(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2008/0269347 A1
`(43) Pub. Date:
`Oct. 30, 2008
`Bruss et al.
`
`US 20080269347A1
`
`(54)
`(75)
`
`(73)
`(21)
`(22)
`
`(60)
`
`EPINEPHRINE FORMULATIONS
`
`Publication Classification
`
`Inventors:
`
`Jon Bruss, Cincinnati, OH (US);
`John McCarty, Miami Springs, FL
`(US); Blair West, Miramar, FL
`(US)
`Correspondence Address:
`FULBRIGHT & JAWORSKI, LLP
`1301 MCKINNEY, SUITE 5100
`HOUSTON, TX 77010-3095 (US)
`Assignee:
`Azopharma, Inc.
`Appl. No.:
`11/864,234
`Filed:
`Sep. 28, 2007
`Related U.S. Application Data
`Provisional application No. 60/847,823, filed on Sep.
`28, 2006.
`
`(51) Int. Cl.
`A63L/35
`A6IP37/08
`
`(2006.01)
`(2006.01)
`
`(52) U.S. Cl. ........................................................ S14/653
`
`ABSTRACT
`(57)
`The present invention generally concerns an epinephrine for
`mulation that has enhanced stability. In particular embodi
`ments, the formulation is an injectable formulation. In spe
`cific aspects, the formulation comprises epinephrine, EDTA,
`and one or more of an antioxidant Such as cysteine, citric acid,
`acetylcysteine, or thioglycerol. The formulations are Suitable
`for any medical condition that is in need of epinephrine,
`although in specific embodiments the medical condition is
`anaphylaxis, asthma, or cardiac arrest.
`
`EPINEPHRINE ANTIOXIDANT STUDY
`CYSTEINE FORMULATIONS
`
`102 - X
`
`
`
`100 :
`
`98.
`
`96 :
`
`94 :
`
`92 :
`
`90 :
`
`88 &www.www.www.www.www.www.axxxxxxxxxxxxxxxxxvi-xxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxx
`
`-- Metabisulfite
`Cysteine/EDTA/Citric Acid
`-- Qysteine/EDTACitric Acid/Thioglycerol
`
`xx
`
`
`
`is as AAY as
`
`
`
`v. Cysteine/EDTA
`See
`
`3REEEFAA.S.S.
`
`yICy
`CeVICVSeine
`
`ADAMIS EXHIBIT 1006
`Page 1 of 12
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`

`

`Patent Application Publication
`
`Oct. 30, 2008 Sheet 1 of 2
`
`US 2008/0269347 A1
`
`EPINEPHRINE ANTIOXIDANT STUDY
`CYSTEINE FORMULATIONS
`
`102 x
`
`9 8
`
`9 4
`
`92 :
`
`90 :
`
`88
`
`O
`
`1
`
`2
`
`4
`
`re. Cysteine/EDTA
`-0-Metabisulfite
`r or Cystiene/EDTA Thioglycerol
`Cysteine/EDTA/Citric Acid
`-- Cysteine/EDTACitric Acid/Thioglycerol -- gine/EDTAAcetylcysteine
`xx
`
`
`
`
`
`FIG. 1
`
`ADAMIS EXHIBIT 1006
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`

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`Patent Application Publication
`
`Oct. 30, 2008 Sheet 2 of 2
`
`US 2008/0269347 A1
`
`EPINEPHRINE ANTIOXIDANT STUDY
`METABSULFITE FORMULATIONS
`
`3.
`E 1OO
`2 95
`C 90
`o S
`
`
`
`O
`
`1
`
`2
`
`4
`
`WEEKS GD 40C/75%RH
`
`-- Metabisulfite
`
`wSw EDTA ONLY
`
`MB With EDTA
`
`M M
`
`M M xo MB with Ascorbic Acid -- Ascorbic Acid Only
`
`FIG 2
`
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`US 2008/0269347 A1
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`Oct. 30, 2008
`
`EPINEPHRINE FORMULATIONS
`
`0001. This application claims priority to U.S. Provisional
`Patent Application Ser. No. 60/847,823, filed Sep. 28, 2006,
`which is incorporated by reference herein in its entirety.
