Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 1 of 47 PageID #: 446
`Case 1:15-cv-OO697-RGA Document 39-9 Filed 01/29/16 Page 1 of 47 PagelD #: 446
`
`EXHIBIT 8
`
`EXHIBIT 8
`
`

`

`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 2 of 47 PageID #: 447
`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 2 of 47 PagelD #: 447
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`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 3 of 47 PageID #: 448
`Case 1:15-cv-OO697-RGA Document 39-9 Filed 01/29/16 Page 3 of 47 PagelD #: 448
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`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 4 of 47 PageID #: 449
`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 4 of 47 PagelD #: 449
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`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 5 of 47 PageID #: 450
`Case 1:15-cv-OO697-RGA Document 39-9 Filed 01/29/16 Page 5 of 47 PagelD #: 450
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`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 6 of 47 PageID #: 451
`Case 1:15-cv-OO697-RGA Document 39-9 Filed 01/29/16 Page 6 of 47 PagelD #: 451
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`

`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 7 of 47 PageID #: 452
`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 7 of 47 PagelD #: 452
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`

`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 8 of 47 PageID #: 453
`Case 1:15-cv-OO697-RGA Document 39-9 Filed 01/29/16 Page 8 of 47 PagelD #: 453
`U77350.0359
`
`METHODS 01-" 'I‘REATM ENT USING A DE-Xi’i-‘IEDETONIIDINE PREMIX
`FORM L‘LA'l‘lON
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`This application is a continuation ofand claims priority under 35.
`
`l...'.S.C. 93120 to
`
`LLS. Serial No. 135541524 tiled July 3, 20}; which is a continuation of US. Serial No.
`
`13.-"'3¢13.6?2 filed January 4, 2012, now US. Patent No. 8,243,158, the contents ofeach of which
`
`are hereby incorporated by reference in their entire-ties, and to each of which priority is claimed.
`
`1. FIELD OF THE INVENTION
`
`[0001]
`
`The present
`
`invention relates
`
`to
`
`patient—rez-tdy, premixed
`
`terminations of
`
`dextiiedetomidine, or a pharmaceuticaliy acceptable salt thereol} that can he used, for example.
`
`in pCI'lOpCfflIiVC care ofa patient or for sedation.
`
`2. BACKGROUND OF THE INVENTION
`
`[0002]
`
`Racemie 4—[1{2,3-dimethylphenyljethyl]—ll-l—imidaxoie, which is known under
`
`the name medetomidine,
`
`is a selective and potent rig—adrenocentor agonisl. Medetomidine has
`
`been used as an untihypertensive agent and as a sedative—analgesic. agent.
`
`It has further been
`
`observed that this compound also nossesses anxiolytic effects and can therefore be used in the
`
`treatment ol‘general anxiety. panic disorder and various types of withdrawal syl‘npiums
`
`[0003!
`
`The
`
`d-cnantiomer of mcdetomidine,
`
`the
`
`generic
`
`name of which
`
`is
`
`dexmedetomidine,
`
`is described in US. Pat. No. 4.910314 as an ng-adrenoceplor agonisi for
`
`general seclatiotuanalgcsia and the treatment of hypertension or anxiety. US. Pat. Nos.
`
`5.344.840 and 5,091,402 discuss dexmedctomidine
`
`in perioperative and epidural use.
`
`respectively. For example? when used in periopcrative care, dexmedctomidine can reduce the
`
`amount ot‘ anesthetic necessary to anesthetize a patient. Additionally; US. Pat. No. 5,304.56?
`
`discusses the use of dexmedetomidinc in treating glaucoma. and US. Pat. No. 5.712.301
`
`discusses the use ol' dextnedetomidinc For pt'e\-'enting rietirodegcneration caused by ethanol
`
`consumption. Furthermore, LLS. Pat. No. amass? discloses methods of sedating a patient
`
`while in an intensive care unit by administering desmedetomidine, or z: pharmaceuticully
`
`acceptable suit therettfl to the patient.
`
`.‘J‘I’lII'TST‘iitiT l
`
`
`HOSPIRA_00000901HOSPIRA_00000901
`HOSPIRA_00000901
`
`

