Page A
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`17 April 2014 (17.04.2014)
`
`P O P C T
`
`(10) International Publication Number
`WO 2014/057365 Al
`
`(51) International Patent Classification:
`A61K 9/08 (2006.01)
`A61K 31/137 (2006.01)
`A61K 47/02 (2006.01)
`
`(21) International Application Number:
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`PCT/IB2013/053520
`
`3 May 20 13 (03.05.2013)
`
`English
`
`English
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
`BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU,
`RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ,
`TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA,
`ZM, ZW.
`IN (84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`(71) Applicant: WOCKHARDT LIMITED [IN/IN]; D-4,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
`MIDC Area, Chikalthana, Aurangabad 43 1210 (IN).
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG).
`
`(30) Priority Data:
`2934/MUM/2012 8 October 2012 (08.10.2012)
`
`(72) Inventors: GUPTA, Amit; House No. 906, Sector 16,
`Haryana, Faridabad 121002 (IN). NAGORI, Rajendra
`Nandlal; B-2, Srushtivihar Housing Soc, Zambad Estate,
`New Shreya Nagar, Aurangabad 43 1210 (IN). MER-
`WADE, Arvind Yekanathsa; Rajendra Prasad Road, Gad-
`ag Betgeri
`- 582102, Karnataka, Belgaum 582102 (IN). Published:
`DEO, Keshav; #A-52, Pranahuti, Narayan Garden, Opp. — with international search report (Art. 21(3))
`Yash Complex, Gotri Road., Gujarat, Vadodara 390021
`(IN). JAIN, Girish Kumar; 4-Sharda Niketan, Teachers'
`Colony, Pitam Pura, Delhi 110 034 (IN).
`
`o (54) Title: STABLE INJECTABLE PHARMACEUTICAL COMPOSITION OF EPINEPHRINE OR SALTS THEREOF
`(57) Abstract: The present
`invention refers to a stabilized injectable pharmaceutical composition of epinephrine or salts thereof
`o comprising sodium metabisuliite, wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisuliite in the com
`o with excellent storage stability and substantially free of overages can be prepared using sodium metabisuliite in said ratios. Particu
`position ranges from about 1 :0.005 to about 1:1.5 by weight. It has been observed that stable injectable epinephrine compositions
`
`larly, it was found that using sodium metabisuliite in said ratios controls levels of adrenaline sulfonate impurity in said pharmaceut
`ical compositions.
`
`ADAMIS EXHIBIT 1011
`
`

`

`STABLE INJECTABLE PHARMACEUTICAL COMPOSITION OF EPINEPHRINE OR SALTS THEREOF
`
`Field Of The Invention
`
`The present invention relates to a stabilized injectable pharmaceutical composition of
`
`epinephrine or salts thereof comprising sodium metabisulfite, wherein the ratio of the
`
`amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges
`
`from about 1:0.005 to about 1: 1 .5 by weight. It has been observed that stable injectable
`
`epinephrine compositions with excellent storage stability and substantially free of
`
`overages can be prepared using sodium metabisulfite in said ratios. Particularly, it was
`
`found that using sodium metabisulfite in said ratios controls levels of adrenaline
`
`sulfonate impurity in said pharmaceutical compositions.
`
`Background Of The Invention
`
`Epinephrine, also known as adrenaline,
`
`is a sympathomimetic
`
`catecholamine.
`
`Chemically, epinephrine is B-(3, 4dihydroxyphenyl)-a-methyl-amino ethanol.
`
`Epinephrine is the drug of choice for
`
`the initial
`
`treatment of anaphylaxis. Many
`
`epinephrine products are commerically available currently. For instance, epinephrine is
`
`marketed in the United States in the form of intramuscular and subcutaneous injection
`
`under trade name Twinject
`
`®
`
`®
`®
`, Auvi-Q , EpiPen Auto-Injector, which contains 0.3 mg
`
`®
`epinephrine, and EpiPen Jr Auto-Injector, which contains 0.1 5mg epinephrine.
`
`It is well known in the art that there is an issue with potency of epinephrine (both in free
`
`base form and ionic form) when used in presence of oxygen and free radicals i.e
`
`degradation of epinephrine is accelerated in the presence of oxygen and free radicals.
`
`Numerous studies have been conducted to address the effect of formulation variables
`
`on the epinephrine degradation kinetics, and attempts have been made to improve the
`formulation stability.
`
`ADAMIS EXHIBIT 1011
`
`Page 1
`
`

