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`Case 1:15-cv-OO697-RGA Document 39-7 Filed 01/29/16 Page 1 of 42 PagelD #: 361
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`EXHIBIT 6
`
`EXHIBIT 6
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`

`

`Case 1:15-cv-00697-RGA Document 39-7 Filed 01/29/16 Page 2 of 42 PageID #: 362
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`PA'l‘L-‘N'l'
`
`077350I 3-4-51
`
`
`
`Showin of So 1011 ofEach Claim Limitation:
`
`
`
`
`'
`'
`"w GEE—M LIMJfI‘ATioSJ '
`
`
`"
`
`__
`
`i
`
`-
`
`surporrfiéon Emmi
`
`l
`
`:
`
`
`
`l. A pliaimL-icenlical composition
`
`See, for example, p. 2, filo; p. 5‘ ‘24; p.
`
`comprising
`
`: 6, Will; Exai‘nplcs i—é.
`
`dcxmcdotoniidiiiEEI—a phorlnacciiiicsilly
`
`_ Soc, for cxamplcjpi 2, 'Il'ifivg; pl '3. 'I'gl4;
`
`acccptobic salt thereof
`
`- pp. 4—5: 1|23; pp. 10-11, 'gl'r-r'lti—il‘);
`
`Exam pics 1-6.
`
`at a concomrmion ofabont 4 pgfm]
`
`Sec, for example:
`
`'1
`2, {[8; p. )1 (:14; p.
`
`ll. $48—49; p. 12, WilSS-fio; Examples:
`
`il—G.
`
`
`
`n-‘hci'cin the composition is liJrl'nlllalCd as a
`
`Soc, for example. pp. 1—2‘ ‘jii; p. 2, ‘2'?—
`
`liquid l'or parenteral administration to a
`
`. 3; p.'3',1l19; pp. 3,1l37; pp.‘)—10.1l'fi43-
`
`subjccl. and
`
`
`
`44; p. ll, ilSU; Examples 1—6.
`
`
`
`wherein the composition
`
`within
`
`Soci for cxampio, p. 2,}16; p, 2, {ill};
`
`a sealed container :15 n prcmixturc.
`
`3, ill); p. 5, '7; p. l2, 1115158: p. 13,
`
`l T|60g Examples 1—6.
`
`
`
`
`
`3. The phamiaccniical compogilion of
`
`claim 1, further comprising sodium
`
`cl'iioridc at a concentration ot‘bctu-‘een
`
`about [11.01 and about 2.0 weigh! pcrccnl.
`
`
`
`3. This pharmaceutical composition of
`
`claim 2,. wherein the sodium chloride. is
`
`l-JYIIFJII'EE HS.
`
`1
`
`lice, for Example, pp. 2-3, ‘51 3; p. 31
`
`'lllfl; p.123¢ 152; p. 1’2? filial—55.;
`
`Examplcs l —6.
`
`
`
`Sec, for example, p. 3, illil; p. i2, 1l52;
`
`p. 1'2, r355; Examples 1-6.
`
`
`
`
`
`U1 Cl“.
`
`
`HOSPIRA_00000058HOSPIRA_00000058
`HOSPIRA_00000058
`
`

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`Case 1:15-cv-00697-RGA Document 39-7 Filed 01/29/16 Page 3 of 42 PageID #: 363
`Case 1:15-cv-OO697-RGA Document 39-7 Filed 01/29/16 Page 3 of 42 PagelD #: 363
`PATENT
`03’7350fi344
`
`CLAIM Lin-IITA'fiON
`
`m T F____
`.
`_
`_
`prcscm at a concentration nfuboul 0.9
`
`”
`- SlIPPOIfi—F‘Ofi Cmm
`
`LIMITAJI‘ION "
`'
`
`i
`
`;
`
`l
`
`
`
`i
`
`,
`|
`
`wei ght purer-:11
`
`_M___
`_____._ _ _—__
`4. The pharmaceutical cmnposition of
`See, for example; p. 21 WE; pp. 13-14‘
`
`claim 1, wl'lercin the conmosirion is
`
`11'562-65; Examples l-fi.
`
`formulated as a total volLu‘nc sclculud from
`
`the group consisting UfZO mL. 50 ml.- and
`
`IUD mL
`
`|
`
`i
`
`
`
`Nu means; plus function Claim elements are. present in The above clain'm.
`
`Thus, claims 1-4 satisfy the. requircmL-JI‘LIS of 35 U.S.C.
`
`111w,
`
`N‘r-‘JE'H'E'L-i‘.
`
`1
`
`5.7
`
`
`HOSPIRA_00000059HOSPIRA_00000059
`HOSPIRA_00000059
`
`

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`Case 1:15-cv-00697-RGA Document 39-7 Filed 01/29/16 Page 4 of 42 PageID #: 364
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`0773.50.03.44
`
`DEXMFDETOMHNNF. PREMIX FORMULATION
`
`1. FIELD OF THE INVENTION
`
`[01.301]
`
`The present
`
`invention relates
`
`to patient-ready, premixed formulations of
`
`dexntedetomidine. or a pharn'iat'tcutically acceptable salt thereof. that can be Used. fet' example,
`
`in perioperative care ot'a patient or for sedation.
