Autoinjector for opioid overdose rescue

Abstract

This disclosure provides devices, delivery systems, medicaments, and methods for use to rescue a subject identified in need thereof from opioid overdose. In certain embodiments, the device is an injection device (such as, an autoinjector) for intramuscular or subcutaneous administration of a medicament comprising a therapeutically effective amount of nalmefene or a pharmaceutically acceptable salt thereof.

Description

TECHNICAL FIELD

[0001] The present disclosure generally relates to medicament injection devices and, in some embodiments, to a needle assisted injector for administering medicaments such as nalmefene. BACKGROUND OF THE INVENTION

[0002] Autoinjectors can be used for the emergency administration of medicament is needed. The administration may be by a non-medical user for self-administration or administration to others. Common situations for such administration includes anaphylaxis and drug overdose.

[0003] For example, pharmaceutical products are sometimes subject to abuse. A particular dose of opioid analgesic may be more potent when administered parenterally as compared to the same dose administered orally. Abusing a pharmaceutical product may result in an overdose that could be fatal. Also, potent opioids can be used as toxic chemical agents intentionally or unintentionally to cause death in humans through exposing humans to lethal doses through aerosolizing or other means of dispersal.

[0004] Symptoms of opioid overdose include, but not limited to, loss of consciousness, unresponsiveness to outside stimulus, being awake but unable to talk, respiratory depression or respiratory cessation, vomiting, limp body, pale or clammy skin, bluish fingernails and lips, slow heartbeat, erratic heartbeat, no heartbeat and eventual death.

[0005] There continues to exist a need in the art for a system comprising an autoinjector that can be utilized to administer a medicament, e.g.. for rescuing a subject from opioid overdose. OBJECTS AND SUMMARY OF THE INVENTION

[0006] It is an object of certain embodiments of this disclosure to provide an autoinjector for administration of a pharmaceutical composition (e.g., a parenteral formulation). In a particular embodiment, the autoinjector is for rescuing a subject from an opioid overdose, or for preventing (or reducing the risk in) a subject from experiencing an opioid overdose.

[0007] It is an object of certain embodiments of this disclosure to provide a system comprising an autoinjector containing a pharmaceutical composition (e.g., a parenteral formulation). In a particular embodiment, the system is for rescuing a subject from an opioid overdose, or for preventing (or reducing the risk in) a subject from experiencing an opioid overdose.

[0008] It is an object of certain embodiments of this disclosure to provide a method for rescuing a subject from an opioid overdose, or for preventing (or reducing the risk in) a subject from experiencing an opioid overdose, utilizing the autoinjector or systems disclosed herein.

[0009] It is an object of certain embodiments of this disclosure to provide a method of prophylactically administering a pharmaceutical composition as disclosed herein to a subject (e.g., a first responder or a member of law enforcement) who is at risk of being exposed to a toxic amount of an opioid agonist (e.g., fentanyl, sufentanyl, carfentanyl, or a salt or derivative thereof), utilizing the autoinjector or systems disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The following detailed description of embodiments of the injection device, will be better understood when read in conjunction with the appended drawings of exemplary embodiments. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown.

[0011] In the drawings:

[0012] Fig. 1 is a perspective view of an injection device in a pre-firing state in accordance with a first exemplary embodiment of the present invention;

[0013] Fig. 2 is a front cross-sectional view of the injection device of Fig. 1 in a pre-firing state;

[0014] Fig. 3 is a side cross-sectional view of the injection device of Fig. 1 in a pre-firing state, taken about a plane 90 degrees from the plane of Fig. 2;

[0015] Fig. 4A is a front view of a front housing of the injection device of Fig. 1;

[0016] Fig. 4B is a side view of the front housing of the injection device of Fig. 1;

[0017] Fig. 5 is a perspective view of a medicament container of the injection device of Fig. 1;

[0018] Fig. 6 is a perspective view of a needle guard of the injection device of Fig. 1;

[0019] Fig. 7 is a perspective view of a ram of the injection device of Fig. 1;

[0020] Fig. 8 is a perspective view of the trigger mechanism of the injection device of Fig. 1;

[0021] Fig. 9 is a front cross-sectional view of the injection device of Fig. 1 in a fired state;

[0022] Fig. 10 is a side cross-sectional view of the injection device of Fig. 1 in a fired state, taken about a plane 90 degrees from the plane of Fig. 9;

[0023] Fig. 11 is a front cross-sectional view of the injection device of Fig. 1 in a locked-out state;

[0024] Fig. 12 is a side cross-sectional view of the injection device of Fig. 1 in a locked-out state, taken about a plane 90 degrees from the plane of Fig. 11;

[0025] Fig. 13 is a front cross-sectional view of a cap of the injection device of Fig. 1; and

[0026] Fig. 14 is a front cross-sectional view of an injection device in a pre-firing state in accordance with a second exemplary embodiment of the present invention.

[0027] Fig. 15(A) is a front view of analmefene autoinjector with the safety cap on; Fig. 15(B) is a front view of the nalmefene autoinjector after the safety cap is removed and the needle guard is exposed; Fig. 15(C) is a front view of the nalmefene autoinjector when the injection device is pressed and activated to deliver the drug; Fig. 15(D) is a front view of the autoinjector device after the drug is delivered.

[0028] Fig. 16 shows a pre-filled syringe (PFS) that is supplied in an auto-injector device.

[0029] Fig. 17 is a chart showing reversal of fentanyl-induced respiratory’ depression in adult healthy volunteers treated with analmefene autoinjector of this disclosure. The vertical line labeled ANTAGONIST is meant to intersect the x axis at time zero.

[0030] Fig. 18 a chart showing reversal of fentanyl-induced respiratory’ depression (mean change in Minute Ventilation from NADIR) by a nalmefene autoinjector of this disclosure.

[0031] Figs. 19(a)-(b) are charts showing plasma concentration-time profiles of nalmefene: (a) 0-12 hours, and (b) 0- 60 minutes following intramuscular (IM) administration of 1.5 mg nalmefene autoinjector of this disclosure and intramuscular (IM) injection of nalmefene (1.0 mg). DETAILED DESCRIPTION

[0032] Referring to the drawings in detail, wherein like reference numerals indicate like elements throughout, there is shown in Figs. 1-14 an injection device, generally designated 100, in accordance with an exemplary embodiment of the present invention. Particularly, Figs. 15 (A)-(D) show an autoinjector device, as one embodiment, used to administer nalmefene hydrochloride injection. Certain embodiment provides that the injection is a 1.5 mg nalmefene dose (expressed as free base).

[0033] Fig. 1 shows an exemplary injection device 100 according to a first exemplary' embodiment of the present disclosure. It is noted that, in the context of this disclosure, the terms ■‘distal” and “proximal” are used in reference to the position of the injection device 100 relative to a user of the injection device 100 when held by a user. Accordingly, a feature located distal to a second feature would be further from the user (i.e., towards an injection end of the injection device 100) and vice versa. A person having ordinary skill in the art will understand alternative embodiments employing certain features herein may be configured as needle-free jet injectors, needle assisted jet injection devices, powered injectors, low-pressure auto-injectors or other mechanized injectors. According to certain exemplary’ embodiments, injection device 100 is a one-time disposable injector. In certain embodiments, injection device 100 may be modified to provide multiple and / or variable dosings upon repeated injections. According to certain exemplary embodiments, injection device 100 is a one-time disposable injector with a lock-out feature. For example, injection device 100 may facilitate an injection of medicament stored within injection device 100 and may include a locking feature that prevents a user from attempting to use injection device 100 again after the medicament has been dispensed. In one embodiment, the locking feature is activated upon dispensing of the medicament and not upon use of injection device 100. For example, the locking feature may be activated, thus preventing injection device 100 from a subsequent attempted use by a user, even in the case where the injection device 100 was not actually used by a user for an injection, but where a trigger mechanism 108 was inadvertently activated (e.g., during transport, handling, etc. of the device) and the medicament was dispensed. Operation of injection device 100, including the locking feature, is described in further detail below.

[0034] According to certain exemplary embodiments, injection device 100 may deliver any suitable liquid drug or medicament. Further, injection device 100 may allow the injection to be administered by individuals that do not have formal training (e.g., self-administered or administered by another individual family member or other caregiver who may not be a formally trained healthcare provider). Accordingly, injection device 100 may be useful in situations where self-injections / caregiver administered injections would be beneficial, including, but not limited to, drug overdose or alcohol dependence. Further, injection device 100 may be used to inject a wide range of drugs. For example, injection device 100 may be used to inject drugs, water soluble medicaments, peptides, proteins, depot formulations and oil soluble medicaments. In one embodiment, the medicament includes an opioid antagonist, including nalmefene or nalmefene hydrochloride. In one embodiment, the injection device 100 is designed to cause a powerful and smooth expulsion of a medicament, which may be necessary for viscous formulations, including but not limited to biologies. In certain embodiments, the injection device 100 is designed to administer the medicament (also referred to as “drug’') very rapidly.

