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`US009283197Bl
`
`c12) United States Patent
`Taneja
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,283,197 Bl
`Mar.15,2016
`
`(54) MORE POTENT AND LESS TOXIC
`FORMULATIONS OF EPINEPHRINE AND
`METHODS OF MEDICAL USE
`
`(71) Applicant: Jugal K. Taneja, Tampa, FL (US)
`
`(72)
`
`Inventor: Jugal K. Taneja, Tampa, FL (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 14/460,845
`
`(22) Filed:
`
`Aug. 15, 2014
`
`(51)
`
`(2006.01)
`
`Int. Cl.
`A61K 311137
`(52) U.S. Cl.
`CPC .................................... A61K 311137 (2013.01)
`( 58) Field of Classification Search
`CPC .................................................... A61K 31/137
`See application file for complete search history.
`
`(56)
`
`CA
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`
`2002643 A * 5/1990
`OTHER PUBLICATIONS
`
`Gherezghiher et al., "Ocular Effects of Adrenergic Stereoisomers in
`the Rabbit," Journal of Ocular Pharmacology, 1985, vol. 1, No. l; pp.
`19-28.*
`MSDS for Hydrochloric Acid Solution, 1.0 M; Scholar Chemistry;
`Jan. 23, 2009. *
`MSDS for Hydrochloric Acid 12N; Scholar Chemistry; Feb. 2,
`2009.*
`* cited by examiner
`Primary Examiner - Sreeni Padmanabhan
`Jody Karol
`Assistant Examiner -
`ABSTRACT
`(57)
`The present invention provides pharmaceutical formulations
`of levorotatory-epinephrine, I-epinephrine, more potent and
`less toxic than existing pharmaceutical formulations of epi(cid:173)
`nephrine, along with methods of producing and using these
`pharmaceutical formulations ofl-epinephrine.
`7 Claims, No Drawings
`
`ADAMIS EXHIBIT 1001
`Page 1 of 5
`
`

`

`US 9,283,197 Bl
`
`1
`MORE POTENT AND LESS TOXIC
`FORMULATIONS OF EPINEPHRINE AND
`METHODS OF MEDICAL USE
`
`FIELD OF THE INVENTION
`
`The present invention provides pharmaceutical formula(cid:173)
`tions of levorotatory-epinephrine (I-epinephrine), more
`potent and less toxic than existing pharmaceutical formula(cid:173)
`tions of epinephrine, along with methods of producing and
`using these pharmaceutical formulations ofl-epinephrine.
`
`BACKGROUND OF THE INVENTION
`
`Epinephrine has a long history of pharmaceutical use that 15
`spans many decades since this catecholamine was first chemi(cid:173)
`cally synthesized at the tum of the twentieth century. Epi(cid:173)
`nephrine is a sympathomimetic drug that acts on both alpha
`and beta adrenergic receptors found ubiquitously throughout
`much of the body. Epinephrine has profound effects on the
`cardiovascular system. Epinephrine has direct myocardial
`stimulation that increases the strength of ventricular contrac(cid:173)
`tion and cardiac output, positive inotropic action; increases
`heart rate, positive chronotropic action; and causes vasocon(cid:173)
`striction in the veins and many vascular beds, positive vaso(cid:173)
`pressor action. Epinephrine remains the first-line inotrope/
`vasopressor in many parts of the world and is recognized by
`the World Health Organization as an essential medicine with
`many medical uses and forms of administration.
`As eye drops, epinephrine provides mydriasis, the dilation
`of the pupil, during intraocular surgery. As a solution for
`nebulization, epinephrine provides bronchodilation and relief
`of bronchospasm to asthmatics and those with chronic
`obstructive pulmonary disease. As a solution combined with
`analgesics for injection, including lidocaine for dental appli(cid:173)
`cations and bupivacaine for epidural analgesia, epinephrine
`improves and lengthens pain relief and sensory blockade
`during surgical procedures. Yet, epinephrine has many life
`saving uses in emergency room settings. As a solution for
`intramuscular or subcutaneous injection, epinephrine helps
`alleviate vasodilation, loss of intravascular fluid volume,
`hypotension, bronchospasm, and other symptoms associated
`with anaphylaxis, severe allergic reactions. Injections of epi(cid:173)
`nephrine can also help stop bleeding, such as bleeding asso(cid:173)
`ciated with peptic ulcers and surgical procedures. As a solu(cid:173)
`tion for intravenous injection, epinephrine is used as a critical
`adjunct in the treatment of cardiac arrest, e.g., to provide
`return of spontaneous circulation. Lastly, intravenous injec(cid:173)
`tion of this vasopressor provides critical care relief of
`hypotension associated with certain types of shock and fluid
`refractory shock, including septic shock.
