111111
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`1111111111111111111111111111111111111111111
`US008338470Bl
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`111111111111
`
`c12) United States Patent
`Roychowdhury et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,338,470 Bl
`*Dec. 25, 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.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 13/541,524
`
`(22) Filed:
`
`Jul. 3, 2012
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 13/343,672, filed on
`Jan. 4, 2012, now Pat. No. 8,242,158.
`
`(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 eta!.
`5,716,988 A *
`2/1998 Ibrahim eta!.
`6,716,867 B1
`4/2004 Aantaa et a!.
`6,806.291 B1 *
`10/2004 Sunkel eta!.
`2010/0094219 A1
`4/2010 Kriesel eta!.
`2010/0197694 A1
`8/2010 Horn
`2010/0305160 A1
`12/2010 Brummett
`2010/0326868 A1
`12/2010 McClainetal.
`201110152271 A1
`6/2011 Horn
`201110230534 A1
`9/2011 Miyawaki et a!.
`2011/0269666 A1
`11/2011 Quintin
`
`FOREIGN PATENT DOCUMENTS
`wo wo 2010/031819
`3/2010
`OTHER PUBLICATIONS
`
`Precedex® Package Insert, Document EN-2680, Hospira, Inc., Sep.
`2010, downloaded on Aug. 10, 2012 from "www.precedex.com/wp(cid:173)
`content/uploads/2010/11/Precedex_Pl.pdf', pp. 1-24.*
`Xylocaine® Package Insert, AstraZeneca LP, 2001 and 2007, down(cid:173)
`loadedonAug. 10,2012 from "www.pdr3d.com/print.php?c=4818",
`pp. 1-30.*
`Venn et a!., British Journal of Anaesthesia, 2002, vol. 88(5), pp.
`669-675.*
`Unger eta!., Biomaterials, vol. 22, 2001, pp. 2031-2037.*
`U.S. Appl. No. 13/343,672, filed Jan. 4, 2012.
`
`U.S. Appl. No. 13/343,672, Apr. 18, 2012 Notice of Allowance.
`U.S. Appl. No. 13/343,672, Apr. 18, 2012 Examiner Initiated Inter(cid:173)
`view Sununary.
`U.S. Appl. No. 13/343,672, Mar. 13, 2012 Response to Office Action
`and Statement of the Substance of the Interview.
`U.S. Appl. No. 13/343,672, Mar. 6, 2012 Applicant Initiated Inter(cid:173)
`view Summary.
`U.S. Appl. No. 13/343,672, Feb. 13,2012 Non-Final Rejection.
`U.S. Appl. No. 13/343,672, Jan. 31, 2012 Decision on Petition to
`Make Special for New Application Under 37 C.F.R. § 1.102 & M.P.
`E.P. § 708.02
`FDA Memorandum from Cynthia G. McCoirnick, M.D., Director,
`Division of Anesthetics, Critical Cu-e and Addiction Drug Products,
`dated Nov. 30, 1999, in connection with the Medical Reviews ofthe
`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, 2001. Downloaded
`on Mar. 7, 2012 from <http://www.accessdata.fda.gov/drugsatfda_
`docs/nda/99/21-038 Precedex.cfm>.
`Precedex™
`Labeling:
`"Dexmedetomidine HCL Draft
`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/dtugsatfda_
`docs/nda/99/21-038_Precedex_prntlbl.pdf> on Jan. 4, 2012.
`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/ 1129>.
`International Search Report and Written Opinion in International
`Application No. PCT/US20 12/042940, mailed Aug. 24, 2012.
`Petersen, "Trends
`in Pharmaceutical Primary Packaging for
`Injectables-Solutions for New Challenges," Drug Development and
`Delivery, Issue Date: Sep. 2012, Posted on: Sep. 5, 2012. Down(cid:173)
`loaded on Sep. 14, 2012 from
`http:/lhttp://www.dtug-dev.com/
`ME2/dirmod.
`asp?sid=4306B 1 E9C3CC4 E07 A4 D64E23 FBD B23 2C
`&nm= Back+ Issues&type= Publishing
`&mod= Publications%3 A %3 AAtiicle
`&mid=8F3A 7027421841978F 18BE895F87F791&tier=4
`&id=C2347A2CEAE1422DAA7E592E47648D77 >.
