Injector and method of assembly

DESCRIPTION

INJECTOR AND ASSEMBLY METHOD

This patent is directed to an injector and in particular a pre-filled injector.

Injectors are used to deliver medical fluids, such as liquid drugs, to a patient. In particular, the injector will deliver the fluid to the patient through a needle, cannula or catheter that defines a flow path for the patient. Certain injectors have a producer-mounted reservoir already connected to the flow path. However, typically the producer supplies these empty reservoirs to the patient or health care professional (eg, physician, nurse, health care worker, etc.), and the reservoir is later filled when used. Alternatively, the injector may be used in combination with a reservoir that is pre-filled to the patient or healthcare provider.

In either case, the injector must be prepared before use. For example, if the reservoir is supplied empty then the reservoir will have to be filled. To do this, a syringe is filled with the drug to be administered, and thereafter the drug is injected into the reservoir through an inlet port. Prior to injection, the inlet port must be sterilized, for example by rubbing the outer surface with an alcohol cloth. Similarly, before connecting the pre-filled reservoir to the flow path in the reciprocating injector, the female connectors should be sterilized by wiping the surface with an alcohol cloth.

In each case, using the injector requires additional material and time. US 2004/133159 and WO 2010/029054 disclose injectors for medication administration.

As set forth in more detail below, the present disclosure discloses an improved injector incorporating advantageous alternatives to the conventional devices and methods discussed above.

The invention is defined in claim 1.

The container wall may be a rigid wall or a flexible wall.

According to any of the foregoing, the mechanical seal may be a unitary flexible wall having an inner surface defining the inner surface of the mechanical seal. The unitary flexible wall may define a septum disposed transversely of the aperture and fixedly attached to the container wall. Alternatively, the container wall may define a hole, and the flexible unit wall may define a movable lid along the hole. In this case, the container wall may define a closed end opposite the lid and an open end where the lid is arranged. The container wall may alternatively define a hole with an opening in continuous communication with a first end of the hole, and the flexible unit wall defining a septum disposed transversely to the opening and fixedly connected to the container wall, the container further comprising a cap disposed within a second end of the hole and movable along the hole.

In the alternative to the preceding paragraph, the mechanical seal may include a flexible wall with an inner surface defining the inner surface of the mechanical seal, and a clean barrier disposed outside the flexible wall to define a clean enclosed area between the flexible wall and the barrier. The end of the container needle is disposed through the clean barrier in the clean area in the state of storage. The container wall may define a hole, and the flexible wall and the clean barrier may each define a lid that is movable along the hole. Additionally, the container may include an opening in continuous communication with the area between the clean barrier and the flexible wall, the opening of which may be formed in the clean barrier or within the inner surface of the container wall. In addition, the container wall may define a closed end opposite the lids and an open end at which the lids are arranged. Alternatively, the container wall may define a hole with an opening in continuous communication with a first end of the hole, and the flexible wall and the clean barrier may each define a septum disposed transversely of the opening, the container further including a lid disposed within a second end of the hole and movable along the hole.

According to any of the foregoing, the fluid delivery system may include a flexible clean tubing connected at a first end to a rigid container needle and at a second end to a rigid injection needle received with a clean cover enclosing the flexible needle. rigid injection.

According to any of the foregoing, the actuator may be adapted to repeatedly move the container needle between the storage and dispensing states.

According to any of the foregoing, the actuator may be adapted to retard the movement of the container needle between the storage and dispensing states upon receipt of information.

According to any of the foregoing, the injector may include a mechanical, electromechanical, or electrical device coupled to the actuator.

According to any of the foregoing, the pharmaceutical product may include a volume of an erythropoiesis stimulating agent, a granulocyte colony stimulating factor, a TNF inhibitor, a pegylated granulocyte colony stimulating factor, a specific antibody against the interleukin, IGF receptor-specific antibody (insulin-like growth factor receptor), TGF-specific antibody, or PCSK9 specific antibody (subtilisin / quexin type 9 pro-protein convertase).

According to another aspect of the present disclosure, a method of mounting an injector may include filling a sterile container reservoir with a drug under sterile conditions, the reservoir being defined by an inner surface of a container wall and an inner surface of a mechanical seal. 0 The method may also include partially inserting the end of a clean, unsheathed rigid container needle through the mechanical seal under clean area conditions subsequent to filling the sterile container to define a storage state, and turning on the container needle. to an actuator in clean area conditions, the actuator being adapted to move the container needle from the storage state to the dispensing state wherein the container needle is disposed across the inner surface of the mechanical seal in the sterile reservoir.

According to this aspect, the container wall may be a rigid wall or a flexible wall.

It is believed that the disclosure will be better understood from the following description, taken into consideration with the accompanying schemes. Some of the figures may have been simplified by omitting selected elements to show other elements more clearly. Such omissions of elements in some figures are not necessarily indicative of the presence or absence of particular elements in any of the exemplary embodiments, except as may be explicitly outlined in the corresponding written description. None of the schemes is necessarily drawn to scale.

Fig. 1 is a cross-sectional view of an embodiment of an injector not according to the present invention with a rigid container needle drawn in a storage state, wherein the needle partially penetrates a unitary wall of the container;

Fig. 2 is a perspective view of a template used with the injector container of Fig. 1 for controlling the penetration of the unitary flexible wall of the container by the container needle;

Fig. 3 is a cross-sectional view of the injector of Fig. 1, with the container needle in a dispensing state wherein the needle penetrates the unitary wall of the container so that it is disposed across an inner flexible wall surface in a sterile reservoir. .

Fig. 4 is a schematic of a production facility where injectors according to the present disclosure may be filled and assembled.

Fig. 5 is a cross-sectional view of an alternative embodiment of an injector not according to the present invention with a rigid container needle unsheathed in a storage state, wherein the needle partially penetrates a unitary wall of the container.

Fig. 6 is a cross-sectional view of an embodiment of an additional alternative injector, not according to the present invention, with a rigid container needle unsheathed in a storage state, wherein the needle partially penetrates a unitary wall of the container.

Fig. 7 is a cross-sectional view of an injector embodiment according to the present disclosure with a rigid container needle in a storage state, wherein the needle partially penetrates a clean but not a flexible wall of a mechanical seal.

Fig. 8 is a cross-sectional view of an alternative embodiment of an injector according to the present disclosure with a rigid container needle in a storage state, wherein the needle partially penetrates a clean barrier, but not a flexible wall; of a mechanical seal.

Fig. 9 is a cross-sectional view of a variant of the embodiment of Fig. 8 including openings for evacuating a clean area between a flexible wall and an externally disposed clean barrier as an associated container needle moves between a state. storage and a distribution state.

Fig. 10 is a cross-sectional view of an additional variant of the embodiment of Fig. 8 including deviations to evacuate a clean area between a flexible wall and an externally disposed clean barrier as an associated container needle moves between a state of storage and a state of distribution;

Fig. 11 is a cross-sectional view of the container of Fig. 10 in an intermediate state, with the deviations in continuous communication with a clean area defined between a flexible wall and a clean barrier;

Fig. 12 is a schematic view of the additional container assembly and fluid delivery system that may be used to maintain aseptic conditions within the container;

Fig. 13 is a cross-sectional view of an injector according to a further embodiment of the present disclosure wherein aseptic conditions are maintained in a reservoir until actuation of the fluid delivery system;

Fig. 14 is a cross-sectional view of a variant of the injector shown in Fig. 13;

Fig. 15 is a cross-sectional view of an additional variant of the injector shown in Fig. 13; and

Fig. 16 is a flowchart illustrating a method of mounting an injector according to the present disclosure.

Generally speaking, an injector according to the present disclosure includes a container, a fluid delivery system and an actuator. Although reference is made to an injector, which in certain situations may refer to a dispensing device that ensures that a defined volume of pharmacological product is dispensed, it is understood that this disclosure further encompasses infusion devices, which in certain circumstances can refer to a dispensing device that ensures that a particular dispensing rate is reached. It should also be understood that the terms injector and infuser may be used interchangeably when referring to embodiments in the specification.

As illustrated in Figs. 1-3 and 5-11, the container may include a wall with an inner surface and a mechanical seal with an inner surface, the inner surfaces of the wall and the mechanical seal defining a sterile closed reservoir filled with a pharmaceutical product. In addition, the fluid delivery system illustrated in these embodiments may include a clean unsheathed rigid container needle having an end disposed only partially through the mechanical seal in a storage state, and disposed through the inner surface of the mechanical seal to the housing. sterile reservoir in a state of distribution. 0 The injector may also include an actuator that is adapted to move the container needle from the storage state to the dispensing state, which may involve movement of the needle relative to the container or container relative to the needle, as discussed in more detail. below.

