NZ607555B2 - Dexmedetomidine premix formulation - Google Patents

Abstract

Provided are liquid ready to use formulations of dexmedetomidine. Preferably the formulations comprise between 0.05 micrograms/mL and 15 micrograms/mL of dexmedetomidine, are stored in sealed glass containers and can be administered without dilution. Dexmedetomidine has analgesic and sedative activity. ty.

Description

DEXMEDETOMIDINE PREMIX ATION CROSS-REFERENCE TO RELATED APPLICATIONS This application. claims priority to US. Application Serial No. ,672 filed January 4, 201.2, the contents of which are hereby incorporated by reference in its entirety. 1. FIELD OF THE INVENTION The present invention relates to patient-ready, premixed formulations It) of dexmedetomidine, or a pharmaceutically acceptable salt thereof, that can be used, for e, in perioperative care of a patient or for sedation. 2. BACKGROUND OF THE INVENTION Racemic 4~['1-(2,3—di'methylphenyl)eth.y1]—IH-imidazole, which is known, under the name medetomidine, is a selective and potent uz—adreiioceptor agonist. Medetomidine has been used as an antihypertensive agent and as a ve- analgesic agent. It has further been observed that this compound also ses anxiolytic s 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 c name of which is dexmedetomidine, is bed in US. Pat. N0. 4,910,214 as an az-adrenoceptor t for general sedation/analgesia and the treatment of hypertension or anxiety.

US. Pat. Nos. 5,344,840 and 5,091,402 discuss dexmedetomidine in perioperative and epidural use, tively. For example, when. used in perioperative care, dexmedetomidine can reduce the amount of anesthetic necessary to anestheti‘ze a patient. Additionally, U.S. Pat. No. 5,304,569 discusses the use of dexmedetomidine in treating glaucoma, and US. Pat. No. 5,712,301 discusses the use of dexmedetomidine for preventing neurodegeneration caused by ethanol consumption.

Furthermore, US. Pat. No. 6,716,867 discloses methods of sedating a patient while in. an ive care unit by administering dexmedetoniidine, or a phannaceutically acceptable salt thereof, to the patient.

NY02z7468961 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 stration of dexmedetomidine via parenteral, intravenous, and oral routes. U.S. Pat. No. 455 describes intramuscular and intravenous administration, while U.S. Pat. Nos. 5,124,157 and 5,217,718 describe a method and device for administering etomidine through the skin.

Additionally, U.S. Pat. No. 301 states that dexmedetomidine can be administered transmucosally.

To date, dexmedetomidine has been provided as a concentrate that must be diluted prior to administration to a patient. The requirement of a dilution step in the preparation of the dexmedetomidine formulation is associated with additional costs and inconvenience, as well as the risk of possible contamination or overdose due to human error.

Thus, a dexmedetomidine formulation that avoids the expense, inconvenience, delay and risk of contamination or overdose would e significant advantages over currently ble concentrated formulations.

The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a t for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this ication (including the claims) they are to be interpreted as specifying the ce of the stated features, integers, steps or components, but not precluding the presence of one or more other features, integers, steps or components, or group thereof. 3. SUMMARY OF THE INVENTION The present ion relates to premixed pharmaceutical compositions of dexmedetomidine, or a pharmaceutically acceptable salt thereof, that are formulated for administration to a patient, without the need to reconstitute or dilute the composition prior to administration. Thus, the compositions of the present invention are formulated as a premixed composition comprising dexmedetomidine.

In another aspect, the t invention relates to a ready to use liquid pharmaceutical composition for eral administration to a subject, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a concentration of about 0.005 to about 50 µg/mL disposed within a sealed glass container, wherein the ready to use liquid pharmaceutical composition is administered to the subject without dilution.

In yet another , the present invention relates to a ready to use liquid pharmaceutical composition for parenteral administration to a subject, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof disposed within a sealed glass container, n the liquid pharmaceutical composition when stored in the glass container for at least five months exhibits no more than about 2% decrease in the concentration of dexmedetomidine.

In certain non-limiting embodiments, the premixed dexmedetomidine composition is a liquid comprising etomidine, or a pharmaceutically acceptable salt thereof, at a concentration of between about 0.05 µg/mL and about 15 µg/mL.

