a circular shape. Moreover, as shown in FIGS. 131 and 135, the flexible body 902 is preferably dome-shaped in an unbiased rest state. The flexible body 902 is formed from a resilient material (e.g., an elastomeric and / or polymeric material), which allows the flexible body 902 to reversibly flex inwardly under load. The flexible body 902 may be formed to have an inherent memory (original shape) in the rest state such that when the load is removed, the flexible body 902 in the deflected state returns to the rest state, allowing the flexible body 902 to reversibly deflect under force and return to an unbiased rest state.

[0151] The flexible body 902 may include a downwardly projecting valve face 906. Preferably, the valve face 906 is a substantially flat surface. As shown by comparing Figures 135 and 136, the valve face 906 preferably moves straight down as the flexible body 902 flexes, such that the valve face 906 is oriented substantially parallel between the flexed state (Figure 136) and the rest state (Figure 135).

[0152] Each flexible valve 900 is disposed at an intersection of flow paths and / or acts as a connection between the flow paths to selectively regulate flow between the flow paths. As shown in FIG. 135 and FIG. 136, each flexible valve 900 may be disposed over an opening 908 to a flow path 910. The valve face 906 is preferably formed with a larger area than the corresponding opening 908 so that the valve face 906 can completely cover the opening 908. As shown in FIG. 136, when the flexible valve 900 is in a deflected state, the valve face 906 presses and engages the sealing surface 912 around the opening 908 such that the opening 908 is completely covered by the valve face 906, thereby blocking the flow path 910. To facilitate the formation of a good seal, the sealing surface 912 is a generally flat surface and is configured to face-engage with the valve face 906 around the opening 908 to form an annular seal. As shown in FIG. 135 and FIG. 136, the sealing surface 912 may be raised.

[0153] To control the opening and closing of the flexible valves 900, each flexible valve 900 may be provided with a leaf spring 914 attached to a boss 916 extending upward from the flexible body 902. As shown in FIG. 131 and FIG. 135, when the flexible body 902 is in an unbiased rest state, the leaf spring 914 may have an unbiased rest state. The leaf spring 914 provides additional restoring force to the flexible valve 900 when returning from the deflected state (FIG. 136) to the unbiased rest state (FIG. 135). As shown in FIG. 136, as the flexible body 902 deflects, the leaf spring 914 also deflects. The leaf spring 914 is formed from a material (e.g., a metallic material and / or a polymeric material) that has an inherent memory (original shape), and when unloaded, the leaf spring 914 is urged toward the unbiased rest state. The restoring force of the leaf spring 914 acts on the flexible body 902 to assist the flexible body 902 in returning to its unbiased, rest state.

[0154] Various configurations may be utilized to selectively open and close the flexible valve 900. The deflected state of the flexible valve 900 may correspond to a closed state (i.e., a state that restricts flow) and the unbiased resting state of the flexible valve 900 may correspond to an open state (i.e., a state that allows flow). A network of flexible valves 900 may selectively control flow through multiple flow paths. As a non-limiting example, an actuator gear 918 may be fixedly mounted to rotate above one or more flexible valves 900. The actuator gear 918 may have a lower surface 920 configured to be aligned with the flexible valve 900 on the rotational arc of the actuator gear 918. As shown in FIG. 136, the lower surface 920 is vertically positioned above the flexible valve 900 to interference-engage the flexible valve 900 and deflect the flexible valve 900 when the flexible valve 900 is in a closed state. The lower surface 920 is preferably a substantially flat surface to allow for continuous engagement with the flexible valve 900 .

[0155] The actuator gear 918 may be provided with one or more radial recesses 922 that may be rotated to align with one or more flexible valves 900. Each of the radial recesses 922 may form a relief that allows the flexible valve 900 to return toward an unbiased rest state, thereby providing an open state for the flexible valve 900. The radial recesses 922 may be disposed on the actuator gear 918 to coordinate the opening and closing of one or more flexible valves 900. For example, multiple radial recesses 922 may be disposed on the actuator gear 918, arranged to accommodate the opening of various combinations of the flexible valves 900. (One of the radial recesses 922 may be disposed to engage a single flexible valve 900, and two or more radial recesses 922 may be disposed separately to simultaneously open two or more flexible valves 900 for coordinated operation.)