[0035] Certain embodiments of the disclosure provide devices useful in rescuing a subject (e.g., a human patient) from an opioid overdose when the devices are employed to administer the subject a therapeutically effective amount of a medicament (such as, a pharmaceutical composition containing a therapeutically effective amount of an opioid antagonist). One embodiment provides that the devices are pre-primed. Another embodiment provides that the devices are injection devices, including but not limited to autoinjectors. Certain embodiments provide that the devices are used to administer the medicament to the subject through subcutaneous injection. Other embodiments provide that the devices are used to administer the medicament through intramuscular injection.

[0036] Also provided are pharmaceutical compositions, methods, drug delivery systems and kits for rescuing a subject from opioid overdose, and / or for reversing adverse effects associated with opioid use or misuse or treating opioid use disorder in a subject identified in need thereof, wherein, in certain embodiments, the subject is administered (e g., through subcutaneous or intramuscular injection) with a medicament using a device of this disclosure.

[0037] Opioid antagonists are medications that block the activation of opioid receptors in central or peripheral nervous systems, thus blocking the effects of opioids. They are useful for rescuing a subject from opioid overdose, and for treating opioid use disorder and other conditions. The opioid antagonist that can be used in accordance with this disclosure includes, but is not limited to, nalmefene, naloxone, naltrexone, methylnaltrexone and a pharmaceutically acceptable salt or solvate thereof.

[0038] In certain embodiments, injection device 100 can be used to inject pharmaceutical compositions containing one or more of opioid antagonists. These pharmaceutical compositions include regulatory approved nalmefene (i.e., nalmetrene) products, such as, Selincro®. and Revex®, as well as those currently under development.

[0039] In certain embodiments, nalmefene or a pharmaceutically acceptable salt or solvate thereof.is the opioid antagonist that is administered through a device of this disclosure to rescue a subject from opioid overdose and / or to treat an opioid use disorder. Nalmefene is a medication that is used in the treatment of opioid overdose and alcohol dependence. Nalmefene is also known as 6-Desoxy-6-methylenenaltrexone, CPH-101, JF-1; Lu AA36143, NIH-10365, and ORF-11676, and has the following structural formula:

[0040] The inj ection device 100 includes a housing 102 having a proximal end and a distal end opposite the proximal end extending along a longitudinal axis La. The injection device 100 may further include various components and / or assemblies housed within housing 102. As shown in Figs. 2, 3 and 9-12, these components may include a medicament container 104, aneedle 106, and a trigger mechanism 108. Housing 102 may be a single piece component, or alternatively, housing 102 may be a multiple piece assembly coupled together, for example, via a snap-fit connection, a press-fit connection, a threaded engagement, adhesives, welding, or the like.

[0041] In one embodiment, the housing 102 includes a front sub-assembly and a rear subassembly coupled together, for example, via a snap-fit connection, a press-fit connection, a threaded engagement, adhesives, welding, or the like. The front sub-assembly may include a needle guard 110, a biasing member 112, a bushing 114, and a front housing 116. The rear subassembly may include a rear cap 118, an energy source 120, a ram 122, the trigger mechanism 108, and a rear housing 124. Providing two sub-assemblies may increase the ability to modulate components in each sub-assembly to allow customization and repeatability in manufacturing.

[0042] As shown in Figs. 2, 3 and 9-12, in one embodiment, the medicament container 104 is disposed at least partially within the front housing 116. The medicament container 104 may contain a medicament comprising an opioid antagonist or a pharmaceutically acceptable salt thereof. The medicament container 104 may be disposed within a sleeve 126 of the front housing 116 when disposed in the injection device 100. The front housing 116 may be coupled to the distal end of the housing 102 via, for example, a snap-fit connection, a press-fit connection, a threaded engagement, adhesives, welding, or the like. According to certain exemplary embodiments, injection device 100 may be configured to inject medicament stored within a prefilled syringe. Prefilled syringes that are manufactured by a blown glass process may have significant dimensional tolerances and unevenness. Accordingly, features of front housing 116 may serve to accommodate the shape irregularities and to properly position and locate a prefilled syringe within injection device 100. Other medicament containers such as prefilled syringes manufactured with polymers may also be accommodated.

[0043] Medicament container 104 may include a cylindrical body 166 configured to hold at least 1 mL of medicament. In some embodiments, the cylindrical body 166 may hold at least 1.5 mL, at least 2 mL, at least 2.5 mL, or at least 3 mL. As shown in Fig. 5, a plunger 130 is provided in the medicament container 104. Plunger 130 may be in association with a ram 122 of the rear sub-assembly, as described in more detail below. During an injection, ram 122 is urged distally along the longitudinal axis La by an energy source 120 to displace plunger 130 distally through medicament container 104, dispensing the medicament through needle 106. Figs. 2-3 showinjection device 100 in a pre-firing state. The operation of injection device 100, including its various stages and positions, are described in further detail below.

[0044] A sleeve 126 is configured to hold the medicament container 104, which may include a needle 106 extending from a distal end thereof. The needle 106 may be in fluid communication with the medicament container 104. A bushing 114 may be disposed within the sleeve 126 to accommodate a proximal end of the medicament container 104. As shown in Fig. 5, the medicament container 104 may include a rim 164 that engages the bushing 114. The rim 164 may be generally circular and have a circumference greater than that of the cylindrical body 166. The bushing 114 may be fixed relative to the housing 102 thereby preventing the medicament container 104 from moving distally relative to the housing 102 during a firing. In certain exemplary embodiments, medicament container 104 may include, for example, a separate glass ampule and a needle, or a pre-filled syringe. In one embodiment, sleeve 126 may include an integral medicament container. The needle 106 may be coupled to the medicament container 104 by threaded communication, snap fit communication, friction fit, or any suitable coupling configuration.

[0045] Additionally, as shown in Figs. 4A-4B, sleeve 126 may include various features, such as projections 128, configured to couple the front housing 116 to the housing 102. For example, projections 128 may be concentrically symmetrical and configured to engage openings in housing 102 to the front housing 116 to the housing 102. In one embodiment, projections 128 are disposed on legs 129, which may be concentrically symmetrical and configured to engage with features of the housing 102. Additionally, sleeve 126 may include locking features, such as locking projections 131, disposed on legs 133, which may be concentrically symmetrical, and may be configured to engage with features of needle guard 110 resulting in locking out injection device 100 to prevent a user from attempting to use an already-fired injection device 100, as discussed in more detail below.

[0046] In one embodiment, housing 102 includes openings configured to engage with sleeve 126 to couple and secure sleeve 126 to housing 102 and includes at least one window that may provide a visual indication of whether or not injection device 100 has been fired. For example, in a pre-firing state, the window may allow a user to see the medicament container 104, along with the stored medicament, and in a fired state, the window shows one or more internal components, such as a portion of trigger mechanism 108 or ram 122, which may be a color specifically selected to alert the user that injection device 100 has been fired, and is, in one embodiment, sufficiently different than other colors visible to a user (in one embodiment, having ordinary eyesight) on inj ection device 100 prior to firing, so as to be conspicuously different to, or contrast from, any other colors present or significantly present. For example, in one embodiment, the color differs from all the other components of injection device 100 pre-firing, or visible by the user pre-firing, so as to be conspicuous (e.g., introducing an entirely new color family). In one embodiment, the new color appearing after firing, is from a non-analogous part of the color wheel, or may contrast, or may be a complementary color, with respect to the colors visible on injection device 100. In one embodiment, the new color signifies caution, such as red or orange, etc. In one embodiment, the colors visible on injection device 100 in the pre-firing condition, and, in one embodiment, including when cap 136 is on and / or off injection device 100, are grays and blues, for instance. In one embodiment, when injection device 100 is fired, the color red is introduced. In one embodiment, this new color may be introduced after firing but prior to needle guard 110 being locked-out in the extended configuration.

[0047] As shown in Fig. 5, needle 106 may include an injecting tip 106a that is configured to penetrate the skin of a user and a hollow bore 106b that is in fluid communication with medicament container 104 to facilitate delivery of medicament from medicament container 104 to a user during an injection. In one embodiment, the needle 106 may be 22 gauge. In some embodiments, the needle 106 is between 22 and 29 gauge. In some embodiments, the needle 106 may be between 25 and 28 gauge, and, in other embodiments, are around 27 gauge, but alternatively other needle gauges may be used where the other components are cooperatively configured to produce the desired injection. In one embodiment, the needle 106 is a 5 / 8"’ staked needle. In some embodiments, the needle 106 is a staked needle between 1 / 2" and 3 / 4” long. In some embodiments, the needle 106 may be between 9 / 16” and 11 / 16”.

