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`US008242158B 1
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`c12) United States Patent
`Roychowdhury et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,242,158 Bl
`Aug. 14, 2012
`
`(54) DEXMEDETOMIDINE PREMIX
`FORMULATION
`
`(75)
`
`Inventors: Priyanka Roychowdhury, San Rafael,
`CA (US); Robert A. Cedergren,
`Libertyville, IL (US)
`
`(73) Assignee: Hospira, Inc., Lake Forest, IL (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 13/343,672
`
`(22) Filed:
`
`Jan.4,2012
`
`(51)
`
`Int. Cl.
`A61K 311164
`(2006.01)
`(52) U.S. Cl. ........................................ 514/396; 514/816
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`5,344,840 A
`9/1994 Maze et al.
`6,716,867 B1
`4/2004 Aantaa et a!.
`2010/0197694 A1
`8/2010 Horn
`2011/0152271 A1
`6/2011 Horn
`201110230534 A1
`9/2011 Miyawaki et a!.
`
`FOREIGN PATENT DOCUMENTS
`wo wo 2010/031819
`3/2010
`
`OTHER PUBLICATIONS
`
`Precedex™
`Labeling:
`Draft
`HCL
`"Dexmedetomidine
`Dexmedetomidine Hydrochloride Injection," FDA approved label,
`dated Dec. 17, 1999, and available online Jul. 26, 2001, pp. 1-13.
`Downloaded from < http://www.accessdata.fda.gov/drugsatfda_
`docs/nda/99/21-038_Precedex_prntlbl.pdf> on Jan. 4, 2012.
`FDA Memorandum from Cynthia G. McCormick, M.D., Director,
`Divison on Anesthetics, Critical Care and Addiction Drug Products,
`dated Nov. 30, 1999, in connection with the Medical Reviews of the
`Precedes ( dexmedetomidine hydrochloride injection) Application
`No. 21-038 submitted to the FDA by Abbott Laboratories on Dec. 18,
`1998, and available on the FDA website Jul. 26, 2001. Downloaded
`on Mar. 7, 2012 from< http://www.accessdata.fda.gov/drugsatfda_
`docs/nda/99/21-038 Precedex.cfm>.
`
`Primary Examiner- James D Anderson
`Assistant Examiner- Gregg Polansky
`(74) Attorney, Agent, or Firm- Baker Botts LLP
`
`(57)
`
`ABSTRACT
`
`The presently disclosed subject matter relates to pharmaceu(cid:173)
`tical compositions comprising dexmedetomidine or a phar(cid:173)
`maceutically acceptable salt thereof wherein the composition
`is formulated as a liquid for parenteral administration to a
`subject, and wherein the composition is disposed within a
`sealed container as a premixture. The pharmaceutical com(cid:173)
`positions can be used, for example, in perioperative care of a
`patient or for sedation.
`
`4 Claims, No Drawings
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`1
`DEXMEDETOMIDINE PREMIX
`FORMULATION
`
`I. FIELD OF THE INVENTION
`
`The present invention relates to patient-ready, premixed
`formulations of dexmedetomidine, or a pharmaceutically
`acceptable salt thereof, that can be used, for example, in
`perioperative care of a patient or for sedation.
`
`2. BACKGROUND OF THE INVENTION
`
`Racemic 4- [1 -(2,3 -dimethylphenyl)ethyl]-1H-imidazole,
`which is known under the name medetomidine, is a selective
`and potent otz-adrenoceptor agonist. Medetomidine has been
`used as an antihypertensive agent and as a sedative-analgesic
`agent. It has further been observed that this compound also
`possesses anxiolytic effects and can therefore be used in the
`treatment of general anxiety, panic disorder and various types
`of withdrawal symptoms.
`The d-enantiomer of medetomidine, the generic name of
`which is dexmedetomidine,
`is described in U.S. Pat. No.
`4,910,214 as an otz-adrenoceptor agonist for general seda-
`tion/analgesia and the treatment of hypertension or anxiety.
