Compositions and methods for emergency rescue

Abstract

Disclosed in certain embodiments is a parenteral formulation comprising a therapeutically effective amount of an emergency rescue active pharmaceutical ingredient and a parenterally acceptable adjuvant in an amount that enhances the absorption of the emergency rescue active pharmaceutical ingredient (ER-API) into the systemic circulation. The enhancement of absorption can be evidenced by a faster onset of action, a faster T max and / or a higher C max and / or a higher AUC last and / or a higher AUC 0.25 and / or a higher AUC 0.5 and / or a higher AUC 0.75 and / or a higher AUC1and / or increased bioavailability compared to a formulation without the adjuvant.

Description

TECHNICAL FIELD

[0001] The present invention relates to the field of emergency rescue for providing an allergic reaction (e.g., anaphylaxis) or poisoning to a subject, a pharmaceutical composition for pre-administering to a subject to prevent an allergic reaction, a method of providing emergency rescue, and a drug delivery system for emergency rescue. BACKGROUND

[0002] Reactions to certain allergens and / or poisons can sometimes be very severe, even fatal. Subjects experiencing symptoms associated with an allergic reaction would benefit from a pharmaceutical product capable of rapidly counteracting, treating, preventing, and / or reducing such symptoms. Similarly, subjects who have inadvertently been exposed to a toxic substance or who are at risk of potential exposure to a toxic substance would benefit from a pharmaceutical product capable of providing an antidote to the toxic substance, counteracting, treating, preventing, and / or reducing symptoms associated with poisoning.

[0003] Allergic and poisoning symptoms include, but are not limited to, anaphylaxis, difficulty breathing, abdominal cramping or pain, chest pain or tightness, diarrhea, difficulty swallowing, dizziness, anxiety, fear, facial flushing, nausea or vomiting, palpitations, swelling of the airways and / or face and / or eyes and / or tongue, confusion, weakness, hives, itching, congestion, rash, throat itching, eye tearing or itching, decreased blood pressure, temporary blockade of severe or life-threatening muscarinic effects, bardsystolic cardiac arrest, and other symptoms indicative of an allergic reaction and / or poisoning.

[0004] To counteract symptoms of an allergic reaction and / or poisoning, emergency personnel or other personnel can administer an antidote, such as an intramuscular injection of an emergency rescue active pharmaceutical ingredient. Given that the administered antidote needs to be absorbed into the bloodstream, there is inevitably a lag time between the time the antidote is administered and the time the antidote reaches a therapeutic level sufficient to effectively counteract the effects of the allergen or poison. Unfortunately, this lag time can result in the antidote therapy not being sufficient to effectively prevent morbidity and death from the effects of the allergic reaction and poisoning in a timely manner.

[0005] There is a need in the art for a pharmaceutical composition for rescuing a subject from an allergic reaction and / or poisoning, and a method of rescuing a subject from an allergic reaction and / or poisoning, by which enhanced absorption is achieved. SUMMARY

[0006] It is an object of certain embodiments of the present application to provide a pharmaceutical composition (e.g., a parenteral formulation or an intranasal formulation) for use in rescuing a subject from an allergic reaction (e.g., anaphylaxis) or a poisoning, or for preventing a subject from experiencing an allergic reaction (e.g., anaphylaxis) (or reducing the risk of a subject experiencing an allergic reaction (e.g., anaphylaxis)).

[0007] It is an object of certain embodiments of the present application to provide a parenteral formulation for use in rescuing a subject from an allergic reaction (e.g., anaphylaxis) or a poisoning, or for preventing a subject from experiencing an allergic reaction (e.g., anaphylaxis) or a poisoning (or reducing the risk of a subject experiencing an allergic reaction (e.g., anaphylaxis) or a poisoning). In one embodiment, the parenteral formulation is suitable for intramuscular administration. In another embodiment, the parenteral formulation is suitable for subcutaneous administration.

[0008] It is an object of certain embodiments of the present application to provide an intranasal formulation for use in rescuing a subject from an allergic reaction (e.g., anaphylaxis) or a poisoning, or for preventing a subject from experiencing an allergic reaction (e.g., anaphylaxis) or a poisoning (or reducing the risk of a subject experiencing an allergic reaction (e.g., anaphylaxis) or a poisoning).

[0009] It is an object of certain embodiments of the present application to provide a method for rescuing a subject from an allergic reaction (e.g., anaphylaxis) or a poisoning, or for preventing a subject from experiencing an allergic reaction (e.g., anaphylaxis) or a poisoning (or reducing the risk of a subject experiencing an allergic reaction (e.g., anaphylaxis) or a poisoning).

[0010] It is an object of certain embodiments of the present application to provide a method of prophylactically administering a pharmaceutical composition as disclosed herein to a subject at risk of exposure to a substance to which the subject is allergic (e.g., pollen, nuts (such as peanuts and tree nuts), milk, eggs, shellfish, wheat, soy, fish, etc.) or to a toxic substance (e.g., a nerve agent poisoning, a pesticide poisoning, etc.).

[0011] It is an object of certain embodiments of the present application to provide a drug delivery system for use in rescuing a subject from an allergic reaction or a poisoning, or for preventing a subject from experiencing an allergic reaction (e.g., anaphylaxis) or a poisoning (or reducing the risk of a subject experiencing an allergic reaction (e.g., anaphylaxis) or a poisoning).

[0012] The above and other objects can be achieved by the present application, which in certain embodiments relates to a pharmaceutical composition for providing emergency rescue to a subject experiencing an allergic reaction or poisoning, or for preventing (or reducing the risk of) an allergic reaction poisoning in a subject. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an emergency rescue active pharmaceutical ingredient (ER-API) and a parenterally acceptable absorption-enhancing amount of an adjuvant that facilitates, enhances, or speeds up the systemic absorption rate of the ER-API following intramuscular or subcutaneous injection, wherein the ER-API is not an opioid antagonist. The adjuvant can be selected from among currently known suitable absorption enhancers, or absorption enhancers for such use that would be readily understood by one of ordinary skill (in the fields of formulation and medicine) to be suitable. In certain non-limiting embodiments, the adjuvant is selected from the group consisting of a nitric oxide inducer, niacin, a niacin derivative, a niacin metabolite, a phosphodiesterase inhibitor, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker, a calcium channel blocker, a nitrate, or a combination thereof. In one embodiment, the adjuvant is magnesium chloride.

[0013] In certain embodiments, the ER-API is epinephrine or atropine or a pharmaceutically acceptable salt thereof or a combination thereof.

[0014] In certain embodiments, the pharmaceutical composition of the present application comprises a therapeutically effective amount of an ER-API and an absorption-enhancing effective amount of a pharmaceutically acceptable adjuvant (e.g., a parenterally acceptable adjuvant or a nasally acceptable adjuvant), wherein the composition provides an onset of action of the ER-API of 5 minutes or less following intramuscular or subcutaneous injection or following intranasal or inhalation administration to a subject experiencing an allergic reaction or at risk of experiencing an allergic reaction.

[0015] In certain embodiments, the composition provides a mean time to maximum plasma concentration of the ER-API of about 2.0 hours or less following intramuscular injection to a population of healthy subjects, or a mean time to maximum plasma concentration of the ER-API of about 1.0 hour or less following subcutaneous injection to a population of healthy subjects.

[0016] In certain embodiments, the present application relates to a method of providing emergency rescue or allergic reaction prevention to a subject experiencing or likely to experience an allergic reaction, the method comprising administering to the subject an intramuscular, subcutaneous, intranasal, or via inhalation a pharmaceutical composition as disclosed herein.

[0017] In certain embodiments, the present application relates to a drug delivery system comprising a device (e.g., an injection device) containing a pharmaceutical composition as disclosed herein. In one embodiment, such a device is suitable for delivering the pharmaceutical composition by injection. In certain embodiments, the composition is placed in a pre-filled syringe, a vial, an injection pen, or an auto-injector. In one embodiment, such a device is suitable for intranasal or via inhalation delivery of the pharmaceutical composition. BRIEF DESCRIPTION OF DRAWINGS

[0018] The above described and other features, nature, and various advantages of the present application will be more apparent from the following detailed description considered in connection with the accompanying drawings, in which:

[0019] Figure 1 A comparison of mean plasma concentration profiles for atropine containing different levels of MgCl2adjuvant (0% (Group 1), 1% (w / v) (Group 2), and 2% (w / v) (Group 3)) at a 0.2 mg dose following intramuscular administration to three dog subjects is described. For dog subjects receiving atropine containing 0% MgCl2at a 0.2 mg dose, 0.9% (w / v) NaCl was used (in Group 1).