[0048] In some embodiments, thin walled needles may be used. A thin walled needle may have the same outer diameter as a staked or “regular wall’' needle of the same gauge, but allow for flow volume of a needle at least one gauge larger. For example, a 22 gauge thin walled needle may allow for the same flow volume as a 21 -gauge regular wall needle. A thin walled needle may have a wall thickness less than 0.05 mm. A thin walled needle may have a wall thickness less than 0.02 mm, 0.03 mm, 0.04 mm, 0.05 mm, 0.06 mm, 0.07 mm, 0.08 mm, or 0.09 mm. A thin walled needle may have a wall thickness between 0.02 mm and 0.09 mm, between 0.03 mm and 0.08 mm, between 0.04 mm and 0.07 mm, and between 0.05 mm and 0.06 mm. In some embodiments, thin walled needles may be used without risk of bending when injection device 100 is configured to act with manual needle insertion prior to injection.

[0049] As shown in Figs. 2-3, in one embodiment, injection device 100 includes a needle guard 110 slidably mounted at least partially within the distal end of housing 102. The needle guard 110 may be configured to engage trigger mechanism 108 to actuate firing of injection device 100. As shown in Figs. 2, 3 and 9-12, in one embodiment, needle guard 110 is slidably movable relative to housing 102 between an extended (e.g., a distal, protective) configuration and a retracted (e.g., proximal) configuration, respectively. In the extended configuration, needle guard 110, in one embodiment, covers needle 106. and in the retracted configuration, needle 106 is not covered by needle guard 110 and is thereby exposed. For example, Figs. 2-3 show needle guard 110 in the extended configuration, and Figs. 9-10 show needle guard 110 in the retracted configuration. As shown in Figs. 2-3, in one embodiment, needle guard 110 is resiliently biased toward the extended configuration via the biasing member 112. which may be disposed, for example, between a distal surface of front housing 116 and an interior surface of a distal end of needle guard 110. In some embodiments, the biasing member 112 includes a compression spring, however, other suitable energy7 sources may be used, such as an elastomer or compressed-gas spring, or a gas generator, or other suitable energy7 storage members.

[0050] As shown in Figs. 9-10, when the needle guard 110 is in the retracted configuration the needle 106 extends from the housing 102 a length X. Length X may be at least 5 mm. In some embodiments, length X is at least 2 mm, at least 3 mm, at least 4 mm, at least 6 mm, at least 7 mm, at least 8 mm, at least 9 mm or at least 10 mm. In some embodiments, length X is between 2 mm and 10 mm, between 3 mm and 9 mm. between 4 mm and 8 mm, or between 5 mm and 7 mm.

[0051] Injection device 100 may be configured to deliver the volume of medicament subcutaneously to the user. In some embodiments, injection device 100 may be configured to deliver the volume of medicament intramuscularly to the user. Length X may be determined based on the specific application of the injection device 100. For example, length X may be greater for intramuscular deliver than subcutaneous.

[0052] As shown in Fig. 6, in an exemplary embodiment, needle guard 110 includes a distal portion 132 and legs 134 extending proximally from the distal portion. In an exemplary embodiment, the distal portion 132 of needle guard 110 includes a skin-contacting member at a distal surface thereof. The distal portion 132 may be shaped generally the same as the housing 102. Distal portion 132 includes an opening (not shown) through which needle 106 can pass.

[0053] Needle guard 110 may further include projections 132a, as shown in Fig. 6. Projections 132a may engage engagement features 138 of cap 136, as shown in Fig. 13, so that needle guard 110 cannot be proximally displaced when engaged with engagement features 138 of cap 136. In an exemplary embodiment, the needle guard 110 includes a stop surface 140. The stop surface 140 may be configured to abut an inside surface of the front housing 116 so as to limit the proximal displacement of needle guard 110. For example, as needle guard 110 is proximally displaced under a force applied by a user during an injection, stop surface 140 will come into contact with an inside surface of the front housing 116 so that needle guard 110 cannot be further proximally displaced. The distance between the skin-contacting member and the stop surface 140 may be adjusted during manufacture to adjust the length X the needle 106 extends from the housing 102.

[0054] In one embodiment, legs 134 of needle guard 110 are configured to be received in openings of front housing 116. Further, legs 134 may include ridges 142 configured to engage grooves of front housing 116, not shown, to facilitate alignment and guiding of legs 134 as needle guard 110 is axially displaced. As shown in Fig. 6, legs 134 also include firing-initiation members, such as camming surfaces 144 at a proximal end of legs 134. In an exemplary embodiment, legs 134 and camming surface 144 may be concentrically symmetrical. Camming surfaces 144 are configured to engage and displace trigger mechanism 108 to initiate a firing of injection device 100. The proximate ends of legs 134 may also be sloped to facilitate legs 134 engaging trigger mechanism 108 when needle guard 110 is displaced from the extended configuration to the retracted configuration.

[0055] Needle guard 110 may have a length sufficient to cover needle 106 in the extended configuration. In some embodiments, the needle guard 110 may remain in the extended configuration when the cap 136 is coupled to the front housing 116. As shown in Figs. 4A-4B, the front housing 116 may include projections 146 extending from a distal end thereof, angled so as to allow the cap 136 to be rotationally tightened thereto. In some embodiments, the cap 136 may be snap fit or friction fit to the front housing 116. In some embodiments, the cap 136 may force the needle guard 110 from the extended configuration toward the retracted configuration into an intermediate configuration when the cap 136 is coupled to the front housing 116. The intermediate configuration may reduce the length of the injection device 100, or may be necessary due to the needle 106 length requiring the needle guard 110 to be longer than the cap 136 can accommodate. The needle guard 110 may partially expose the needle 106 within the cap 136 when the cap 136 is fixed to the front housing 116. This intermediate configuration may also be referred to as the storing configuration of the needle guard 110.

[0056] As shown in Figs. 11-12, the injection device 100 may be in a “locked-out” state when the needle guard 110 moves from the retracted configuration to the extended configuration following a firing. For example, the “locked-ouf’ state can be observed after the user has removed injection device 100 from the injection site. In the retracted configuration nothing is restraining needle guard 110 against the force of biasing member 112, and accordingly, needle guard 110 is distally displaced from the retracted configuration to the extended configuration under the force of biasing member 112, thereby covering needle 106. As needle guard 110 moves distally from the retracted configuration to the extended configuration under the force of biasing member 112, projections 146, which are flexed in a radially outward direction, engage the proximal surface of the front housing 116 and a proximal surface of opening 148 of the ram 122 to further prevent movement thereof. As shown in Fig. 11, the association of projections 146 with proximal surface of opening 148 of the ram 122 prevents needle guard 110 from being displaced proximally, and the association of projections 146 with the proximal surface of the front housing 116 prevents needle guard 110 from being displaced distally. Thus, needle guard 110 is in a locked position, thereby locking-out injection device 100 such that needle 106 is covered and needle guard 110 is locked in place so that a user cannot attempt a subsequent injection. Afterwards, the user may affix cap 136 back onto the distal end of injection device 100.

[0057] Advantageously, in one embodiment, this “locked-out” state is not dependent on displacement of needle guard 110, but rather, is dependent on dispensing of the medicament stored in medicament container 104 and / or movement of ram 122. For example, injection device 100 becomes locked-out in situations where the medicament is inadvertently dispensed, even if needle guard 110 has not been displaced. Injection device 100 may become locked-out in any instance where energy source 120 is activated and ram 122 is distally displaced, causing ram rod 158 to displace plunger 130. thereby dispensing the medicament in the medicament container 104 through the needle 106.

[0058] As shown in Fig. 3, in one embodiment, a rear cap 118 includes a ram holding member 156. Ram holding member 156 may be a projection extending distally from a proximal surface of the rear cap 118. The ram holding member 156 may be configured to engage a trigger engagement member 154 of ram 122. For example, as shown in Fig. 3, in one embodiment, ram holding member 156 may be a bell-shaped projection, and may engage with a complementary shaped feature (e.g., trigger engagement member 154) of ram 122. In one embodiment, ram holding member 156 and the trigger engagement member 154 of ram 122 may include a circular crosssection.

[0059] As shown in Fig. 7, ram 122 may be a generally cylindrical member. Ram 122 may include at least one opening extending therethrough to accommodate and receive features of the other components of the injection device 100. For example, ram 122 may include openings 148 at a distal end thereof shaped and sized to receive the legs 134 of needle guard 110. Opening 148 may allow legs 134 of needle guard 110 to slide relative to the ram 122 when the needle guard 110 moves between the extended configuration to the retracted configuration. Although shown as a single piece, ram 122 may be a multiple-piece assembly that may be coupled together, for example, via a snap-fit connection, a press-fit connection, a threaded engagement, adhesives, welding, or other suitable couplings. Ram 122 may preferably include various features that may be configured to facilitate firing of injection device 100 to dispense the medicament stored in medicament container 104.

[0060] Ram 122 may further include openings 150 at a proximal end thereof shaped and sized to receive the legs 152 of the trigger mechanism 108. Opening 150 may allow legs 152 of trigger mechanism 108 to slide relative to the ram 122 when the trigger mechanism 108 moves proximally when engaged by the needle guard 110 moving from the extended configuration to the retracted configuration.