`U.S. Pat. Nos. 5,344,840 and 5,091,402 discuss dexmedeto-
`midine in perioperative and epidural use, respectively. For
`example, when used in perioperative care, dexmedetomidine
`can reduce the amount of anesthetic necessary to anesthetize
`a patient. Additionally, U.S. Pat. No. 5,304,569 discusses the
`use of dexmedetomidine in treating glaucoma, and U.S. Pat.
`No. 5,712,301 discusses the use of dexmedetomidine for
`preventing neurodegeneration caused by ethanol consump-
`tion. Furthermore, U.S. Pat. No. 6,716,867 discloses methods
`of sedating a patient while in an intensive care unit by admin-
`istering dexmedetomidine, or a pharmaceutically acceptable
`salt thereof, to the patient.
`Dexmedetomidine can be administered to a patient in a
`variety of ways. For example, U.S. Pat. Nos. 4,544,664 and
`4,910,214 disclose the administration of dexmedetomidine
`via parenteral, intravenous, and oral routes. U.S. Pat. No.
`4,670,455 describes intramuscular and intravenous adminis-
`tration, while U.S. Pat. Nos. 5,124,157 and 5,217,718
`describe a method and device for administering dexmedeto-
`midine through the skin. Additionally, U.S. Pat. No. 5,712,
`301 states that dexmedetomidine can be administered trans-
`
`mucosally.
`To date, dexmedetomidine has been provided as a concen-
`trate that must be diluted prior to administration to a patient.
`The requirement of a dilution step in the preparation of the
`dexmedetomidine formulation is associated with additional
`
`costs and inconvenience, as well as the risk of possible con-
`tamination or overdose due to human error. Thus, a dexme-
`detomidine formulation that avoids the expense, inconve-
`nience, delay and risk of contamination or overdose would
`provide significant advantages over currently available con-
`centrated formulations.
`
`3. SUMMARY OF THE INVENTION
`
`The present invention relates to premixed pharmaceutical
`compositions of dexmedetomidine, 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 com-
`position comprising dexmedetomidine.
`
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`the premixed
`In certain non-limiting embodiments,
`dexmedetomidine composition is a liquid comprising dexme-
`detomidine, or a pharmaceutically acceptable salt thereof, at
`a concentration of between about 0.05 ug/mL and about 15
`ug/mL.
`In other non-limiting embodiments, the premixed dexme-
`detomidine composition is a liquid comprising dexmedeto-
`midine at a concentration of about 4 ug/mL.
`In other non-limiting embodiments, the premixed dexme-
`detomidine composition comprises dexmedetomidine mixed
`or dissolved in a sodium chloride saline solution.
`
`In certain embodiments, the premixed dexmedetomidine
`composition is disposed within a sealed container or vessel.
`In certain embodiments, the dexmedetomidine composi-
`tion is disposed in a container or vessel and is formulated as
`a premixture.
`In certain embodiments, the premixed dexmedetomidine
`composition is disposed within a sealed container as a total
`volume of about 20 mL, 50 mL or 100 mL.
`the premixed
`In certain non-limiting embodiments,
`dexmedetomidine composition of the present invention com-
`prises dexmedetomidine, or a pharmaceutically acceptable
`salt thereof, at a concentration of between about 0.05 ug/mL
`and about 15 ug/mL, and sodium chloride at a concentration
`of between about 0.01 and about 2.0 weight percent.
`In other non-limiting embodiments, the premixed dexme-
`detomidine composition of the present invention comprises
`dexmedetomidine, or a pharmaceutically acceptable salt
`thereof, at a concentration of about 4 ug/mL and sodium
`chloride at a concentration of about 0.90 weight percent.
`In certain embodiments, the compositions of the present
`invention are formulated as a pharmaceutical composition for
`administration to a subject for sedation, analgesia or treat-
`ment of anxiety or hypertension.
`The present invention also relates to the perioperative treat-
`ment of a patient to reduce the response of the autonomic
`nervous system to stimuli during an operation by administer-
`ing a dexmedetomidine composition of the invention.
`In other non-limiting embodiments, the dexmedetomidine
`compositions of the present invention can be administered as
`an anxiolytic 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.