[0156] The flexible valve 900 may be provided with a generally planar sliding contact 924 to slide along the lower surface 920 as the flexible valve 900 rotates. The sliding contact 924 may be integrally formed with the leaf spring 914, for example, from a single bent piece of metal. As will be appreciated by those skilled in the art, the sliding contact 924 may be omitted if the lower surface 920 interference-engages with the boss 916 and / or flexible body 902 to cause a corresponding deflection of the flexible valve 900.

[0157] As shown in FIG. 134, to allow a reversible transition between the lower surface 920 and the radial recesses 922, a ramp 926 may be disposed at a radial end of each radial recess 922 to allow a gradual, rather than stepwise, transition between the lower surface 920 and the radial recesses 922. Each radial recess 922 may be provided with a ceiling 928 to limit the upward movement of the flexible valve 900. As shown in FIG. 135, the ceiling 928 is preferably disposed to limit the flexible valve 900 from fully returning to an unbiased rest state. This allows the flexible valve 900 to press into engagement with the respective ceiling 928. For each radial recess 922, the ramp 926 may be defined as a ramp extending between the corresponding ceiling 928 and the lower surface 920.

[0158] As shown in FIG. 118A, the actuator gear 918 may be provided with teeth 930 formed to mesh with a worm gear 932. The worm gear 932 may be rotatably, preferably reversibly, driven by a motor to allow reversible rotation of the actuator gear 918. The motor may be the same motor that drives the pump 18 and / or the gear plate 510. FIG. 118B shows an alternative configuration of the actuator gear 918 engaging the worm gear 932. As shown as a block connection, the actuator gear 918 meshes with the worm gear 932 in a similar manner as shown in FIG. 118A.

[0159] As shown in FIG. 119, multiple flexible valves 900 may be radially aligned to overlap the actuator gear 918. This allows the actuator gear 918 to selectively engage the multiple flexible valves 900 to selectively open and close the flexible valves 900. The configuration of the lower surface 920 and the radial recesses 922 allows for various configurations that may open and close the flexible valves 900. For example, as shown in FIG. 134, a first actuator gear 918A having three radial recesses 922 circumferentially spaced apart at the periphery of the lower surface 920 may be utilized, while a second actuator gear 918B having a single radial recess 922 may be utilized. Furthermore, the radial length of the radial recesses 922 allows multiple flexible valves 900 to be simultaneously open. For example, as shown in the first actuator gear 918A, one of the radial recesses 922A has a radial length sufficient to span two flexible valves 900. As shown in FIG. 118A, the first actuator gear 918A and the second actuator gear 918B are meshed with a first worm gear 932A and a second worm gear 932B, respectively, to allow independent control thereof. This provides additional versatility in regulating the flow of fluid. FIG. 118A shows the first worm gear 932A and the second worm gear 932B disposed generally parallel on either side of the first actuator gear 918A and the second actuator gear 918B. As will be understood by those skilled in the art, the first worm gear 932A and the second worm gear 932B may be disposed in various positions. For example, as shown in FIG. 118B, the first worm gear 932A and the second worm gear 932B may be disposed along intersecting directions and / or adjacent to each other.

[0160] 132 and 133 show the leaf springs 914 stacked on the first actuator gear 918A and on the second actuator gear 918B. As shown, the amount of leaf springs 914 associated with each of the first actuator gear 918A and the second actuator gear 918B may be different, such that a different amount of the flexible valve 900 may be controlled by each.