[0061] As shown in Fig. 7, the ram 122 may include trigger engagement members 154 extending proximally therefrom. Although the trigger engagement member 154 is shown as projections, alternative implementations are contemplated such as an elongated tab. a thinned tab, a recess, a protrusion, a bulge, a thread, etc., that may engage a ram holding member 156 of the rear cap 118. As discussed above, ram holding member 156 may be a bulb extending distally from the rear cap 118 within the housing 102 such that trigger engagement members 154 prevent the ram 122 from moving distally when engaged. In some embodiments, there may be one trigger engagement member 154, and in some embodiments, there may be more than one trigger engagement member 154 spaced circumferentially around the ram 122.

[0062] As shown in Figs. 2, 3 and 9-12, ram 122 may also include a ram rod 158 extending distally along the longitudinal axis La from a proximal end thereof. Ram rod 158 may extend from a generally central portion of the proximal end of the ram 122. Ram rod 158 may extend beyond the length of the ram 122 into the medicament container 104 to engage the plunger 130. The plunger may include a receiver 160 shaped and sized to accommodate the distal end of the ram rod 158. The receiver 160 may ensure that the ram rod 158 engages a center portion of the plunger 130. In some embodiments, the ram rod 158 is coupled to the plunger 130. The ram rod 158 may move the plunger 130 relative to the medicament container 104 when the injection device 100 is fired.

[0063] As shown in Figs. 2-3, injection device 100, in certain embodiments, includes trigger mechanism 108. In one embodiment, ram 122 is slidably mounted within housing 102 and is engaged by energy source 120. Energy source 120 may engage a distal end of the ram 122. In an exemplary embodiment, energy source 120 includes a compression spring, however, other suitable energy sources may be used, such as an elastomer or compressed-gas spring, or a gas generator, or other suitable energy storage members. In Figs. 2-3, ram 122 is in a pre-firing proximal-most position. During an injection, ram 122 is urged distally by energy released by energy source 120. Once an injection is completed, ram 122 is disposed in a distal-most position. In this distal position, needle guard 110 is locked-out and extends over needle tip 106a so that a user cannot attempt a subsequent injection and the needle guard 110 may function as sharps protection.

[0064] While injection device 100 may deliver an injection of about 0.5 mL per injection, other volumes may be injected in alternative embodiments. In certain embodiments, injection device 100 may delivery an injection of about 1 ml per injection, about 1.5 ml per injection, about 2 ml per injection, about 2.5 ml per injection, about 3 ml per injection, or about 3.5 ml per injection. In certain embodiments, injection device 100 may deliver an injection of greater than 0.5 mL per injection, greater than 1 mL per injection, greater than 1.5 mL per injection, greater than 2 mL per injection, greater than 2.5 mL per injection, greater than 3 mL per injection, or greater than 3.5 mL per injection. In other embodiments, injection device 100 may deliver an injection in a range of about 0.2 mL to about 3 mL, in a range of about 0.5 mL to about 2.75 mL, in a range of about 0.75 mL to about 2.5 mL, in a range of about 1 mL to about 2.25 mL. in a range of about 1.25 mL to about 2 mL, or in a range of about 1.5 mL to about 1.75 mL.

[0065] In one embodiment, injection device 100 may inject 0.5 ml of a medicament dissolved in an aqueous solution in about 0.1 sec., about 0.2 sec., about 0.3 sec., about 0.4 sec., about 0.5 sec., about 0.6 sec., about 0.7 sec., about 0.8 sec., about 0.9 sec., about 1.0 sec., or any range determinable from the preceding times (for example, about 0.5 sec. to about 1.0 sec. or about 0.4 sec. to about 0.6 sec.). In one embodiment, injection device 100 may inject the medicament at a flow rate of at least 2.5 mL / sec. The flow rate may be at least 3 mL / sec, at least 3.5 mL / sec, at least 4 mL / sec, at least 4.5 mL / sec, at least 5 mL / sec, or at least 5.5 mL / sec. The flow rate may be between 2.5 mL / sec to 5.5 mL / sec. between 3 mL / sec to 5 mL / sec, or between 3.5 mL / sec to 4.5 mL / sec.

[0066] To initiate firing of the injection device 100, movement of the needle guard 110 from the extended configuration to the retracted configuration causes the trigger engagement member 154 to disengage from the ram 122, thereby allowing the energy source 120 to move the plunger 130 relative to the medicament container 104 to expel the medicament through the needle 106. As shown in Fig. 3, blocking portions 162 of trigger mechanism 108 may prevent trigger engagement member 154 of the ram 122 from moving axially when the needle guard 110 is in the extended configuration. Blocking portions may have an interior configuration shaped to receive the trigger engagement member 154 to prevent rotation thereof relative to the trigger mechanism 108. During proximal movement of the needle guard 110 and distal movement of the trigger mechanism 108, the blocking portions 162 may move relative to the ram 122 and no longer engage trigger engagement member 154. When the blocking portions 162 no longer prevent radial movement of the trigger engagement member 154, the distal force produced by the energy source 120 on the ram 122 causes the trigger engagement member 154 to flex radially outward around the ram holding member 156. The ram 122 is thereby free to move relative to the housing 102 and causes the ram rod 158 to move the plunger 130 relative to the medicament container 104. As shown in Figs. 9-10, during a firing, the ram 122 forces the ram rod 158 to eject the volume of medicament contained in the medicament container 104.

[0067] As shown in Fig. 13, in one embodiment, injection device 100 includes a cap 136. The cap 136 may be removably affixable to a distal end of housing 102. In one embodiment, the cap 136 may be removably affixable to the distal end of front housing 116. For example, cap 136 may be removably affixed to the distal end of housing 102 via a threaded engagement and rear cap 118 may include features (e.g., projections) configured to engage a portion of the proximal end of housing 102 (e.g., openings) to couple rear cap 118 to housing 102. The cap 136 may include a barrel 139 extending along the longitudinal axis La shaped and sized to receive the needle 106 therein. The barrel 139 may extend at least partially along a length of the cap 136. A proximal end of the barrel 139 may be open to receive the needle 106 and / or a portion of the medicament container 104. A distal end of the barrel 139 may be closed to prevent the needle 106 from being exposed while the cap 136 is coupled to the housing 102. The barrel 139 may include an engagement lip 141 extending radially inward therefrom. The engagement lip 141 may extend around a circumference of the barrel 139. In one embodiment, the barrel 139 may include more than one engagement lip 141 spaced circumferentially apart. The engagement lip 141 may be configured to engage a needle shield 243 covering the needle 106, as shown in Fig. 14. In one embodiment, the distal end of the cap 136 may be open and shaped to allow the needle shield 243 to extend therethrough. Removal of the cap 136 may remove the needle shield 243 from the needle 106 to prepare for an injection.

[0068] When affixed to injection device 100, the cap 136 may ensure that an injection is not triggered by an inadvertent application of a force to needle guard 110. In one embodiment, the cap 136 includes two engagement features 138. As shown in Fig. 13, the cap 136 may include engagement features 138. Engagement features 138 may be threads configured to threadedly engage other features of injection device 100. For example, engagement feature 138 may be configured to secure cap 136 to the distal end of housing 102 or be configured to threadedly engage a distal portion of front housing 116. In one embodiment, engagement feature 138 may be configured to threadedly engage features (e.g., threads) of needle guard 110 to prevent proximal displacement of needle guard 110.

[0069] In another aspect of the present disclosure, a method of delivering an opioid antagonist or a pharmaceutically acceptable salt thereof is provided. The method may include providing an injector, pressing the needle guard against an injection site of a user with sufficient force to move the needle guard from the extended configuration to the retracted configuration, thereby inserting the needle to an insertion depth, and causing the energy’ source to move the plunger through the medicament container expelling the medicament through the needle, wherein the medicament flows through the needle at a flow rate of at least 2.5 mL / sec. In some embodiments, the injector may include a medicament container containing the medicament comprising an opioid antagonist or a pharmaceutically acceptable salt thereof, a needle coupled to a proximal end of the medicament container and in fluid communication with the medicament container, the retractable needle guard, the needle guard movable between an extended configuration and a retracted configuration, a ram configured to move a plunger coupled to a proximal end thereof relative to the medicament container, and an energy source engaging a distal end of the ram, the energy source configured to move the ram proximally relative to the housing. In some embodiments, the injector further comprises a housing having a proximal end and a distal end opposite the proximal end extending along a longitudinal axis and a trigger member configured to engage the ram and prevent movement thereof when the needle guard is in the extended configuration.

[0070] Fig. 14 illustrates a second exemplary embodiment of an injection device, generally-designated 200, having a pin-like safety mechanism 268. The injection device 200 may be an auto-injector, needle-free jet injector, needle assisted jet injection device, powered injector, low-pressure auto-injector or other mechanized injector.

[0071] The injection device 200 includes ahousing 202 having a proximal end and a distal end opposite the proximal end extending along a longitudinal axis La. The injection device 200 may further include various components and / or assemblies housed within housing 202. As shown in Fig. 14, these components may include a medicament container 204, a needle 206, and a trigger mechanism 208. Housing 202 may be a single piece component, or alternatively, housing 102 may be a multiple piece assembly coupled together, for example, via a snap-fit connection, a press-fit connection, a threaded engagement, adhesives, welding, or the like.