`
`2. BACKGROUND OF THE INVENTION
`
`[0002]
`
`Racennc 4—[1—(2,3—dimethylphenyl)ethyll—1t-"lvimidazole which is linowri under
`
`the name ntedetotnidine.
`
`is a selective and potent (Lg-adrenoeeptor agonist. h-ledetomidine has
`
`been used as an antihypertensive agent and as a sedative—analgesic agent.
`
`It has further been
`
`observed that this compound also possesses anxioly'tic effects and can therefore be used in the
`
`treatment or‘gcneral auntie-t}!t panic disorder and various types ofwithdrawal symptoms.
`
`[[1003]
`
`the
`
`d—enantioiner of medetomidine,
`
`the
`
`generic
`
`name
`
`of which
`
`is
`
`destnedctomidine.
`
`is described in LS. Pat. No. 4,9“),214 as an rig—adrcnoceptor agonist for
`
`general
`
`sedation-“analgesia and the treatment of hypertension or anxiety.
`
`U.S. Pat. Nos.
`
`5.344.840 and 5.091.402 discuss destnedetomidine in perioperative and epidural use,
`
`respectively. For example. when used in perioperaliw care: desrnedetomidine can reduce the
`
`amount ot‘anesthetic necessary to anesthetize a patient. Additionally. US. Pat. No. 5,304,569
`
`discusses the use of dcstncdctmnidinc in treating glaucoma, and US. Pat. No. 5,?12.301
`
`discusses the use of demtedetotnidine for preventing neurodegeneration caused by ethanol
`
`consunmtion. Ft‘tnhennore. US. Pat. No. 6.716.867 discloses methods of scdating a patient
`
`while in an intensive care unit by administering desntedetornidine. or a pharmaceutically
`
`acceptable salt tl'iereol', to the patient.
`
`[0004]
`
`Dexmedetotnidinc can be administered to a patient
`
`in a variety of ways.
`
`For
`
`example.
`
`L...S.
`
`Pat. Nos.
`
`£1,544,664
`
`and
`
`4,910,214
`
`disclose
`
`the
`
`administration
`
`of
`
`desmedeten-iitline via parenteraL intravenous, and oral routes.
`
`lift, Pat. No. 4,6?l),453 describes
`
`intramuscular and intravenous administration, while US. Pat. Nos. 5594.157 and 5.217.718
`
`T‘lYflL’fi‘SE-‘lltl
`
`I
`
`
`HOSPIRA_00000080HOSPIRA_00000080
`HOSPIRA_00000080
`
`

`

`Case 1:15-cv-00697-RGA Document 39-7 Filed 01/29/16 Page 5 of 42 PageID #: 365
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`{tififiotfldii
`
`describe a method and det'iee for administering dexmcdetomidine through the skin, Additionally,
`
`US. Pat. T‘s—lo. 5,?12,301 states that dexmedetomidine can be administered transmueosaily.
`
`[0005]
`
`To date. desmedetomidine has been provided as a concentrate that must be
`
`diluted prior to administration to a patient. The requirement of a diiution step in the preparation
`
`of the dcxtnedetomidine fornntlation is associated with additirnial costs and inconvenience, as
`
`well as
`
`the risk of possible contamination or overdose due to human error.
`
`Thus,
`
`E1
`
`dexmcdetomidine formulation that avoids the expense,
`
`inconvenience, deiay and risk of
`
`Contamination or overdose 't\-'onld provide significant adx-antages over currently available
`
`crntcentratcd h‘nnntlations,
`
`3. SUM MARY OF THE INVENTION
`
`[titlllol
`
`The present
`
`invention relates
`
`to premised pharimtceutieal compositions of
`
`dexmedetomidinc, or
`
`a pltarmaceutiealiy acceptable sail
`
`thereof,
`
`that are formulated for
`
`administration to a patient, without the need to reconstitute or dilute the composition prior to
`
`administration Thus. the compositions of the present invention are formulated as a premised
`
`composition comprising, t‘iexmedetolnidine.
`
`[(1007]
`
`In
`
`certain
`
`non-limiting
`
`embodiments,
`
`the
`
`premised
`
`dexmedetomidine
`
`composition is a liquid comprising dexniedctomidine, or a phai'niaceuticali_x-' acceptable salt
`
`thereof, at a concentration ofhetweert about 0.05 tigfmi, and about 15 tigi’mL,
`
`[0008]
`
`in other non-limiting embodiments, the premixed dexmedetomidine composition
`
`is :1 liquid ctnnprising dexmedetomidine at a concentration ol’ahont 4 pgi’inL.