[0020] Figure 2 A comparison of mean plasma concentration profiles for atropine containing different levels of MgCl2adjuvant (0% (Group 1), 1% (w / v) (Group 2), and 2% (w / v) (Group 3)) at a 0.2 mg dose following intramuscular administration to three dog subjects is described. For dog subjects receiving atropine containing 0% MgCl2at a 0.2 mg dose, 0.9% (w / v) NaCl was used (in Group 1).

[0021] DEFINITIONS

[0022] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" includes a single active agent as well as a mixture of two or more different active agents; and reference to "an excipient" includes a single excipient as well as a mixture of two or more different excipients, and the like.

[0023] As used herein, the term "about," in connection with a measured quantity or time, means + / - 10% of the quantity or time, as would be expected by a person of ordinary skill in the art when performing such measurements and exercising a level of care, comparable to that expected by a person of ordinary skill in the art. In certain embodiments, the term "about" includes + / - 10% of the recited number, such that "about 10" would include 9 to 11, or 1 hour would include 54 minutes to 66 minutes.

[0024] As used herein, the term "active agent" refers to any material intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved by a governmental agency for that purpose. This term with respect to a particular agent includes pharmaceutically active agents and all pharmaceutically acceptable salts, solvates, and crystalline forms thereof, where the salts, solvates, and crystalline forms are therapeutically active.

[0025] As used herein, the terms "therapeutically effective amount" and "effective amount" refer to the amount or rate of administration of an active agent needed to produce a desired therapeutic result.

[0026] The term "subject" refers to a human or animal that has exhibited clinical manifestations of an allergic reaction that suggest the need for rescue treatment; or a human or animal that is at risk of exposure to an allergen or a poison, who is treated prophylactically with an ER-API. The term "subject" can include a human or animal (e.g., a dog) who is a patient being treated appropriately by a medically trained person with an ER-API to treat, prevent, or reduce the risk of an allergic reaction or a poisoning. The term "subject" can also include any person who, in the opinion of an unclinically trained bystander, is experiencing an allergic reaction such as anaphylactic shock, difficulty breathing, abdominal cramping or pain, chest pain or tightness, diarrhea, difficulty swallowing, dizziness (lightheadedness), anxiety, fear, facial flushing, nausea or vomiting, palpitations, swelling of the airways and / or face and / or eyes and / or tongue, unconsciousness, weakness, hives, itching, congestion, rash, scratchy throat, watery or itchy eyes, decreased blood pressure, and other symptoms suggestive of an allergic reaction. The term "subject" can also include any person who, in the opinion of an unclinically trained bystander, is experiencing a poisoning reaction such as temporary blockage of severe or life-threatening muscarinic effects, asystole of the slow contracting heart type, and other symptoms suggestive of poisoning.

[0027] The terms "treatment of" and "treating" include the administration of one or more active agents to reduce the severity of a disorder.

[0028] The terms "prevention of" and "preventing" include avoiding the onset of a disorder by prophylactically administering an active agent.

[0029] The term“condition” or“conditions” refers to those medical conditions typically considered to be a result of an allergic reaction or poisoning, such as anaphylactic shock, difficulty breathing, abdominal cramping or pain, chest pain or tightness, diarrhea, difficulty swallowing, dizziness (lightheadedness), anxiety, fear, facial flushing, nausea or vomiting, palpitations, swelling of the airways and / or face and / or eyes and / or tongue, unconsciousness, weakness, hives, itching, hyperemia, rash, itchy throat, eye tearing or itching, decreased blood pressure, temporary blockade of severe or life-threatening muscarinic effects, cardiac arrest of the slow-twitching heart rate type, or combinations thereof, which can be treated, ameliorated, or prevented by timely administration of an effective amount of an ER- API to the subject.

[0030] The term“adjuvant” refers to an agent incorporated into a pharmaceutical composition to enhance absorption of an active agent, for example, by increasing C max , shortening T max , increasing one or more of AUC last , AUC 0.25 , AUC 0.5 , AUC 0.75 , AUC1, shortening onset time, or increasing bioavailability, or any combination of these. An adjuvant can be inactive in all other respects, or in addition to enhancing absorption of an active agent, can provide an intended or unintended pharmacological effect.

[0031] The term“absorption enhancement” refers to a formulation comprising an adjuvant having an increased C max and / or a shortened T max and / or a shortened onset time and / or an increased AUC last and / or an increased AUC 0.25 and / or an increased AUC 0.5 and / or an increased AUC 0.75 and / or an increased AUC1 and / or an increased bioavailability, or any combination of these, as compared to the same formulation without the adjuvant.

[0032] The term“parenteral” means administration by injection, implantation, or infiltration via a route such as intravenous, intraarterial, intracardiac, intraspinal, intraosseous, intraarticular, intrasynovial, intradermal, subcutaneous, or intramuscular.

[0033] The term“injection” means administration to a discrete site through the skin of a human or animal or to a tissue of a human or animal.

[0034] The term“implantation” means administration to a discrete site by embedding a pharmaceutical composition into the skin, tissue, muscle, tendon, joint, or other body part of a human or animal.

[0035] The term "penetration" means administration into a discrete injection site, or a surgical site or open wound.

[0036] T 1 / 2 is a pharmacokinetic term referring to the time required for half of the initial dose of an administered active agent to be eliminated from the body of a subject.

[0037] T max is a pharmacokinetic term referring to the time at which Cmax is observed.

[0038] C max is a pharmacokinetic term referring to the maximum plasma concentration of an active agent.

[0039] MRT last is a pharmacokinetic term referring to the mean residence time calculated to the last observable time point (e.g., MRT2 refers to the mean residence time calculated to two hours).

[0040] AUC last is a pharmacokinetic term referring to the area under the curve of plasma concentration as a function of time calculated to the last observable time point (e.g., AUC2 refers to the area under the curve calculated to two hours).

[0041] AUC ∞ is a pharmacokinetic term referring to the area under the curve of plasma concentration as a function of time extrapolated to infinity.

[0042] Unless otherwise indicated herein, the recitation of a range of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated in the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to illustrate the materials and methods and does not pose a limitation on the scope of the disclosure. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the disclosure. DETAILED DESCRIPTION

[0043] Dosage forms and pharmaceutical compositions

[0044] According to various embodiments, the present application relates to pharmaceutical compositions for emergency rescue of an allergic reaction or a poisoning. In certain embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of an ER-API and a parenterally acceptable adjuvant (e.g., a pharmaceutically acceptable adjuvant) that facilitates the rate of absorption of the ER-API following intramuscular or subcutaneous injection. Suitable adjuvants for use in the present application can include a nitric oxide inducer, a niacin, a niacin derivative, a niacin metabolite, a local anesthetic, a phosphodiesterase inhibitor, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker, a calcium channel blocker, a nitrate, and combinations thereof. In certain embodiments, such a pharmaceutical composition provides a faster onset of action of the ER-API compared to the same pharmaceutical composition without the adjuvant.

[0045] The ER-API can be any emergency rescue active pharmaceutical ingredient currently known, or readily appreciated by one of ordinary skill (in the fields of formulation and medicine) for such use in effectively countering or preventing an allergic reaction or a poisoning. In certain embodiments, suitable ER-APIs include epinephrine, atropine, their pharmaceutically acceptable salts, or combinations thereof. In certain embodiments, the ER-API is epinephrine or a pharmaceutically acceptable salt thereof. In certain embodiments, the ER-API is atropine or a pharmaceutically acceptable salt thereof.

[0046] In certain embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of an ER-API and a parenterally acceptable adjuvant, wherein the formulation provides an onset of action (i.e., the first detectable therapeutic effect associated with the ER-API, such as a detectable reduction or alleviation of any symptom associated with the allergic reaction or the poisoning) of less than about 5 minutes following intramuscular or subcutaneous injection to a subject experiencing an allergic reaction or a poisoning, or pre-treatment against potential allergen or poison exposure.

[0047] In certain embodiments, the pharmaceutical composition provides an onset of action (i.e., countering at least one symptom of the allergic reaction or the poisoning) of about 4 minutes or less, about 3 minutes or less, about 2 minutes or less, or about 1 minute or less following intramuscular or subcutaneous injection to a subject experiencing an allergic reaction or a poisoning, or pre-treatment due to potential allergen or poison exposure. In certain embodiments, the pharmaceutical composition provides an onset of action (i.e., countering at least one symptom of the allergic reaction or the poisoning) of from greater than about 5 seconds, greater than about 10 seconds, greater than about 15 seconds, greater than about 30 seconds, greater than about 45 seconds, or greater than about 1 minute to about 2 minutes or less, about 3 minutes or less, about 4 minutes or less, or about 5 minutes or less, or any sub-range therein, following intramuscular or subcutaneous injection to a subject experiencing an allergic reaction or a poisoning, or pre-treatment against potential allergen or poison exposure.