`

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`0779500359
`
`[0004]
`
`Dexmedctomidine can be administered to a patient in a variety ol‘ ways. For
`
`example, US.
`
`Pat. Nos.
`
`4,544,664
`
`and
`
`4.9]U,214
`
`disclose
`
`the.
`
`administration
`
`of
`
`desmedetomidine via parenteral. intravenous, and oral routes. US. Pat. No. 4,6?U,455 describes
`
`intramusoular and intravenous administration, while US. Pat. Nos. 5,124,157 and 5,21?,?13
`
`describe a method and device For administering dexmedetomidine through the skin. Additionally,
`
`US. Pat. No. 5,712,301 states that demredetomidine can be administered transmucosallv.
`
`[0005]
`
`To date, dexmedetomidine has been provided as a concentrate that must be
`
`diluted poor to t-idministration to a patient. The requirement ol‘ a dilution step in the preparation
`
`of the dexmedetomidine formulation is associated with additional costs and inconvenience, as
`
`well as
`
`the risk of possible contamination or overdose due to human error.
`
`Thus, a
`
`dexmedetomidine Formulation that avoids the expense,
`
`inconvenience, delay and risk of
`
`contamination or overdose would provide significant advantages over currently available
`
`concentrated formulations
`
`3. SUMMARY OF THE INVENTION
`
`[0006]
`
`The present
`
`invention relates
`
`to premised pharmaceutical compositions of
`
`dextnedetomidine. or a pharmaceutically acceptable salt.
`
`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 premixed
`
`composition comprisng dexmedetomidine.
`
`[0007]
`
`In
`
`certain
`
`non~limiting
`
`embodiments,
`
`the
`
`premixed
`
`dexmedetornidine
`
`composition is a [iquid comprising dexmedetomidinc, or a pharmaceuticalIy acceptable. salt
`
`thereof, at a concentration oi’ between about 0.05. portal. and about 15 rig-"'niL.
`
`[0008]
`
`In other non-limiting embodiments. the premixed dexinedetomidine composition
`
`is a liquid comprising dexmedetomidine at a concentration of about 4 pg.-’niL.
`
`liltifl9|
`
`in other nondimiting embodiments, the premixed dexntedettnnidine composition
`
`comprises deionedetomidine mixed or dissolved in a sodium chloride saline solution.
`
`In certain embodiments, the premixed dexmedetomidine composition is disposed
`[0010]
`within a sealed container or vessel.
`
`[0011}
`
`In certain embodiments,
`
`the dcxmedetomitline composition is disposed in a
`
`container or vessel and is lormulated as a premixtare.
`
`\ via. Twat-T l
`
`r-J
`
`
`HOSPIRA_00000902HOSPIRA_00000902
`HOSPIRA_00000902
`
`

`

`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 10 of 47 PageID #: 455
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`0?.735tlt)359
`
`[0012]
`
`in certain embodiments, the premixed deamedetomidine composition is disposed
`
`within a sealed container as a total volume of about 20 inL, 50 ml; or 100 mL.
`
`{001M
`
`in
`
`eenain
`
`non-limiting
`
`embodiments,
`
`the
`
`premixed
`
`dexmedetomidinc
`
`composition of the present
`
`invention comprises dcsmcdetomidine, or a phannaceutically
`
`acceptable salt thereol’, at a concentration of between about 0.05.. piston. and about 15 ttgi’mb.
`
`and Sodium chloride at a concentration ol‘ between about U.Ui and about 2.0 weight percent.
`
`[0014]
`
`in other non—limiting embodiments, the premised desmedetomidinc composition
`
`of the present
`
`invention comprises dexmedetomidine, or a pharmaceutically acceptable salt
`
`thereof, at a concentration of about 4 ughnl. and sodium chloride at a concentration of about
`
`0.90 weight percent.
`
`[0015]
`
`In certain embodiments, the compositions of the present invention are lormulated
`
`as a phannaceutical composition for administration to a subject
`
`for sedation, analgesia or
`
`treatment oi" anxiety or hypertensimi.
`
`[0016]
`
`line present invention also relates to the perioperative treatment of a patient
`
`to
`
`reduce the response of the autonomic nervous system to stimuli during an operation by
`
`administering a dcxmedetomidine composition oi" the invention.
`
`[0017}
`
`In other non—limiting embodiments,
`
`the desmcdetomidine compositions of the
`
`present
`
`invention can be. administered as an anxiolytie analgesic to a patient.
`
`in certain
`
`embodiments, the composition can be administered as a premedication prior to an operation with
`
`or without administration of an amount of an anesthetic effective. to achieve a desired level of
`
`local or general anesthesia.
`
`["018]
`
`in other non~limiting embodiments,
`
`the. desmedetomidine compositions oi" the
`
`present invention can be administered as a sedative.
`
`in certain embodiments. the composition is
`
`administered preoperativer to potentiate the effect of an at'icsthetie, wherein administration of
`
`the composition reduces the amount of anesthetic required to achieve a desired level of
`
`anesthesia.
`
`[0019]
`
`In certain embodiments of the present invention. the premixed dcsmcdetomidine
`
`composition is administered parenterally as a liquid, orally,
`
`trtnisdet‘mally,
`
`intravenously.
`
`intran'iusc'ularly‘, subcutaneously, or via an implantable pump.
`
`.‘~l\r'[|3'?5?llfi7 |
`
`
`HOSPIRA_00000903HOSPIRA_00000903
`HOSPIRA_00000903
`
`

