(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2012/002.9085A1
`MacKay
`(43) Pub. Date:
`Feb. 2, 2012
`
`US 2012002.9085A1
`
`(54) STABILIZATION OF QUINOL COMPOSITION
`SUCH AS CATECHOLAMINEDRUGS
`
`(76) Inventor:
`
`Jon MacKay, Spokane, WA (US)
`
`(21) Appl. No.:
`(22) Filed:
`
`12/846,656
`Jul. 29, 2010
`O
`O
`Publication Classification
`
`(51) Int. Cl.
`A6 IK3I/I67
`A6IP 23/00
`A6 IK3I/38
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`(52) U.S. Cl. ......................................... 514/626; 514/653
`(57)
`ABSTRACT
`Compositions and methods are provided for obtaining stabi
`lized quinol compositions, such as catecholamine drugs (e.g.,
`epinephrine solutions), and also for obtaining stable pharma
`ceutical formulations that comprise a stabilized quinol com
`position and a second pharmacologically active component
`Such as a local anesthetic or other active drug ingredient
`having a reversibly protonated amine group. Stability is
`achieved through the inclusion of an appropriately selected
`pH buffer and a thiol agent, based on redox and pH buffering
`principles including pKa of the buffer and of the reversibly
`protonated amine group.
`
`ADAMIS EXHIBIT 1021
`Page 1 of 21
`
`

`

`Patent Application Publication
`
`Feb. 2, 2012 Sheet 1 of 2
`
`US 2012/002.9085A1
`
`
`
`Time (Days)
`
`1.
`
`3
`
`7
`
`FIGURE 1
`
`Solution A appearance
`containing 2.5 mg/mL
`CVSteine
`Clear, Colorless Solution.
`No change in
`appearance. No
`Orecipitate present.
`Clear, Colorless solution.
`No change in
`appearance. No
`precipitate present.
`Clear, Colorless Solution.
`No change in
`appearance. No
`precipitate present.
`Clear, Colorless Solution.
`No change in
`appearance. No
`Orecipitate present.
`Clear, Colorless Solution.
`No change in
`appearance. No
`Orecipitate present.
`Clear, Colorless Solution.
`No change in
`appearance. No
`Orecipitate present.
`
`Solution B appearance
`without 2.5 mg/mL cysteine
`
`Solution initially clear with
`rapid discoloration. Solution
`light pink in Color. No
`Orecipitate present.
`Solution dark pink in Color.
`No precipitate present.
`
`Solution dark pink to red in
`Color. No precipitate present.
`
`Solution red to brown in Color
`with dark brown to black
`precipitate present.
`
`Solution red to brown in Color
`with dark brown to black
`precipitate present.
`
`Solution red to brown in Color
`with dark brown to black
`precipitate present.
`
`Solution A contains 1.0 mg/ml epinephrine, 15 mM sodium
`phosphate adjusted to pH 6.8, and 2.5 mg/ml. Cysteine. Solution B Contains
`1.0 mg/ml epinephrine and 15 mM sodium phosphate adjusted to pH 6.8.
`
`ADAMIS EXHIBIT 1021
`Page 2 of 21
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`

`

`Patent Application Publication
`
`Feb. 2, 2012 Sheet 2 of 2
`
`US 2012/002.9085A1
`
`FIGURE 2
`
`
`
`Y
`
`s
`
`:
`(A) efteo
`
`ADAMIS EXHIBIT 1021
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`US 2012/002.9085 A1
`
`Feb. 2, 2012
`
`STABILIZATION OF QUINOL COMPOSITION
`SUCH AS CATECHOLAMINEDRUGS
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`0001
`0002 The present invention relates to compositions and
`methods for preserving and maintaining the structural integ
`rity, chemical stability and biological activity of quinol-con
`taining compositions. More specifically, the invention relates
`to improved stability of quinol-containing compositions such
`as epinephrine and other catecholamine drugs, and of phar
`maceutical formulations that include quinol compositions
`and other active drugs such as drugs having amine groups that
`can be reversibly protonated.