`

`U.S. Patent No. 3,149,035 discloses use of bisulphite and boric acid to enhance stability
`
`of the catechol amines.
`
`U.S. Patent No. 3,966,905 discloses catecholamine solutions at mild pH are suitable for
`
`physiological use.
`
`Several
`
`literatures suggests that there is an increase in stability of epinephrine when
`
`stored in gas-tight containers with an inert gas (e.g. nitrogen) purging, and/or limiting or
`
`protecting the epinephrine formulation from direct
`
`light exposure or storing in a
`
`Inspite of using sodium metabisulfite controlling the
`secondary opaque package.
`degradation of epinephrine however continues to be an issue. In addition, interaction of
`
`sodium metabisulfite with epinephrine further leads to complications.
`
`Currently marketed products of epinephrine as discussed above includes sodium
`
`metabisulfite as an antioxidant as it prevents degradation of the product due to oxidation
`
`that may take place during manufacturing, filling, storage, and environmental
`on the formulation.
`
`influence
`
`®
`Currently marketed products of epinephrine i.e EpiPen Auto-Injector containing 0.3 mg
`
`®
`epinephrine and EpiPen Jr Auto-Injector containing 0.15 mg of epinephrine comprises
`®
`of same amount of sodium metabisulfite i.e. 0.5 mg. It is also observed that EpiPen Jr
`®
`in EpiPen Auto-
`
`Auto-Injector product generally degrades relatively faster than that
`
`Injector, presumably due to exposure of the product to substantial vacant space left in
`
`the cartridge.
`
`®
`Moreover, Currently marketed products of epinephrine i.e the EpiPen Auto-Injector
`
`products contains more than about 20% of the epinephrine overages. This is in order to
`
`compensate the amount of epinephrine degraded during manufacture or over storage.
`
`Such overages however, may either lead to undesirable side effects due to dose
`
`inaccuracy or generate more degradation products in the product.
`
`ADAMIS EXHIBIT 1011
`
`Page 2
`
`

`

`Further, currently marketed products contain 0.3mg or 0.1 5mg in 2.0ml solution, of
`
`which only 0.3ml is injected and rest 1.7ml
`
`is discarded, which leads to lots of wastage.
`
`Since said product
`
`is used in severe anaphylactic reactions, so controlling impurities
`
`and improvement of stability is critical. Hence,
`
`there exists an enduring need for
`
`improved and stable pharmaceutical
`
`composition of epinephrine, which exhibits
`
`excellent storage stability and does not require addition of epinephrine overages.
`
`Summary Of The Invention
`
`In one aspect,
`
`the present
`
`invention provides a stabilized injectable pharmaceutical
`
`composition comprising epinephrine or salt thereof and sodium metabisulfite, wherein
`
`the ratio of the amount of epinephrine or salt thereof
`
`to sodium metabisulfite in the
`
`composition ranges from about 1:0.005 to about 1: 1 .5by weight.
`
`In another aspect, the present invention provides a stabilized injectable pharmaceutical
`
`composition comprising epinephrine or salt thereof and sodium metabisulfite, wherein
`
`the ratio of the amount of epinephrine or salt thereof
`
`to sodium metabisulfite in the
`
`composition ranges from about 1:0.005 to about 1: 1 .5 by weight characterized in that
`
`said composition contains epinephrine having purity equal to or greater than 98%.
`
`In another aspect, the present invention provides a stabilized injectable pharmaceutical
`
`composition comprising epinephrine or salt thereof and sodium metabisulfite, wherein
`
`the ratio of the amount of epinephrine or salt thereof
`
`to sodium metabisulfite in the
`
`composition ranges from about 1:0.005 to about 1: 1 .5 by weight characterized in that
`
`said composition contains total impurity of 4% or less.
`
`In another aspect, the present invention provides a stabilized injectable pharmaceutical
`
`composition comprising epinephrine or salt thereof and sodium metabisulfite, wherein
`
`the ratio of the amount of epinephrine or salt thereof
`
`to sodium metabisulfite in the
`
`composition ranges from about 1:0.005 to about 1: 1 .5 by weight characterized in that
`
`said composition contains no single impurity of greater than 3%.
`
`ADAMIS EXHIBIT 1011
`
`Page 3
`
`