`In other non-limiting embodiments, the dexmedetomidine
`compositions of the present invention can be administered as
`a sedative. In certain embodiments, the composition is admin-
`istered preoperatively to potentiate the effect ofan anesthetic,
`wherein administration of the composition reduces the
`amount of anesthetic required to achieve a desired level of
`anesthesia.
`
`In certain embodiments of the present invention, the pre-
`mixed dexmedetomidine
`composition is
`administered
`parenterally as a liquid, orally, transdermally, intravenously,
`intramuscularly, subcutaneously, or via an implantable pump.
`
`4. DETAILED DESCRIPTION
`
`The present invention is based in part on the discovery that
`dexmedetomidine prepared in a premixed formulation that
`does not require reconstitution or dilution prior to adminis-
`tration to a patient, remains stable and active after prolonged
`storage. Such premixed formulations therefore avoid the co st,
`inconvenience, and risk ofcontamination or overdose that can
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`3
`be associated with reconstituting or diluting a concentrated
`dexmedetomidine formulation prior to administration to a
`patient.
`For clarity and not by way of limitation, this detailed
`description is divided into the following sub-portions:
`(4.1) Definitions;
`(4.2) Pharmaceutical formulations; and
`(4.3) Methods of using premixed dexmedetomidine com-
`positions.
`
`4.1 Definitions
`
`The terms used in this specification generally have their
`ordinary meanings in the art, within the context of this inven-
`tion and in the specific context where each term is used.
`Certain terms are discussed below, or elsewhere in the speci-
`fication, to provide additional guidance to the practitioner in
`describing the compositions and methods ofthe invention and
`how to make and use them.
`
`According to the present invention, the term “dexmedeto-
`midine” as used herein refers to a substantially pure, optically
`active dextrorotary stereoisomer ofmedetomidine, as the free
`base or pharmaceutically acceptable salt. In one, non-limiting
`embodiment, dexmedetomidine has the formula (S)-4-[1-(2,
`3-dimethylphenyl)ethyl]-3H-imidazole. A pharmaceutically
`acceptable salt of dexmedetomidine can include inorganic
`acids such as hydrochloric acid, hydrobromic acid, sulfuric
`acid, nitric acid, phosphoric acid and the like, and organic
`acids such as acetic acid, propionic acid, glycolic acid, pyru-
`vic acid, oxalic acid, malic acid, malonic acid, succinic acid,
`maleic acid, fumaric acid, tartaric acid, citric acid, benzoic
`acid, cinnamic acid, mandelic acid, methanesulfonic acid,
`ethanesulfonic acid, p-toluenesulfonic acid, and salicylic
`acid. Preferably, the dexmedetomidine salt is dexmedetomi-
`dine HCl. In other non-limiting embodiments, dexmedetomi-
`dine comprises the structure depicted below in Formula 1:
`
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`Formula 1
`
`40
`
`CH3
`
`CH3
`
`CH3
`
`N
`
`H
`
`</ |N
`
`The terms “premix” or “premixture” as used herein refers
`to a pharmaceutical formulation that does not require recon-
`stitution or dilution prior to administration to a patient. For
`example, in contrast to non-premixed formulations of dexme-
`detomidine, 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.
`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 inven-
`tion are “ready to use” upon removing the compositions from
`a sealed container or vessel.
`
`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 ves sel as a one dose per container or vessel
`formulation.
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`4
`
`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 com-
`pounds and compositions of the invention have application in
`veterinary medicine as well, e.g., for the treatment of domes-
`ticated species such as canine, feline, and various other pets;
`farm animal species such as bovine, equine, ovine, caprine,
`porcine, etc.; wild animals, e.g., in the wild or in a zoological
`garden; and avian species, such as chickens, turkeys, quail,
`songbirds, etc.
`The term “purified” as used herein refers to material that
`has been isolated under conditions that reduce or eliminate
`
`i.e., contaminants,
`the presence of unrelated materials,
`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 mate-
`rial. Preferably, purified material substantially free of con-
`taminants is at least 95% pure; more preferably, at least 97%
`pure, and more preferably still at least 99% pure. Purity can be
`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 accept-
`able to regulatory authorities for safe administration to a
`human or non-human animal.