In other non-limiting ments, the premixed etomidine composition is a liquid comprising dexmedetomidine at a concentration of about 4 µg/mL.

In other miting embodiments, the premixed dexmedetomidine composition ses 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. 0773500356 In certain embodiments, the dexmedetornidine composition is disposed in a container or vessel and is formulated as a premixture.

In certain embodiments, the ed dexmedetomidine composition is disposed within a sealed container as a total volume of about 20 mL, 50 mL or 100 UI mL. in certain non—limiting ments, the premixed dexmedetomidine composition of the present invention comprises dexmedetomidine, or a pharmaceutically acceptable salt thereof, at a concentration of between about 0.05 rig/ml; and about 15 ug/mL, and sodium chloride at a concentration of n about 0.0] and about 2.0 weight percent. in other non-limiting embodiments, the premixed dexmedetomidine composition of the present invention comprises dexmedetomidine, or a pharmaceutically acceptable salt thereof, at a concentration of about 4 ug/mL and sodium. chloride at a concentration of about 0.90 weight percent.

In certain ments, the compositions of the present invention are ated as a pharmaceutical ition. for administration to a subject for sedation, sia or treatment of anxiety or hypertension.

The present invention also relates to the perioperative treatment of a patient to reduce the response of the mic nervous system to stimuli during an operation by administering a dexmedetomidine composition. of the invention.

In other non—limiting embodiments, the dexmedetomidine compositions of the present invention can be administered as an ytic analgesic to a patient. In certain embodiments, the ition 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 l anesthesia.

In other non~1imiting ments, the dexmedetomidine compositions of the present invention can be administered as a sedative. In certain embodiments, the composition is administered ratively to potentiate the effect of an anesthetic, wherein administration of the composition reduces the amount of DJ 0 anesthetic required to achieve a desired level of anesthesia.

In n embodiments of the present invention, the premixed. dexmedetomidine composition is administered parenterally as a liquid, orally, transdennally, intravenously, intramuscularly, subcutaneously, or via an implantable pump.

NYOZ:74€>896.! 0773500356 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 administration to a patient, remains stable and active after prolonged storage. Such. premixed formulations therefore avoid the cost, inconvenience, and risk of contamination or overdose that can be associated with tituting or diluting a concentrated etomidine ation prior to administration to a patient.

For clarity and not by way of limitation, this ed description is divided. into the following sub—portions: (4.1) Definitions; (4.2) ceutical formulations; and (4.3) Methods of using premixed dexmedetomidine compositions. 4.1 Definitions The terms used in this specification generally have their ordinary meanings in the art, within the context of this invention and in the specific context where each term is used. Certain terms are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner in describing the compositions and methods of the invention and how to make and use them.

According to the present invention, the term "dexmedetomidine" as used herein refers to a substantially pure, optically active dextrorotary stereoisomer of medetomidine, as the free base or ceutical]y able salt. .ln one, non— limiting ment, dexmedetomidine has the a (S)—4—[l—(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 c acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, furnaric acid, tartaric acid, citric acid, c acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p~toluenesulfonic acid, and salicylic acid. Preferably, the dexmedetomidine salt NYOZ:746896.1 077350.0356 is dexmedetomidine HCl. In other non—limiting embodiments, dexmedetomidine comprises the structure depicted beiow in Formula I: £11 Formula I The terms “premix” or “premixture” as used herein. refers to a pharmaceutical formulation that does not require titution or on. prior to administration to a patient. For example, in st to non-premixed formulations of dexmedetomidine, the premixed compositions provided herein are suitable for administration to a patient without on 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 which refer to premixed compositions that are suitable for administration to a patient without dilution. For example, in certain embodiments, the compositions of the present invention are “ready to use” upon removing the compositions from a sealed ner or .

In certain embodiments, the compositions of the present invention can be formulated as a “single use dosage,” which refers to a ed composition that is disposed within a sealed container or vessel as a one dose per container or vessei formulation.

