111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US0086481 06B2
`
`(12) United States Patent
`Roychowdhury et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,648,106 B2
`*Feb.l1,2014
`
`(54) DEXMEDETOMIDINE PREMIX
`FORMULATION
`
`(71) Applicant: Hospira, Inc., Lake Forest, IL (US)
`
`(72)
`
`Inventors: Priyanka Roychowdhury, Foster City,
`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.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 13/867,861
`
`(22) Filed:
`
`Apr. 22, 2013
`
`(65)
`
`Prior Publication Data
`
`US 2013/0237576 Al
`
`Sep. 12, 2013
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 13/678,260, filed on
`Nov. 15, 2012, now Pat. No. 8,436,033, which is a
`continuation of application No. 13/541,524, filed on
`Jul. 3, 2012, now Pat. No. 8,338,470, which is a
`continuation of application No. 13/343,672, filed on
`Jan. 4, 2012, now Pat. No. 8,242,158.
`
`(51)
`
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 311164
`C07D 233156
`(52) U.S. Cl.
`USPC ......................... 514/396; 514/816; 548/346.1
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`OTHER PUBLICATIONS
`U.S. Appl. No. 13/343,672, filed Jan. 4, 2012.
`U.S. Appl. No. 13/541,524, filed Jul. 3, 2012.
`U.S. Appl. No. 13/678,148, filed Nov. 15, 2012.
`U.S. Appl. No. 13/678,260, filed Nov. 15, 2012.
`U.S. Appl. No. 13/343,672, Jul. 18, 2012 Issue Fee payment.
`U.S. Appl. No. 13/343,672, Apr. 18, 2012 Notice of Allowance.
`U.S. Appl. No. 13/343,672, Mar. 13, 2012 Response to Non-Final
`Office Action (Accelerated Exam).
`U.S. Appl. No. 13/343,672, Feb. 13, 2012 Non-Final Office Action.
`U.S. Appl. No. 13/541,524, Nov. 20,2012 Issue Fee payment.
`U.S. Appl. No. 13/541,524, Oct. 22, 2012 Notice of Allowance.
`U.S. Appl. No. 13/541,524, Sep. 17, 2012 Response to Non-Final
`Office Action and Terminal Disclaimer filed.
`U.S. Appl. No. 13/541,524, Aug. 17,2012 Non-Final Office Action.
`U.S. Appl. No. 13/678,148, May 9, 2013 Issue Fee payment.
`U.S. Appl. No. 13/678,148, Jan. 11, 2013 Notice of Allowance.
`U.S. Appl. No. 13/678260, Apr. 8, 2013 Issue Fee payment.
`U.S. Appl. No. 13/678,260, Jan. 8, 2013 Notice of Allowance
`"Dexmedetomidine HCL Draft
`Labeling:
`Precedex™
`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,
`Division of Anesthetics, Critical Care and Addiction Drug Products,
`dated Nov. 30, 1999, in connection with the Medical Reviews of the
`Precedex (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, 200 l. Downloaded
`on Mar. 7, 2012 from <http://www.accessdata.fda.gov/drugsatfda~
`docs/nda/99/21-038~Precedex.dfm>.
`Petersen, "Trends
`in Pharmaceutical Primary Packaging for
`Injectables-Solutions for New Challenges," Drug Development and
`DelivetJ!, Issue Date: Sep. 2012, Posted on: Sep. 5, 2012. Down(cid:173)
`loaded on Sep. 14, 2012 from< http://v;rww.drug-dev.com/ME2/
`dirmod.asp?mod=Publications%3A %3AArticle
`&mid=8F3A 7027421841978F 18BE895F87F87F791&tier=4
`&id=C2347A2CEAE1422DAA7E592E47648D77 >
`Precedex® Package Insert, Document EN-2680, Hospira, Inc., Sep.
`2010, downloaded on Aug. 10, 2012 from <URL:http://www.