`

`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 11 of 47 PageID #: 456
`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 11 of 47 PagelD #: 456
`t_l7?350.0359
`
`4. DETAILED DESCRIPTION
`
`[0020]
`
`The present
`
`invention is based in part on the discovery that dexmedeturnidine
`
`prepared in a premixed Formulation that does: not require reconstitution or dilution prior to
`
`administration to a patient, remains stable and active after prolonged storage. Such premixed
`
`formulations therefore avoid the. cost, inconvenience, and risk ol' contamination or overdose that
`
`can be associated with reconstituting or diluting a concentrated dexmedctomidine formulation
`
`prior to administration to a patient.
`
`[0021}
`
`For clarity and not by way ot‘ limitation, this detailed description is divided into
`
`the following sub—portions:
`
`(4.1) Definitions:
`
`(4:2)
`
`Pharmaceutical formulations; and
`
`(4.3} Methods oi’using premixed dexmedetomidine cttsmpositions
`
`4.1
`
`[0022]
`
`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 below, or elsct-vhcrc 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 invention, the term “dexmedctoinitlinfi as used herein
`
`refers to a substantially pure, optically active dextrorotar} steretiiisomer ot~ medetomidine, as the
`
`tree
`
`base
`
`or pharmaceutically acceptable
`
`salt.
`
`In
`
`one,
`
`non—limiting
`
`embodiment.
`
`dez-tmedetomidine has
`
`the
`
`formula
`
`(S'J-«fl—[l—(2,3~dimethylphenyl)ethyll—3H-itnidazole.
`
`A
`
`pharmaceutically acceptable salt of dexmedetomidine can include inorganic acids such as
`
`hydrochloric acid, l1}-’dl‘0bt'0111ic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and
`
`organic acids such as acetic acid, propionie acid, glycolie acid, pyruvic acid, oxalic acid. inalic
`
`acid, malonlc acid, succinic acid, maleie acid,
`
`tiuniarie acid,
`
`tartaric acid, citric acid, henzoic
`
`acid, cinnach acid, mandelic acid, methancsul'fonic acid, etltanesulfonic acid, p-toluencsrdlonic
`
`acid, and salicylic acid. Prcfierabljr, the dexmedetomidine salt is dexmedetomidine HC].
`
`In other
`
`non-limiting embodiments, dcxmcdctornidine comprises the structure depicted below in Formula
`
`1:
`
`ll\'032757t'lt'.7_]
`
`
`HOSPIRA_00000904HOSPIRA_00000904
`HOSPIRA_00000904
`
`

`

`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 12 of 47 PageID #: 457
`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 12 of 47 PagelD #: 457
`0 7’3 50.03.59
`
`CH3
`
`cu3
`
`N/1
`
`H.
`
`l-‘ormula I
`
`10024]
`
`The terms “pron-tin” or “premixture” as used herein refers to a pharmaceutical
`
`formulation that does not require reconstitution or dilution prior to administration to a patient.
`
`For example,
`
`in contrast
`
`to non—premixed Formulations of dexmedetomidine,
`
`the premixed
`
`compositions provided herein are suitch for administration to a patient without dilution by. for
`
`example, a clinician, hospital personnel, caretaker. patient or any other individual.
`
`{0025]
`
`In certain embodiments,
`
`the compositions of the present
`
`invention can be
`
`formulated as "ready to use“ compositions which refer to premixed compositith that are.
`
`suitable for administration to a patient without dilution. For example, in certain etnhodintents=
`
`the compositions of the present invention are “ready to use" upon retrieving:1 the compositions
`
`from a sealed container or vessel.
`
`[0026]
`
`In certain embodiments,
`
`the compositions of the. present
`
`invention can be
`
`formulated as a “single use dosage.” which refers to a premixed 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.
`
`51 non-human
`
`mammal or a non—human animal. Although the animal subject
`
`is preferably a human,
`
`the
`
`eompmtnds and compositions of" the invention have application in veterinary medicine as well,
`
`tag. for the treatment of domesticated species such as canine, feline. and various other pets; farm
`
`animal species such as bovine. equine, ovine, eaprine. porcine. ctc.; wild animals. are, in the.
`
`wild or in a zoological garden; and avian species. such as chickens. turkeys, quail. songbirds- etc.
`
`[0028]
`
`The term “purified” as used herein refers to material that has been isolated under
`
`conditions that reduce or eliminate the presence of uru‘elated materials,
`
`i.e., contaminants,
`
`including native materials from which the material
`
`is obtained. As used herein,
`
`the term
`
`“substantially free” is used operationally,
`
`in the context of analytical
`
`testing, of the material.
`
`a‘J‘i’t‘llifii't'iE-Tl
`
`
`HOSPIRA_00000905HOSPIRA_00000905
`HOSPIRA_00000905
`
`

