Case 1:15-cv-00697-RGA Document 48-1 Filed 05/04/16 Page 1 of 17 PageID #: 862
`Case 1:15-cv—00697-RGA Document 48-1 Filed 05/04/16 Page 1 of 17 PagelD #: 862
`
`EXHIBIT A
`
`EXHIBIT A
`
`

`

`Case 1:15-cv-00697-RGA Document 48-1 Filed 05/04/16 Page 2 of 17 PageID #: 863
`case 1:15'CV'00697'RGA Document“8'1||||Illllllll‘fllfillll‘lllllillll’lllilliillIlllFlIIllll111111111111163
`
`USOO9320712B2
`
`(12) United States Patent
`US 9,320,712 B2
`(10) Patent N0.:
`
`(45) Date of Patent: *Apr. 26, 2016
`Roychowdhury et a1.
`
`(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-
`claimer.
`
`(21)
`
`Appl. No.: 14/177,008
`
`(22)
`
`Filed:
`
`Feb. 10, 2014
`
`5,798,113 A
`5,814,607 A
`5,846,233 A
`5,879,327 A
`6,716,867 B1
`6,806,291 B1
`8,242,158 B1
`8,324,260 B1
`8,338,470 B1
`8,436,033 B1
`8,455,527 B1
`8,507,542 B2
`8,648,106 B2
`2002/0044966 A1
`2010/0094219 A1
`2010/0197694 A1
`2010/0305160 A1
`2010/0326868 A1
`2011/0152271 A1
`2011/0230534 A1
`2011/0269666 A1
`2013/0096170 A1
`2013/0096172 A1
`2014/0005243 A1
`
`8/1998 Dionne et a1.
`9/1998 Patton
`12/1998 Lilley et a1.
`3/1999 Moreau Defarges et a1.
`4/2004 Aantaa et a1.
`10/2004 Sunkel et a1.
`8/2012 Roychowdhury et a1.
`12/2012 Garcia da Rocha et a1.
`12/2012 Roychowdhury et a1.
`5/2013 Roychowdhury et a1.
`6/2013 Roychowdhury et a1.
`8/2013 Garcia da Rocha et a1.
`2/2014 Roychowdhury et a1.
`4/2002 Bartholomaeus et a1.
`4/2010 Kriesel et a1.
`8/2010 Horn
`12/2010 Brummett
`12/2010 McClain et a1.
`6/2011 Horn
`9/2011 Miyawaki et a1.
`11/2011 Quintin
`4/2013 Garcia da Rocha et a1.
`4/2013 Garcia da Rocha et a1.
`1/2014 Garcia da Rocha et a1.
`
`Prior Publication Data
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`W0
`W0
`W0
`ZA
`
`19749724 A1
`WO 99/24023 A2
`WO 2010/031819
`WO 2010/132882 A2
`9810272 A
`
`6/1999
`5/1999
`3/2010
`11/2010
`5/1999
`
`OTHER PUBLICATIONS
`
`Carollo et a1., “Dexmedetomidine: Areview of clinical applications”,
`Current Opinion in Anesthesiology, 21:457-461 (2008).
`Szumita et a1., “Sedation and analgesia in the intensive care unit:
`Evaluating the role of dexmedetomidine”, Am. J. Health-System
`Pharm., 64:37-44 (2007).
`U.S.App1.N0. 13/867,861, Jan. 2, 2014 Issue Fee payment.
`U.S.App1.N0. 13/867,861, Oct. 2, 2013 Notice ofAllowance.
`U.S.App1.N0. 13/343,672, Jul. 18, 2012 Issue Fee payment.
`U.S. Appl. No. 13/343,672, Apr. 18, 2012 Notice ofAllowance.
`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.App1.N0. 13/541,524, Nov. 20, 2012 Issue Fee payment.
`U.S. Appl. No. 13/541,524, Oct. 22, 2012 Notice ofAllowance.
`U.S. Appl. No. 13/541,524, Sep. 17, 2012 Response to Non-Final
`Office Action and Terminal Disclaimer filed.
`U.S.App1.N0. 13/541,524, Aug. 17,2012 Non-Final Office Action.
`U.S.App1.N0. 13/678,148, May 9, 2013 Issue Fee payment.