`precedex.com/wp-content/uploads/20 10/ 11/Precedex~PI.pdf>, pp.
`1-24.
`
`(56)
`
`References Cited
`
`(Continued)
`
`U.S. PATENT DOCUMENTS
`
`4,910,214 A
`5,344,840 A
`5,716,988 A
`6,716,867 B1
`6,806,291 B1
`8,242.158 B1
`8,338,470 B1
`8,436,033 B1
`8,455,527 B1
`2010/0094219 A1
`2010/0197694 A1
`2010/0305160 A1
`2010/0326868 A1
`2011/0152271 A1
`2011/0230534 A1
`2011/0269666 A1
`
`3/1990 Karjalainen eta!.
`9/1994 Maze et al.
`2/1998 Ibrahim eta!.
`4/2004 Aantaa et a!.
`10/2004 Stmkel eta!.
`8/2012 Roychowdhury et al.
`12/2012 Roychowdhury et al.
`5/2013 Roychowdhury et al.
`6/2013 Roychowdhury et al.
`4/2010 Kriesel eta!.
`8/2010 Horn
`12/2010 Brummett
`12/2010 McClainetal.
`6/2011 Horn
`9/2011 Miyawaki et a!.
`11/2011 Quintin
`
`FOREIGN PATENT DOCUMENTS
`
`wo wo 2010/031819
`
`3/2010
`
`Primary Examiner- Savitha Rao
`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 peri operative care of a
`patient or for sedation.
`
`9 Claims, No Drawings
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1001 – Page 1
`
`

`
`US 8,648,106 B2
`2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Short, "Use of dexmedetomidine for primary sedation in a general
`intensive care unit." Critical Care Nurse (online), Epub Oct. 29, 2009
`[Retrieved on Aug. 13, 2012], voL 30, No.1, pp. 29-38, Feb. 2010,
`Retrieved from the internet: <URL:http://ccn.aacnjournals.org/con(cid:173)
`tent/30/ 1/29>.
`Unger, et aL, "Adsorption ofxenobiotics to plastic tubing incorpo(cid:173)
`rated into dynamic in vitro systems used in pharmacological
`research-limits and progress", Biomaterials, 22:2031-2037 (200 1 ).
`
`Venn, et aL, "Pharmacokinetics of dexmedetomidine infusions for
`sedation of postoperative patients requiring intensive care", British
`Journal ofAnaesthesia, 88(5):669-675 (2002).
`Xylocaine® Package Insert, AstraZeneca LP, 2001 and 2007, down(cid:173)
`loaded on Aug. 10, 2012 from <URL:http://www.pdr3d.com/print.
`php?c=4818>, pp. 1-30.
`International Search Report and Written Opinion in International
`Application No. PCT/US2012/042940, dated Aug. 24, 2012.
`"Product Monograph: PRECEDEX, Dexmedetomidine Hydrochlo(cid:173)
`ride for Injection, 100mcg/mL in a 2 mL glass vial", Hospira Health
`Care Corporation, pp. 1-29 (Aug. 12, 2009) http://www.gisoura.ca/
`english_docs/Precedex_Eng_PM -pdf.
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1001 – Page 2
`
`

`
`US 8,648,106 B2
`
`1
`DEXMEDETOMIDINE PREMIX
`FORMULATION
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`2
`nience, delay and risk of contamination or overdose would
`provide significant advantages over currently available con(cid:173)
`centrated formulations.
`
`3. SUMMARY OF THE INVENTION
`
`This application is a continuation of and claims priority
`under 35 U.S.C. §120 to U.S. Ser. No. 13/678,260 filed Nov.
`15,2012, which is a continuation ofU.S. Ser. No. 13/541,524
`filed Jul. 3, 2012, now U.S. Pat. No. 8,338,470, which is a
`continuation of U.S. Ser. No. 13/343,672 filed Jan. 4, 2012,
`now U.S. Pat. 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
`
`The present invention relates to patient-ready, premixed
`formulations of dexmedetomidine, or a pharmaceutically
`acceptable salt thereof, that can be used, for example, in
`peri operative care of a patient or for sedation.