`0003 2. Description of the Related Art
`0004. A number of chemical compounds having uses in
`the drug and food industries for a variety of purposes exhibit
`instabilities leading to oxidative degradation, which compro
`mises their effectiveness and engenders undesirable costs
`associated with obtaining fresh reagents, discarding degraded
`reagents, and monitoring inventories of reagents that have
`only limited shelf-life. Among such chemical compounds are
`those that contain a quinol (dihydroxybenzene) moiety which
`can detrimentally undergo oxidative degradation to a corre
`sponding quinone structure, which in turn may be compro
`mised by further chemical degradation.
`0005 Exemplary compounds include members of the cat
`echolamines (e.g., epinephrine, norepinephrine, levonorde
`frin; see, e.g., U.S. Pat. No. 5,002,973.), a family of com
`pounds which includes naturally occurring neurotransmitters
`and also includes a number of synthetic products having
`applications as drugs in a wide variety of indications.
`0006 Catecholamines and other quinol compounds are
`Susceptible to oxidation in Solution (e.g., aqueous solution)
`that may be accompanied by a loss of pharmacological activ
`ity, and under current storage practices such oxidized com
`pounds can be further converted to degradation products hav
`ing potentially harmful properties. For instance, the
`catecholamine epinephrine is rapidly oxidized in aqueous
`Solution, degrading to adrenochrome and adrenalone. (e.g.,
`Kalyanaraman et al., 1984.J. Biol. Chem. 259:354; Kirchhoe
`fer et al., 1986 Am J. Hosp. Pharm. 43:1741; Stepensky et al.,
`2004.J. Pharm Sci. 93:969; Newton et al., 1981 Am. J. Hosp.
`Pharm. 38:1314) At acidic pH values, degradation of epi
`nephrine has also been reported to result from conversion of
`the biologically active L-enantiomer to the inactive D-enan
`tiomer, yielding a racemic mixture of undesirably reduced
`potency (Stepensky et al., 2004.J. Pharm Sci. 93:969).
`0007 Presently available pharmaceutical formulations of
`catecholamine drug products and their structurally related
`analogues are typically plagued by efforts to stabilize the
`catecholamines, which efforts often result in disadvantageous
`and unwanted properties of the product. Many current epi
`nephrine formulations, for example, contain bisulfite and/or
`metabisulfite additives that are included as mild reducing
`agents, and which are believed to inhibit oxidative degrada
`tion of the catecholamine. (e.g., Dalton-Bunnow, 1985 Am. J.
`Hosp. Pharm. 42:2220; Grubstein et al., 1992 Drug Dev. Ind.
`Pharm. 18:1549) These reducing agents, however, readily
`react with epinephrine to generate sulfonated derivatives that
`lack epinephrine biological activity. (e.g., Schroeter et al.
`1958.J. Am. Pharmaceut. Assoc. 47:723; Hajratwala, 1975.J.
`Pharmaceut. Sci. 64:45) Additionally, allergic reactions to
`the bisulfite preservatives are often observed, such that for
`
`mulations containing bisulfites will be contraindicated in
`individuals having Such allergies. (e.g., Campbell et al., 2001
`Anesth. Prog. 48:21; Smolinske, 1992 Clin. Toxicol. 30:597)
`Moreover, epinephrine is unstable in solution for even brief
`time periods and must be kept at an acidic pH in order to avoid
`extremely rapid degradation that is associated with attempts
`to prepare epinephrine Solutions having neutral pH values.
`(Robinson et al., 2000 Anesthesia 55:853; Newton et al., 1981
`Am. J. Hosp. Pharm. 38:1314)
`0008 Another problem associated with efforts to provide
`storage conditions for quinol compounds relates to pharma
`ceutical formulations that contain a quinol compound along
`with a second pharmaceutical agent. For example, the quinol
`compound epinephrine is often included for its desirable
`pharmacological activity as a vasoconstrictor informulations
`of local anesthetics, including amino ester local anesthetics
`(e.g., procaine) and amino amide local anesthetics (e.g.,
`lidocaine). Many of these local anesthetics comprise an
`amine-containing compound having at least one amine group
`that is capable of being reversibly protonated. Such pharma
`ceutical formulations are typically provided in relatively
`acidic condition (e.g., pH-4) in an effort to preserve the
`quinol compound, which as described above, tends to degrade
`rapidly at pH values closer to neutrality.