[0161] The flexible valves 900 may be supported by a valve module 934, as shown in FIG. 119. On the valve module 934, the first set of valves 900A may be radially aligned with the actuator gear 918A, and the second set of valves 900B may be radially aligned with the actuator gear 918B. The leaf springs 914 of each of the first set of valves 900A and the second set of valves 900B may radiate from a central disk 936 (936A, 936B) attached to a central post 938 (938A, 938B). The leaf springs 914 and the corresponding central disks 936A, 936B may be integrally formed from a single piece, such as stamped metal. The first actuator gear 918A and the second actuator gear 918B are attached to the central posts 938A, 938B, respectively, so as to be rotatable about the central posts 938A, 938B.

[0162] As shown in Figures 121A-131, the valve module 934 is preferably formed as a multi-layer structure having various passages defined therein. As shown in Figure 131, the valve module 934 may be a four-layer structure having a top layer 934A, a first middle layer 934B, a second middle layer 934C, and a base layer 934D. The top layer 934A includes a number of openings 940, each corresponding to one of the flexible valves 900. As shown in Figure 119, a boss portion 916 may extend through the openings 940 for engaging the leaf spring 914.

[0163] As shown in FIGS. 121A-121B, the flexible body 902 of each of the flexible valves 900 is exposed through a respective one of the openings 940. As shown in FIGS. 135-136, the top layer 934A overlies the first middle layer 934B. The edge 904 of each flexible valve 900 is preferably sandwiched between and secured therebetween the top layer 934A and the first middle layer 934B. A notch 935 may be formed in the top layer 934A and / or the first middle layer 934B to accommodate the edge 904. Each of the notches 935 may be annular and disposed to surround a respective opening 940. The edge 904 may be secured by friction fit, welding, adhesive, fusion, or the like.

[0164] As shown in FIGS. 122A-123B, the wells 937 may be defined in the first intermediate layer 934B in one-to-one correspondence and alignment with the openings 940. As shown in FIGS. 135 and 136, the sealing surface 912 of each flexible valve 900 is defined on the lower surface 939 of the corresponding well 937. As described above, the sealing surface 912 may be elevated from the lower surface 939 (see FIG. 122B). Alternatively, as shown in FIG. 122A, the sealing surface 912 may be approximately flush with the lower surface 939. Additionally, the openings 908 may be formed in the first intermediate layer 934B to extend from each of the wells 937 to the lower surface 941 of the first intermediate layer 934B. Additionally, for each of the wells 937, a secondary opening 943 is formed to extend from the corresponding lower surface 939 to the lower surface 941.

[0165] As shown in FIGS. 125-130, the second intermediate layer 934C may be a plated shape having an upper surface 942 and an opposing lower surface 944. A first fluid channel 946A may be formed in the upper surface 942 to define a flow path. The first fluid channel 946A may extend from a first opening 948A formed in an edge 950 of the second intermediate layer 934C and terminate at a location axially aligned with the well 937. Thus, as shown in FIG. 124, a first intermediate layer 934B may be provided on the second intermediate layer 934C to define a closed flow path from a location along the edge 950 to the various wells 937. For example, as shown in FIG. 124, a first fluid channel 946A1 extends from a first opening 948A1 and terminates in alignment with an opening 908A of the well 937A. The interface between the opening 908A and the first fluid channel 946A1 is defined in the lower surface 941 of the first middle layer 934B.

[0166] Further, a second fluid channel 946B may be formed in the lower surface 944 to define a flow path. Further, one or more through holes 952 may be formed in the second middle layer 934C to extend between the upper surface 942 and the lower surface 944. The through holes 952 allow vertical flow through the second middle layer 934C. The second fluid channel 946B may extend from a second opening 948B formed in the edge 950. As shown in FIG. 125, the first opening 948A is formed in the edge 950 along the upper surface 942, and the second opening 948B is formed in the edge 950 along the lower surface 944. The base layer 934D covers the second fluid channel 946B to define a closed fluid path (flow path) through the second fluid channel 946B.