As illustrated in Figs. 1, 3, and 4-6, the mechanical seal may be a flexible unit wall having an inner surface defining the inner surface of the mechanical seal, and the end of the container needle may be disposed partially on the unit wall. Alternatively, as illustrated in Figs. 7th 11, the mechanical seal may include a flexible wall with an inner surface defining the surface of the mechanical seal, and a clean barrier disposed outside the flexible wall to define a closed clean area between the flexible wall and the clean barrier. According to such embodiments, the end of the container needle is disposed through the clean barrier in the clean area in the state of storage.

Further alternatives will be discussed in the context of each of the embodiments illustrated herein.

Referring then to Fig. 1, an injector 100 is illustrated. The injector 100 includes a container 102, a fluid delivery system 104, and an actuator 106.

Container 102 (which may also be referred to herein as a cartridge) includes a wall 110 with an inner surface 112 and an outer surface 114. Although a unitary (ie, one-piece) wall 110 has been illustrated in Fig. 1 which defines both. inner and outer surfaces 112, 114, it will be understood that according to other embodiments, the wall 110 may include a plurality of layers, with different layers defining the inner and outer surfaces 112, 114.

According to certain embodiments of the present disclosure, wall 110 is rigid.

In other embodiments, wall 110 may be flexible, either according to the nature of the wall defining material or according to the nature of the wall structure (eg, a bellows construction). Wall 110 may be made, for example, of glass, metal, or polymer. In particular, polymer versions may be made, for example, of polycarbonate, polypropylene, polyethylene (such as high density polyethylene), polytetrafluoroethylene, cycloefin polymer, cycloefin copolymer, Crystal Zenith olefin polymer (available from through Daiko Seiko, Lda., Japan), nylon, or engineering resins. For flexible wall versions 110, butyl rubber, silicone based rubber, latex based rubber, covered rubber such as multi-layer polymer films may include polyethylene (such as low polyethylene). density) and propylene.

Wall 110 may be generally cylindrical in shape, with a shoulder 120 separating a first cylindrical section 122 having a first transverse diameter from a second cylindrical section 124 having a second transverse diameter, the first transverse diameter being smaller than the second. transverse diameter. Wall 110 may also define two opposite open ends, 126, 128. Wall 110, or more specifically the inner surface 112 of wall 110, may also define a hole 130.

Container 102 may include a unitary flexible wall 140 (which may also be referred to as a seal or septum) having an inner surface 142 and an outer surface 144. The wall 140 may be disposed at the first open end 126 defined by the wall 110 and be fixedly connected to the wall 110 of the container 102, so that relative movement between the wall 140 and the wall 110 is limited, e.g. from wall 140 to wall 110 along the open end or opening 126. In addition, interior surfaces 112, 142 of wall 110 and flexible wall 140 may define at least in part a sterile enclosed reservoir 150 which is filled with a drug product 160, described in more detail below. Wall 140 may be made, for example, of bromobutyl, chlorobutyl, or chlorobromobutyl rubber, fluoropolymer rubber, natural rubber, silicone-based rubber, silicone, or santoprene.

Container 102 may further include a cap or piston 170 with inner and outer surfaces 172, 174. Piston 170 may be received at end 128 defined by wall 110, and may be movable along bore 130 between ends 126, 128 of container 102. According to such an embodiment, the reservoir 150 into which the drug product 160 is disposed may be defined by the inner surfaces 112, 142, 172 of the walls 110, 140 and the piston 170.

The container 102 may be used in conjunction with the fluid delivery system 104, the relevant portions of which are illustrated in Fig. 1. In particular, the fluid delivery system 104 may include a clean, unsheathed rigid container needle 180 having an end 182. As illustrated, the end 182 is only partially disposed on the flexible wall 140 in a storage state. Penetration of end 182 of needle 180 into wall 140 may be controlled by a number of methods and / or mechanisms. For example, Fig. 2 illustrates a template that can be used in combination with container 102 to control the depth at which end 182 penetrates wall 140.

The fluid delivery system 104 may further include an injection needle 190 having an end 192. The end 192 of the injection needle 190 may be covered with a shield 194 to prevent contact with and contamination of the end 192. container 180 and injection needle 190 may be connected by a cannula or tube 200, which may be a flexible cannula according to certain embodiments of the present disclosure. Needle 190, such as needle 180, may be made, for example, of stainless steel.

Fluid delivery system 104 may be used in conjunction with actuator 106, previously mentioned and shown schematically in Fig. 1. Actuator 106 may be adapted to move container needle 180 between the storage state illustrated in Fig. 1. and a dispensing state illustrated in Fig. 3. In the dispensing state, the container needle 180 is disposed through the inner surface 142 of the flexible wall 140 in the sterile reservoir 150.

The movement of needle 180 between states can occur in a variety of ways. For example, needle 180 may be held fixed with respect to injector housing 100, and container 102 may move relative to needle 180 and housing. Alternatively, the container 102 may remain fixed relative to the housing, and the needle 180 may be moved relative to the container 102 and the housing. Movement of both container 102 and needle 180 with respect to injector housing 100 may still be possible. It will be understood that all of these actions may be encompassed within the statement that actuator 106 is adapted to move container needle 180 between storage states. and distribution.

Actuator 106 may be mechanical, electromechanical, or electric. For example, actuator 106 may include a solenoid, motorized lever, motor with associated gears, etc. It may even be possible to provide a tab or button attached to the container 102 or needle 180 to allow the user to manually achieve relative movement between the container 102 and needle 180. In fact, the container 102 may be received within a tab or button which is pressed into the housing when the injector 100 is activated to move the container 102 relative to the (fixed) needle 180.

Actuator 106 may move container needle 180 between storage and dispensing states by moving needle 180 from storage state to dispensing state, or moving needle 180 from dispensing state to storage state. In fact, the actuator may move container needle 180 between storage and dispensing states repeatedly (ie, multiple times or repetitions). In addition, actuator 106 may move container needle 180 immediately upon receipt of an information or signal (eg, as generated by depressing or manipulating a button, switch or other input device, which may be mechanical, electromechanical or coupled to actuator 106), or may slow the movement of the container needle 180 between the storage and dispensing states for a period of time after receipt of the information. According to a particular embodiment, actuator 106 may slow the movement of needle 180 from storage state to dispensing state until after such a time delay.

As previously mentioned, the reservoir 150 is described as sterile while the container needle 180 is described as clean. These terms describe the condition of reservoir 150 or needle 180 as a consequence of their mounting under conditions that ensure a specified level of contamination-free, in which a sterile object or device is understood to have a relatively higher level of contamination-free. compared to a clean object or device. By way of non-limiting example, the concepts of sterility and cleanliness may be discussed with reference to the scheme of Fig. 4, the discussion of which applies not only to the embodiment illustrated in Figs. 1 and 3, but to all embodiments described herein, will be recognized.

Fig. 4 illustrates a production facility 250, and may be used to discuss a production process that is performed within installation 250. It will be noted that installation 250 is divided into a plurality of areas 252, 254, 256, 258, 260, 262, 264, 266, 268, which may be maintained by the use of permanent or semi-permanent walls or barriers. As will be understood, certain areas or regions may be divided without barriers or walls and may simply be separated at an organizational level. Additionally, it will be appreciated that a larger or smaller number of areas or an alternative arrangement of areas may be used, such numbers or arrangements of areas being readily determinable by one skilled in the art.

Container components 102 (walls 110, 140, and cap / piston 170) would enter facility 250 through area 252, where components are sterilized using e-ray technology, for example. Alternatively, the container components may be sterilized by other currently known sterilization procedures (eg, treatment with chlorine dioxide or hydrogen peroxide in the gas phase) or further developed as the components enter facility 250 at 252, 264, 266. Container 102 would then pass to area 254 for filling with the drug product. Area 254 can function as a Class 100 aseptic clean area. A Class 100 clean area is an area whose particle size of 0.5 pm or greater per cubic foot of air is less than 100. Once the filler is filled and the lid 170 is disposed at the end 128 of the container 102, the container 102 and the pharmaceutical 160 are moved through the transfer area 256 (also operated as a clean Class 100 area, where certain embodiments are also provided). aseptic) before being received within storage area 258.

Containers 102 move from storage area 258 to inspection area 260 (aseptic in certain embodiments), where containers 102 are inspected prior to assembly with fluid delivery system 104, actuator 106, and other elements of the container. 100. Because the drug product 160 is contained within the sealed container 102 at this time, the inspection area may function as a Class 10,000 clean area. Upon inspection, the pre-filled container 102 may be moved from inspection area 260 to mounting area 262.

