Drug injector systems, methods, and devices

Abstract

The present disclosure relates to systems and devices for administering an active agent to a subject. The provided device includes a housing, a spring release, an outer cap detachably engaged with and rotatable with the spring release, a diluent ejector having a stopper, a mixing spring adjacent to the diluent ejector and providing a bias to the diluent ejector within the housing, a powder barrel having a first tearable seal member and a second tearable seal member, a barbed crown positioned near the second tearable seal member and configured to pierce the second tearable seal member in response to proximal translation of the powder barrel within the housing, and a fluid chamber disposed between the stopper and the first tearable seal member. A method for producing an active pharmaceutical agent is also described.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 384,385, filed November 18, 2022, entitled "SYSTEMS, METHODS, AND APPARATUSES FOR DRUG INJECTORS," the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to a device comprising a needle for administering an active agent to a subject, the active agent being in solid form in one chamber isolated from a diluent or pharmaceutically acceptable carrier in another chamber, the device being capable of exposing the active agent to the diluent or pharmaceutically acceptable carrier for reconstitution, mixing, or dissolution prior to administration. [Background technology]

[0003] Emergency injections have long been utilized in response to many forms of extremely time-sensitive, life-threatening events, such as overdose, anaphylaxis, angioedema, or adrenal insufficiency (AI). The urgent and essential nature of the active ingredient necessitates accurate and rapid drug delivery. Indeed, while certain naloxone and epinephrine-containing auto-injectors offer dosing systems that are easier to operate and administer, steroid injectors, while equally essential, continue to suffer from cumbersome delivery systems that rely on reconstitution, resulting in a suboptimal administration device for drug preparation and delivery. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Provisional Application No. 63 / 384,385 [Non-patent literature]

[0005] [Non-Patent Document 1] Remington, Pharmaceutical Sciences, 17th ed., Mack Publishing, Easton, PA, 1985, p. 1418 [Non-patent document 2] Chapter 1 of Goodman and Gilman, The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill, New York, 2001 [Non-patent document 3] Remington, Gennaro (ed.), The Science and Practice of Pharmacy, 19th ed., Mack Publishing, Easton, PA, 1995 [Non-patent document 4] E.W. Martin, "Remington's Pharmaceutical Sciences" Summary of the Invention [Problem to be solved by the invention]

[0006] For example, certain conventional designs require an individual to inject bacteriostatic water or bacteriostatic saline into a sterile vial containing dry hydrocortisone powder, with the diluent contained in the upper vial being connected and attached to the lower vial containing the active dry hydrocortisone component. This in turn requires the difficult manipulation of different or multiple vials to mix, draw, and administer the reconstituted mixture, all within a very short, life-threatening time frame. Even in the case of the relatively simple Act-o-vial® and similar drug mixing systems, the systems require an average of 12 or more injection steps by the user. Therefore, a simplified reconstitution device is needed. [Means for solving the problem]

[0007] The present disclosure provides solutions to the above-identified problems relating to systems, methods, and devices for transporting, storing, reconstituting, and injecting active pharmaceutical agents.

[0008] One aspect of the present disclosure provides a syringe for delivering a solution made up of an active pharmaceutical agent and a diluent to a subject. The syringe includes a housing. The syringe includes a spring release. The syringe includes an outer cap releasably engaged with and rotatable with the spring release. The syringe includes a diluent ejector having a stopper. The syringe includes a mixing spring adjacent to the diluent ejector, providing a bias to the diluent ejector within the housing. The syringe includes a powder barrel having a first tearable seal member and a second tearable seal member. The syringe includes a barbed crown disposed near the second tearable seal member and configured to pierce the second tearable seal member in response to proximal translation of the powder barrel within the housing. The syringe includes a fluid chamber disposed between the stopper and the first tearable seal member.

[0009] Another aspect of the present disclosure provides a method for administering an active pharmaceutical agent to a subject through a syringe. The method includes twisting an outer cap of the syringe to activate mixing of the active pharmaceutical agent and a diluent. The method of activating mixing includes actuating a spring release to release a mixing spring such that the mixing spring provides an axial force to the diluent ejector, translating the diluent ejector proximally through the syringe. The method of activating mixing includes piercing a first tearable seal member with the diluent ejector and providing an axial force to the powder barrel such that the diluent ejector and the powder barrel translate proximally through the syringe toward the barbed crown. The method of activating mixing includes piercing a second tearable seal member disposed proximally of the diluent ejector and the powder barrel through the barbed crown to initiate mixing of the active pharmaceutical agent and the diluent into an at least partially mixed solution. A method of activating mixing includes passing the at least partially mixed solution between the crowns of the barbs toward the mixing chamber sealing member via force from the mixing spring, and causing the force of the at least partially mixed solution passing through the crowns of the barbs to translate the mixing chamber sealing member proximally, forming a mixing chamber that thoroughly mixes the active pharmaceutical agent and diluent into a thoroughly mixed solution.

[0010] Another aspect of the present disclosure provides a method of assembling a syringe. The method includes inserting a powder barrel containing an active pharmaceutical agent into a syringe barrel. The method includes adding a diluent into the syringe barrel. The method includes inserting a diluent ejector into the syringe barrel such that the diluent is disposed between the diluent ejector and the powder barrel, thereby creating a sterile, sealed assembly for the diluent and active pharmaceutical agent.

[0011] These and other aspects of the present invention are described below in the detailed description and accompanying drawings. Other aspects and features of examples of the present invention will become apparent to those skilled in the art upon review of the following description of specific representative examples of the present invention in combination with the drawings. While features of the present invention may be discussed with respect to certain examples and figures, all examples of the present invention may include one or more of the features discussed herein. Furthermore, while one or more examples may be discussed as having certain advantageous features, one or more such features may also be used in the various examples of the present invention discussed herein. Similarly, while representative examples may be discussed below as examples of devices, systems, or methods, it should be understood that such representative examples may be implemented in various devices, systems, and methods of the present invention.

[0012] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate numerous examples of the presently disclosed subject matter and serve to explain the principles of the presently disclosed subject matter. The drawings are not intended to limit the scope of the presently disclosed subject matter in any way. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 is a side cross-sectional view of a syringe according to an aspect of the present disclosure. [Figure 2A] FIG. 1 is a view of the interior of a syringe barrel, according to an aspect of the present disclosure. [Figure 2B] FIG. 1 is a diagram of a diluent ejector and powder barrel according to an aspect of the present disclosure. [Figure 2C] FIG. 1 is a cross-sectional view of the distal end of an assembled syringe barrel, in accordance with an aspect of the present disclosure. [Figure 3] 1 is a cross-sectional schematic diagram illustrating a crown of barbs according to an aspect of the present disclosure. FIG. [Figure 4A] 1 illustrates a syringe latch according to an aspect of the present disclosure. [Figure 4B] 1 illustrates a latch being inserted into a syringe barrel, according to an aspect of the present disclosure. [Figure 5] 1 illustrates a needle and needle hub being inserted into a syringe barrel, according to an aspect of the present disclosure. [Figure 6A] 1 illustrates a needle cap assembled over a syringe barrel, according to an aspect of the present disclosure. [Figure 6B] FIG. 10 is a detailed view of the proximal end of the needle cap, according to an aspect of the present disclosure. [Figure 7A] 1 illustrates a needle cap assembled over a syringe barrel, according to an aspect of the present disclosure. [Figure 7B] FIG. 10 is a detailed view of a needle cap passageway according to an aspect of the present disclosure. [Figure 8A] FIG. 1 is a detailed view of two powder barrels, with the bottom barrel showing its cross-section, according to an embodiment of the present disclosure. [Figure 8B] 1 illustrates a powder barrel assembled within a syringe barrel, according to an aspect of the present disclosure. [Figure 9] 8C illustrates a diluent being added to the syringe shown in FIG. 8B, according to an embodiment of the present disclosure. [Figure 10A] 1 illustrates an exploded diluent ejector and corresponding stopper according to an aspect of the present disclosure. [Figure 10B] 10B illustrates the diluent ejector and corresponding stopper of FIG. 10A placed into the syringe barrel of FIG. 9, according to an embodiment of the present disclosure. [Figure 11] 10C illustrates a diluent ejector and corresponding stopper assembled into the syringe barrel of FIG. 10B, according to an embodiment of the present disclosure. [Figure 12] 1 illustrates a spring canister and spring release according to an aspect of the present disclosure. [Figure 13A] FIG. 10 is a detailed view of a spring receptacle engaged with a spring release, according to an aspect of the present disclosure. [Figure 13B] FIG. 1 is an elevational view of a spring receptacle engaged with a spring release, according to an aspect of the present disclosure. [Figure 14] 13C illustrates the spring release of FIG. 13B being inserted into the partially assembled syringe shown in FIG. 11, according to an embodiment of the present disclosure. [Figure 15] 15 illustrates a mixing spring being added to the syringe shown in FIG. 14 according to an aspect of the present disclosure. [Figure 16] 1 is a perspective view of the distal end of a syringe showing a mixing spring added to the end of the syringe and showing the release ring of the spring release engaged with the spring reservoir, in accordance with an aspect of the present disclosure; FIG. [Figure 17A] 16 is a perspective view of the distal end of the mixing spring of FIG. 15 inserted into a syringe barrel, in accordance with an aspect of the present disclosure. FIG. [Figure 17B] FIG. 10 is a side view of a syringe showing a retaining clip being added to the cap away from the mixing spring, in accordance with an aspect of the present disclosure. [Figure 18] FIG. 17C is a cross-sectional view of the distal end of the syringe after adding the retaining clip of FIG. 17B, in accordance with an aspect of the present disclosure. [Figure 19] FIG. 1 is a side elevation view of the housing and cap exterior, according to an aspect of the present disclosure. [Figure 20] 19 shows the assembled syringe barrel of FIG. 18 inserted into the housing of FIG. 19, in accordance with an embodiment of the present disclosure. [Figure 21] FIG. 1 is a side elevational view of an assembled syringe according to an aspect of the present disclosure. [Figure 22A] 10A-10C illustrate rotation of the cap exterior to actuate the syringe, according to aspects of the present disclosure. [Figure 22B] 10A-10C illustrate rotation of the cap exterior to actuate the syringe, according to aspects of the present disclosure; [Figure 22C] 10A-10C illustrate rotation of the cap exterior to actuate the syringe, according to aspects of the present disclosure. [Figure 23A] 1 is a partial perspective view of a syringe according to an aspect of the present disclosure, showing an external cap on the syringe; [Figure 23B]1 is a partial perspective view of a syringe according to an aspect of the present disclosure, showing the outer cap removed so the syringe is ready for injection; [Figure 24A] 1 is a cross-sectional view of a mixing chamber according to an embodiment of the present disclosure, showing the progression of the latch as it releases from engagement with the needle hub to deliver the reconstituted active pharmaceutical agent. The position of the latch during reconstitution is shown. [Figure 24B] 1 is a cross-sectional view of a mixing chamber according to an embodiment of the present disclosure, showing the progression of the latch as it is released from engagement with the needle hub to deliver the reconstituted active pharmaceutical agent. 2 shows the latch disengaged from the needle hub and progressing distally during injection. [Figure 24C] 1 is a cross-sectional view of a mixing chamber according to an embodiment of the present disclosure, showing the progression of the latch as it is released from engagement with the needle hub to deliver the reconstituted active pharmaceutical agent; [Figure 25A] 10 illustrates a needle cap lockout feature according to an aspect of the present disclosure. 11 illustrates the barrel pin in the resting slot (before injection). [Figure 25B] 10 illustrates a needle cap lockout feature according to an aspect of the present disclosure. 11 illustrates the barrel pin in the lockout slot (after injection). [Figure 26A] 1A and 1B show alternative designs for a syringe according to aspects of the present disclosure, each showing a syringe barrel with only a single distal stopper and no powder barrel at all; [Figure 26B] 10A-10C illustrate alternative designs for a syringe according to aspects of the present disclosure. 10B-10C illustrate a device having only a first tearable seal member and a second tearable seal member, without any powder barrel or corresponding powder barrel stopper. [Figure 27] 1 is a flow chart illustrating a method for administering an active pharmaceutical agent to a subject through a syringe, according to an aspect of the present disclosure. [Figure 28] 1 is a flow chart illustrating at least a portion of a method for assembling a syringe, according to an aspect of the present disclosure. [Figure 29] 1 is a flow chart illustrating at least a portion of a method for assembling a syringe according to an aspect of the present disclosure. [Figure 30] 1 is a flow chart illustrating at least a portion of a method for assembling a syringe according to an aspect of the present disclosure. [Figure 31] 1 is a flow diagram illustrating a method of making an active pharmaceutical agent according to an aspect of the present disclosure. [Figure 32] FIG. 32 is a table showing test results of spray dried hydrocortisone sodium succinate when prepared using the method of FIG. 31 . [Figure 33] 1 is a table showing example spray drying conditions for hydrocortisone sodium succinate, according to an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0014] Specific examples of the present invention will now be described in detail with reference to the figures, in which like reference numerals indicate functionally similar or identical elements. The examples provide solutions for drug syringes and syringe systems that offer simplified, user-friendly, and safety features. The described syringes and syringe systems include a reconstitution device that allows for one-step activation and reconstitution. The active pharmaceutical agent is maintained separate from the diluent, and combination can be completed by proximal movement of the diluent ejector through the system. The syringe features described herein can also include a lockout feature that prevents unintentional reuse of a used device.

