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

Abstract

Provided herein is a method for making a drug delivery device, the drug delivery device comprising a body having at least one fluid duct for carrying a drug from at least one reservoir to a needle for injection into a patient, the at least one fluid duct being open along a first surface of the body, the method comprising the steps of providing an ultraviolet light-permeable barrier over the entire first surface of the body to at least cover the at least one fluid duct, and exposing the first surface of the body to ultraviolet light so that the ultraviolet light can pass through the barrier to decontaminate the at least one fluid duct.

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 a manufacturing facility, and the sterilized equipment is packaged, for example in a pouch, to maintain sterility until the time of use. Separately, drugs are prepared, maintained in a sterile state, and introduced into the drug delivery device at the time of use.

[0003] Prior art has also developed techniques for producing pre-filled drug delivery devices. These types of drug delivery devices are pre-loaded with drugs at the manufacturing facility and packaged as a single combination product, where the device and drug are sterilized as a single unit (called terminal sterilization) and remain sterile until the time of use. However, most drugs, especially proteins, cannot withstand terminal sterilization conditions, so this approach has limited application.

[0004] Finally, in the prior art, another technique has also been developed for making pre-filled drug delivery devices. In this technique, the drug delivery device is sterilized, a sterile drug is prepared separately, and the drug is filled into a pre-sterilized container using aseptic techniques, which is then loaded into the drug delivery device, and the drug delivery device and container are separately maintained in a sterile state. However, in order to maintain the sterility of the drug and fluid pathways in the drug delivery device, a sterile fluid connection must be made between the drug delivery device and the container. The present invention provides a novel means for achieving a sterile connection step in a non-sterile environment, which can be achieved either during assembly by the manufacturer or immediately before use.

[0005] Additionally, additional pharmaceutical preparation steps may be required at the time of use, such as reconstitution of a dry pharmaceutical. The present invention provides a novel means to accomplish the reconstitution process immediately prior to use.

[0006] 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 drugs from a single injection device. The present invention provides an apparatus that can be loaded with one or more drugs in the ratios prescribed for that particular patient in ready-to-use liquid or reconstituted solid form (e.g., freeze-dried, spray-dried dispersion, spray-freeze-dried), suspension, or combinations thereof, and can reconstitute the dry drugs and automatically administer these drugs in sequence to the patient. Summary of the Invention

[0007] In one aspect, provided herein is a method of making a drug cartridge containing a lyophilized drug, the method comprising the steps of: providing a storage component having a rigid cartridge support and a collapsible and deformable reservoir for containing one or more drug components, the cartridge support having a fill port defining an open passageway to the reservoir, the fill port having a tapered portion that converges toward the reservoir to define a reduced diameter opening; filling the reservoir with one or more liquid drug components through the fill port; and providing a plug adapter configured for attachment to the storage component, the plug adapter having a fluid outlet and a narrow end extending to a neck end. the one or more liquid drug components in the reservoir are freeze-dried, and after the one or more liquid drug components have been freeze-dried, the neck portion is further inserted into the fill port to a vent-closed position in which the neck end is received in the reduced diameter opening.

[0008] In a further aspect, there is provided herein a method of making a drug cartridge containing a lyophilized drug, the method comprising the steps of providing a storage component having a rigid cartridge support and a collapsible and deformable reservoir for containing one or more drug components, the cartridge support having a fill port defining an open passageway to the reservoir, the fill port having an inner surface with at least one vent passageway formed therein; filling the reservoir with one or more liquid drug components through the fill port; providing a plug adapter configured for attachment to the reservoir component, the plug adapter having a fluid outlet and an elongated neck extending to a neck end, the plug adapter having at least one seal formed on an outer surface of the neck and configured to have an internal lumen extending from the fluid outlet through the neck; inserting the neck into the fill port to a vent-open position in which the at least one seal is not located between the at least one vent passage and the reservoir; exposing the one or more liquid drug components in the reservoir to lyophilization conditions with the neck in the vent-open position to lyophilize the one or more liquid drug components; and after the one or more liquid drug components are lyophilized, further inserting the neck into the fill port to a vent-closed position in which the at least one seal is located between the at least one vent passage and the reservoir.