`
`[0009]
`
`in other non—limiting, embodiments, the premixed dexrnedetomidine composition
`
`comprises dexmedetomidine mixed or dissolved in a sodium chloride saline solution.
`
`[0010}
`
`In cenain embodiments, the promised desmedetomidine composition is disposed
`
`within a sealed container or vessel.
`
`[0011]
`
`In certain embodiments,
`
`the dexntedetomidine composition is disposed in a
`
`container or vessel and is formulated as a premisture.
`
`[(1012]
`
`In certain embodiments, the premixed dexmedetoi-nidine composition is disposed
`
`within a sealed container as a total volume of about 20 mL, 5.0 ml} or 100 mL.
`
`[0013]
`
`in
`
`certain
`
`non-limiting
`
`embodiments,
`
`the
`
`premixed
`
`dexmedetomidine
`
`composition ot"
`
`the present
`
`invention comprises dexmedetomidine, or a pharmaceuticelly
`
`i‘JYCE'TBf-lllll
`
`l
`
`f
`
`
`HOSPIRA_00000081HOSPIRA_00000081
`HOSPIRA_00000081
`
`

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`0773500344
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`acceptable salt thereof, at a concentration of between about 0.05 ugr‘mL and about
`
`)5.
`
`tig;’iiii-_.
`
`and sodium chloride at a concentration ofbctwcen about 0.01 and about 2.0 \-t-'eig,lit percent.
`
`[0014]
`
`in other non—limiting embodiments. the premixed dexmedettnnidine composition
`
`ot’ the present
`
`invention comprises dcxmedetomidine, or a pharmaceutically acceptable salt
`
`thereof. at a concentration of about 4 ugr’inL and sodium chloride at a concentration of about
`
`0.90 weight percent.
`
`[0015!
`
`In certain embodiments, the compositions of the present invention are formulated
`
`as a pharmaceutical composition for administration to a subject
`
`for sedation, analgesia or
`
`treatment ol‘anitiety or hypertension.
`
`{0016;
`
`The present
`
`invention also relates to the. perionerstivc treatment of a patient to
`
`reduce the response of the autonomic nervous system to stimuli during an operation by
`
`administering a dexmcdetrmiidinc composition ofthe invention.
`
`1001?}
`
`in other non-limiting embodiments.
`
`the dcxntcdctornidine compositions of the
`
`present
`
`invci'ition can be administered as an anxiolytic analgesic to a patient.
`
`In certain
`
`embodiments. the composition can be administered as a preniedication prior to an operation with
`
`or without administration of an amount of an anesthetic effective to achieve a desired level ol‘
`
`locat 0r general anesthesia.
`
`[0018]
`
`in other non-limiting embodiments.
`
`the dcxmedetomidine compositions ol" the
`
`present invention can be administered as a sedative.
`
`In certain embodiments, the composition is
`
`administered preoperatively to potentiatc the effect of an anesdtetic, wherein administration of
`
`the composition reduces the amount of anesthetic required to achieve a desired level of
`
`anesthesia.
`
`10019}
`
`in certain embodiments oi" the present invention, the premixed dc'xnicdctomidinc
`
`composition is administered parenterallv as a liquid. orally,
`
`transdei‘inallv.
`
`intravenously.
`
`intt'aniuscuiarlv. subcutaneously, or via an inmlantable pump.
`
`4. DETAILED DESCRIPTION
`
`{(1020}
`
`The present
`
`invention is based in part on the discovery that dexmedetOmidinc
`
`prepared in a premixed lorniulation that does not require reconstitution or dilution prior to
`
`administration to a patient. remains stable and active after prolonged storage. Such premixed
`
`i--.' 'i’tr'l Tin-I ll: I
`
`ha
`
`
`HOSPIRA_00000082HOSPIRA_00000082
`HOSPIRA_00000082
`
`

`

`Case 1:15-cv-00697-RGA Document 39-7 Filed 01/29/16 Page 7 of 42 PageID #: 367
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`07113500344
`
`formulations therefore avoid the cost, inconvenience, and risk of contamination or overdose that
`
`can be associated with reconstituting or diluting. a concentrated dcxmcdctornidine formulation
`
`prior to administration to a patient.
`
`will]!
`
`For clarity and not by way of limitation, this detailed description is divided into
`
`the following sub-portions:
`
`(4i) Definitions;
`
`(4.2)
`
`Pharmaceutical forrnulatioris; and
`
`[4.3) Methods of using premixed dexmedctomidine compositions.
`
`4.1 Definitions
`
`Will]
`
`The terms used in this specification generally have their ordinary meanings in the
`
`art, within the context of this invention and in the specific context where each term is used.
`
`Certain terms are discussed beloi-t'. or elsewhere in the specification,
`
`to provide additional
`
`guidance to the practitioner in describing the compositions and methods of the invention and
`
`how to make and use them.