[0015] Referring now to FIG. 1 , this figure provides an example cross-sectional view of a syringe 100 in accordance with aspects of the present disclosure. Features of the syringe 100 can be discussed in terms of a device activation progression. The syringe 100 can be activated by twisting the outer cap 202 relative to the outer housing 200. Twisting can activate a mixture of the active pharmaceutical agent 404 and the diluent 402, thereby “reconstituting” the active pharmaceutical agent 404. The outer cap 202 can engage with a spring release 102 positioned distally of the outer cap 202, and twisting (or turning) the outer cap 202 can further turn the spring release 102 within the housing 200. For clarity, when referring to “proximal” or “distal” in this disclosure, it is understood to be from the perspective of a person self-administering an injection using the syringe 100. For example, the portion of the syringe 100 closest to the person is “proximal,” and the portion farthest from the person is “distal.” Thus, in Figure 1, the portion to the right of the figure is "proximal" as it is towards the skin of a person self-administering an injection.

[0016] Referring again now to the spring release 102, actuation of the spring release 102 causes the mixing spring 104 to release the diluent ejector 106, moving it proximally through the syringe 100. As can be seen in FIG. 1 , the mixing spring 104 can be positioned within a spring reservoir 105, which can be releasably engageable with the spring release 102 (e.g., via a cam 232 on the spring release 102 engaging a groove 220 in the spring reservoir 105; see FIGS. 16 and 18 ). The diluent ejector 106 can include a stopper 107. The syringe 100 can also include a powder barrel 108 containing the active pharmaceutical agent 404. The powder barrel 108 can include a proximal stopper 110 and a distal stopper 112. The proximal stopper 110 and the distal stopper 112 provide a fluid-tight seal between them and the syringe barrel 208 (see, e.g., FIG. 2A ) so that fluid must pass through the powder barrel 108. The distal stopper 112 can include a first tearable seal member 116, and the proximal stopper 110 can include a second tearable seal member 114. The active pharmaceutical agent 404 is contained between the first tearable seal member 116 and the second tearable seal member 114. A fluid chamber 302 is defined between the first tearable seal member 116 and the stopper 107 of the diluent ejector 106, and the diluent 402 is contained within this fluid chamber 302. The tearable seal members 114, 116 can be a foil material, such as a metal foil material, because foil can be easily pierced during operation of the device. Other pierceable materials are contemplated.

[0017] When the mixing spring 104 releases its compression and provides a bias to the diluent ejector 106, driving the ejector proximally, the proximal tip of the diluent ejector 106 pierces the first tearable seal member 116. At this point, the diluent 402 in the fluid chamber 302 can flow proximally into the powder barrel 108. The positive pressure created in the fluid chamber 302 as a result of the fluid and diluent ejector 106 moving proximally causes the powder barrel 108 to move even further proximally toward the crown of barbs 118. The crown of barbs 118 then pierces the second tearable seal member 116, and the diluent 402 and partially reconstituted active pharmaceutical agent 404 flow through the powder barrel 108, through the crown of barbs 118, and toward the mixing chamber sealing member 122. The mixing chamber sealing member 122 provides a fluid-tight seal between itself and the syringe barrel 208 (see, e.g., FIG. 2A), such that fluid cannot advance proximally through the mixing chamber sealing member 122 unless the sealing member is punctured (as defined below and shown in more detail in FIGS. 24A-24C).

[0018] As the pressure and diluent ejector 106 continue to move the fluid proximally, the mixing chamber sealing member 122 is forced proximally, forming the mixing chamber 120 that moves to fully reconstitute the active pharmaceutical agent 404. The proximal movement of the mixing chamber sealing member 122 compresses the injection spring 134 under positive pressure. The mixing chamber sealing member 122 also includes a latch 136 extending therefrom that is positioned to engage the needle hub 126 proximally therewith. The needle cap sealing member 130 seals the area between the needle hub 126 and the needle cap 128. The needle 124 is secured within the needle hub 126, and does not translate within the syringe 100 as the mixing chamber sealing member 122 moves proximally. As such, the distal end of the needle 124 pierces the mixing chamber sealing member 122 as it moves proximally. When the mixing chamber sealing member 122 is moved proximally enough, the latch 136 engages and connects with the needle hub 126. Once the latch 136 engages with the needle hub 126, the mixing chamber 120 can be considered fully formed and is ready to fully reconstitute the active pharmaceutical agent 404. After reconstitution, the syringe 100 is ready for injection.

[0019] The outer cap 202 can be removed (see FIG. 23B ), and the proximal end 132 of the needle cap 128 can be placed against the patient's skin. The proximal end 132 of the needle cap 128 can include a needle stopper sealing member 138 that can be pierced by the needle 124. As shown, the needle 124 can rest within the needle stopper sealing member 138 when the syringe 100 is in an unactuated configuration. An operator of the syringe 100 can then move the housing 200 toward the skin, and in doing so, the needle cap 128 moves distally relative to the housing 200, thereby exposing the distal end of the needle 124. A platform 139 at the distal end of the needle cap 128 can disengage the latch 136 from the needle hub 126 to begin the injection process. The injection spring 134 is decompressed, re-creating a positive pressure within the mixing chamber 120, which can be relieved by the reconstituted active pharmaceutical agent 404 flowing through the needle 124, into the distal end of the needle 124 and into the patient.

[0020] Upon administering the reconstituted active pharmaceutical agent 404, the user of the syringe 100 can retract the needle from the patient's skin and re-cover the needle 124 with the needle cap 128. To do so, the needle cap spring 140 can extend and force the proximal end 132 of the needle cap 128 back over the needle 124. As described in more detail in Figures 25A and 25B, a lockout mechanism can be provided to ensure that a used syringe 100 cannot be reused.

[0021] 2A and 2B are views of an internal syringe barrel 208 (see FIG. 2A ) and a view of a diluent ejector 106 and a powder barrel 108 (see FIG. 2B ), according to an embodiment of the present disclosure. In FIG. 2A , the internal syringe barrel 208 is transparent to show the locations of, for example, the mixing chamber sealing member 122, the injection spring 134, the needle cap sealing member 130, and the needle cap spring 140. The internal syringe barrel 208 can be positioned within the housing 200 (see FIG. 1 ), and features create flow paths for the diluent 402 and the active pharmaceutical agent 404. The distal end (i.e., the top of FIG. 2A ) of the internal syringe barrel 208 can include a barrel lip 209 that can interact with a retaining clip 222 (see FIG. 18 ). FIG. 2B shows the diluent ejector 106 with a corresponding stopper 107, and the powder barrel 108 with corresponding proximal and distal stoppers 110 and 112. 2C is a cross-sectional view of the distal end of an assembled syringe barrel 208, according to an embodiment of the present disclosure, showing the location of the diluent ejector 106, the corresponding chambers (i.e., the fluid chamber 302, the powder chamber 304, and the mixing chamber 120), and additional features of the assembled, unactivated syringe barrel 208, as described herein.

[0022] FIG. 3 is a cross-sectional schematic diagram illustrating a crown of barbs 118, according to an aspect of the present disclosure. In either embodiment, crown of barbs 118 provides a sharpened edge distally for piercing or tearing second tearable seal member 114 as powder barrel 108 translates proximally. As can be seen in FIG. 3 , in one example, crown of barbs 118 can include one or more protrusions 119A extending from the interior of syringe barrel 208. These protrusions can extend from the material of syringe barrel 208 toward second tearable seal member 114. Between protrusion(s) 119A are channels 119B that allow at least partially reconstituted active pharmaceutical agent 404 from powder barrel 108 to pass into mixing chamber 120. However, it will be appreciated that the crown of barbs 118 described in this disclosure can be a single protrusion that pierces or tears the second tearable seal member 114, and is in no way intended to limit the crown of barbs 118 to appearing like the jagged features shown in Figure 3. In other words, the term "crown of barbs" is not intended to imply a structural limitation that the crown of barbs be perfectly circular, like the crown of barbs shown in Figure 3, but is intended only to indicate that one or more protrusions extend distally from the location of the crown of barbs to pierce or perforate the second tearable seal member 114.