[0009] In yet another aspect, there is provided herein a method of making a drug delivery device, the method comprising the steps of pre-filling a reservoir of at least one drug cartridge with one or more drug components, the drug cartridge having a fluid outlet and a lumen for conveying the one or more drug components from the reservoir to the fluid outlet; sterilizing the lumen of the drug cartridge; forming a seal across the sterilized lumen to limit the ingress of contaminants; and locating the fluid outlet in a fluid duct formed in a body of the drug delivery device. the steps of assembling the pre-filled drug cartridge to the body so that the sterile lumen is isolated from the fluid outlet by the seal and the fluid duct extends from the fluid outlet to an opening in the first surface of the body; providing an ultraviolet light-permeable barrier over the entire first surface of the body to cover at least the opening; and exposing the first surface of the body to ultraviolet light so that ultraviolet light can pass through the barrier and decontaminate the fluid duct and the fluid outlet through the opening.

[0010] In still yet another aspect, there is provided herein a method of making a drug delivery device, the method comprising the steps of pre-filling a reservoir of at least one drug cartridge with one or more drug components, the drug cartridge having a fluid outlet and a lumen for conveying the one or more drug components from the reservoir to the fluid outlet; sterilizing the lumen of the drug cartridge; forming a seal across the sterilized lumen to limit the ingress of contaminants; and connecting the fluid outlet to a fluid duct formed in a body of the drug delivery device. the pre-filled drug cartridge being assembled into the body such that the sterile lumen is isolated from the fluid outlet by the seal and the fluid duct extends from the fluid outlet to an opening in the first face of the body; providing an electron beam permeable barrier over the entire first face of the body to cover at least the opening; and exposing the first face of the body to the electron beam such that the electron beam can pass through the barrier to decontaminate the fluid duct and the fluid outlet.

[0011] In another aspect, provided herein is a method of making a drug delivery device, the method comprising: providing a storage component including a reservoir for containing one or more drug components and a fill port defining an open passageway to the reservoir; filling the reservoir with one or more drug components through the fill port; providing a plug adapter configured for attachment to the storage component, the plug adapter having a fluid outlet and a lumen extending from the fluid outlet; sterilizing the lumen of the plug adapter; forming a seal on the plug adapter within the lumen to limit ingress of contaminants, the sterilized lumen being isolated from the fluid outlet by the seal; and after forming the seal on the plug adapter, attaching the plug adapter to the storage component in forming a drug cartridge. The method includes the steps of: attaching the plug adapter such that a portion of the sterilized lumen extends through the fill port and communicates with the reservoir; assembling the drug cartridge to the body of the drug delivery device such that the fluid outlet is aligned with a fluid duct formed in the body, the fluid duct extending from the fluid outlet to an opening in the first surface of the body; providing an ultraviolet-permeable barrier over the entire first surface of the body to cover at least the opening; and exposing the first surface of the body to ultraviolet light so that ultraviolet light can pass through the barrier and decontaminate the fluid duct and the fluid outlet through the opening.