`
`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. Prefer-
`
`ably, as used herein, the term “pharmaceutically acceptable”
`means approved by a regulatory agency of the Federal or a
`state government or listed in the U.S. Pharmacopeia or other
`generally recognized pharmacopeia for use in animals, and
`more particularly in humans. The term “carrier” refers to a
`diluent, adjuvant, excipient, dispersing 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 Phar-
`maceutical Sciences” by Philip P. Gerbino, 21st Edition (or
`previous editions).
`The term “pharmaceutical composition” as used in accor-
`dance with the present invention relates to compositions that
`can be formulated in any conventional manner using one or
`more pharmaceutically acceptable carriers or excipients. A
`“pharmaceutically acceptable” carrier or excipient, as used
`herein, means approved by a regulatory agency of the Federal
`or a state government, or as listed in the U.S. Pharmacopoeia
`or other generally recognized pharmacopoeia for use in mam-
`mals, and more particularly in humans.
`The term “dosage” is intended to encompass a formulation
`expressed in terms of ug/kg/day, ug/kg/hr, mg/kg/day or
`mg/kg/hr. The dosage is the amount of an ingredient admin-
`istered 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 ug ofthe agent. The dose depends on the concentration
`of the agent in the formulation, e.g., in moles per liter (M),
`mass per volume (m/v), or mass per mass (m/m). The two
`terms are closely related, as a particular dosage results from
`the regimen of administration of a dose or doses of the for-
`mulation. The particular meaning in any case will be apparent
`from context.
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`effective
`The terms “therapeutically effective dose,
`amount,” and “therapeutically effective amount” refer to an
`amount sufficient to produce the desired effect.
`In some non-limiting embodiments, a “therapeutically
`effective dose” means an amount sufficient 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 of the
`host. Alternatively, a therapeutically effective amount is suf-
`ficient 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 15
`those of skill in the art.
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`isms such as bacteria and fungi. The carrier can be a solvent
`or dispersion medium containing, for example, water, saline,
`ethanol, polyol (for 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. The preventions of the action of microor-
`ganisms can be brought about by various antibacterial and
`antifungal agents, for example, parabens, chlorobutanol, phe-
`nol, benzyl alcohol, sorbic acid, and the like.
`In many cases, it will be preferable to include isotonic
`agents, for example, sugars or sodium chloride. Prolonged
`absorption of the injectable compositions can be brought
`about by the use in the compositions of agents delaying
`absorption, for example, aluminum monosterate and gelatin.
`Sterile injectable solutions may be prepared by incorporating
`the dexmedetomidine in the required amounts in the appro-
`priate solvent with various of the other ingredients enumer-
`ated above, as required, followed by filter or terminal steril-
`ization. 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 inj ectable solu-
`tions, the preferred methods of preparation are vacuum dry-
`ing and the freeze-drying technique which yield a powder of
`the active ingredient plus any additional desired ingredient
`from previously sterile-filtered solution thereof.
`Preferably the formulation may contain an excipient. Phar-
`maceutically acceptable excipients which may be included in
`the formulation are buffers such as citrate buffer, phosphate
`buffer, acetate buffer, and bicarbonate buffer; amino acids;
`urea; alcohols; ascorbic acid; phospholipids; proteins, such as
`serum albumin, collagen, and gelatin; salts such as EDTA or
`EGTA, and sodium chloride; liposomes; polyvinylpyrolli-
`done; sugars, such as dextran, mannitol, sorbitol, and glyc-
`erol; propylene glycol and polyethylene glycol (e.g., PEG-
`4000, PEG-6000); glycerol; glycine; lipids; preservatives;
`suspending agents; stabilizers; 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-limiting examples of stabilizers include antioxi-
`dants. Buffer systems for use with the formulations include
`citrate; acetate; bicarbonate; and phosphate buffers.
`The formulation also may contain a non-ionic detergent.
`Preferred non-ionic detergents include Polysorbate 20,
`Polysorbate 80, Triton X-100, Triton X-114, Nonidet P-40,
`Octyl ot-glucoside, Octyl B-glucoside, Brij 35, Pluronic, and
`Tween 20.