`0009 Acidic formulations of such local anesthetics, how
`ever, suffer from other drawbacks, in particular, the problem
`that the low pH favors the presence of the protonated form of
`the reversibly protonated amine group. This problem mani
`fests itself in an undesirably delayed onset of the desired
`pharmacological activity—anesthetic effect—insofar as the
`charge of the protonated amine group hinders the ability of
`the local anesthetic to traverse cellular membranes for pur
`poses of exerting its pharmacological activity intracellularly.
`Hence, the anesthetic effect is delayed, and the efficiency of
`drug utilization at the desired local site is decreased by cir
`culatory system clearance from the region of protonated drug
`molecules that have not yet equilibrated with the deproto
`nated form in the extracellular environment as a prelude to
`plasma membrane transit. Moreover, the acidic pH of such
`formulations typically results in pain experienced by the
`recipient at the site of injection, a seemingly inevitable con
`sequence of the low pH used to protect the quinol compound.
`0010 Clearly there remains a need for improved formula
`tions of active drug compounds Such as quinol compounds,
`and for improved pharmaceutical formulations containing
`both quinol compounds and active drug compounds having
`amine groups that can be reversibly protonated. The present
`invention provides improved compositions and methods that
`address these needs, and offers other related advantages.
`
`BRIEF SUMMARY OF THE INVENTION
`0011. In certain embodiments, the present invention pro
`vides a stable pharmaceutical formulation, comprising (a) a
`first composition that comprises at least one quinol com
`pound having a first desired pharmacological activity; (b) a
`second composition that comprises at least one local anes
`thetic compound, said local anesthetic compound comprising
`at least one amine group that is capable of being reversibly
`protonated, and being capable of reversibly binding to a Volt
`age-gated Na channel in a cell membrane to thereby alter
`Na" movement through the voltage-gated Na channel; (c) at
`least one thiol agent; and (d) at least one pH buffer that
`maintains a Substantially constant pH in the pharmaceutical
`formulation, wherein the pH is greater than about pH 5.5. In
`
`ADAMIS EXHIBIT 1021
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`US 2012/002.9085 A1
`
`Feb. 2, 2012
`
`certain embodiments the quinol compound is present in a
`reduced form. In certain embodiments the quinol compound
`comprises an ortho-quinol moiety or a para-quinol moiety. In
`certain embodiments at least one quinol compound comprises
`a catecholamine.
`0012. In certain embodiments at least one quinol com
`pound comprises a compound of Formula (I):
`
`R2 R3
`
`HO
`
`HO
`
`21
`N-
`(R'),
`
`Z
`
`R R5
`
`wherein:
`0013 n is 0, 1, 2 or 3
`I0014) each R" is the same or different and independently
`hydrogen, alkyl, hydroxyl, alkoxide, —OC(O)alkyl, —OC
`(O)aralkyl, aralkyl, amino or halo;
`0015 R and R are the same or different and indepen
`dently hydrogen, hydroxyl, alkoxide, alkyl, oxo. —OC(O)
`alkyl, —OC(O)aralkyl, amino, monoalkylamino, dialky
`lamino or halo;
`0016 R and R are the same or different and indepen
`dently hydrogen, hydroxyl, alkoxide, NR, NHNH, or
`lower alkyl,
`(0017 Z is NR,-COOH or CR7:
`0018 each R is the same or different and independently
`hydrogen, alkyl, aralkyl; or
`0019 RandR together with the atoms to which they are
`attached form a heterocycle; and
`I0020 each R" is the same or different and independently
`hydrogen, alkyl, aralkyl, -COOH, amino. —C(O)Oalkyl,
`—C(O)Caryl, —C(O)Caralkyl, - NHNH, monoalky
`lamino, dialkylamino,
`0021 as a single Stereoisomer, a mixture of stereoisomers,
`or as a racemic mixture of stereoisomers; or as a pharmaceu
`tically acceptable salt thereof.