[0072] In one embodiment, the housing 202 includes a front sub-assembly and a rear subassembly coupled together, for example, via a snap-fit connection, a press-fit connection, a threaded engagement, adhesives, welding, or the like. The front sub-assembly may include a needle guard 210, a biasing member 212, a bushing 214, and a front housing 216. The rear sub assembly may include a rear cap 218. an energy source 220, a ram 222, the trigger mechanism 208, and a rear housing 224. Providing two sub-assemblies may increase the ability to modulate components in each sub-assembly to allow customization and repeatability in manufacturing. A cap 236 may be releasably coupled to the front housing 216 and may receive a needle shield 243 therein.

[0073] In one embodiment, the pin-like safety mechanism 268 is used to keep a high force spring compressed during assembly of the injection device 200.

[0074] The term “about’" or “approximately"’ is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number, which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number. It should be appreciated that all numerical values and ranges disclosed herein are approximate values and ranges, whether “about” is used in conjunction therewith. It should also be appreciated that the term “about,” as used herein, in conjunction with a numeral refers to a value that may be ±0.01% (inclusive), ±0.1% (inclusive), ±0.5% (inclusive), ±1% (inclusive) of that numeral, ±2% (inclusive) of that numeral, ±3% (inclusive) of that numeral, ±5% (inclusive) of that numeral, ±10% (inclusive) of that numeral, or ±15% (inclusive) of that numeral. It should further be appreciated that when a numerical range is disclosed herein, any numerical value falling within the range is also specifically disclosed. Drug Delivery System

[0075] Another aspect of this disclosure provides a drug delivery system comprising an injection device of the disclosure and a pharmaceutical composition (also referred to as “medicament”) described below. In certain embodiments, the injection device is pre-filled with the pharmaceutical composition prior to the administration to a subject identified as in need.

[0076] In certain embodiments, the pharmaceutical composition is disposed within a prefilled syringe (PFS) before the PFS is placed into the injection device. Another embodiment provides that the pharmaceutical composition is disposed within a vial before the vial is placed into the inj ection device. Another example is that the pharmaceutical composition is disposed within a pen before the pen is lodged into the injection device.

[0077] One embodiment of this disclosure provides a nalmefene hydrochloride injection, auto-injector (NAI) as a single-dose device containing 1.5 mg of nalmefene (expressed as free acid or base form). The NAI 1.5 mg is designed to be delivered intramuscularly (IM) or subcutaneously (SC) for the emergency treatment of known or suspected opioid overdose and to provide an additional treatment option for reversal of opioid overdose in the community setting. In certain embodiments, the NAI 1.5 mg is an automated drug delivery device for the 1M / SC administration ofnalmefene. Certain embodiments provide a NAI 1.5 mg as a single-dose, disposable device that may be used by non-medically trained responders (such as caregivers, relatives, friends and bystanders) in the community setting as well as by medically trained personnel in a community or health care setting. Pharmaceutical Compositions

[0078] Another aspect of this disclosure is draw n to a system comprising an injector device as disclosed therein that contains a pharmaceutical composition (also referred to as ■‘medicament7’) efficacious to rescue a subject (e.g., a human being) from opioid overdose, and / or for treating opioid use disorder and other conditions. Certain embodiments provide that the pharmaceutical composition includes a therapeutically effective amount of one or more opioid antagonists. Suitable opioid antagonist includes, such as, nalmefene, naloxone, naltrexone, methylnaltrexone and a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical composition (or ‘'medicament”) comprises nalmefene and a pharmaceutically acceptable salt or solvate thereof.

[0079] The pharmaceutical composition of this disclosure may further comprise a parentally acceptable adjuvant. In certain embodiments, the adjuvant may be an angiotensin converting enzyme (ACE) inhibitor (e.g., enalapril, captopril, lisinopril, benazepril, enalaprilat, espirapril, fosinopril, moexipril, quinapril, ramipril, perindopril, trandolapril), an angiotensin receptor blocker (e.g., valsartan, losartan, irbesartan, telmisartan, eprosartan, candesartan, olmesartan, saprisartan. tasosartan, elisartan), a calcium channel blocker (e.g.. amlodipine, anipamil, bamidipine, benidipine, bepridil. darodipine, diltiazem, efonidipine, felodipine. isradipine. lacidipine, lercanidipine, lidoflazine, manidipine, mepirodipine, nicardipine, nifedipine, niludipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, perhexiline, tiapamil, verapamil), nitrate chloride, magnesium chloride (MgCh), or a combination thereof. In one embodiment, the pharmaceutical composition comprises magnesium chloride (MgCh).

[0080] In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of nalmefene or a pharmaceutically acceptable salt or solvate thereof and a parentally acceptable adjuvant (e.g., magnesium chloride). Certain embodiment provides that the pharmaceutical composition is a nalmefene hydrochloride composition at a dose from about 0.1 mg to about 5.0 mg or about 0.5 mg to about 3.0 mg, for example, at a dose of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, or 3.0 mg (all doses are expressed in free base or free acid form). One embodiment provides that the pharmaceutical composition is a 1.5 mg dose of nalmefene based on an equivalent dose of nalmefene hydrochloride.

[0081] In one embodiment, the parentally acceptable adjuvant comprises magnesium chloride (MgCh). Magnesium chloride may be present in the pharmaceutical composition at about 0.1% to about 5.0% or at about 0.5% to about 3.0% (w / v). One embodiment provides that magnesium chloride is present at about 0.7% to about 1.5% or about 0.8% to about 1.0% w / v (e.g., 0.94% w / v) of the pharmaceutical composition.

[0082] Certain embodiments provide that the pharmaceutical composition (or medicament), when administered (e.g., intramuscularly or subcutaneously) through a device of this disclosure, provides a time to onset of action (e.g., counteracting at least one symptom of an opioid overdose, or measurable concentration of the opioid antagonist) of about 4 minutes or less, about 3 minutes or less, about 2 minutes or less or about 1 minute or less upon administration to a subject experiencing an opioid agonist overdose. In other embodiments, the pharmaceutical composition provides a time to onset of action of about 4 minutes or less, about 3 minutes or less, about 2 minutes or less or about 1 minute or less in treating opioid use disorder and / or other conditions in a subject identified in need thereof. In one embodiment, the NAI 1.5 mg of this disclosure provides the onset of action at about 2.5 minutes.

[0083] In certain embodiments, the pharmaceutical composition, when administered (e.g., intramuscularly or subcutaneously) through a device of this disclosure, provides a mean time to maximum plasma concentration (Tmax) of nalmefene of about 1 hour or less, about 30 minutes or less, about 20 minutes or less, about 15 minutes or less, about 10 minutes or less, about 5 minutes or less, or about 2 minutes, or from about 5 to 60 minutes, post administration to a population of subjects (e.g., healthy subjects) less than that of a comparative pharmaceutical composition but without the adjuvant (e.g., magnesium chloride). In one embodiment, the pharmaceutical composition, administered through a device of this disclosure, provides the Tmax of nalmefene at about 15 minutes.

[0084] Another embodiment provides that the pharmaceutical composition, after administration intramuscularly or subcutaneously through a device of this disclosure, provides a Tmax in a value less (e.g.. about 15 minutes less) than that of a comparative pharmaceutical composition but without the adjuvant (e.g., magnesium chloride).

[0085] In certain embodiments, the pharmaceutical composition utilized in this disclosure comprising a therapeutically effective amount of nalmefene or a pharmaceutically acceptable salt thereof and a parenterally acceptable adjuvant (e.g., magnesium chloride), wherein the formulation provides a mean time to maximum plasma concentration of nalmefene (Tmax) that is shorter than the mean time to maximum plasma concentration of nalmefene of a comparative formulation without the adjuvant and / or not through a device of this disclosure, post intramuscular or subcutaneous injection to a population of subjects (e.g., healthy subjects, or otherwise healthy subjects). For instance, the mean Tmax achieved by the method of this disclosure may be about 1.1 times shorter, about 1.2 times shorter, about 1.3 times shorter, about 1.4 times shorter, about 1.5 times shorter, about 1.6 times shorter, about 1.7 times shorter, about 1.8 times shorter, about 1.9 times shorter, about 2 times shorter, about 3 times shorter, about 4 times shorter, or about 5 times shorter than that of a comparative formulation without the adjuvant and / or not through a device of this disclosure.

[0086] In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of nalmefene or a pharmaceutically acceptable salt thereof and a parenterally acceptable adjuvant, wherein the formulation provides a mean maximum plasma concentration of nalmefene (Cmax) of 1 ng / mL to about 50 ng / mL, about 5 ng / mL to about 20 ng / mL, about 7 ng / mL to about 18 ng / mL, about 9 ng / mL to about 16 ng / mL, about 2 ng / mL to about 25 ng / mL, about 4 ng / mL to about 21 ng / mL, about 10 ng / mL to about 21 ng / mL, about 5 to about 18 ng / mL, about 4 ng / mL to about 10 ng / mL, or about 12.5 ng / mL to about 21 ng / mL, post intramuscular or subcutaneous injection to a population of subjects (e.g., healthy subjects, or otherwise healthy subjects). In one embodiment, the NAI 1.5 mg of this disclosure provides Cmax of nalmefene at about 4 to 12 ng / mL (e g., 8.1 ± 3.9 ng / mL).