[0012] In yet another aspect, provided herein is a method of making a drug delivery device, the method comprising the steps of: providing a storage component including a reservoir for containing one or more drug components and a fill port defining an open passageway to the reservoir; filling the reservoir with one or more drug components through the fill port; providing a plug adapter configured for attachment to the storage component, the plug adapter having a fluid outlet and a lumen extending from the fluid outlet; sterilizing the lumen of the plug adapter; forming a seal on the plug adapter within the lumen to limit ingress of contaminants, the sterilized lumen being isolated from the fluid outlet by the seal; and after forming the seal on the plug adapter, attaching the drug cartridge to the plug adapter. the plug adapter is attached to the reservoir component when forming a ridge, the plug adapter being attached such that a portion of the sterilized lumen extends through the fill port and communicates with the reservoir; assembling the drug cartridge to the body of the drug delivery device such that the fluid outlet is aligned with a fluid duct formed in the body, the fluid duct extending from the fluid outlet to an opening in a first surface of the body; providing an electron beam permeable barrier over the entire first surface of the body to cover at least the opening; and exposing the first surface of the body to the electron beam such that an electron beam can pass through the barrier and decontaminate the fluid duct and the fluid outlet through the opening.

[0013] In yet another aspect, provided herein is a method of making a drug delivery device, the drug delivery device comprising a body having at least one fluid duct for carrying a drug from at least one reservoir to a needle for injection into a patient, the at least one fluid duct being open along a first side of the body, the method comprising providing an ultraviolet light-permeable barrier over the entire first side of the body to at least cover the at least one fluid duct, and exposing the first side of the body to ultraviolet light such that the ultraviolet light can pass through the barrier to decontaminate the at least one fluid duct.

[0014] In another aspect, provided herein is a method of making a drug delivery device, the drug delivery device comprising a body having at least one fluid duct for carrying a drug from at least one reservoir to a needle for injection into a patient, the at least one fluid duct being open along a first side of the body, the method comprising the steps of providing an electron beam permeable barrier over the entire first side of the body to at least cover the at least one fluid duct, and exposing the first side of the body to an electron beam such that the electron beam can pass through the barrier to decontaminate the at least one fluid duct.

[0015] Any of the above-mentioned methods of making a drug delivery device may be modified to utilize pulsed light for decontamination instead of ultraviolet light or an electron beam, using a barrier configured to transmit the pulsed light. In other words, a drug delivery device may be made in the same manner as any of the above-mentioned methods, except for the use of pulsed light to cause decontamination (utilizing a pulsed light permeable barrier).

[0016] Advantageously, the present invention provides a drug cartridge that is compatible with lyophilization.

[0017] Also, advantageously, the present invention allows for controlled sterilization of drug pathways after pre-loading of drug cartridges for drug delivery devices, separate from assembly, to limit adverse effects on the loaded drug, which may provide enhanced protection for biologics sensitive to radiation-based sterilization techniques.

[0018] 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).

[0019] 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).

[0020] 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.

[0021] 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.

[0022] 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).

[0023] 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.

[0024] 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]

[0025] [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. [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. [Diagram 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 oriented 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. [Diagram 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 mounted on 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. [Figure 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. [Fig. 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. [Figure 89B] FIG. 89B is a cross-sectional view of the drug cartridge of FIG. 89A. [Figure 90] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Figure 91] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Figure 92] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Figure 93] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Figure 94] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Figure 95] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Figure 96] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Figure 97] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Figure 98] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Figure 99] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Figure 100] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Figure 101]1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Figure 102] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Figure 103] 1 illustrates an alternative embodiment of a drug cartridge that can be used with a drug delivery device according to the present invention. [Figure 104] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Figure 105] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Fig. 106] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Figure 107] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Figure 108] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Fig. 109] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Figure 110] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Figure 111] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Figure 112] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Figure 113] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Fig. 114] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Figure 115] 1 illustrates a seal that can be used with a drug cartridge according to the present invention. [Fig. 116] 16 shows an actuator for opening the seal shown in FIGS. 104-115 according to the present invention. [Figure 117] 16 shows an actuator for opening the seal shown in FIGS. 104-115 according to the present invention. [Figure 118]16 shows an actuator for opening the seal shown in FIGS. 104-115 according to the present invention. [Figure 119] 16 shows an actuator for opening the seal shown in FIGS. 104-115 according to the present invention. [Figure 120] 16 shows an actuator for opening the seal shown in FIGS. 104-115 according to the present invention. [Figure 121] 16 shows an actuator for opening the seal shown in FIGS. 104-115 according to the present invention. [Figure 122] 16 shows an actuator for opening the seal shown in FIGS. 104-115 according to the present invention. [Figure 123] 16 shows an actuator for opening the seal shown in FIGS. 104-115 according to the present invention. [Figure 124] 16 shows an actuator for opening the seal shown in FIGS. 104-115 according to the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] 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.