`

`In another aspect, the present invention provides a stabilized injectable pharmaceutical
`
`composition comprising epinephrine or salt thereof and sodium metabisulfite, wherein
`
`the ratio of the amount of epinephrine or salt thereof
`
`to sodium metabisulfite in the
`
`composition ranges from about 1:0.005 to about 1: 1 .5 by weight characterized in that
`
`said composition contains adrenaline sulfonate impurity of about 3.0% or less at RRT
`
`0.15.
`
`In another aspect, the present invention provides a stabilized injectable pharmaceutical
`
`composition comprising epinephrine or salt thereof and sodium metabisulfite, wherein
`
`the ratio of the amount of epinephrine or salt thereof
`
`to sodium metabisulfite in the
`
`composition ranges from about 1:0.005 to about 1: 1 .5 by weight characterized in that
`
`said composition contains noradrenaline impurity of about 0.1 % or less.
`
`In another aspect, the present invention provides a stabilized injectable pharmaceutical
`
`composition comprising epinephrine or salt thereof and sodium metabisulfite, wherein
`
`the ratio of the amount of epinephrine or salt thereof
`
`to sodium metabisulfite in the
`
`composition ranges from about 1:0.005 to about 1: 1 .5 by weight characterized in that
`
`said composition contains adrenalone impurity of about 0.5% or less.
`
`In another aspect, the present invention provides a stabilized injectable pharmaceutical
`
`composition comprising epinephrine or salt thereof and sodium metabisulfite, wherein
`
`the ratio of the amount of epinephrine or salt thereof
`
`to sodium metabisulfite in the
`
`composition ranges from about 1:0.005 to about 1: 1 .5 by weight characterized in that
`
`said composition contains N-benzyl adrenalone impurity of about 0.1 % or less.
`
`In another aspect, the present invention provides a stabilized injectable pharmaceutical
`
`composition comprising epinephrine or salt thereof and sodium metabisulfite, wherein
`
`the ratio of the amount of epinephrine or salt thereof
`
`to sodium metabisulfite in the
`
`composition ranges from about 1:0.005 to about 1: 1 .5 by weight characterized in that
`
`said composition contains impurity observed at RRT 0.17, RRT 0.2, or RRT 0.73 of
`
`about 0.5% or less.
`
`ADAMIS EXHIBIT 1011
`
`Page 4
`
`

`

`In another aspect, the present invention provides a stabilized injectable pharmaceutical
`
`composition comprising epinephrine or salt thereof and sodium metabisulfite, wherein
`
`the ratio of the amount of epinephrine or salt thereof
`
`to sodium metabisulfite in the
`
`composition ranges from about 1:0.005 to about 1: 1 .5 by weight characterized in that
`
`said composition contains retains at least 90% w/w of total potency of epinephrine after
`
`storage at 25°C and 60% relative humidity for at least 3 months.
`
`In another aspect, the present invention provides a stabilized injectable pharmaceutical
`
`composition comprising epinephrine or salt thereof, sodium metabisulfite, one or more
`
`tonicity-adjusting agents, one or more pH adjusting agents, aqueous vehicle, and
`
`optionally one or more other pharmaceutically acceptable excipients, wherein the ratio
`
`of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition
`
`ranges from about 1:0.005 to about 1: 1 .5 by weight.
`
`In another aspect, the present invention provides a process for preparation of stable
`
`injectable pharmaceutical composition comprising epinephrine or salt
`
`thereof, which
`
`process comprises of mixing epinephrine or salt thereof, sodium metabisulfite, aqueous
`
`vehicle, and optionally one or more other pharmaceutically acceptable excipients,
`
`wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in
`
`the composition ranges from about 1:0.005 to about 1: 1 .5 by weight.
`
`In another aspect,
`
`the present
`
`invention provides use of a stable injectable
`
`pharmaceutical composition comprising epinephrine or salt
`
`thereof and sodium
`
`metabisulfite, wherein the ratio of the amount of epinephrine or salt thereof to sodium
`
`metabisulfite in the composition ranges from about 1:0.005 to about 1: 1 .5 by weight
`
`for
`
`the preparation of medicaments useful for treating allergic reactions (Type I) including
`
`anaphylaxis to stinging insects and biting insects, allergen immunotherapy,
`
`foods,
`
`drugs, diagnostic testing substances and other allergens, as well as idiopathic
`
`anaphylaxis or exercise-induced anaphylaxis, comprising administering to human
`
`patient in need thereof.
`
`In another aspect, the present invention provides a stabilized injectable pharmaceutical
`
`composition comprising 0.3mg of epinephrine or salt
`
`thereof and 0.3mg of sodium
`
`ADAMIS EXHIBIT 1011
`
`Page 5
`
`