`
`[0023]
`
`According to the present iti\-’€lll.l0l‘t,
`
`the tenn "desmcdctomidine" as used herein
`
`relers to a substantially pure, Optically active dextrorotary stereoisonier nl‘ niedetontidinc, as the
`
`tree
`
`base
`
`or pharmaceutically
`
`acceptable
`
`salt.
`
`In
`
`one, nondimitiug embodiment,
`
`dexmedetomidine has
`
`the
`
`tunnels
`
`[S_)-~*l~ll~(2.3-dirnethylphenyljethyl]—3H—imidazolc,
`
`A
`
`phannaceutically acceptable salt of dexmedctomidinc can include inorganic. acids such as
`
`h_\_-'droehloric acid, hydrohromic acid, sulfuric acid, nitric. acid, phosphoric acid and the like, and
`
`organic acids such as acetic acid, propionie acid, glycolic acid, pyruvic acid, oxalic acid, medic
`
`acid, ntalonic acid, succinie acid, maleic acid,
`
`illn‘tfil‘li' acid, tartaric acid, citric acid, henzoic
`
`acid, cinnainic acid. mandclic acid, methanesuli‘nnic acid, ethancsul {ionic acid, p—tolucnesulfonic
`
`acid, and salicylic acid. Preferably, the dexmedetomidinc salt is dexmet‘letomidine 11C].
`
`In other
`
`non—limiting?T embodiments, dexmedetomidinc comprises the structure depicted below in Formula
`
`I:
`
`l-JYOE'FFEHH I
`
`
`HOSPIRA_00000083HOSPIRA_00000083
`HOSPIRA_00000083
`
`

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`Case 1:15-cv-00697-RGA Document 39-7 Filed 01/29/16 Page 8 of 42 PageID #: 368
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`ti??35t'l.t_i344
`
`CH3
`
`<N~NJ
`
`H
`
`\
`
`Formula 1
`
`10024]
`
`The terms “premix” or “premixture” as used herein refers to a pharmaceutical
`
`forn'iul‘dtion that does not require reconstitution or dilution prior to administration to a patient.
`
`For example,
`
`in contrast
`
`to nan-premixed formulations of desmetletomidine,
`
`the premixed
`
`compositions provided herein are suitable for administration to a patient Without dilution by, for
`
`example, a clinician, hospital personnel, caretaker, patient or any other individual.
`
`1002 U. ]
`
`In certain embodiments.
`
`the compositions of the present
`
`invention can be
`
`formulated as “ready to use" compositions which refer to premixed compositions that are
`
`suitable for administration to a patient without dilution. For example, in certain embodiments,
`
`the compositions of the present invention are “ready to use" upon removing the compositions
`
`from a sealed container or vessel.
`
`[0036}
`
`in certain embodiments,
`
`the compositions of the present
`
`invention can be
`
`formulated as a “single use dosage.” which refers to a premised composition that
`
`is disposed
`
`within a sealed container or vessel as a one dose per container or vessel formulation.
`
`[0027]
`
`According to the invention. a "subject" or "patient" is a human. a non—human
`
`mammal or a non—human animal. Although the animal subject
`
`is preferably a human,
`
`the
`
`compounds and compositions of the invention hare application in veterinary medicine as Well,
`
`tag, for the treatment ot'domestieated species such as canine, feline, and various other pets; farm
`
`animal species such as bovine. equine, (wine, caprine. porcine. etc; wild animals,
`
`in the
`
`wild or in a zoologicai garden; and avian species, Such as chickens. turkeys. quail, songbirds, etc.
`
`[[1023]
`
`The term “purified” as used herein refers to material that has been isolated under
`
`conditions that reduce or eliminate the presence of unrelated materials,
`
`i.e., contaminants,
`
`including native materials from which the material
`
`is obtained. As used herein,
`
`the term
`
`"Substantially free" is Used operatiorially,
`
`in the Context of analytical
`
`testing of the l‘li'dltjt‘ifil.
`
`l’rel'erably, purified material substantially free of contaminants is at
`
`least Hill-"i: pure; more
`
`t-t‘t"t_'l2' o 1-1 l e l
`
`
`HOSPIRA_00000084HOSPIRA_00000084
`HOSPIRA_00000084
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`

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`OWBSUttELH
`
`preferably, at
`
`least 97% pure? and more. preferany still at
`
`least 99%: pure, Purity can he
`
`evaluated. for example. by chromatography or any other methods known in the art. In a specific
`
`embodiment, purified means that
`
`the level of contaminants is below a level aCCeptahle to
`
`regulatory authorities for safe administration to a human or non—human anin'tal.