[0027] 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.

[0028] 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).

[0029] 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 on 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. 90-91). 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.

[0030] 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.

[0031] 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.

[0032] 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).

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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 92-103, 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.).

[0044] 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 Figures 92-95, a fill port 38 may be provided in the upper portion 30A. Note that in Figure 94, 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. A lumen 36 is provided to extend from the reservoir 26 to the fluid outlet 34 and defines a flow path from the reservoir 26 to the fluid outlet 34. 90, 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, thereby reducing the footprint of the drug delivery device 10. The wings 27A of the reservoir section 14A may be tessellated such that when mounted to the body 12, there is substantially no gap between the reservoir section 14A and the body 12.

[0045] In the configuration of Figures 92-103, 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 proximate to the fill port 38. This allows the lumen 36 to be positioned above the majority of the reservoir 26 when the drug cartridge 14 is in an upright position for filling. This is preferred for lyophilization.

[0046] 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. 92 to 103, 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.

[0047] 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. 96, the filling port 38 may be provided with an adjustable vent plug 38A to facilitate lyophilization of the drug in the reservoir 26.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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).

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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 telescopic 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 placed 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] Alternatively, as shown in Figures 99-101, the vent plug 38A may be provided with a protruding bead 55 on its outer surface 46. The vent plug 38A may have a hollow portion 38B on its upper surface that 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 Figure 97, 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 around the protruding bead 55 spaced away 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. 98, 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. 102.

[0072] 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 position.

[0073] 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. 94) 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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 .

[0080] As shown in FIG. 95, 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.

[0081] 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. 104-115, a well 1900 may be formed in the wing 27A along the lumen 36. A movable seal element 1902 is provided located in the well 1900. The well 1900 is formed along the lumen 36 to block a fluid path therein to the fluid outlet 34. As shown in Fig. 107, the movable seal element 1902 protrudes from the first surface 27C of the wing 27A in the closed state. As shown in Figs. 108 and 110, 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. 112-114, 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. 115, 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.

[0082] 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 Figures 108-109, a drive actuator 1912 may be utilized to apply pressure to the movable seal element 1902 causing its displacement.

[0083] 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 seated within the sealing surface 1904.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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 seated 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 formed 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.

[0089] 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.

[0090] 67A, in a pre-use state, a proximal end 434 of delivery cannula 406 may be disposed in a hub channel 436. A proximal seal 438 may be provided to seal across a proximal end 440 of hub channel 436.

[0091] 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.

[0092] 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.

[0093] 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 .

[0094] 66, the pressing member 430 may be placed (housed) in a recess 448 formed in the body 12 so as to be immovably fixed relative to the body 12. The barrel 400 is displaced distally relative to the body 12, which allows the pressing 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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).

[0102] 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.

[0103] 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.

[0104] 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 .

[0105] 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 .

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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 90-91, 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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, if necessary, a diluent may be pumped through the fluid duct 22 to reconstitute the dry drug components (pharmaceutical components) in the drug cartridge(s) 14 and then extract the reconstituted liquid drug (liquid drug) using negative pressure.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

Claims

1. A method of manufacturing a drug delivery device, comprising: providing at least one drug cartridge having a reservoir, a fluid outlet, and a lumen that communicates the reservoir with the fluid outlet; sterilizing the lumen of the drug cartridge; filling the reservoir with one or more drug components through the sterilized lumen; forming a seal over the entire sterilized lumen to restrict ingress of contaminants; assembling the filled drug cartridge to the body of the drug delivery device such that the fluid outlet is aligned with a fluid duct formed in the body of the drug delivery device, wherein the sterilized lumen is isolated from the fluid outlet by the seal and the fluid duct extends from the fluid outlet to an opening in a first surface of the body; providing an ultraviolet transmissive barrier over the entire first surface of the body to cover at least the opening; exposing the first surface of the body to ultraviolet light such that the ultraviolet light can pass through the barrier and decontaminate the fluid duct and the fluid outlet; and a method comprising the steps of.