`

`metabisulfite in 0.3ml of solution, wherein the said 0.3ml of solution is delivered
`
`completely in single injection.
`
`In another aspect, the present invention provides a stabilized injectable pharmaceutical
`composition comprising 0.1 5mg of epinephrine or salt thereof and 0.3mg of sodium
`
`metabisulfite in 0.3ml of solution, wherein the said 0.3ml of solution is delivered
`
`completely in single injection.
`
`Embodiments of
`
`the pharmaceutical composition may include one or more of
`
`the
`
`following features. For example,
`
`the pharmaceutically acceptable excipients may
`
`include solubilizers, anti-oxidants, buffering agents, pH adjusting agents, co-solvents,
`
`chelating agents, stabilizers, preservatives,
`
`lubricants,
`
`tonicity adjusting agents,
`
`cryoprotectants and the like known to the art used either alone or in combination
`
`thereof.
`
`Detailed Description Of The Invention
`
`The inventors of the present
`
`invention have surprisingly found that while making an
`
`injectable composition of epinephrine, amount of sodium metabisulfite plays a critical
`
`role in order to control degradation due to oxidation as well as in controlling impurities. It
`
`was surprisingly found that epinephrine reacts with sodium metabisulfite,
`
`thereby
`
`leading to formation of adrenaline sulfonate impurity. In particular, the inventors have
`
`found that judicial amount of sodium metabisulfite can effectively curb the oxidation of
`
`epinephrine and eventually control generation of sulfonate impurity along with a wide
`
`range of several other epinephrine impurities. As a result,
`
`inventors of
`
`the present
`
`invention have found a novel way of preparing the injectable pharmaceutical
`
`composition of epinephrine which can exhibit excellent storage stability.
`
`The inventors of the present invention further surprisingly found that judicial amount of
`
`sodium metabisulfite can retain epinephrine potency in the composition during the
`
`manufacture as well as over the storage period, thus may eliminate the need of adding
`
`epinephrine overages.
`
`ADAMIS EXHIBIT 1011
`
`Page 6
`
`

`

`The present
`
`invention relates to novel and stabilized injectable pharmaceutical
`
`compositions of epinephrine and process of preparing such compositions.
`
`The stabilized injectable pharmaceutical composition of the present invention comprises
`
`epinephrine or salt thereof and sodium metabisulfite, characterized in that the ratio of
`
`the amount of epinephrine or salt thereof
`
`to sodium metabisulfite in the composition
`
`ranges from about 1:0.005 to about 1: 1 .5 by weight.
`
`The stabilized injectable pharmaceutical composition of the present invention comprises
`
`epinephrine or salt
`
`thereof and sodium metabisulfite, characterized in that
`
`the
`
`composition is substantially free of epinephrine overages.
`
`The term "epinephrine" used throughout the specification refers to not only epinephrine
`
`per se, but also its pharmaceutically acceptable salts, pharmaceutically acceptable
`
`solvates,
`
`pharmaceutically
`
`acceptable
`
`hydrates,
`
`pharmaceutically
`
`acceptable
`
`enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable
`
`polymorphs and pharmaceutically acceptable prodrugs thereof.
`
`The term "substantially free" used throughout the specification refers to pharmaceutical
`
`compositions of epinephrine comprising less than about 10% by weight of epinephrine
`
`overages.
`
`The "stabilized injectable pharmaceutical composition" of the present invention refers to
`
`injectable compositions characterized by epinephrine having purity equal to or greater
`
`than 98% by weight or total
`
`impurity of 4% or less or no single impurity of greater than
`
`3% or adrenaline sulfonate impurity of about 3.0% or less at RRT 0.15 or noradrenaline
`
`impurity of about 0.1 % or less or adrenalone impurity of about 0.5% or less or N-benzyl
`
`adrenalone impurity of about 0.1 % or less.
`
`In an embodiment, the stabilized injectable pharmaceutical composition of the present
`
`invention retains at least 90% w/w of total potency of epinephrine after storage at 25°C
`
`and 60% relative humidity for at least 3 months.
`
`ADAMIS EXHIBIT 1011
`
`Page 7
`
`