[0167] As shown in FIG. 124, pairs of first fluid channels 946A, second fluid channels 946B, and / or through-holes 952 may be aligned with each well 937 such that the flexible valves 900 can selectively control flow therebetween. The openings 908 and secondary openings 943 of each flexible valve 900 are aligned with the first fluid channels 946A and / or through-holes 952 to control flow therebetween. When each of the flexible valves 900 is open (as shown in FIG. 135), the corresponding openings 908 and corresponding secondary openings 943 in the corresponding wells 937 are unobstructed, allowing flow therebetween. When the flexible valves 900 are closed (as shown in FIG. 136), the corresponding openings 908 are blocked, restricting flow through the corresponding wells 937. FIGS. 137 and 138 show the flow paths to the flexible valves 900.

[0168] The flexible valve 900 can be selectively opened and closed to control flow between the first fluid channel 946A and the second fluid channel 946B. The through-hole 952 allows communication with the second fluid channel 946B and regulates flow through the second fluid channel 946B. For example, as shown in FIG. 124, the through-hole 952A can be aligned with the secondary opening 943A of the well 937A. The through-hole 952A then extends to the second fluid channel 946B1, which extends to the through-hole 952B and is aligned with the secondary opening 943B of the well 937B. The first fluid channel 946A2 can extend from the first opening 948A2 to the opening 908B. The circuit allows selective flow between first openings 948A1, 948A2 by opening and closing flexible valves 900 associated with wells 937A, 937B.

[0169] The valve module 934 may be formed as a monolithic structure with multiple layers of the valve module 934 bonded or secured together. Each layer of the valve module 934 is preferably plate-like with substantially parallel opposing faces. All features formed on each layer are preferably recessed into the face (i.e., do not protrude from the face). This allows for stacking with full face engagement between the layers. This allows for a liquid-tight seal around the flow path. The layers of the valve module 934 may be formed of polymeric and / or metallic materials and may be stacked and joined by any known means, including, but not limited to, bonding, gluing, fusing, and mechanical fastening (e.g., interlocking elements, fasteners, etc.). The layers of the valve module 934 may be formed with features defined in the layers (e.g., by molding, 3D printing) and / or may be formed as a plate-like blank and then processed by material removal to define the features (e.g., by milling, drilling, laser cutting, etching, etc.). Additionally, while the valve module 934 is described with four layers, one skilled in the art will appreciate that a varying amount of layers may be utilized in which the above-mentioned features are partially or entirely formed. For example, a third intermediate layer may be provided that defines additional fluid channels and / or through holes, thereby allowing for additional three-dimensional variability (e.g., allowing fluid paths to be formed without intersecting).

[0170] As will be appreciated by those skilled in the art, flexible valve 900 may be configured to adjust flow control over various flow paths to achieve various functions. For example, as described above, flexible valve 900 may be used within drug delivery device 10 to regulate flow between reservoir 26, pump 18, and needle 15 to allow reconstitution (with or without circulation) and drug delivery to a patient.

[0171] As mentioned above, the flexible valves 900 may be provided in various quantities as separately controlled subsets to allow for separate but coordinated control. For example, as mentioned above, with the first actuator gear 918A and the second actuator gear 918B, the first set of six valves 900A are controlled separately from the second set of three valves 900B. FIG. 139C is a view similar to FIG. 124, but marked to show a schematic possible arrangement of the first set of valves 900A and the second set of valves 900B, with each valve individually labeled (900A1-900A6 and 900B1-900B3). This configuration allows operation as a multi-position type valve, such as the control valve CV, secondary valve SV, and primary valve PV described above in connection with FIGS. 90-94.

[0172] For example, referring to Figures 94A and 94B, a first set of valves 900A and a second set of valves 900B can be used as a control valve CV, a second control valve CV2, and a third control valve CV3. In particular, the first set of valves 900A (900A1-900A6) can function as a combined second control valve CV2 and a third control valve CV3. The second set of valves 900B (900B1-900B3) can function as a control valve CV. Figures 139A and 139B show schematic diagrams of the first set of valves 900A and the mechanisms by which they are fluidly coupled. Additionally, the first actuator gear 918A is shown diagrammatically with "clock hand" indicia representing radial recesses 922 that allow for both connections between valves 900A that are spaced 180 degrees apart (e.g., between valves 900A2 and 900A3) and connections between adjacent valves 900A (e.g., between valves 900A5 and 900A1 and between valves 900A4 and 900A6). Figure 134 shows the radial recesses 922 in an arrangement on the first actuator gear 918A that allows for the "clock hand" connections shown in Figure 139A.