`
`FIELD OF THE INVENTION
`0002 The fields of the present invention include at least
`molecular biology, cell biology, and medicine. In certain
`fields of the invention, there are new compositions of epi
`nephrine and devices and methods of using Such epinephrine
`formulations.
`
`BACKGROUND OF THE INVENTION
`0003 Epinephrine, or (-)-3,4-Dihydroxy-(methylamino)
`methylbenzyl alcohol, is an endogenous adrenergic neu
`rotransmitter synthesized and stored in the adrenal medulla. It
`is a polar compound characterized structurally by a catechol
`(a dihydroxybenzene) and an amine, and it is commonly
`available in a salt form. Epinephrine is water soluble and
`interacts in a variety of ways, depending on the type of recep
`tor areas of target cells.
`0004 Epinephrine is one of the neural hormones respon
`sible for the regulation of the heart, blood pressure, airway
`resistance, and energy metabolism. It is classified as a sym
`pathomimetic drug, acting on both alpha and beta receptors.
`Epinephrine generates an inotropic effect, wherein it
`increases the heart rate, the force of contraction of the heart,
`narrows the blood vessels thus increasing blood pressure,
`reduces airway resistance to make it easier to breath, and
`raises blood glucose and blood fatty acids to Supply the body
`energy during stress. Epinephrine is available in a variety of
`formulations suited for different clinical indications and
`routes of administration, for example by injection, by inha
`lation, or topically. Its uses include at least the following:
`combating low blood pressure during hemorrhagic orallergic
`shock, opening the airways during asthmatic attack; restrict
`ing the distribution of locally administered drugs such as local
`anesthetics; reducing nasal congestion; and/or performance
`aid in emergency situations.
`0005 Epinephrine can be prepared synthetically by one of
`several processes readily available to one in the art. One such
`process starts with 1,2-dihydroxybenzene that is converted
`successively to (chloroacetyl)catechol with chloroacetyl
`chloride, then to (methyl-aminoacetyl)catechol with methy
`lamine and to racemic epinephrine by hydrogenation. The
`racemic form is resolved with D-tartaric acid to provide a
`white to nearly-white powder that is sensitive to light, air,
`heat, or alkaline conditions. Salts with acids are readily
`formed and provide some stability. The hydrochloride, sul
`phate, and bitartrate salts are known in the art.
`0006 Allergic emergencies, such as anaphylaxis, are a
`growing concern, given the increasing awareness of members
`of the public of their frequency and potential severity. Ana
`phylaxis is a Sudden, severe, systemic allergic reaction that
`can be fatal, in many cases, if left untreated. Anaphylaxis can
`involve various areas of the body, such as the skin, respiratory
`tract, gastrointestinal tract, and cardiovascular system. Acute
`symptoms occur from within minutes to two hours after con
`tact with the allergy-causing Substance, but in rare instances
`onset may be delayed by as much as four hours. Contact with
`anaphylaxis-inducing agents, and the severity of the resulting
`
`anaphylactic reaction, can be extremely unpredictable.
`Accordingly, allergists recommend that persons who have a
`personal or family history of anaphylaxis be prepared to
`self-administer emergency treatment at all times. Addition
`ally, adults charged with caring for children who are at risk for
`anaphylaxis should also be prepared to administer anti-ana
`phylactic first aid.
`0007. The symptoms of anaphylaxis include one or more
`of the following, generally within 1 to about 15 minutes of
`exposure to the antigen: agitation, a feeling of uneasiness,
`flushing, palpitations, paresthesias, pruritus, throbbing in the
`ears, coughing, Sneezing, urticaria, angioedema, difficulty
`breathing due to laryngeal edema or brochospasm, nausea,
`Vomiting, abdominal pain, diarrhea, shock, convulsions,
`incontinence, unresponsiveness and death. An anaphylactic
`reaction may include cardiovascular collapse, even in the
`absence of respiratory symptoms.