`Although epinephrine has many uses, including many life
`saving uses, existing liquid formulations of epinephrine are
`associated with reduced potency, less desirable effects, or
`have the potential to cause harm. Formulations of epinephrine
`are plagued by two major problems, racemization and oxida(cid:173)
`tion. Racemization is the enantiomeric conversion of I-epi(cid:173)
`nephrine into its less biologically active dextrorotatory iso(cid:173)
`form, d-epinephrine, which has a significantly low pressor
`effect; about one-fifteenth that of I-epinephrine. The d-iso- 60
`form may also affect adrenergic receptor subtypes differently
`than the 1-isoform, resulting in substandard and undesirable
`effects. Because the United States Pharmacopeia, USP,
`monograph for epinephrine injection does not include speci(cid:173)
`fications for d-epinephrine content, only total epinephrine 65
`content, manufacturers of epinephrine drug products are not
`required to test the chirality of their formulation and signifi-
`
`2
`cant racemization occurs, thus leading to a less potent product
`with less desirable effects. In actuality, the d-epinephrine
`isoform should be classified as an impurity in an I-epineph(cid:173)
`rine drug product. It is believed that the epinephrine injection
`USP monograph does not include specifications for d-epi(cid:173)
`nephrine because preventing its formation through racemiza(cid:173)
`tion had proven too challenging. Whereas, oxidation of epi(cid:173)
`nephrine can be prevented to a certain extent, including the
`use of antioxidants. The oxidation of epinephrine's alcohol
`10 group forms its less potent ketone form, known as adrenal one,
`which has little if any beta adrenergic activity. Racemization
`and oxidation of epinephrine are associated with reduced
`potency and less desirable effects as the impurities d-epineph-
`rine and adrenalone form at the expense ofl-epinephrine.
`Drug manufacturers try to deal with the problem of oxida-
`tion by adding bisulfite antioxidants and increasing overages,
`both of which have the potential to cause harm to patients.
`Preservatives, such as sodium metabisulfite, are added to
`epinephrine formulations as antioxidants to reduce oxidation
`20 and to help keep formulations sterile. Sterilization techniques
`themselves often result in the loss of total epinephrine, and
`I-epinephrine, which may be compensated with increased
`overages. Sodium bisulfite and sodium metabisulfite,
`bisulfites, can cause mild to severe, life-threatening allergic
`25 reactions, including anaphylaxis or asthmatic episodes in sus(cid:173)
`ceptible individuals, especially those with sulfite sensitivi(cid:173)
`ties. So while epinephrine is indicated for treating anaphy(cid:173)
`laxis, the presence of sulfites in its formulation puts
`susceptible patients at great risk of exacerbating their ana-
`30 phylaxis to the point of death. And for patients who are in
`other critical situations, such as cardiac arrest or septic shock,
`such sulfite reactions could greatly worsen the critical condi(cid:173)
`tion of these vulnerable patients. Most formulations also use
`overages of active pharmaceutical ingredient to compensate
`35 for degradation of epinephrine content and activity over the
`course of the product's shelf-life. This results in epinephrine
`drug products released after manufacturing with a higher than
`expected activity, which could be hazardous to patients as
`causing higher infusion and injection doses, thereby increas-
`40 ing side effects such as tachycardia.
`In addition to the degradants d-epinephrine and adrena(cid:173)
`lone, which have been mentioned to have little pharmacologi(cid:173)
`cal activity compared with I-epinephrine,
`lesser other
`degradants include adrenochrome and adrenolotin. A poten-
`45 tially toxic impurity, epinephrine sulfonate, forms by sulfona(cid:173)
`tion reaction in epinephrine drug products containing sulfites.