[0048] In other embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of ER- API and a parenterally acceptable adjuvant, wherein the formulation provides a mean time to maximum plasma concentration of ER- API of about 2.0 hours or less following intramuscular injection to a population of subjects (e.g., healthy or otherwise healthy subjects), or a mean time to maximum plasma concentration of ER- API of about 1.0 hour or less following subcutaneous injection to a population of subjects (e.g., healthy or otherwise healthy subjects).

[0049] In other embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of ER- API and a parenterally acceptable adjuvant, wherein the formulation provides a mean time to maximum plasma concentration of ER- API of about 2 hours or less, about 1.5 hours or less, about 1 hour or less, about 0.75 hours or less, about 0.5 hours or less, about 20 minutes or less, about 15 minutes or less, about 10 minutes or less, about 5 minutes or less, about 3 minutes or less, or about 1 minute or less following intramuscular injection to a population of subjects (e.g., healthy or otherwise healthy subjects). In other embodiments, the formulation provides a mean time to maximum plasma concentration of ER- API of any of from about 0.1 hour or more, about 0.2 hours or more, about 0.3 hours or more, or about 0.4 hours or more to about 0.5 hours or less, about 1 hour or less, about 1.5 hours or less, or about 2.0 hours or less following intramuscular injection to a population of subjects (e.g., healthy or otherwise healthy subjects).

[0050] In other embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of ER- API and a parenterally acceptable adjuvant, wherein the formulation provides a mean time to maximum plasma concentration of ER- API of about 2 hours or less, about 1.5 hours or less, about 1 hour or less, about 0.9 hours or less, about 0.8 hours or less, about 0.75 hours or less, about 0.7 hours or less, about 0.6 hours or less, about 0.5 hours or less, about 20 minutes or less, about 15 minutes or less, about 10 minutes or less, about 5 minutes or less, about 3 minutes or less, or about 1 minute or less following subcutaneous injection to a population of subjects (e.g., healthy or otherwise healthy subjects). In other embodiments, the formulation provides a mean time to maximum plasma concentration of ER- API of about 0.1 hour or more, about 0.2 hours or more, about 0.3 hours or more, or about 0.4 hours or more to about 1.0 hours or about 0.5 hours or less following subcutaneous injection to a population of subjects (e.g., healthy or otherwise healthy subjects).

[0051] In certain embodiments, the composition provides a mean time for epinephrine to reach maximum plasma concentration (T

[0052] In certain embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof and a parenterally acceptable adjuvant, wherein the formulation provides a mean time for epinephrine to reach maximum plasma concentration (T max ) of about 2.0 hours or less, about 1.5 hours or less, about 1 hour or less, about 0.9 hours or less, about 0.8 hours or less, about 0.75 hours or less, about 0.7 hours or less, about 0.6 hours or less, about 0.5 hours or less, about 20 minutes or less, about 15 minutes or less, about 10 minutes or less, about 5 minutes or less, about 3 minutes or less, or about 1 minute or less, upon intramuscular or subcutaneous injection to a population of subjects (e.g., healthy or otherwise healthy subjects), and also provides a treatment onset time of less than 5 minutes, about 4 minutes or less, about 3 minutes or less, about 2 minutes or less, or about 1 minute or less, upon intramuscular or subcutaneous injection to a subject experiencing an allergic reaction or intoxication or in need of pretreatment due to exposure to a potential allergen or poison.

[0053] In certain embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof and a parenterally acceptable adjuvant, wherein the formulation provides a mean time for epinephrine to reach maximum plasma concentration (T max ) that is shorter than the mean time for epinephrine to reach maximum plasma concentration (T max ) of a comparative formulation that does not contain the adjuvant, upon intramuscular or subcutaneous injection to a population of subjects (e.g., healthy or otherwise healthy subjects). For example, the mean T max of the present application can 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, or about 2 times shorter than the mean T

[0054] In certain embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof and a parenterally acceptable adjuvant, wherein the formulation provides an average maximum plasma concentration (C max ) of epinephrine of at least about 15 ng / mL per 0.3 mg of epinephrine or a pharmaceutically acceptable salt thereof after intramuscular or subcutaneous administration to a population of subjects (e.g., healthy or otherwise healthy subjects).

[0055] In certain embodiments, the formulation provides an average maximum concentration of epinephrine of at least about 1 ng / mL, at least about 3 ng / mL, at least about 5 ng / mL, at least about 7 ng / mL, at least about 10 ng / mL, at least about 12 ng / mL, at least about 15 ng / mL, at least about 18 ng / mL, or at least about 20 ng / mL per 0.3 mg of epinephrine or a pharmaceutically acceptable salt thereof after intramuscular or subcutaneous administration to a population of subjects (e.g., healthy or otherwise healthy subjects).

[0056] In certain embodiments, the formulation provides an average maximum concentration of epinephrine of about 50 ng / mL or less, about 45 ng / mL or less, about 40 ng / mL or less, about 35 ng / mL or less, about 30 ng / mL or less, about 28 ng / mL or less, about 26 ng / mL or less, about 24 ng / mL or less, or about 22 ng / mL or less per 0.3 mg of epinephrine or a pharmaceutically acceptable salt thereof after intramuscular or subcutaneous administration to a population of subjects (e.g., healthy or otherwise healthy subjects).

[0057] In certain embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof and a parenterally acceptable adjuvant, wherein the formulation provides an average maximum plasma concentration (C max ) of epinephrine that is higher than the average maximum plasma concentration of epinephrine of a comparative formulation without the adjuvant after intramuscular or subcutaneous injection to a population of subjects (e.g., healthy or otherwise healthy subjects). For example, the C max may be about 1.1 times higher, about 1.2 times higher, about 1.3 times higher, about 1.4 times higher, about 1.5 times higher, about 1.6 times higher, about 1.7 times higher, about 1.8 times higher, about 1.9 times higher, or about 2 times higher than the C max of the comparative formulation without the adjuvant.

[0058] In certain embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof and a parenterally acceptable adjuvant, wherein the formulation provides an AUC last , AUC last , AUC last , or AUC1 that is higher than the AUC last , AUC 0.25 , AUC 0.5 , AUC 0.75 , or AUC1 of a comparative formulation without the adjuvant following intramuscular or subcutaneous injection to a population of subjects (e.g., healthy or otherwise healthy subjects). For example, the AUC 0.25 , AUC 0.5 , AUC 0.75 , or AUC1 can be about 1.1 fold, about 1.2 fold, about 1.3 fold, about 1.4 fold, about 1.5 fold, about 1.6 fold, about 1.7 fold, about 1.8 fold, about 1.9 fold, or about 2 fold higher than the AUC 0.25 , AUC 0.5 , AUC 0.75 , or AUC1 of a comparative formulation without the adjuvant.

[0059] In certain embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof and a parenterally acceptable adjuvant, wherein the formulation provides an AUC 0.25 , AUC 0.5 , AUC 0.75 , or AUC1 that is higher than the AUC 0.25 , AUC 0.5 , AUC 0.75 , or AUC1 of a corresponding epinephrine of a comparative formulation without the adjuvant following intramuscular or subcutaneous injection to a population of subjects (e.g., healthy or otherwise healthy subjects). For example, the AUC 0.25 , AUC 0.5 , AUC 0.75 , or AUC1 can be about 1.1 fold, about 1.2 fold, about 1.3 fold, about 1.4 fold, about 1.5 fold, about 1.6 fold, about 1.7 fold, about 1.8 fold, about 1.9 fold, or about 2 fold higher than the AUC 0.25 , AUC 0.5 , AUC 0.75 , or AUC1 of a comparative formulation without the adjuvant.

[0060] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of atropine or a pharmaceutically acceptable salt thereof and a parenteral-acceptable adjuvant, wherein said formulation provides, upon intramuscular or subcutaneous injection into a subject population (e.g., healthy or otherwise healthy subjects), an average time (T0) for atropine to reach its maximum plasma concentration in approximately 3.0 hours or less, approximately 2.5 hours or less, approximately 2.0 hours or less, approximately 1.5 hours or less, approximately 1 hour or less, approximately 0.9 hours or less, approximately 0.8 hours or less, approximately 0.75 hours or less, approximately 0.7 hours or less, approximately 0.6 hours or less, approximately 0.5 hours or less, approximately 20 minutes or less, approximately 15 minutes or less, or approximately 10 minutes or less, approximately 5 minutes or less, approximately 3 minutes or less, or approximately 1 minute or less. max ).