[0087] Other embodiments provide that the pharmaceutical composition, upon administration through a device of this disclosure to a population of subjects (eg., healthy subjects), provides a mean plasma concentration of nalmefene greater than that of a comparative pharmaceutical composition but without the adjuvant and / or not through a device of this disclosure. For example, the pharmaceutical composition provides the maximum plasma concentration (Cmax) of nalmefene that is about 1.1 times greater, about 1.2 times greater, about 1.3 times greater, about 1.4 times greater, about 1.5 times greater, about 1.6 times greater, about 1.7 times greater, about 2 times greater, about 2.2 times greater, about 2.5 times greater, about 2.7 times, or about 3.0 times greater than that of a comparative pharmaceutical composition but without the adjuvant and / or not through a device of this disclosure.

[0088] In one embodiment, the pharmaceutical composition provides a mean plasma concentration of nalmefene 2.5 minutes post administration (AUCo-2.5min) that is about 1.5 times greater, about 2.0 times greater, about 2.5 times greater, or about 3.0 times greater than that of a comparative pharmaceutical composition administered through the same method but without the adjuvant. In another embodiment, the pharmaceutical composition provides a mean plasma concentration of nalmefene five hours post administration (AUCo-5min) that is about 1.5 times greater, about 2.0 times greater, about 2.25 times greater, about 2.5 times greater, or about 3.0 times greater than that of a comparative pharmaceutical composition administered through the same method but without the adjuvant.

[0089] In other embodiments, after intramuscular (IM) or subcutaneous (SC) administration of a pharmaceutical composition of this disclosure to healthy adult subjects, the median Tmax of the opioid antagonist (e.g.. nalmefene) achieved by a device of this disclosure was less than the median Tmax achieved for a corresponding IM or SC injection but not administered though the said device. Certain embodiments provide that the median Tmax of the opioid antagonist (e.g., nalmefene) achieved by an auto-injector of this disclosure was about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes, or about 2 minutes less than the median Tmax achieved for a corresponding IM or SC injection but not administered though the said auto-inj ector.

[0090] In one embodiment, after IM or SC administration of a nalmefene composition to healthy adult subjects, the median Tmax of nalmefene achieved by an auto-injector of this disclosure is about 15 minutes less than the median Tmax achieved for a corresponding IM or SC injection of the nalmefene composition but not though the autoinjector.

[0091] In certain embodiments, the pharmaceutical composition, when administered (e.g., intramuscularly or subcutaneously) through a device of this disclosure provides a mean T1 / 2 of nalmefene of about 5 hours to about 20 hours, of about 7 hours to about 15 hours, of about 8 hours to about 12 hours or about 9 hours to about 10 hours post intramuscular or subcutaneous injection to a population of subjects (e.g., otherwise healthy subjects).

[0092] In certain embodiments, the pharmaceutical composition comprising a therapeutically effective amount of nalmefene or a pharmaceutically acceptable salt thereof and a parenterally acceptable adjuvant (e.g., magnesium chloride), provides a mean elimination half-life (T1 / 2) that is shorter than the T1 / 2 of nalmefene of a comparative formulation without the adjuvant and / or not through a device of this disclosure., post intramuscular or subcutaneous injection to a population of subjects (e.g., healthy subjects, or otherwise healthy subjects). For instance, the mean T1 / 2 achieved by the method of this disclosure may be about 1.1 times shorter, about 1.2 times shorter, about 1.3 times shorter, about 1.4 times shorter, about 1.5 times shorter, about 1.6 times shorter, about 1.7 times shorter, about 1.8 times shorter, about 1.9 times shorter, about 2 times shorter, or about 2.5 times shorter than that of a comparative formulation without the adjuvant and / or not through a device of this disclosure. In one embodiment, the NAI 1.5 mg of this disclosure provides the T1 / 2 of nalmefene at 9. Ih ± 2.4 h.

[0093] In other embodiments, the pharmaceutical composition of this disclosure provide T1 / 2 longer than the T1 / 2 of nalmefene of a comparative formulation without the adjuvant and / or not through a device of this disclosure, post intramuscular or subcutaneous injection to a population of subjects. For instance, the mean T1 / 2 achieved by the method of this disclosure may be about 1.1 times longer, about 1.2 times longer, about 1.3 times longer, about 1.4 times longer, about 1.5 times longer, about 1.6 times longer, about 1.7 times longer, about 1.8 times longer, about 1.9 times longer, about 2 times longer, or about 2.5 times longer than that of a comparative formulation without the adjuvant and / or not through a device of this disclosure.

[0094] In certain embodiments, the pharmacokinetic values described herein may be obtained from an individual subject (healthy or in therapeutic need thereof) or from a plurality of subjects (healthy or in therapeutic need thereof)post an intramuscular or subcutaneous administration of any of the pharmaceutical compositions disclosed herein with the disclosed device. Prophylactic Treatment

[0095] It is an object of certain embodiments of this disclosure to provide a method to prevent or minimize an overdose of an opioid agonist in a subject that is at risk for exposure to an opioid agonist by administenng a pharmaceutical composition with the device disclosed herein. For example, law enforcement personnel, first medical responders, or drug-sniffing canines can be pre-treated with an opioid antagonist with he disclosed device prior to entering an environment or locale (e.g., a crime scene or emergency situation) where they suspect that opioids (e.g.. fentanyl, carfentanyl or sufentanyl) may have been intentionally or unintentionally released, or are otherwise present. Also, workers at environmental disaster areas involving opioids may be pretreated to avoid toxicity of opioids that may be present in the environment. Acceptable Excipients and Other Uses

[0096] The pharmaceutical compositions utilized in the devices disclosed herein may comprise one or more pharmaceutically acceptable carriers and excipients appropriate for intramuscular or subcutaneous administration. Examples of possible pharmaceutically acceptable earners and excipients are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (6th Edition. 2009 Publication), which is incorporated by reference herein. Carriers and excipients suitable for intramuscular and subcutaneous formulations include, but are not limited to, antioxidants, buffering agents, diluents, surfactants, solubilizers, stabilizers, hydrophilic polymers, preservatives, osmotic agents, isotonicity agents, pH adjusting agents, solvents, co-solvents, viscosity agents, gelling agents, suspending agents or combinations thereof. The systems, devices and methods disclosed herein may alternatively be used for the treatment of alcohol dependence (e.g., alcohol use disorder), constipation and other conditions that may be treated with opioid antagonists. For example, this disclosure is also directed to a method of treating alcohol dependence in a subject in need thereof. The method may comprise administering any of the pharmaceutical compositions disclosed herein w ith the disclosed device to a subject in need thereof for the treatment of alcohol dependence and / or its symptoms. In some embodiments, the method may further comprise, before the administering step, identifying that the subject is experiencing a symptom of alcohol dependence.

[0097] A retrospective analysis of CDC Wide-Ranging Online Data for Epidemiologic Research (WONDER) on opioid poisoning between January 1, 1999 - December 31, 2016, identified thousands of deaths of children and adolescents from prescription and illicit opioid poisonings during this timeframe. In certain embodiments, the disclosure further provides a method of treating pediatric patients (e.g., children of less than 12 years old) through a pre-filled device (e..g. a device of this disclosure). In certain embodiments, the method is for reversal of opioid overdose in the pediatric patients. The pediatric patients may need drug rescue due to, e.g., receiving procedural sedation with an opioid; being in the PICU receiving fentanyl; being in a postoperative setting where opioids are used, and opioid reversal is needed; and being at a high risk of accidental / unintentional opioid ingestion such as (i) children who live in households where opioids have been prescribed to a member of the household, (ii) children who live in households where the parent or caregiver uses opioids, (iii) children who live in households where proper storage and disposal of opioids is not practiced, and children have easy access to opioids; (iv) children under five who are at a higher risk because of their natural curiosity and a tendency to explore their environment by putting objects into their mouth; and (v) pediatric patients who are receiving opioids for pain management.