`Due to the deficiencies in existing pharmaceutical formu(cid:173)
`lations ofl-epinephrine, the identity, strength, quality, purity,
`and/or potency of the drug product cannot be adequately
`50 assured, or neither can its safety. There exists a great need for
`a liquid formulation of I-epinephrine that is both preserva(cid:173)
`tive-free and sulfite-free, with minimal overage, if any, and
`with minimal levels of degradants, including d-epinephrine,
`while maintaining a sterility guarantee. The present invention
`55 fulfills this great medical need by teaching improved I-epi(cid:173)
`nephrine formulations, providing new methods of their
`preparation, and providing methods of safer medicinal use to
`achieve an improved standard of patient care.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Past solutions of epinephrine have included a microbial
`preservative in order to assure the sterility of the drug product,
`even ifthe drug product was a single-use vial used immedi(cid:173)
`ately after opening. Sulfites were able to counter the oxidative
`behavior of epinephrine by reacting with residual oxygen in
`its container instead of reacting with epinephrine, and thus,
`
`ADAMIS EXHIBIT 1001
`Page 2 of 5
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`US 9,283,197 Bl
`
`3
`sequestered the free oxygen. When dissolution of the epi(cid:173)
`nephrine was carried out by means of addition of diluted
`hydrochloric acid, HCI, some excess of acid could maintain a
`low pH near 2.2 and slow the degradation of epinephrine, also
`by forming inactive sulphonic acid.
`Improved methods of preparation of sulfite-free pharma(cid:173)
`ceutical formulations of epinephrine included the compound(cid:173)
`ing of the drug substance, followed by initial filtration, filling
`and sterilization. In order to produce and assure a sterile
`pharmaceutical solution of epinephrine as a drug product for 10
`injectable use, and without including preservatives such as
`metabisulfites, terminal heat sterilization following filling
`and/or final filtration under aseptic conditions during filling
`must be employed.
`The compounding step utilized an active I-epinephrine 15
`pharmaceutical ingredient base, such as I-epinephrine hydro(cid:173)
`chloride, USP. This compounding step was performed to
`place the solid/powder active pharmaceutical ingredient into
`aqueous solution. Water for injection was the solvent. Mixing
`alone will not bring I-epinephrine into aqueous solution 20
`adequately. The pH of the solution must be lowered in order
`for the I-epinephrine base to dissolve properly. The pH can be
`lowered with an acid, such as an organic acid, and preferably
`I Normal (IN) hydrochloric acid that serves as a dissolution
`agent and a pH adjuster. Since the final solution will be 25
`injected into patients, the tonicity of the solution must be
`increased with a tonicity agent. Although various tonicity
`agents can be employed, the present methods preferably
`employ the use of sodium chloride as a tonicity agent. The
`batch formula per mL was 1.I mg epinephrine base as the 30
`drug substance, 8.6 mg sodium chloride as the tonicity agent,
`7 .26 g hydrochloric acid (IN) as the dissolution agent, addi(cid:173)
`tional hydrochloric acid (IN) as a pH adjuster to lower pH to
`2.2 to 2.6, and 987.04 mg water for injection as a solvent.
`Ideally, the compounding step and subsequent filtration step 35
`were conducted under inert nitrogen atmosphere to help pre(cid:173)
`vent exposure of epinephrine and its solution to oxygen. It can
`be seen from this batch formula that a high IO% overage of
`epinephrine base was used to compensate for degradation
`over time, when the desired final concentration is I mg/mL 40
`epinephrine.
`The compounded solution of I-epinephrine was then fil(cid:173)
`tered, such as by a 0.22 micrometer filter and transferred to a
`sterilized, preferably glass, vessel. Filtration of the com(cid:173)
`pounded solution removed any particulates, whether bacterial 45
`or undissolved ingredients.
`The filtered solution of epinephrine was then filled into
`sterilized or sterile containers using sterilized filling equip(cid:173)
`ment. Sterile containers included, but were not limited to,
`glass ampules, glass vials with caps, glass bottles with caps, 50
`and syringes to make prefilled syringes or autoinjectors. To
`help protect the epinephrine solution against oxidation since
`no metabisulfites were used in the formulation, the filling step
`was performed under an inert atmosphere of nitrogen that is
`essentially devoid of oxygen to reduce the residual oxygen 55
`content in the empty space of the filled container. This filling
`step could be performed under aseptic conditions along with
`additional filtration, such as by a 0.22 micrometer filter inte(cid:173)
`grated with the filling equipment. Alternatively, or addition(cid:173)
`ally, filled containers could be sterilized by heat, such as by 60
`using an autoclave or by steam sterilization. Terminal steril(cid:173)
`ization at a temperature above the boiling point of water, such
`terminal sterilization at I2I ° C., with overkill conditions
`assured sterility guarantee of the final drug product. For
`example, a F0 of IO minutes by means of a steered steriliza- 65
`ti on cycle was initially chosen to reduce the thermal stress on
`the epinephrine solution. Because thermal stress was not
`
`4
`found to degrade epinephrine, over-kill conditions of steril(cid:173)
`ization could be used. Degradation of epinephrine was found
`mainly attributed to exposure to oxygen, which was directly
`related to nitrogen purge accuracy during the production and
`filling phases, instead of thermal treatment.