[0023] Figure 4A shows latch 136 extending from mixing chamber sealing member 122. Figure 4B shows latch 136 and mixing chamber sealing member 122 being inserted into syringe barrel 208. Figure 5 shows adding needle 124, needle hub 126, and injection spring 134 into syringe barrel 208 after inserting latch 136 and mixing chamber sealing member 122.

[0024] FIG. 6A shows a needle cap 128 added over the partially assembled syringe barrel 208 of FIG. 5, and FIG. 6B shows a detailed view of a needle stopper sealing member 138 at the proximal end 132 of the needle cap 128. The needle cap 128 can be slid downward until one or more barrel pins 210 on the syringe barrel 208 slide into passages 212 in the needle cap 128. FIG. 7A shows the needle cap 128 secured onto the syringe barrel 208, with one or more barrel pins 210 inserted into stationary slots 214. Thus, the needle cap 128 may also include a distally extending platform 139. The lockout mechanism provided by passages 212 is described in more detail herein with reference to FIGS. 25A and 25B.

[0025] FIGURE 8A is a detailed view of two powder barrels 108, with the lower powder barrel 108 shown in cross section, according to an embodiment of the present disclosure. FIGURE 8B shows the powder barrels 108 assembled within a syringe 208, such as the syringe barrel 208 of FIGURE 7A. As shown in FIGURE 9, when the powder barrel 108 and active pharmaceutical agent 404 therein are inserted into the syringe barrel 208, the distal stopper 112 and first tearable sealing member 116 provide a walled-off area within the syringe barrel 208 so that the diluent 402 can be added into the syringe barrel 208.

[0026] Figure 10A shows the unassembled diluent ejector 106 and corresponding stopper 107. The stopper 107 can be made from an elastomeric material that forms a fluid-tight seal around the moving diluent ejector 106, so that when the diluent ejector 106 moves proximally, it pushes the diluent proximally. In Figure 10B, the diluent ejector 106 and corresponding stopper 107 are inserted into a syringe barrel 208 to form a fluid chamber (see Figure 1) and seal the diluent therein. Figure 11 shows the syringe after the diluent ejector 106 and corresponding stopper 107 have been inserted.

[0027] Each of Figures 12-18 highlights details of the spring release 102 mechanism described above. Referring now to Figure 12, spring reservoir 105 can be engaged with spring release 102 (see Figure 16 for details regarding how release ring 228 can be provided to engage spring reservoir 105). Spring reservoir 105 can be open at one end (the distal end) and closed at the other end. Figure 13A illustrates the engagement of (i) cam 232 on spring release 102 with (ii) groove 220 on spring reservoir 105. As shown in Figure 14, once spring reservoir 105 is engaged with spring release 102, the two-piece combination can be assembled onto a partially assembled syringe 100 (e.g., the partially assembled syringe shown in Figure 11). As mentioned above, the open end of the spring container 105 may be oriented distally so that the compound spring 104 may be inserted into the open end, as shown in FIG.

[0028] FIG. 16 shows the distal end of the syringe 100 with the mixing spring 104 inserted, with the release ring 228 engaged with the groove 220 in the spring reservoir 105. It is noted that the view of FIG. 16 is a partial cross-sectional view, thereby removing the distal-most portions of the spring reservoir 105 and mixing spring 104 to more easily show the engagement of the groove 220. The release ring 228 may include one or more spring arms 230. The example shown in FIG. 16 includes three spring arms 230 positioned around the spring reservoir 105, as three spring arms 230 are a sufficient number to ensure central positioning of the spring reservoir 105 within the release ring 228. Each spring arm 230 includes a cam 232 that extends into the groove 220. The spring arms 230 are deflectable outward such that, upon deflection, the cams 232 move out of the grooves 220, releasing the spring container 105 and driving the diluent ejector 106 (see FIG. 1 ) proximally. This outward deflection of the spring arms 230 can be actuated by a torsion mechanism in the spring release 102. As described above, reconstitution can be initiated by releasing the mixing spring 104 to drive the diluent ejector 106, and then twisting the outer cap 202 to twist the spring release 102 and deflect the spring arms 230 outward. Additionally, the amount of “twist” required to activate mixing can be adjusted by adjusting how far the spring release 102 needs to move and rotate to deflect the spring arms 230. For example, the syringe 100 can be configured so that the outer cap 202 (and thus the spring release 102) must be twisted between 0° and 20° before the spring arm 230 moves along the lever extension 226 sufficiently to release the spring container 102.This is such that the step of twisting the external cap 202 includes twisting the external cap 202 between 0° and 45° relative to the housing 200 before the cam 232 is separated from the groove 220; such that the step of twisting the external cap 202 includes twisting the external cap 202 between 0° and 90° relative to the housing 200 before the cam 232 is separated from the groove 220; such that the step of twisting the external cap 202 includes twisting the external cap 202 between 0° and 135° relative to the housing 200 before the cam 232 is separated from the groove 220; and such that the step of twisting the external cap 202 includes twisting the external cap 202 between 0° and 180° relative to the housing 200 before the cam 232 is separated from the groove 220. The method can be operated such that twisting the outer cap 202 includes twisting the outer cap 202 between 0° and 225° relative to the housing 200 before the cam 232 is disengaged from the groove 220, such that twisting the outer cap 202 includes twisting the outer cap 202 between 0° and 270° relative to the housing 200 before the cam 232 is disengaged from the groove 220, such that twisting the outer cap 202 includes twisting the outer cap 202 between 0° and 315° relative to the housing 200 before the cam 232 is disengaged from the groove 220, such that twisting the outer cap 202 includes twisting the outer cap 202 between 0° and 360° relative to the housing 200 before the cam 232 is disengaged from the groove 220, or such that twisting the outer cap 202 includes twisting the outer cap 202 more than 360° relative to the housing 200 before the cam 232 is disengaged from the groove 220.

[0029] Each spring arm 230 may be deflectable by a feature that acts as a ramp within the syringe 100. In some examples, the ramp may be a lever extension 226 extending from the distal end of the syringe barrel 208, for example. In other examples, as shown in FIG. 16, the ramp may be a lever extension 226 extending from the retaining clip 222 (see also FIG. 18). Referring now to FIG. 17A, a diagram shows the mixing spring 104 inserted into the spring container 105 prior to compressing the mixing spring 104. In FIG. 17B, the retaining clip 222 may be inserted at the distal end of the syringe 100 to compress and accommodate the mixing spring 104. As shown, the retaining clip 222 may include a connecting extension 224 extending therefrom that may engage with the barrel lip 209 to retain the compressed mixing spring 104. 18 is a cross-sectional view of the distal end of syringe 100 after the addition of retaining clip 222 of FIG. 17B, in accordance with an embodiment of the present disclosure. The figure provides a detailed view of the engagement of barrel lip 209 with connecting extension 224. At this time, cam 232 also extends into groove 220, and rotation of spring release 102 causes spring arm 230 to follow along lever extension 226 and deflect outward.

[0030] Figures 19 and 20 illustrate the final assembly process of the syringe. Figure 19 is a side elevation view of the housing 200 and outer cap 202, according to an embodiment of the present disclosure. The housing 200 and outer cap 202 can be combined prior to insertion of the assembled syringe barrel 208. Figure 20 shows the assembled syringe barrel 208 of Figure 18 inserted into the housing 200 of Figure 19, according to an embodiment of the present disclosure. Figure 21 is a side elevation view of the assembled syringe 100, according to an embodiment of the present disclosure. Figures 19 and 20 also provide views of an optional window into the housing 200 that can provide visual information related to the status of reconstitution. The housing 200 can include a powder sight window 204 located near the location of the powder barrel 108. The powder sight window 204 can provide a view of the powder barrel 108 before or during the initial mixing of the active pharmaceutical agent and diluent. For example, the powder sight window 204 can be positioned to view the active pharmaceutical agent 404 in the powder barrel 108 prior to reconstitution, and when the diluent ejector 106 pierces the first tearable seal member 116, the powder sight window 204 can indicate that this initial piercing has occurred. The housing 200 can also include a reconstitution window 206 located in the wall of the housing 200 at a location proximal to the crown of barbs 118 (i.e., near the mixing chamber 120). The reconstitution window 206 can provide a view of the interior of the syringe 100 near the location of final mixing of the active pharmaceutical agent 404 and diluent 402. The windows 204, 206 can be a translucent plastic material or can simply be openings in the wall of the housing 200.

[0031] Figures 22A-22C illustrate the rotation of the outer cap 202 to actuate reconstitution, according to an embodiment of the present disclosure. Figure 22A shows the syringe 100 in an initial state. Figure 22B shows the syringe 100 with the outer cap 202 twisted until the mixing spring 104 is actuated, as described above. Figure 22C shows the syringe 100 with the outer cap 202 removed. Figures 23A and 23B are partially transparent views of the syringe 100 primed by twisting and removing the outer cap 202.

[0032] 24A-24C are cross-sectional views of the mixing chamber 120, providing details of the progression of the latch 136 as it is released from engagement with the needle hub 126 to deliver the reconstituted active pharmaceutical agent 404 through the needle 124. As can be seen in FIG. 24A, at this point the syringe 100 is primed and ready to inject. The needle 124 then extends distally of the mixing chamber sealing member 122, so that the reconstituted active pharmaceutical agent 404 can be delivered therethrough by again moving the mixing chamber sealing member 122 distally. To release the latch 136 from the needle hub 126, a platform 129 on the needle cap 128 (see FIG. 6B) can contact the proximal end of the latch 136, which extends through the needle hub 126. This disengages the latch 136, and the injection spring 134 pushes the mixing chamber sealing member 122 distally, expelling the fluid from the needle 124. The syringe may include some feedback mechanism during this delivery process. For example, initial contact between the platform 129 and the latch 136 can provide audible and / or tactile feedback when the latch 136 disengages from the needle hub 126. In FIG. 24B , the mixing chamber sealing member 122 is pushed distally, expelling more fluid. Other feedback mechanisms may occur or be activated toward the end of the injection. The needle hub 126 may include a hub extension 234 that extends distally and includes an extended ramp 236. The latch 136 may include a latch ramp 238 that can engage with the extended ramp 236. For example, when latch 136 is pushed distally along with mixing chamber sealing member 122, extension ramp 236 can lean against latch ramp 238 to provide audible and / or tactile feedback that fluid injection is nearly complete. In Figure 24C, the injection is complete.

[0033] 25A and 25B illustrate a needle cap 128 lockout feature in accordance with an embodiment of the present disclosure. FIG. 25A shows the barrel pin 210 within the stationary slot 214, which is a configuration the syringe 100 may be in prior to an injection. When an injection is administered and the housing 200 is moved proximally, pressing the needle cap 128 against the skin, the barrel pin 210 passes by the baffle 218 and then travels along the passageway 212. After the injection, the needle cap spring 140 (see FIG. 1 ) pushes the needle cap 128 back outward to cover the needle 124, and in doing so, the barrel pin 210 tracks back through the passageway 212 and contacts the baffle 218, which rotates the needle cap 128 so that the barrel pin 210 advances into the lockout slot 216. In FIG. 25B, barrel pin 210 is in lockout slot 216 and needle 124 remains shrouded to prevent inadvertent reuse of a used device.