`(Continued)
`
`Primary Examiner 7 Savitha Rao
`Assistant Examiner 7 Gregg Polansky
`(74) Attorney, Agent, or Firm 7 Baker Botts L.L.P.
`
`(57)
`
`ABSTRACT
`
`The presently disclosed subject matter relates to pharmaceu-
`tical compositions comprising dexmedetomidine or a phar-
`maceutically acceptable salt thereofwherein 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-
`positions can be used, for example, in perioperative care of a
`patient or for sedation.
`
`8 Claims, No Drawings
`
`(65)
`
`(63)
`
`US 2014/0155446 A1
`
`Jun. 5,2014
`
`Related U.S. Application Data
`
`Continuation of application No. 13/867,861, filed on
`Apr. 22, 2013, now Pat. No. 8,648,106, which is a
`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.
`
`Int. Cl.
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`A61K 31/41 74
`A61K 9/08
`A61K 31/4164
`U.S. Cl.
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`CPC ............. .. A61K 9/08 (2013.01); A61K 31/4164
`(2013.01); A61K31/4174 (2013.01); YIOS
`514/816 (2013.01)
`
`Field of Classification Search
`None
`
`See application file for complete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,407,957 A
`4,544,604 A
`4,670,455 A
`4,910,214 A
`5,091,402 A
`5,124,157 A
`5,217,718 A
`5,304,569 A
`5,344,840 A
`5,520,639 A
`5,654,007 A
`5,704,911 A
`5,712,301 A
`5,716,988 A
`5,780,014 A
`
`10/1983 Lim
`10/1985 Usuiet a1.
`6/1987 Virtanen et a1.
`3/1990 Karjalainen et a1.
`2/1992 Kalso et a1.
`6/1992 Colleyet a1.
`6/1993 Colleyet a1.
`4/1994 Lammintausta et a1.
`9/1994 Maze et a1.
`5/1996 Peterson et a1.
`8/1997 Johnson et a1.
`1/1998 Parsons
`1/1998 Jaatinen et a1.
`2/1998 Ibrahimet a1.
`7/1998 Eljamal et a1.
`
`

`

`Case 1:15-cv-00697-RGA Document 48-1 Filed 05/04/16 Page 3 of 17 PageID #: 864
`Case 1:15-cv-OO697-RGA Document 48-1 Filed 05/04/16 Page 3 of 17 PagelD #: 864
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`US 9,320,712 B2
`
`Page 2
`
`retrieved online
`
`
`
`
`
`mentireport/human/002268/WC5001 15632.pdf.
`Mar. 31, 2014. XP-002722522.
`Extended European Search Report for EPApplication No. 12823 234,
`dated Mar. 31,2014.
`Trissel et a1., “Compatibility Screening of Precedex During Simu-
`latedY-Site Administration with Other Drugs”, International Journal
`of Pharmaceutical Compounding, 6(3):230-233 (2002).
`“Summary Basis of Decision (SBD) Precedex, Dexmedetomidine
`Hydrochloride, 100 ug/mL, solution, Hospira Healthcare Corpora-
`tion”, Submission Control No. 126931, Health Products and Food
`Branch of Canada (20 pages) (Sep. 23, 2010).
`“DEXDOMITOR: EPARiProduct Information, Annex, 1, Sum-
`mary of Product Characteristics”, European Medicines Agency, (43
`pages) (Nov. 19, 2009).
`“DEXDOR: EPARiProduct Information, Annex, 1, Summary of
`Product Characteristics”, European Medicines Agency, (25 pages)
`(Oct. 4, 2011).
`L.S.App1.\lo. 13/343,693, Jul. 3, 2012 Non-Final Office Action.
`L.S. Appl. No. 13/343,693, Dec. 21, 2012 Response to Non-Final
`Office Action.
`L .S. Appl. \Io. 13/343,693, Apr. 11, 2013 Final Office Action.
`L.S.App1.\lo. 13/343,693, Sep. 11, 2013 Amendment and Request
`for Continued Examination (RCE).
`L .S. Appl. \Io. 13/343,693, Oct. 2, 2014 Non-Final Office Action.
`L.S. Appl. No. 13/343,693, Dec. 31, 2014 Response to Non-Final
`Office Action.