`0022. In certain embodiments the quinol compound com
`prises a compound selected from 1,2-dihydroxybenzene (cat
`echol, pyrocatechol), 1,4-dihydroxybenzene, epinephrine,
`norepinephrine, dopamine, dobutamine, isoproterenol,
`racepinephrine, arbutamine, carbidopa, deoxyepinephrine,
`dioxethedrine, 3-(3,4-dihydroxyphenyl)-alanine (L-, D- or
`DL-DOPA), dopexamine, droxidopa, ethylnorepinephrine,
`hexoprenaline, isoetharine, methyldopa, N-methylepineph
`rine, nordefrin, rimiterol, epinephrine bitartrate, L-epineph
`rine-D-hydrogentartate, adrenalone (CAS 99-45-6), arb
`utamine (CAS 128470-16-6), benserazide (CAS 322-35-0),
`carbidopa (CAS 28860-95-9), deoxyepinephrine (CAS 501
`15-5), dioxethdrine (CAS 497-75-6), dobutamine (CAS
`34368-04-02), dopa (CAS 63-84-3), dopamine (CAS 51-61
`6), dopexamine (CAS 86197-47-9), droxidopa (CAS 23651
`95-8), epinephrine (CAS 51-43-4), ethylnorepinephrine
`(CAS536-24-3), fluorodopa (CAS92812-82-3), hexoprena
`line (CAS 3215-70-1), isoetharine (CAS530-08-5), isoprot
`erenol (CAS 7683-59-2), levodopa (CAS 59-92-7), methyl
`dopa (CAS 555-30-6), N-methylepinephrine (CAS 554-99
`4), nordefrin (CAS 6539-57-7), norepinephrine (CAS 51-41
`2), protokylol (CAS 136-70-9), rimiterol (CAS 32953-89-2),
`
`nordihydroguaiaretic acid and tetrahydropapaveroline (CAS
`4747-99-3). In certain embodiments the quinol compound
`comprises epinephrine.
`0023. In certain embodiments the thiol agent is selected
`from cysteine, N-acetylcysteine, glutathione, monothioglyc
`erol, cysteine ethyl ester, homocysteine, Coenzyme A, dithio
`threitol, 2-mercaptoethanol. 2,3-dimercapto-1-propanol. 2.3-
`butanedithiol,
`2-mercaptoethylamine,
`ethanedithiol,
`propanedithiol, 3-mercapto-2-butanol, dimercapto-propane
`1-sulfonic acid, dimercaptosuccinic acid, trithiocyanuric
`acid, 2,5-dimercapto-1,3,4-thiadiazole, 3,4-dimercaptotolu
`ene, 1,4-dimercapto-2,3-butanediol. 1,3-propanedithiol, 1,4-
`butanedithiol, N-Acetylpenicillamine, ACV. N-amyl mercap
`tan, bucillamine, N-butyl mercaptan, sec-butyl bercaptan,
`tert-butyl mercaptan, captopril, cysteamine, DBHBT 2.3-
`dimercapto-1-propanesulfonic acid, dimercaprol, dithiosali
`cylic acid, 1.2-ethanedithiol, ethanethiol, isobutyl mercaptan,
`mecysteine, 2-mercaptoethanol, MESNA, methanethiol,
`pantetheline, penicillamine, 1,3-propanedithiol, Succimer,
`thioacetic acid, thiobenzyl alcohol, thiocyanic acid, thioglyc
`erol, thioglycolic acid, thiolactic acid, thiomalic acid, thion
`alide, 1-thiosorbitol, tiopronin, tixocortol and trithiocarbonic
`acid. In certain embodiments the thiol agent is N-acetylcys
`teine.