`
`In other non-limiting embodiments a therapeutic response
`may be any response that a user (e.g., a clinician) will recog-
`nize as an effective response to the therapy. Thus, a therapeu-
`tic response will generally be an induction of a desired effect, 20
`such as, for example, sedation or analgesia.
`The term “about” or “approximately” as used herein means
`within an acceptable error range for the particular value as
`determined by one of ordinary skill in the art, which will
`depend in part on how the value is measured or determined, 25
`i.e., the limitations of the measurement system. For example,
`“about” can mean within 3 or more than 3 standard devia-
`
`tions, per the practice in the art. Alternatively, “about” can
`mean a range of up to 20%, preferably up to 10%, more
`preferably up to 5%, and more preferably still up to 1% of a 30
`given value. Alternatively, particularly with respect to bio-
`logical systems or processes, the term can mean within an
`order of magnitude, preferably within 5-fold, and more pref-
`erably within 2-fold, of a value.
`
`35
`
`4.2 Pharmaceutical Compositions
`
`The compounds and compositions of the invention may be
`formulated as pharmaceutical compositions by admixture
`with a pharmaceutically acceptable carrier or excipient. In 40
`certain non-limiting embodiments, the compounds or com-
`positions are provided in a therapeutically effective amount to
`an animal, such as a mammal, preferably a human, in need of
`treatment therewith for inducing a sedative, anxiolytic, anal-
`gesic, or anesthetic effect.
`In certain non-limiting embodiments, dexmedetomidine is
`formulated as a composition, wherein the dexmedetomidine
`is the only therapeutically active ingredient present in the
`composition. In another non-limiting embodiments, dexme-
`detomidine is formulated as a composition, wherein the 50
`dexmedetomidine is formulated in combination with at least
`
`45
`
`one or more other therapeutically active ingredient. The for-
`mulation is preferably suitable for parenteral administration,
`including, but not
`limited to,
`intravenous, subcutaneous,
`intramuscular and intraperitoneal administration; however, 55
`formulations suitable for other routes of administration such
`as oral, intranasal, mucosal or transdermal are also contem-
`plated.
`The pharmaceutical formulations suitable for injectable
`use, such as, for example, intravenous, subcutaneous, intra- 60
`muscular and intraperitoneal administration, include sterile
`aqueous solutions or dispersions and sterile powders for the
`extemporaneous preparation of sterile inj ectable solutions or
`dispersion. In all cases, the form can be sterile and canbe fluid
`to the extent that easy syringability exists. It can be stable 65
`under the conditions of manufacture and storage and can be
`preserved against the contaminating action of microorgan-
`
`The parenteral formulations ofthe present invention can be
`sterilized. Non-limiting examples of sterilization techniques
`include filtration through a bacterial-retaining filter, terminal
`sterilization, incorporation of sterilizing agents, irradiation,
`and heating.
`The route of administration may be oral or parenteral,
`including intravenous, subcutaneous, intra-arterial, intraperi-
`toneal, ophthalmic,
`intramuscular, buccal, rectal, vaginal,
`intraorbital, intracerebral, intradermal, intracranial, intraspi-
`nal, intraventricular, intrathecal, intracisternal, intracapsular,
`intrapulmonary, intranasal, transmucosal, transdermal, or via
`inhalation.
`
`Administration of the above-described parenteral formu-
`lations may be by periodic injections of a bolus of the prepa-
`ration, or may be administered by intravenous or intraperito-
`neal administration from a reservoir which is external (e. g., an
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`intravenous bag) or internal (e.g., a bioerodable implant, a
`bioartificial or organ). See, e.g., US. Pat. Nos. 4,407,957 and
`5,798,113, each incorporated herein by reference in their
`entireties. Intrapulmonary delivery methods and apparatus
`are described, for example,
`in US. Pat. Nos. 5,654,007,
`5,780,014, and 5,814,607, each incorporated herein by refer-
`ence in their entireties. Other useful parenteral delivery sys-
`tems include ethylene-vinyl acetate copolymer particles,
`osmotic pumps, implantable infusion systems, pump deliv-
`ery, encapsulated cell delivery, liposomal delivery, needle-
`delivered injection, needle-less injection, nebulizer, aeoro-
`solizer, electroporation, and transdermal patch. Needle-less
`injector devices are described in US. Pat. Nos. 5,879,327;
`5,520,639; 5,846,233 and 5,704,911, the specifications of
`which are herein incorporated herein by reference in their
`entireties. Any of the formulations described herein can be
`administered in these methods.