`L .S. Appl. \Io. 13/343,693, Mar. 5, 2015 Final Office Action.
`L .S. Appl. \Io. 13/343,693, Aug. 4, 2015 Amendment and Request
`for Continued Examination (RCE).
`L .S. Appl. \Io. 13/726,496, Feb. 7, 2013 Non-Final Office Action.
`L.S. Appl. No. 13/726,496, Mar. 7, 2013 Response to Non-Final
`Office Action.
`L .S. Appl. \Io. 13/726,496, May 6, 2013 Non-Final Office Action.
`L .S. Appl. No. 13/726,496, May 6, 2013 Applicant Initiated Inter-
`view Summary.
`L.S. Appl. No. 13/726,496, Jun. 6, 2013 Response to Non-Final
`Office Action.
`L .S. Appl. \Io. 13/726,496, Jul. 22, 2013 Final Office Action.
`L .S. Appl. No. 13/726,496, Sep. 23, 2013 Response after Final
`Action.
`L.S.App1.\lo. 13/726,496, Jan. 17, 2014 Amendment and Request
`for Continued Examination (RCE).
`L .S. Appl. \Io. 13/726,496, Mar. 13, 2014 Non-Final Office Action.
`L.S. Appl. No. 13/726,496, Jul. 14, 2014 Response to Non-Final
`Office Action.
`L .S. Appl. \Io. 13/726,496, Jul. 25, 2014 Final Office Action.
`L.S. Appl. No. 13/726,496, Sep. 25, 2014 Response after Final
`Action.
`L .S. Appl. \Io. 13/726,496, Oct. 21, 2014 Amendment and Request
`for Continued Examination (RCE).
`L .S. Appl. \Io. 13/726,496, Dec. 19, 2014 Non-Final Office Action.
`L.S. Appl. No. 13/726,496, May 19, 2015 Response to Non-Final
`Office Action.
`L.S.App1.\lo. 13/726,496, Jun. 1,2015 Final Office Action.
`L .S. Appl. \Io. 13/963,885, Apr. 9, 2015 Non-Final Office Action.
`L.S. Appl. No. 13/963,885, Aug. 4, 2015 Response to Non-Final
`Office Action.
`L .S. Appl. \Io. 13/343,672, Mar. 6, 2012 Applicant Initiated Inter-
`view Summary.
`L.S.App1.\lo. 13/471,403, Jul. 5, 2012 Non-Final Office Action.
`L.S. Appl. No. 13/471,403, Aug. 6, 2012 Response to Non-Final
`Office Action.
`L.S.App1.\lo. 13/471,403, Sep. 26, 2012 Notice ofAllowance.
`.S.App1. \Io. 13/471,403, Oct. 24, 2012 Issue Fee Payment.
`.S.App1. \Io. 13/678,148, Feb. 22, 2013 Applicant Initiated Inter-
`iew Summary.
`L.S.App1.\lo. 13/678,148, Apr. 8,2013 Issue Fee Payment.
`L .S. Appl. \Io. 13/678,260, Feb. 21, 2013 Applicant Initiated Inter-
`view Summary.
`L .S. Appl. \Io. 13/726,479, Mar. 6, 2013 Notice ofAllowance.
`L .S. Appl. \Io. 13/726,479, Jun. 6, 2013 Issue Fee Payment.
`L .S. Appl. \Io. 13/343,693, Oct. 1, 2015 Non-Final Office Action.
`
`
`
`LLv
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`U.S.App1.No. 13/678,148, Jan. 11,2013 Notice ofAllowance.
`U.S.App1.No. 13/678,260, Apr. 8,2013 Issue Fee payment.
`U.S.App1.No. 13/678,260, Jan. 8, 2013 Notice ofAllowance.
`“Dexmedetomidine
`HCL
`Draft
`Labeling:
`PrecedexTM
`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/99/21-038iPrecedexiprntlblpdf> 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, 2001. Downloaded
`on Mar. 7, 2012 from <http://www.accessdata.fda.gov/drugsatfdai
`docs/nda/99/21-038,Precedex.cfm>, 46 pages.