Similar to inspection area 260, mounting area 262 may be operated as a Class 10, 000 clean area. Materials passing into the clean area of ​​areas 264, 266 may be sterile, or may be sterilized. using, for example, e-ray technology. Within mounting area 262, fluid delivery system 104 is connected to container 102 after sterilization of wall surface / septum 140, for example by rubbing surface 144 with an alcohol cloth. Due to the low level of cleanliness, fluid dispensing system 104 may be referred to as clean, but not necessarily as sterile. However, because container needle 180 does not penetrate through wall 140, reservoir 150 and drug product 160 (ie, at a higher level of cleanliness) are kept sterile. The remainder of injector 100 may also be mounted in this area 262 prior to passage of injector 100 through packing area 268, with certain aspects of the injector (eg, actuator 106) potentially being mounted with container 102 or dispensing system. 104 prior to assembly of container 102 and fluid dispensing system 104.

It will be recognized that the embodiment of injector 100 illustrated in Figs. 1 and 3 is merely an exemplary embodiment according to the present disclosure. For this purpose, Figs. 5 and 6 illustrate variants of the injector illustrated in Figs. 1 and 3.

According to the embodiment of Fig. 5, the injector 300 includes a container 302, a fluid delivery system 304 and an actuator 306. Similarly to the embodiment of Figs. 1 and 3, container 302 includes a wall 310 with inner and outer surfaces 312, 314. In addition, wall 310 may have two opposite ends 320, 322 with inner surface 312 of wall 310 defining a hole 324 between the ends. opposite 320, 322.

However, unlike container 102, container 302 has a fixed socket 326 enclosing end 320. In addition, although container 302 has a flexible unit wall 330 with inner and outer surfaces 332, 334, wall 330 is disposed. inside end 322 of container 302, and thus assumes the role of cap / piston 170 in container 102. Consequently, wall 330 is movable along hole 324 between opposite ends 320, 322. In addition, interior surfaces 312, 332 of walls 310, 330 define a sterile reservoir 340 in which a pharmacological product 350 is disposed.

According to this embodiment, fluid dispensing system 304 may include a clean and unsheathed rigid container needle 360 ​​having an end 362. End 362 of needle 360, such as end 182 of needle 180, is only partially arranged on flexible wall 330 in a storage state, with actuator 306 causing end 362 to move between storage state and state. wherein the end 362 is disposed through the inner surface 332 of the flexible wall 330 in the sterile reservoir 340. Container needle 360 ​​may be in continuous communication with injection needle 370, having an end 372 covered with a shield 374, through a cannula 380 received within a piston rod 382, ​​for example, whose rod 382 may be used. for moving cap / piston 330 between ends 320, 322 of container 302.

Fig. 6 shows a variant closely connected to that shown in Fig. 5. According to the variant illustrated in Fig. 6, a container has a wall 390 with inner and outer surfaces 392, 394. However, unlike the containers previously discussed, wall 390 defines a closed end 396 and an open end 398. The container also includes a flexible wall 400, such as wall 330 in the embodiment of Fig. 5, whose wall 400 is movable along the container between open end 398 and closed end 396. According to this embodiment, a separate structure is not required to close one end 396, 398 because wall 390 already defines itself, the closed end 396. For this purpose, the closed end 396 may be resized to be radially larger than shown in Fig. 6.

Having therefore discussed a plurality of embodiments in which a mechanical seal includes only one flexible unit wall, an additional plurality of embodiments will be discussed with reference to Figs. 7 - 11, wherein the mechanical seal includes a plurality of walls and / or seals. This structure may be referred to as a compartmentalized seal (or septum with reference to Fig. 7, or cap with reference to Figs. 8-11).

Referring first to Fig. 7, an injector 450 includes a container 452, a fluid delivery system 454, and an actuator 456.

Container 452 includes a wall 460 with an inner surface 462 and an outer surface 464. Like the container of Figs. 1 and 2, wall 460 may have a generally cylindrical shape, with a shoulder 470 separating first cylindrical section 472 having a first transverse diameter from a second cylindrical section 474 having a second transverse diameter with the first lower transverse diameter than the second transverse diameter. Wall 460 may further define two opposite open ends, 476, 478. Wall 460, or more specifically the inner surface 462 of wall 460, may also define a hole 480.

Unlike the container 102 of Figs. 1 and 3, container 452 of Fig. 7 has a mechanical seal that includes more than one single unit wall, container mechanical seal 452 includes a flexible wall 490 and a clean barrier 492. Flexible wall 490 has an inner surface 494 and an outer surface 496, while the clean barrier 492 has an inner surface 498 and an outer surface 500. Interior surfaces 462, 494 of wall 460 and flexible wall 490 define a sterile enclosed reservoir 510 filled with a pharmaceutical 520. On the other hand, clean barrier 492 is disposed externally to flexible wall 490 to define a clean enclosed area 530 between. flexible wall 490 and clean barrier 492. The clean area 530 may be defined by the inner surface 462 of the wall 460, the outer surface 496 of the flexible wall 490, and the inner surface 498 of the clean barrier 492.

As illustrated, container 452 may also include a lid or piston 540 with inner and outer surfaces 542, 544. Piston 540 may be received within end 478 defined by wall 460, and may be moved along hole 480 between ends. 476, 478 of container 452. According to such an embodiment, the reservoir 510 within which the drug product 520 is disposed may be defined by the inner surfaces 462, 494, 542 of the walls 460, 490 and piston 540.

The embodiment of Fig. 7 also includes fluid dispensing system 454 comprising a clean, unsheathed rigid container needle 550 having an end 552 disposed through the clean barrier 492 to the clean area 530 in a storage state, and disposed through the inner surface 494 of the flexible wall 490 to the sterile reservoir 510 in a dispensing state. In this sense, the container needle 550 only partially penetrates the mechanical seal. Fluid delivery system 454 may also include an injection needle 560 with an end 562 at least initially covered with a needle guard 564 to prevent tip contact and contamination 562. Container needle 550 and injection needle 560 may be connected by a cannula or tube 570, which may be a flexible cannula according to certain embodiments of the present disclosure.

As was the case with the embodiments of Figs. 1 and

3, the present disclosure includes a number of variants for the embodiment illustrated in Fig. 7, the variants of which are illustrated in Figs. 8-11.

The embodiment of Fig. 8 is similar to the embodiment of Fig. 7 in that the embodiment of Fig. 5 was similar to that of Figs. 1 and 3. In particular, the mechanical seal of an injector 600 according to the embodiment of Fig. 8 is disposed in a container 602 in place of the cap / piston 540 shown relative to container 452. That is, the container 602 includes a wall 604 defining a hole 606, and a flexible wall 608 and a clean barrier 610, each defining a lid that is movable along hole 606. Although in the illustrated embodiment wall 604 If container 602 does not define open and closed opposite ends, such an alternative is possible according to the present disclosure similarly to Fig.

6.

Figs. 9-11 illustrate variants to the embodiment illustrated in Fig. 8, the variants of which include additional features to allow the area or region between the flexible wall and the clean barrier to be evacuated or exhausted. These additional features may be referred to as openings, valves, or bypasses, but all of these structures allow gases to escape from the area or region between the flexible wall and the clean barrier when an actuator moves the associated container needle from a storage state to a state of distribution. This is not to suggest that the inner wall and outer barrier cannot remain separated, for example by use of a spacer or spacers, in accordance with other embodiments of the present disclosure. However, the alternatives of Figs. 9 11 illustrate options for evacuating the clean area to embodiments where inner wall and outer barrier approach.

A container 650 is illustrated in Fig. 9 including a wall 652 and a mechanical seal, the mechanical seal including a flexible wall 654 and a clean barrier 656. Flexible wall 654 has an inner surface 658 and an outer surface 660, while the Clean barrier 654 has an inner surface 662 and an outer surface 664. An inner surface 668 of wall 652 and inner surface 658 of flexible wall 654 define a closed sterile reservoir 670 filled with a pharmaceutical 680. On the other hand, the clean barrier 656 is disposed externally to the flexible wall 654 to define a closed clean area. 690 between flexible wall 654 and clean barrier 656. The clean area 690 may be defined by the inner surface 668 of the wall 652, the outer surface 660 of the flexible wall 652, and the inner surface 662 of the clean barrier 656.

As also illustrated in Fig. 10, a fluid dispensing system 700 including a container needle 702 is used in conjunction with the mechanical seal. Container needle 702 is illustrated in the storage state, wherein container needle 702 is disposed through the clean barrier 656 such that an end 704 of needle 702 is disposed in the clean area 690. End penetration 704 into flexible wall 654 and inlet to reservoir 670 in a dispensing state are not shown. It will be recognized that needle 702 is not drawn to scale, particularly in relation to its length, as is true for other embodiments illustrated herein.

In contrast to the previously discussed embodiments, the container 650 illustrated in Fig. 9 includes at least one opening 710. The openings 710 are in continuous communication with the clean area 690 between the clean barrier 656 and the flexible wall 654. The openings 710 are selectively actuated to allow entrapped gas between the clean barrier 656 and the flexible wall 654 to escape through the openings 710 when the mechanical seal is moved between the illustrated storage state and the distribution state where the barrier 656 is advanced. towards flexible wall 654 to allow end 704 of container needle 702 to penetrate through wall 654. However, the openings 710 may be in a sealed state with respect to the environment until triggered, for example, by a change in pressure within the clean area 690.