2. The seal is formed by an elastomeric valve, The method according to claim 1.

3. With the elastomeric valve forming the seal, most of the elastomeric valve is received within the sterilized lumen, The method according to claim 2.

4. The elastomeric valve is movable within the lumen to release the seal of the sterilized lumen and allow communication between the fluid duct and the reservoir, The method according to claim 3.

5. The elastomeric valve has a spool shape having a first enlarged land and a second enlarged land connected to each other by an elongated core, With the elastomeric valve forming the seal, the first enlarged land is received in a valve seat formed at the boundary between the fluid outlet and the inner cavity to form the seal, The method according to claim 4.

6. The inner cavity includes a first portion extending from the storage portion and a second portion disposed laterally with respect to the first portion, The valve seat is disposed at a first end in the second portion, A second end in the second portion is open, The second enlarged land is received between the first portion and the second end in the second portion so as to seal the sterilized inner cavity and limit the entry of contaminants from the second end, The method according to claim 5.

7. Even when the elastomeric valve moves to release the seal of the sterilized inner cavity, the second enlarged land continues to remain between the first portion and the second end, The method according to claim 6.

8. The body defines a second fluid duct extending from the opening and communicating with the opening, The second fluid duct is formed on the first surface of the body and covered by the barrier, The method according to claim 1.

9. The seal is formed by a removable film, The method according to claim 1.

10. The seal is formed by a perforable film, The method according to claim 1.

11. The seal is formed by a seal sheet joined to the seal surface, The seal sheet is separable from the seal surface, The method according to claim 1.

12. The barrier is a polymer film, The method according to claim 1.

13. The polymer film has a single layer, The method according to claim 12.

14. The polymer film has a plurality of layers, The method according to claim 12.

15. The polymer film includes one or more of a fluoropolymer, a fluoropolymer copolymer, a polyimide, a polymethylpentene, a silicone, a cyclic olefin copolymer, and a cyclic olefin polymer, The method according to claim 12.

16. A method for manufacturing a drug delivery device, providing at least one drug cartridge having a reservoir, a fluid outlet, and a lumen communicating the reservoir with the fluid outlet; sterilizing the lumen of the drug cartridge; filling the reservoir with one or more drug components through the sterilized lumen; forming a seal over the entire sterilized lumen so as to limit the entry of contaminants; assembling the filled drug cartridge to the body of the drug delivery device such that the fluid outlet is aligned with a fluid duct formed in the body of the drug delivery device, wherein the sterilized lumen is isolated from the fluid outlet by the seal and the fluid duct extends from the fluid outlet to an opening in a first surface of the body; Providing an electron beam transmissive barrier over the entire first surface of the body so as to cover at least the opening; Exposing the first surface of the body to an electron beam such that the electron beam can pass through the barrier to decontaminate the fluid duct and the fluid outlet; A method comprising the steps of. **Claim 17** The seal is formed by an elastomeric valve; The method according to claim 16. **Claim 18** With the elastomeric valve forming the seal, most of the elastomeric valve fits within the sterilized lumen; The method according to claim 17. **Claim 19** The elastomeric valve is movable within the lumen so as to release the seal of the sterilized lumen and allow communication between the fluid duct and the reservoir; The method according to claim 18. **Claim 20** The elastomeric valve has a spool shape with a first enlarged land and a second enlarged land connected to each other by an elongated core; With the elastomeric valve forming the seal, the first enlarged land is received in a valve seat formed at the boundary between the fluid outlet and the lumen to form the seal; The method according to claim 19. **Claim 21** The lumen includes a first portion extending from the reservoir and a second portion disposed laterally with respect to the first portion; The valve seat is disposed at a first end in the second portion; A second end in the second portion is open; The second enlarged land is received in the second portion between the first portion and the second end so as to seal the sterilized lumen and limit the entry of contaminants from the second end; The method according to claim 20.

