077350.0364
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`METHODS OF TREATMENT USING A DEXMEDETOMIDINE PREMIX
`FORMULATION
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`This application is a continuation of and claims priority under 35 U.S.C. § 120 to
`
`U.S. Serial No. 13/541,524 filed July 3, 2012, which is a continuation of U.S. Serial No.
`
`13/343,672 filed January 4, 2012, now U.S. Patent No. 8,242,158, the contents of each of which
`
`are hereby incorporated by reference in their entireties, and to each of which priority is claimed.
`
`1. FIELD OF THE INVENTION
`
`(0001]
`
`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
`
`[0002]
`
`Racemic 4-[1-(2,3-dimethylphenyl)ethyl]-lH-imidazole, which is known under
`
`the name medetomidine, is a selective and potent a2-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.
`
`[0003]
`
`The d-enantiomer of medetomidine,
`
`the generic name of which
`
`is
`
`dexmedetomidine, is described in U.S. Pat. No. 4,910,214 as an a 2-adrenoceptor agonist for
`
`general sedation/analgesia and the treatment of hypertension or anxiety. U.S. Pat. Nos.
`
`5,344,840 and 5,091,402 discuss dexmedetomidine
`
`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
`
`consumption. Furthermore, U.S. Pat. No. 6,716,867 discloses methods of sedating a patient
`
`while in an intensive care unit by administering dexmedetomidine, or a pharmaceutically
`
`acceptable salt thereof, to the patient.
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`[0004]
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`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 administration, while U.S. Pat. Nos. 5,124,157 and 5,217,718
`
`describe a method and device for administering dexmedetomidine through the skin. Additionally,
`
`U.S. Pat. No. 5,712,301 states that dexmedetomidine can be administered transmucosally.
`
`[0005]
`
`To date, dexmedetomidine has been provided as a concentrate 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 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.
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`3. SUMMARY OF THE INVENTION
`
`[0006]
`
`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
`
`composition comprising dexmedetomidine.
`
`[0007]
`
`In
`
`certain non-limiting
`
`embodiments,
`
`the premixed dexmedetomidine
`
`composition is a liquid comprising dexmedetornidine, or a pharmaceutically acceptable salt
`
`thereof, at a concentration of between about 0.05 µg/rnL and about 15 µg/mL.
`
`[0008]
`
`In other non-limiting embodiments, the premixed dexmedetornidine composition
`
`is a liquid comprising dexmedetomidine at a concentration of about 4 µg/mL.
`
`[0009]
`
`In other non-limiting embodiments, the premixed dexrnedetomidine composition
`
`comprises dexmedetomidine mixed or dissolved in a sodium chloride saline solution.
`
`[0010]
`
`In certain embodiments, the premixed dexmedetomidine composition is disposed
`
`within a sealed container or vessel.
`[0011]
`
`In certain embodiments, the dexmedetomidine composition is disposed m a
`
`container or vessel and is formulated as a prernixture.
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`[0012]
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`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.
`
`[0013]
`
`In
`
`certain non-limiting
`
`embodiments,
`
`the premixed dexmedetomidine
`
`composition of the present invention comprises dexmedetomidine, or a pharmaceutically
`
`acceptable salt thereof, at a concentration of between about 0.05 µg/mL and about 15 µg/mL,
`
`and sodium chloride at a concentration of between about 0.01 and about 2.0 weight percent.
`
`[0014]
`
`In other non-limiting embodiments, the premixed dexmedetomidine composition
`
`of the present invention comprises dexmedetomidine, or a pharmaceutically acceptable salt
`
`thereof, at a concentration of about 4 µg/mL 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 of anxiety or hypertension.
`[0016]
`
`The 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
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`administering a dexmedetomidine composition of the invention.
`
`[0017]
`
`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.
`[0018]
`
`In other non-limiting embodiments, the dexmedetomidine compositions of the
`
`present invention can be administered as a sedative. In certain embodiments, the composition is
`
`administered preoperatively to potentiate the effect of an anesthetic, wherein administration of
`
`the composition reduces the amount of anesthetic required to achieve a desired level of
`
`anesthesia.
`
`[0019]
`composition is administered parenterally as a liquid, orally, transdermally, intravenously,
`
`In certain embodiments of the present invention, the premixed dexmedetomidine
`
`intramuscularly, subcutaneously, or via an implantable pump.