As illustrated, the openings 710 are disposed within the clean barrier 656, and extend between the inner surface 662 and the outer surface 664 of the barrier 656. A flap 712 covers the end of the aperture 710 near the outer surface 664, sealing therefrom. mode the end of aperture 710 until the aperture activates, thus preserving the cleanliness of the area 690 between the clean barrier 656 and the flexible wall 654. Alternatively, openings 710 may be arranged, for example, in wall 652 of container 650.

Figs. 10 and 11 illustrate a further variant of the system of Fig. 8, wherein a container 720 includes a wall 722 and a mechanical seal, the mechanical seal including a flexible wall 724 and a clean barrier 726. The flexible wall 724 has an inner surface. 728 and an outer surface 730, while the clean barrier 726 has an inner surface 732 and an outer surface 734. An inner surface 738 of the wall 722 and the inner surface 728 of the flexible wall 724 define a closed sterile reservoir 740 filled with drug 750. On the other hand, the clean barrier 726 is disposed externally to the flexible wall 724 to define an enclosed clean area. 760 between flexible wall 724 and clean barrier 726. The clean area 760 may be defined by the inner surface 738 of the wall 722, the outer surface 730 of the flexible wall 722, and the inner surface 732 of the clean barrier 726.

As also illustrated in Fig. 10, fluid dispensing system 770 including a container needle 772 is used in conjunction with the mechanical seal. The container needle 772 is illustrated in the storage state, where the container needle 772 is disposed across the clean barrier 726 such that an end 774 of the needle 772 is disposed in the clean area 760. The penetration of end 774 into flexible wall 724 and inlet to reservoir 740 in a dispensing state are not shown.

In contrast to the previously discussed embodiments, the container 720 shown in Fig. 10 includes at least one offset or opening 780. The offset 780 is in continuous communication with the reservoir 740. Offsets 780 are selectively actuated to allow entrapped gas between clean barrier 726 and wall 724 to escape through offsets 780 to reservoir 740 when the mechanical seal is moved between the illustrated storage and distribution states, where clean barrier 726 is advanced toward flexible wall 724 to allow end 774 of container needle 772 to penetrate through wall 724.

However, the offsets 780 are not in continuous communication with the clean area 760 until the flexible wall 724 has moved from the storage state shown in Fig. 10 to an intermediate state shown in Fig. 11. As illustrated in Figs. 10 and 11, the offsets 780 may be defined on the inner surface 738 of the wall 722, and as illustrated may take the form of a groove 782 formed on the wall 722. The groove 782 may have a distal end 784 and a proximal end 786. As will be recognized, the reservoir 740 is in a sealed condition with respect to the clean area 760 until the outer surface 730 of the flexible wall 724 exceeds the distal end 784 of the grooves. 782. However, after the outer surface 730 of the flexible wall 724 exceeds the distal end 784 of the grooves 782, trapped gases between the clean barrier 726 and the flexible wall 724 may be exhausted to the reservoir 740. This may facilitate movement of the barrier 726 and needle 770 towards flexible wall 724.

While all of the foregoing embodiments have focused in one way or another on a fluid dispensing system partially disposed through a mechanical seal, there are other alternatives where the receiver needle is not disposed through the mechanical seal, or where the container needle is arranged completely through the mechanical seal. Three such alternatives are illustrated in Figs. 12 - 14.

Fig. 12 illustrates an injector 800 with a container 802, a fluid dispensing system 804 and an actuator 806. Similarly to the embodiments illustrated above, actuator 806 would cause the fluid dispensing system 804 to be arranged through a mechanical seal associated with a container 802 in a dispensing state, and thus in continuous communication with the interior of the container 802.

However, as mentioned above, in the storage state illustrated in Fig. 12, the fluid dispensing system is not even partially disposed through the mechanical seal.

To this end, container 802 includes at least one flexible wall 810 which may be in the form of a septum or a lid according to the present disclosure. The flexible wall 810 has an inner surface 812 and an outer surface 814. Additionally, fluid dispensing system 804 includes a container needle 816, an injection needle 818, and a flexible conduit 820 connecting the container needle 816 and the injection needle 818. Both container needle 816 and injection needle 818 are received within a cover 822, 824 which preserves the cleanliness of needle 816, 818. Cover 822 may be referred to as a tab, while cover 824 may be referred to as a protector. Also included is an alcohol cloth 826 disposed between flexible wall 810 and cover 822, the cloth 826 of which may be maintained under airtight conditions to maintain alcohol saturation.

According to the present disclosure , prior to the actuation of actuator 806, the cloth 826 is removed from the flexible wall 810 and the cover 822. For example, one end of the cloth 826 may be disposed outside the injector housing 800 to allow the end to be grasped and the cloth 826 to be pulled out of the injector 800. Alternatively, the end of the cloth 826 may be attached to another aspect of the injector 800, such as a coating that covers an adhesive surface of injector 800 which will be attached to the patient, so that when the coating is removed to expose the adhesive surface. , the cloth 826 is also pulled out from gun 800. Removing the cloth sterilizes wall 810 surface 814 and opposite tab 822 surface 828. Actuator 806 will subsequently move container needle 816 through tab 822 and flexible wall 810.

Figs. 13 and 14, on the other hand, illustrate embodiments in which the container needle is disposed through the flexible wall (defining the cap or septum) and an opening is used to seal the injection needle reservoir. The opening may also be used to control the flow of the pharmaceutical product from the reservoir into the container. Thus, the aperture may be used to measure a quantity of drug from the reservoir, or to slow the flow of a drug until a time has elapsed in relation to receiving input device information (eg, button or switch), for example.

As such, Fig. 13 illustrates an injector 850 with a container 852, a fluid dispensing system 854 and an actuator 856. The container 852 includes at least one flexible wall 860 which may be in the form of a septum according to shape. illustrated embodiment. The flexible wall 860 has an inner surface 862 and an outer surface 864. Additionally, the fluid dispensing system 854 includes a container needle 866, an injection needle 868, and a flexible cannula or tubing 870 that connects container needle 866 and injection needle 868. Injection needle 868 may be received inside a cover 872 that preserves needle cleanliness 868.

On the other hand, the container needle 866 (and in particular an end 874 of the container needle 866) is disposed through a flexible wall 860 through the inner surface 862. The needle 866 is thus in continuous communication with a reservoir. sterile 880 and a pharmacological product 890 disposed within the reservoir 880. Continuous communication between the container needle 866 and the injection needle 868 is interrupted by an opening 900 disposed within or along the flexible tubing 870, whose opening 900 may define a boundary between the sterile portion of the injector 850 and the clean portion of the nozzle. 850. Thus, unlike the other embodiments discussed above with respect to Figs. 1 - 12, injector 856 actuator 856 is not used to move container needle 866 relative to flexible wall 860, instead manipulating the opening between a closed state where continuous communication between needles 866, 868 is interrupted, and an open state wherein the container needle 866 is in continuous communication with the injection needle 868.

It will be recognized that valve 900 can take a variety of configurations and shapes, two of which are illustrated in Figs. 13 and 14. In particular, Fig. 13 illustrates an embodiment of injector 850 wherein a rotary opening 900 is disposed in flexible tubing 870, or has an internal plug that is in continuous communication with the fluid path defined between the container needle 866 and injection needle 868. Fig. 14, in contrast, illustrates an injector embodiment where a pinch valve 902 is disposed along flexible tubing 870, thereby cooperating with an outer surface of tubing 870 to interrupt continuous communication between container needle 866 and needle. of injection 868.

Embodiments as illustrated in Figs. 13 and 14 will also work well with a container having a permanently attached needle, such as the container being in the form of a syringe, for example.

It will be further understood that the embodiments illustrated in Figs. 13 and 14 may be further modified to incorporate a mechanical seal including a plurality of walls and / or seals, as illustrated in Fig. 7, for example. Fig. 15 illustrates such an embodiment.

In particular, Fig. 15 illustrates an injector 920 with a container 922, a fluid dispensing system 924, an actuator 926, and a mechanical seal 928. The fluid dispensing system 924 may include a container needle 930, a reciprocating needle. 932, and a flexible cannula or tubing 934 connecting the container needle 930 and the injection needle 932. The injection needle 932 may be received within a cover 936 which preserves the cleanliness of the needle 932. Needle 932 may also be in continuous communication with a sterile reservoir 940 and a pharmaceutical 942 disposed within reservoir 940 via a valve 944 disposed within or along flexible tubing 934. In this respect, injector 920 is similar to those illustrated. in Figs. 13 and 14.