`
`In yet another non-limiting embodiment, the therapeutic
`compound can be delivered in a controlled or sustained
`release system. For example, a compound or composition
`may be administered using intravenous infusion, an implant-
`able osmotic pump, a transdermal patch, liposomes, or other
`modes of administration. In one embodiment, a pump may be
`used (see Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201;
`Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989,
`N. Engl. J. Med. 321:574). In another embodiment, poly-
`meric materials can be used (see Langer and Wise eds., 1974,
`Medical Applications of Controlled Release, CRC Press:
`Boca Raton, Fla.; Smolen and Ball eds., 1984, Controlled
`Drug Bioavailability, Drug Product Design and Performance,
`Wiley, N.Y.; Ranger and Peppas, 1983, J. Macromol. Sci.
`Rev. Macromol. Chem., 23:61; Levy et al., 1985, Science
`228: 190; During et al., 1989, Ann. Neurol., 25:351; Howard
`et al., 9189, J. Neurosurg. 71:105). In yet another embodi-
`ment, a controlled release system can be placed in proximity
`of the therapeutic target, i.e., the brain, thus requiring only a
`fraction of the systemic dose (see, e.g., Goodson, 1984, in
`Medical Applications of Controlled Release, Vol. 2, pp. 115-
`138).
`the premixed
`In certain non-limiting embodiments,
`dexmedetomidine composition comprises dexmedetomidine,
`or a pharmaceutically acceptable salt thereof, at a concentra-
`tion of between about 0.005 ug/mL and about 100 ug/mL, or
`between about 0.005 ug/mL and about 50 ug/mL, or between
`about 0.005 ug/mL and about 25 ug/mL, or between about
`0.005 ug/mL and about 15 ug/mL, or between about 0.005
`ug/mL and about 10 ug/mL, or between about 0.005 ug/mL
`and about 7 ug/mL, or between about 0.005 ug/mL and about
`5 ug/mL, or between about 0.005 ug/mL and about 4 ug/mL,
`or between about 0.005 ug/mL and about 3 ug/mL, or
`between about 0.005 ug/mL and about 2 ug/mL, or between
`about 0.005 ug/mL and about 1 ug/mL, or between about
`0.005 ug/mL and about 0.5 ug/mL, or between about 0.005
`ug/mL and about 0.05 ug/mL.
`the premixed
`In certain non-limiting embodiments,
`dexmedetomidine composition comprises dexmedetomidine,
`or a pharmaceutically acceptable salt thereof, at a concentra-
`tion of between about 3.5 ug/mL and about 4.5 ug/mL, or
`between about 3 ug/mL and about 5 ug/mL, or between about
`2.5 ug/mL and about 5.5 ug/mL, or between about 2 ug/mL
`and about 6 ug/mL, orbetween about 1.5 ug/mL and about 6.5
`ug/mL, or between about 1 ug/mL and about 7 ug/mL, or
`between about 0.5 ug/mL and about 10 ug/mL.
