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`US 8,455,527 B1
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`21
`
`Helvoet FM 259/0 OmniflexPlus® fluoropolymer coated
`rubber stoppers (Helvoet Pharma, Datwyler USA, Penn-
`sauken, N.J.) were evaluated. Chemical compatibility testing
`was favorable; upon autoclave no change in potency or pH
`was observed and no significant amount of impurities
`detected. The OmniflexPlus® coated stopper from Helvoet,
`was examined for determining the self sealing characteristics
`of the stopper when penetrated multiple times with hypoder-
`mic needle. This is a dye ingress test. The new stopper/vial/
`3-piece overseal combination passed this test. Helvoet Omni-
`flexPlus® coated stopper passed the Rocky Mount pressure
`test at the required 80 psi criterion. These stoppers, vials and
`overseals were also evaluated by Tech Ops for functional
`testing to confirm that the stoppers can be pierced without
`being pushed into the vial. All testing indicated that the stop-
`pers are acceptable for use.
`Feasibility stability studies were conducted by preparing a
`batch of Precedex® Injection 4 ug/mL and filling into 50 mL
`vials with the Helvoet OmniflexPlus® stoppers followed by
`autoclaving. Samples were stored under accelerated (40°
`C./75% relative humidity,
`inverted) and long term (250
`C./60% relative humidity) conditions. Initial testing showed
`no loss in potency, no change in pH, and virtually no measur-
`able impurities. The 1 month stability testing of samples
`stored inverted at 40° C. showed slight drop in potency (2%).
`This trend in potency drop continued at 2 months under
`accelerated conditions with further 2% drop in potency. After
`3 months under accelerated conditions the potency values
`remain unchanged as compared to that of 2 months, indicat-
`ing that potency values have leveled off. Similar trend in drop
`of potency during the first three months of storage was
`observed for long term stability conditions (25° C./60% rela-
`tive humidity) but the percent drop was less. The total percent
`drop in potency over three months under long term conditions
`was 1.1%. Stability testing at 4 and 5 months for samples
`stored under accelerated and long term conditions confirmed
`that potency values had almost leveled off, with small drop in
`potency values. During 1 month impurity testing numerous
`small impurity peaks that totaled over 0.5% of the drug peak
`were observed. A placebo batch was prepared to confirm
`whether the peaks are related to the stopper or the drug.
`Results indicated that impurities were related to the stopper.
`Plastic vials were also evaluated for Precedex® premix
`Injection 4 mcg/mL. Two types ofplastic vials were used: CZ
`resin and poly propylene vials. West 4432 Teflon coated 20
`mm elastomer stopper (West Pharmaceutical Services, Inc.)
`was used for both the plastic vials. The pH, potency and
`impurities of Precedex® Injection 4 mcg/mL filled in plastic
`vials and stored under accelerated conditions over a period of
`3 months was determined. Similar trend in potency drop was
`observed. The total % impurities were found to increase over
`a period of 3 months for both CZ resin vials and polypropy-
`lene vials, but the total % of impurities of CZ resin vials was
`less than that of polypropylene vials. CZ resin vials were
`found to better as compared to polypropylene vials in terms of
`drop in potency and total impurities.
`Since the drug is present at such a low concentration 4
`ug/mL, even ppb levels of impurities would have a significant
`contribution toward the impurity limit. Moreover the Prece-
`dex® related substances method was developed to detect
`organic impurities at ppb levels. This method requires detec-
`tion at non-discriminating low wavelength of 210 nm and
`high injection volume of 500 pl, which render it highly sen-
`sitive to detect any organic impurity,
`including stopper
`extractables.
`
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`Extractables
`
`22
`
`West 4432/50 Teflon 2 Coated Elastomer Stoppers (West
`Pharmaceutical Services, Inc.)
`The West 4432/50 Teflon 2 coated elastomer stopper, 20
`mm is used for Precedex® Injection 4 ug/mL, 20 mL presen-
`tation. The stoppers have been qualified for use based on the
`results of compendial biological, physiochemical and other
`characterization tests. The related substance testing of Prece-
`dex® Injection has not shown any unidentified peaks that
`exceed the specification of NMT 0.2%, suggesting that
`extractables are not an issue for Precedex® Injection in this
`container closure system.
`Helvoet FM 259/0 Omniflex® Fluoropolymer Coated Rub-
`ber Stoppers (Helvoet Pharma, Datwyler USA, Pennsauken,
`N.J.)