`0008 According to the Merck Manual, immediate treat
`ment with epinephrine is imperative for the successful treat
`ment of anaphylaxis (Merck Manual, 17.sup.th Ed., 1053
`1054 (1999)). The recommended dose is about 0.01 mL/Kg in
`adults: usually about 0.3 to 0.5 mL of a 1:1000 dilution of
`epinephrine in a suitable carrier. While the dose may be given
`manually, Such as either subcutaneously or intramuscularly,
`for example, in recent years automatic injectors have become
`an accepted first aid means of delivering epinephrine. It is
`recommended that persons at risk of anaphylaxis, and persons
`responsible for children at risk for anaphylaxis, maintain one
`or more automatic epinephrine injectors in a convenient place
`at all times. It is further recommended that, if the symptoms of
`anaphylaxis persist after the first dose of epinephrine is
`injected, the patient should be treated with a second dose of
`epinephrine (about 0.3 mL of the 1:1000 dilution).
`0009 Certain formulations of epinephrine are known.
`Epinephrine Injection, USP is a sterile, non-pyrogenic solu
`tion administered parenterally by the intravenous or intracar
`diac (left ventricular chamber) routes, or via endotracheal
`tube into the bronchial tree. Each milliliter (mL) of the 1:10,
`000 solution contains epinephrine 0.1 mg: sodium chloride
`8.16 mg; sodium metabisulfite added 0.46 mg; citric acid,
`anhydrous 2 mg and sodium citrate, dihydrate 0.6 mg added
`as buffers. Sodium metabisulfite is used with Epinephrine
`formulations as a preservative. Sodium metabisulfite has
`been associated with severe allergic reactions. The formula
`tion may contain additional citric acid and/or Sodium citrate
`for pH adjustment. pH 3.3 (2.2 to 5.0).
`00.10
`Epinephrine Injection, USP is administered by
`intravenous injection and/or in cardiac arrest, by intracardiac
`injection into the left ventricular chamber or via endotracheal
`tube directly into the bronchial tree. The adult intravenous
`dose for hypersensitivity reactions or to relieve broncho
`spasm usually ranges from 0.1 to 0.25 mg (1 to 2.5 mL of
`1:10,000 solution), injected slowly. Neonates may be given a
`dose of 0.01 mg per kg of body weight; for the infant 0.05 mg
`is an adequate initial dose and this may be repeated at 20 to 30
`minute intervals in the management of asthma attacks.
`0011. In cardiac arrest, 0.5 to 1.0 mg (5 to 10 mL of
`1:10,000 solution) may be given. During a resuscitation
`effort, 0.5 mg (5 mL) should be administered intravenously
`every five minutes. Intracardiac injection may be adminis
`tered, if there has not been sufficient time to establish an
`intravenous route. The intracardiac dose usually ranges from
`0.3 to 0.5 mg (3 to 5 mL of 1:10,000 solution). Also contem
`
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`US 2008/0269347 A1
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`plated is dose delivery from vials with formulation compris
`ing concentrated epinephrine solution and/or storage at room
`temperature.
`0012 Because of its catechol nucleus, epinephrine oxi
`dizes easily and darkens slowly on exposure to air. Dilute
`solutions are partially stabilized by the addition of chlorobu
`tanol and by reducing agents, such as Sodium bisulfate or
`ascorbic acid. As the free amine, it is available in an oil
`solution for inhalation. Like other amines it forms salts with
`acids including the hydrochloride, the borate, and the bitar
`trate. The bitartrate has the advantage of being less acidic and
`is used in the eye because its solutions have a pH close to that
`of lacrimal fluid. Epinephrine is destroyed readily in alkaline
`Solutions by aldehydes, weak oxidizing agents and oxygen of
`the air.
`0013 Along with its advantages, Epinephrine has several
`disadvantages that include a short duration of action, decom
`position of its salts in Solution, vasoconstriction action fre
`quently followed by vasodilation and inactivity on oral
`administration.