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`4. DETAILED DESCRIPTION
`
`[0020]
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`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
`
`administration to a patient, remains stable and active after prolonged storage. Such premixed
`
`formulations therefore avoid the cost, inconvenience, and risk of contamination or overdose that
`
`can be associated with reconstituting or diluting a concentrated dexrnedetomidine formulation
`
`prior to administration to a patient.
`
`[0021)
`
`For clarity and not by way of limitation, this detailed description is divided into
`
`the following sub-portions:
`
`( 4.1) Definitions;
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`( 4.2) Phannaceutical formulations; and
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`(4.3) Methods of using premixed dexmedetomidine compositions.
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`4.1 Definitions
`
`[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 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 invention, the term "dexmedetomidine" as used herein
`
`refers to a substantially pure, optically active dextrorotary stereoisomer of medetomidine, as the
`
`free base or pharmaceutically acceptable salt.
`
`In one, non-limiting embodiment,
`
`dexmedetornidine has
`
`the formula (S)-4-[l-(2,3-dirnethylphenyl)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, pyruvic 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 dexmedetomidine HCl. In other
`
`non-limiting embodiments, dexmedetomidine comprises the structure depicted below in Formula
`
`I:
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`CH;
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`CH;
`
`CHs
`
`Formula |
`
`N
`
`NH
`
`[0024]
`
`The terms “premix” 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 suitable 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 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.
`
`[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, a non-human
`
`mammal or a non-human animal. Although the animal subject
`
`is preferably a human,
`
`the
`
`compounds and compositions of the invention have application in veterinary medicine as well,
`
`e.g., for the treatment of domesticated 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.
`
`[0028]
`
`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.c., 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.
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`Preferably, purified material substantially free of contaminants 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 acceptable to
`
`regulatory authorities for safe administration to a human 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 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 Pharmaceutical Sciences"
`
`by Philip P. Gerbino, 21st 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 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 mammals, and more particularly in humans.
`
`(0031]
`
`The term "dosage" is intended to encompass a formulation expressed in terms of
`
`µg/kg/day, µg/kg/hr, mg/kg/day or mg/kg/hr. 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, e.g., an absolute unit dose expressed in mg
`
`or µg of the 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 formulation. The particular meaning in any case will be apparent from context.
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`[0032]
`
`The
`
`terms
`
`"therapeutically effective dose,"
`
`"effective
`
`amount,"
`
`and
`
`"therapeutically effective amount" refer to an amount sufficient to produce the desired effect.
`
`[0033]
`
`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 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 of skill in the art.
`
`[0034]
`
`In other non-limiting embodiments a therapeutic response may be any response
`
`that a user (e.g., 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 of ordinary 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 20%,
`
`preferably up to 10%, more preferably up to 5%, and more preferably still up to 1 % of a given
`
`value. Alternatively, particularly with respect to biological systems or processes, the term can
`
`mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold,
`
`of a value.
`
`4.2 Pharmaceutical Compositions
`
`[0036]
`
`The compounds and compositions of the invention may be formulated as
`
`pharmaceutical compositions by admixture with a pharmaceutically acceptable carrier or
`
`excipient. In certain non-limiting embodiments, the compounds or compositions 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, analgesic, or anesthetic effect.
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`[0037]
`
`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, dexmedetomidine is formulated as a
`
`composition, wherein the dexmedetomidine is formulated in combination with at least one or
`
`more other therapeutically active ingredient. The formulation 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
`
`such as oral, intranasal, mucosa! or transdermal are also contemplated.
`
`[0038]
`
`The pharmaceutical formulations suitable for injectable use, such as, for example,
`
`intravenous, subcutaneous, intramuscular and intraperitoneal administration, include sterile
`
`aqueous solutions or dispersions and sterile powders for the extemporaneous 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 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 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
`
`microorganisms can be brought about by various antibacterial and antifungal agents, for
`
`example, parabens, chlorobutanol, phenol, benzyl alcohol, sorbic acid, and the like.
`
`[0039]
`
`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 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 injectable solutions, the
`
`preferred methods of preparation are vacuum drying and the freeze-drying technique which yield
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`a powder of the active ingredient plus any additional desired ingredient from previously sterile(cid:173)
`
`filtered solution thereof.
`
`{0040J
`
`Preferably the formulation may contain an excipient. Pharmaceutically 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; polyvinylpyrollidone; sugars, such as dextran, mannitol,
`
`sorbitol, and glycerol; 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(cid:173)
`
`limiting examples of stabilizers include antioxidants. Buffer systems for use with the
`
`formulations include citrate; acetate; bicarbonate; and phosphate buffers.