`The Helvoet Omniflex® fluoropolymer coated FM259/0
`gray bromobutyl 28 mm rubber stoppers (Helvoet Pharma,
`Datwyler USA, Pennsauken, N.J.) (ready-to-use) are used for
`Precedex® Injection 4 ug/mL, 50 and 100 mL presentations.
`The stoppers have been qualified for use based on the results
`of compendial biological, physiochemical and other charac-
`terization tests performed
`During related substances analysis ofthe exhibit batches of
`Precedex® 4 ug/mL Injection, unidentified impurity peaks
`were observed in chromatograms of 50 and 100 mL presen-
`tation samples. During investigation ofthe source ofchemical
`constituents
`responsible for
`the ‘unidentified impurity
`peaks’, it was found that these peaks also appeared in chro-
`matograms of 0.9% NaCl placebo formulation filled into 50
`mL vials with Helvoet FM259/0 rubber stoppers (Helvoet
`Pharma, Datwyler USA, Pennsauken, N.J.), but were absent
`in those of 0.9% NaCl placebo formulation filled into glass
`ampoules. Additionally identical peaks were observed in
`chromatograms of Helvoet FM259/O rubber stopper (Hel-
`voet Pharma, Datwyler USA, Pennsauken, N.J.) extract solu-
`tion analyzed by Precedex® related substances method. The
`extract was prepared by autoclaving (121 ° C. for 60 minutes)
`30 stoppers in 300 mL purified water, yielding an extract of 2
`cm2 stopper surface area per mL water. The results from these
`investigative studies confirmed that ‘unidentified impurity
`peaks’ observed at specific relative retention times were not
`dexmedetomidine HCl related, but were extractables from
`Helvoet rubber stoppers used in the container/closure system.
`It was expected that stopper extractables would be detected at
`such low limits of detection, i.e. ppb levels, as a highly sen-
`sitive LC-UV 210 nm related substances method was used for
`
`a highly potent very low concentration (4 ug/mL) product.
`The chemical constituents responsible for peaks in specific
`relative retention times were determined to be extractables
`
`from 28 mm Helvoet FM259/O rubber stoppers (Helvoet
`Pharma, Datwyler USA, Pennsauken, N.J.), part of container
`closure system for Precedex® Injection 50 and 100 mL.
`Moreover no peaks were found in these specific relative reten-
`tion times in chromatograms of forced degradation samples
`of dexmedetomidine HCl or Precedex® Injection filled in
`ampoules. Hence in the calculation of single largest related
`sub stance and total related sub stances, peaks in relative reten-
`tion time ranges: 0.71-0.80, 1.10-1.30, 1.50-1.80 are
`excluded.
`
`In an effort to quantify the highest levels of observed indi-
`vidual extractable and total extractable, dexmedetomidine
`HCl was used as a surrogate standard for all stopper extract-
`ables. Since, the Helvoet FM259/O rubber stopper (Helvoet
`Pharma, Datwyler USA, Pennsauken, N.J.) extractables
`responsible for the peaks in Precedex® related substances
`profile could not be identified. Through 6 months stability
`testing the highest % of extractables was observed in Prece-
`
`CC-JA044
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`CC-JA044
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`

`

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`US 8,455,527 B1
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`23
`dex® stability samples stored at 300 C./65% relative humidity
`for 3 months. The largest individual extractable % peak area
`was found to be 0.95% or 38 ppb and total extractable % peak
`area, calculated by adding the % peak areas of all the peaks in
`the RRT of 0.71-0.80, 1.10-1.30, 1.55-1.80, was found to be
`2.7% or 108 ppb.
`Helvoet FM259/O rubber stoppers (Helvoet Pharma,
`Datwyler USA, Pennsauken, N.J.) passed the ‘Elastomeric
`Closures for Injections’ testing. As per Helvoet technical
`documentation the total amount of extractables was deter-
`
`mine to be 0.8 mg/100 mL or 8 ppm for a total surface area of
`100 cm2. The surface area of a 28 mm Helvoet stopper is
`approximately 6.45 cm2,
`the total acceptable amount of
`extractable for each 28 mm Helvoet FM259/O rubber stopper
`(Helvoet Pharma, Datwyler USA, Pennsauken, N.J.) on an
`average would be 0.05 mg/ 100 mL or 500 ppb. Additionally
`as per USP the total organic content of purified water should
`not exceed 0.5 mg/L or 500 ppb. The highest levels of
`observed extractables in Precedex® Injection are at least 5
`times lower than the acceptable levels of extractable in puri-
`fied water and acceptable levels of extractable in the qualified
`Helvoet stoppers.