`0024. In certain embodiments the pH buffer is present
`under conditions and in Sufficient quantity to maintain a pH
`that is from about pH 5.5 to about pH 9.0, or from about pH
`5.5 to about pH 8.5, or from about pH 5.5 to about pH 8.25, or
`from about pH 5.75 to about pH 7.75, or from about pH 6.0 to
`about pH 7.5, or from about pH 6.6 to about pH 7.3, or from
`about pH 6.5 to about pH 7.1, or from about pH 6.3 to about
`pH 6.9. In certain embodiments the pH buffer comprises a
`compound that is selected from Tris (8.3), Tricine (8.15),
`citrate (pKa=5.4), acetate (4.75), phosphate (7.2), borate
`(9.24), HEPES (7.55), HEPPS (8), MES (6.15), ACES (6.9),
`imidazole (7), diethylmalonic acid (7.2), MOPS (7.2), PIPES
`(6.8), TES (7.5), carbonate, bicarbonate, malate, pyridine,
`piperazine, Succinate, histidine, maleate, Bis-Tris, pyrophos
`phate, histidine, MOPSO, BES, DIPSO, MOBS, TAPSO,
`triethanolamine, POPSO, cacodylic acid, ADA, Bis-Tris pro
`pane and HEPPSO. In certain embodiments the pH buffer
`comprises sodium phosphate. In certain embodiments the
`quinol compound comprises epinephrine, the thiol agent is
`N-acetylcysteine and the pH buffer comprises sodium phos
`phate.
`0025. In certain embodiments the amine group that is
`capable of being reversibly protonated has a pKa of from
`about pH 7.5 to about pH 9.3, or a pKa of from about pH 7.6
`to about pH 9.2, or a pKa of from about pH 7.7 to about pH
`9.1, or a pKa of from about pH 7.8 to about pH 9.0, or a pKa
`of from about pH 7.9 to about pH 8.9, or a pKa of from about
`pH 8.0 to about pH 8.8, or a pKa of from about pH 8.1 to about
`pH 8.7, or a pKa of from about pH 8.2 to about pH 8.6, or a
`pKa of from about pH 8.3 to about pH 8.5.
`0026. In certain embodiments the local anesthetic com
`pound is selected from the group consisting of an amino ester
`anesthetic and an amino amide anesthetic. In certain embodi
`ments the cell membrane is a plasma membrane. In certain
`embodiments the cell membrane is present in a neuron. In
`certain embodiments the cell membrane is selected from a
`plasma membrane, a mitochondrial membrane, an endoplas
`mic reticulum membrane, a lysozomal membrane, an exo
`cytic vacuolar membrane and an endocytic vacuolar mem
`brane. In certain embodiments the second composition
`
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`US 2012/002.9085 A1
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`comprises a compound that is selected from lidocaine, pro
`poxycaine, procaine, prilocalne, bupivacaine, Articaine, Ben
`Zocaine, Chloroprocaine, Cocaine, Dibucaine, Etidocaine,
`Hexylcaine, Mepivicaine, Piperocaine, Ropivacaine and Tet
`racaine. In certain embodiments the first composition com
`prises epinephrine and the second composition comprises
`lidocaine. In certain embodiments the first composition com
`prises epinephrine, the second composition comprises
`lidocaine, and the thiol agent comprises N-acetylcysteine. In
`certain embodiments the first composition comprises epi
`nephrine, the second composition comprises lidocaine, the
`thiol agent comprises N-acetylcysteine and the pH buffer
`comprises sodium phosphate. In certain embodiments the
`stable pharmaceutical formulation comprises a first compo
`sition that comprises at least one quinol compound having a
`first desired pharmacological activity; a second composition
`that comprises at least one local anesthetic compound that is
`capable of reversibly binding to a voltage-gated Na channel
`in a cell membrane to thereby alter Na' movement through
`the Voltage-gated Na channel; at least one thiol agent; and at
`least one pH buffer that maintains a substantially constant pH
`in the pharmaceutical formulation, wherein the pH is greater
`than about pH 5.5. In one further embodiment the local anes
`thetic compound is lidocaine. In certain other further embodi
`ments of the above-described stable pharmaceutical formu
`lations,
`the formulation comprises an acceptable
`pharmaceutical carrier.
`0027. In certain other embodiments of the above described
`stable pharmaceutical formulations, the first composition is
`present at a mass-to-volume ratio in the formulation that is
`between 1:500,000 and 1:10,000. In certain other further
`embodiments, the isolated quinol compound is present at one
`of: (a) at least from about 0.05 percent weight-to-volume to
`about 0.5 percent weight-to-volume, (b) at least from about
`0.01 percent weight-to-volume to about one percent weight
`to-volume, (c) at least from about 0.5 percent weight-to
`Volume to about two percent weight-to-volume, (d) at least
`from about 0.75 percent weight-to-volume to about three
`percent weight-to-volume, (e) at least from about one percent
`weight-to-volume to about four percent weight-to-volume,
`(f) at least from about two percent weight-to-volume to about
`five percent weight-to-volume, and (g) at least from about 2.5
`percent weight-to-volume to about six percent weight-to
`Volume.