`

`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 13 of 47 PageID #: 458
`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 13 of 47 PagelD #: 458
`{1.7 330.0359
`
`Preferably, purified material substantially free oi" contaminants is at
`
`least 95% pure; more
`
`preferably, at
`
`least 9TH: pure, and more preferably still at
`
`least 999-6 pure. Purity can be
`
`evaluated. for example, by chromatography or any other methods idiot-W1 in the art. in a Specific
`
`embodiment, purified means that
`
`the level of contaminants is below a level acceptable to
`
`regulatory authorities for safe administration to a htnnan or non~human animal.
`
`[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 reactions when administered
`
`to a human Preferably, as used herein, the term “pharmaceutically acceptable” means approved
`
`by a regulatory agency ol‘thc Federal or a state gox-enutmnt or listed in the US. Pharmacopcla or
`
`other generally recognized pharmacOpeia For use in animals, and more particularly in humans.
`
`The term “carrier”T refers to a diluent, adjuvant, cxcipient, diapersing agent or vehicle with which
`
`the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water
`
`and oils. For example, water, aqueous solutions, saline solutions, aqueous dextrose or glycerol
`
`solutions
`
`can be
`
`employed as carriers, particularly
`
`for
`
`injectable
`
`solutions. Suitable
`
`pharmaceutical carriers are described in. for example. “Remington's Phannaceutical Sciences"
`
`by Philip P. (ierhino, 21st Edition {or previous editions).
`
`{UU30I
`
`The term “pharmaceutical composition" as used in accordance with the present
`
`invention relates to compositions that can he l'ormulated in any conventional manner using one
`
`or more pharrnaceutieally 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 as
`
`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
`
`ugfltgr’day'. uglkgt’hr,
`
`titgt'kgr’day or mgt'ltglhr. The dosage is
`
`the amount
`
`til~ 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, e.g,., an absolute unit dose expressed in mg
`
`or pg of the agent.
`
`the dose depends on the concentration of the agent in the formulation, c,g._._
`
`in moles per liter (M), mass per volume (mi’vl, or mass per mass loam). The two terms are
`
`closely related, as a particular dosage results from the regimen of administration of a dose or
`
`doses ofthe formulation. The particular meaning in any case will be apparent from context.
`
`N Yul 1 T5 Tue 7 |
`
`
`HOSPIRA_00000906HOSPIRA_00000906
`HOSPIRA_00000906
`
`

`

`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 14 of 47 PageID #: 459
`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 14 of 47 PagelD #: 459
`07’735t10359
`
`[0032]
`
`The
`
`terms
`
`“therapeutically
`
`ell'ective
`
`dose,“
`
`“effectiy-e
`
`amount,”
`
`and
`
`"therapeutically effective amount" refer to an amount sufficient to produce the desired effect.
`
`H3033]
`
`in some non-limiting ctnbodimerits= a “therapeutically efleetivc- dose" means an
`
`amount suliicient to reduce by at least about 15%. preferably by at least 50%, more preferably by
`
`at least 90%, and most preferably prevent, a clinically significant deficit in the activity. function
`
`and response oi" the host. .-’\lternatively, a therapeutically ei‘l'ectii'e amount is sufficient to cause
`
`an improvement in a clinically significant condition in the host. These 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 of the subject, and other criteria, which can be readily
`
`determined according to standard good medical practice by those ofsltill in the art.
`
`{0034}
`
`In other non~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. a
`
`therapeutic response will generally be an induction of a desired effect. such as. for example,
`
`sedation or analgesia.
`
`[0035]
`
`The term “about” or “approximately” as used herein means within an acceptable
`
`error range for the particular value- as determined by one ofot‘dinat‘y 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 of up to 209%.
`
`preferably up to ltl‘l-a, more preferably up to 5%, and more preferany still up to 1% oi’a given
`
`value. Alternatively. particularly with respect to biological systems or processes, the term can
`
`mean within an order ot‘magnitude, preferably within 5~t‘old. and more preferably within E—tbld,
`
`ot'a value.
`
`4.2 Pharmaceutical Compositions
`
`{0036]
`
`The compounds and compositions of the invention may be formulated as
`
`plian'naceutical compositions by admixture with a phannaceutically acceptable carrier or
`
`escipient.
`
`in certain non-innitng embodiments. the compounds or compositions are provided in
`
`a therapeutically cftcctive amount to an animal, such as a mammal, preferably a human, in need
`
`ol‘trcatment therewith for inducing. a sedative, anxiolytic, analgesic. or anesthetic effect.
`
`\‘Yt'_'rf3'?57l.lt'.~? i
`
`
`HOSPIRA_00000907HOSPIRA_00000907
`HOSPIRA_00000907
`
`