`

`Extent of the stability have been observed to be more pronounced on four specific
`
`impurities (RRT 0.15, RRT 0.17, RRT 0.20, and RRT 0.73) out of a large number of
`
`impurities that affect
`
`the stability not only in the presence or absence of sodium
`
`metabisulfite but also under normal atmospheric condition, or inert atmosphere, or the
`
`exposure to oxygen. Some of the specific impurities formed which had a significant
`
`influence on the stability are as given below.
`
`?)-l -(3,4-dA3,'droxyphen3d)-2-(me
`amino r
`n ) i
`r s i l or ate
`C H1 NO
`Exact Mass: 247.05
`Mol. Wt.: 247 27
`
`4- ( R) - 1-hydr x -2 -(m ethyl amino)
`ethyl)b enz ene- 1, - c oi
`
`Exact Mass: 1 3 .09
`Mol. W t : 1 3 .2
`
`4- (R) - 1-hyc!roxy-2- (m ethyl amino)
`ethyl) cycloliexa-3,5-
`iiene-l,2-dione
`C H N 0
`Exact Mass: 181 .07
`Mol. Wt.: 18 1. 19
`
`ADAMIS EXHIBIT 1011
`
`Page 8
`
`

`

`RRT 0.17
`
`)cyclohex a-
`4-(2-l ¾r i xy acet
`3,5-iiene-l
`,2- cione
`C H 0
`Exact Mass: 166.03
`Mol. Wt: 166 .13
`
`x y-2- (methyl amino)
`4-((J - 1-h
`- 1,2-diol N-oxide
`etliyi)benze
`C H N0
`Exact Mass: 199.08
`Mol. Wt: 199.2
`
`In an embodiment, the stabilized injectable pharmaceutical composition comprises total
`
`impurity of about 4% or less when stored at 25°C and 60% relative humidity for at least
`
`3 months.
`
`In another embodiment, the stabilized injectable pharmaceutical composition comprises
`
`adrenaline sulfonate impurity of about 3% or less when stored at 25°C and 60% relative
`
`humidity for at least 3 months.
`
`ADAMIS EXHIBIT 1011
`
`Page 9
`
`

`

`In a further embodiment,
`
`the stabilized
`
`injectable
`
`pharmaceutical
`
`composition
`
`comprises noradrenaline impurity of about 0.05% or less when stored at 25°C and 60%
`
`relative humidity for at least 3 months.
`
`In a further embodiment,
`
`the stabilized
`
`injectable
`
`pharmaceutical
`
`composition
`
`comprises adrenalone impurity of about 0.3% or less when stored at 25°C and 60%
`
`relative humidity for at least 3 months.
`
`In a further embodiment,
`
`the stabilized
`
`injectable
`
`pharmaceutical
`
`composition
`
`comprises N-benzyl adrenalone impurity of about 0.05% or less when stored at 25°C
`
`and 60% relative humidity for at least 3 months.
`
`In a further embodiment,
`
`the stabilized
`
`injectable
`
`pharmaceutical
`
`composition
`
`comprises impurity observed at RRT 0.17, RRT 0.20, or RRT 0.73 of about 0.5% or less
`
`when stored at 25°C and 60% relative humidity for at least 3 months.
`
`Various methods of analyzing (characterization and quantification)
`
`the impurities are
`
`well established in the art. Various spectoroscopic techniques, such as NMR, MS,
`
`IR
`
`etc. and chromatographic techniques, such as HPLC, HPLC-TLC, HPLC-CE and
`
`hyphenated methods, such as LC-MS-MS, HPLC-DAD-MS, HPLC-NMR, GC-MS & LC-
`
`MS can be used for analyzing impurities.
`
`Related substances of Epinephrine were performed by reverse phase chromatography
`(250 x 4.6) mm, 5 m h
`separated in gradient mode with resolution more than 3.0. The detection was carried out
`
`using Cosmosil AR-II, C-18,
`
`columns. All impurities were
`
`at optimum wavelength 210 nm
`
`The pharmaceutical composition of the present invention may be developed in the form
`
`of a dosage form suitable of parenteral administration. The parenteral
`
`route of
`
`administration
`
`of
`
`the
`
`compositions
`
`comprises
`
`subcutaneous,
`
`intramuscular,
`
`intravenous,
`
`transdermal,
`
`intradermal,
`
`intranasal,
`
`intraarterial and intraperitoneal
`
`ADAMIS EXHIBIT 1011
`
`Page 10
`
`