`0028 Turning to other embodiments, the present inven
`tion provides a method of stabilizing a quinol compound,
`comprising contacting (a) at least one isolated quinol com
`pound; (b) at least one thiol agent; and (c) a pH buffer that
`maintains a Substantially constant pH, and thereby stabilizing
`the quinol compound. In another embodiment there is pro
`vided a method of stabilizing a quinol compound, comprising
`contacting (a) at least one isolated quinol compound; (b) at
`least one thiol agent; and (c) a pH buffer that maintains a
`Substantially constant pH, to produce a stabilized quinol com
`position, wherein said stabilized quinol composition com
`prises the stabilized quinol composition as described above,
`and thereby stabilizing the quinol compound. In another
`embodiment there is provided a method of stabilizing a phar
`maceutical formulation, comprising contacting (a) a pharma
`ceutical formulation, (b) at least one thiol agent, and (c) a pH
`buffer that maintains a substantially constant pH, wherein the
`pH is greater than about pH 5.5, wherein the pharmaceutical
`formulation of (a) comprises (i) a first composition that com
`prises at least one quinol compound having a first desired
`
`pharmacological activity, and (ii) a second composition that
`comprises at least one local anesthetic compound, said local
`anesthetic compound comprising an amine-containing com
`pound having a second desired pharmacological activity and
`at least one amine group that is capable of being reversibly
`protonated, and thereby stabilizing the pharmaceutical for
`mulation.
`0029. In another embodiment there is provided a method
`of stabilizing a pharmaceutical formulation, comprising: con
`tacting (a) a pharmaceutical formulation which comprises (i)
`a first composition that comprises at least one quinol com
`pound having a first desired pharmacological activity, and (ii)
`a second composition that comprises at least one local anes
`thetic compound, said local anesthetic compound comprising
`an amine-containing compound having a second desired
`pharmacological activity and at least one amine group that is
`capable of being reversibly protonated, (b) at least one thiol
`agent, and (c) a pH buffer that maintains a Substantially con
`stant pH, wherein according to certain further embodiments
`the pH is greater than about pH 5.5, to produce a stable
`pharmaceutical formulation, wherein said stable pharmaceu
`tical formulation comprises the stable pharmaceutical formu
`lation as described above, and thereby stabilizing the phar
`maceutical formulation.
`0030. In certain other embodiments the invention provides
`a method of treating a subject, comprising administering to
`the Subject a stabilized quinol composition, comprising (a) at
`least one isolated quinol compound; (b) at least one thiol
`agent; and (c) at least one pH buffer that maintains a substan
`tially constant pH in the stabilized quinol composition,
`wherein in certain further embodiments the pH is greater than
`about pH 5.5. In certain further embodiments the stabilized
`quinol composition comprises at least any one of the above
`described Stabilized quinol compositions.
`0031. In certain other embodiments the invention provides
`method of treating a Subject, comprising administering to said
`Subject a stable pharmaceutical formulation, comprising (a) a
`first composition that comprises at least one quinol com
`pound having a first desired pharmacological activity; (b) a
`second composition that comprises at least one amine-con
`taining compound having a second desired pharmacological
`activity and at least one amine group that is capable of being
`reversibly protonated; (c) at least one thiol agent; and (d) at
`least one pH buffer that maintains a substantially constant pH
`in the pharmaceutical formulation, wherein in certain further
`embodiments the pH is greater than about pH 5.5. In certain
`other further embodiments the stable pharmaceutical formu
`lation comprises at least any one of the stable pharmaceutical
`formulations as described above.