According to the invention, a “subject” or “patient” is a human, 21 non— human mammal or a non—human animal. Although the animal t is preferably a human, the compounds and compositions of the invention have application in nary medicine as well, e.g., for the treatment of domesticated s such as canine, feline, and various other pets; farm animal species such as bovine, , ovine, caprine, porcine, etc.; wiid animals, e.g., in the wild or in a zoological garden; and avian species, such as chickens, turkeys, quail, songbirds, etc.

NY021746896.1 077350.0356 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 als from which the material is ed. As used herein, the term “substantially free” is used operationally, in, the context of analytical, testing of the material. Preferably, purified material substantially free of contaminants is at least 95% pure; more preferably, at least 97% pure, and more preferably still at least 99% pure. Purity can be evaluated, for example, by chromatography or any other methods known in the art. In a specific embodiment, purified means that the level of contaminants is below a level acceptable to regulatory authorities for safe administration to a human or man animal.

The term “pharmaceutically able,” when used in connection with the ceutical compositions of the invention, refers to molecular entities and compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a human. Preferably, as used herein, the term “pharmaceutically able” means approved by a regulatory agency of the Federal. or a state government or listed in the US. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in. humans. The term “carrier” refers to a diluent, adjuvant, excipient, sing agent or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils. For e, water, aqueous solutions, saline solutions, aqueous dextrose or glycerol ons can be ed as carriers, particularly for injectable solutions. Suitable pharmaceutical. carriers are described in, for e, “Remington‘s Pharmaceutical Sciences” by Philip P. Gerbino, 21 st Edition (or previous editions).

[\J U1 The term “pharmaceutical composition” as used in accordance with the present invention relates to compositions that can be fonnulated in any conventional manner using one or more phamiaceutically acceptable rs or excipients. A “phannaceutically 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 US.

DJ 0 Pharmacopoeia or other generally recognized pharmacopoeia for use in mammals, and more particularly in humans.

The term “dosage” is intended to encompass a formulation expressed in terms of day, ,ug/kg/hr, mg/kg/day or mg/kg/hr. The dosage is the amount of an ient administered in accordance with a particular dosage regimen. A “dose” N'YO2z746896.l - 6 _ 0773500356 is an amount of an agent administered to a mammal in a unit volume or mass, e.g., an absolute unit dose expressed in mg or pg of the agent. The dose depends on the concentration of the agent in the formulation, e. g., in moles per liter (M), mass per volume (in/v), or mass per mass (in/m). The two terms are closely related, as a particular dosage results from the regimen, of stration of a dose or doses of the formulation. The particular meaning in any case will be apparent from context.

The terms “therapeutically effective dose,7’ ‘6effective amount,” and peutically effective amount” refer to an amount sufficient to produce the desired effect. in some miting 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 ty, function and response of the host. Alternatively, a therapeutically effective amount is sufficient to cause an improvement in a clinically significant condition in the host. These parameters will depend on the severity of the condition being treated, other actions, such, as diet modification, that are implemented, the weight, age, and sex of the subject, and other criteria, which can be readily determined according to rd 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 ian) will recognize as an ive response to the y. Thus, a therapeutic 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 . For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with Lu 0 t to biological systems or processes, the term can mean within an order of magnitude, preferably within 5—fold, and more preferably within 2—fold, of a value.

NY02:746896.l 0773500356 4.2 Pharmaceutical Compositions The compounds and compositions of the invention may be formulated as ceutical compositions by ure with a pharmaceutically acceptable LA r or excipient. In certain non~limiting embodiments, the compounds or itions are provided in a eutically effective amount to an animal, such as a mammal, preferably a human, in need of treatment therewith for inducing a sedative, anxiolytic, analgesic, or anesthetic effect.

In certain non—limiting embodiments, dexmedetomidine is formulated as a composition, wherein the dexmedetomidine is the only therapeutically active ingredient t in the composition. In another non~limiting embodiments, dexmedetomidine is formulated as a composition, wherein the dexmedetomidine is formulated. in combination with at least one or more other therapeutically active ingredient. The formulation is preferably suitable for parenteral administration, including, but not limited to, intravenous, subcutaneous, intramuscular and intraperitoneal administration; however, formulations suitable for other routes of administration such as oral, intranasal, mucosal or ermal. are also contemplated.