However, the mechanical seal 928 of injector 920 also has a flexible wall 950 and a clean barrier 952. Flexible wall 950 and clean barrier 952 each have interior and exterior surfaces, with the interior surface of flexible wall 950 being defined in the sterile reservoir 940. On the other hand, the barrier clears

952 is arranged externally to flexible wall 950 to define a clean enclosed area 954 between flexible wall

950 and clean wall 952 where a clean end 956 of container needle 930 may be disposed.

In this regard, the embodiment of Fig. 15 has two potential barriers: one in the form of valve 944 and a second in the form of placing end 956 within the clean area 954. In fact, valve 944 can be controlled to provide a delay in injecting drug 942 after bringing the container needle 930 into the flexible wall 950 into reservoir 940.

As will be appreciated, devices according to the present disclosure may have one or more advantages over conventional technology, any one or more of which may be present in a particular embodiment according to the features of the present disclosure included therein. of achievement. As an example, these embodiments maintain sterility of the drug until use time. As another example, the likelihood of mixing of the drug product prior to time of use is limited or avoided. As a further example, unwanted distribution of the drug product prior to the time of use is limited or avoided.

For illustrative purposes only, Fig. 16 provides an additional method 1000 for mounting dispensing devices according to any of the embodiments disclosed above. Method 1000 follows the general processing flow outlined above with respect to Fig.

4 However, instead of referring to clean area classifications according to US Federal Standard 209E, reference is made to clean areas according to GMP EU standards. In addition, method 1000 provides optional additional paths (represented as a left or right branch) that can be followed in mounting the dispensing device. Accordingly, method 1000 of Fig. 16 may be seen as supplementary to the above discussion concerning Fig. 4.

Method 1000 for mounting dispensing systems begins at block 1002. The containers used in the device are initially stored in sealed vats. As mentioned above, these containers may or may have been sterilized at a certain time. In block 1002, the vats are unloaded, for example using an automatic unloader in a clean Class C area. In block 1004, the Tyvek seal is peeled off (eg by a robot) and removed, for example, in an area operated as a Class A clean area, perhaps within an insulator in an otherwise operated area as a Class C clean area.

The containers are filled and the lids are attached, and the containers are then housed in open vats in block 1006 in an area operated as a Class A clean area, perhaps within an insulator in an area otherwise operated as a Class C clean area. From this point, two alternative paths or branches are possible.

Filled containers may be left in the open vats in block 1008. The vats may be transported and loaded to a storage area (eg, a cold area) in block 1010.

If the path of block 1008, 1010 is followed, then method 1000 may continue with the vats to be transported for processing to an inspection area in block 1012. The filled containers are then dislodged from the open vats in block 1014, and supplied to an automated inspection machine in block 1016. Automated inspection of filled containers takes place in block 1016, followed by additional semi-automated or manual operational inspection in block 1018.

Alternatively, the vats may be resealed and refilled, and identified in block 1020. For example, the vats may be resealed with Tyvek (eg, using a refilled Bausch + Strobel vat sealer), and later identified in a clean area Class C in block 1020. Vats may later be stored or even shipped, if necessary, in blocks 1022, 1024.

After storage or transport is completed, the vats are unloaded using, for example, an automatic unloader in block 1026. In block 1028, the Tyvek seal is removed and removed. The filled containers may then be dislodged for inspection in block 1030. Actions in blocks 1026, 1028, 1030 are performed in a clean area. Class C. An automated inspection can then be performed using a visual inspection machine designed to operate in a clean area Class C in block 1032.

Following either procedure, the filled and inspected containers can then be transferred to trays rondo in block 1034.

According to a first procedure, the rondo trays can be sent directly to storage in block 1036. If the path of block 1036 is followed, then the rondo trays will be transferred for processing to the device mounting area in block 1038. Containers they are dislodged in block 1040, and mounted with other dispensing device elements in block 1042 to define a mounted dispensing device (eg, an injector or an infuser).

Alternatively, the containers may be moved into vats, which are sealed, loaded and identified in block 1044. For example, the vats may be resealed with Tyvek, loaded, and subsequently identified in a Class C area. they can then be stored, or even sent for further processing if necessary, to blocks 1046, 1048. After storage or transport is completed, the vats are unloaded using, for example, an automatic unloader in block 1050. In block 1052 the Tyvek seal is removed and the containers are dislodged. The filled containers can then be mounted with the other elements of the dispensing device in block 1054. Actions in blocks 1050, 1052, 1054 can all take place in a clean Class C.

In either event, the assembled devices are packaged in block 1056, and the packaged and assembled devices are stored in block 1058. Finally, the packaged and assembled devices are transported to the distributor and / or other distribution actions in the block. 1060

Other advantages not specifically listed herein may also be recognized. In addition, other variants and alternatives are still possible.

As an example, while actuator operation has been described with respect to the above embodiments of moving, for example, the container needle from a storage state to a dispensing state, it will be understood that the actuator may also move the container needle from dispensing state to storage state. For example, if a dose of drug less than the reservoir volume has to be delivered (as may be the case where the injector is designed to be programmed to deliver an adjustable dose to the patient's needs (eg, patient Pediatric adult)), then the actuator may move the container needle from the storage state to the dispensing state before dose delivery, and from the dispensing state to the storage state after dose distribution. Movement from the dispensing state to the storage state will, in effect, reseal the container and close the fluid path to the patient. This sequence of motion between the storage state and the distribution state may be repeated. As noted above, maintaining a closed fluid path to the beginning of dispensing is advantageous as it reduces the opportunity for unwanted dispensing of the drug product to the patient and / or mixing the drug product with the patient's body fluids.

Injectors according to the present disclosure may be used with a variety of pharmacological products, including colony stimulating factors such as granulocyte colony stimulating factor (G - CSF), may be administered to increase the number of immune cells (eg , white blood cells) found in the bone marrow or peripheral blood. Such G-CSF agents include, but are not limited to, Neupogen® (filgrastim) and Neulasta® (pegfilgrastim).

In other embodiments, the injector may be used with various other products including, for example, an erythropoiesis stimulating agent (ESA), which may be in a liquid or lyophilized form. An ESA is any molecule that stimulates erythropoiesis, such as Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (betaepoetin methoxypolyethylene glycol), Hematide®, MRK - 2578, INS - 22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (epoetin zeta), Binocrit® (epoetin alfa), Epoetin alfa Hexal, Abseamed® (epoetin alfa), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alfa, epoetin beta, epoetin zeta, epoetin theta, and epoetin delta, such as molecules or variants or analogs thereof as disclosed in the following patents or patent applications: US Pat. We. 4,703,008; 5,441,861; 5,547,933; 5,618,696; 5,621,080; 5,756,349; 5,767,078; 5,773,569; 5,955,422; 5,986,047; 6,583,272; 7,084,246; and 7,271,689; and PCT Publ. We. WO 91/05867; WO 95/05465; WO 96/40772; WO 00/24893; WO 01/81405; and WO 2007/136752.

An ESA may be an erythropoiesis stimulating protein. As used herein, erythropoiesis stimulating protein means any protein that directly or indirectly causes activation of the erythropoietin receptor, for example by binding to and causing dimerization of the receptor.

Erythropoiesis stimulating proteins include erythropoietin and variants, analogs, or derivatives thereof that bind and activate the erythropoietin receptor; antibodies that bind to the erythropoietin receptor and activate the receptor; or peptides that bind and activate the erythropoietin receptor. Erythropoiesis-stimulating proteins include, but are not limited to epoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin iota, epoetin zeta, and analogues thereof, erythropoietin pegylated, erythropoietin carbamylated, EMI peptides and mimetics (including EMP3) mimetics. Exemplary erythropoietin stimulating proteins include erythropoietin, darbepoetin, erythropoietin agonist variants, and peptides or antibodies that bind and activate the erythropoietin receptor (and include compounds described in US Publ. Nos. 2003/0215444 and 2006/0040858) such as molecules erythropoietin or variants or analogs thereof as disclosed in the following patents or patent applications: US Pat. We. 4,703,008; 5,441,868; 5,547,933; 5,618,698; 5,621,080; 5,756,349; 5,767,078; 5,773,569; 5,955,422; 5,830,851;

5, 856, 298; 5, 986, 047; 6, 030,086; 6, 310,078; 6, 391, 633;

6, 583,272; 6, 586, 398; 6, 900,292; 6, 750,369; 7,030,226;

7,084,245; and

2003/0077753;

2004/0071694;

2004/0175379;

2004/0266690;

2005/0107297;

2005/0137329;

2005/0158822;

2005/0181482;

2005/0244409;

7,217,689; US

2003/0082749;

2004/0091961;

2004/0175824;

2005/0019914;

2005/0107591;

2005/0142642;

2005/0158832;

2005/0192211;

2006/0088906; and

Publ. We.

2003/0143202;

2004/0143857;

2004/0229318;

2005/0026834;

2005/0124045;

2005/0143292;

2005/0170457;

2005/0202538;

2006/0111279; and

2002/0155998;

2004/0009902;

2004/0157293;

2004/0248815;

2005/0096461;

2005/0124564;

2005/0153879;

2005/0181359;

2005/0227289;

PCT Publ. We.