`
`[0029]
`
`The term "pharmaceutically acceptable,” when used in connection with the
`
`pharmaceutical compositions of the invention refers to molecular entities and compositions that
`
`are physiologically tolerable and do not typically produce untoward t‘cactio is when administered
`
`to a human. Preferably, as used herein, the term “pharmaceutically acceptable” means approved
`
`by a regulatory agency ofthe Federal or a slate gtwemment or listed in the US. l’harrnaeopeia or
`
`other generally recognized pharmacopeia for use. in animals: and more particularly in humans
`
`The. term "carrier" refers to a diluenL adjuvant, excipicnc dispersing agent or vehicle with which
`
`the compound is administered. Such pharmaceutical carriers can he sterile liquids, such as water
`
`and oils. For example; water. aqueous solutions saline solutions, aqueous dextrose or glycerol
`
`solutions
`
`can he
`
`employed as
`
`carriers, particularly
`
`l'or
`
`injectahlc
`
`solutions. Suitable
`
`pharmaceutical carriers are described in, for examples. "Remington's Pharmaceutical Sciences"
`
`by Philip P. (icrhino, Blst Edition (or previous editions}.
`
`[0030]
`
`The term "pharmaceutical composition" as used in accordance with the present
`
`invention relates to compositions that can be formulated in any conventional manner using one
`
`or more pl‘iarinaceutically acceptable carriers or excipients. A "pharmaceutically acceptable“
`
`carrier or excipient, as used herein, means approved by a regulatory agency oi" the Federal or a
`
`state government? or
`
`listed in the US. Pharmacopoeia or other generally recognized
`
`pharmacopoeia for use in mammals, and more particularly in humans.
`
`[0031]
`
`The term "dosage" is intended to encompass a Formulation expressed in terms of
`
`tig.t'.l<.gf'day,
`
`tigt’kgthr, mgr’kgtday or mgfltgfhn The dosage is the amount of an ingredient
`
`administered in accordance with a particular dosage regimen. A “dose” is an amount of an agent
`
`administered to a mammal in a unit volume or mass.
`
`an absolute unit dose expressed in mg
`
`or pg of the agent. The dose depends on the concentration of the agent in the liirmulation. cg,
`
`in moles per liter {M}, mass per volume [nirle or mass per mass (mini). The two terms are
`
`closely related as a particular dosage results from the regimen ot" admii'iistration of a dose or
`
`doses of the formulation The particular meaning in any case will be apparent li‘om contest.
`
`NVlIE'TETl-l ill!
`
`
`HOSPIRA_00000085HOSPIRA_00000085
`HOSPIRA_00000085
`
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`0773500344
`
`[0032]
`
`The
`
`terms
`
`“therapeutically
`
`el‘l‘ective
`
`dime,"
`
`"effective
`
`amount,"
`
`and
`
`"therapeutically effective amount“ refer to an amount sufficient to produce the desired effect.
`
`[0033]
`
`in some non—limiting emhodirnctits, a “therapeutically et‘tecuve dose” means an
`
`amount sufficient to reduce by at least about 15%, prcl'erahly h}: at least Still/ti, more proletany by
`
`at least 90%;, and most preferably prevent, a clinically significant deficit in the activity, function
`
`and response of the host. Alternatively. a therapeutically el‘l‘ectivc amount is sufficient to cause
`
`an improvement in a clinically significant condition in the host. 'l'hese parameters will depend on
`
`the severity of the condition being treated, other actions, such as diet modification,
`
`that are
`
`implemented, the weight, age, and sex ol‘ the subject, and other criteria, which can be readilyr
`
`determined according to standard good medical practice by those ol’sltill in the art.
`
`{0034]
`
`In other nun—limiting embodiments a therapeutic response may be any response
`
`that a user leg, a clinician) will recognize as an effective response to the therapy, Thus,
`
`E
`
`therapeutic response will generally be an induction til“ at desired effect. such as, for example,
`
`sedation or analgesia.
`
`“1035]
`
`The term "about" or “approximately” as used herein means within an acceptable
`
`error range tor the particular value as determined by one ofordinarv skill in the art, which will
`
`depend in part on how the value is measured or determined,
`
`i.e.,
`
`the limitations of the
`
`measurement system.
`
`For example, “about” can mean within '3 or more than 3 standard
`
`deviations, per the practice in the art. Alternatively, "about" can mean a range (it up to Etl‘ltt,
`
`preferably up to 1092:, more preferably up to 5%, and more preferably still up to lit; til at given
`
`value. Alternatively, particularly with respect to biological systems or processes- the term can
`
`mean within an order of magnitude, prelet'abl} vvithin 5-fold, and more preferably within 2~t‘old.
`
`til‘a value.
`
`4.2 Pharmaceutical Compositions
`
`[(1056]
`
`The compounds and compositions ol‘
`
`the invention may be forinult‘tted as
`
`pharn-iaecutical compositions by admixture with a pharn-taecuticallv acceptable carrier or
`
`excipicnt.
`
`in certain l'ltll'l-llt‘l‘lilll‘lg embodiments. the compounds or compositions are provided in
`
`a therapeutically effective amount to an animal, such as a mammal, preferably a human, in need
`
`oftret-itnient therewith for inducing a sedative, anxiolytic, analaesie, or anesthetic effect.