`The above steps described the overall manufacturing pro(cid:173)
`cess in making a drug product of preservative-free, sulfite(cid:173)
`free solution of epinephrine. Specifically, it was found that
`this process inclusive of a I 0% overage and an in-process pH
`range of 2.2 to 2.6 produced an epinephrine solution that
`could support a shelf-life of a 2 mL glass ampule containing
`I mL epinephrine solution for at least 48 months when stud(cid:173)
`ied in a climatic chamber at 25° C. for a maximum storage
`time of 60 months, in a climatic chamber at 30° C. for a
`maximum storage time of I 2 months, and in a climatic cham(cid:173)
`ber at 40° C. for a maximum storage time of 6 months.
`However, this drug product produced by this manufactur(cid:173)
`ing process with an in-process pH of approximately 2.5 was
`found to be inferior, and not only because of its high I 0%
`overage. It was decided to test this epinephrine solution for
`d-epinephrine content even though there is no such rationale
`by USP or the industry to do so. When tested for d-epineph(cid:173)
`rine content by a chiral HPLC analytical method, it was
`unexpectedly found that approximately I 4 % of the I-epineph(cid:173)
`rine had been racemized into d-epinephrine at the product's
`release. After storage at 25° C. for 6 months, at least I 9% of
`the I-epinephrine was converted to d-epinephrine. The drug
`product produced in this manner would contain less than 90%
`I-epinephrine in well under a year, and for all practical pur(cid:173)
`poses, was unsuitable for use.
`Producing an epinephrine drug product with a high I-epi(cid:173)
`nephrine content, such as greater than 90%, throughout its
`shelf-life of over one year seemed impossible in a preserva(cid:173)
`tive-free, sulfite-free solution, and had never been accom(cid:173)
`plished before. Increasing overages above I 0% was not a
`viable solution. Terminal sterilization of the epinephrine
`solution only contributed to about 4% racemization, so elimi(cid:173)
`nating heat sterilization and depending solely on aseptic fil(cid:173)
`tration would not solve the racemization problem, nor have as
`strong of a final sterility guarantee in this antimicrobial-free
`solution. Lowering the in-process pH was not believed pos(cid:173)
`sible due to oxidation issues. The lower the pH was to 2.2, the
`lower the impact was of potential oxygen residues in the
`solution. The thought of raising the in-process pH above the
`2.2-2.6 of previous methods, and allowing for additional oxi(cid:173)
`dation in an antioxidant-free solution, was contradictory to
`one skilled in the art.
`Inadvertently, increasing the in-process pH to 2.8-3.3,
`unexpectedly reduced the racemization of I-epinephrine to
`d-epinephrine at release by approximately two-thirds, from
`I4% to 5%, respectively. To the contrary, these results led to
`the discovery that in a preservative-free, sulfite-free, I-epi(cid:173)
`nephrine solution, racemization was a more significant prob(cid:173)
`lem than expected, even more so than oxidation. This discov(cid:173)
`ery led to new methods of manufacturing sulfite-free,
`I-epinephrine solution with an in-process pH of 2.8 to 3.3,
`approximately 3.0, which was a nonobvious solution to the
`problem of racemization. Most importantly, with these new
`methods, overages could greatly be reduced.
`The new method of preparing a I mg/mL solution ofl-epi(cid:173)
`nephrine, such as in a glass ampule, has a revised batch
`formula per mL of: approximately I .03 mg epinephrine base,
`as the drug substance, 8.6 mg sodium chloride as the tonicity
`agent, 7 .26 g hydrochloric acid (IN) as the dissolution agent,
`additional hydrochloric acid (IN) as a pH adjuster to lower
`pH only to 2.8 to 3 .3, and 987. I I mg water for injection as a
`solvent. The compounding of the drug substance, followed by
`
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`Page 3 of 5
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`US 9,283,197 Bl
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`5
`initial filtration, filling and sterilization are all conducted
`under inert nitrogen atmosphere to help prevent exposure of
`epinephrine and its solution to oxygen.