[0061] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of atropine or a pharmaceutically acceptable salt thereof and a parenteral acceptable adjuvant, wherein said formulation provides, upon intramuscular or subcutaneous injection into a subject population (e.g., healthy or otherwise healthy subjects), a mean time (T0) to reach maximum plasma concentration of atropine compared to a comparative formulation without adjuvant. max The average time for atropine to reach its maximum plasma concentration is short. For example, the average T0 of this invention... max The average T can be compared with that of the comparator formulation without adjuvant. max Short by approximately 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, or 2 times.

[0062] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of atropine or a pharmaceutically acceptable salt thereof and a parenteral-acceptable adjuvant, wherein said formulation provides, upon intramuscular or subcutaneous administration to a subject population (e.g., healthy or otherwise healthy subjects), a mean maximum plasma concentration (C0.05) of at least about 12 ng / mL of atropine per 2 mg atropine or a pharmaceutically acceptable salt thereof. max ).

[0063] In some embodiments, the formulation provides, upon intramuscular or subcutaneous administration to a subject population (e.g., healthy or otherwise healthy subjects), a mean maximum concentration of atropine of at least about 12 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, or at least about 30 ng / mL per 2 mg atropine or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the formulation provides, upon intramuscular or subcutaneous administration to a subject population (e.g., healthy or otherwise healthy subjects), an average maximum concentration of atropine per 2 mg atropine or a pharmaceutically acceptable salt thereof of about 100 ng / mL or less, about 75 ng / mL or less, about 50 ng / mL or less, about 45 ng / mL or less, about 40 ng / mL or less, about 35 ng / mL or less, about 30 ng / mL or less, about 25 ng / mL or less, or about 20 ng / mL or less.

[0065] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of atropine or a pharmaceutically acceptable salt thereof and a parenteral-acceptable adjuvant, wherein said formulation, upon intramuscular or subcutaneous injection into a subject population (e.g., healthy or otherwise healthy subjects), provides a mean maximum plasma concentration (C0) of atropine compared to a comparative formulation without adjuvant. max High mean maximum plasma concentration of atropine. For example, C max It can be compared with the C of the formulation without adjuvants. max Approximately 1.1 times higher, approximately 1.2 times higher, approximately 1.3 times higher, approximately 1.4 times higher, approximately 1.5 times higher, approximately 1.6 times higher, approximately 1.7 times higher, approximately 1.8 times higher, approximately 1.9 times higher, or approximately 2 times higher.

[0066] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of atropine or a pharmaceutically acceptable salt thereof and a parenteral-acceptable adjuvant, wherein the formulation provides an AUC of atropine in a comparative formulation without adjuvant after intramuscular or subcutaneous injection into a subject population (e.g., healthy or otherwise healthy subjects). last High or low AUC last For example, AUC last The AUC can be compared with that of a formulation without adjuvants. last The difference is approximately 1.1 times higher or lower, 1.2 times higher or lower, 1.3 times higher or lower, 1.4 times higher or lower, 1.5 times higher or lower, 1.6 times higher or lower, 1.7 times higher or lower, 1.8 times higher or lower, 1.9 times higher or lower, or 2 times higher or lower.

[0067] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of atropine or a pharmaceutically acceptable salt thereof and a parenteral-acceptable adjuvant, wherein the formulation provides a corresponding AUC of atropine in a comparative formulation without adjuvant after intramuscular or subcutaneous injection into a subject population (e.g., healthy or otherwise healthy subjects). 0.25 AUC 0.5 AUC 0.75 Or AUC1 high AUC0.25 AUC 0.5 AUC 0.75 Or AUC1. For example, AUC 0.25 AUC 0.5 AUC 0.75 Alternatively, AUC1 can be compared with the corresponding AUC of the comparative formulation without adjuvant. 0.25 AUC 0.5 AUC 0.75 Or AUC1 is about 1.1 times higher, about 1.2 times higher, about 1.3 times higher, about 1.4 times higher, about 1.5 times higher, about 1.6 times higher, about 1.7 times higher, about 1.8 times higher, about 1.9 times higher, or about 2 times higher.

[0068] In some embodiments, the pharmacokinetic values ​​described herein can be obtained from a single subject (healthy or therapeutically necessary) or multiple subjects (healthy or therapeutically necessary) following parenteral administration of any of the pharmaceutical compositions disclosed herein.

[0069] The adjuvant's function is to promote or accelerate the systemic absorption of ER-APIs (e.g., adrenaline or a pharmaceutically acceptable salt thereof, or atropine or a pharmaceutically acceptable salt thereof) after intramuscular or subcutaneous injection. In some embodiments, the adjuvant is a vasodilator. The vasodilator may be an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker, calcium channel blocker, nitrate, or magnesium chloride.

[0070] In some embodiments, the adjuvant is magnesium chloride, and in amounts ranging from, for example, about 0.1% (w / v) to about 50% (w / v), about 0.1% (w / v) to about 30% (w / v), about 5% (w / v) to about 30% (w / v), about 1% (w / v) to about 25% (w / v), about 15% (w / v) to about 25% (w / v), about 0.5% (w / v) to about 5% (w / v), about 0.5% (w / v) to about 1% (w / v), about 0.5% (w / v) to about 1.5% (w / v), 1.5% (w / v) to 3.5% (w / v), and about 0.5% (w / v) to about 3%. The concentrations present in the pharmaceutical composition are 5% (w / v), about 0.5% (w / v) to about 3.0% (w / v), about 2.5% (w / v) to about 3% (w / v), about 2.0% (w / v) to about 4% (w / v), about 2.0% (w / v) to about 3.0% (w / v), about 4.5% (w / v) to about 5% (w / v), about 0.9% (w / v), about 1% (w / v), about 2% (w / v), about 2.8% (w / v), about 3% (w / v), about 4.7% (w / v), about 5% (w / v), about 10% (w / v), about 15% (w / v), or about 20% (w / v).

[0071] In certain embodiments, the adjuvant is magnesium chloride and is present in any of the pharmaceutical compositions described herein at a concentration ranging from about 0.1% (w / v) to about 10% (w / v), about 0.2% (w / v) to about 5% (w / v), or about 0.3% (w / v) to about 3% (w / v), or any single concentration value or sub-range therein.

[0072] ACE inhibitors can include, for example, enalapril, captopril, lisinopril, benazepril, enalaprilat, spirapril, fosinopril, moexipril, quinapril, ramipril, perindopril, trandolapril, their pharmaceutically acceptable salts, and combinations thereof. Angiotensin receptor blockers can be selected from, for example, valsartan, losartan, irbesartan, telmisartan, eprosartan, candesartan, olmesartan, saprisartan, tasosartan, elisartan, their pharmaceutically acceptable salts, and combinations thereof. Calcium channel blockers can be selected from, for example, amlodipine, anipamil, barnidipine, benidipine, bepridil, darodipine, diltiazem, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, lidoflazine, manidipine, mybefradil, nicardipine, nifedipine, nilvadipine, nisoldipine, nitrendipine, perhexiline, tiapamil, verapamil, their pharmaceutically acceptable salts, or combinations thereof.

[0073] In certain embodiments, the adjuvant comprises a nitric oxide inducer. The nitric oxide inducer can be, for example, an amino acid (e.g., arginine). The nitric oxide inducer can be selected from, without limitation, the group consisting of L-arginine, L-homoarginine, N-hydroxy-L-arginine, their nitrosated analogs, their nitrosylated analogs, their precursors, and combinations thereof. The nitrosated analogs can be selected from, for example, the group consisting of nitrosated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosated L-homoarginine, and combinations thereof. The nitrosylated analogs can be selected from, for example, the group consisting of nitrosylated L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosylated L-homoarginine, and combinations thereof. Further, the precursors can be selected from, for example, the group consisting of citrulline, ornithine, glutamine, lysine, and combinations thereof. In one embodiment, the adjuvant is L-arginine and is present in the pharmaceutical composition at a concentration ranging from, for example, about 0.1% to about 50%, about 5% to about 30%, about 15% to about 25%, or about 20% (w / v) L-arginine of the unit pharmaceutical composition.

[0074] In certain embodiments, the nitric oxide inducer comprises an arginase inhibitor, a substrate for nitric oxide synthase, nitroglycerin, nitropentaerythritol, and combinations thereof. In certain embodiments, the arginase inhibitor can be, for example, selected from the group consisting of N-hydroxy-L-arginine, 2(S)-amino-6-boronohexanoic, or combinations thereof. In other embodiments, the substrate for nitric oxide synthase is selected from the group consisting of a cytokine, adenosine, bradykinin, calreticulin, bisacodyl, phenolphthalein, and combinations thereof.