`
`l‘iYDE:T§24 H" l
`
`
`HOSPIRA_00000086HOSPIRA_00000086
`HOSPIRA_00000086
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`

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`Case 1:15-cv-00697-RGA Document 39-7 Filed 01/29/16 Page 11 of 42 PagelD #: 371
`t'i'??350.03-2t4
`
`["037]
`
`in certain rum-limiting embodiments, desmedeiomidine is
`
`formulated as
`
`a
`
`composition, wherein the destnedetomidine is the only therapeutically active ingredient present
`
`in the composition.
`
`in another non—limiting embodiments, dexmedetomidine is formulated as a
`
`cortiposition. wherein the dcxmedetomidine is tormulated in combination with at least one or
`
`more other tl'terapeuticall)= active ingredient. The formulation is preferably suitable for parenteral
`
`adnunistration,
`
`including. but not
`
`limited to,
`
`intravenous, subcutaneous,
`
`intramuscular and
`
`intraperitoneal administration; however, formulations suitable for other routes of administration
`
`SUCl‘l as oral, intranasal, mucosal or h‘ansdermal are also contemplated.
`
`[0033]
`
`The pharmaceutical formulations suitable for iniectable use, such as,
`
`l'or example,
`
`intravenous, subcutaneous.
`
`intramuscular and intraperitoneal admuustration,
`
`include sterile
`
`aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of
`
`sterile injectahle solutions or dispersion. In all cases, the form can he sterile and can he. Fluid to
`
`the extent that easy syringabilitv exists. it can be stable under the conditions of manufacture and
`
`storage and can be preserved against
`
`the contaminating action of microorganisms such as
`
`bacteria and fungi. The carrier can be a solvent or dispersion mediun‘i containing, for example,
`
`water, saline, ethanol, polon (for example, glycerol, propylene glycol, and polyethylene glycol,
`
`and the like), suitable mixtures thereof. and oils. The proper fluidity can be maintained,
`
`tor
`
`example, by the use o la ct'iatirig such as lecithin, by the maintenance ofthe required particle size
`
`in the case 01" dispersion and by the use ol‘ suture-{ants 'l‘hc preventions of the actiOn ot‘
`
`microorganisms can he brought about by various antibacterial and antifungal agents,
`
`for
`
`example. parabens, chlorohutanol, phenol, henzyl alcohol, sorhie acid, and the like.
`
`[0039]
`
`in many cases. it will he preferable to include isotonic agents. for example. sugars
`
`or sodium chloride. Prolonged absl'irption ol'the injectahle con-ipositions can be brought about by
`
`the use in the compositions of agents delaying absorption, for example, aluminum monostcrate
`
`and gelatin. Sterile injectable solutions may he prepared by incorporating the tlexmedetomidine
`
`in the required amounts in the appropriate solvent with various of the other
`
`ingredients
`
`enumerated above, as required, followed by filter or terminal sterilization. Generally, dispersions
`
`are prepared by incorporating the various sterilized active ingredients into a sterile vol-iicle which
`
`contains the basic dispersion medium and the required other ingredients from those enumerated
`
`above.
`
`in the case of sterile powders for the preparation of sterile injectahlc solutions,
`
`the
`
`preferred methods of preparation are vacuum drying and the freeze—drying technique which yield
`
`H Yul-7124 1 ill
`
`,2-
`
`
`HOSPIRA_00000087HOSPIRA_00000087
`HOSPIRA_00000087
`
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`

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`Case 1:15-cv-00697-RGA Document 39-7 Filed 01/29/16 Page 12 of 42 PagelD #: 372
`(073500344
`
`:1 powder of the active ingredient plus any additional desired ingredient from previously sterile-
`
`tiltered solution thereoll
`
`[0040]
`
`Preferany the formulation may contain an excipicnt. Pharmaceutically acceptable
`
`excipients which may be included in the formulation are bullets such as citrate butler, phosphate
`
`buffer, acetate bulTer, and bicarbonate buffer; amino acids; urea; alcohols; ascorbic acid;
`
`phospholipids; proteins, such as serum albumin. collagen. and gelatin; salts such as FDTA or
`
`EGTA, and sodium chloride; liposornes; polyvinylpyrollidone; sugars, such as dcxtran, niannitol,
`
`Sol-into], and glycerol; propylene glycol and polyethylene glycol (erg, PRICE-4000, PEG-6000};
`
`glycerol; glycine; lipids; preservatives; suspending agents; stabilize-rs, and dyes. As used herein,
`
`the term “stabilizer” refers to a compound optionally used in the pharmaceutical compositions of
`
`the present invention in order to avoid the. need for sulphite salts and increase storage life. Non—
`
`litniting examples of stabilizers include antioxidants.
`
`Buffer systems for use with the
`
`formulations include citrate; acetate; bicarbonate; and phosphate butters.