`

`injection or infusion.
`
`In an embodiment
`
`the injection includes aqueous vehicle based
`
`injection and oil based injection (e.g. depot injection).
`
`The pharmaceutical composition of
`
`the present
`
`invention further comprises various
`
`pharmaceutically acceptable excipients suitable for parenteral administration. Such
`
`excipient
`
`includes, but not
`
`limited to pH adjusting agents or buffers, co-solvents,
`
`chelating agents, isotonicity adjusting agents, preservatives, and aqueous vehicle.
`
`Examples of suitable pH adjusting agents includes, but not limited to hydrochloric acid,
`
`citric acid, ascorbic acid, acetic acid,
`
`tartaric acid, phosphoric acid, metaphosphoric
`
`acid, polymetaphosphoric acid, carbonic acid, sodium hydroxide, potassium hydroxide,
`
`sodium citrate, potassium citrate,
`
`sodium bicarbonate, potassium bicarbonate,
`
`ammonium carbonate, sodium hydrogen phosphate, potassium hydrogen phosphate,
`
`ethanolamine, diethanolamine, triethanolamine, hexane-1 ,2-diamine, sodium carbonate,
`
`sodium potassium tartrate, potassium metaphosphate, potassium polymetaphosphate,
`
`and sodium metaphosphate. The pH of
`
`the pharmaceutical composition preferably
`
`ranges from 2.2 to 5.0.
`
`Examples of suitable buffers includes, but not limited to pharmaceutically acceptable
`
`salts and acids of acetate, glutamate, citrate,
`
`tartrate, benzoate,
`
`lactate, histidine or
`
`other amino acids, gluconate, phosphate, malate, succinate, formate, propionate, and
`
`carbonate.
`
`Examples of suitable co-solvents includes, but not limited to ethanol, glycerol, propylene
`
`glycol, polyethylene glycol, and different oils.
`
`Examples of
`
`suitable chelating agents
`
`includes, but not
`
`limited to calcium
`
`ethylenediaminetetraacetic acid (EDTA), calcium diethylenetriaminepentaacetic acid
`
`(DTPA), calcium hydroxyethylenediaminetriacetic
`
`acid (HEDTA), calcium ethylene
`
`glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), calcium nitrilotriacetic acid
`
`(NTA), calcium citrate, and calcium salt derivatives thereof.
`
`ADAMIS EXHIBIT 1011
`
`Page 11
`
`

`

`Examples of suitable isotonicity adjusting agents includes, but not limited to anhydrous
`
`or hydrous forms of sodium chloride, dextrose, sucrose, xylitol,
`
`fructose, glycerol,
`
`sorbitol, mannitol, potassium chloride, mannose, calcium chloride, magnesium chloride
`
`and other inorganic salts.
`
`The pharmaceutical composition of the present invention may be hypotonic, isotonic or
`
`hypertonic.
`
`In an embodiment,
`
`the pharmaceutical composition have a tonicity from
`
`about 250 to about 350 mOsm/kg.
`
`Examples of suitable preservative include, but not limited to benzyl alcohol, propyl and
`
`methyl paraben.
`
`The present
`
`invention also provides for a process of manufacturing aqueous
`
`epinephrine
`
`compositions. The
`
`process
`
`involves mixing
`
`epinephrine,
`
`sodium
`
`metabisulfite, water, and optionally other pharmaceutically acceptable excipients
`
`together.
`
`The composition may be rendered non-pyrogenic,
`
`if
`
`required, by passing through
`
`Tangential Flow Filtration System (TFF) before sterilization. The composition may be
`sterilized by membrane filter of 0.22 m h
`
`pore size.
`
`The process of manufacturing the aqueous epinephrine compositions of the present
`
`invention further may comprises sterilization of the composition. The compositions may
`
`be sterilized by known and acceptable methods. In an embodiment, the composition is
`
`sterilized by filtering through a sterilizing grade filter. Preferably, the solution is filtered
`through 0.2 m h
`
`sterilizing grade filters.
`
`After sterilization,
`
`it may be desirable to aseptically place the filtered solutions into
`
`sterile containers such as vials, ampoules, or cartridges of the pre-filled syringes. In an
`
`embodiment, after aseptically placing the filtered solution into the cartridge of prefilled
`
`syringes, the air in the cartridge is purged with an inert gas, such as nitrogen, and then
`
`the filled cartridge is sealed in the pre-filled syringe.
`
`ADAMIS EXHIBIT 1011
`
`Page 12
`
`