`

`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 15 of 47 PageID #: 460
`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 15 of 47 PagelD #: 460
`t't??35tl_tl359
`
`[0037]
`
`in certain nen~limiting embodiments, dexrnedetomidine is
`
`formulated as
`
`a
`
`composition, wherein the dcxntcdetornidine is the only therapeutically active ingredient present
`
`in the composition.
`
`in another non—limiting embodiments. desmedetomidine is formulated as a
`
`composition. wherein the dexmedetornidine is formulated in combination with at least one or
`
`more other therapeutically active ingredient. The torrnulation is preferably suitable for parenteral
`
`administration,
`
`including. but not
`
`limited to.
`
`intravenous, subcutaneous,
`
`intramuscular and
`
`intraperitoneal administration; however. formulations suitable for other routes of administration
`
`Sttch as oral. intranasal. mucosal or transdermal are also contemplated.
`
`[0038]
`
`The pharmaceutical tormulations suitable for injectahle use. such as, for example.
`
`intravenous. subcutaneous.
`
`intramuscular and intraperitoncal administration,
`
`include sterile
`
`aqueous solutions or dispersions and sterile powders for the estemporancous preparation of
`
`sterile injectable solutions or dispersion. in all cases. the form can be sterile and can be fluid to
`
`the extent that easy syringability exists.
`
`it can be stable under the conditions of ntanulacture and
`
`storage and can he preserved against
`
`the contaminating action of microorganisms such as
`
`bacteria. and fungi. The carrier can be a solvent or dispersion medium containing. for example.
`
`water. saline. ethanol. polyol {tor example, glycerol. propylene glycol. and polyethylene glycol.
`
`and the like}. suitable mixtures thereof. and oils. The proper fluidity can be maintained, for
`
`example. by the use of a coating, such as lecithin. by the maintenance of the required particle size
`
`in the case of dispersion and by the use of surfactants.
`
`'l‘hc prcventions of the action of
`
`microorganisms can be brought about by various antibacterial and antifungal agents.
`
`for
`
`example. parabens. ehlorobutanol. phenol, benzyl alcohol. sorbic acid. and the liltc.
`
`[0039]
`
`in many cases. it will be preferable to include isotonic agents. for example. sugars
`
`or sodium chloride. Prolonged absorption of the injectablc compositions can be brought about by
`
`the uSe in the composititms of agents delaying absorption, for example. aluminum tnonosterate
`
`and gelatin. Sterile injectable solutions may be prepared by incorporating the dcxmedetomidinc
`
`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 vehicle 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 injectablc solutions.
`
`the
`
`preferred methods of preparation are vacuum drying. and the [revere—drying technique which yield
`
`NY-{JE 75TH“? l
`
`
`HOSPIRA_00000908HOSPIRA_00000908
`HOSPIRA_00000908
`
`

`

`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 16 of 47 PageID #: 461
`Case 1:15-cv-00697-RGA Document 39-9 Filed 01/29/16 Page 16 of 47 PagelD #: 461
`t)??350.tl359
`
`a powder of the active ingredient plus any additional desired ingredient from previously sterile-
`
`iiltered solution thereof.
`
`[00le
`
`Preferably the litnnulation may contain an excipient. Pharmaceutically acceptable
`
`excipients which may be included in the formulation are boilers such as citrate buffer. phosphate
`
`buffer, acetate buffer, and bicarbonate buffer; amino acids; urea; aleohols; ascorbic acid:
`
`phospliolipids; proteins. sueh as serum albumin. collagen, and ge atin; salts such as ED’IZA or
`
`EGTA, and sodium chloride; liposoines: polyvinylpyroilidone; sugars, such as destran, mttnnitol_.,
`
`sorbitol, and glycerol; propylene glycol and polyethylene glycol (cg, PEG—40th), PEG-6000};
`
`glycerol; glycine; lipids; preservatives; suspending agents; stabilizers; and