[0034] 26A and 26B illustrate alternative designs for a syringe 100 in accordance with aspects of the present disclosure. FIG. 26A illustrates a syringe barrel 208 with only a single distal stopper 112 and no powder barrel 108 at all. In this example, there is no powder barrel defining a powder chamber 304, as was the case in the example illustrated in FIG. 1. In the example illustrated in FIG. 26A, the powder chamber 304 is defined at one end by the distal stopper 112 with the first tearable sealing member 116 and at the other end by the mixing chamber sealing member 122 (shown slid distally in this resting, unactuated position). A flow path 119B can extend between the powder chamber 304 and the mixing chamber sealing member 122. In some examples, the syringe barrel 208 can have a narrowed area 306 around the powder chamber 304. In this example, when the diluent ejector 106 is actuated proximally, the proximal tip of the diluent ejector 106 pierces the first tearable seal member 116. At this point, the diluent 402 in the fluid chamber 302 can flow proximally into the powder chamber 304. The positive pressure created in the powder chamber 304 as a result of the fluid moving proximally through the flow path 119B causes the mixing chamber seal member 122 to move proximally. As such, the mixing chamber 120 is formed, and the reconstitution process can proceed as in the other examples outlined above.

[0035] FIG. 26B shows a syringe 208 without a powder barrel 108 at all and without any corresponding stopper between the diluent ejector 106 and the mixing chamber sealing member 122. In this example, the powder chamber 304 is defined on one end by the first tearable seal member 116 and on the other end by the second tearable seal member 114. A flow path 119B can extend between the second tearable seal member 114 and the mixing chamber sealing member 122. In some examples, the syringe 208 can have a narrowed area 306 around the powder chamber 304. In this example, when the diluent ejector 106 is proximally actuated, the proximal tip of the diluent ejector 106 pierces the first tearable seal member 116. At this point, the diluent 402 in the fluid chamber 302 can flow proximally into the powder chamber 304. As the fluid moves proximally into the powder chamber 304, the positive pressure created within the powder chamber 304 tears the second tearable seal member 114. At this time, the at least partially mixed active pharmaceutical agent 404 flows through the flow path 119B, moving the mixing chamber sealing member 122 proximally. As such, the mixing chamber 120 forms, and the reconstitution process can proceed as in the other examples outlined above. In some alternative examples, the device shown in FIG. 26B may not include the second tearable seal member 114, similar to the device shown in FIG. 26A. In this example, the powder chamber 304 extends from the first tearable seal member 116 to the mixing chamber sealing member 122.

[0036] 27 is a flow diagram illustrating a method 2700 of administering an active pharmaceutical agent to a subject through a syringe 100, according to an aspect of the present disclosure. The method 2700 may include a step 2705 of actuating the spring release 102 to release the mixing spring 104, such that the mixing spring 104 provides an axial force to the diluent ejector 106 to translate the diluent ejector 106 proximally through the syringe 100. The method 2700 may include a step 2710 of piercing the first tearable seal member 116 with the diluent ejector 106 and providing an axial force to the powder barrel 108, such that the diluent ejector 106 and the powder barrel 108 translate proximally through the syringe 100 toward the barbed crown 118. Method 2700 may include step 2715 of piercing diluent ejector 106 and second tearable seal member 114 positioned proximally of powder barrel 108 via crown of barbs 118, thereby initiating mixing of active pharmaceutical agent 404 and diluent 402 into an at least partially mixed solution. Method 2700 may include step 2720 of passing the at least partially mixed solution between crown of barbs 118 toward mixing chamber sealing member 122 via force from mixing spring 104, wherein the force of the at least partially mixed solution passing crown of barbs 118 translates mixing chamber sealing member 122 proximally, forming a mixing chamber that thoroughly mixes active pharmaceutical agent 404 and diluent 402 into a thoroughly mixed solution (402+404). Method 2700 may end after passing step 2720, or additional steps may be performed, according to embodiments described herein.

[0037] FIG. 28 is a flow diagram illustrating at least a portion of a method 2800 of assembling a syringe 100, according to an aspect of the present disclosure. Method 2800 can include step 2805 of inserting a powder barrel 108 containing an active pharmaceutical agent 404 into a syringe barrel 208. Method 2800 can include step 2810 of adding a diluent 402 to the syringe barrel 208. Method 2800 can include step 2815 of inserting a diluent ejector 106 into the syringe barrel 108 to position the diluent between the diluent ejector 106 and the powder barrel 108, thereby creating a sterile, sealed assembly for the diluent 402 and active pharmaceutical agent 404. Method 2800 can end after inserting step 2815, or additional steps can be performed, according to embodiments described herein. For example, steps described with respect to FIG. 28 can be performed in addition to the steps described with respect to FIG. 28.

[0038] FIG. 29 is a flow diagram illustrating at least a portion of a method 2900 of assembling a syringe 100, according to an aspect of the present disclosure. Method 2900 can include step 2905 of covering a syringe barrel 208 with a spring container 105 comprising a spring release 102. Method 2900 can include step 2910 of capping the spring container 105 with a retaining clip 222 comprising a mixing spring 104. Method 2900 can include step 2915 of inserting the syringe barrel 208 and spring container 105 into housing 200. Method 2900 can end after inserting step 2915, according to embodiments described herein, or additional steps can be performed. For example, the steps described in FIG. 30 can be performed in addition to the steps described with respect to FIG. 28 and / or FIG. 29.

[0039] 30 is a flow diagram illustrating at least a portion of a method 3000 of assembling a syringe 100 according to an aspect of the present disclosure. Method 3000 may include step 3005 of connecting mixing chamber sealing member 122 to latch 136. Method 3000 may include step 3010 of inserting mixing chamber sealing member 122 and latch 136 into syringe barrel 208. Method 3000 may include step 3015 of inserting needle 124 and injection spring 134 into syringe barrel 208. Method 3000 may include step 3020 of at least partially covering syringe barrel 208 with needle cap 128. Method 3000 may end after covering step 3020, or additional steps may be performed, according to embodiments described herein.

[0040] In any of the examples described herein, the syringe 100 can deliver, for example, hydrocortisone succinate sodium salt, hydrocortisone phosphate, and / or hydrocortisone acetate. However, as will be appreciated, other active agents can be included. In some examples, the active agent can be spray-dried or freeze-dried, and the spray-dried or freeze-dried product can be placed in the powder barrel 108. In certain examples, it may be advantageous to spray-dry hydrocortisone succinate sodium salt. Spray drying can be a simple, single step from solution to powder, whereas freeze-drying requires additional milling or micronization. Spray drying provides consistent particle size and flowability, and particle engineering can adjust the size distribution as needed. As such, the present disclosure also provides a solution for spray-drying hydrocortisone succinate sodium salt contained in the powder barrel 108.

[0041] 31 is a flow diagram illustrating a method 3100 of making an active pharmaceutical agent (e.g., active pharmaceutical agent 404) according to an embodiment of the present disclosure. Method 3100 may include step 3105 of adding approximately 1.95 g of hydrocortisone 21-hemisuccinate API into 50 mL of acetone and stirring until a completely dissolved solution is achieved. Method 3100 may include step 3110 of adding approximately 100 mL of WFI into the completely dissolved solution. Method 3100 may include step 3115 of adding approximately 0.1 N NaOH while stirring until a resulting solution having a pH of 7.4 is achieved. Method 3100 may include step 3120 of heating the resulting solution to 25° C. using a rotary evaporator under vacuum to remove the acetone, thereby leaving a final solution having a volume of approximately 50 mL. Method 300 may include step 3125 of adding approximately 12.2 mg of anhydrous sodium phosphate monobasic and approximately 133 mg of disodium phosphate dibasic to the final solution and stirring to dissolve. Method 3000 may include step 3130 of adjusting the pH of the final solution to 7.4. Method 3100 may end after adjusting step 3130, or additional steps may be performed, as described or recognized herein.

[0042] The steps outlined above were performed to confirm the purity produced by such method 3100, and the data is provided in the table shown in Figure 32. The spray-dried powder tested (labeled "Modern HSS" in the table) was analyzed by RP-HPLC to compare the purity / impurity profile to that of the API, hydrocortisone succinate, and the RLD, Solu-Cortef™, measured on the same chromatographic system. The data (area %) along with the relevant United States Pharmacopeia (USP) definitions are shown in Figure 32.

[0043] Compared to the supplied API, the "latest HSS" shows increased levels of hydrocortisone (a hydrolysis product) and an unknown impurity at RRT 0.57. The impurities found at RRT 1.13 and RRT 1.53 are derived from the API and are not of concern because the API is supplied as GMP grade suitable for human use. USP has specifications for hydrocortisone succinate of 1% or less of any individual impurity and 2% or less of total impurities. The API meets these specifications.

[0044] USP also has a regulation for hydrocortisone sodium succinate injection. The regulation allows for no more than 6.7% free hydrocortisone. The regulation does not address impurity levels in HSS injection preparations. In short, "modern HSS" meets the required purity regulation.

[0045] The final solution can be spray dried. Spray drying of a therapeutic agent is understood to mean a process of exposing the therapeutic agent to an elevated temperature and then cooling the therapeutic agent, thereby providing an evaporation effect. In the present invention, the final solution of HSS can be spray dried according to the parameters shown in Figure 33. For example, the HSS can be spray dried at an inlet temperature of 82°C to 150°C and an outlet temperature of 50°C to 90°C, e.g., at an inlet temperature of 147°C to 150°C and an outlet temperature of 90°C, at an inlet temperature of 111°C and an outlet temperature of 70°C, at an inlet temperature of 95°C to 99°C and an outlet temperature of 60°C, at an inlet temperature of 82°C and an outlet temperature, etc. (See Figure 33). The active pharmaceutical agent can be spray dried using nitrogen.

[0046] Examples of the present disclosure can be implemented according to at least the following provisions.

[0047] Clause 1: A syringe for delivering a solution made up of an active pharmaceutical agent and a diluent to a subject, the syringe comprising: a housing (200); a spring release (102); an outer cap (202) releasably engaging the spring release (102) and rotatable therewith; a diluent ejector (106) having a stopper (107); and a mixing spring (104) adjacent to the diluent ejector (106) providing a bias to the diluent ejector (106) within the housing (200). a powder barrel (108) having a first tearable seal member (116) and a second tearable seal member (114); a barbed crown (118) positioned adjacent the second tearable seal member (114) and configured to pierce the second tearable seal member (114) in response to the powder barrel (108) moving proximally in translation within the housing (200); and a syringe having a fluid chamber (302) disposed between the stopper (107) and the first tearable seal member.