`With less than or no more than a 6% overage, and prefer(cid:173)
`ably a 3% overage, a viable shelf-life of at least one year, e.g.,
`at least 15 months, was achieved with the new method with
`more than 90% I-epinephrine content at the end of the shelf(cid:173)
`life. A sealed 2 mL glass ampule served as the container for
`the 1 mL drug product that was tested. However, the drug
`product solution of the present invention can be made in
`larger volumes in other sterile containers, including glass
`vials and bottles, and syringes and autoinjectors; including
`autoinjectors conducive with the preservative-free formula(cid:173)
`tion. The new and improved formulation with reduced over(cid:173)
`age also has less than or no more than 6.5% total impurities,
`including less than or no more than 6% d-epinephrine and less
`than or no more than 0.5% adrenalone at release; and less than
`or no more than 12.5% total impurities, including less than or
`no more than 12% d-epinephrine and less than or no more
`than 0.5% adrenalone through a shelf-life of at least 12
`months, and preferably through a shelf-life of at least 15
`months. If aseptic filtration is used without terminal steriliza(cid:173)
`tion, these new methods would allow an I-epinephrine drug
`product to be prepared without any overage of epinephrine
`base, so that exactly 1.00 mg of epinephrine base is used per
`mL in the compounding step.
`These inventive methods have discovered and achieved
`new limits for an injectable liquid pharmaceutical formula(cid:173)
`tion ofl-epinephrine sterile solution; less than or no more than
`about 6% d-epinephrine at release, and less than or no more 30
`than about 12% d-epinephrine through a shelf-life of at least
`12 months; which has never been accomplished before, even
`if preservatives/sulfites are optionally included in the formu(cid:173)
`lation as alternate embodiments (e.g., preservatives/sulfites
`up to about 1 mg per mL, such as sodium metabisulfite). 35
`Although these injectable liquid pharmaceutical formula(cid:173)
`tions of I-epinephrine sterile solution introduced by this
`invention can be produced having any desirable concentra(cid:173)
`tion ofl-epinephrine, they are preferably compounded in an
`aqueous solution as approximately 1.0 to 1.06 mg/mL 1-epi- 40
`nephrine, and further include a tonicity agent, and include no
`more than about 6% d-epinephrine and no more than about
`0.5% adrenalone at release, and no more than about 12%
`d-epinephrine and no more than about 0.5% adrenalone over
`a shelf-life of at least 12 months. Such injectable liquid phar- 45
`maceutical formulations of I-epinephrine sterile solution
`taught by this invention have uncompromised potency of
`I-epinephrine at release and through their shelf-life.
`The present invention therefore provides improved meth(cid:173)
`ods of formulating safer and more reliable pharmaceutical 50
`preparations of epinephrine for medicinal use. Unlike other
`epinephrine formulations, these improved formulations are
`preservative-free and sulfite-free so that there are no safety
`issues for anaphylaxis and no toxic epinephrine sulfonate
`byproducts. These improved epinephrine formulations have 55
`no need for high overages, and use minimal overages, if any
`to assure reliable dosage. The present methods of this inven(cid:173)
`tion preferably use I-epinephrine hydrochloride, USP as the
`active pharmaceutical ingredient base, although other I-epi(cid:173)
`nephrine active ingredients and salts and combinations 60
`thereof can be employed, including epinephrine bitartrate.
`The present methods of this invention preferably use sterile
`containers including, but not limited to, glass ampules, glass
`vials with caps, glass bottles with caps, and syringes to make
`prefilled syringes or autoinjectors. Other inert gases, instead 65
`of or in addition to nitrogen, can be used for the manufactur(cid:173)
`ing process. Other concentrations of sulfite-free, 1-epineph-
`
`6
`rine solution greater or lower than approximately 1 mg/mL
`can also be prepared using these new methods and in-process
`pH under nitrogen (inert gas) atmosphere, where nitrogen
`(inert gas) purge accuracy is inversely related to oxygen expo(cid:173)
`sure during the production and filling phases.