[0075] In other embodiments, the adjuvant comprises niacin, a niacin derivative, a niacin metabolite, or combinations thereof. The niacin derivative can be, for example, selected from the group consisting of acifran, acipimox, niacin pentaerythritol ester, isonicotinic acid, isonicotinohydrazide, a pyridine carboxylic acid derivative, 3-pyridineacetic acid, 5-methylnicotinic acid, pyridazine-4-carboxylic acid, pyrazine-2-carboxylic acid, and combinations thereof. In certain embodiments, the niacin derivative is an ester of niacin, for example an alkyl ester of niacin, such as niacin methyl ester. In other embodiments, the niacin metabolite can be, for example, selected from the group consisting of aurofuscin, nicotinamide, 6-hydroxynicotinamide, N-methylnicotinamide, nicotinamide-N-oxide, N-methyl-2-pyridone-5-carboxamide, N-methyl-4-pyridone-5-carboxamide, and combinations thereof. In certain embodiments, the adjuvant is niacin and is present in the pharmaceutical composition at a concentration ranging from about 0.1% to about 15%, about 0.5% to about 5%, about 1%, about 2%, or about 3% (w / v) niacin of the pharmaceutical composition.

[0076] In certain embodiments, the adjuvant comprises a local anesthetic. The local anesthetic can be, for example, an ester-based local anesthetic or an amide-based local anesthetic. The ester-based local anesthetic can be, for example, selected from the group consisting of benzocaine, chloroprocaine, propoxycaine, tetracaine, and combinations thereof. In addition, the amide-based local anesthetic can be, for example, selected from the group consisting of articaine, bupivacaine, dibucaine, lidocaine, mepivacaine, prilocaine, ropivacaine, and combinations thereof.

[0077] In certain embodiments, the adjuvant comprises a phosphodiesterase inhibitor. The phosphodiesterase inhibitor may, for example, be selected from the group consisting of a phosphodiesterase 1 inhibitor, a phosphodiesterase 2 inhibitor, a phosphodiesterase 3 inhibitor, a phosphodiesterase 4 inhibitor, a phosphodiesterase 5 inhibitor, and combinations thereof. In other embodiments, the phosphodiesterase inhibitor may, for example, be selected from the group consisting of vinpocetine, EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine), anagrelide, enoximone, cilomilast, etazolate, gallopamil, ibudilate, lycopendine, rolipram, pentifylline, pirmast, dipyridamole, ladalafil, avanafil, sildenafil, tadalafil, udenafil, vardenafil, milrinone, amrinone, and combinations thereof.

[0078] In certain embodiments, the pharmaceutical compositions and dosage forms disclosed herein comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1% to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, or about 80% (w / v) of the adjuvant in unit dosage form. In certain embodiments, the pharmaceutical compositions and dosage forms disclosed herein comprise about 0.1% to about 30%, about 0.5% to about 25%, or about 1% to about 20% (w / v) of the adjuvant in unit dosage form.

[0079] Active agents

[0080] The delivery systems and pharmaceutical compositions disclosed herein include various active agents or pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, phosphates, and the like; organic acid salts such as formates, acetates, trifluoroacetates, maleates, tartrates, and the like; sulfonates such as methanesulfonates, benzenesulfonates, p-toluenesulfonates, and the like; amino acid salts such as arginates, aspartates, glutamates, and the like, and metal salts such as sodium salts, potassium salts, cesium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; organic amine salts such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, and the like.

[0081] The delivery systems and pharmaceutical compositions disclosed herein include an emergency rescue active pharmaceutical ingredient (ER-API). In certain embodiments, the ER-API is epinephrine, atropine, or a pharmaceutically acceptable salt thereof or a combination thereof.

[0082] In certain embodiments, the ER-API is epinephrine or a pharmaceutically acceptable salt thereof, which is present in a pharmaceutical formulation, and suitable for parenteral administration, in a range of about 0.001 mg / ml to about 10 mg / ml, about 0.005 mg / ml to about 9 mg / ml, about 0.01 mg / ml to about 8 mg / ml, about 0.05 mg / ml to about 7 mg / ml, about 0.1 mg / ml to about 5 mg / ml, about 0.3 mg / ml to about 2.5 mg / ml, about 0.5 mg / ml to about 1.5 mg / ml, or about 1 mg / ml.

[0083] In certain embodiments, the ER-API is epinephrine or a pharmaceutically acceptable salt thereof, and the pharmaceutical formulation (e.g., parenteral formulation) can comprise a dose (epinephrine base dose) from any of about 0.05 mg, about 0.1 mg, about 0.15 mg, or about 0.2 mg to any of about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, or about 0.5 mg.

[0084] In certain embodiments, the pharmaceutical composition is a parenteral formulation comprising a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof and a parenterally acceptable absorption enhancing amount of magnesium chloride, wherein the parenterally acceptable absorption enhancing amount of magnesium chloride ranges from about 0.1% (w / v) to about 10% (w / v), about 0.2% (w / v) to about 5% (w / v), or about 0.3% (w / v) to about 3% (w / v), or any single concentration value or sub-range therein.

[0085] In certain embodiments, the ER-API is atropine or a pharmaceutically acceptable salt thereof, which is present in a pharmaceutical formulation, and suitable for parenteral administration, in a range of about 0.001 mg / ml to about 10 mg / ml, about 0.005 mg / ml to about 9 mg / ml, about 0.01 mg / ml to about 8 mg / ml, about 0.05 mg / ml to about 7 mg / ml, about 0.1 mg / ml to about 5 mg / ml, about 0.3 mg / ml to about 2.5 mg / ml, about 0.5 mg / ml to about 1.5 mg / ml, or about 1 mg / ml.

[0086] In certain embodiments, the ER-API is atropine or a pharmaceutically acceptable salt thereof, and the pharmaceutical formulation (e.g., parenteral formulation) can comprise a dose of any of about 0.05 mg, about 0.1 mg, about 0.15 mg, or about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, or about 0.5 mg to any of about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, or about 5 mg (atropine base dose).

[0087] In certain embodiments, the pharmaceutical composition is a parenteral formulation comprising a therapeutically effective amount of atropine or a pharmaceutically acceptable salt thereof and a parenterally acceptable absorption enhancing amount of magnesium chloride, wherein the parenterally acceptable absorption enhancing amount of magnesium chloride ranges from about 0.1% (w / v) to about 10% (w / v), about 0.2% (w / v) to about 5% (w / v), or about 0.3% (w / v) to about 3% (w / v), or any single concentration value or sub-range therein.

[0088] Prophylactic and therapeutic treatment

[0089] It is an object of certain embodiments of the present application to provide a method of preventing or minimizing an allergic reaction or poisoning in a subject at risk of exposure to an allergen or a toxicant. For example, law enforcement personnel or first medical responders can be pre-treated with an ER-API according to the present application prior to entering an environment or a place that they suspect can have a toxicant (e.g., a nerve agent) intentionally or unintentionally released or otherwise present (e.g., a crime scene or an emergency situation). In addition, workers in an area of an environmental disaster involving an allergen or a toxicant can receive pre-treatment to avoid the toxicity of the allergen or toxicant that can be present in the environment. In embodiments involving prophylactic treatment methods, the composition administered can include, but is not limited to, a pharmaceutical composition as disclosed herein. For example, administration of an ER-API for prophylactic treatment can utilize a formulation presently disclosed for intramuscular or subcutaneous administration, or can utilize a route of oral, nasal, pulmonary, transdermal, rectal, or intravenous administration of the ER-API.

[0090] Pharmaceutically acceptable excipients

[0091] The pharmaceutical compositions according to the present application can comprise one or more pharmaceutically acceptable carriers and excipients suitable for intramuscular or subcutaneous administration. Examples of possible pharmaceutically acceptable carriers and excipients are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (6th edition, published in 2009), which is incorporated herein by reference. Carriers and excipients suitable for intramuscular and subcutaneous formulations include, but are not limited to, antioxidants, buffering agents, diluents, surfactants, solubilizers, stabilizers, hydrophilic polymers, additional absorption or permeation enhancers, preservatives, penetrants, isotonic agents, pH adjusting agents, solvents, co-solvents, viscosity agents, gelling agents, suspending agents, or combinations thereof.

[0092] Suitable surfactants for the formulations disclosed herein include, but are not limited to, polysorbate 80 NF, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trilaurate, sorbitan trioleate, sorbitan tristearate, and the like, and combinations thereof.