[0173] The placement of the first set of valves 900A1 may form a first fluid channel 946A and a second fluid channel 946B in the second intermediate layer 934C, as shown in Figures 139D and 139E. Figures 139D and 139E are similar to Figures 129 and 130, but are marked to show the fluid connections with the first set of valves 900A and the second set of valves 900B, as well as with various features of the drug delivery device 10. Note further that fluid connections are made to and from the pump 18. The pump 18 is unidirectional, so that flow may be directed in one direction throughout the system, for example, through a closed loop in which the pump 18 is placed. This is slightly different from the configuration shown in Figures 94A and 94B. The first set of valves 900A are arranged as shown in Fig. 139D and Fig. 139E, and in relation to Fig. 94, the diluent is first drawn from the reservoir 26j through the secondary valve SVd and passed through the pump 18. The diluent may be directed through a fluid channel via the control valve CV to the second set of valves 900B and delivered to the target reservoir 26. The pump 18 may then draw the mixture from the target reservoir 26 through the pump 18 and direct it to the mixing vessel (mixing chamber) MC. The pump 18 may draw the mixture from the mixing vessel MC and direct the flow towards the needle 15 to deliver to the patient. In all, this process requires three passes through the pump 18. This process may be modified to increase the number of passes through the pump 18, for example for circulation of the drug mixture. Rotational adjustment of the first actuator gear 918A selectively opens the valves 900A1-900A6 to allow the flow to achieve the desired treatment. Note that the flow may not be continuous, but rather at a fixed rate. It is desirable to keep the diameter of the fluid channels to a minimum to best ensure that the suction created by pump 18 can adequately draw in fluid as needed, while avoiding compressibility issues with pockets of air or other residual gas.

[0174] As shown in Fig. 140A-B, the second set of valves 900B (900B1-900B3) can selectively direct flow to additional valves such as second control valves SVa, SVb, SVc to one or more target reservoirs 26. As shown in Fig. 134, the second actuator gear 918B can be formed with one of the radial recesses 922, which allows each of the valves 900B1-900B3 to be individually selected, as represented by the single "clock hand" in Fig. 140A. The second set of valves 900B can perform the function of the control valve CV shown in Figs. 94A and 94B. Fig. 139D shows possible flows between the first set of valves 900A and the second set of valves 900B.

[0175] The valve module 934 may be provided as a stand-alone element that can be coupled to adjacent elements as part of the drug delivery device 10. As shown in Figs. 141-148B, the valve module 934 may be integrally formed with a part of the drug delivery device 10, such as being coupled to or integrally formed with a part of the body 12. As shown in Figs. 142 and 147, the actuator gear 918 (918A, 918B) may be disposed inside the valve module 934 so as to be completely contained within the drug delivery device 10. In this manner, as shown in Figs. 148A-148B, the flexible valve 900 may be configured to bend downward (toward the inside) when opening (see Fig. 148B). The valve module 934 may be formed in multiple layers as described above, and the first fluid channel 946A and / or the second fluid channel 946B are in fluid communication with one or more of the fluid duct 22 and / or the outlet duct 25. The diluent reservoir 26j may be provided in a form similar to that shown in and described in connection with FIG. 104 so as to cover a portion of the body 12 including the valve module 934. A printed circuit board 1000 or the like may also be provided so as to cover a portion of the body 12. The printed circuit board 1000 may provide electrical connections between the various components and support elements (e.g. control elements (EEPROM, microcontroller, etc.)) and / or power storage regulation elements (for power storage, voltage regulation, etc.). The stacked arrangement of multiple elements provides a compact profile for the drug delivery device 10.