`The present invention also includes methods of using these
`more potent and less toxic liquid formulations ofl-epineph(cid:173)
`rine as eye drops to provide mydriasis during intraocular
`surgery; as a solution for nebulization to provide bronchodi-
`10 lation and relief of bronchospasm to asthmatics and those
`with chronic obstructive pulmonary disease; as a solution
`combined with analgesics for injection, including lidocaine
`for dental applications and tumescent anesthesia and tumes(cid:173)
`cent liposuction; and bupivacaine for epidural analgesia, to
`15 improve and lengthen pain relief and sensory blockade during
`surgical procedures; as a solution for intramuscular or sub(cid:173)
`cutaneous injection to counter symptoms associated with
`anaphylaxis or to help stop bleeding associated with peptic
`ulcers and surgical procedures; as a solution for intravenous
`20 injection in the treatment of cardiac arrest, to provide return of
`spontaneous circulation; and as a solution for intravenous
`injection to relieve hypotension associated with certain types
`of shock and fluid refractory shock, including septic shock.
`Other variations and embodiments of the invention
`25 described herein will now be apparent to those of skill in the
`art without departing from the disclosure of the invention or
`the coverage of the claims to follow.
`What is claimed is:
`1. A liquid pharmaceutical formulation of preservative(cid:173)
`free and sulfite-free, 1 mg per mL I-epinephrine sterile solu(cid:173)
`tion for uses including injection; said liquid pharmaceutical
`formulation having a pH between 2.8 and 3.3; said liquid
`pharmaceutical formulation compounded in an aqueous solu(cid:173)
`tion as 1.0 to 1.06 mg/mL I-epinephrine, and further including
`a tonicity agent; said liquid pharmaceutical formulation hav(cid:173)
`ing no more than 6.5% total impurities at release, including no
`more than 6% d-epinephrine and no more than 0.5% adrena(cid:173)
`lone, and no more than 12 .5% total impurities over a shelf-life
`ofat least 12 months, including no more than 12% d-epineph(cid:173)
`rine and no more than 0.5% adrenalone; said liquid pharma(cid:173)
`ceutical formulation stored in a container with an inert gas
`prior to use.
`2. The said liquid pharmaceutical formulation of claim 1
`compounded in an aqueous solution preferably as 1.03
`mg/mL I-epinephrine.
`3. The said liquid pharmaceutical formulation of claim 1
`further having no more than 12.5% total impurities over a
`shelf-life of at least 15 months, including no more than 12%
`d-epinephrine and no more than 0.5% adrenalone.
`4. A liquid pharmaceutical formulation of preservative(cid:173)
`free and sulfite-free, 1 mg per mL I-epinephrine sterile solu(cid:173)
`tion for uses including injection; said liquid pharmaceutical
`formulation having a pH between 2.8 and 3.3; said liquid
`pharmaceutical formulation compounded as 1.0 to 1.06
`mg/mL I-epinephrine, along with 8.6 mg/mL sodium chloride
`as the tonicity agent, 7.26 mg/mL of 1 Normal hydrochloric
`acid as the dissolution agent, 987 .11 mg/mL water for injec(cid:173)
`tion as a solvent, and with additional hydrochloric acid to
`adjust pH; said liquid pharmaceutical formulation having less
`than 6.5% total impurities at release, including less than 6%
`d-epinephrine and less than 0.5% adrenalone, and less than
`12.5% total impurities over a shelf-life of at least 12 months,
`including less than 12% d-epinephrine and less than 0.5%
`adrenalone.
`5. The said liquid pharmaceutical formulation of claim 4
`compounded in an aqueous solution as 1.03 mg/mL I-epi(cid:173)
`nephrine.
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`US 9,283,197 Bl
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`7
`6. An injectable liquid pharmaceutical formulation of
`I-epinephrine sterile solution; said liquid pharmaceutical for(cid:173)
`mulation having a pH between 2.8 and 3.3; said injectable
`liquid pharmaceutical formulation compounded in an aque(cid:173)
`ous solution as 1.0 to 1.06 mg/mL I-epinephrine, and further 5
`including a tonicity agent; said liquid pharmaceutical formu(cid:173)
`lation including no more than about 6% d-epinephrine and no
`more than about 0.5% adrenalone at release, and no more than
`about 12% d-epinephrine and no more than about 0.5%
`adrenalone over a shelf-life of at least 12 months.
`7. The said injectable liquid pharmaceutical formulation of
`claim 6 further having a concentration of 1 mg per mL I-epi(cid:173)
`nephrine.
`
`10
`
`* * * * *
`
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