`
`2. BACKGROUND OF THE INVENTION
`
`25
`
`The present invention relates to premixed pharmaceutical
`compositions of dexmedetomidine, or a pharmaceutically
`acceptable salt thereof, that are fommlated for administration
`10 to a patient, without the need to reconstitute or dilute the
`composition prior to administration. Thus, the compositions
`of the present invention are fonnulated as a premixed com(cid:173)
`position comprising dexmedetomidine.
`In certain non-limiting embodiments, the premixed
`15 dexmedetomidine composition is a liquid comprising dexme(cid:173)
`detomidine, or a pharmaceutically acceptable salt thereof, at
`a concentration of between about 0.05 ~tg/mL and about 15
`~g/mL.
`In other non-limiting embodiments, the premixed dexme-
`20 detomidine composition is a liquid comprising dexmedeto(cid:173)
`midine at a concentration of about 4 ~g/mL.
`In other non-limiting embodiments, the premixed dexme(cid:173)
`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.
`Racemic 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole,
`In certain embodiments, the dexmedetomidine composi-
`which is known under the name medetomidine, is a selective
`and potent a 2-adrenoceptor agonist. Medetomidine has been
`tion is disposed in a container or vessel and is formulated as
`a premixture.
`used as an antihypertensive agent and as a sedative-analgesic
`In certain embodiments, the premixed dexmedetomidine
`agent. It has further been observed that this compound also 30
`composition is disposed within a sealed container as a total
`possesses anxiolytic effects and can therefore be used in the
`volume of about 20 mL, 50 mL or 100 mL.
`treatment of general anxiety, panic disorder and various types
`In certain non-limiting embodiments, the premixed
`of withdrawal symptoms.
`dexmedetomidine composition of the present invention com-
`The d-enantiomer of medetomidine, the generic name of
`which is dexmedetomidine, is described in U.S. Pat. No. 35 prises dexmedetomidine, or a pharmaceutically acceptable
`salt thereof, at a concentration of between about 0.05 ~g/mL
`4,910,214 as an a
`-adrenoceptor agonist for general seda-
`2
`and about 15 ~g/mL, and sodiun1 chloride at a concentration
`tion/analgesia and the treatment of hypertension or anxiety.
`of between about O.Ql and about 2.0 weight percent.
`U.S. Pat. Nos. 5,344,840 and 5,091,402 discuss dexmedeto-
`In other non-limiting embodiments, the premixed dexme-
`midine in peri operative and epidural use, respectively. For 40 detomidine composition of the present invention comprises
`example, when used in perioperative care, dexmedetomidine
`dexmedetomidine, or a pharmaceutically acceptable salt
`can reduce the amount of anesthetic necessary to anesthetize
`thereof, at a concentration of about 4 ~tg/mL and sodium
`a patient. Additionally, U.S. Pat. No. 5,304,569 discusses the
`chloride at a concentration of about 0.90 weight percent.
`use of dexmedetomidine in treating glaucoma, and U.S. Pat.
`In certain embodiments, the compositions of the present
`No. 5, 712,301 discusses the use of dexmedetomidine for 45 invention arefonnulated as a pharmaceutical composition for
`preventing neurodegeneration caused by ethanol consump-
`administration to a subject for sedation, analgesia or treat-
`tion. Furthennore, U.S. Pat. No. 6,716,867 discloses methods
`ment of anxiety or hypertension.
`of sedating a patient while in an intensive care unit by admin-
`The present invention also relates to the peri operative treat-
`istering dexmedetomidine, or a pharmaceutically acceptable
`ment of a patient to reduce the response of the autonomic
`salt thereof, to the patient.
`50 nervous system to stimuli during an operation by administer-
`Dexmedetomidine can be administered to a patient in a
`ing a dexmedetomidine composition of the invention.