`0032. In certain other embodiments the invention provides
`a method for the manufacture of a medicament fortherapeutic
`treatment of a Subject with a stabilized quinol composition,
`said method comprising contacting (a) at least one isolated
`quinol compound; (b) at least one thiol agent; and (c) a pH
`buffer that maintains a substantially constant pH, wherein in
`certain further embodiments the pH is greater than about pH
`5.5. In certain other further embodiments the stabilized
`quinol composition comprises at least any one of the above
`described Stabilized quinol compositions. In another embodi
`ment there is provided a method for the manufacture of a
`medicament for therapeutic treatment of a subject with a
`stable pharmaceutical formulation, said method comprising
`contacting (a) a pharmaceutical formulation, (b) at least one
`thiol agent, and (c) a pH buffer that maintains a Substantially
`
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`
`constant pH, wherein the pH is greater than about pH 5.5,
`wherein the pharmaceutical formulation of (a) comprises (i) a
`first composition that comprises at least one quinol com
`pound having a first desired pharmacological activity, and (ii)
`a second composition that comprises at least one local anes
`thetic compound, said local anesthetic compound comprising
`an amine-containing compound having a second desired
`pharmacological activity and at least one amine group that is
`capable of being reversibly protonated. In certain further
`embodiments the stable pharmaceutical formulation com
`prises at least any one of the above-described stable pharma
`ceutical formulations.
`0033. These and other aspects of the present invention will
`become apparent upon reference to the following detailed
`description. All references disclosed herein are hereby incor
`porated by reference in their entirety as if each was incorpo
`rated individually.
`
`BRIEF DESCRIPTION OF THE DRAWING(S)
`0034 FIG. 1 shows a table of the analysis by appearance of
`quinol containing Solutions (epinephrine) with and without a
`thiol agent (cysteine).
`0035 FIG. 2 shows a graph of the relationship between
`reducing potential (voltage) and pH for cysteine as an exem
`plary thiol agent.
`
`DETAILED DESCRIPTION OF THE INVENTION
`0036. The present invention relates to compositions and
`methods whereby quinol compounds such as catecholamines
`may be beneficially and desirably stabilized in solution. Con
`trary to long held beliefs that acidic pH environments are
`needed to stabilize quinol compounds, unexpectedly and as
`disclosed herein for the first time, Such compounds may be
`protected from oxidative damage at higher pH levels than
`have been commonly believed to be capable of supporting
`stable preservation of such compounds, including pH levels at
`or near the physiological pH values typically found in mam
`malian tissues (e.g., human plasma, skin, muscle tissue, etc.).
`In certain preferred embodiments, stabilized quinol compo
`sitions may be obtained that display little or no oxidative
`degradation over extended periods of time, by storage in
`Solution in the presence of thiol-containing compounds and
`suitable buffers under conditions and in sufficient quantities
`to maintain a Substantially constant pH. Surprisingly, stabi
`lized quinol compositions and related methods as disclosed
`herein also provide the advantage of resisting degradation by
`racemization of biologically and/or pharmacologically active
`enantiomeric forms, thereby preserving the potency of Such
`quinol compounds by inhibiting the appearance of racemic
`mixtures containing inactive enantiomers.
`0037. The invention will in certain embodiments accord
`ingly offer the advantages of a stabilized quinol composition,
`Such as advantages associated with longer shelf-life, conve
`nience of not having to reconstitute a dried or concentrated
`preparation immediately prior to use, reduced costs for main
`taining and replacing inventory, reduced waste of materials
`and energy caused by having to discard degraded and out
`dated preparations and packaging materials, and related eco
`nomic efficiencies. In certain embodiments the invention will
`find uses in a variety of contexts such as in pharmacies,
`hospitals and/or homes, in mobile or emergency medical aid
`kits, for travelers (especially to remote areas), for medical
`facilities lacking reliable refrigerated storage or hygienic
`
`conditions for sterile reconstitution of an injectable drug, and
`other contexts where stable, long-term storage of a stable
`pharmaceutical Solution at ambient temperature may offer
`convenience, safety and/or cost-savings. Certain embodi
`ments thus stabilize quinol compounds by protecting them
`against Oxidative damage in aqueous Solution, even during
`prolonged storage at typical ambient temperatures (e.g., 18,
`19, 20, 21, 22, 23, 24, 25, 26 or 27°C.), or at lower or higher
`temperatures.