[0176] Figure 142 shows the drug delivery device 10 of Figure 141 but with the reservoir 26j removed. Figure 143 shows the drug delivery device 10 of Figure 141 but with the reservoir 26j removed and the barrier 102 removed from the body 12. Figure 144 shows a see-through view of Figure 143 to show the internal passageways.

[0177] 145 and 146 show a valve module 934 that can be used in the drug delivery device 10 of FIG. 141. As shown, the multi-layer structure of the valve module 934 provides rigidity to the valve module 934. Elements such as the control 20, the pump 18, and one or more motors may be attached to the valve module 934 such that they are supported by the valve module 934. This allows for pre-assembly and post-assembly to form the drug delivery device 10.

[0178] Referring to Fig. 146, the flow paths formed by the fluid ducts 22 between the first and second set of valves 900A and 900B described above and the reservoir 26 are configured in a valve module 934 as shown diagrammatically in Figs. 91-94. The reservoir 26 is not shown in Fig. 146, but the locations of the valve arrangement (primary valves PV and secondary valves SV) used to control flow to and from the reservoir 26 are marked. These locations within the drug delivery device 10 may be formed as valve seats, as described above.

[0179] As will be appreciated by those skilled in the art, the valve module 934 may be formed in various configurations (including footprints) to cover and provide fluidic connections between various components of the drug delivery device 10. FIGS. 149-155 show alternative exemplary embodiments of the valve module 934. As shown in FIG. 151, the valve module 934 may be configured to cover the diluent reservoir 26j formed as a low-profile foldable reservoir as described above, the first actuator gear 918A and the second actuator gear 918B, the mixing vessel MC, and the pump 18. As shown in FIGS. 152-154, the valve module 934 may define a fluid duct 22 for fluidly connecting the components as described above. As shown in FIG. 155, one or more fluid ducts may be defined by a tube (fluid duct) 22′.

[0180] 156-167 show an exemplary fluid flow of the drug delivery device 10 according to the above description. FIG. 156-159 show fluid being drawn from the reservoirs under negative pressure of the pump 18. FIG. 156-157 show fluid being drawn from the reservoirs 26a, 26b, 26c through the secondary valve SVa, the second set of valves 900B3, and the first set of valves 900A4 into the pump 18. As shown in FIG. 158, fluid can be drawn from the reservoirs 26d, 26e, 26f into the pump 18 through the secondary valve SVc, the second set of valves 900B1, and the first set of valves 900A4. Additionally, as shown in FIG. 159, fluid can be drawn from the reservoirs 26g, 26h, 26i into the pump 18 through the secondary valve SVb, the second set of valves 900B2, and the first set of valves 900A4. As mentioned above, the use of primary valves (PVa-PVi) can control the flow from the individual reservoirs. Figure 160 shows that fluid (diluent) is drawn from the diluent reservoir 26j to the pump 18 via fluid duct 22', secondary valve SVd and a first set of valves 900A5.

[0181] As shown in FIG. 161, fluid may be drawn from the mixing vessel MC to the pump 18 through a first set of valves 900A2.

[0182] 156-161 show the flows on the negative or suction side of the pump 18. In other words, all of these flows are drawn into the pump 18. Once drawn into the pump 18, the fluid can be forced to a target location under the positive pressure of the pump 18 as directed by the adjusted valves. For example, FIG. 162 shows fluid being forced from the pump 18 through the first set of valves 900A1 into the mixing vessel MC. Thus, by combining any of the fluid flows in FIG. 156-160 with the flows in FIG. 162, fluid can be drawn from any of the reservoirs 26a-26i and the diluent reservoir 26j and forced into the mixing vessel MC.