[0098] In other embodiments, the disclosure is directed to treating pediatric patients of 12 years old to less than 17 years old through a pre-filled device (e.g., a device of this disclosure). In one embodiment, when the NAI of this disclosure is utilized, safety and efficacy of nalmefene in the patients of 12 years to 17 years of age can be reasonably extrapolated based on the data from the adult population, because no or few PK differences are expected between the adult population and the pediatric patients 12 years of age to 17 years of age. One of the extrapolation approaches is described in the FDA 2022 Draft Guidance "General Clinical Pharmacology) Considerations for Pediatric Studies for Drugs Including Biological Products. ” EXAMPLES Example 1 Nalmefene Autoiniector

[0099] Nalmefene Hydrochloride Injection, Autoinjector C‘NAI”) utilizes the autoinjector device of this disclosure. As shown in Fig. 15, the autoinjector device is cylindrical in shape with a safety cap on one end enclosing the needle guard (Fig. 15 A). Removing the safely cap removes the needle shield from the syringe and exposes the needle guard (Fig. 15B). Injection is accomplished by first placing the needle guard perpendicular to the injection site. The device is then pushed against the injection site to retract the needle guard and expose the needle (Fig. 15C) until the device is activated to automatically depress the syringe plunger stopper and deliver the drug. A clear viewing window enables visualization of the contained drug product prior to use.

[00100] Following activation, the view through this window is blocked by an orange shutter serving as a visual indicator to the user that the drug has been delivered (Fig. 15D). After the activated device is pulled away from the injection site, the needle guard extends to cover the needle and locks into place.

[00101] Once activated, it is not possible to re-trigger the device as the needle shield reextends and locks into place which serves to prevent re-exposure to the needle, thus providing sharps protection and preventing sharps-related injuries to the patient or caregiver.

[00102] Nalmefene Hydrochloride Injection, Auto-Injector, 1.5 mg is supplied as a prefilled syringe (PFS) in an auto-injector device. The PFS contains the drug product solution within a single-dose USP Type I clear glass syringe barrel with a staked stainless-steel needle, a needle shield, and a plunger stopper, as shown in Fig. 16.

[00103] Nalmefene hydrochloride composition supplied in the PFS is described in detail below in Table 1. Table 1 INGREDIENT WEIGHT / UNIT % (W / V) REFERENCE TO STANDARD NALMEFENE HYDROCHLORIDE j 1.5 mg 0.30% In-house Standard MAGNESIUM CHLORIDE2 i 4.7 mg 0.94% USP / EP HYDROCHLORIC ACID j QS to pH 3.9 QS to pH 3.9 NF / EP WATER FOR INJECTION QS to 0.50 mL QSto 100% USP / EP 1 Concentration expressed as nalmefene free-base 2 Formula: MgC12.6H2O, magnesium chloride hexahydrate QS: quantity sufficient Filtered Nitrogen is used to pressurize vessels during the sterile filtration and syringe filling processes Example 2 Pivotal Pharmacodynamic Study A pivotal pharmacodynamic study to evaluate onset of action and duration of action of the NAI of Example 1 was conducted. Each NAI delivers 1.5 mg nalmefene (equivalent to 1.7 mg nalmefene hydrochloride) in 0.5 mL solution, which is thus referred to as NAI 1.5 mg. .In this study, on each occasion, an opioid (fentanyl)-induced respiratory depression (OIRD) was induced in approximately 24 subjects (non-dependent, with a history of prior opioid use) with an intravenous fentanyl infusion in which fentanyl concentrations were gradually increased until functional OIRD [defined as an approximately 50% reduction from baseline minute ventilation (MV)], was achieved or the maximum permitted fentanyl titration duration was reached. Following which, the fentanyl infusion rate was decreased to maintain the achieved fentanyl concentration for the remaining duration of the reversal session. NAI 1.5 mg IM was administered shortly following attainment of OIRD. The subjects were then monitored for changes in MV over 90 minutes. Following NAI 1.5 mg IM administration the time to onset of effect, that is onset of reversal of respiratory depression, was observed to be between 2.5 to 5 minutes (Figs. 17 & 18). At 5 minutes mean change in MV from NADIR was 4.42 L / min (Fig. 18). Full recovery of respiratory drive was noted between 5 and 15 minutes after Auto-Injector administration (Figs. 17 & 18). Example 3 Pharmacokinetic study In a pharmacokinetic study in healthy adult subjects, the relative bioavailability of NAI 1.5 mg administered intramuscularly was compared to a single dose of Reference nalmefene 1.0 mg (an FDA approved generic under ANDA 212955 of Revex®) administered as an intramuscular injection. The pharmacokinetic parameters obtained in this study are shown in Table 2 and the plasma concentration time profiles of nalmefene are presented in Figs. 19 (a) & (b). Table 2 Parameter NAI 1.5 mg Nalmefene IM 1.0 mg Tmax (h)a 0.250(0.083-1.00) 0.50 (0.083-2.00) Cmax (ng / rnL) 8.14(47.5) 2.51 (32.6) AUCo-2.5min (ng-hr / mL) 0.011 (288) 0.001 (241) AUCo-5min (ng-hr / mL) 0.077 (144) 0.010(209) AUCo-lOmin (ng-hr / mL) 0.442 (85.8) 0.072 (107) AUCo-15min (ng-hr / mL) 0.986 (62.7) 0.189 (64.8) AUCo-2Omin (ng-hr / mL) 1.47 (51.3) 0.362 (48.3) AUCo-3Omin (ng-hr / mL) 2.41 (39.3) 0.707 (40.7) AUCo-inf (ng-hr / mL) 30.9(16.0) 18.4(21.0) Frei (%) 113 (13.0) NA Ty2 (h) 9.07 (26.6) 7.74 (24.25) a Tmax presented as median (range); NA: Not applicable After NAI 1.5 mg IM administration to healthy adult subjects, the median Tmax was 0.250 hours (i.e., 15 minutes), compared to 0.5 hours (30 minutes) for the intramuscular nalmefene 1 mg injection. The mean bioavailability (Frei) ofNAI was 1.13 relative to intramuscular administration of nalmefene Img. After NAI 1.5 mg IM administration, plasma concentrations have a Ti2of 9.07 (%CV 26.2) hours. Cmax and AUC were greater for NAI 1.5 IM compared to nalmefene 1.0 mg IM. The mean bioavailability (Frei) ofNAI was 1.13 relative to intramuscular administration of nalmefene Img. In summary, the nalmefene systemic exposures after NAI 1.5 IM injection (Cmax . PAUCs, and AUC) were higher compared to nalmefene systemic exposures after reference nalmefene 1.0 mg IM injection. Example 4 a) Pediatric Pharmacokinetic, Pharmacodynamic and Safety Study in Children From Birth to Less Than 12 Years of Age Below is a preliminary outline of a study design to establish pharmacokinetics (PK) and pharmacodynamics (PD) in the pediatric population from birth to less than 12 years of age. Table 3 Study Design A PK, PD, and safety study of nalmefene in children from birth to less than 12 years of age Objectives • characterize PK profiles of nalmefene • explore specific dose range for nalmefene use in children • evaluate PD • evaluate safety Study Duration To be based on input from subject matter experts. Age Group Children from birth to less than 12 years of age. Potential Populations • pediatric patients receiving procedural sedation with an opioid • pediatric patients who are in the PICU receiving fentanyl • pediatric patients in the postoperative setting where opioids were used, and opioid reversal is needed • pediatric patients who are at a high risk of accidental / unintentional opioid ingestion; such as o children who live in households where opioids have been prescribed to a member of the household o households where the parent or caregiver uses opioids o households where proper storage and disposal of opioids is not practiced, and children have easy access to opioids o children under five are at a higher risk because of their natural curiosity and a tendency to explore their environment by putting objects into their mouth • pediatric patients who are receiving opioids for pain management Input from subject matter experts are utilized to minimize risk in this vulnerable population. Study Drug Nalmefene Hydrochloride injection Dose To be determined. Endpoints • Physiologically based pharmacokinetic (PBPK) modeling or population pharmacokinetic approach • Safety endpoints: ECGs, physical examinations, vital signs, adverse events • PD endpoints: evaluation of clinical response measured by improved respiratory rate, oxygen saturation and level of consciousness Endpoints are further elucidated with input from subject matter experts. Sample Size Sample size is to be estimated after completing feasibility studies with input from subject matter experts Ethical Considerations These are highly vulnerable populations and research involving them requires careful planning and additional safeguards need to be implemented to protect the rights and welfare of this population and to ensure safety. b) Consultation with Subject Matter Experts A diverse, multidisciplinary’ group of subject matter experts (SME) are engaged to generate comprehensive insights and recommendations into research methodology, feasibility, potential 5 populations, clinical setting, enrollment strategies, pediatric clinical trial design, dosing and protocol development. SMEs across a broad range of specialties are used, including pediatric anesthesiologists, neonatologists. pediatricians, pediatric surgeons, pediatric emergency medicine specialists, pediatric critical care specialists, pediatric pharmacokinetic experts, ethicists, statisticians, patient 10 advocates, legal experts and researchers with experience in pediatric healthcare and epidemiology' to contribute to designing and executing this study appropriately. Input from SMEs inform study design, including target populations, endpoints, and dose, while considering feasibility of required studies. In addition, as these pediatric populations are highly vulnerable, any research conduct requires careful planning and additional safeguards to be implemented to protect the rights and welfare of this population and to ensure safety.