`In certain non-limiting embodiments,
`the premixed
`dexmedetomidine composition comprises dexmedetomidine
`at a concentration of about 0.5 ug/mL, or about 1 ug/mL, or
`about 1.5 ug/mL, or about 2 ug/mL, or about 2.5 ug/mL, or
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`about 3 ug/mL, or about 3.5 ug/mL, or about 4 ug/mL, or
`about 4.5 ug/mL, or about 5 ug/mL, or about 5.5 ug/mL, or
`about 6 ug/mL, or about 6.5 ug/mL, or about 7 ug/mL, or
`about 7.5 ug/mL, or about 8 ug/mL, or about 8.5 ug/mL, or
`about 9 ug/mL, or about 9.5 ug/mL, or about 10 ug/mL, or
`about 10.5 ug/mL, or about 11 ug/mL, or about 11.5 ug/mL,
`or about 12 ug/mL, or about 12.5 ug/mL, or about 13 ug/mL,
`or about 13.5 ug/mL, or about 14 ug/mL, or about 14.5
`ug/mL, or about 15 ug/mL, or about 15.5 ug/mL, or about 16
`ug/mL, or about 16.5 ug/mL, or about 17 ug/mL, or about
`17.5 ug/mL, or about 18 ug/mL, or about 18.5 ug/mL or about
`19 ug/mL, or about 19.5 ug/mL, or about 20 ug/mL.
`In certain non-limiting embodiments,
`the premixed
`dexmedetomidine composition comprises dexmedetomidine
`at a concentration of about 4 ug/mL.
`the premixed
`In certain non-limiting embodiments,
`dexmedetomidine composition is formulated as a liquid.
`In certain non-limiting embodiments,
`the premixed
`dexmedetomidine composition is formulated at a pH 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 dexmedetomidine composition
`is formulated at a pH of between about 2 and about 10, or
`between about 4 and about 8, or between about 4 and about 7.
`In other non-limiting embodiments, the premixed dexme-
`detomidine composition is formulated at a pH of between
`about 4.7 and about 6.2. In a preferred non-limiting embodi-
`ment, the premixed dexmedetomidine composition is formu-
`lated at a pH of between about 4.5 and about 7.0.
`In other non-limiting embodiments, the premixed dexme-
`detomidine composition comprises dexmedetomidine mixed
`or dissolved in a sodium chloride saline solution. The saline
`
`solution can comprise sodium chloride present at a concen-
`tration of between about 0.05 weight percent and about 10
`weight percent, or between about 0.05 weight percent and
`about 5 weight percent, or between about 0.05 weight percent
`and about 3 weight percent, or between about 0.05 weight
`percent and about 2 weight percent, or between about 0.05
`weight percent and about 1 weight percent. In one preferred,
`non-limiting embodiment, the sodium chloride is present at a
`concentration of about 0.9 weight percent.
`In certain embodiments, the weight percent of the saline
`solution is a percent weight/weight of the premix composi-
`tion. In certain embodiments, the weight percent of the saline
`solution is a percent weight/volume of the premix composi-
`tion.
`
`the premixed
`In certain non-limiting embodiments,
`dexmedetomidine composition of the present invention com-
`prises dexmedetomidine, or a pharmaceutically acceptable
`salt thereof, at a concentration of between about 0.05 ug/mL
`and about 15 ug/mL, and sodium chloride at a concentration
`of between about 0.01 and about 2.0 weight percent.
`In other non-limiting embodiments, the premixed dexme-
`detomidine composition of the present invention comprises
`dexmedetomidine, or a pharmaceutically acceptable salt
`thereof, at a concentration of about 4 ug/mL and sodium
`chloride at a concentration of about 0.90 weight percent.
`In one non-limiting example, the 0.9% NaCl solution is
`formulated by mixing 9.0 g NaCl/1000 mL of water. In cer-
`tain embodiments, the premix compositions of the present
`invention are formulated by adding 0. 1 1 8 g dexmedetomidine
`HCl plus 9.0 g NaCl into the same 1000 mL of water. The
`solution can then be mixed with addition 0.9% NaCl solution
`to achieve a desired concentration of dexmedetomidine, for
`example, 4 ug/mL.
`
`CC-JA007
`
`CC-JA007
`
`
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`Case 1:15-cv-00697-RGA Document 45-1 Filed 04/28/16 Page 8 of 43 PageID #: 615
`Case 1:15-cv-OO697-RGA Document 45-1 Filed 04/28/16 Page 8 of 43 PagelD #: 615
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`US 8,242,158 B1
`
`9
`the premixed
`In certain non-limiting embodiments,
`dexmedetomidine composition of the present invention is
`disposed in a container or vessel that can ma