[0048] Clause 2: The syringe of clause 1, further comprising a mixing chamber sealing member (122) movable within the housing (200) in response to positive pressure generated by the diluent ejector (106) translating proximally via the mixing spring (104).

[0049] Clause 3: The syringe of clause 2, further comprising: a latch (136) connected to the mixing chamber sealing member (122); and a needle hub (126) engageable with the latch (136).

[0050] Clause 4: The syringe of clause 2 or 3, further comprising a needle (124); a needle cap (128); and a needle cap spring (140).

[0051] Clause 5: The syringe of clause 2, wherein the outer cap (202) can be twisted between 0° and 20° with the spring release (102).

[0052] Clause 6: The syringe of clause 2, wherein the outer cap (202) can be twisted between 0° and 45° with the spring release (102).

[0053] Clause 7: The syringe of clause 2, wherein the outer cap (202) can be twisted between 0° and 90° with the spring release (102).

[0054] Clause 8: The syringe of clause 2, wherein the outer cap (202) can be twisted between 0° and 135° by the spring release (102).

[0055] Clause 9: The syringe of clause 2, wherein the outer cap (202) can be twisted between 0° and 180° by the spring release (102).

[0056] Clause 10: The syringe of clause 2, wherein the outer cap (202) can be twisted between 0° and 225° by the spring release (102).

[0057] Clause 11: The syringe of clause 2, wherein the outer cap (202) can be twisted between 0° and 270° by the spring release (102).

[0058] Clause 12: The syringe of clause 2, wherein the outer cap (202) can be twisted between 0° and 315° by the spring release (102).

[0059] Clause 13: The syringe of clause 2, wherein the outer cap (202) can be twisted between 0° and 360° by the spring release (102).

[0060] Clause 14: The syringe of clause 2, wherein the step of twisting the outer cap (202) includes the step of twisting the outer cap (202) by more than 360 degrees.

[0061] Clause 15: The syringe of any one of clauses 2 to 14, further comprising an active pharmaceutical agent (404) disposed within the powder barrel (108).

[0062] Clause 16: The syringe of clause 15, wherein the active pharmaceutical agent (404) is a spray-dried powder accumulated in the powder barrel (108).

[0063] Clause 17: A syringe according to clause 16, wherein the active pharmaceutical ingredient (404) is hydrocortisone succinate sodium salt.

[0064] Clause 18: The syringe of clause 16, wherein the powder barrel (108) contains more than 75 mg of spray-dried powder.

[0065] Clause 19: The syringe of any one of clauses 1 to 18, wherein the outer cap (202) is engageable with the housing (200) to conceal and protect the needle cap (128).

[0066] Clause 20: The syringe of any one of clauses 1 to 19, wherein the cross section of the housing (200) has a teardrop shape.

[0067] Clause 21: The syringe of any one of clauses 1 to 20, wherein the housing (200) includes a powder sight glass (204) located near the location of the powder barrel (108).

[0068] Clause 22: The syringe of any one of clauses 1 to 21, wherein the housing (200) includes a powder sight window (204) positioned near the location of the powder barrel (108), the powder sight window (204) providing a view of the powder barrel (108) prior to or during initial mixing of the active pharmaceutical agent and diluent.

[0069] Clause 23: A syringe of any one of clauses 1 to 22, wherein the housing (200) is provided with a reconstitution window (206) located within the wall of the housing (200) proximal to the crown of spines (118), the reconstitution window (206) providing a view of the interior of the syringe near the location of final mixing of the active pharmaceutical agent and diluent.

[0070] Clause 24: The syringe of clause 23, wherein the housing (200) further comprises a powder sight window (204) positioned near the location of the powder barrel (108), the powder sight window (204) providing a view of the powder barrel (108) prior to or during initial mixing of the active pharmaceutical agent and diluent.

[0071] Clause 25: The syringe of any one of clauses 1 to 24, further comprising a spring container (105) engaged with the mixing spring (104) near the diluent ejector (106), the spring container (105) being releasably engageable with the spring release (102), and disengaging the spring container (105) from the spring release (102) thereby releasing the bias of the spring container (105) and activating the diluent ejector (106).

[0072] Clause 26: The syringe of clause 25, wherein the spring container (105) comprises an outer circumferential groove (220); the spring release (102) comprises a spring arm (230) with an extending cam (232), the cam (232) extending into the outer circumferential groove (220); and the spring arm (230) is configured to deflect radially to disengage the cam (232) from the outer circumferential groove (220).

[0073] Clause 27: The syringe of clause 26, further comprising a retaining clip (222) engaged with the housing (200) distal to the mixing spring (104), the retaining clip (222) having a lever extension (226) extending proximally into the housing (200).

[0074] Clause 28: The syringe of clause 27, wherein the lever extension (226) is positioned adjacent to and engageable with the spring arm (230), and the spring arm (230) is configured to engage with the lever extension (226) in response to rotation of the spring release (102), thereby radially deflecting the spring arm (230).

[0075] Clause 29: A method of administering an active pharmaceutical agent to a subject through a syringe, comprising: twisting a cap of the syringe to activate mixing of the active pharmaceutical agent and a diluent, wherein activating mixing comprises: actuating a spring release to release a mixing spring such that the mixing spring provides an axial force to the diluent ejector to translate the diluent ejector proximally through the syringe; piercing a first tearable sealing member with the diluent ejector and providing an axial force to the powder barrel such that the diluent ejector and the powder barrel translate proximally through the syringe toward the crown of the barbs; piercing a diluent ejector and a second tearable sealing member positioned proximally of the powder barrel via the barb, thereby initiating mixing of the active pharmaceutical agent and diluent into an at least partially mixed solution; and passing the at least partially mixed solution between the crowns of the barbs towards a mixing chamber sealing member via force from a mixing spring, wherein the force of the at least partially mixed solution passing through the crowns of the barbs translates the mixing chamber sealing member proximally to form a mixing chamber that thoroughly mixes the active pharmaceutical agent and diluent into a thoroughly mixed solution.

[0076] Clause 30: The method of clause 29, further comprising the step of preparing the thoroughly mixed solution for injection, the preparing step comprising: piercing the mixing chamber sealing member with the needle in response to proximal translation of the mixing chamber sealing member; and proximal translation of a latch secured to the mixing chamber sealing member toward the needle hub via force from the mixing spring on the active pharmaceutical agent and diluent, wherein the proximal translation of the mixing chamber sealing member and the latch loads the injection spring.

[0077] Clause 31: The method of clause 30, wherein the preparing step further comprises biasing the latch such that the latch engages upon bias and prevents movement of the needle hub, thereby holding the injection spring in a compressed position.

[0078] Clause 32: The method of clause 30 or 31, further comprising the steps of removing the outer cap from the syringe; and injecting the thoroughly mixed solution, the injecting step comprising: placing the proximal end of the needle cap on the skin of the subject and moving the syringe housing proximally such that the needle cap translates distally relative to the housing and independently of the needle so that the proximal end of the needle proximally exits the needle cap; translating the needle hub distally within the syringe in response to the distal translation of the needle cap to create pressure in the thoroughly mixed solution between the needle hub and the diluent ejector; and delivering the thoroughly dissolved solution through the needle via the pressure.

[0079] Clause 33: The method of Clause 32, further comprising the steps of removing the needle from the skin by pulling the syringe away from the subject; and covering the needle with the needle cap via the needle cap spring.

[0080] Clause 34: The method of clause 33, further comprising the step of causing the needle cap to permanently cover the needle via the needle cap spring.

[0081] Clause 35: The method of any one of clauses 32-34, wherein delivering the thoroughly mixed solution comprises delivering approximately 1 mL of the thoroughly mixed solution.

[0082] Clause 36: The method of any one of clauses 32 to 35, wherein delivering the thoroughly mixed solution comprises delivering less than 1 mL of the thoroughly mixed solution.

[0083] Clause 37: The method of any one of clauses 32 to 36, wherein the step of delivering the thoroughly mixed solution comprises delivering approximately 2 mL of the thoroughly mixed solution.

[0084] Clause 38: The method of any one of clauses 32 to 37, wherein delivering the thoroughly mixed solution comprises delivering less than 2 mL of the thoroughly mixed solution.

[0085] Clause 39: The method of any one of clauses 32 to 38, wherein delivering the thoroughly mixed solution comprises delivering more than 2 mL of the thoroughly mixed solution.

[0086] Clause 40: The method of any one of clauses 32-39, wherein the step of delivering the thoroughly mixed solution can be completed at any angle relative to the horizontal.

[0087] Clause 41: The method of any one of clauses 29 to 40, wherein the active pharmaceutical ingredient is a spray-dried powder accumulated in a powder barrel.

[0088] Clause 42: The method of clause 41, wherein the active pharmaceutical ingredient is hydrocortisone succinate sodium salt.

[0089] Clause 43: The method of clause 41 or 42, wherein the powder barrel contains more than 75 mg of spray-dried powder.

[0090] Clause 44: The method of any one of clauses 29 to 43, wherein the step of twisting the outer cap includes the step of twisting the outer cap relative to the housing between 0° and 20°.

[0091] Clause 45: The method of any one of clauses 29 to 43, wherein the step of twisting the outer cap includes the step of twisting the outer cap relative to the housing between 0° and 45°.

[0092] Clause 46: The method of any one of clauses 29 to 43, wherein the step of twisting the outer cap includes the step of twisting the outer cap relative to the housing between 0° and 90°.

[0093] Clause 47: The method of any one of clauses 29 to 43, wherein the step of twisting the outer cap includes the step of twisting the outer cap relative to the housing between 0° and 135°.

[0094] Clause 48: The method of any one of clauses 29 to 43, wherein the step of twisting the outer cap includes the step of twisting the outer cap relative to the housing between 0° and 180°.

[0095] Clause 49: The method of any one of clauses 29 to 43, wherein the step of twisting the outer cap includes the step of twisting the outer cap relative to the housing between 0° and 225°.

[0096] Clause 50: The method of any one of clauses 29 to 43, wherein the step of twisting the outer cap includes the step of twisting the outer cap relative to the housing between 0° and 270°.

[0097] Clause 51: The method of any one of clauses 29 to 43, wherein the step of twisting the outer cap includes the step of twisting the outer cap relative to the housing between 0° and 315°.

[0098] Clause 52: The method of any one of clauses 29 to 43, wherein the step of twisting the outer cap includes the step of twisting the outer cap relative to the housing between 0° and 360°.

[0099] Clause 53: The method of any one of clauses 29 to 43, wherein the step of twisting the outer cap includes the step of twisting the outer cap relative to the housing by more than 360°.

[0100] Clause 54: The method of any one of clauses 29 to 52, wherein the active pharmaceutical agent and diluent are automatically and thoroughly mixed in the mixing chamber in 20 seconds or less.