`Petersen,
`“Trends
`in Pharmaceutical Primary Packaging for
`Inj ectables7Solutions for New Challenges,” Drug Development and
`Delivery, Issue Date: Sep. 2012, Posted On: Sep. 5, 2012. Down-
`loaded on Sep. 14, 2012 from < http://www.drug-dev.com/ME2/
`dirmod.asp?sid:4306B1E9C3CC4E07A4D64E23FBDB232C
`&nm:Back+Issues&type:Publishing
`&mod:Publications%3A%3AArticle
`&mid:8F3A7027421841978F18BE895F87F791&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/2010/11/Precedex,PI.pdf>, pp.
`1-24.
`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-
`tent/30/1/29>.
`Unger, et a1., “Adsorption of xenobiotics to plastic tubing incorpo-
`rated into dynamic in vitro systems used in pharmacological
`researchilimits and progress”, Biomaterials, 22:2031-2037 (2001).
`Venn, et a1., “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-
`loaded on Aug. 10, 2012 from <URL:http://www.pdr3d.com/print.
`php7cfll818>, pp. 1-30.
`International Search Report and Written Opinion in International
`Application No. PCT/US2012/042940, dated Aug. 24, 2012.
`“Product Monograph: Precedex, Dexmedetomidine Hydrochloride
`for Injection, 100mcg/mL in a 2 mL glass vial”, Hospira HealthCare
`Corporation, pp. 1-29 (Aug. 12, 2009) http://www.gisoura.ca/
`englishidocs/PrecedexiEngRPM-pdf.
`Petrick, et al., “Review of current knowledge of plastic intravenous
`fluid containers”, Am J. Hosp. Pharm., 34:357-362 (2007).
`Nedich, “Selection of containers and closure systems for injectable
`products”, Am J. Hosp. Pharma, 40:1924-1927 (1983).
`Kobo, Bunji, Medicine and Drug Journal, 24(10):2257-2265
`(1988)4(In Japanese).
`Office Action received on Feb. 12, 2014 from Japanese Application
`No. 2013-273409 (English translation).
`“Saikin no Shinyaku 2005” (New Drugs 2005 in Japan), Yakuji Nippo
`Co., Ltd, pp. 1-8 (May 27, 2005)4(In Japanese).
`Namaki, Noriyuki, “Premixed Parenteral Solution and Safety Man-
`agement”, Journal of Pharmaceutical Science and Technology,
`65(5):289-296 (2005)4(In Japanese). (An English translation is
`enclosed).
`Office Action received on May 2, 2014 from Japanese Application
`No. 2014-011233 (English translation).
`Anonymous, “Assessment report Dexdor Dexmedetomidine Proce-
`dure No. EMENH/C/002268”, European Medicines Agency, pp.
`1-79 (2011) retrieved from internet: URL:http://www.ema.europa.
`eu/doc s/eniGB/documentilibrary/EPARi-iPubliciassess-
`
`

`

`Case 1:15-cv-00697-RGA Document 48-1 Filed 05/04/16 Page 4 of 17 PageID #: 865
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`US 9,320,712 B2
`
`Page 3
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`U.S. Appl. No. 13/726,496, Sep. 29, 2015 Amendment and Request
`for Continued Examination (RCE).
`U.S. Appl. No. 13/726,496, Oct. 21, 2015 Applicant Initiated Inter-
`view Summary.
`U.S. Appl. No. 13/726,496, Dec. 4, 2015 Notice ofAllowance.
`U.S. Appl. No. 13/963,885, Nov. 19, 2015 Final Office Action.
`Chrysostomou et al., “Dexmedetomidine: A Novel Drug for the
`Treatment of Atrial and Junctional Tachyarrhythmias During the
`Perioperative Period for Congenital Cardiac Surgery: A Preliminary
`Study” Pediatric Anesthesiology. vol. 107, No. 5, Nov. 2008.
`Easley et a1 ., “Pro: Dexmedetomidine Should Be Used for Infants and
`Children Undergoing Cardiac Surgery” Journal of Cardiothoracic
`and VascularAnesthesia. vol. 22, Issue 1, Feb. 2008, pp. 147-151.
`Easley et al., “Dexmedetomidine for the treatment of postanesthesia
`shivering in children” Pediatric Anesthesia. 17: 341-346, 2007.