`0014. The primary determinant of catecholamine stability
`in intravenous admixtures is the pH of the solution. Epineph
`rine hydrochloride is unstable in dextrose (5% in water) at a
`pH above 5.5. The pH of optimum stability is from about 3 to
`about 4. In one study, the decomposition rate increased two
`fold (from 5 to 10% in 200 days at 30° C.) when the pH was
`increased form 2.5 to 4.5. Epinephrine hydrochloride is rap
`idly destroyed by alkali or by oxidizing agents including
`halogens, permanganates, chromate, nitrates, nitrites and
`salts of easily reducible metals such as iron, copper, and zinc.
`In alkaline solution and when exposed to air or light, it turns
`pink from oxidation to adenochrome and then brown from the
`formation of polymers. Epinephrine should not be mixed with
`aminophline-containing Solutions because of the alkalinity
`of these solutions. In one evaluation with aminophylline
`stored at 25°C., a color change was noted after about 8 hours
`and only 40% of the initial drug was still present in the
`admixture at 24 hours.
`0015 Instability has also been observed when drugs are
`combined with epinephrine. For example, when lidocaine
`hydrochloride is mixed with epinephrine hydrochloride the
`buffering capacity of the lidocaine raises the pH of the intra
`venous admixtures above 5.5, the maximum necessary for
`stability of the epinephrine, to about 6. Under these condi
`tions, the epinephrine hydrochloride will begin to deteriorate
`within several hours.
`
`SUMMARY OF THE INVENTION
`0016. The present invention concerns particular formula
`tions of epinephrine, which itself may also be referred to as
`epi, adrenaline, epinephrin, or adrenalin, for example, and it
`has a chemical formula of CHNO. The formulation is
`injectable, in particular embodiments. In certain aspects of
`the invention, the formulation has no sodium metabisulfite
`and has enhanced stability, such as being able to refrain from
`degradation before a certain period of time. In a particular
`embodiment, the formulation is enhanced to remain effective
`under any condition that would otherwise degrade the formu
`lation, at least for an amount of time greater than that for an
`epinephrine formulation without a stability-enhancing agent,
`which in at least some cases may be an antioxidant. In specific
`cases, the formulation is enhanced to be stable in light, oxy
`gen, and/or heat conditions and/or after an amount of time no
`less than 12 months. In specific cases, the formulation is
`
`enhanced to be stable for at least 12, 13, 14, 15, 16, 17, 18, 19,
`20, 21, 22, 23, or 24 months, for example.
`0017. In particular aspects of the invention, the epineph
`rine formulation comprises ethylenediamine tetraacetic acid
`(also referred to as EDTA, H4EDTA, diaminoethanetetraace
`tic acid, edetic acid, edetate, edetate disodium, ethylenedini
`trilotetraacetic acid, versene, or ethylene diamine tetracetic
`acid) and one or more antioxidants. Although any Suitable
`antioxidant may be employed, in specific aspects the antioxi
`dant is cysteine, citric acid, thioglycerol, ascorbic acid, ace
`tylcysteine, or a combination thereof.
`0018. The formulations of the invention may be employed
`for any medical condition that epinephrine is useful. In par
`ticular embodiments, the epinephrine is utilized for anaphy
`laxis, cardiac arrest, or asthma, for example. Epinephrine is
`the preferred treatment for anaphylaxis even though the prod
`uct contains Sodium metabisulfite, which in other products
`may cause allergic-type reactions including anaphylactic
`symptoms or life-threatening asthma in certain Susceptible
`persons.
`0019. The invention may be applied to any individual, but
`in specific embodiments the invention is useful for a mammal,
`including a human, dog, cat, horse, cow, goat, sheep, and so
`forth.
`0020. In a particular embodiment of the invention, there is
`an injectable pharmaceutical composition comprising epi
`nephrine, EDTA and at least one antioxidant, wherein the
`antioxidant is selected from the group consisting of cysteine,
`citric acid, thioglycerol, acetylcysteine, and a combination
`thereof.