22. Even if the elastomeric valve moves to release the seal of the sterilized inner cavity, the second enlarged land continues to remain between the first portion and the second end, The method according to claim 21.

23. The body defines a second fluid duct that extends from the opening and communicates with the opening, The second fluid duct is formed on the first surface of the body and is covered by the barrier, The method according to claim 16.

24. The seal is formed by a removable film, The method according to claim 16.

25. The seal is formed by a perforable film, The method according to claim 16.

26. The seal is formed by a seal sheet joined to the seal surface, The seal sheet is separable from the seal surface, The method according to claim 16.

27. The barrier is a polymer film, The method according to claim 16.

28. The polymer film has a single layer, The method according to claim 27.

29. The polymer film has a plurality of layers, The method according to claim 27.

30. The polymer film includes one or more of a fluoropolymer, a fluoropolymer copolymer, a polyimide, a polymethylpentene, a silicone, a cyclic olefin copolymer, and a cyclic olefin polymer. The method according to claim 27.

31. The electron beam is of low energy. The method according to claim 16.

32. A method for manufacturing a drug delivery device, comprising: providing a reservoir component including a reservoir for containing one or more drug components and a filling port defining an opening passage to the reservoir; filling the reservoir with one or more drug components through the filling port; providing a plug adapter configured to be attachable to the reservoir component, the plug adapter having a fluid outlet and a lumen extending from the fluid outlet; sterilizing the lumen of the plug adapter; forming a seal on the plug adapter within the lumen so as to limit the entry of contaminants, and isolating the sterilized lumen from the fluid outlet by the seal; after forming the seal on the plug adapter, attaching the plug adapter to the reservoir component when forming a drug cartridge, the plug adapter being attached such that a part of the sterilized lumen extends through the filling port and communicates with the reservoir; assembling the drug cartridge to the body such that the fluid outlet is aligned with a fluid duct formed in the body of the drug delivery device, the fluid duct extending from the fluid outlet to an opening in a first surface of the body; providing an ultraviolet-transmissive barrier over the entire first surface of the body so as to cover at least the opening; exposing the first surface of the body to ultraviolet light so that the ultraviolet light can pass through the barrier and decontaminate the fluid duct and the fluid outlet; A method comprising.

33. The seal is formed by an elastomeric valve; The method according to claim 32.

34. With the elastomeric valve forming the seal, most of the elastomeric valve fits within the sterilized lumen; The method according to claim 33.

35. The elastomeric valve is movable within the lumen so as to release the seal of the sterilized lumen and allow communication between the fluid duct and the reservoir; The method according to claim 34.

36. The elastomeric valve has a spool shape having a first enlarged land and a second enlarged land connected to each other by an elongated core; With the elastomeric valve forming the seal, the first enlarged land is received in a valve seat formed at the boundary between the fluid outlet and the lumen to form the seal; The method according to claim 35.

37. The lumen includes a first portion extending from the reservoir and a second portion disposed laterally with respect to the first portion; The valve seat is disposed at a first end in the second portion; A second end in the second portion is open; The second enlarged land is received between the first portion and the second end in the second portion so as to seal the sterilized lumen and limit the entry of contaminants from the second end; The method according to claim 36.