[0093] Suitable isotonic agents for the pharmaceutical compositions disclosed herein include, but are not limited to, dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine, and the like, and combinations thereof.

[0094] Suitable suspending agents for the formulations disclosed herein include, but are not limited to, microcrystalline cellulose, sodium carboxymethylcellulose NF, polyacrylic acid, magnesium aluminum silicate, xanthan gum, and the like, and mixtures thereof. In certain embodiments, the pharmaceutical compositions can comprise one or more suspending agents in an amount of about 0.1 wt% to about 15 wt%, or about 0.25 wt% to about 10 wt%, or about 1 wt% to about 8 wt%, based on the total weight of the pharmaceutical composition.

[0095] Methods of providing emergency rescue

[0096] In certain embodiments, the present disclosure relates to a method of providing emergency rescue to a subject in need thereof. The method comprises administering to a subject in need thereof an ER- API and optionally an adjuvant, such that onset of action of the ER-API is achieved within a sufficient time to reverse or partially reverse an allergic reaction or poisoning. In certain embodiments, the present invention is directed to the emergency administration to a subject experiencing a medical emergency caused by an allergic reaction (e.g., anaphylactic shock) or poisoning. In such cases, the pharmaceutical composition will typically be administered by a medical practitioner, emergency medical technician, law enforcement officer, family member, acquaintance, or bystander upon observation of the subject experiencing symptoms of an allergic reaction or poisoning. In some embodiments, the method further comprises, prior to the administering step, identifying that the subject is experiencing an allergic reaction or poisoning.

[0097] The allergic reaction or poisoning treated by the present invention can be caused by any allergen or poison currently known, or those readily understood by one of ordinary skill (in the fields of formulation and medicine) to be useful for such a purpose, including but not limited to any of the following: chemical nerve agents, pesticide poisoning, allergens (e.g., pollen, nuts (such as peanuts and tree nuts), milk, eggs, shellfish, wheat, soy, fish, insect bites, bee stings, etc.), or combinations thereof.

[0098] In some embodiments, the ER-API and the adjuvant are each administered separately. In other embodiments, the ER-API and the adjuvant are administered together as a combination in a single dosage form. In some embodiments, the ER-API and the adjuvant are both administered via the same route of administration, i.e., intramuscularly or subcutaneously. In other embodiments, the ER-API and the adjuvant are administered via different routes of administration.

[0099] In one embodiment, the ER-API and the adjuvant are both administered to a subject in need thereof via intramuscular administration.

[0100] In another embodiment, the ER-API and the adjuvant are administered to a subject in need thereof via subcutaneous administration.

[0101] Intranasal formulations

[0102] In certain embodiments, the present invention relates to pharmaceutical formulations suitable for intranasal or via inhalation administration. The intranasal pharmaceutical formulation can comprise a therapeutically effective amount of an ER-API (e.g., epinephrine or atropine or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable adjuvant (e.g., an intranasally acceptable adjuvant) that facilitates the rate of absorption of the ER-API following intranasal or inhalation administration. The adjuvant can include any of the adjuvants described above, such as magnesium chloride.

[0103] In certain embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of an ER-API and an intranasally acceptable adjuvant, wherein the formulation provides a shorter onset of action (i.e., the first detectable therapeutic effect associated with administration of the ER-API, such as a detectable reduction or decrease in any symptoms associated with an allergic reaction or intoxication) than the onset of action of a comparative pharmaceutical composition that does not contain the intranasally acceptable adjuvant.

[0104] In other embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of an ER-API and an intranasally acceptable adjuvant, wherein the formulation provides a mean time to maximum plasma concentration after intranasal or via inhalation administration to a population of subjects (e.g., healthy or otherwise healthy subjects) that is shorter than the mean time to maximum plasma concentration of a comparative pharmaceutical composition that does not contain the intranasally acceptable adjuvant. For example, the mean T max may be about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, about 2 times, about 3 times, or about 4 times shorter than the mean T max For example, about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, about 2 times, about 3 times, or about 4 times shorter.

[0105] In certain embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of an ER-API and an intranasally acceptable adjuvant, wherein the formulation provides a higher mean maximum plasma concentration of the ER-API (C max ) after intranasal administration to a population of subjects (e.g., healthy or otherwise healthy subjects) than the mean maximum plasma concentration of the ER-API (C max may be about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, about 2 times, about 3 times, or about 4 times higher than the C max may be about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, about 2 times, about 3 times, or about 4 times higher than the C

[0106] In certain embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of an ER-API and an intranasally acceptable adjuvant, wherein the formulation provides a higher AUC 0-inf after intranasal administration to a population of subjects (e.g., healthy or otherwise healthy subjects) than the AUC inf . For example, the AUC inf may be about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, about 2 times, about 3 times, or about 4 times higher than the AUC infabout 1.1 fold, about 1.2 fold, about 1.3 fold, about 1.4 fold, about 1.5 fold, about 1.6 fold, about 1.7 fold, about 1.8 fold, about 1.9 fold, or about 2 fold, about 4 fold, about 6 fold, about 8 fold, or about 10 fold.

[0107] In certain embodiments, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of an ER-API and an intranasally acceptable adjuvant, wherein the formulation provides an AUC 0.25 , AUC 0.5 , AUC 0.75 , or AUC1that is higher than the corresponding AUC 0.25 , AUC 0.5 , AUC 0.75 , or AUC1of a comparative formulation without the adjuvant after intranasal administration to a population of subjects (e.g., healthy or otherwise healthy subjects). For example, the AUC 0.25 , AUC 0.5 , AUC 0.75 , or AUC1may be about 1.1 fold, about 1.2 fold, about 1.3 fold, about 1.4 fold, about 1.5 fold, about 1.6 fold, about 1.7 fold, about 1.8 fold, about 1.9 fold, or about 2 fold, about 4 fold, about 6 fold, about 8 fold, or about 10 fold higher than the corresponding AUC 0.25 , AUC 0.5 , AUC 0.75 , or AUC1of a comparative formulation without the adjuvant.

[0108] In certain embodiments, the mean time to maximum plasma concentration, maximum plasma concentration, and / or AUC inf of a pharmaceutical composition for intranasal or via inhalation administration can fall within the same ranges as described above for parenteral formulations.

[0109] In certain embodiments, the pharmacokinetic values described herein can be obtained from a single subject (a single healthy or therapeutically in need thereof subject) or a plurality of subjects (a plurality of healthy or therapeutically in need thereof subjects) following intranasal administration or via inhalation administration of any of the pharmaceutical compositions disclosed herein suitable for intranasal administration or via inhalation administration.

[0110] The adjuvant functions to promote or hasten the rate of systemic absorption of the ER-API (e.g., epinephrine or a pharmaceutically acceptable salt thereof, or atropine or a pharmaceutically acceptable salt thereof) following intranasal administration or following administration via inhalation. In certain embodiments, the adjuvant is magnesium chloride.

[0111] In some embodiments, the adjuvant is magnesium chloride and is present in the intranasal pharmaceutical composition at a concentration ranging from, for example, about 0.1% (w / v) to about 50% (w / v), about 0.1% (w / v) to about 30% (w / v), about 5% (w / v) to about 30% (w / v), about 1% (w / v) to about 25% (w / v), about 15% (w / v) to about 25% (w / v), about 0.5% (w / v) to about 5% (w / v), about 0.5% (w / v) to about 1% (w / v), about 0.5% (w / v) to about 1.5% (w / v), about 1.5% (w / v) to about 2.5% (w / v), about 0.5% (w / v) to about 3.5% (w / v), about 0.5% (w / v) to about 3.0% (w / v), about 2.5% (w / v) to about 3% (w / v), about 2.0% (w / v) to about 4% (w / v), about 2.0% (w / v) to about 3.0% (w / v), about 4.5% (w / v) to about 5% (w / v), about 0.9% (w / v), about 1% (w / v), about 2% (w / v), about 2.8% (w / v), about 3% (w / v), about 4.7% (w / v), about 5% (w / v), about 10% (w / v), about 15% (w / v), or about 20% (w / v).

[0112] In certain embodiments, any of the intranasal or inhaled pharmaceutical compositions include magnesium chloride as an adjuvant at a concentration ranging from about 0.1% (w / v) to about 10% (w / v), about 0.2% (w / v) to about 5% (w / v), or about 0.3% (w / v) to about 3% (w / v), or any single concentration value or sub-range therein.

[0113] In certain embodiments, the pharmaceutical compositions for intranasal or via inhalation administration can be aqueous solutions, suspensions, or emulsions. Such pharmaceutical compositions can be administered to a subject via a device suitable for intranasal administration, such as, but not limited to, a nasal sprayer / atomizer device, a metered multi-dose spray pump, a single or double dose spray device.