[0183] The pump 18 may also push fluid into any of the reservoirs 26a-26i. For example, as shown in Figs. 163-164, fluid may be pushed from the pump 18 through the first set of valves 900A3, the second set of valves 900B, and the secondary valve SVa into any of the reservoirs 26a, 26b, and 26c. Similarly, fluid may be pushed from the pump 18 (through the first set of valves 900A3, the second set of valves 900B1, and the secondary valve SVc) into any of the reservoirs 26d, 26e, and 26f (see Fig. 165), and (through the first valve 900A3, the second set of valves 900B2, and the secondary valve SVb) into any of the reservoirs 26g, 26h, and 26i (see Fig. 166). Thus, by combining the fluid flows of any of Figures 163-166 with the fluid flows of Figure 161, fluid may be drawn from mixing vessel MC and forced into any of reservoirs 26a-26i, for example to facilitate circulation of drug as described above. Additionally, primary valves PVa-PVi may be utilized to control flow to the individual reservoirs.

[0184] The flows as described above allow access to the drug and diluent while mixing and circulating as needed. When the drug is ready to be administered, it may be drawn into the pump 18 and forced from the pump 18 through a first set of valves 900A6 and fluid ducts 22' into the needle 15 as shown in FIG. 167. The needle 15 is utilized to deliver the drug to the patient.

[0185] Figures 168-172 show examples of complete flows, each showing pump 18 pulling from an initial position and pushing to a target position. Figure 168 shows diluent being pulled from diluent reservoir 26j and pushed into one of reservoirs 26a, 26b, or 26c. This allows for the introduction of diluent as a first step if the drug is initially in solid or slurry form in either reservoir. Similar flows can be used to supply diluent to any of reservoirs 26d-26i.

[0186] Fig. 169 shows how fluid is drawn from one of the reservoirs 26a, 26b, 26c and forced into the mixing vessel MC. A similar flow can be used to draw fluid from one of the reservoirs 26d-26i and force it into the mixing vessel MC.

[0187] Figure 170 shows the reverse flow to Figure 169. In the flow of Figure 170, fluid is drawn from the mixing vessel MC and forced into one of the reservoirs 26a, 26b, or 26c. Again, a similar flow can be used to draw fluid from the mixing vessel and pump the fluid into one of the reservoirs 26d-26i.

[0188] 171 shows fluid being drawn from one of reservoirs 26a, 26b, 26c and forced into needle 15, ready for administration of the drug. A similar flow can be used to draw fluid from one of reservoirs 26d-26 and force it into needle 15.

[0189] Fig. 172 shows fluid (diluent) being drawn from the diluent reservoir 26j and forced into the needle 15. This allows flushing of the fluid duct 22' leading to the needle 15 and the needle 15 itself. This also allows priming to be established if required.

Claims

1. A body having a plurality of fluid ducts and at least one outlet duct formed in the plurality of fluid ducts, A plurality of drug cartridges attached to the body, each of the plurality of drug cartridges having a reservoir for containing at least one drug, The first drug cartridge has a fluid outlet, The first fluid duct is aligned to extend from the fluid outlet, A seal adjustable between a first state in which the fluid outlet is sealed and a second state in which the fluid outlet is not sealed is formed by a seal sheet joined to a seal surface, selectively sealing the fluid outlet, The seal sheet is fixed to a movable seal element, Displacement of the movable seal element causes the seal sheet to peel from the seal surface, causing the seal to displace from the first state to the second state. A drug delivery device.

2. The movable seal element has a plurality of open passages aligned with the fluid outlet when the seal is in the second state, the drug delivery device according to claim 1.

3. The plurality of open passages are provided at a plurality of radial positions around the movable seal element, the drug delivery device according to claim 2.

4. The movable seal element is displaced in response to pressure applied to the movable seal element, the drug delivery device according to claim 1.

5. The movable seal element is initially housed within a well, and the seal surface is disposed around the well, the drug delivery device according to claim 1.

6. The drug delivery device according to claim 5, wherein the movable seal element protrudes from the well, causing the seal sheet to peel off from the seal surface. **Claim 7** The drug delivery device according to claim 5, wherein the fluid outlet has a flaring portion communicating with the inside of the well and a tapered portion communicating with the outside of the well. **Claim 8** The drug delivery device according to claim 1, wherein the seal sheet is a thermoplastic film.

Images