`variety of ways. For example, U.S. Pat. Nos. 4,544,664 and
`In other non-limiting embodiments, the dexmedetomidine
`4,910,214 disclose the administration of dexmedetomidine
`compositions of the present invention can be administered as
`via parenteral, intravenous, and oral routes. U.S. Pat. No.
`an anxiolytic analgesic to a patient. In certain embodiments,
`4,670,455 describes intramuscular and intravenous adminis- 55 the composition can be administered as a premedication prior
`tration, while U.S. Pat. Nos. 5,124,157 and 5,217,718
`to an operation with or without administration of an amount
`describe a method and device for administering dexmedeto-
`of an anesthetic effective to achieve a desired level oflocal or
`midine through the skin. Additionally, U.S. Pat. No. 5,712,
`general anesthesia.
`301 states that dexmedetomidine can be administered trans-
`In other non-limiting embodiments, the dexmedetomidine
`mucosally.
`60 compositions of the present invention can be administered as
`To date, dexmedetomidine has been provided as a concen-
`a sedative. In certain embodiments, the composition is admin-
`trate that must be diluted prior to administration to a patient.
`istered preoperatively to potentiate the effect of an anesthetic,
`The requirement of a dilution step in the preparation of the
`wherein administration of the composition reduces the
`dexmedetomidine fonnulation is associated with additional
`amount of anesthetic required to achieve a desired level of
`costs and inconvenience, as well as the risk of possible con- 65
`anesthesia.
`tamination or overdose due to hun1an error. Thus, a dexme(cid:173)
`In certain embodiments of the present invention, the pre(cid:173)
`detomidine fommlation that avoids the expense, inconve-
`mixed dexmedetomidine composition
`is administered
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1001 – Page 3
`
`

`
`US 8,648,106 B2
`
`3
`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(cid:173)
`tration 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
`dcxmcdetomidinc 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) Phannaceutical formulations; and
`(4.3) Methods of using premixed dexmedetomidine com(cid:173)
`positions.
`
`4.1 Definitions
`
`The terms used in this specification generally have their
`ordinary meanings in the art, within the context of this inven(cid:173)
`tion and in the specific context where each tenn is used.
`Certain terms are discussed below, or elsewhere in the speci(cid:173)
`fication, to provide additional guidance to the practitioner in
`describing the compositions and methods of the invention and
`how to make and use them.
`According to the present invention, the term "dexmedeto(cid:173)
`midine" 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, dexmedetomidine has the formula (S)-4-[1-(2, 35
`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- 40
`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- 45
`dine HCI. In other non-limiting embodiments, dexmedetomi(cid:173)
`dine comprises the structure depicted below in Fommla I:
`
`4
`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(cid:173)
`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 vessel as a one dose per container or vessel
`1 o formulation.
`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(cid:173)
`pounds and compositions of the invention have application in
`15 veterinary medicine as well, e.g., for the treatment of domes(cid:173)
`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,
`20 songbirds, etc.
`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
`25 obtained. As used herein, the term "substantially free" is used
`operationally, in the context of analytical testing of the mate(cid:173)
`rial. Preferably, purified material substantially free of con(cid:173)
`taminants is at least 95% pure; more preferably, at least 97%
`pure, and more preferably still at least 99% pure. Purity can be
`30 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(cid:173)
`able to regulatory authorities for safe administration to a
`human or non-human animal.
`The term "phannaceutically acceptable," when used in
`cmmection with the phannaceutical 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 governn1ent or listed in the U.S. Pharmacopeia or other
`generally recognized pham1acopeia 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 exan1ple, "Remington's Phar-
`maceutical Sciences" by PhilipP. Gerbino, 21st Edition (or
`previous editions).
`The term "pharmaceutical composition" as used in accor-
`55 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
`60 or a state government, or as listed in the U.S. Pharmacopoeia
`or other generally recognized pharmacopoeia for use in mam(cid:173)
`mals, and more particularly in humans.