`
`Jooste et al., “Acute hemodynamic changes after rapid intravenous
`bolus dosing of dexmedetomidine in pediatric heart
`transplant
`patients undergoing routine cardiac catheterization” Anesth Analg.,
`Dec. 2010; 111(6):1490-6.
`Mansour EE, “Bis-guided evaluation of dexmedetomidine vs.
`midazolam as anaesthetic adjuncts in off-pump coronary artery
`bypass surgery (OPCAB)” Saudi Journal ofAnaesthesia, 2009. vol.
`3:1, pp. 7-14.
`Center for Drug Evaluation, China Food and Drug Administration
`edited, “Corpus of Drug Technological Evaluation, Part I”, Dec. 31,
`2006, pp. 281-283.
`Center for Drug Evaluation, China Food and Drug Administration
`edited, “Corpus of Drug Technological Evaluation, Part I”, Dec. 31,
`2006, pp. 156-158.
`Meng Shengnan, “Pharmaceutics”, Shanghai Science and Technol-
`ogy Press, Sep. 31, 2011, pp. 41-43.
`Zhu Zhaojing, “Pharmaceutics”, Science Press, Beijing, pp. 82-87,
`the section “Infusion”, Jun. 30, 2010.
`Chinese Office Action dated Feb. 6, 2016 in Chinese Application No.
`201280003734.4 (with English Translation).
`
`

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`US 9,320,712 B2
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`2
`
`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. Ser. No. 13/867,861, filedApr.
`22, 2013, which is a continuation ofU.S. Ser. No. 13/678,260
`filed Nov. 15, 2012, now U.S. Pat. No. 8,436,033, which is a
`continuation of U.S. Ser. No. 13/541,524 filed Jul. 3, 2012,
`now U.S. Pat. No. 8,338,470, which is a continuation ofU.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 incorpo-
`rated 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
`perioperative care of a patient or for sedation.
`
`2. BACKGROUND OF THE INVENTION
`
`Racemic 4- [1 -(2,3 -dimethylphenyl)ethyl]-1H-imidazole,
`which is known under the name medetomidine, is a selective
`and potent otz-adrenoceptor agonist. Medetomidine has been
`used as an antihypertensive agent and as a sedative-analgesic
`agent. It has further been observed that this compound also
`possesses anxiolytic effects and can therefore be used in the
`treatment of general anxiety, panic disorder and various types
`of withdrawal symptoms.
`The d-enantiomer of medetomidine, the generic name of
`which is dexmedetomidine,
`is described in U.S. Pat. No.
`4,910,214 as an otz-adrenoceptor agonist for general seda-
`tion/analgesia and the treatment of hypertension or anxiety.
`U.S. Pat. Nos. 5,344,840 and 5,091,402 discuss dexmedeto-
`midine in perioperative and epidural use, respectively. For
`example, when used in perioperative care, dexmedetomidine
`can reduce the amount of anesthetic necessary to anesthetize
`a patient. Additionally, U.S. Pat. No. 5,304,569 discusses the
`use of dexmedetomidine in treating glaucoma, and U.S. Pat.
`No. 5,712,301 discusses the use of dexmedetomidine for
`preventing neurodegeneration caused by ethanol consump-
`tion. Furthermore, U.S. Pat. No. 6,716,867 discloses methods
`of sedating a patient while in an intensive care unit by admin-
`istering dexmedetomidine, or a pharmaceutically acceptable
`salt thereof, to the patient.
`Dexmedetomidine can be administered to a patient in a
`variety of ways. For example, U.S. Pat. Nos. 4,544,664 and
`4,910,214 disclose the administration of dexmedetomidine
`via parenteral, intravenous, and oral routes. U.S. Pat. No.
`4,670,455 describes intramuscular and intravenous adminis-
`tration, while U.S. Pat. Nos. 5,124,157 and 5,217,718
`describe a method and device for administering dexmedeto-
`midine through the skin. Additionally, U.S. Pat. No. 5,712,
`301 states that dexmedetomidine can be administered trans-
`
`mucosally.
`To date, dexmedetomidine has been provided as a concen-
`trate that must be diluted prior to administration to a patient.
`The requirement of a dilution step in the preparation of the
`dexmedetomidine formulation is associated with additional
`
`costs and inconvenience, as well as the risk of possible con-
`tamination or overdose due to human error. Thus, a dexme-
`detomidine formulation that avoids the expense, inconve-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`nience, delay and risk of contamination or overdose would
`provide significant advantages over currently available con-
`centrated formulations.