`0038. The present invention also offers the further unex
`pected advantage of decreasing the discomfort associated
`with administration of quinol compositions of the prior art,
`and of pharmaceutical formulations that contain a quinol
`composition along with another pharmacologically active
`ingredient, which compositions and formulations have typi
`cally comprised substantially acidic solutions (e.g., pH 2-4)
`and as Such cause pain upon hypodermic injection into a
`Subject. By contrast, according to certain embodiments of the
`present invention a pH buffer is present that maintains a
`Substantially constant pH in the stabilized quinol composi
`tion, preferably a pH that is at or near a physiological pH at the
`site of administration into the body of the subject. Such a pH
`may in certain embodiments be from about pH 5.5 to about
`pH 9, from about pH 5.5 to about pH 8.5, from about pH 5.5
`to about pH 8.25, from about pH 5.5 to about pH 8.0, from
`about pH 5.75 to about pH 7.75, more preferably about pH 6
`to about pH 8, from about pH 6 to about pH 7.5, from about
`pH 6.6 to about pH 7.3, about pH 6.5 to about pH 7.1, about
`pH 6.3 to about pH 6.9, about pH 6.5 to about pH 7.8, about
`pH 6.8 to about pH 7.6, about 7 to about 7.5, or from about pH
`7.1 to about 7.4, preferably from about pH 7.2 to about 7.4,
`from about pH 7.3 to about 7.6, or another pH that those
`familiar with the art will recognize is substantially similar to
`the pH at a physiological site of parenteral administration of
`the composition, such that the pain induced by introducing an
`acidic composition at Such a site can be avoided.
`0039. Certain related embodiments thus provide previ
`ously unforeseen advantages associated with pharmaceutical
`formulations containing both a first composition comprising
`at least one quinol compound having a first desired pharma
`cological activity, for instance, a catecholamine Such as epi
`nephrine, and a second active drug compound that comprises
`an amine group that is capable of being reversibly protonated
`at physiological pH, such a second active drug compound
`having a second desired pharmacological activity, which may
`be the same or different from the first desired pharmacologi
`cal activity. Preferably the first and second desired pharma
`cological activities are beneficially co-administered. For
`example, the combination of a vasoconstrictor (Such as the
`quinol compound epinephrine) with a local anesthetic that is
`capable of reversibly binding to a voltage-gated Na channel
`in a cell membrane (such as the amino amide anesthetic
`lidocaine) provides advantageously complementary pharma
`cological properties (which in the present example are
`believed according to non-limiting theory to include
`improved retention of the local anesthetic at or near the site of
`injection, by virtue of decreased dilution due to the vasocon
`striction caused by epinephrine).
`0040. A surprising and heretofore unrecognized benefit
`afforded by certain invention embodiments disclosed herein
`is that stabilized quinol compositions and/or stable pharma
`ceutical formulations may be administered that have pH val
`ues closer to physiological pH values than previously con
`templated, in a manner that both reduces the level of pain
`
`ADAMIS EXHIBIT 1021
`Page 7 of 21
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`

`US 2012/002.9085 A1
`
`Feb. 2, 2012
`
`experienced by the recipient upon parenteral administration
`(e.g., hypodermic injection), and that facilitates transport
`across cell membranes of compound(s) having desired phar
`macological activities, such as active drug ingredients having
`amine groups that can be reversibly protonated. According to
`non-limiting theory, such benefits derive from (a) reduced
`pain that results from neutral and not acidic pH of the admin
`istered solution, and (b) improved transmembrane transit of a
`pharmacologically active drug ingredient having an amine
`group that is capable of being reversibly protonated, which
`results from maintenance by neutral or near-neutral pH of
`amine groups in the unprotonated, and therefore uncharged,
`form at the point where the drug crosses the hydrophobic
`interior of the plasma membrane. Hence, and further accord
`ing to theory, more rapid manifestation of a desired pharma
`cological effect is made possible by these embodiments.
`0041 Accordingly and as described in greater detail
`below, the invention thus derives from the discovery of here
`tofore unappreciated benefits to be obtained by exploiting a
`combination of interactions among established principles of
`chemical eq