`

`The present invention further refers to the use of the above defined composition for the
`
`preparation of medicaments useful
`
`for treating allergic reactions (Type I)
`
`including
`
`anaphylaxis to stinging insects (e.g., order Hymenoptera, which include bees, wasps,
`
`hornets, yellow jackets and fire ants) and biting insects (e.g.,
`
`triatoma, mosquitos),
`
`allergen
`
`immunotherapy,
`
`foods,
`
`drugs,
`
`diagnostic
`
`testing
`
`substances
`
`(e.g.,
`
`radiocontrast media) and other allergens, as well as idiopathic anaphylaxis or exercise-
`
`induced anaphylaxis.
`
`The present invention is further illustrated by the following examples which are provided
`
`merely to be exemplary of the invention and do not limit the scope of the invention.
`
`Certain modifications and equivalents will be apparent to those skilled in the art and are
`
`intended to be included within the scope of the present invention.
`
`Example 1: Epinephrine Injection 0.3mg/0.3ml_
`
`Table 1
`
`ADAMIS EXHIBIT 1011
`
`Page 13
`
`

`

`WO2014/057365
`
`PCT/IB2013/053520
`
`14
`
`ADAMIS EXHIBIT 1011
`Page 14
`
`ADAMIS EXHIBIT 1011
`
`Page 14
`
`

`

`Example 2 : Epinephrine Injection 0.15mg/0.3ml_
`
`Table 2
`
`Process: Sodium chloride was dissolved in water
`
`for
`
`injection under continuous
`
`nitrogen sparging. 1N HCI solution was added to adjust the pH. Epinephrine and sodium
`
`metabisulfite were sequentially added to the solution under stirring to get clear solution.
`
`Final volume of the solution was made with water for injection. pH of the final solution
`
`can be adjusted using HCI solution if required. The solution was then subjected to
`filtration through 0.22m membrane filter. The solution was then filled in sterile 1ml_ pre-
`filled syringes.
`
`ADAMIS EXHIBIT 1011
`
`Page 15
`
`

`

`Example 3: Comparative Stability Study of effect of Sodium metabisulfite
`concentration on stability of Epipen/Epipen Jr. v Epinephrine composition of the
`invention
`
`Table 3
`
`Result of
`
`the stability study conducted on the composition of
`
`the present
`
`invention
`
`(Composition 2 & 4) indicates that epinephrine composition containing 0.3 mg sodium
`
`metabolite exhibits excellent storage stability relative to epinephrine composition
`
`containing 0.5 mg sodium metabolite over the storage period.
`
`ADAMIS EXHIBIT 1011
`
`Page 16
`
`

`

`A stabilized injectable pharmaceutical composition of epinephrine or salt thereof
`
`comprising sodium metabisulfite, wherein the ratio of the amount of epinephrine
`or salt
`thereof
`to sodium metabisulfite in the composition ranges from about
`
`1:0.005 to about 1: 1 .5 by weight, characterized in that said composition contains
`
`epinephrine having purity equal to or greater than 98% by weight.
`
`A stabilized injectable pharmaceutical composition of epinephrine comprising
`
`sodium metabisulfite, wherein the ratio of
`
`the amount of epinephrine or salt
`
`thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to
`
`about 1: 1 .5 by weight, characterized in that said composition contains total
`
`impurity of less than 4%.
`
`A stabilized injectable pharmaceutical composition of epinephrine comprising
`
`sodium metabisulfite, wherein the ratio of
`
`the amount of epinephrine or salt
`
`thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to
`
`about 1: 1 .5 by weight, characterized in that said composition contains no single
`
`impurity of greater than 3%.
`
`A stabilized injectable pharmaceutical composition of epinephrine or salt thereof
`
`comprising sodium metabisulfite, wherein the ratio of the amount of epinephrine
`
`or salt
`
`thereof
`
`to sodium metabisulfite in the composition ranges from about
`
`1:0.005 to about 1: 1 .5 by weight, characterized in that said composition is
`
`substantially free of epinephrine overages.
`
`The stabilized injectable pharmaceutical composition of claim 1, wherein the
`
`composition comprises adrenaline sulfonate less than about 3.0% or less at RRT
`
`0.15.
`
`The stabilized injectable pharmaceutical composition of claim 1, wherein the
`
`composition comprises less than about 0.5% impurity observed at RRT 0.17,
`
`RRT 0.2, or RRT 0.73.
`
`ADAMIS EXHIBIT 1011
`
`Page 17
`
`