`
`3. SUMMARY OF THE INVENTION
`
`The present invention relates to premixed pharmaceutical
`compositions of dexmedetomidine, or a pharmaceutically
`acceptable salt thereof, that are formulated for administration
`to a patient, without the need to reconstitute or dilute the
`composition prior to administration. Thus, the compositions
`of the present invention are formulated as a premixed com-
`position comprising dexmedetomidine.
`the premixed
`In certain non-limiting embodiments,
`dexmedetomidine composition is a liquid comprising dexme-
`detomidine, or a pharmaceutically acceptable salt thereof, at
`a concentration of between about 0.05 ug/mL and about 15
`ug/mL.
`In other non-limiting embodiments, the premixed dexme-
`detomidine composition is a liquid comprising dexmedeto-
`midine at a concentration of about 4 ug/mL.
`In other non-limiting embodiments, the premixed dexme-
`detomidine composition comprises dexmedetomidine mixed
`or dissolved in a sodium chloride saline solution.
`
`In certain embodiments, the premixed dexmedetomidine
`composition is disposed within a sealed container or vessel.
`In certain embodiments, the dexmedetomidine composi-
`tion is disposed in a container or vessel and is formulated as
`a premixture.
`In certain embodiments, the premixed dexmedetomidine
`composition is disposed within a sealed container as a total
`volume of about 20 mL, 50 mL or 100 mL.
`the premixed
`In certain non-limiting embodiments,
`dexmedetomidine composition of the present invention com-
`prises dexmedetomidine, or a pharmaceutically acceptable
`salt thereof, at a concentration of between about 0.05 ug/mL
`and about 15 ug/mL, and sodium chloride at a concentration
`of between about 0.01 and about 2.0 weight percent.
`In other non-limiting embodiments, the premixed dexme-
`detomidine composition of the present invention comprises
`dexmedetomidine, or a pharmaceutically acceptable salt
`thereof, at a concentration of about 4 ug/mL and sodium
`chloride at a concentration of about 0.90 weight percent.
`In certain embodiments, the compositions of the present
`invention are formulated as a pharmaceutical composition for
`administration to a subject for sedation, analgesia or treat-
`ment of anxiety or hypertension.
`The present invention also relates to the perioperative treat-
`ment of a patient to reduce the response of the autonomic
`nervous system to stimuli during an operation by administer-
`ing a dexmedetomidine composition of the invention.
`In other non-limiting embodiments, the dexmedetomidine
`compositions of the present invention can be administered as
`an anxiolytic analgesic to a patient. In certain embodiments,
`the composition can be administered as a premedication prior
`to an operation with or without administration of an amount
`of an anesthetic effective to achieve a desired level of local or
`
`general anesthesia.
`In other non-limiting embodiments, the dexmedetomidine
`compositions of the present invention can be administered as
`a sedative. In certain embodiments, the composition is admin-
`istered preoperatively to potentiate the effect ofan anesthetic,
`wherein administration of the composition reduces the
`amount of anesthetic required to achieve a desired level of
`anesthesia.
`
`In certain embodiments of the present invention, the pre-
`mixed dexmedetomidine
`composition is
`administered
`
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`3
`parenterally as a liquid, orally, transderrnally, intravenously,
`intramuscularly, subcutaneously, or Via an implantable pump.
`
`4. DETAILED DESCRIPTION
`
`The present invention is based in part on the discovery that
`dexmedetomidine prepared in a premixed formulation that
`does not require reconstitution or dilution prior to adminis-
`tration to a patient, remains stable and active after prolonged
`storage. Such premixed formulations therefore avoid the co st,
`inconvenience, and risk ofcontamination or overdose that can
`be associated with reconstituting or diluting a concentrated
`dexmedetomidine formulation prior to administration to a
`patient.
`For clarity and not by way of limitation, this detailed
`description is divided into the following sub-portions:
`(4.1) Definitions;
`(4.2) Pharmaceutical formulations; and
`(4.3) Methods of using premixed dexmedetomidine com-
`positions.