`The term "dosage" is intended to encompass a fonnulation
`expressed in tem1s of J.tg/kg/day, J.tglkg/hr, mg/kg/day or
`65 mg/kg/hr. The dosage is the amount of an ingredient admin(cid:173)
`istered in accordance with a particular dosage regimen. A
`"dose" is an amount of an agent administered to a mann11al in
`
`Formula I 50
`
`The tem1s "premix" or "premixture" as used herein refers
`to a pharmaceutical fonnulation that does not require recon(cid:173)
`stitution or dilution prior to administration to a patient. For
`example, in contrast to non-premixed formulations of dexme(cid:173)
`detomidine, the premixed compositions provided herein are
`suitable for administration to a patient without dilution by, for
`example, a clinician, hospital persmmel, caretaker, patient or
`any other individual.
`In certain embodiments, the compositions of the present
`invention can be formulated as "ready to use" compositions
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1001 – Page 4
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`

`
`US 8,648,106 B2
`
`5
`a unit volume or mass, e.g., an absolute unit dose expressed in
`mg or jlg 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 for(cid:173)
`mulation. The particular meaning in any case will be apparent
`from context.
`The terms "therapeutically effective dose," "effective
`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(cid:173)
`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
`those of skill in the art.
`In other non-limiting embodiments a therapeutic response
`may be any response that a user (e.g., a clinician) will recog(cid:173)
`nize as an effective response to the therapy. Thus, a therapeu(cid:173)
`tic response will generally be an induction of a desired effect,
`such as, for example, sedation or analgesia.
`The tern1 "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 devia(cid:173)
`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
`given value. Alternatively, particularly with respect to bio(cid:173)
`logical systems or processes, the term can mean within an
`order of magnitude, preferably within 5-fold, and more pref(cid:173)
`erably within 2-fold, of a value.
`
`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
`certain non-limiting embodiments, the compounds or com(cid:173)
`positions are provided in a therapeutically effective ammmt to
`an animal, such as a manm1al, preferably a human, in need of
`treatment therewith for inducing a sedative, anxiolytic, anal(cid:173)
`gesic, or anesthetic efiect.
`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(cid:173)
`detomidine is formulated as a composition, wherein the
`dexmedetomidine is formulated in combination with at least
`one or more other therapeutically active ingredient. The for(cid:173)
`mulation 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, mucosal or transdermal are also contem(cid:173)
`plated.
`
`6
`The pharmaceutical formulations suitable for injectable
`use, such as, for example, intravenous, subcutaneous, intra(cid:173)
`muscular 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 microorgan-
`10 isms such as bacteria and fungi. The carrier can be a solvent
`or dispersion medium containing, for example, water, saline,
`ethanol, pol yo! (for example, glycerol, propylene glycol, and
`polyethylene glycol, and the like), suitable mixtures thereof,
`and oils. The proper fluidity can be maintained, for example,
`15 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(cid:173)
`ganisms can be brought about by various antibacterial and
`antifungal agents, for example, parabens, chlorobutanol, phe-
`20 no!, 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
`25 absorption, for example, aluminummonosterate and gelatin.
`Sterile injectable solutions may be prepared by incorporating
`the dexmedetomidine in the required amounts in the appro(cid:173)
`priate solvent with various of the other ingredients enumer(cid:173)
`ated above, as required, followed by filter or terminal steril-
`30 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 injectable solu-
`35 tions, the preferred methods of preparation are vacuum dry(cid:173)
`ing and the freeze-drying teclmique 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-
`40 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
`45 EGTA, and sodium chloride; liposomes; polyvinylpyrolli(cid:173)
`done; sugars, such as dextran, mam1itol, sorbitol, and glyc(cid:173)
`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
`50 term "stabilizer" refers to a compound optionally used in the
`pharn1aceutical 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(cid:173)
`dants. Buffer systems for use with the fonnulations include
`55 citrate; acetate; bicarbonate; and phosphate buffers.