[0114] In certain embodiments, the pharmaceutical formulation (e.g., formulation for inhalation) comprises a (ER-API) dose of about any one of about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.125 mg, about 0.15 mg, about 0.175, or about 0.2 mg to about 0.225 mg, about 0.25 mg, about 0.275 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, or about 0.5 mg per inhalation.

[0115] In certain embodiments, the pharmaceutical composition is a formulation suitable for intranasal administration or for administration via inhalation, and comprises a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof and an absorption-enhancing amount of magnesium chloride, wherein the absorption-enhancing amount of magnesium chloride ranges from about 0.1% (w / v) to about 10% (w / v), about 0.2% (w / v) to about 5% (w / v), or about 0.3% (w / v) to about 3% (w / v), or any single concentration value or sub-range therein.

[0116] In certain embodiments, the pharmaceutical composition is a formulation suitable for intranasal administration or for administration via inhalation, and comprises a therapeutically effective amount of atropine or a pharmaceutically acceptable salt thereof and an absorption-enhancing amount of magnesium chloride, wherein the absorption-enhancing amount of magnesium chloride ranges from about 0.1% (w / v) to about 10% (w / v), about 0.2% (w / v) to about 5% (w / v), or about 0.3% (w / v) to about 3% (w / v), or any single concentration value or sub-range therein.

[0117] Drug delivery systems and kits

[0118] In certain embodiments, the present application relates to a drug delivery system or kit comprising an injection device and any of the pharmaceutical formulations disclosed herein (e.g., parenteral). In certain embodiments, the injection device is pre-filled with the pharmaceutical formulation. In certain embodiments, the injection device is a syringe, a vial, an injection pen, or an auto-injector pre-filled with the pharmaceutical formulation disclosed herein.

[0119] In certain embodiments, the present application relates to a drug delivery system or kit comprising a device for intranasal administration or administration via inhalation (e.g., a nasal spray / atomizer device, a metered multi-dose spray pump, a single-dose or double-dose spray device). In certain embodiments, the device for intranasal administration or administration via inhalation is pre-filled with the pharmaceutical formulation.

[0120] In certain embodiments, the drug delivery system or kit comprises the active agent and the adjuvant in separate containers (e.g., separate vials, separate syringe barrels, separate compartments, etc.). In one embodiment, the ER-API (e.g., epinephrine or a pharmaceutically acceptable salt thereof, or atropine or a pharmaceutically acceptable salt thereof) is in one container, and the adjuvant (e.g., MgCl2) is in another container; and the ER-API is mixed with the adjuvant prior to administration (e.g., parenteral, intranasal, or via inhalation).

[0121] In certain embodiments, the active agent (e.g., an ER-API such as epinephrine or a pharmaceutically acceptable salt thereof, or atropine or a pharmaceutically acceptable salt thereof) is in solution or powder form in the drug delivery system or kit. In certain embodiments, the adjuvant is in solution or powder form in the drug delivery system or kit.

[0122] In one embodiment, the drug delivery system or kit comprises a solution of an active agent (e.g., an ER-API such as epinephrine or a pharmaceutically acceptable salt thereof, or atropine or a pharmaceutically acceptable salt thereof) in one container and a solution of an adjuvant (e.g., MgCl2) in another container. The active agent solution and the adjuvant solution are mixed prior to administration. In one embodiment, the active agent solution is in one compartment of an auto-injector (or device for intranasal administration or administration via inhalation) and the adjuvant solution is in another compartment of the auto-injector (or device for intranasal administration or administration via inhalation), and the two solutions are mixed in the auto-injector (or device for intranasal or administration via inhalation) prior to administration (e.g., parenterally, intranasally, or via inhalation). In another embodiment, the active agent solution is in one vial and the adjuvant solution is in another vial, and the contents of the vials are mixed prior to administration (e.g., by transferring the contents of one vial to the other vial with a syringe and needle, which can be part of the kit described herein).

[0123] In one embodiment, the drug delivery system or kit described herein comprises a solution of an active agent (e.g., an ER-API such as epinephrine or a pharmaceutically acceptable salt thereof, or atropine or a pharmaceutically acceptable salt thereof) in one container and a powder of an adjuvant (e.g., MgCl2) in another container. The active agent solution and the adjuvant powder are mixed prior to administration. In one embodiment, the active agent solution is in one compartment of an auto-injector (or device for intranasal administration or administration via inhalation) and the adjuvant powder is in another compartment of the auto-injector (or device for intranasal administration or administration via inhalation), and the powder and the solution are mixed in the auto-injector (or device for intranasal or administration via inhalation) prior to administration. In another embodiment, the active agent solution is in one vial (or pre-filled syringe barrel, etc.) and the adjuvant powder is in another vial, and the active agent solution can be added to the adjuvant powder (e.g., by transferring the active agent solution to the adjuvant powder container with a syringe and needle, which can be part of the kit described herein) to suspend or dissolve the adjuvant powder prior to administration (e.g., parenterally, intranasally, or via inhalation).

[0124] In one embodiment, the drug delivery system or kit described herein comprises a powder of an active agent (e.g., an ER-API, such as epinephrine or a pharmaceutically acceptable salt thereof, or atropine or a pharmaceutically acceptable salt thereof) in one container and a solution of an adjuvant (e.g., MgCh) in another container. The active agent powder and the adjuvant solution are mixed prior to administration (e.g., parenterally, intranasally, or via inhalation). In one embodiment, the active agent powder is in one compartment of an auto-injector (or device for intranasal or inhalation administration), the adjuvant solution is in another compartment of the auto-injector (or device for intranasal or inhalation administration), and the powder and the solution are mixed in the auto-injector (or device for intranasal or inhalation administration) prior to administration. In another embodiment, the active agent powder is in one vial, the adjuvant solution is in another vial (or pre-filled syringe barrel, etc.), and the adjuvant solution is added to the active agent powder (e.g., by transferring the adjuvant solution to the active agent powder container with a syringe and needle, which can be part of the kit described herein) prior to administration (e.g., parenterally, intranasally, or via inhalation) to suspend or dissolve the active agent powder.

[0125] In one embodiment, the drug delivery system or kit described herein comprises a powder of an active agent (e.g., an ER-API, such as epinephrine or a pharmaceutically acceptable salt thereof, or atropine or a pharmaceutically acceptable salt thereof) in one container, a powder of an adjuvant (e.g., MgCh) in another container, and a solvent in yet another container. The active agent powder, the adjuvant powder, and the solvent are mixed prior to administration. In one embodiment, the active agent powder is in one compartment of an auto-injector (or device for intranasal or inhalation administration), the adjuvant powder is in another compartment of the auto-injector (or device for intranasal or inhalation administration), and the solvent is in yet another compartment of the auto-injector, such that the powder is suspended or dissolved in the solvent prior to administration (e.g., parenterally, intranasally, or via inhalation). In another embodiment, the active agent powder is in one vial, the adjuvant powder is in another vial, and the solvent is in yet another vial (or pre-filled syringe barrel, etc.), and the solvent is added to the active agent powder and / or the adjuvant powder (e.g., by transferring the solvent to the active agent powder and / or adjuvant powder containers with a syringe and needle, which can be part of the kit described herein) prior to administration (e.g., parenterally, intranasally, or via inhalation) to suspend or dissolve the powder.

[0126] In certain embodiments, the drug delivery system or kit described herein comprises the active agent (e.g., an ER-API, such as epinephrine or a pharmaceutically acceptable salt thereof, or atropine or a pharmaceutically acceptable salt thereof) and the adjuvant (e.g., MgCh) combined together in powder form in one container, and the pharmaceutically acceptable solvent is stored in another container prior to administration (e.g., parenteral, intranasal, or via inhalation). In one embodiment, the active agent powder and the adjuvant powder are mixed together in one compartment of an auto-injector (or device for intranasal or via inhalation administration), and the pharmaceutically acceptable solvent can be stored in another compartment of the auto-injector (or device for intranasal or via inhalation administration) such that the powder mixture is suspended or dissolved in the solvent prior to administration. In another embodiment, the active agent powder and the adjuvant powder are mixed together in one vial, and the solvent can be located in another vial (or pre-filled syringe barrel, etc.), and the solvent is added to the powder mixture (e.g., by transferring the solvent into the powder mixture container with a syringe and needle, which can be part of the kit described herein) prior to administration (e.g., parenteral, intranasal, or via inhalation) to suspend or dissolve the powder mixture.