`* cited by examiner
`
`Primary Examiner- Jeffrey S. Ltmdgren
`Assistant Examiner- Gregg Polansky
`(74) Attorney, Agent, or Firm- Baker Botts LLP
`
`ABSTRACT
`(57)
`The presently disclosed subject matter relates to phannaceu(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.
`
`7 Claims, No Drawings
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1001 – Page 1
`
`

`

`US 8,338,470 Bl
`
`1
`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. application Ser. No. 13/343,672
`filed Jan. 4, 2012, the contents of which are hereby incorpo(cid:173)
`rated by reference in its entirety.
`
`1. FIELD OF THE INVENTION
`
`l11e present invention relates to patient-ready, premixed
`formulations of dexmedetomidine, or a pham1aceutically
`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]-lH-imidazole,
`which is known under the name medetomidine, is a selective
`and potent a 2-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 25
`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 a 2-adrenoceptor agonist for general seda(cid:173)
`tion/analgesia and the treatment of hypertension or anxiety. 30
`U.S. Pat. Nos. 5,344,840 and 5,091,402 discuss dexmedeto(cid:173)
`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 35
`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(cid:173)
`tion. Furthem1ore, U.S. Pat. No. 6,716,867 discloses methods
`of sedating a patient while in an intensive care unit by admin- 40
`istering dexmedetomidine, or a pham1aceutically 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 45
`via parenteral, intravenous, and oral routes. U.S. Pat. No.
`4,670,455 describes intramuscular and intravenous adminis(cid:173)
`tration, while U.S. Pat. Nos. 5,124,157 and 5,217,718
`describe a method and device for administering dexmedeto(cid:173)
`midine through the skin. Additionally, U.S. Pat. No. 5,712, 50
`301 states that dexmedetomidine can be administered trans(cid:173)
`mucosally.
`To date, dexmedetomidine has been provided as a concen(cid:173)
`trate that must be diluted prior to administration to a patient.
`The requirement of a dilution step in the preparation of the 55
`dexmedetomidine formulation is associated with additional
`costs and inconvenience, as well as the risk of possible con(cid:173)
`tamination or overdose due to human error. Thus, a dexme(cid:173)
`detomidine formulation that avoids the expense, inconve(cid:173)
`nience, delay and risk of contamination or overdose would
`provide significant advantages over currently available con(cid:173)
`centrated fonnulations.
`
`2
`acceptable salt thereof, that are fonnulated 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(cid:173)
`position comprising dexmedetomidine.
`In certain non-limiting embodiments, the premixed
`dexmedetomidine composition is a liquid comprising dexme(cid:173)
`detomidine, or a pharmaceutically acceptable salt thereof, at
`a concentration of between about 0.05 flg/mL and about 15
`10 f.Lg/mL.
`In other non-limiting embodiments, the premixed dexme(cid:173)
`detomidine composition is a liquid comprising dexmedeto(cid:173)
`midine at a concentration of about 4 flg/mL.
`In other non-limiting embodiments, the premixed dexme-
`15 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-
`20 tion is disposed in a container or vessel and is fommlated 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.
`In certain non-limiting embodiments, the premixed
`dexmedetomidine composition of the present invention com(cid:173)
`prises dexmedetomidine, or a pham1aceutically acceptable
`salt thereof, at a concentration of between about 0.05 flg/mL
`and about 15 ~tg/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(cid:173)
`detomidine composition of the present invention comprises
`dexmedetomidine, or a pharmaceutically acceptable salt
`thereof, at a concentration of about 4 flg/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(cid:173)
`ment of anxiety or hypertension.
`The present invention also relates to the peri operative treat(cid:173)
`ment of a patient to reduce the response of the autonomic
`nervous system to stimuli during an operation by administer(cid:173)
`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 oflocal 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(cid:173)
`istered 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.
`In certain embodiments of the present invention, the pre(cid:173)
`mixed dexmedetomidine composition
`is administered
`60 parenterally as a liquid, orally, transdemally, intravenously,
`intramuscularly, subcutaneously, or via an implantable pump.