`
`{0041]
`
`the timnulation also may contain a non—ionic. detergent. Preferred non-ionic
`
`detergents include Polysorhale 2t}, I‘olysm‘hak SO, Triton X-Itltl, Triton X—l lit, Nonidet P40;
`
`Octyl rt-glucosicic, Uetyl ti—gltieoside, Brij 3.5, Pluronie. and 'l'wcen '20.
`
`111042}
`
`The parenteral formulations of the present
`
`invention can be sterilized, Non-
`
`limitng examples ofstcrilization techniques include filtration through a bacterial—retaining filter,
`
`terminal sterilization, incorporation of sterilizing agents, irradiation, and heating.
`
`[0043]
`
`The route of administration may be oral or parenteral- including intravenous,
`
`subcutaneous, ultra—arterial, intraperitoneal, ophthalmic. intramuscular. hnccal, rectal, vaginal,
`
`intraorhital,
`
`intraeerehrai,
`
`intradermal.
`
`intrneranial.
`
`intraspinal.
`
`intraventrieular,
`
`intrathecal,
`
`intraeisternal,
`
`intracapsular,
`
`intrapnlmonary,
`
`intranasal.
`
`transmueosal.
`
`transdermal, or via
`
`inl'ialation.
`
`[0044]
`
`r‘tdrninistration ot‘thc- above-descride parenteral formulations may he by periodic
`
`injections ol‘ a bolus of the preparation, or may be administered by intravenous or intraperitonenl
`
`administration l'rom a reservoir \-\-'hieh is external leg. an intravenous bag) or internal tea, a
`
`biocrodablc implant, a bioartilicial or organ). See, e.g., US. Pat. Nos. 4,407,957 and 5,798,] l 3,
`
`each incorporated herein by reference.
`
`in their entircties. lntrapalmonary delivery methods and
`
`apparatus are described, for example,
`
`in US. Pat. Nos, 5,654,007, 5,?Btl,tll4, and 5,8l4,60?,
`
`each incorporated herein by reference in their cntiret‘ie—s. Other useful parenteral delivery systems
`
`NYC‘ELFB'E-l l t‘..|
`
`.9-
`
`
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`

`Case 1:15-cv-00697-RGA Document 39-7 Filed 01/29/16 Page 13 of 42 PageID #: 373
`Case 1:15-cv-00697-RGA Document 39-7 Filed 01/29/16 Page 13 of 42 PagelD #: 373
`0773500344
`
`include ethylene—vinyl acetate copolymer particles, osmotic pumps,
`
`implantable infusion
`
`systems. pump delivery. encapsulated cell debt-cry,
`
`liposonial delivery, needle-delivered
`
`injection. needle—less injection, nebulizcr, aeorosolizer, electroporation, and transdcrinal patch.
`
`Needle-less injector devices are described in US. Pat. Nos. 5,879,32?;5,520,6391 5,846,333 and
`
`5304,91],
`
`the specifications of which are herein incorporated herein by reference in their
`
`entireties. Any oftbe formulations deseribed herein can be administered in these methods.
`
`[0045]
`
`In yet another non-limiting embodiment,
`
`the tberapeutic. compound can be
`
`delivered in a controlled or sustained release system. For example, a compound or composition
`
`may be administered using, intravenous infusion, an implantable osmotic pump, a transdcrrnal
`
`patch, liposontes, or other modes of administration. In one embodiment, a pump .Ina_\_-' be used
`
`{see Sel’ton, 193?, CRC Crit. Rel. Biomed. Lug. 14:20]; Buchwald et al., l980, Surgery 835.07;
`
`Saudek et al., 1989, N. Engl. J. Med. 32|15T4t In another embodin'ient, polymeric materials can
`
`be used {see Langer and Wise eds,
`
`INT-l, Medical Applications ol‘ Controlled Release, CRC
`
`Press: Boca Raton, Fla; Sniolen and Ball eds, 198-4, Controlled Drug Bioavailability, Drug
`
`Product Design and Performance, Wiley, NY; Ranger and l‘eppas, 1.983,
`
`.1. Macromol. Sci.
`
`Rev. Macromol. Chem, 231(1; Levy et al., 1985, Science 3282030; During ct al.. 1989, Ann.
`
`Neurol. 25:351: [toward et at, 9189,
`
`lNeurosurg. 711l05).
`
`In yet another embodiment, a
`
`controlled release sysrern can be placed in proximit}r ol‘tbe therapeutic target, i.e.. the brain. thus
`
`requiring only a fraction oftbe systemic dose (see, eg, Goodson, 1984, in Medical Applications
`
`of Controlled Release, Vol. 2, pp. 115-138).
`
`[0046}
`
`in
`
`certain
`
`non—limiting
`
`embodiments.