`
`[0041]
`
`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 a-glucoside, Octyl p-glucoside, Brij 35, Pluronic, and Tween 20.
`
`[0042]
`
`The parenteral formulations of the present invention can be sterilized. Non(cid:173)
`
`Iimiting examples of sterilization 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, intra-arterial, intraperitoneal, ophthalmic, intramuscular, buccal, rectal, vaginal,
`
`intraorbital, intracerebral, intradermal, intracranial, intraspinal, intraventricular, intrathecal,
`
`intracisternal, intracapsular, intrapulmonary, intranasal, transmucosal, transdermal, or via
`
`inhalation.
`
`[0044]
`
`Administration of the above-described parenteral formulations may be by periodic
`
`injections of a bolus of the preparation, or may be administered by intravenous or intraperitoneal
`
`administration from a reservoir which is external (e.g., an intravenous bag) or internal (e.g., a
`
`bioerodable implant, a bioartificial or organ). See, e.g., U.S. 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 U.S. Pat. Nos. 5,654,007, 5,780,014, and 5,814,607,
`
`each incorporated herein by reference in their entireties. Other useful parenteral delivery systems
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`include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion
`
`systems, pump delivery, encapsulated cell delivery, liposomal delivery, needle-delivered
`
`injection, needle-less injection, nebulizer, aeorosolizer, electroporation, and transdermal patch.
`
`Needle-less injector devices are described in U.S. 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.
`
`[0045)
`
`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 implantable 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, polymeric 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.
`
`Neural., 25:351; Howard et al., 9189, J.Neurosurg. 71:105). In yet another embodiment, 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).
`
`[0046]
`
`In
`
`certain non-limiting
`
`embodiments,
`
`the premixed dexmedetomidine
`
`composition comprises dexmedetomidine, or a pharmaceutically acceptable salt thereof, at a
`
`concentration of between about 0.005 µg/mL and about 100 µg/mL, or between about 0.005
`
`µg/mL and about 50 µg/mL, or between about 0.005 µg/mL and about 25 µg/mL, or between
`
`about 0.005 µg/mL and about 15 µg/mL, or between about 0.005 µg/mL and about 10 µg/mL, or
`
`between about 0.005 µg/mL and about 7 µg/mL, or between about 0.005 µg/mL and about 5
`
`µg/mL, or between about 0.005 µg/mL and about 4 µg/mL, or between about 0.005 µg/mL and
`
`about 3 µg/mL, or between about 0.005 µg/mL and about 2 µg/mL, or between about 0.005
`
`µg/mL and about 1 µg/mL, or between about 0.005 µg/mL and about 0.5 µg/mL, or between
`
`about 0.005 µg/mL and about 0.05 µg/mL.
`
`NY02:758386. l
`
`- 10 -
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1051 – Page 10
`
`

`

`077350.0364
`
`[0047J
`
`In certain non-limiting embodiments,
`
`the premixed dexmedetomidine
`
`composition comprises dexmedetomidine, or a pharmaceutically acceptable salt thereof, at a
`
`concentration of between about 3.5 µg/mL and about 4.5µg/mL, or between about 3 µg/mL and
`
`about 5 µg/mL, or between about 2.5 µg/mL and about 5.5 µg/mL, or between about 2 µg/mL
`
`and about 6 µg/mL, or between about 1.5 µg/mL and about 6.5 µg/mL, or between about 1
`
`µg/mL and about 7 µg/mL, or between about 0.5 µg/mL and about 10 µg/mL.
`
`[0048]
`
`In
`
`certain non-limiting embodiments,
`
`the premixed dexmedetomidine
`
`composition comprises dexmedetomidine at a concentration of about 0.5 µg/mL, or about 1
`
`µg/mL, or about 1.5 µg/mL, or about 2 µg/mL, or about 2.5 µg/mL, or about 3 µg/mL, or about
`
`3.5 µg/mL, or about 4 µg/mL, or about 4.5 µg/mL, or about 5 µg/mL, or about 5.5 µg/mL, or
`
`about 6 µg/mL, or about 6.5 µg/mL, or about 7 µg/mL, or about 7.5 µg/mL, or about 8 µg/mL, or
`
`about 8.5 µg/mL, or about 9 µg/mL, or about 9.5 µg/mL, or about 10 µg/mL, or about 10.5
`
`µg/mL, or about 11 µg/mL, or about 11.5 µg/mL, or about 12 µg/mL, or about 12.5 µg/mL, or
`
`about 13 µg/mL, or about 13 .5 µg/mL, or about 14 µg/mL, or about 14. 5 µg/mL, or about 15
`
`µg/mL, or about 15.5 µg/mL, or about 16 µg/mL, or about 16.5 µg/mL, or about 17 µg/mL, or
`
`about 17.5 µg/mL, or about 18 µg/mL, or about 18.5 µg/mL or about 19 µg/mL, or about 19.5
`
`µg/mL, or about 20 µg/mL.