[0101] Clause 55: The method of clause 32, further comprising the step of providing an audible cue upon complete delivery of the thoroughly mixed solution through the needle.

[0102] Clause 56: A method of assembling a syringe, the method comprising the steps of: inserting a powder barrel containing an active pharmaceutical agent into the syringe; adding a diluent to the syringe; and inserting a diluent ejector into the syringe so as to position the diluent between the diluent ejector and the powder barrel, thereby producing a sterile sealed assembly for the diluent and active pharmaceutical agent.

[0103] Clause 57: The method of clause 56, further comprising the steps of: covering the syringe barrel with a spring container having a spring release; capping the spring container with a combined spring and retainer clip; and inserting the syringe barrel and spring container into the housing.

[0104] Clause 58: The method of clause 56 or 57, further comprising the steps of: connecting the mixing chamber sealing member to the latch; inserting the mixing chamber sealing member and the latch into the syringe; inserting a needle and injection spring into the syringe; and at least partially covering the syringe with a needle cap.

[0105] Clause 59: The method of any one of clauses 56-58, further comprising the step of forming an active pharmaceutical agent comprising: adding approximately 1.95 mg of hydrocortisone 21-hemisuccinate API into 50 mL of acetone and stirring until a completely dissolved solution is achieved; adding approximately 100 mL of WFI to the completely dissolved solution; adding approximately 0.1 N NaOH while stirring until a solution having a resulting pH of 7.4 is achieved; heating the resulting solution to 25°C using a rotary evaporator under vacuum to remove the acetone, thereby leaving a final solution having a volume of approximately 50 mL; adding approximately 12.2 mg of sodium phosphate monobasic anhydrous and approximately 133 mg of sodium phosphate dibasic anhydrous to the final solution and stirring to dissolve; and adjusting the pH of the final solution to 7.4.

[0106] Clause 60: The method of clause 59, wherein the step of forming the active pharmaceutical agent further comprises spray drying the final solution using nitrogen.

[0107] Clause 61: The method of Clause 60, further comprising spray drying the final solution at an inlet temperature of 82°C to 150°C and an outlet temperature of 50°C to 90°C.

[0108] Article 62: A method of making an active pharmaceutical ingredient, comprising: adding approximately 1.95 g of hydrocortisone 21-hemisuccinate API into 50 mL of acetone and stirring until a completely dissolved solution is achieved; adding approximately 100 mL of WFI to the completely dissolved solution; adding approximately 0.1 N NaOH while stirring until achieving a resulting solution having a pH of 7.4; heating the resulting solution to 25°C using a rotary evaporator under vacuum to remove acetone, thereby leaving a final solution with a volume of approximately 50 mL; adding approximately 12.2 mg of anhydrous sodium dihydrogen phosphate and approximately 133 mg of disodium hydrogen phosphate to the final solution and stirring to dissolve; and Adjusting the pH of the final solution to 7.4 A method comprising:

[0109] Clause 63: The method of Clause 62, wherein the step of forming the active pharmaceutical agent further comprises spray drying the final solution using nitrogen.

[0110] Clause 64: The method of clause 62 or 63, further comprising the step of spray drying the final solution at an inlet temperature of 82°C to 150°C and an outlet temperature of 50°C to 90°C.

[0111] Article 65: A syringe for delivering a solution made up of an active pharmaceutical agent and a diluent to a subject, comprising: Enclosure; spring release; an outer cap releasably engaging the spring release and rotatable with the spring release; a diluent discharger with a stopper; a mixing spring adjacent the diluent ejector that provides a bias to the diluent ejector within the housing; mixing chamber sealing member; a fluid chamber proximal to the stopper; powder chamber; and a first tearable sealing member positioned between the fluid chamber and the powder chamber; A syringe comprising:

[0112] Clause 66: The syringe of Clause 65, wherein the diluent ejector is configured to translate proximally to at least partially tear the first tearable sealing member, thereby allowing the diluent contained in the fluid chamber to enter the powder chamber and mix with the active pharmaceutical agent positioned within the powder chamber.

[0113] Clause 67: The syringe of Clause 65, wherein the first tearable sealing member is disposed at least partially within the stopper.

[0114] Clause 68: The syringe of clause 65, further comprising a second tearable sealing member positioned between the powder chamber and the mixing chamber sealing member.

[0115] Clause 69: The syringe of Clause 68, further comprising a flow path disposed between the second tearable sealing member and the mixing chamber sealing member.

[0116] Article 70: a latch connected to the mixing chamber sealing member; and Needle hub engageable with latch 66. The syringe of clause 65, further comprising:

[0117] Article 71: needle; needle caps; and Needle cap spring 66. The syringe of clause 65, further comprising:

[0118] Clause 72: The syringe of clause 65, wherein the outer cap can be twisted between 0° and 20° by spring release.

[0119] Clause 73: The syringe of clause 65, wherein the outer cap can be twisted between 0° and 45° by spring release.

[0120] Clause 74: The syringe of clause 65, wherein the outer cap can be twisted between 0° and 90° by a spring release.

[0121] Clause 75: The syringe of clause 65, wherein the outer cap can be twisted between 0° and 135° by spring release.

[0122] Clause 76: The syringe of clause 65, wherein the outer cap can be twisted between 0° and 180° by a spring release.

[0123] Clause 77: The syringe of clause 65, wherein the outer cap can be twisted between 0° and 225° by a spring release.

[0124] Clause 78: The syringe of clause 65, wherein the outer cap can be twisted between 0° and 270° by spring release.

[0125] Clause 79: The syringe of clause 65, wherein the outer cap can be twisted between 0° and 315° by spring release.

[0126] Clause 80: The syringe of clause 65, wherein the outer cap can be twisted between 0° and 360° by spring release.

[0127] Clause 81: A syringe described in any one of clauses 65 to 80, wherein the step of twisting the outer cap includes a step of twisting the outer cap more than 360 degrees.

[0128] Clause 82: A syringe according to any one of clauses 65 to 81, further comprising an active pharmaceutical agent, the active pharmaceutical agent being a spray-dried powder stored in the powder chamber.

[0129] Clause 83: A syringe according to clause 82, wherein the active pharmaceutical ingredient is hydrocortisone succinate sodium salt.

[0130] Clause 84: A syringe as described in any one of clauses 65 to 83, wherein the outer cap is engageable with the housing to cover and protect the needle cap.

[0131] Clause 85: A syringe according to any one of clauses 65 to 84, wherein the cross section of the housing has a teardrop shape.

[0132] Clause 86: A syringe according to any one of clauses 65 to 85, wherein the housing is provided with a powder viewing window located near the location of the powder chamber.

[0133] Clause 87: A syringe as described in any one of clauses 65 to 86, wherein the housing is provided with a powder sight glass located near the location of the powder chamber, the powder sight glass providing a view of the powder chamber as the active pharmaceutical ingredient and diluent are initially mixed.

[0134] Clause 88: A syringe described in any one of clauses 65 to 87, wherein the housing has a reconstitution window located inside the wall of the housing, proximal to the powder chamber, the reconstitution window providing a view of the interior of the syringe near where the active pharmaceutical agent and diluent are finally mixed.

[0135] Clause 89: The syringe of clause 88, wherein the housing further comprises a powder sight glass located near the location of the powder chamber, the powder sight glass providing a view of the powder chamber as the active pharmaceutical agent and diluent are initially mixed.

[0136] Clause 90: A syringe as described in any one of clauses 65 to 89, further comprising a spring container located near the diluent ejector and engaged with the mixing spring, the spring container being releasably engageable with the spring release, and disengaging the spring container from the spring release to release the bias of the spring container and activate the diluent ejector.

[0137] Clause 91: The syringe of clause 90, wherein the spring container has a peripheral groove; the spring release has a spring arm with an extending cam, the cam extending into the peripheral groove; and the spring arm is configured to deflect radially to disengage the cam from the peripheral groove.

[0138] Clause 92: The syringe of clause 91, further including a retaining clip engaged with the housing distal to the mixing spring, the retaining clip having a lever extension extending proximally into the housing.

[0139] Clause 93: The syringe of clause 92, wherein the lever extension is positioned adjacent to the spring arm and is engageable with the spring arm, and the spring arm is configured to engage with the lever extension in response to rotation of the spring release, thereby radially deflecting the spring arm.

[0140] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present disclosure, which will be limited only by the appended claims.

[0141] Ranges may be expressed herein as ranging from "about" one particular value and / or to "about" another particular value. When such a range is expressed, the range from the one particular value and / or to the other particular value is considered to be specifically contemplated and disclosed unless the context specifically dictates otherwise. Similarly, when values ​​are expressed as approximations, the use of the antecedent "about" or "approximately" is understood to indicate that the particular value forms another specifically contemplated embodiment that is to be considered disclosed unless the context clearly dictates otherwise. Furthermore, it is understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint, unless the context specifically dictates otherwise. As used herein, when referring to measurable values, such as amounts, durations, etc., the terms "about" or "approximately" are intended to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or ±0.1% from the specified value, as such variations are appropriate for carrying out the disclosed methods.

[0142] "Optional" or "optionally" means that the subsequently described event, circumstance, or substance may or may not occur or exist, and that the description includes instances in which the event, circumstance, or substance occurs or exists, as well as instances in which it does not occur or exist.

[0143] The term "and / or," as used in the specification and claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements present together in some cases and independently in other cases. Unless expressly indicated to the contrary, other elements may optionally be present other than the elements specifically named by the "and / or" clause, whether related or unrelated to the elements specifically named. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer to, in some embodiments, A without B (optionally including elements other than B); in other embodiments, B without A (optionally including elements other than A); in yet other embodiments, both A and B (optionally including other elements); etc.

[0144] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable diluent" refers to an excipient, carrier, or diluent that can be administered to a subject with a drug or pharmaceutical composition disclosed herein, and that is inert or unable to eliminate the pharmacological activity of the active agent of the pharmaceutical composition. In some embodiments, a pharmaceutically acceptable carrier is one that does not destroy or unable to eliminate the pharmacological activity of the active agent / vaccine and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the active agent. As used herein, the term "pharmaceutically acceptable salt" of a nucleic acid can be an acid or base salt that is generally considered in the art to be suitable for use in contact with human or animal tissues without undue toxicity, irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, malic acid, glycolic acid, fumaric acid, sulfuric acid, sulfamic acid, sulfanilic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, 2-hydroxyethylsulfonic acid, nitric acid, benzoic acid, 2-acetoxybenzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, pamoic acid, succinic acid, fumaric acid, maleic acid, propionic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, acetic acid, and alkanoic acids such as HOOC-(CH)-COOH, where n is 0 to 4. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. Those skilled in the art will be aware of additional pharmaceutically acceptable salts for the accumulated virus-specific antigens or polynucleotides provided herein from this disclosure and knowledge in the art.Such salts include those listed in Remington, "Pharmaceutical Sciences," 17th ed., Mack Publishing, Easton, PA, 1985, p. 1418. In general, pharmaceutically acceptable acid or base salts can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base form of such compound with a stoichiometric amount of the appropriate base or acid in a suitable solvent.