The pharmaceutical formulations suitable for inj ectable use, such as, for example, intravenous, subcutaneous, intramuscular and intraperitoneal administration, include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the form can be sterile and can be fluid to the extent that easy syringability exists. It can be stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a t 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 e, by the use of a coating such, as lecithin, by the maintenance of the required le size in the case of dispersion and by the use of surfactants. The preventions of the action of microorganisms can. be brought about by s antibacterial and antifungal agents, for example, parabens, chlorobutanol, , benzyl alcohol, sorbic acid, and the like.

In many cases, it will be preferable to include ic agents, for ex ample, sugars or sodium chloride. ged tion of the injectable NYtl2:746896. l 0773500356 compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monosterate and gelatin. Sterile injectable solutions may be ed by incorporating the dexmedetomidine in the required amounts in the appropriate solvent with various of the other ingredients ated U) above, as ed, followed by filter or terminal. sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from. those enumerated. above. In the case of sterile powders for the preparation of sterile injectable ons, the preferred methods of preparation are vacuum drying and the -drying technique which yield. a powder of the active ingredient plus any additional. desired ingredient from previously sterilefiltered solution f.

Preferably the formulation. may contain an. cxcipient. Pharmaceutically acceptable excipients which may be ed in the formulation are buffers such, as citrate buffer, phosphate buffer, acetate , and bicarbonate buffer; amino acids; l5 urea; alcohols; ascorbic acid; phospholipids; proteins, such as serum albumin, collagen, and gelatin; salts such as EDTA or EGTA, and sodium chioride; iiposomes; polyvin‘ylpyroilidone; sugars, such as dextran, mannitol, sorbitol, and glycerol; ene glycol and polyethylene glycol (e.g., PEG—4000, PEG~6000); glycerol; glycine; lipids; preservatives; suspending agents; stabilizers; and dyes. As used herein, the term “stabilizer” refers to a compound optionally used in the phannaceutical compositions of the present invention in order to avoid the need for sulphite salts and increase storage iife. Non—limiting examples of stabilizers include idants. Buffer systems for use with the ations include citrate; acetate; bicarbonate; and phosphate buffers.

The formulation also may contain a non—ionic detergent. Preferred non— ionic detergents include Polysorbate 20, Polysorbate 80, Triton X~l 00, Triton X414, Nonidet P—40, Octyl d~glucoside, Octyl B-glucoside, Brij 35, Pluronic, and Tween 20.

The parenteral formulations of the present invention can be sterilized.

Non—limiting examples of sterilization techniques include filtration through a bacterial—retaining filter, terminal sterilization, incorporation of sterilizing agents, irradiation, and heating.

The route of administration may be oral or parenteral, including enous, aneous, intra—arterial, intraperitoneai, ophthalmic, intramuscular, buccal, rectal, vaginal, intraorbital, erebral, intradennal, intracranial, intraspinal, NY02:7468%.1 _ 9 - 0773500356 intraventricular, intrathecal, intracisternal, intracapsular, ulmonary, intranasal, transmucosal, transdermal, or via inhalation.

Administration of the above-described parenteral formulations may be by periodic injections of a bolus of the preparation, or may be administered by intravenous or eritoneal administration from a reservoir which is external. (e. g., an intravenous bag) or internal (e. g., a bioerodable implant, a bioartificial or organ).

See, e.g., US. Pat. Nos. 4,407,957 and 5,798,113, each orated herein by reference in their entireties. ulmonary delivery methods and apparatus are described, for example, in US. Pat. Nos. 5,654,007, 5,780,014, and 607, each incorporated herein by reference in their entireties. Other useful parenteral delivery systems include ethylene—vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, pump ry, encapsulated cell ry, liposomal delivery, needle—delivered injection, needle—less injection, nebulizer, aeorosolizer, electroporation, and transderrnal patch, —less injector devices are described in 11.8. Pat. Nos. 327; 5,520,639; 5,846,233 and 5,704,91 l, the specifications of which are . incorporated herein by reference in their entireties. Any of the formulations described herein can be administered in these s.