`USP ‘In vitro cytotoxicity test’ and USP ‘Intracutaneous
`test and systemic injection test’ were performed on Helvoet
`stopper extracts. The results show that stoppers meet the
`requirements of these tests, confirming the safety of the stop-
`pers and any stopper related extractables. The ‘In vitro cyto-
`toxicity test’ was repeated for Helvoet 28 mm stoppers that
`were used in the exhibit batch to demonstrate the safety of the
`stoppers. The stopper extract was prepared by autoclaving the
`stoppers at 121° C. for 1 hour in 0.9% NaCl yielding an
`extract of 2 cm2 stopper surface area per mL water. This
`extraction condition closely mimics Precedex® Injection
`manufacturing conditions and also meets the extraction
`requirements of USP ‘In vitro cytotoxicity test’ testing. Pre-
`cedex® injection is formulated in 0.9% NaCl and the final
`product i.e. Precedex® Injection in container-closure is auto-
`claved at 121° C. for 20-40 minutes. Additionally while inves-
`tigating the source of ‘unidentified impurity peaks’ Helvoet
`FM259/O rubber stopper (Helvoet Pharma, Datwyler USA,
`Pennsauken, N.J.) aqueous extracts were prepared by auto-
`claving the stoppers at 121° C. for one hour and then tested by
`the Precedex® related substances method. The results dem-
`
`onstrated that the chemical constituents responsible for the
`peaks were also present in the Helvoet FM259/O rubber
`stopper (Helvoet Pharma, Datwyler USA, Pennsauken, N.J.)
`aqueous extracts. The stoppers passed the USP 87 testing
`indicating that the stopper extractables are non cytotoxic.
`According to Helvoet Pharma, Helvoet FM259/O Omni-
`flex® fluoropolymer coated rubber
`stoppers
`(Helvoet
`Pharma, Datwyler USA, Pennsauken, N.J.) have been used
`for other marketed products, and there have been no reported
`cases of toxicity issues arising due to stopper extractables.
`Identification of Extractables
`
`Diligent efforts were made to characterize and identify the
`extractables. Helvoet’s extractables report lists a number of
`potential extractable compounds. From Helvoet’s list, the
`most likely to be responsible for the peaks observed in the
`Precedex® chromatograms were selected:
`BHT
`
`Irganox- l 07 6
`Irganox-1010
`Stearic Acid
`Palmitic Acid
`
`Sulphur
`Samples of these compounds were obtained, and solutions
`were prepared and injected into an HPLC using the Prece-
`
`24
`
`dex® related substances method. None of these compounds
`matched the relative retention time of the stopper extractable
`peaks in Precedex® sample chromatograms. In general, the
`substances listed above are all too hydrophobic (retained too
`long on the C18 column with the isocratic mobile phase that
`is used for the method, 40% aqueous phosphate buffer pH
`7.0/60% methanol).
`Since these peaks were also observed in the chromato-
`grams of Helvoet FM259/O rubber stopper (Helvoet Pharma,
`Datwyler USA, Pennsauken, N.J.) extract solution, a concen-
`trated stopper extract solution was prepared by first by auto-
`claving a large number of stoppers in purified water, and then
`concentrating the extract by liquid-liquid extraction into
`dichloromethane and then rotovaping and re-suspending the
`residue into a small volume of methanol/water. LC-UV
`
`analysis of this concentrated stopper extract show the same
`peaks of interest as observed in Precedex® chromatogram,
`but at much higher levels (approx 100 times larger peak size).
`This concentrated extract solution was then analyzed by LC-
`MS using the Waters Q-TOF instrument with the electrospray
`source in positive ion mode and observed at least one of the
`peaks of interest in the mass spec TIC chromatogram, the
`mass spectrum of the peak has been obtained and appears to
`have what might be the molecular ion peak at m/z 158; exact
`mass analysis of this peak and its pattern of isotope peaks
`predicts some empirical formulas. Compounds with these
`empirical formula and known usage in the rubber industry
`were tested but without success.