`[0049]
`
`In
`
`certain non-limiting embodiments,
`
`the premixed dexmedetomidine
`
`composition comprises dexmedetomidine at a concentration of about 4 µg/mL.
`[0050]
`
`In
`
`certain non-limiting embodiments,
`
`the premixed dexmedetomidine
`
`composition is formulated as a liquid.
`
`[0051]
`
`In
`
`certain non-limiting embodiments,
`
`the premixed dexmedetomidine
`
`composition is formulated at a pH of between about 1 and about 10, or between about l 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 dexmedetomidine
`
`composition is formulated at a pH of between about 4.7 and about 6.2.
`
`In a preferred non(cid:173)
`
`limiting embodiment, the premixed dexmedetomidine composition is formulated at a pH of
`
`between about 4.5 and about 7.0.
`
`NY02:758386. l
`
`- 11 -
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1051 – Page 11
`
`

`

`077350.0364
`
`[0052]
`
`In other non-limiting embodiments, the premixed dexmedetomidine composition
`
`comprises dexmedetomidine mixed or dissolved in a sodium chloride saline solution. The saline
`
`solution can comprise sodium chloride present at a concentration 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.
`
`[0053]
`
`In certain embodiments, the weight percent of the saline solution is a percent
`
`weight/weight of the premix composition. In certain embodiments, the weight percent of the
`
`saline solution is a percent weight/volume of the premix composition.
`
`[0054]
`
`In certain non-limiting
`
`embodiments,
`
`the premixed dexmedetomidine
`
`composition of the present invention comprises dexmedetomidine, or a pharmaceutically
`
`acceptable salt thereof, at a concentration of between about 0.05 µg/mL and about 15 µg/mL,
`
`and sodium chloride at a concentration of between about 0.01 and about 2.0 weight percent.
`
`[0055]
`
`In other non-limiting embodiments, the premixed dexmedetomidine composition
`
`of the present invention comprises dexmedetomidine, or a pharmaceutically acceptable salt
`
`thereof, at a concentration of about 4 µg/mL and sodium chloride at a concentration of about
`
`0.90 weight percent.
`
`[0056]
`
`In one non-limiting example, the 0.9% NaCl solution is formulated by mixing 9.0
`
`g NaCl I 1000 mL of water. In certain embodiments, the premix compositions of the present
`
`invention are formulated by adding 0.118 g dexmedetomidine HCl plus 9.0 g NaCl into the same
`
`1000 mL ofwateL The solution can then be mixed with addition 0.9% NaCl solution to achieve
`
`a desired concentration of dexmedetomidine, for example, 4 µg/mL.
`
`[0057]
`
`In
`
`certain non-limiting
`
`embodiments,
`
`the premixed dexmedetomidine
`
`composition of the present invention is disposed in a container or vessel that can maintain the
`
`sterility of, or prevent the contamination of, a premixed dexmedetomidine composition that is
`
`purified or substantially free of any contaminants.
`
`In certain non-limiting embodiments, the
`
`container or vessel is a sealed container or vessel.
`
`[0058)
`
`In certain non-limiting embodiments, the dexmedetomidine composition of the
`
`present invention is disposed in a container or vessel and is formulated as a premixture.
`
`NY02:758386. I
`
`- 12 -
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1051 – Page 12
`
`

`

`077350.0364
`
`[0059]
`
`In
`
`certain non-limiting
`
`embodiments,
`
`the premixed dexmedetomidine
`
`composition of the present invention is disposed in a container or vessel and is formulated as a
`
`single use dosage.
`
`In certain non-limiting embodiments, the premixed dexmedetomidine
`
`composition of the present invention is disposed in a container or vessel and is formulated as a
`
`dosage for multiple use.
`
`[0060]
`
`In certain non-limiting embodiments, the container or vessel includes, but is not
`
`limited to, glass vials (for example, but not limited to, flint glass vials), ampoules, plastic flexible
`
`containers, for example, but not limited to, PVC (polyvinyl chloride) containers, VisIV™ plastic
`
`contai