[0127] In certain embodiments, the drug delivery system or kit described herein includes a needle having a needle gauge of about 18 to about 35. For example, a needle for parenteral administration of any of the pharmaceutical compositions described herein (whether a separate needle or a needle of an auto-injector device) can be 18 gauge, 20 gauge, 21 gauge, 22 gauge, 23 gauge, 25 gauge, 27 gauge, 29 gauge, 31 gauge, or 33 gauge.

[0128] The previously disclosed concentration ranges and / or values for the active agent and / or adjuvant expressed in % (w / v) refer to the final concentration when all components are mixed together prior to administration.

[0129] Examples

[0130] The following examples are set forth to assist in understanding the application and should not be construed as specifically limiting the application described and claimed herein. Such variations of the application, including the substitution of all equivalents now known or later developed, that would be within the purview of one skilled in the art, as well as minor changes or

[0131] Example 1 : Epinephrine Study Design

[0132] The absorption of epinephrine (0.2 mg dose, 1 mg / mL concentration) containing different concentrations of MgCl2 adjuvant (0% MgCl2 in saline sample, 1% MgCl2 in water, and 2% MgCl2 in water) was tested. Each epinephrine formulation was administered intramuscularly to three canine subjects. Eight blood samples were collected from each subject at different time points (before administration, 2.5 minutes after administration, 5 minutes after administration, 10 minutes after administration, 20 minutes after administration, 30 minutes after administration, 60 minutes after administration, and 120 minutes after administration) to assess the pharmacokinetic characteristics of epinephrine absorption. Details of the epinephrine study design, referring to Groups 1–3, are summarized in Table 1 below. Plasma concentrations of epinephrine after intramuscular administration in dogs with different concentrations of MgCl2 are summarized in... Figure 1 And in Table 2 below.

[0133] Table 1 – Study Design of Adrenaline

[0134]

[0135] Table 2 – Summary of Adrenaline Pharmacokinetic Data

[0136]

[0137]

[0138] *ND – Undetermined

[0139] like Figure 1 As shown in Table 2, the epinephrine formulations containing MgCl2 (Groups 2 and 3) achieved a higher C10 concentration than the epinephrine formulations without MgCl2. max .from Figure 1 As can also be observed in Table 2, compared with the epinephrine formulation without MgCl2, the epinephrine formulation containing 2% MgCl2 shortened the T-segmentation time. max Furthermore, the AUC observed in adrenaline formulations containing MgCl2 was... last Higher than adrenaline formulations without MgCl2. Based on the above data, and without being interpreted as limiting, it is believed that MgCl2 increases C... max and / or reduce T max and / or increase AUC last This enhances the absorption of adrenaline.

[0140] Example 2: Atropine Study Design

[0141] Atropine (0.2 mg dose, 1 mg / mL concentration) containing different concentrations of MgCl2 adjuvant (0% MgCl2 in normal saline-like sample, 1% MgCl2 in water, and 2% MgCl2 in water) was tested for absorption. Each atropine formulation was administered intramuscularly to three dog subjects. Eight blood samples were collected from each subject at various time points (pre-dose, 2.5 minutes post-dose, 5 minutes post-dose, 10 minutes post-dose, 20 minutes post-dose, 30 minutes post-dose, 60 minutes post-dose, and 120 minutes post-dose) to assess the pharmacokinetic profile of atropine absorption. Details of the atropine study design are summarized in Table 3 below for Groups 4-6. Plasma concentrations of atropine following intramuscular administration in dogs with different concentrations of MgCl2 are summarized in Figure 2 and Table 4 below.

[0142] Table 3 - Study Design

[0143]

[0144]

[0145] Table 4 - Atropine Pharmacokinetic Data Summary

[0146]

[0147] ND - Not determined

[0148] As shown in Figure 2 and Table 4, the atropine formulation containing 1% MgCl2 (Group 5) achieved a higher C max max than the atropine formulation without MgCl2 (Group 4). In addition, the AUC last observed in the atropine formulations containing MgCl2 (Group 5 and Group 6) were higher than the atropine formulation without MgCl2 (Group 4). Without being bound by theory, based on the data above, it is believed that MgCl2 enhances the absorption of atropine by increasing the C max max and / or decreasing the T max max and / or increasing the AUC last .

[0149] In the preceding description, numerous specific details are set forth such as specific materials, dimensions, processes parameters, etc. in order to provide a thorough understanding of the present application. Particular features, structures, materials, or characteristics can be combined in any suitable manner in one or more embodiments. The words "example" or "exemplary" are used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as "example" or "exemplary" is not necessarily to be construed as preferred or advantageous over other aspects or designs. Rather, use of the words "example" or "exemplary" is intended to present concepts in a concrete fashion. As used in this application, the term "or" is intended to mean an inclusive "or" rather than an exclusive "or". That is, unless specified otherwise, or clear from context, "X includes A or B" is intended to mean any of the natural inclusive permutations. That is, if X includes A; X includes B; or X includes both A and B, then "X includes A or B" is satisfied under any of the foregoing instances. Reference throughout this specification to "an embodiment", "certain embodiments", or "one embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "an embodiment", "certain embodiments", or "one embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment.

[0150] The application has been described with reference to certain exemplary embodiments thereof. Accordingly, the specification and drawings are to be regarded in an illustrative rather than a restrictive sense. Various modifications and changes can be made by those of ordinary skill in the art which fall within the scope of the present application as defined by the appended claims.

Claims

1. A parenteral formulation comprising a therapeutically effective amount of an emergency rescue active pharmaceutical ingredient (ER-API) and a parenterally acceptable absorption enhancing amount of an adjuvant, wherein the ER-API is epinephrine or a pharmaceutically acceptable salt thereof, or wherein the ER-API is atropine or a pharmaceutically acceptable salt thereof, and wherein the adjuvant is magnesium chloride.

2. The parenteral formulation of claim 1, wherein the formulation facilitates the rate of systemic absorption of the ER-API after injection compared to the same formulation without the adjuvant.

3. The parenteral formulation of claim 1, wherein the formulation provides a shorter onset of action time for emergency rescue after intramuscular or subcutaneous injection to a subject experiencing an allergic reaction or poisoning compared to the same formulation without the adjuvant.

4. The parenteral formulation of claim 1, wherein the formulation provides an onset of action time for emergency rescue after intramuscular or subcutaneous injection to a subject experiencing an allergic reaction or poisoning of about 5 minutes or less, about 4 minutes or less, about 3 minutes or less, about 2 minutes or less, and about 1 minute or less.

5. The parenteral formulation of claim 1, wherein the formulation provides a mean time to maximum plasma concentration of the ER-API after intramuscular or subcutaneous administration to a population of healthy subjects of about 2.0 hours or less.

6. The parenteral formulation of claim 1, wherein the formulation provides a mean time to maximum plasma concentration of the ER-API after intramuscular or subcutaneous injection to a population of healthy subjects of about 1.5 hours or less, about 1 hour or less, about 0.75 hours or less, about 0.5 hours or less, about 20 minutes or less, about 15 minutes or less, about 10 minutes or less, about 5 minutes or less, about 3 minutes or less, or about 1 minute or less.

7. The parenteral formulation of claim 1, wherein the adjuvant increases the rate of systemic absorption of the ER-API after intramuscular or subcutaneous injection.

8. The parenteral formulation of claim 1, wherein the adjuvant is present in the parenteral formulation in an amount of about 0.1% (w / v) to about 50% (w / v).

9. The parenteral formulation of any one of claims 1 to 8 for use in a method of providing emergency rescue to a subject experiencing an allergic reaction or poisoning.

10. Use of the parenteral formulation of any one of claims 1 to 8 in the manufacture of a medicament for providing emergency rescue to a subject experiencing an allergic reaction or poisoning.

11. A drug delivery system comprising an injection device containing the formulation of any one of claims 1 to 8.

12. A kit comprising a therapeutically effective amount of an emergency rescue active pharmaceutical ingredient (ER-API) and an absorption enhancing amount of a parenterally acceptable adjuvant, wherein the ER-API and the adjuvant are independently in solution or in powder form, wherein the ER-API and the adjuvant are stored in separate containers or in one container, wherein the ER-API is epinephrine or a pharmaceutically acceptable salt thereof, or wherein the ER-API is atropine or a pharmaceutically acceptable salt thereof, and wherein the adjuvant is magnesium chloride.

13. The kit of claim 12, further comprising an injection device.

14. The kit of claim 13, wherein the injection device is an auto-injector.

15. The kit of claim 14, wherein the auto-injector is pre-loaded with a solution of the ER-API, a solution of the parenterally acceptable adjuvant, or both.

16. The kit of any one of claims 12 to 15, further comprising a syringe and a needle.

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