`
`4.1 Definitions
`
`The terms used in this specification generally have their
`ordinary meanings in the art, within the context of this inven-
`tion and in the specific context where each term is used.
`Certain terms are discussed below, or elsewhere in the speci-
`fication, to provide additional guidance to the practitioner in
`describing the compositions and methods ofthe invention and
`how to make and use them.
`
`According to the present invention, the term “dexmedeto-
`midine” as used herein refers to a substantially pure, optically
`active dextrorotary stereoisomer ofmedetomidine, as the free
`base or pharmaceutically acceptable salt. In one, non-limiting
`embodiment, dexmedetomidine has the formula (S)-4-[1-(2,
`3-dimethylphenyl)ethyl]-3H-imidazole. A pharmaceutically
`acceptable salt of dexmedetomidine can include inorganic
`acids such as hydrochloric acid, hydrobromic acid, sulfuric
`acid, nitric acid, phosphoric acid and the like, and organic
`acids such as acetic acid, propionic acid, glycolic acid, pyru-
`vic acid, oxalic acid, malic acid, malonic acid, succinic acid,
`maleic acid, fumaric acid, tartaric acid, citric acid, benzoic
`acid, cinnamic acid, mandelic acid, methanesulfonic acid,
`ethanesulfonic acid, p-toluenesulfonic acid, and salicylic
`acid. Preferably, the dexmedetomidine salt is dexmedetomi-
`dine HCl. In other non-limiting embodiments, dexmedetomi-
`dine comprises the structure depicted below in Formula I:
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`CH3
`
`CH3
`
`CH3
`
`N
`
`H
`
`</ |N
`
`The terms “premix” or “premixture” as used herein refers
`to a pharmaceutical formulation that does not require recon-
`stitution or dilution prior to administration to a patient. For
`example, in contrast to non-premixed formulations of dexme-
`detomidine, the premixed compositions provided herein are
`suitable for administration to a patient without dilution by, for
`example, a clinician, hospital personnel, caretaker, patient or
`any other individual.
`In certain embodiments, the compositions of the present
`invention can be formulated as “ready to use” compositions
`
`Formula I
`
`50
`
`55
`
`60
`
`65
`
`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-
`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
`formulation.
`
`According to the invention, a “subject” or “patient” is a
`human, a non-human mammal or a non-human animal.
`Although the animal subj ect is preferably a human, the com-
`pounds and compositions of the invention have application in
`veterinary medicine as well, e.g., for the treatment of domes-
`ticated species such as canine, feline, and various other pets;
`farm animal species such as bovine, equine, ovine, caprine,
`porcine, etc.; wild animals, e.g., in the wild or in a zoological
`garden; and avian species, such as chickens, turkeys, quail,
`songbirds, etc.
`The term “purified” as used herein refers to material that
`has been isolated under conditions that reduce or eliminate
`
`i.e., contaminants,
`the presence of unrelated materials,
`including native materials from which the material
`is
`obtained. As used herein, the term “substantially free” is used
`operationally, in the context of analytical testing of the mate-
`rial. Preferably, purified material substantially free of con-
`taminants is at least 95% pure; more preferably, at least 97%
`pure, and more preferably still at least 99% pure. Purity can be
`evaluated, for example, by chromatography or any other
`methods known in the art. In a specific embodiment, purified
`means that the level of contaminants is below a level accept-
`able to regulatory authorities for safe administration to a
`human or non-human animal.
`
`The term “pharmaceutically acceptable,” when used in
`connection with the pharmaceutical compositions of the
`invention, refers to molecular entities and compositions that
`are physiologically tolerable and do not typically produce
`untoward reactions when administered to a human. Prefer-
`
`ably, as used herein, the term “pharmaceutically acceptable”
`means approved by a regulatory agency of the Federal or a
`state government or listed in the U.S. Pharmacopeia or other
`generally recognized pharmacopeia for use in animals, and
`more particularly in humans. The term “carrier” refers to a
`diluent, adjuvant, excipient, dispersing agent or vehicle with
`which the compound is administered. Such pharmaceutical
`carriers can be sterile liquids, such as water and oils. For
`example, water, aqueous solutions, saline solutions, aqueous
`dextrose or glycerol solutions can be employed as carriers,
`particularly for injectable solutions. Suitable pharmaceutical
`carriers are described in, for example, “Remington’s Phar-
`maceutical Sciences” by Philip P. Gerbino, 21st Edition (or
`previous editions).