`0021. In another embodiment of the invention, there is an
`injectable pharmaceutical composition consisting essentially
`of epinephrine, EDTA, and at least one stability-enhancing
`agent, wherein the antioxidant is selected from the group
`consisting of cysteine, citric acid, thioglycerol, acetylcys
`teine, and a combination thereof.
`0022. In a further embodiment of the invention, there is a
`composition comprising a pharmaceutical composition com
`prising epinephrine, EDTA, and at least one antioxidant,
`wherein the antioxidant is selected from the group consisting
`of cysteine, citric acid, thioglycerol, acetylcysteine, and a
`combination thereof, and an injection apparatus. The phar
`maceutical composition may be housed in the injection appa
`ratus or housed separately from the injection apparatus. The
`injection apparatus may be further defined as a Syringe. The
`injection apparatus may be further defined as an autoinjector.
`0023. In an additional embodiment of the invention, there
`is a method of improving at least one symptom of an epineph
`rine-requiring medical condition in an individual in need
`thereof, comprising injecting into the individual a formula
`tion comprising epinephrine; EDTA; a pharmaceutically
`acceptable carrier, and at least one antioxidant, wherein the
`antioxidant is selected from the group consisting of cysteine,
`citric acid, thioglycerol, acetylcysteine, and a combination
`thereof. In a specific embodiment of the invention, the medi
`cal condition is anaphylaxis, asthma or cardiac arrest. The
`formulation may be housed in an injection apparatus or
`housed separately from an injection apparatus. The injection
`may be by an autoinjector. The injection may be in the thigh
`of the individual, intracardially into the individual, or endot
`racheally into the individual, for example.
`0024. In another embodiment of the invention, there is a
`method of treating anaphylaxis in an individual comprising
`injecting into the individual a formulation, said formulation
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`US 2008/0269347 A1
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`Oct. 30, 2008
`
`comprising epinephrine; EDTA; a pharmaceutically accept
`able carrier, and at least one antioxidant, wherein the antioxi
`dant is selected from the group consisting of cysteine, citric
`acid, thioglycerol, acetylcysteine, and a combination thereof,
`wherein the formulation is injected by an auto-injector.
`0025. In a further embodiment of the invention, there is a
`method of treating a pediatric individual in need of treatment
`for anaphylaxis comprising injecting into the individual a
`formulation comprising epinephrine; EDTA; and at least one
`stability enhancing agent, wherein the stability enhancing
`agent is selected from the group consisting of cysteine, citric
`acid, thioglycerol, acetylcysteine, and a combination thereof.
`0026. The foregoing has outlined rather broadly the fea
`tures and technical advantages of the present invention in
`order that the detailed description of the invention that fol
`lows may be better understood. Additional features and
`advantages of the invention will be described hereinafter
`which form the subject of the claims of the invention. It
`should be appreciated by those skilled in the art that the
`conception and specific embodiment disclosed may be
`readily utilized as a basis for modifying or designing other
`structures for carrying out the same purposes of the present
`invention. It should also be realized by those skilled in the art
`that Such equivalent constructions do not depart from the
`spirit and scope of the invention as set forth in the appended
`claims. The novel features which are believed to be charac
`teristic of the invention, both as to its organization and method
`of operation, together with further objects and advantages
`will be better understood from the following description
`when considered in connection with the accompanying fig
`ures. It is to be expressly understood, however, that each of the
`figures is provided for the purpose of illustration and descrip
`tion only and is not intended as a definition of the limits of the
`present invention.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`0027. For a more complete understanding of the present
`invention, reference is now made to the following descrip
`tions taken in conjunction with the accompanying drawings.
`0028 FIG. 1 illustrates an epinephrine antioxidant study
`with cysteine formulations.