`
`Solvent extracts of the stoppers were prepared and ana-
`lyzed by gas chromatography-mass spectrometry. Analysis
`revealed the presence of two low molecular weight rubber
`oligomers previously reported by Helvoet. These oligomers
`are not commercially available for identification confirma-
`tion; however, their hydrophobic character makes it unlikely
`that they would elute near dexmedetomidine in the related
`substances HPLC method.
`
`A pure extractable sample was isolated by combining mul-
`tiple fractions collected from repeated HPLC separations of a
`stopper extract. Attempts to obtain an EI+ mass spectrum by
`direct probe mass spectrometry and gas chromatography-
`mass spectrometry were unsuccessful, suggesting that the
`stopper extractable is nonvolatile and possibly thermally
`labile.
`
`The pure extractable sample was analyzed by IR and
`elemental analysis. Both of these techniques suggested that
`the extractable contains only carbon, oxygen and hydrogen.
`No indication ofnitrogen, sulfur or any other heteroatom was
`observed.
`
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`The chemical additives that perform variety of functions,
`including plasticizers, fillers, etc are the most significant
`source of chemical entities observed as extractables. There
`
`55
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`60
`
`65
`
`are several reasons which makes identifying the extractables
`challenging and at times impossible. Each functional additive
`category contains representatives from several molecular
`structures. For example, consider the category of anti-
`degradants, subcategory antioxidants, which includes aro-
`matic amines, sterically hindered phenols, phosphites, phos-
`phonites, and thioethers. To further complicate the picture,
`chemical additives are often not pure compounds but mix-
`tures of related structures. For examples “Abietic Acid”
`which is an organic chemical filler used in certain types of
`rubber, in reality is a complex mixture ofchemical entities, all
`of which could appear as extractables/leachables. Chemical
`additives can also react and degrade within the rubber/poly-
`mer matrix during or subsequent to compounding process. As
`an example ofthis consider, the trivalent phosphorus, or phos-
`phate antioxidant, a common tradename for which is Irgafos
`
`CC-JA045
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`CC-JA045
`
`

`

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`US 8,455,527 B1
`
`25
`168. This compound reacts with and thereby destroys oxidiz-
`ing agents, such as hydroperoxides, to form the correspond-
`ing pentavalent phosphorus species, or phosphate.
`In addition to the foregoing, the following must also be
`considered when analyzing extractables/leachables:
`Monomers and high molecular weight oligomers derived
`from incomplete polymerization reactions.
`Surface residues, such as heavy oils and degreasing agents
`on the surface of metal canisters and containers.
`Chemical additives on the surfaces of container closure
`
`such as mould
`fabrication machinery,
`component
`release agents, antistatic and antislip agents, etc.
`The present invention is not to be limited in scope by the
`specific embodiments described herein.
`Indeed, various
`modifications of the invention in addition to those described
`
`herein will become apparent to those skilled in the art from
`the foregoing description. Such modifications are intended to
`fall within the scope of the appended claims.
`Patents, patent applications, publications, product descrip-
`tions, and protocols are cited throughout this application, the
`disclosures of which are incorporated herein by reference in
`their entireties for all purposes.
`
`What is claimed is:
`
`1. A method of providing sedation to a patient in need
`thereof, the method comprising administering to the patient
`an effective amount of a composition, wherein the composi-
`tion comprises dexmedetomidine or a pharmaceutically
`acceptable salt thereof at a concentration of about 0.005 to
`about 50 ug/mL, wherein the composition is a ready to use
`liquid pharmaceutical composition for parenteral administra-
`tion to the patient disposed within a sealed glass container.
`
`26
`2. The method of claim 1, wherein the dexmedetomidine or
`pharmaceutically acceptable salt thereof is at a concentration
`of about 0.05 to about 15 ug/mL.
`3. The method of claim 1, wherein the dexmedetomidine or
`pharmaceutically acceptable salt thereof is at a concentration
`ofabout 0.5 to about 10 ug/mL.
`4. The method of claim 1, wherein the dexmedetomidine or
`pharmaceutically acceptable salt thereof is at a concentration
`ofabout 1 to about 7 ug/mL.
`5. The method of claim 1, wherein the dexmedetomidine or
`pharmaceutically acceptable salt thereof is at a concentration
`of about 4 ug/mL.
`6. The method of claim 1, wherein the composition is
`administered perioperatively.
`7. The method of claim 6, wherein the composition is
`administered before or after surgery.
`8. The method of claim 1, wherein the composition is
`administered to the patient in an intensive care unit.