[0145] As used herein, the terms "subject," "individual," "host," and "patient" are used interchangeably herein and refer to an individual vertebrate, including a mammal or human, particularly, but not limited to, a human, in need of diagnosis, treatment, therapy, or drug injection. Mammals include, but are not limited to, murines, apes, humans, livestock, cattle, pigs, goats, sheep, horses, dogs, game animals, and pets. The methods described herein are applicable to both human therapy and veterinary applications. In some instances throughout the present disclosure, the term "patient" refers to a human patient suffering from a particular disease or disorder. In some embodiments, the subject is a mammal, and in other embodiments, the subject is a human.

[0146] For any therapeutic agent described herein, the therapeutically effective amount may be initially determined from preliminary in vitro studies and / or animal models. The therapeutically effective dose may also be determined from human data. The applied dose can be adjusted based on the relative bioavailability and potency of the administered agent. Adjusting the dose to achieve maximum efficacy based on the above and other well-known methods is within the ability of one of ordinary skill in the art. The general principles for determining therapeutic efficacy found in Chapter 1 of Goodman and Gilman, "The Pharmacological Basis of Therapeutics," 10th ed., McGraw-Hill, New York, 2001, incorporated herein by reference, are summarized below. Pharmacokinetic principles provide a basis for modifying dosage regimens to achieve the desired therapeutic effect while minimizing unacceptable side effects. Plasma concentrations of drugs can be measured and correlated with a therapeutic window, providing further guidance for modifying dosages. Pharmaceuticals are considered pharmaceutically equivalent if they contain the same active ingredient, have the same strength or concentration, dosage form, and route of administration. Two pharmaceutically equivalent drug products are considered to be bioequivalent if, under suitable test conditions, there are no significant differences in the rate and extent of bioavailability of the active ingredient in the two products.

[0147] As used herein, the terms "comprising" (and any form of "comprising" such as "comprises" and "comprised"), "having" (and any form of "having" such as "have"), "including" (and any form of "comprising" such as "include"), or "containing" (and any form of "containing" such as "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0148] As used herein, the term "about" means that a numerical value is approximate and that small variations do not significantly affect the practice of the disclosed embodiments. As used herein, the terms "about" or "approximately" when referring to a measurable value, such as an amount, duration, etc., are intended to encompass variations of ±10%, ±5%, ±1%, or ±0.1% from the specified value, such that such variations are appropriate for carrying out the disclosed methods. When limiting a numerical value, unless the context dictates otherwise, "about" means that the numerical value can vary by ±10%, ±5%, ±4%, ±3%, ±2%, or ±1% and still remain within the scope of the disclosed embodiments.

[0149] In this specification and in the concluding claims, references to parts by weight of a particular element or component in a composition indicate the weight relationship between that element or component and the other elements or components in the composition or article to which the parts by weight are expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are included in the compound.

[0150] Weight percent (wt.%) of an ingredient is based on the total weight of the formulation or composition it is in, unless specifically stated to the contrary. As used herein, the term "any" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not occur.

[0151] As used herein, the term "carrier" refers to a diluent, adjuvant, or excipient with which a compound is administered. Pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Pharmaceutical carriers can also be saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. Additionally, auxiliary substances, stabilizers, thickeners, lubricants, and coloring agents can be used. Pharmaceutical compositions contain the compound in a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers refer to sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders to be reconstituted into sterile injectable solutions or dispersions immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. The compounds can be formulated with pharmaceutically acceptable carriers or diluents, as well as any other known adjuvants and excipients, according to conventional techniques, such as those disclosed in Remington, Gennaro (ed.), "The Science and Practice of Pharmacy," 19th ed., Mack Publishing, Easton, PA, 1995. The phrase "pharmaceutically acceptable carrier" is art-recognized and includes any pharmaceutically acceptable substance, composition, or vehicle suitable for administering the compounds of the present invention to a mammal. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials involved in carrying or transporting the subject drug from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.Examples of substances that can function as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solution; and other non-toxic compatible substances used in pharmaceutical formulations. Suitable pharmaceutical carriers are reported in E.W. Martin, "Remington's Pharmaceutical Sciences," which is incorporated herein by reference in its entirety.

[0152] Wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives, and antioxidants can also be added to the compositions.

[0153] Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0154] Unless the context specifically dictates otherwise, it should be understood that each and every individual value and subrange of values ​​falling within an expressly disclosed range is also specifically contemplated and disclosed. The foregoing applies regardless of whether any or all of these embodiments are expressly disclosed in any particular instance.

Claims

1. A syringe for administering to a subject a solution made up of an active pharmaceutical agent and a diluent; Housing; Spring release; an outer cap releasably engaging said spring release and rotatable therewith; a diluent discharger with a stopper; a mixing spring adjacent the diluent ejector that provides a bias to the diluent ejector within the housing; a powder barrel including a first tearable seal member and a second tearable seal member; a barbed crown disposed adjacent the second tearable seal member and configured to pierce the second tearable seal member in response to proximal translation of the powder barrel within the housing; and a fluid chamber disposed between the stopper and the first tearable sealing member; A syringe comprising:

2. 10. The syringe of claim 1, further comprising a mixing chamber sealing member movable within the housing in response to positive pressure created by proximal translation of the diluent ejector through the mixing spring.

3. a latch connected to the mixing chamber sealing member; and a needle hub engageable with said latch The syringe of claim 2 further comprising:

4. needle; needle caps; and needle cap spring; The syringe of claim 2 further comprising:

5. 3. The syringe of claim 2, wherein the outer cap can be twisted between 0° and 20° with the spring release.

6. 3. The syringe of claim 2, wherein the outer cap can be twisted between 0° and 45° by the spring release.

7. 3. The syringe of claim 2, wherein the outer cap can be twisted between 0° and 90° with the spring release.

8. 3. The syringe of claim 2, wherein the outer cap can be twisted between 0° and 135° by the spring release.

9. 3. The syringe of claim 2, wherein the outer cap can be twisted between 0° and 180° with the spring release.

10. 3. The syringe of claim 2, wherein the outer cap can be twisted between 0° and 225° by the spring release.

11. 3. The syringe of claim 2, wherein the outer cap can be twisted between 0° and 270° by the spring release.

12. 3. The syringe of claim 2, wherein the outer cap can be twisted between 0° and 315° by the spring release.

13. 3. The syringe of claim 2, wherein the outer cap can be twisted between 0° and 360° with the spring release.

14. 3. The syringe of claim 2, wherein twisting the outer cap comprises twisting the outer cap greater than 360 degrees.

15. 3. The syringe of claim 2, further comprising the active pharmaceutical agent disposed within the powder barrel.

16. 16. The syringe of claim 15, wherein the active pharmaceutical agent is a spray-dried powder stored in the powder barrel.

17. 17. The syringe of claim 16, wherein the active pharmaceutical agent is hydrocortisone succinate sodium salt.

18. 17. The syringe of claim 16, wherein the powder barrel contains greater than 75 mg of the spray-dried powder.

19. The syringe of claim 1 , wherein the outer cap is engageable with the housing to conceal and protect a needle cap.

20. The syringe of claim 1 , wherein the cross section of the housing comprises a teardrop shape.

21. 10. The syringe of claim 1, wherein the housing includes a powder sight glass located near the location of the powder barrel.

22. 10. The syringe of claim 1, wherein the housing comprises a powder sight window located near the location of the powder barrel, the powder sight window providing a view of the powder barrel prior to or during initial mixing of the active pharmaceutical agent and the diluent.

23. 10. The syringe of claim 1, wherein the housing comprises a reconstitution window located within a wall of the housing proximal to the crown of the barbs, the reconstitution window providing a view of the interior of the syringe near the location of final mixing of the active pharmaceutical agent and the diluent.

24. 24. The syringe of claim 23, wherein the housing further comprises a powder sight window located near the location of the powder barrel, the powder sight window providing a view of the powder barrel prior to or during initial mixing of the active pharmaceutical agent and the diluent.

25. 2. The syringe of claim 1, further comprising a spring container adjacent to the diluent ejector and engaged with the mixing spring, the spring container being releasably engageable with the spring release, and wherein disengagement of the spring container from the spring release releases the bias of the spring container and activates the diluent ejector.

26. the spring container includes a circumferential groove; the spring release includes a spring arm with an extending cam, the cam extending into the circumferential groove; the spring arm is configured to bias radially to disengage the cam from the circumferential groove.

26. The syringe of claim 25.

27. 27. The syringe of claim 26, further comprising a retaining clip engaged with the housing distal to the mixing spring, the retaining clip comprising a lever extension extending proximally into the housing.

28. 28. The syringe of claim 27, wherein the lever extension is positioned adjacent to and engageable with the spring arm, the spring arm configured to engage the lever extension in response to rotation of the spring release to radially deflect the spring arm.

29. 1. A method of administering an active pharmaceutical agent to a subject via a syringe, comprising: twisting the outer cap of the syringe to activate mixing of the active pharmaceutical agent and diluent. Including, The step of activating the mixing comprises: actuating a spring release to release the mixing spring such that the mixing spring provides an axial force on the diluent ejector to translate the diluent ejector proximally through the syringe; piercing a first tearable seal member with the diluent ejector and applying an axial force to the powder barrel such that the diluent ejector and powder barrel translate proximally through the syringe toward a crown of barbs; piercing the diluent ejector and a second tearable sealing member disposed proximally of the powder barrel through the barb crown to initiate mixing of the active pharmaceutical agent and the diluent into an at least partially mixed solution; and passing the at least partially mixed solution between the crowns of the barbs toward a mixing chamber sealing member via force from the mixing spring, wherein the force of the at least partially mixed solution passing through the crowns of the barbs translates the mixing chamber sealing member proximally to form a mixing chamber that thoroughly mixes the active pharmaceutical agent and the diluent into a thoroughly mixed solution. A method comprising:

30. further comprising the step of preparing the thoroughly mixed solution for injection, said preparing step comprising: piercing the mixing chamber sealing member with a needle in response to the mixing chamber sealing member translating proximally; and translating a latch secured to the mixing chamber sealing member proximally toward a needle hub via a force from the mixing spring on the active pharmaceutical agent and the diluent, the proximal translation of the mixing chamber sealing member and the latch loading an injection spring.

30. The method of claim 29, comprising:

31. 31. The method of claim 30, wherein the preparing step further comprises biasing the latch such that the latch engages upon bias to immobilize the needle hub and hold the injection spring in a compressed position.