`0029 FIG. 2 illustrates an epinephrine antioxidant study
`with metabisulfite formulations.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`I. Definitions
`
`0030. In keeping with long-standing patent law conven
`tion, the words “a” and “an' when used in the present speci
`fication in concert with the word comprising, including the
`claims, denote “one or more.” Some embodiments of the
`invention may consist of consist essentially of have, and/or
`include one or more elements, method steps, and/or methods
`of the invention. It is contemplated that any method or com
`position described herein can be implemented with respect to
`any other method or composition described herein.
`0031. The term “anaphylaxis' as used herein refers to an
`acute hypersensitivity reaction as a result of exposure to an
`antigen, such as a previously encountered antigenor to a drug,
`for example. In specific embodiments, the symptoms may
`include rapidly progressing urticaria, respiratory distress,
`vascular collapse, systemic shock, and/or death.
`
`0032. The term “antioxidant’ as used herein refers to a
`material that will prevent oxidation or be preferentially oxi
`dized.
`0033. The term “autoinjector” as used herein refers to an
`apparatus wherein an individual may administer a formula
`tion, Such as a pharmaceutical formulation, to themselves. In
`specific embodiments, the autoinjector delivers a single dose.
`In other specific embodiments part or all of the autoinjector is
`disposable and/or portable. In specific embodiments, part or
`all of the autoinjector is opaque, and in further specific
`embodiments at least one part of the autoinjector that is
`opaque is the part that houses the pharmaceutical formula
`tion. An auto-injector may be supplied separately from the
`pharmaceutical formulations, in alternative embodiments.
`The auto-injector, or any other injection apparatus, may com
`prise an exchangeable vessel for replacing the pharmaceuti
`cal formulation, such as an insert, cartridge, vial, and so forth.
`Such an exchangeable vessel may be glass or plastic, for
`example.
`0034. The term “epinephrine-requiring medical condi
`tion” as used herein refers to any medical condition wherein
`administration of epinephrine to an individual having the
`condition has a pharmacologically beneficial effect, such as
`improving at least one symptom of the medical condition. In
`specific aspects of the invention, the medical condition com
`prises acute hypersensitivity, such as anaphylactic reaction to
`one or more drugs; to animal serums, such as from a bee,
`wasp, or ant; to plant allergens, including peanuts; and to
`otherallergens). In other embodiments, the medical condition
`comprises an asthmatic condition, Such as to relieve broncho
`spasm. In additional embodiments, the medical condition
`comprises cardiac arrest or Stokes-Adams Syndrome.
`0035. The term “injectable” as used herein refers to a
`composition that is suitable to be delivered to an individual in
`an injection, such as with an injection device, including one
`that employs a syringe or a cartridge, which may be housed in
`a manual injection device or an auto-injection device, for
`example. In particular aspects, an injectable formulation is
`transferable by injection, as opposed to an aerosol, for
`example, which is not.
`0036. The term “pediatric individual' as used herein refers
`to an individual that is equal to or less than 18 years of age.
`0037. The term “stability-enhancing agent” as used herein
`refers to one or more agents that increase the stability of
`epinephrine. Such as by increasing the amount of time before
`the epinephrine degrades to an unusable form. In specific
`embodiments, the agent prolongs the efficacy of epinephrine
`over time and/or upon Subjection to conditions that degrade
`epinephrine to a form having reduced efficacy, such exem
`plary conditions being air, heat, and/or light. In particular
`embodiments, the stability-enhancing agent may be consid
`ered a preservative and/or antioxidant yet itself does not
`destabilize the formulation. Useful but exemplary antioxi
`dants include one or more of cysteine, acetylcysteine,
`thioglycerol, citric acid, or a combination thereof. Therefore,
`in specific embodiments the agent is absent in a pharmaceu
`tical formulation of the invention or is removable therefrom.