[00104] It will be appreciated by those skilled in the art that changes could be made to the exemplary embodiments shown and described above without departing from the broad inventive concepts thereof. It is to be understood that the embodiments and claims disclosed herein are not limited in their application to the details of construction and arrangement of the components set forth in the description and illustrated in the drawings. Rather, the description and the drawings provide examples of the embodiments envisioned. The embodiments and claims disclosed herein are further capable of other embodiments and of being practiced and carried out in various ways.

[00105] Specific features of the exemplary embodiments may or may not be part of the claimed invention and various features of the disclosed embodiments may be combined. Unless specifically set forth herein, the terms “a”, “an” and “the” are not limited to one element but instead should be read as meaning “at least one”. Finally, unless specifically set forth herein, a disclosed or claimed method should not be limited to the performance of their steps in the order written, and one skilled in the art can readily appreciate that the steps may be performed in any practical order.

Claims

1. An injector, comprising:a housing having a proximal end and a distal end opposite the proximal end extending along a longitudinal axis;a medicament container disposed within the housing, the medicament container containing a medicament comprising an opioid antagonist or a pharmaceutically acceptable salt thereof;a needle coupled to a proximal end of the medicament container and in fluid communication with the medicament container;a trigger mechanism comprising:a needle guard retractably coupled to the proximal end of the housing, the needle guard movable between an extended configuration and a retracted configuration;a ram configured to move a plunger coupled to a proximal end thereof relative to the medicament container;a trigger member configured to engage the ram and prevent movement thereof when the needle guard is in the extended configuration; andan energy source engaging a distal end of the ram, the energy source configured to move the ram proximally relative to the housing, wherein movement of the needle guard from the extended configuration to the retracted configuration disengages the trigger member from the ram, thereby allowing the energy source to move the plunger relative to the medicament container to expel the medicament through the needle.

2. The injector of claim 1, wherein the needle guard moves from the extended configuration to the retracted configuration in response to a user pressing the needle guard against an injection site.

3. The injector of claim 2, wherein the needle guard moves from the retracted configuration to the extended configuration when the user removes the injector from the injection site.

4. The injector of claim 3, wherein the needle guard is moved from the retracted configuration to the extended configuration by a biasing member.

5. The injector of claim 3. wherein the needle guard is prevented from moving relative to the housing when moved from the retracted configuration to the extended configuration.

6. The injector of claim 5. wherein the injector is a single-use injector.

7. The injector of claim 1, wherein movement of the needle guard from the extendedconfiguration to the retracted configuration exposes the needle.

8. The injector of claim 7, wherein the needle extends from the needle guard at least 5 mm when the needle guard is in the retracted configuration.

9. The injector of claim 8. wherein the needle is configured to administer the medicament subcutaneously.

10. The injector of claim 8, wherein the needle is configured to administer the medicament intramuscularly.

11. The injector of claim 1, wherein the medicament container contains a volume of about 0.5 mL of the medicament.

12. The injector of claim 11, wherein the trigger mechanism is configured to expel the volume of the medicament.

13. The injector of claim 12, wherein the trigger mechanism expels the volume of the medicament in less than 0.2 second.

14. The injector of claim 12, wherein the trigger mechanism expels the volume of the medicament at a rate of at least 2.5 mL / sec.

15. The injector of claim 1, wherein the opioid antagonist or pharmaceutically acceptable salt thereof is nalmefene or nalmefene hydrochloride.

16. An injector, comprising:a housing having a proximal end and a distal end opposite the proximal end extending along a longitudinal axis;a medicament container containing a medicament comprising an opioid antagonist or a pharmaceutically acceptable salt thereof;a needle coupled to a proximal end of the medicament container and in fluid communication with the medicament container;a trigger mechanism comprising;a needle guard retractably coupled to the proximal end of the housing, the needle guard movable between an extended configuration and a retracted configuration;a ram configured to move a plunger coupled to a proximal end thereof relative to the medicament container;a trigger member configured to engage the ram and prevent movement thereof when the needle guard is in the extended configuration; andan energy7 source engaging a distal end of the ram, the energy' source configured to move the ram proximally relative to the housing, wherein movement of the needle guard from the extended configuration to the retracted configuration disengages the trigger member from the ram, thereby allowing the energy source to move the plunger relative to the medicament container to expel the medicament through the needle,wherein the medicament container contains a volume of about 0.5 mL of the medicament, andwherein the trigger mechanism expels the volume of the medicament at a rate of at least 2.5 mL / sec.

17. The injector of claim 16, wherein the opioid antagonist or pharmaceutically acceptable salt thereof is nalmefene or nalmefene hydrochloride.

18. A method of delivering an opioid antagonist or a pharmaceutically acceptable salt thereof comprising:providing an injector, the injector comprising:a medicament container containing the medicament comprising an opioid antagonist or a pharmaceutically acceptable salt thereof;a needle coupled to a proximal end of the medicament container and in fluid communication with the medicament container;a retractable needle guard, the needle guard movable between an extended configuration and a retracted configuration;a ram configured to move a plunger coupled to a proximal end thereof relative to the medicament container; andan energy source engaging a distal end of the ram. the energy source configured to move the ram proximally;pressing the needle guard against an injection site of a user with sufficient force to move the needle guard from the extended configuration to the retracted configuration, thereby inserting the needle to an insertion depth; andcausing the energy source to move the plunger through the medicament container expelling the medicament through the needle,wherein the medicament flows through the needle at a flow rate of at least 2.5 mL / sec.

19. The method of claim 18, wherein the injector further comprises:a housing having a proximal end and a distal end opposite the proximal end extending along a longitudinal axis; anda trigger member configured to engage the ram and prevent movement thereof when the needle guard is in the extended configuration.

20. The method of claim 18, wherein the opioid antagonist or pharmaceutically acceptable salt thereof is nalmefene or nalmefene hydrochloride.

21. A method of rescuing a subject identified in need thereof from opioid overdose, comprising administering to the subject a medicament comprising a therapeutically effective amount of an opioid antagonist or a pharmaceutically acceptable salt thereof, wherein said medicament is intramuscularly or subcutaneously delivered through an injector, and said injector comprisesa housing having a proximal end and a distal end opposite the proximal end extending along a longitudinal axis;a medicament container containing a medicament comprising an opioid antagonist or a pharmaceutically acceptable salt thereof;a needle coupled to a proximal end of the medicament container and in fluid communication with the medicament container;a trigger mechanism comprising:a needle guard retractably coupled to the proximal end of the housing, the needle guard movable between an extended configuration and a retracted configuration;a ram configured to move a plunger coupled to a proximal end thereof relative to the medicament container;a trigger member configured to engage the ram and prevent movement thereof when the needle guard is in the extended configuration; andan energy source engaging a distal end of the ram. the energy source configured to move the ram proximally relative to the housing, wherein movement of the needle guard from the extended configuration to the retracted configuration disengages the trigger member from the ram, thereby allowing the energy source to move the plunger relative to the medicament container to expel the medicament through the needle,wherein the medicament container contains a volume of about 0.5 mL of the medicament, andwherein the trigger mechanism expels the volume of the medicament at a rate of at least 2.5 mL / sec.

22. The method of claim 21, wherein the opioid antagonist or pharmaceutically acceptable salt thereof is nalmefene or nalmefene hydrochloride.

23. The method of claim 22, wherein a Tmax of the opioid antagonist achieved by the method is less than Tmax of the opioid antagonist achieved for an IM or SC injection but without using the injector.

24. A method of rescuing a pediatric patient identified in need thereof from opioid overdose, comprising administering to the pediatric patient a medicament comprising a therapeutically effective amount of an opioid antagonist or a pharmaceutically acceptable salt thereof, wherein said medicament is intramuscularly or subcutaneously delivered to the pediatric patient through an auto-injector.25    The method of claim 24, wherein the pediatric patient is less than 12 years old.

26. The method of claim 24, wherein the pediatric patient is 12 years old to less than 17 yearsold.

27. The method of any of claims 24-26, wherein the auto-injector comprisesa housing having a proximal end and a distal end opposite the proximal end extending along a longitudinal axis;a medicament container containing a medicament comprising an opioid antagonist or a pharmaceutically acceptable salt thereof;a needle coupled to a proximal end of the medicament container and in fluid communication with the medicament container;a trigger mechanism comprising:a needle guard retractably coupled to the proximal end of the housing, the needle guard movable between an extended configuration and a retracted configuration;a ram configured to move a plunger coupled to a proximal end thereof relative to the medicament container;a trigger member configured to engage the ram and prevent movement thereof when the needle guard is in the extended configuration; andan energy source engaging a distal end of the ram, the energy source configured to move the ram proximally relative to the housing, wherein movement of the needle guard from the extended configuration to the retracted configuration disengages the trigger member from the ram, thereby allowing the energy source to move the plunger relative to the medicament container to expel the medicament through the needle,wherein the medicament container contains a volume of about 0.5 mL of the medicament, andwherein the trigger mechanism expels the volume of the medicament at a rate of at least 2.5 mL / sec.

28. The method of any of claims 24-27, wherein the opioid antagonist or pharmaceutically acceptable salt thereof is nalmefene or nalmefene hydrochloride.

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