`
`4. DETAILED DESCRIPTION
`
`3. SUMMARY OF THE INVENTION
`
`The present invention relates to premixed phannaceutical
`compositions of dexmedetomidine, or a pham1aceutically
`
`65
`
`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-
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1001 – Page 2
`
`

`

`US 8,338,470 Bl
`
`3
`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
`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) Phannaceutical formulations; and
`(4.3) Methods of using premixed dexmedetomidine com(cid:173)
`positions.
`
`4.1 DEFINITIONS
`
`15
`
`4
`refers to a premixed composition that is disposed within a
`sealed container or vessel as a one dose per container or vessel
`formulation.
`According to the invention, a "subject" or "patient" is a
`human, a non-human mannnal 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
`veterinary medicine as well, e.g., for the treatment of domes(cid:173)
`ticated species such as canine, feline, and various other pets;
`10 fann animal species such as bovine, equine, ovine, caprine,
`porcine, etc.; wild mlimals, 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
`the presence of unrelated materials, i.e., contaminants,
`including native materials from wllich the material is
`obtained. As used herein, the tem1 "substantially free" is used
`operationally, in the context of analytical testing of the mate(cid:173)
`rial.
`Preferably, purified material substantially free of contallli-
`nants is at least 95% pure; more preferably, at least 97% pure,
`and more preferably still at least 99% pure. Purity can be
`evaluated, for exalllp!e, by chromatography or any other
`methods known in the art. In a specific embodiment, purified
`means that the level of contaminm1ts is below a level accept(cid:173)
`able to regulatory authorities for safe administration to a
`human or non-humm1 animal.
`The term "pham1aceutically 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(cid:173)
`ably, as used herein, the term "pharmaceutically acceptable"
`means approved by a regulatory agency of the Federal or a
`state govennnent or listed in the U.S. Phannacopeia or other
`generally recognized phannacopeia for use in animals, and
`more particularly in humans. The term "carrier" refers to a
`40 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
`exmnple, water, aqueous solutions, saline solutions, aqueous
`dextrose or glycerol solutions can be employed as carriers,
`45 particularly for injectable solutions. Suitable pharmaceutical
`carriers are described in, for example, "Remington's Phar(cid:173)
`maceutical Sciences" by Pllilip P. Gerbino, 21st Edition (or
`previous editions).
`The term "pharmaceutical composition" as used in accor-
`50 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
`55 or a state govermnent, 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 tem1 "dosage" is intended to encompass a formulation
`expressed in tenns of llglkg/day, llg/kg/hr, mg/kg/day or
`60 mg/kg/hr. The dosage is the alllount 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 mall1ll1al in
`a unit volume or mass, e.g., an absolute unit dose expressed in
`mg or 11g of the agent. The dose depends on the concentration
`65 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 terms used in tins 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 term is used.
`Certain terms are discussed below, or elsewhere in the speci- 20
`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 25
`active dextrorotary stereoisomer ofmedetomidine, as the free
`base or phannaceutically acceptable salt. In one, non-limiting
`embodiment, dexmedetomidine has the formula (S)-[l-(2,3-
`dimethylphenyl)ethyl]-3H-imidazole. A phannaceutically
`acceptable salt of dexmedetomidine can include inorgmlic 30
`acids such as hydrochloric acid, hydrobromic acid, sulfuric
`acid, nitric acid, phosphoric acid and the like, and orgmlic
`acids such as acetic acid, propionic acid, glycolic acid, pyru(cid:173)
`vic acid, oxalic acid, malic acid, malonic acid, succinic acid,
`maleic acid, fumaric acid, tartaric acid, citric acid, benzoic 35
`acid, cinnamic acid, mandelic acid, methanesulfonic acid,
`ethm1esulfonic acid, p-toluenesulfonic acid, m1d salicylic
`acid. Preferably, the dexmedetomidine salt is dexmedetomi(cid:173)
`dine HCI. In other non-limiting embodiments, dexmedetomi(cid:173)
`dine comprises the structure depicted below in Formula I:
`
`Formula!
`
`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
`exm11ple, 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(cid:173)
`tion are "ready to use" upon removing the compositions ±rom
`a sealed container or vessel.