`
`II. Embodiments of the Invention
`0038. The present invention concerns compositions,
`devices for delivery of the compositions, routes of adminis
`tration, and methods for treating any medical condition for
`which epinephrine is Suitable for alleviating at least one
`symptom. Although the epinephrine formulations of the
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`invention may be employed for any medical condition that
`would be improved thereby, in particular cases the medical
`condition for which the inventive composition is employed is
`an allergic reaction, including in the context of an allergic
`emergency, such as anaphylaxis, for example. Treatment of
`anaphylaxis concerns ameliorating or alleviating at least one
`symptom of anaphylaxis. In particular cases, the epinephrine
`formulation of the invention is employed to facilitate periph
`eral vascular resistance via alpha-stimulated vasoconstriction
`in cardiac dysrhythmias, such as cardiac arrest, that leads to
`impaired or totally inhibited cardiac output, such that blood is
`directed to the core of the body. Such a formulation and
`amount thereof is employed so long as there is no increased
`cardiac irritability to an medically unacceptable level.
`0039. Furthermore, the invention provides kits for treating
`epinephrine-required medical conditions, including allergic
`emergencies, such as anaphylaxis. The compositions of the
`present invention provide Surprisingly-enhanced Stability
`over other formulations. The stability enhancements provide
`benefits at least in terms of patient safety, enhanced shelflife,
`reduced waste, reduced cost, and/or improved convenience
`for the user. The compositions of the present invention pro
`vide formulations that are stable at room temperature and can
`be stored without the need for refrigeration. As such, the
`devices or kits can be placed on emergency crash carts and
`medical kits in clinics, emergency rooms, airplanes, Schools,
`public places, restaurants, residences, on a person, or in
`urgent care centers or hospitals for easy access in emergency
`situations, for example.
`0040. Such treatment may be, and in most cases is, tem
`porary, in particular embodiments of the invention. The for
`mulations, methods, and kits of the invention are suitable for
`any setting in which epinephrine is required for medical pur
`pose. In specific embodiments of the invention, the method or
`kit of the invention provides emergency relief from at least
`one symptom of anaphylaxis for a time Sufficient for the
`patient to seek professional medical assistance. Thus, devices
`and kits of the invention are well-suited for inclusion in first
`aid kits in professional child care settings and homes, for
`example, especially where one or more persons at risk for
`anaphylaxis are known to dwell. They may also be conve
`niently carried by those who are at risk for anaphylaxis or
`those who are charged with caring for those who are at risk for
`anaphylaxis. They are also well-suited for inclusion in So
`called crash carts in medical emergency rooms. The methods
`of the invention are suitable for treating persons who are at
`risk for allergic emergencies, such as anaphylaxis, in any of
`the exemplary aforementioned settings.
`0041
`Epinephrine is typically administered in anaphy
`laxis by injection under the skin, or into a muscle, although
`any route of administration may be Suitable. Injections can be
`given by a health care professional in a clinic or hospital
`setting. Alternatively, an auto-injector form, for example,
`provides a convenient applicator for the health-care profes
`sional or for self-administration by patients who suffer a
`severe allergic response to certain stimuli.
`0042 Epinephrine is commonly administered parenter
`ally by means of an injection device. Common injection
`devices range from a simple manual syringe system to an
`auto-injector. A manual syringe system would include a
`Syringe comprising a barrel and a plunger and an appropri
`ately-sized needle. Such simple syringes may be adapted to
`accept pre-filled cartridges, be packaged with the drug for
`mulation loaded in the Syringe, or used with vials, for
`
`example. Formulated drugs such as epinephrine may be pre
`pared and filled into ampoules, prefilled cartridges, Syringes,
`or vials that may be single or multi-dose containers, for
`example.
`0043. An exemplary epinephrine formulation for use in
`the treatment of the medical condition may be delivered by
`intramuscular injection, in specific embodiments. In specific
`embodiments, the injection device would provide 2 mL of the
`epinephrine formulation of the invention and deliver a single
`dose of 0.3 mLepinephrine from a 1:1000 dilution (0.3 mg) of
`a sterile solution. Alternately, the injection device may pro
`vide 2 mL of the epinephrine formulation of the invention and
`deliver a single dose of 0.3 mL of epinephrine from a 1:2000
`dilution (0.15 mg) of a sterile solution.