`9. The method of claim 1, wherein the patient is non-
`ventilated or intubated.
`10. The method of claim 1, wherein the patient is critically
`
`ill.
`
`11. The method of claim 1, wherein the composition is
`administered by an intravenous infusion.
`12. The method of claim 1, wherein the composition is
`administered as an anxiolytic.
`13. The method of claim 1, wherein the composition is
`administered as an adjunct to an anesthetic.
`14. The method of claim 1, wherein the composition is
`administered as an analgesic.
`15. The method of claim 1, wherein the composition is
`administered as an anti-hypertensive agent.
`*
`*
`*
`*
`*
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`CC-JA046
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`CC-JA046
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`

`

`Case 1:15-cv-00697-RGA Document 45-2 Filed 04/28/16 Page 4 of 56 PageID #: 654
`Case 1:15-cv—00697-RGA Document 45-2 Filed 04/28/16 Page 4 of 56 PagelD #: 654
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`EXHIBIT 4
`
`EXHIBIT 4
`
`CC-JA047
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`CC-JA047
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`

`

`Case 1:15-cv-00697-RGA Document 45-2 Filed 04/28/16 Page 5 of 56 PageID #: 655
`111111
`1111111111111111111111111111111111111111111111111111111111111
`US0086481 06B2
`
`c12) United States Patent
`Roychowdhury et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,648,106 B2
`*Feb.11,2014
`
`(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
`
`(63)
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`Related U.S. Application Data
`
`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.
`
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 311164
`C07D233/56
`U.S. Cl.
`USPC ......................... 514/396; 514/816; 548/346.1
`Field of Classification Search
`None
`See application file for complete search history.
`
`References Cited
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`"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, 2001. 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
`Delivery, Issue Date: Sep. 2012, Posted on: Sep. 5, 2012. Down(cid:173)
`loaded on Sep. 14, 2012 from< http://www.drug-dev.com/ME2/
`dirmod.asp?mod~Publications%3A %3AArticle
`&mid~8F3A 7027421841978F 18BE895F87F87F791&tier~
`&id~C2347A2CEAE1422DAA7E592E47648D77 >.
`Precedex® Package Insert, Document EN-2680, Hospira, Inc., Sep.
`2010, downloaded on Aug. 10, 2012 from <URL:http://www.
`precedex.corn/wp-content/uploads/20 10/ 111Precedex_PI.pdf>, pp.
`1-24.
`
`(Continued)
`
`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 perioperative care of a
`patient or for sedation.
`
`wo wo 2010/031819
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`3/2010
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`9 Claims, No Drawings
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`(56)
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`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/l/29>.
`Unger, eta!., "Adsorption of xenobiotics 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 a!., "Pharmacokinetics of dexmedetomidine infusions for
`sedation of postoperative patients requiring intensive care", British
`Journal of Anaesthesia, 88(5):669-675 (2002).
`X ylocaine® 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.
`
`CC-JA049
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`Case 1:15-cv-00697-RGA Document 45-2 Filed 04/28/16 Page 7 of 56 PageID #: 657
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`US 8,648,106 B2
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`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, m
`perioperative 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 formulated 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 formulated as a premixed com(cid:173)
`position comprising dexmedetomidine.
`the premixed
`In certain non-limiting embodiments,
`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 flg/mL and about 15
`f.tg/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 flg/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.
`In certain embodiments, the dexmedetomidine composi(cid:173)
`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-
`35 prises dexmedetomidine, or a pharmaceutically acceptable
`salt thereof, at a concentration of between about 0.05 flg/mL
`and about 15 flg/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-
`40 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
`45 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
`50 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,
`55 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
`60 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
`65 anesthesia.
`In certain embodiments of the present invention, the pre(cid:173)
`mixed dexmedetomidine composition
`is administered
`
`Racemic 4-[1-(2,3-dimethylphenyl)ethyl]-1H-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 30
`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 a 2-adrenoceptor agonist for general seda(cid:173)
`tion/analgesia and the treatment of hypertension or anxiety.
`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
`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. Furthermore, U.S. Pat. No. 6,716,867 discloses methods
`of sedating a patient while in an intensive care unit by admin(cid:173)
`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(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,
`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
`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-
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`US 8,648,106 B2
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`3
`parenterally as a liquid, orally, transdermally, intravenously,
`intramuscularly, subcutaneously, or via an implantable pump