`The fornmlation 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 ~-glucoside, Brij 35, Pluronic, and
`60 Tween 20.
`The parenteral fonnulations of the present invention can be
`sterilized. Non-limiting examples of sterilization techniques
`include filtration through a bacterial-retaining filter, tenninal
`sterilization, incorporation of sterilizing agents, irradiation,
`65 and heating.
`The route of administration may be oral or parenteral,
`including intravenous, subcutaneous, intra-arterial, intra peri-
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1001 – Page 5
`
`

`
`US 8,648,106 B2
`
`7
`toneal, ophthalmic, intramuscular, buccal, rectal, vaginal,
`intraorbital, intracerebral, intradermal, intracranial, intraspi(cid:173)
`nal, intraventricular, intrathecal, intracisternal, intracapsular,
`intrapulmonary, intranasal, transmucosal, transdermal, or via
`inhalation.
`Administration of the above-described parenteral formu(cid:173)
`lations may be by periodic injections of a bolus of the prepa(cid:173)
`ration, or may be administered by intravenous or intraperito(cid:173)
`neal 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 refer(cid:173)
`ence in their entireties. Other usefl!l parenteral delivery sys(cid:173)
`tems include ethylene-vinyl acetate copolymer particles,
`osmotic pumps, implantable infusion systems, pump deliv(cid:173)
`ery, encapsulated cell delivery, liposomal delivery, needle(cid:173)
`delivered injection, needle-less injection, nebulizer, aeoro(cid:173)
`solizer, 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 25
`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(cid:173)
`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.l4:201;
`Buchwald eta!., 1980, Surgery 88:507; Saudek et al., 1989,
`N. Engl. J. Med. 321:574). In another embodiment, poly- 35
`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. 40
`Rev. Macromol. Chern., 23:61; Levy eta!., 1985, Science
`228:190; During et al., 1989,Ann. Neural., 25:351; Howard
`et al., 9189, J. Neurosurg. 71:105). In yet another embodi(cid:173)
`ment, a controlled release system can be placed in proximity
`of the therapeutic target, i.e., the brain, thus requiring only a 45
`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, 50
`or a pharmaceutically acceptable salt thereof, at a concentra(cid:173)
`tion of between about 0.005 ~-tg/mL and about 100 ~-tg/mL, or
`between about 0.005 ~tg/mL and about 50 ~tg/mL, or between
`about 0.005 ~J.g/mL and about 25 IJ.g/mL, or between about
`0.005 ~J.g/mL and about 15 ~J.g/mL, or between about 0.005 55
`~J.g/mL and about 10 ~J.g/mL, or between about 0.005~-tg/mL
`and about 7~-tg/mL, or between about 0.005~-tg/mL and about
`5 ~J.g/mL, or between about 0.005 ~J.g/mL and about 4 ~tg/mL,
`or between about 0.005 ~tg/mL and about 3 ~tg/mL, or
`between about 0.005 ~J.g/mL and about 2 ~tg/mL, or between 60
`about 0.005 ~J.g/mL and about 1 ~J.g/mL, or between about
`0.005 ~J.g/mL and about 0.5 ~J.g/mL, or between about 0.005
`~J.g/mL and about 0.05 IJ.g/mL.
`the premixed
`In certain non-limiting embodiments,
`dexmedetomidine composition comprises dexmedetomidine, 65
`or a pharmaceutically acceptable salt thereof, at a concentra(cid:173)
`tion of between about 3.5 ~J.g!mL and about 4.5 ~tg/mL, or
`
`8
`between about 3 ~J.g/mL and about 5 ~J.g/mL, or between about
`2.5 ~J.g/mL and about 5.5 ~J.g/mL, or between about 2 ~J.g!mL
`and about 6~-tg/mL, or between about 1.5~-tg/m