`0044 Automatic injectors, such as those exemplary
`devices disclosed in U.S. Pat. Nos. 5,358,489: 5,540,664;
`5,665,071 and 5,695,472, for example, are known in the art.
`In general, all automatic injectors comprise a Volume of epi
`nephrine solution to be injected. In general, automatic injec
`tors include a reservoir for holding the epinephrine solution,
`which is in fluid communication with a needle for delivering
`the drug, as well as a mechanism for automatically deploying
`the needle, inserting the needle into the patient, and delivering
`the dose into the patient. An illustrative and exemplary auto
`matic injector is described in U.S. patent application Ser. No.
`10/817,224 (U.S. Patent Application Publication No. 2005/
`0222539), which is incorporated herein in its entirety.
`0045 Exemplary injectors provide about 0.3 mL of epi
`nephrine solution at about a concentration of either 0.5 or 1
`mg of epinephrine per mL of solution (1:2000 or 1:1000,
`respectively). Each injector is capable of delivering a dose of
`epinephrine and any epinephrine left in the automatic injector
`(generally about 90% of the original volume of epinephrine)
`is unavailable for delivery and must be discarded.
`0046 Additionally, the automatic injectors deliver a uni
`form volume of 0.3 mL of epinephrine to the patient, whether
`that patient is an adult or a child. Whereas, the adult version
`delivers 0.3 mL of a 1:1000 dilution of epinephrine, the
`pediatric version delivers 0.3 mL of a 1:2000 dilution of
`epinephrine. This volume of medicine may present discom
`fort to smaller children, but any discomfort is offset by the
`life-saving nature of epinephrine in treating severe anaphy
`laxis. However, a further object of the invention is to fill the
`need for a composition and method of treating anaphylaxis in
`a person of less than about 30 Kg, wherein a smaller dose of
`epinephrine can be delivered to the patient.
`0047 Thus, treatment of a medical condition, such as an
`allergic emergency that includes treatment of anaphylaxis,
`for which the invention is especially well-suited. In addition,
`treatment of allergic emergency includes treatment of other
`allergic conditions that may be treated with epinephrine. For
`example, the symptoms of anaphylactoid reactions to drugs
`closely mimic those of anaphylaxis and are treated in a similar
`manner. In cases where it is not clear whether the reaction is
`a systemic immunological response (anaphylaxis) or a sys
`temic toxic response (anaphylactoid reaction), the accepted
`first line of treatment is with epinephrine. In this sense, treat
`ment of an allergic emergency encompasses treatment of
`anaphylaxis, an anaphylactoid response or both.
`0048. In some embodiments, the present invention pro
`vides a method of treating an allergic emergency, such as
`anaphylaxis, in a patient, comprising administering to the
`patient epinephrine. The method includes automatically
`injecting into a patient in need thereof a dose of epinephrine
`
`ADAMIS EXHIBIT 1006
`Page 7 of 12
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`US 2008/0269347 A1
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`Oct. 30, 2008
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`consisting essentially of about 0.3 mL of an epinephrine
`Solution. The concentration of epinephrine in the epinephrine
`Solution is about 1 mg of epinephrine per mL of Solution. In
`Some embodiments, in addition to the approximately 1 mg of
`epinephrine per mL, the Solution also contains one or more
`inactive ingredients, such as EDTA, cysteine, acetylcysteine,
`thioglycerol, a pH buffer, an ingredient that provides isoto
`nicity, or mixtures thereof.
`0049. The smaller dose of epinephrine 0.15 mg/unit dose
`(0.3 mL), is especially Suitable for treating Smaller patients
`with body weights less than 30 Kg. Thus, in some embodi
`ments in which the dose is about 0.15 mg, the weight of the
`patient weighs less than about 30 Kg. In particular embodi
`ments, the patient weighs less than about 15 Kg.
`0050. In certain aspects, the epinephrine formulation of
`the present invention prepared for administration as a