WO 91/05867; WO 95/05465; WO 99/66054; WO 00/24893; WO

<td> 01/81405;</td><td>WO</td><td>00/61637; WO</td><td> 01/36489;</td><td>WO</td><td> 02/014356;</td><td>WO</td>

<td> 02/19963;</td><td>WO</td><td>02/20034; WO</td><td> 02/49673;</td><td>WO</td><td> 02/085940;</td><td>WO</td>

<td> 03/029291;</td><td>WO</td><td>2003/055526; WO</td><td colspan="2"> 2003/084477;</td><td colspan="2">WO2003 / 094858;</td>

WO 2004/002417; WO 2004/002424; WO 2004/009627; WO

2004/024761; WO 2004/033651; WO 2004/035603; WO 2004/043382;

WO 2004/101600; WO 2004/101606; WO 2004/101611; WO

2004/106373; WO 2004/018667; WO 2005/001025; WO 2005/001136;

WO 2005/021579; WO 2005/025606; WO 2005/032460; WO

2005/051327; WO 2005/063808; WO 2005/063809; WO 2005/070451;

WO 2005/081687; WO 2005/084711; WO 2005/103076; WO

2005/100403; WO 2005/092369; WO 2006/50959; WO 2006/02646; and WO 2006/29094.

Examples of other pharmacological products for use with the device may include, but are not limited to antibodies such as Vectibix® (panitumumab), Xgeva® (denosumab) and Prolia® (denosamab); other biological agents such as Enbrel® (etanercept, TNF / Fc receptor fusion protein, TNF blocker), Neulasta® (pegfilgrastim, pegylated filgastrim, pegylated G-CSF, pegylated Met-hu-G-CSF), Neupogen® (filgrastim, G-CSF, Met-hu-G-CSF), and Nplate® (romiplostim); small pharmacological molecules such as Sensipar® (cinacalcet). The device may also be used with a therapeutic antibody, polypeptide, protein or other chemical, such as iron, ferumoxytol, iron dextran, ferric glyconate, and saccharized ferric oxide, for example. The pharmaceutical product may be in liquid form or reconstituted in lyophilized form.

Particular illustrative proteins include specific proteins defined below, including fusions, fragments, analogs, variants or derivatives thereof:

Specific OPGL antibodies, peptibodies, and related proteins, and the like (also referred to as specific RANKL antibodies, peptibodies, and the like), including human and fully humanized OPGL specific antibodies, particularly fully humanized monoclonal antibodies, including but not limited to antibodies described in PCT Publ. At the. WO 03/002713, as specific OPGL antibodies and antibody related proteins, particularly those having the sequences defined, particularly, but not limited to those denoted: 9H7; 18B2; 2D8; 2E11; 16E1; and 22B3, including specific OPGL antibodies having either the light chain of SEQ ID NO: 2 as defined in Figure 2 and / or the heavy chain of SEQ ID NO: 4 as defined in Figure 4;

Myostatin binding proteins, peptibodies, and related proteins, and the like, including myostatin-specific peptibodies, particularly those described in US Publ. No. 2004/0181033 and PCT Publ. At the. WO 2004/058988, particularly in parts pertaining to myostatin-specific peptibodies, including but not limited to mTN8 - 19 family peptibodies, including those of SEQ ID NOS: 305 - 351, including TN8-ΙΟΙ to TN8 - 19 - 40 TN8-19 conl and TN8-19 con 2; mL2 family peptibodies of SEQ ID NOS: 357 - 383; the mL15 family of SEQ ID NOS: 384 - 409; the mL17 family of SEQ ID NOS: 410 - 438; the mL20 family of SEQ ID NOS: 439 - 446; the mL21 family of SEQ ID NOS: 447-452; the mL24 family of SEQ ID NOS: 453 - 454; and those of SEQ ID NOS: 615 - 631;

IL-4 receptor specific antibodies, peptibodies, and related proteins, and the like, in particular those whose inhibitory activities are mediated by IL binding

- 4 and / or IL - 13 to the recipient, including those described in PCT Publ. No. WO 2005/047331 or PCT Appl. PCT / US2004 / 03742 and in US Publ. At the. 2005/112694, in pertinent parts of IL-4 receptor specific antibodies, in particular such antibodies as those described in particular, and without limitation, designated as: L1H1; L1H2; L1H3; L1H4; L1H5; L1H6; L1H7; L1H8; L1H9; L1H10; L1H11; L2H1; L2H2; L2H3; L2H4; L2H5; L2H6; L2H7; L2H8; L2H9; L2H10; L2H11; L2H12; L2H13; L2H14; L3H1; L4H1; L5H1; L6H1;

Specific antibodies to Interleukin 1 receptor 1 (IL1 - R1), peptibodies, and related proteins, and the like, including but not limited to those described in US Publ. No. 2004 / 097712A1, in pertinent parts of IL1 - R1 specific binding proteins, in particular monoclonal antibodies, especially, without limitation, to those designated: 15CA, 26F5, 27F2, 24E12, and 10H7;

Ang2-specific antibodies, peptibodies, and related proteins, and the like, including but not limited to those described in PCT Publ. No. WO 03/057134 and US Publ. At the. 2003/0229023, in particular pertaining to Ang2-specific antibodies and peptibodies, and the like, especially those with sequences described and including, but not limited to: LI (N); L1 (N) WT; L1 (N) 1K WT; 2xL1 (N); 2xL1 (N) WT; Con4 (N), Con4 (N) 1KWT, 2xCon4 (N) 1K; L1C; L1C 1K; 2xL1C; Con4C; Con4C 1K; 2xCon4C 1K; Con4 L1 (N); Con4 - L1C; TN - 12 - 9 (N); C17 (N); TN8 - 8 (N); TN8 - 14 (N); Con 1 (N), also including Ang 2 antibodies and formulations such as those described in PCT Publ. No. WO 2003/030833, in particular Ab526; Ab528; Ab531; Ab533; Ab535; Ab536; Ab537; Ab540; Ab543; Ab544; Ab545; Ab546; A551;

Ab553; Ab555; Ab558; Ab559; Ab565; AbFlAbFD; ABFE; AbFJ;

AbFK; AbGlD4; AbGClE8; AbHlCl2; AblAl; AblF; AblK, AblP; and AblP, in their various permutations as described;

NGF-specific antibodies, peptibodies, and related proteins, and the like including, but not limited to, those described in US Publ. No. 2005/0074821 and US Patent No. 6,919,426, particularly for NGF-specific antibodies and related proteins in this regard, including in particular but not limited to NGF-specific antibodies designated 4D4, 4G6, 6H9, 7H2, 14D10 and 14D11 ;

Specific antibodies to CD22, peptibodies, and related proteins, and the like, such as those described in US Patent No. 5,789,554 for CD22 specific antibodies and related proteins, in particular CD22 specific human antibodies, such as, but not limited to humanized and fully human antibodies, including but not limited to humanized and fully human monoclonal antibodies, including in particular but not limiting to CD22 specific IgG antibodies such as, for example, a dimer of a hLL2 monoclonal human-mouse gamma chain disulfide linked to a hLL2 monoclonal human-mouse kappa chain, including, but not limited to, for example, the fully humanized CD22 specific antibody in Epratuzumab, CAS number 501423 - 23 - 0;

IGF - 1 receptor specific antibodies, peptibodies, and related proteins, and the like, such as those described in PCT Publ. WO 06/069202, for specific antibodies against the IGF - 1 receptor and related proteins, including but not limited to IFG-1 specific antibodies designated L1H1, L2H2, L3H3, L4H4,

L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13,

<td>L14H14,</td><td>L15H15,</td><td>L16H16,</td><td>L17H17,</td><td>L18H18,</td><td>L19H19,</td><td>L20H20,</td>

<td>L21H21,</td><td>L22H22,</td><td>L23H23,</td><td>L24H24,</td><td>L25H25,</td><td>L26H26,</td><td>L27H27,</td>

<td>L28H28,</td><td>L29H29,</td><td>L30H30,</td><td>L31H31,</td><td>L32H32,</td><td>L33H33,</td><td>L34H34,</td>

<td>L35H35,</td><td>L36H36,</td><td>L37H37,</td><td>L38H38,</td><td>L39H39,</td><td>L40H40,</td><td>L41H41,</td>

<td>L42H42,</td><td>L43H43,</td><td>L44H44,</td><td>L45H45,</td><td>L46H46,</td><td>L47H47,</td><td>L48H48,</td>

<td>L49H49,</td><td>L50H50,</td><td>L51H51,</td><td>L52H52, and</td><td colspan="3">IGF binding fragments</td>

- IR and its derivatives;

Also among non-limiting examples of anti IGF - IR antibodies for use in the methods and compositions of the present invention are those described in:

(i) US Publ. No. 2006/0040358 (published on February 23, 2006), 2005/0008642 (published on January 13, 2005), 2004/0228859 (published on November 18, 2004), including but not limited to, for example, IA antibody ( DSMZ DSM ACC 2586 Deposit No.), antibody 8 (DSMZ DSM ACC 2589 Deposit No.), antibody 23 (DSMZ DSM ACC 2588 Deposit No.) and antibody 18 as described;

(ii) PCT Publ. No. WO 06/138729 (published December 28, 2006) and WO 05/016970 (published February 24, 2005), and Lu et al., 2004, J Biol. Chem. 279: 2856 - 65, including but not limited to 2F8, A12, and IMO - A12 antibodies, as described;

(iii) PCT Publ. No. WO 07/012614 (published on February 1, 2007), WO 07/000328 (published on January 4, 2007), WO 06/013472 (published on February 9, 2006), WO 05/058967 (published on June 30 , 2005), and WO 03/059951 (published June 24, 2003);

(iv) US Publ. No. 2005/0084906 (published April 21, 2005), including but not limited to antibody 7010, chimeric antibody C7C10, antibody h7C10, antibody

7Η2Μ, chimeric antibody * 7C10, GM 607 antibody, humanized antibody 7C10 version 1, humanized antibody 7C10 version 2, humanized antibody 7C10 version 3, and 7H2HM antibody as described;

(v) US Publ. We. 2005/0249728 (published on November 10, 2005), 2005/0186203 (published on August 25, 2005), 2004/0265307 (published on December 30, 2004), and 2003/0235582 (published on December 25, 2003) and Maloney et al., 2003, Cancer Res. 63: 5073 - 83, including but not limited to antibody EM164, resurged EM164, humanized EM164, huEM164 vl, 0, huEM164 vl, 2, and huEM164 vl, 3 such as described;

(vi) US Pat. No. 7,037,498 (published May 2, 2006), US Publ. We. 2005/0244408 (published November 30, 2005) and 2004/0086503 (published May 6, 2004), and Cohen, et al., 2005, Clinical Cancer Res. 11: 2063-73, eg, CP-751,871 antibody, including but not limited to each of the antibodies produced by hybridomas having ATCC accession numbers PTA 2792, PTA-2788, PTA-2790, PTA-2791, PTA-2789, PTA - 2793, and antibodies 2,12,1, 2,13,2, 2,14,3, 3,1,1, 4,9,2, and 4,17,3, as described;

(vii) US Publ. We. 2005/0136063 (published June 23, 2005) and 2004/0018191 (published January 29, 2004), including but not limited to the 19D12 antibody and an antibody comprising a polynucleotide heavy chain encoded in plasmid 15H12 / 19D12 HCA (y4 ) deposited with the ATCC under number PTA - 5214 and a light chain encoded by a polynucleotide in plasmid 15H12 / 19D12 LCF (k) deposited with the ATCC under number PTA - 5220 as described; and (viii) US Publ. At the. 2004/0202655 (published in October

14, 2004), including but not limited to antibodies

<td>PINT</td><td>- 6A1, PINT - 7A2, PINT - 7A4, PINT - 7A5, PINT -</td>

<td>7A6,</td><td>PINT - 8A1, PINT - 9A2, PINT - 11A1, PINT - 11A2,</td>

<td>PINT</td><td>- 11A3, PINT - 11A4, PINT - 11A5, PINT - 11A7,</td>

<td>PINT</td><td>- 11A12, PINT - 12A1, PINT - 12A2, PINT - 12A3,</td>

<td>PINT</td><td>12A4, and PINT-12A5 as described; in</td>

particularly with respect to antibodies, peptibodies, and related proteins and the like mentioned which target IGF - 1 receptors;

B - 7 related protein 1 specific antibodies, peptibodies, related proteins and the like (B7RP - 1 is also referred to in the literature as B7H2, ICOSL, B7h, and CD275), in particular B7RP specific fully human monoclonal IgG2 antibodies, in particular antibody. Fully human monoclonal IgG2 that binds to an epitope on the first immunoglobulin-like domain of B7RP - 1, especially those that inhibit the interaction of B7Rp - 1 with its natural receptor, ICOS, particularly in activated T cells, especially in all the foregoing aspects, those disclosed in US Publ. No. 2008/0166352 and PCT Publ. At the. WO 07/011941 for antibodies and related proteins, including but not limited to antibodies designated as follows: 16H (having light and heavy chain variable sequences SEQ ID NO: 1 and SEQ ID NO: 7, respectively); 5D (having light and heavy chain variable sequences SEQ ID NO: 2 and SEQ ID NO: 9, respectively); 2H (having light and heavy chain variable sequences SEQ ID NO: 3 and SEQ ID NO: 10, respectively); 43H (having light and heavy chain variable sequences SEQ ID NO: 6 and SEQ ID NO: 14, respectively); 41H (having light and heavy chain variable sequences SEQ ID NO: 5 and SEQ ID NO: 13, respectively); and 15H (having light and heavy chain variable sequences SEQ ID NO: 4 and SEQ ID NO: 12, respectively);

Specific IL-15 antibodies, peptibodies, and related proteins, and the like, such as, in particular, humanized monoclonal antibodies, particularly antibodies such as those disclosed in US Publ. We. 2003/0138421; 2003/023586; and 2004/0071702; and US Patent No. 7,153,507 for IL-15 specific antibodies and related proteins, including peptibodies, including particularly, but not limited to, IL-15 HuMax antibodies and related proteins, such as, for example, 146B7;

IFN specific gamma antibodies, peptibodies, and related proteins and the like, especially human IFN gamma antibodies, particularly fully humanized IFN gamma antibodies, such as, for example, those described in US Publ. No. 2005/004353 for IFN gamma specific antibodies, in particular, for example, antibodies designated 1118; 1118 *; 1119; 1121; and 1121 *. All of the heavy and light chain sequences of these antibodies, as well as the sequences of the heavy and light chain variable regions and complementarity determining regions, as disclosed in US Publication and Thakur et al. , Mol. Immunol. 36: 1107-1115 (1999) set forth above. In addition, a description of the properties of these antibodies is provided in the preceding US Publication. Specific antibodies include those having the heavy chain of SEQ ID NO: 17 and the light chain of SEQ ID NO: 18; those having the heavy chain variable region of SEQ ID NO: 6 and the light chain variable region of SEQ ID NO: 8; those having the heavy chain of SEQ ID NO: 19 and the light chain of SEQ ID NO: 20; those having the heavy chain variable region of SEQ ID NO: 10 and the light chain variable region of SEQ ID NO: 12; those having the heavy chain of SEQ ID NO: 32 and the light chain of SEQ ID NO: 20; those having the heavy chain variable region of SEQ ID NO: 30 and the light chain variable region of SEQ ID NO: 12; those having the heavy chain sequence of SEQ ID NO: 21 and the light chain sequence of SEQ ID NO: 22; those having the heavy chain variable region of SEQ ID NO: 14 and the light chain variable region of SEQ ID NO: 16; those having the heavy chain of SEQ ID NO: 21 and the light chain of SEQ ID NO: 33; and those having the heavy chain variable region of SEQ ID NO: 14 and the light chain variable region of SEQ ID NO: 31, as disclosed in the preceding US Publication. A specific antibody contemplated is antibody 1119 as disclosed in the preceding US Publication, and having a complete heavy chain of SEQ ID NO: 17 as disclosed and having a complete light chain of SEQ ID NO: 18 as disclosed;

TALL - 1 specific antibodies, peptibodies, and related proteins, and the like, and other TALL specific binding proteins, such as those described in US Publ. We. 2003/0195156 and 2006/0135431 for TALL - 1 binding proteins, in particular molecules of Tables 4 and 5B;

Parathyroid hormone (PTH) specific antibodies, peptibodies, and related proteins, and the like, as described in US Patent No. 6,756,480, particularly in pertinent parts to PTH-binding proteins;

Thrombopoietin receptor (TPO - R) specific antibodies, peptibodies, and related proteins, and the like, as described in US Patent No. 6,835,809, particularly in pertinent portions of TPO - R binding proteins;

Hepatocyte growth receptor (HGF) specific antibodies, peptibodies, and related proteins, and the like, including targeting HGF / SF: cMet (HGF / SF: c - Met) taxis, such as fully humanised monoclonal antibodies that neutralize factor Hepatocyte Growth Rate / Dispersing Factor (HGF / SF) described in US Publ. No. 2005/0118643 and PCT Publ. WO 2005/017107, huL2G7 described in US Patent No. 7,220,410 and OA - 5d5 described in US Patent Nos. 5,686,292 and 6,468,529 and in PCT Publ. No. WO 96/38557, particularly pertinent to HGF binding proteins;

TRAIL - R2 specific antibodies, peptibodies, related proteins and the like, such as those described in US Patent No. 7,521,048, particularly in pertinent parts to TRAIL - R2 binding proteins;