`
`the
`
`premised
`
`dexniedetoniidine
`
`composition comprises dcxtnedctmnidinc, or a pliarmaceutically acceptable salt
`
`thereof. at a
`
`concentratitm of" between about 0.005 pgi’n'il. and about
`
`l00 ugi‘niL, or between about 0.005
`
`trglmL and about 5.0 ugi’ntL, or between about 0.005 pig'me and about 25 tig.-’iitl,, or between
`
`about 0.005 ugfml. and about 15 egg-"nib, or between about 0.005 to;an and about 10 ttgr'tnl; 01‘
`
`between about 0.005 uglmls and about ? ugi'mL, or between about. 0.005 pgz’nil. and about 5
`
`tigi’mL or between about tHltIJS pgi'tnl. and about 4 pgi’ml... or between about 0.005 pgr'nil. and
`
`about 3 pgme, or between about 0.005 pgnnL and about '2 ugi’ml, or betu-‘een about 0.005
`
`pghnL and about 1 opium, or between about 0.005 gig/nil. and about 0.5. pgz‘rnL, or between
`
`about 0.005 pig-"title and about 0.05 ttgr'mL
`
`L‘JYD'}.
`
`'33.“. 4 10. |
`
`-lU-
`
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`Case 1:15-cv-00697-RGA Document 39-7 Filed 01/29/16 Page 14 of 42 PagelD #: 374
`t_t?7350.0344
`
`[0047]
`
`In
`
`certain
`
`non—limiting
`
`el't‘tboditneuts,
`
`tbe
`
`premixed
`
`dexmedetomidtne
`
`composition comprises dexmcdetomidino. or a pburutaeeutically acceptable salt
`
`thereof. a! a
`
`concentration of between about 3.5 ugftuL and about 4.5ttgr'mL. or between about 3 ugt’mi, and
`
`about 5 ttgr’mL, or between about 3.5 ugtm]. and about 5.5 ug."ntl'._. or between about 2 ugz’tttb
`
`and about 6 ttgr’h’lL. or between about 1.5 ugt’utL and about 6.5 ugt’mL, or between about
`
`|
`
`ugimi. and about 7 ugt'uti...‘ or between about 0.5 pg,me and about it) ughnb.
`
`[0048]
`
`In Certain
`
`non—limiting
`
`embodiments.
`
`the
`
`premixed
`
`dexntedetomidine
`
`Ct‘uttpt‘tsittoo comprises dexmedetomtdine at a concentration of about 0.5 ttgr’mL, or about
`
`I
`
`ugfntL, or about 1.5 ugx‘mL, or about 2 aged? or about 2.5 ungL, or about .3 ugz’t'uL. or about
`
`3.5 ugh-111.; or about 4 ugimL. or about 4.5 gig-"nth, or about :3 ughuL, or about 5.5 tut-"nu... or
`
`about 6 outed" or about 6.5 ugt’ntl., or about '? ugtuti... or about 7.5 tug/tub. or about 3 ug.’tttl.. or
`
`about 8.5 ugt'mL. or about 9 ugtmL. or about 9.5 ugx’mL. or about 10 ugouL. or about 10.5
`
`ttgrrtttL. or about !
`
`l ugs’mL, or about
`
`1 1.5 ttg.-"'mf.., or about 12 tightth or about 12.5 ttgme. or
`
`about 13 ugt’ntL, or about 13.5 ugtmL. or about 14 ugfntL. or about 14.5 ttgttnL, or about 15
`
`ugr‘mL. or about 15.5 ttgftt’tL. or about to tLgfrmL. or about 16.5 ugttttL. or about 1? ug-‘mL, or
`
`about 17.5 ttgt‘mL, or about 18 ugt'mL. or about 18.5 ugt’ml. or about 19 ugt’mL, or about 19.5
`
`ogs'mL. or about ’20 ttgr'ml.
`
`100-49)
`
`In
`
`certain
`
`non—limiting
`
`embodiments.
`
`the
`
`premixed
`
`dexmedetomidine
`
`composition etunprtues dexmedetomidiue at a concentration ofzibout 4 ttgflt‘tib.
`
`10050]
`
`In
`
`eettain
`
`nou-litttitiug
`
`embodiments,
`
`the
`
`premixed
`
`dexmedetotnidine
`
`composition it; formulated as a liquid.
`
`[0051]
`
`In
`
`certain
`
`tum-limiting
`
`on‘tbodituents,
`
`the
`
`premixed
`
`dexmedetou'tidioe
`
`ct'ut'tpositiou is listtmuiuted at a pit of between about 1 and about 10. or between about
`
`1 and
`
`about 8, or between about 1 and about 6, or between about 1 and about 4, or between about 1 and
`
`about 2.
`
`In other non—limiting embodiments,
`
`the premixed demuedetontidiue composition is
`
`fiJtmubtted at a pH. t'tl‘beto'eeo about 2 and about 10, or between about 4 and about 8. or betw een
`
`about 4 and about ?.
`
`In other non-Jinuting embodiments.
`
`the premixed demnedetomidine
`
`compos