`The term “pharmaceutical composition” as used in accor-
`dance with the present invention relates to compositions that
`can be formulated in any conventional manner using one or
`more pharmaceutically acceptable carriers or excipients. A
`“pharmaceutically acceptable” carrier or excipient, as used
`herein, means approved by a regulatory agency of the Federal
`or a state government, or as listed in the U.S. Pharmacopoeia
`or other generally recognized pharmacopoeia for use in mam-
`mals, and more particularly in humans.
`The term “dosage” is intended to encompass a formulation
`expressed in terms of ug/kg/day, ug/kg/hr, mg/kg/day or
`mg/kg/hr. The dosage is the amount of an ingredient admin-
`istered in accordance with a particular dosage regimen. A
`“dose” is an amount of an agent administered to a mammal in
`
`

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`5
`a unit volume or mass, e. g., an absolute unit dose expressed in
`mg or ug ofthe agent. The dose depends on the concentration
`of the agent in the formulation, e.g., in moles per liter (M),
`mass per volume (m/v), or mass per mass (m/m). The two
`terms are closely related, as a particular dosage results from
`the regimen of administration of a dose or doses of the for-
`mulation. The particular meaning in any case will be apparent
`from context.
`a,
`cc
`
`effective
`The terms “therapeutically effective dose,
`amount,” and “therapeutically effective amount” refer to an
`amount sufficient to produce the desired effect.
`In some non-limiting embodiments, a “therapeutically
`effective dose” means an amount sufficient to reduce by at
`least about 15%, preferably by at least 50%, more preferably
`by at least 90%, and most preferably prevent, a clinically
`significant deficit in the activity, function and response of the
`host. Alternatively, a therapeutically effective amount is suf-
`ficient to cause an improvement in a clinically significant
`condition in the host. These parameters will depend on the
`severity of the condition being treated, other actions, such as
`diet modification, that are implemented, the weight, age, and
`sex of the subject, and other criteria, which can be readily
`determined according to standard good medical practice by
`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-
`nize as an effective response to the therapy. Thus, a therapeu-
`tic response will generally be an induction of a desired effect,
`such as, for example, sedation or analgesia.
`The term “about” or “approximately” as used herein means
`within an acceptable error range for the particular value as
`determined by one of ordinary skill in the art, which will
`depend in part on how the value is measured or determined,
`i.e., the limitations of the measurement system. For example,
`“about” can mean within 3 or more than 3 standard devia-
`
`tions, per the practice in the art. Alternatively, “about” can
`mean a range of up to 20%, preferably up to 10%, more
`preferably up to 5%, and more preferably still up to 1% of a
`given value. Alternatively, particularly with respect to bio-
`logical systems or processes, the term can mean within an
`order of magnitude, preferably within 5-fold, and more pref-
`erably within 2-fold, of a value.
`
`4.2 Pharmaceutical Compositions
`
`The compounds and compositions of the invention may be
`formulated as pharmaceutical compositions by admixture
`with a pharrnaceutically acceptable carrier or excipient. In
`certain non-limiting embodiments, the compounds or com-
`positions are provided in a therapeutically effective amount to
`an animal, such as a mammal, preferably a human, in need of
`treatment therewith for inducing a sedative, anxiolytic, anal-
`gesic, or anesthetic effect.
`In certain non-limiting embodiments, dexmedetomidine is
`formulated as a composition, wherein the dexmedetomidine
`is the only therapeutically active ingredient present in the
`composition. In another non-limiting embodiments, dexme-
`detomidine is formulated as a composition, wherein the
`dexmedetomidine is formulated in combination with at least
`
`one or more other therapeutically active ingredient. The for-
`mulation is preferably suitable for parenteral administration,
`including, but not
`limited to,
`intravenous, subcutaneous,
`intramuscular and intraperitoneal administration; however,
`formulations suitable for other routes of administration such
`as oral, intranasal, mucosal or transderrnal are also contem-
`plated.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`The pharmaceutical formulations suitable for injectable
`use, such as, for example, intravenous, subcutaneous, intra-
`muscular and intraperitoneal administration, include s