`In certain embodiments, the compositions of the present
`invention can be formulated as a "single use dosage," which
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1001 – Page 3
`
`

`

`US 8,338,470 Bl
`
`5
`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 tenus "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 eflect,
`such as, for example, sedation or analgesia.
`The tenn "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.
`
`6
`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(cid:173)
`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
`10 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-
`15 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
`20 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-
`25 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-
`30 tions, the preferred methods of preparation are vacuum dry(cid:173)
`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-
`35 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
`senun albumin, collagen, and gelatin; salts such as EDTA or
`40 EGTA, and sodium chloride; liposomes; polyvinylpyrolli-
`done; sugars, such as dextran, maunitol, sorbitol, and glyc-
`The compounds and compositions of the invention may be
`era!; propylene glycol and polyethylene glycol (e.g., PEG-
`formulated as phannaceutical compositions by admixture
`4000, PEG-6000); glycerol; glycine; lipids; preservatives;
`with a pharmaceutically acceptable carrier or excipient. In
`suspending agents; stabilizers; and dyes. As used herein, the
`certain non-limiting embodiments, the compmmds or com-
`positions are provided in a therapeutically effective amount to 45 tenn "stabilizer" refers to a compound optionally used in the
`an animal, such as a mammal, preferably a human, in need of
`pharmaceutical compositions of the present invention in
`treatment therewith for inducing a sedative, anxiolytic, anal-
`order to avoid the need for sulphite salts and increase storage
`gesic, or anesthetic effect.
`life. Non-limiting examples of stabilizers include antioxi-
`In certain non-limiting embodiments, dexmedetomidine is
`dants. Buffer systems for use with the formulations include
`formulated as a composition, wherein the dexmedetomidine 50 citrate; acetate; bicarbonate; and phosphate buffers.
`is the only therapeutically active ingredient present in the
`The formulation also may contain a non-ionic detergent.
`composition. In another non-limiting embodiments, dexme-
`Preferred non-ionic detergents include Polysorbate 20,
`detomidine is formulated as a composition, wherein the
`Polysorbate 80, Triton X -100, Triton X -114, Nonidet P-40,
`dexmedetomidine is formulated in combination with at least
`Octyl a-glucoside, Octyl r3-glucoside, Brij 35, Pluronic, and
`one or more other therapeutically active ingredient. The for- 55 Tween 20.
`mulation is preferably suitable for parenteral administration,
`The parenteral fonnulations of the present invention can be
`including, but not limited to, intravenous, subcutaneous,
`sterilized. Non-limiting examples of sterilization techniques
`intramuscular and intraperitoneal administration; however,
`include filtration through a bacterial-retaining filter, terminal
`formulations suitable for other routes of administration such
`sterilization, incorporation of sterilizing agents, irradiation,
`as oral, intranasal, mucosal or transdennal are also contem- 60 and heating.
`plated.
`The route of administration may be oral or parenteral,
`The pharmaceutical formulations suitable for injectable
`including intravenous, subcutaneous, intra-arterial, intra peri-
`use, such as, for example, intravenous, subcutaneous, intra-
`toneal, ophthalmic, intramuscular, buccal, rectal, vaginal,
`muscular and intraperitoneal administration, include sterile
`intraorbital, intracerebral, intradennal, intracranial, intraspi-
`aqueous solutions or dispersions and sterile powders for the 65 nal, intraventricular, intrathecal, intracisternal, intracapsular,
`extemporaneous preparation of sterile injectable solutions or
`intrapulmonary, intranasal, transmucosal, transdern1al, or via
`dispersion. In all cases, the fonn can be sterile and can be fluid
`inhalation.
`
`4.2 PHARMACEUTICAL COMPOSITIONS
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1001 – Page 4
`
`

`

`US 8,338,470 Bl
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`7
`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 extemal (e.g., an
`intravenous bag) or intemal (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 useful 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. A.ny of the formulations described herein can be 20
`administered in these methods.