32. removing the outer cap from the syringe; and injecting the thoroughly mixed solution Further comprising: The step of injecting comprises: placing a proximal end of a needle cap on the skin of the subject and moving the syringe housing proximally such that the needle cap translates distally relative to the housing and independently of the needle such that the proximal end of the needle proximally exits the needle cap; translating the needle hub distally within the syringe in response to the distal translation of the needle cap to create pressure in the thoroughly mixed solution between the needle hub and the diluent ejector; and delivering the thoroughly mixed solution through the needle via the pressure. Including, 31. The method of claim 30.

33. removing the needle from the skin by pulling the syringe away from the subject; and Covering the needle with the needle cap via a needle cap spring 33. The method of claim 32, further comprising:

34. 34. The method of claim 33, further comprising the step of causing the needle cap to permanently cover the needle via the needle cap spring.

35. 33. The method of claim 32, wherein the step of delivering the thoroughly mixed solution comprises delivering approximately 1 mL of the thoroughly mixed solution.

36. 33. The method of claim 32, wherein the step of delivering the thoroughly mixed solution comprises delivering less than 1 mL of the thoroughly mixed solution.

37. 33. The method of claim 32, wherein the step of delivering the thoroughly mixed solution comprises delivering approximately 2 mL of the thoroughly mixed solution.

38. 33. The method of claim 32, wherein the step of delivering the thoroughly mixed solution comprises delivering less than 2 mL of the thoroughly mixed solution.

39. 33. The method of claim 32, wherein the step of delivering the thoroughly mixed solution comprises delivering more than 2 mL of the thoroughly mixed solution.

40. 33. The method of claim 32, wherein the step of delivering the thoroughly mixed solution can be completed at any angle relative to the horizontal.

41. 30. The method of claim 29, wherein the active pharmaceutical agent is a spray-dried powder accumulated in the powder barrel.

42. 42. The method of claim 41, wherein the active pharmaceutical agent is hydrocortisone succinate sodium salt.

43. 42. The method of claim 41, wherein the powder barrel contains greater than 75 mg of the spray-dried powder.

44. 30. The method of claim 29, wherein twisting the outer cap comprises twisting the outer cap relative to the housing between 0° and 20°.

45. 30. The method of claim 29, wherein twisting the outer cap comprises twisting the outer cap relative to the housing between 0° and 45°.

46. 30. The method of claim 29, wherein the step of twisting the outer cap comprises twisting the outer cap between 0° and 90° relative to the housing.

47. 30. The method of claim 29, wherein the step of twisting the outer cap comprises twisting the outer cap relative to the housing between 0° and 135°.

48. 30. The method of claim 29, wherein the step of twisting the outer cap comprises twisting the outer cap relative to the housing between 0° and 180°.

49. 30. The method of claim 29, wherein the step of twisting the outer cap comprises twisting the outer cap relative to the housing between 0° and 225°.

50. 30. The method of claim 29, wherein the step of twisting the outer cap comprises twisting the outer cap relative to the housing between 0° and 270°.

51. 30. The method of claim 29, wherein twisting the outer cap comprises twisting the outer cap relative to the housing between 0° and 315°.

52. 30. The method of claim 29, wherein twisting the outer cap comprises twisting the outer cap relative to the housing between 0° and 360°.

53. 30. The method of claim 29, wherein the step of twisting the outer cap comprises twisting the outer cap relative to the housing greater than 360 degrees.

54. 30. The method of claim 29, wherein the active pharmaceutical agent and the diluent are automatically and thoroughly mixed in the mixing chamber in 20 seconds or less.

55. 33. The method of claim 32, further comprising providing an audible cue when the thoroughly mixed solution is completely delivered through the needle.

56. 1. A method of assembling a syringe, comprising: inserting a powder barrel containing an active pharmaceutical agent into a syringe; adding a diluent to the syringe; and inserting the diluent ejector into the syringe barrel to position the diluent between the diluent ejector and the powder barrel, creating a sterile sealed assembly for the diluent and the active pharmaceutical agent. A method comprising:

57. covering the syringe barrel with a spring reservoir having a spring release; capping the spring container with a combined spring and retainer clip; and Inserting the syringe barrel and the spring container into a housing.

57. The method of claim 56, further comprising:

58. connecting a mixing chamber sealing member to the latch; inserting the mixing chamber sealing member and the latch into the syringe barrel; Inserting a needle and injection spring into the syringe barrel; and at least partially covering the syringe with a needle cap.

57. The method of claim 56, further comprising:

59. The method further includes the step of formulating the active pharmaceutical agent, the step of formulating the active pharmaceutical agent comprising: adding approximately 1.95 g of hydrocortisone 21-hemisuccinate API into 50 mL of acetone and stirring until a completely dissolved solution is achieved; adding approximately 100 mL of WFI to the fully dissolved solution; adding approximately 0.1 N NaOH while stirring until achieving a resulting solution having a pH of 7.4; heating the resulting solution to 25°C using a rotary evaporator under vacuum to remove acetone, leaving a final solution having a volume of approximately 50 mL; adding approximately 12.2 mg of anhydrous sodium dihydrogen phosphate and approximately 133 mg of disodium hydrogen phosphate to the final solution and stirring to dissolve; and adjusting the pH of the final solution to 7.4 57. The method of claim 56, comprising:

60. 60. The method of claim 59, wherein the step of forming the active pharmaceutical agent further comprises spray drying the final solution using nitrogen.

61. 61. The method of claim 60, further comprising spray drying the final solution at an inlet temperature of 82°C to 150°C and an outlet temperature of 50°C to 90°C.

62. 1. A method of making an active pharmaceutical agent, comprising: adding approximately 1.95 g of hydrocortisone 21-hemisuccinate API into 50 mL of acetone and stirring until a completely dissolved solution is achieved; adding approximately 100 mL of WFI to the fully dissolved solution; adding approximately 0.1 N NaOH while stirring until achieving a resulting solution having a pH of 7.4; heating the resulting solution to 25°C using a rotary evaporator under vacuum to remove acetone, leaving a final solution having a volume of approximately 50 mL; adding approximately 12.2 mg of anhydrous sodium dihydrogen phosphate and approximately 133 mg of disodium hydrogen phosphate to the final solution and stirring to dissolve; and adjusting the pH of the final solution to 7.4 A method comprising:

63. 63. The method of claim 62, wherein the step of forming the active pharmaceutical agent further comprises spray drying the final solution using nitrogen.

64. 63. The method of claim 62, further comprising spray drying the final solution at an inlet temperature of from 82°C to 150°C and an outlet temperature of from 50°C to 90°C.

65. 1. A syringe for administering to a subject a solution made up of an active pharmaceutical agent and a diluent, comprising: Housing; Spring release; an outer cap releasably engaging said spring release and rotatable therewith; a diluent discharger with a stopper; a mixing spring adjacent the diluent ejector that provides a bias to the diluent ejector within the housing; a mixing chamber sealing member; a fluid chamber proximal to the stopper; a powder chamber; and a first tearable seal member disposed between the fluid chamber and the powder chamber; A syringe comprising:

66. 66. The syringe of claim 65, wherein the diluent ejector is configured to translate proximally to at least partially tear the first tearable sealing member, thereby allowing diluent contained within the fluid chamber to enter the powder chamber and mix with the active pharmaceutical agent positioned therein.

67. 66. The syringe of claim 65, wherein the first tearable sealing member is disposed at least partially within a stopper.

68. 66. The syringe of claim 65, further comprising a second tearable seal member disposed between the powder chamber and the mixing chamber seal member.

69. 69. The syringe of claim 68, further comprising a flow path disposed between the second tearable seal member and the mixing chamber seal member.

70. a latch connected to the mixing chamber sealing member; and a needle hub engageable with said latch 66. The syringe of claim 65, further comprising:

71. needle; needle caps; and Needle cap spring 66. The syringe of claim 65, further comprising:

72. 66. The syringe of claim 65, wherein the outer cap can be twisted between 0° and 20° with the spring release.

73. 66. The syringe of claim 65, wherein the outer cap can be twisted between 0° and 45° with the spring release.

74. 66. The syringe of claim 65, wherein the outer cap can be twisted between 0° and 90° with the spring release.

75. 66. The syringe of claim 65, wherein the outer cap can be twisted between 0° and 135° with the spring release.

76. 66. The syringe of claim 65, wherein the outer cap can be twisted between 0° and 180° with the spring release.

77. 66. The syringe of claim 65, wherein the outer cap can be twisted between 0° and 225° with the spring release.

78. 66. The syringe of claim 65, wherein the outer cap can be twisted between 0° and 270° with the spring release.

79. 66. The syringe of claim 65, wherein the outer cap can be twisted between 0° and 315° with the spring release.

80. 66. The syringe of claim 65, wherein the outer cap can be twisted between 0° and 360° with the spring release.

81. 66. The syringe of claim 65, wherein twisting the outer cap comprises twisting the outer cap greater than 360 degrees.

82. 66. The syringe of claim 65, further comprising an active pharmaceutical agent, wherein the active pharmaceutical agent is a spray-dried powder stored in the powder chamber.

83. 83. The syringe of claim 82, wherein the active pharmaceutical agent is hydrocortisone succinate sodium salt.

84. 66. The syringe of claim 65, wherein the outer cap is engageable with the housing to conceal and protect a needle cap.

85. 66. The syringe of claim 65, wherein the cross section of the housing comprises a teardrop shape.

86. 66. The syringe of claim 65, wherein the housing includes a powder sight glass located near the location of the powder chamber.

87. 66. The syringe of claim 65, wherein the housing comprises a powder sight glass located near the location of the powder chamber, the powder sight glass providing a view of the powder chamber as it is initially mixing the active pharmaceutical agent and the diluent.

88. 66. The syringe of claim 65, wherein the housing comprises a reconstitution window located within a wall of the housing proximal to the powder chamber, the reconstitution window providing a view of the interior of the syringe near the location of final mixing of the active pharmaceutical agent and the diluent.

89. 89. The syringe of claim 88, wherein the housing further comprises a powder sight window located near the location of the powder chamber, the powder sight window providing a view of the powder chamber as the active pharmaceutical agent and the diluent are initially mixed.

90. 66. The syringe of claim 65, further comprising a spring container adjacent to the diluent ejector and engaged with the mixing spring, the spring container being releasably engageable with the spring release, and wherein disengagement of the spring container from the spring release releases the bias of the spring container and activates the diluent ejector.

91. the spring container includes a circumferential groove; the spring release includes a spring arm with an extending cam, the cam extending into the circumferential groove; the spring arm is configured to bias radially to disengage the cam from the circumferential groove.

91. The syringe of claim 90.

92. 92. The syringe of claim 91, further comprising a retaining clip engaged with the housing distal to the mixing spring, the retaining clip comprising a lever extension extending proximally into the housing.

93. 93. The syringe of claim 92, wherein the lever extension is positioned adjacent to and engageable with the spring arm, and the spring arm is configured to engage the lever extension in response to rotation of the spring release to radially deflect the spring arm.

Images