`

`7 . A stabilized injectable pharmaceutical composition comprising epinephrine,
`
`sodium metabisulfite, wherein the ratio of
`
`the amount of epinephrine or salt
`
`thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to
`about 1: 1 .5 by weight, characterized in that said composition retains at least 90%
`
`w/w of
`
`total potency of epinephrine after storage at 25°C and 60% relative
`
`humidity for at least 3 months.
`
`8 . A stabilized injectable pharmaceutical
`
`composition comprising 0.3mg of
`
`epinephrine or salt
`
`thereof and 0.3mg of sodium metabisulfite in 0.3ml of
`
`solution, wherein the said 0.3ml of solution is delivered completely in single
`
`injection.
`
`9. A stabilized injectable pharmaceutical composition comprising 0.1 5mg of
`
`epinephrine or salt
`
`thereof and 0.3mg of sodium metabisulfite in 0.3ml of
`
`solution, wherein the said 0.3ml of solution is delivered completely in single
`
`injection.
`
`ADAMIS EXHIBIT 1011
`
`Page 18
`
`

`

`A . CLASSIFICATION
`O F SUBJECT MATTER
`INV. A61K9/08
`A61K47/02
`ADD.
`
`A61K31/137
`
`According to International Patent Classification
`
`(IPC) o r t o both national classification
`
`and IPC
`
`B . FIELDS SEARCHED
`
`Minimum documentation
`A61K
`
`searched
`
`(classification
`
`system followed by classification
`
`symbols)
`
`Documentation
`
`searched other than minimum documentation
`
`to the extent
`
`that such documents
`
`are included
`
`in the fields searched
`
`Electronic data base consulted during the international
`search (name of data base and, where practicable,
`EPO-Internal
`, BIOSIS, EMBASE, FSTA, WPI Data
`
`search terms used)
`
`C . DOCUMENTS
`
`CONSIDERED
`
`T O B E RELEVANT
`
`Category*
`
`Citation of document, with indication, where appropriate,
`
`of the relevant passages
`
`Relevant
`
`to claim No.
`
`WO 2010/139751 A2 (ALK A G [CH] ; BAI LLI E
`ALAN J [GB] ; MACDONALD KENNETH [GB] ;
`P0RTE0US PAM) 9 December 2010 (2010-12-09)
`page 10,
`l i ne 20 - page 13 ,
`l i ne 23
`exampl es
`page 2 ,
`
`l i nes 19-26
`
`" EPI PEN 0.3 mg"
`I n :
`" Physi ci ans ' Desk Reference,
`edi t i on" ,
`2008, Thomson Heal thcare
`USA, XP055071470,
`ISBN : 978-1-56-363660-8
`pages 1035-1036,
`page 1035 ,
`r i ght-hand col umn
`
`62
`
`Inc, Montval e
`
`1-7
`
`8,9
`
`1-7
`
`8,9
`
`□ Further documents
`
`are listed in the continuation
`
`of Box C .
`
`See patent
`
`family annex.
`
`* Special categories
`
`of cited documents
`
`:
`
`"T"
`
`filing date o r priority
`published after the international
`later document
`date and not in conflict with the application
`but cited to understand
`the principle o r theory underlying the invention
`
`the claimed invention cannot be
`relevance;
`"X" document of particular
`considered
`novel o r cannot b e considered
`to involve a n inventive
`step when the document
`is taken alone
`"Y" document of particular
`relevance;
`the claimed invention cannot be
`considered
`to involve a n inventive step when the document
`is
`combined with one o r more other such documents,
`such combination
`being obvious to a person skilled in the art
`
`"&" document member of the same patent
`
`family
`
`"A" document defining the general state of the art which is not considered
`to be of particular
`relevance
`"E" earlier application
`o r patent but published o n o r after
`filing date
`is
`claim(s) orwhich
`may throw doubts o n priority
`"L" documentwhich
`cited to establish the publication
`date of another
`citation o r other
`special
`reason (as specified)
`"O" document
`referring to a n oral disclosure,
`means
`prior to the international
`"P" document published
`the priority date claimed
`
`use, exhibition o r other
`
`filing date but
`
`later