`In yet another non-limiting embodiment, the therapeutic
`compound can be delivered in a controlled or sustained
`release system. For exan1ple, 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 pUlllp may be
`used (see Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201;
`Buchwald eta!., 1980, Surgery 88:507; Saudek eta!., 1989,
`N. Engl. J. Med. 321 :574). In another embodiment, poly(cid:173)
`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. 35
`Rev. Macromol. Chem., 23:61; Levy et a!., 1985, Science
`228; 190; During et al., 1989, Alll1. Neural., 25:351; Howard
`eta!., 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 40
`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(cid:173)
`tion of between about 0.005 Jlg/mL and about 100 Jlg/mL, or
`between about 0.005 Jlg/mL and about 50 Jlg/mL, or between
`about 0.005 Jlg/mL and about 25 Jlg/mL, or between about
`0.005 Jlg/mL and about 15 Jlg/mL, or between about 0.005
`~tg/mL and about 10 Jlg/mL, or between about 0.005 Jlg/mL
`and about 7 Jlg/mL, or between about 0.005 Jlg/mL and about
`5 Jlg/mL, or between about 0.005 Jlg/mL and about 4 ~tg/mL,
`or between about 0.005 Jlg/mL and about 3 Jlg/mL, or
`between about 0.005 Jlg/mL and about 2 Jlg/mL, or between
`about 0.005 Jlg/mL and about 1 Jlg/mL, or between about
`0.005 Jlg/mL and about 0.5 Jlg/mL, or between about 0.005
`Jlg/mL and about 0.05 Jlg/mL.
`the premixed
`In certain non-limiting embodiments,
`dexmedetomidine composition comprises dexmedetomidine,
`or a pharmaceutically acceptable salt thereof, at a concentra(cid:173)
`tion of between about 3.5 Jlg/mL and about 4.5 Jlg/mL, or
`between about 3 Jlg/mL and about 5 Jlg/mL, or between about
`2.5 Jlg/mL and about 5.5 Jlg/mL, or between about 2 Jlg/mL
`and about 6 J,!g/mL, or between about 1.5 Jlg/mL and about 6.5
`Jlg/mL, or between about 1 ~tg/mL and about 7 Jlg/mL, or
`between about 0.5 J,!g/mL and about 10 J,!g/mL
`
`8
`In certain non-limiting embodiments, the premixed
`deX111edetomidine composition comprises dexmedetomidine
`at a concentration of about 0.5 Jlg/mL, or about 1 Jlg/mL, or
`about 1.5 Jlg/mL, or about 2 Jlg/mL, or about 2.5 Jlg/mL, or
`about 3 ~tg/mL, or about 3.5 Jlg/mL, or about 4 Jlg/mL, or
`about 4.5 Jlg/mL, or about 5 Jlg/mL, or about 5.5 Jlg/mL, or
`about 6 ~tg/mL, or about 6.5 ~tg/mL, or about 7 Jlg/mL, or
`about 7.5 ~tg/mL, or about 8 ~tg/mL, or about 8.5 ~tg/mL, or
`about 9 ~tg/mL, or about 9.5 ~tg/mL, or about 10 Jlg/mL, or
`1 o about 10.5 ~tg/mL, or about 11 Jlg/mL, or about 11.5 Jlg/mL,
`or about 12 Jlg/mL, or about 12.5 Jlg/mL, or about 13 Jlg/mL,
`or about 13.5 Jlg/mL, or about 14 Jlg/mL, or about 14.5
`Jlg/mL, or about 15 Jlg/mL, or about 15.5 Jlg/mL, or about 16
`Jlg/mL, or about 16.5 Jlg/mL, or about 17 ~tg/mL, or about
`15 17.5 Jlg/mL, or about 18 Jlg/mL, or about 18.5 Jlg/mL or about
`19 JlglmL, or about 19.5 Jlg/mL, or about 20 Jlg/mL.
`In certain non-limiting embodiments, the premixed
`dexmedetomidine composition comprises dexmedetomidine
`at a concentration of about 4 Jlg/mL.
`In certain non-limiting embodiments, the premixed
`deX111edetomidine composition is formulated as a liquid.
`In certain non-limiting embodiments, the premixed
`deX111edetomidine composition is formulated at a pH of
`between about 1 and about 10, or between about 1 and about
`25 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 bet