Activin A specific antibodies, peptibodies, related proteins, and the like, including but not limited to those described in US Publ. No. 2009/0234106, particularly in pertinent parts of Activin A binding proteins;

Specific antibodies to PCSK9 (Subtilisin / Quexin pro-protein convertase), peptibodies, related proteins and the like, including but not limited to those described in US Patent No. 8,030,457, WO 11/0027287 and WO

09/026558, particularly in pertinent parts to PCSK9 binding proteins;

TGF - beta specific antibodies, peptibodies, related proteins, and the like, including but not limited to those described in US Patent No. 6,803,453 and US Publ. No. 2007/0110747, particularly in pertinent parts to TGF - beta binding proteins;

Specific antibodies against beta-amyloid proteins, peptibodies, related proteins, and the like, including but not limited to those described in PCT Publ. No. Wo 2006/081171, particularly in pertinent parts of proteins which bind to beta - amyloid proteins. A contemplated antibody is an antibody having a heavy chain variable region comprising SEQ ID NO: 8 and a light chain variable region comprising SEQ ID No: 6 as disclosed in the International Publication;

C - Kit specific antibodies, peptibodies, related proteins, and the like, including but not limited to those described in Publ. No. 2007/0253951, particularly in pertinent parts of proteins that bind to the c - Kit receptor and / or other stem cell receptors;

OX40L specific antibodies, peptibodies, related proteins, and the like, including but not limited to those described in US Appl. No. 11 / 068,289, particularly pertinent to proteins that bind to the OX40L receptor and / or other 0X040 receptor binders; and

Other exemplary proteins include Activase® (alteplase, tPA); Aranesp® (darbepoetin alfa); Epogen® (epoetin alfa, erythropoietin); Avonex® (interferon beta - la); Bexxar® (tositumomab, anti - CD22 monoclonal antibody); Betaseron® (interferon - beta); Campath® (alemtuzumab, anti-CD52 monoclonal antibody); Dynepo® (epoetin delta); Velcade® (bortezomib); MLN0002 (anti - α4β7 monoclonal antibody);

MLN1202 (CCR2 anti-chemokine receptor monoclonal antibody); Enbrel® (etanercept, TNF / FC receptor fusion protein, TNF blocker); Eprex® (epoetin alfa); Erbitux® (cetuximab, anti - EGFR / HER1 / c - ErbB - 1); Genotropin® (somatropin, Human Growth Hormone); Herceptin® (trastuzumab, HER2 / neu anti-receptor monoclonal antibody (erbB2)); Humatrope® (somatropin, Human Growth Hormone); Humira® (adalimumab); insulin in solution; Infergen® (interferon alfacon - 1); Natrecor® (nesiritide; B-type recombinant human natriuretic peptide (hBNP)); Kineret® (anakinra); Leukine® (sargamostim, rhuGM - CSF); LymphoCide® (epratuzumab, anti-CD22 monoclonal antibody); Benlysta® (lymphostat B, belimumab, anti - BlyS monoclonal antibody); Metalyse® (tenecteplase, t-PA analog); Mircera® (betaepoetin-methoxypolyethylene glycol); Mylotarg® (gemtuzumab ozogamycin); Raptiva® (efalizumab); Cimzia® (certolizumab pegol, CDP 870); Soliris® (eculizumab); pexelizumab (anti - C5 complement), Numax ® (MEDI-524); Lucentis® (ranibizumab); Panorex® (17 - IA, edrecolomab);

Trabio® (lerdelimumab); TheraCimhR3 (nimotuzumab); Omnitarg (pertuzumab, 2C4); Osidem® (IDM - 1); OvaRex® (B43,13; Nuvion® (visilizumab); cantuzumab mertansine (huC242 - DM1); NeoRecormon® (beta epoetin); Neumega® (oprelvekin, interleukin-11 human); Neulasta® (pegylated filgastrim, G-CSF, pegylated Pegylated Met - hu - G - CSF), Neupogen ® (filgrastim, G - CSF, Met - hu - G - CSF), OKT3 ® Orthoclone (muromonab - CD3, anti - CD3 monoclonal antibody); Procrit ® (epoetin alfa); Remicade® (infliximab, anti - TNFα monoclonal antibody); Reopro® (abciximab, anti monoclonal antibody

GP IIb / IIIa receptor); Actemra® (anti-IL6 receptor monoclonal antibody); Avastin® (bevacizumab), Hu- Max - CD4 (zanolimumab); Rituxan® (rituximab, anti - CD20 monoclonal antibody); Tarceva® (erlotinib); Roferon -A®- (interferon alfa - 2a); Simulect® (basiliximab); Prexige® (lumiracoxib); Synagis® (palivizumab); 146B7 - CHO (anti - IL 15 antibody, see US Patent No. 7,153,507); Tysabri® (natalizumab, anti-a4 integrin monoclonal antibody); Valortim® (MDX 1303, anti-B protective antigen monoclonal antibody. anthracis); ABthrax®; Vectibix® (panitumumab); Xolair® (omalizumab); ETI211 (anti - MRSA monoclonal antibody); IL - 1 inhibitor (the human IgG1 Fc portion and extracellular domains of both IL - 1 receptor components (the Type I receptor and receptor accessory protein)); VEGF inhibitor (VEGFR1 Ig domains fused to IgG1 Fc); Zenapax® (daclizumab); Zenapax® (daclizumab, anti - IL - 2Ra monoclonal antibody); Zevalin® (ibritumomab tiuxetan); Zetia® (ezetimibe); Orencia® (atacicept, TA - Cl - Ig); anti - CD80 monoclonal antibody (galiximab); anti - CD23 monoclonal antibody (lumiliximab); BR2 - Fc (huBR3 / huFc fusion protein, soluble BAFF antagonist); CNTO 148 (golimumab, anti - TNFα monoclonal antibody); HGS ETR1 (mapatumumab; anti-Receptor human monoclonal antibody

-1 TRAIL); HuMaX - CD20 (ocrelizumab, anti-CD20 human monoclonal antibody); HuMax - EGFR (zalutumumab); M200 (volociximab, α5β1 anti-integrin monoclonal antibody); MDX

- 010 (ipilimumab, anti CTLA - 4 monoclonal antibody and VEGFR

- 1 (BMI - 18F1); anti - BR3 monoclonal antibody; C. difficile MDX - 066 Monoclonal Anti-Toxin Antibodies A and B (CDA

-1) and MDX-1388; anti - CD22 dsFv - PE38 conjugates (CAT

- 3888 and CAT - 8015); anti - CD25 monoclonal antibody (HuMax

TAC); anti - CD3 monoclonal antibody (NI - 0401); adecatumumab; anti - CD30 monoclonal antibody (MDX-060); MDX - 1333 (anti - IFNAR); anti - CD38 monoclonal antibody (HuMax CD38); anti-CD40L monoclonal antibody; anti - Crypto monoclonal antibody; anti - CTGF Phase I Idiopathic Pulmonary Fibrosis Fibrinogen (FG - 3019); anti - CTLA4 monoclonal antibody; anti - eotaxinal monoclonal antibody (CAT 213); anti - FGF8 monoclonal antibody; anti-ganglioside monoclonal antibody GD2; anti ganglioside monoclonal antibody GM2; anti - human GDF - 8 monoclonal antibody (MYO - 029); anti - GM - CSF Receptor monoclonal antibody (CAM - 3001); anti - HepC monoclonal antibody (HuMax HepC); anti-IFNa monoclonal antibody (MEDI - 545, MDX - 1103); anti - IGF1R monoclonal antibody; anti monoclonal antibody

- IGF - IR (HuMax - Inflam); anti IL12 monoclonal antibody (ABT - 874); anti - IL12 / IL23 monoclonal antibody (CNTO 1275); anti-IL13 monoclonal antibody (CAT-354); anti - IL2Ra monoclonal antibody (HuMax - TAC); anti - IL5 Receptor monoclonal antibody; anti-integrin receptor monoclonal antibody (MDX - 018, CNTO 95); anti Colitis Ulcerosa IP10 monoclonal antibody (MDX - 1100); anti - antibody LLY; BMS

- 66513; anti-Manose Receptor / hCGP monoclonal antibody (MDX - 1307); anti - mesothelin dsFV - PE38 conjugate (CAT - 5001); anti - PD1 monoclonal antibody (MDX -1106 (ONO - 4538)); anti - PDFGRa antibody (BMI - 3g3); anti - TGF3 monoclonal antibody (GC - 1008); anti - human TRAIL 2 Receptor monoclonal antibody (HGS - ETR2); anti - TWEAK monoclonal antibody; anti VEGFR / Flt - 1 monoclonal antibody; anti - ZP3 monoclonal antibody (HuMaz - ZP3); NVS Antibody # 1; and NVS Antibody # 2.