38. Even if the elastomeric valve moves to release the seal of the sterilized inner cavity, the second enlarged land continues to remain between the first portion and the second end. The method according to claim 37. **Claim 39** The body defines a second fluid duct that extends from the opening and communicates with the opening. The second fluid duct is formed on the first surface of the body and covered by the barrier. The method according to claim 32. **Claim 40** The seal is formed by a removable film. The method according to claim 32. **Claim 41** The seal is formed by a perforable film. The method according to claim 32. **Claim 42** The barrier is a polymer film. The method according to claim 32. **Claim 43** The polymer film has a single layer. The method according to claim 42. **Claim 44** The polymer film has a plurality of layers. The method according to claim 42. **Claim 45** The polymer film includes one or more of a fluoropolymer, a fluoropolymer copolymer, a polyimide, a polymethylpentene, a silicone, a cyclic olefin copolymer, and a cyclic olefin polymer. The method according to claim 42. **Claim 46** A method of manufacturing a drug delivery device, comprising: providing a reservoir component including a reservoir for containing one or more drug components and a filling port defining an open passage to the reservoir; Filling one or more drug components into the reservoir through the filling port; Providing a plug adapter configured to be attachable to the reservoir component, the plug adapter having a fluid outlet and a lumen extending from the fluid outlet; Sterilizing the lumen of the plug adapter; Forming a seal on the plug adapter within the lumen to limit ingress of contaminants, with the sterilized lumen being isolated from the fluid outlet by the seal; After forming the seal on the plug adapter, attaching the plug adapter to the reservoir component when forming the drug cartridge, with the plug adapter being attached such that a portion of the sterilized lumen extends through the filling port and communicates with the reservoir; Assembling the drug cartridge to the body such that the fluid outlet is aligned with a fluid duct formed in the body of the drug delivery device, with the fluid duct extending from the fluid outlet to an opening in a first surface of the body; Providing an electron beam transmissive barrier over the entire first surface of the body so as to cover at least the opening; Exposing the first surface of the body to an electron beam such that the electron beam can pass through the barrier and decontaminate the fluid duct and the fluid outlet; A method comprising.

47. The seal is formed by an elastomeric valve; The method according to claim 46.

48. With the elastomeric valve forming the seal, most of the elastomeric valve is contained within the sterilized lumen; The method according to claim 47.

49. The elastomeric valve is movable within the lumen to release the seal of the sterilized lumen and enable communication between the fluid duct and the reservoir. The method according to claim 48.

50. The elastomeric valve has a spool shape having a first enlarged land and a second enlarged land connected to each other by an elongated core. With the elastomeric valve forming the seal, the first enlarged land is received in a valve seat formed at the boundary between the fluid outlet and the lumen to form the seal. The method according to claim 49.

51. The lumen includes a first portion extending from the reservoir and a second portion disposed laterally with respect to the first portion. The valve seat is disposed at a first end in the second portion. A second end in the second portion is open. The second enlarged land is received in the second portion between the first portion and the second end so as to seal the sterilized lumen and limit the entry of contaminants from the second end. The method according to claim 50.

52. Even when the elastomeric valve moves to release the seal of the sterilized lumen, the second enlarged land continues to remain between the first portion and the second end. The method according to claim 51.

53. The body defines a second fluid duct extending from the opening and communicating with the opening. The second fluid duct is formed on the first surface of the body and covered by the barrier. The method according to claim 52.

54. The seal is formed by a removable film. The method according to claim 46.

55. The seal is formed by a perforable film, The method according to claim 46.

56. The barrier is a polymer film, The method according to claim 46.

57. The polymer film has a single layer, The method according to claim 56.

58. The polymer film has a plurality of layers, The method according to claim 56.

59. The polymer film includes one or more of a fluoropolymer, a fluoropolymer copolymer, a polyimide, a polymethylpentene, a silicone, a cyclic olefin copolymer, and a cyclic olefin polymer, The method according to claim 56.

60. The electron beam is of low energy, The method according to claim 46.

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