In. yet another non-limiting embodiment, the eutic compound can be delivered in a controlled or sustained release system. For example, a compound or composition may be administered using intravenous infusion, an implantable osmotic pump, a transdennal patch, mes, or other modes of administration. In one embodiment, a pump may be used (see Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 1.41201; Buchwald et 211., 1980, Surgery 88:507; Saudek et al., l989, N. Engl. J. Med. 321 :5 74). ]n another embodiment, polymeric materials can be used (see Langer and Wise eds, 1974, Medical Applications of Controlled Release, CRC Press: Boca Raton, Fla; Smolen and Ball eds, 1984, Controlled Drug Bioavailability, Drug Product Design and Performance, Wiley, N.Y.; Ranger and Peppas, 1983, J.

Macromol. Sci. Rev. Macromol. Chem, 23:61; Levy et 211., 1985, Science 228: 190; During et al., 1989, Ann. Neurol, 25:35] ; Howard et al., 9189, J.Neurosurg. 71 :105).

In yet another embodiment, a controlled e system can be placed in. proximity of the therapeutic , i.e., the brain, thus requiring only a fraction of the systemic dose (see, e. g, Goodson, 1984, in Medical Applications of Controlled Release, Vol. 2, pp. 115-138).

NY02z746896.l - 10 .. 0773500356 In, certain miting embodiments, the premixed dexmedetomidine composition comprises dexmedetomidine, or a ceutically acceptable salt thereof, at a concentration of between about 0.005 ug/mL and about 100 ug/mL, or between about 0.005 ug/mL and about 50 ug/mL, or between, about 0.005 ug/mL and about 25 ug/mb, or between about 0.005 ug/mL and about 15 ug/rnL, or between about 0.005 ug/mL and about 10 ug/mL, or between about 0.005 uglmL and about 7 ttg/mL, or between about 0.005 ug/mL and about 5 ug/mL, or between about 0.005 ug/tnL and about 4 ug/mL, or between about 0.005 ug/mL and about 3 ug/mL, or between about 0.005 ug/mjL and about 2 ug/mL, or n about 0.005 ug/mL and about 1 rig/mt... or between about 0.005 gig/ml. and about 0.5 ug/mL, or between about 0.005 ug/mL and about 0.05 ug/mL.

In n non-limiting embodiments, the premixed dexmedetomidine composition comprises dexmedetomidine, or a pharmaceutically acceptable salt thereof, at a tration of between about 3.5 ug/mL and about 4.5ug/mL, or between about 3 ug/mL and about 5 ug/mL, or between about 2.5 ug/mL and about .5 ug/mL, or between about 2 ug/niL and about 6 ug/InL, or between about 1.5 ug/mL and about 6.5 ug/mL, or between about 1 ug/mL and about 7 uglmL, or between about 0.5 ug/mL and about 10 ug/mL.

In certain non—limiting embodiments, the premixed dexmedetomidine composition comprises dexmedetomidine at a concentration of about 0.5 ug/mL, or about 1 ug/mL, or about 1.5 ug/ml., or about 2 ttg/mL, or about 2.5 ug/mL, or about 3 ug/mL, or about 3.5 ug/mL, or about 4 ug/mL, or about 4.5 ug/mL, or about 5 ug/inL, or about 5.5 ug/mL, or about 6 ug/mL, or about 6.5 ug/mL, or about 7 ug/mL, or about 7.5 ug/mL, or about 8 ug/mL, or about 8.5 ug/mL, or about 9 ug/mL, or about 9.5 ug/mL, or about 10 ug/mL, or about 10.5 ug/mL, or about 11 ug/mL, or about 11.5 ug/mL, or about 12 ug/mL, or about 12.5 ,Ltg/mL, or about 13 ug/mL, or about 13.5 ug/mL, or about 1.4 ug/mL, or about 14.5 ug/mL, or about 15 ug/mL, or about 15.5 ug/mL, or about 16 ug/mL, or about 16.5 ug/mL, or about 17 ug/mL, or about 17.5 ug/mL, or about 18 ug/mL, or about 18.5 ug/mL or about 19 ug/mL, or about 19.5 ug/mL, or about 20 ug/mL.

In certain non—limiting embodiments, the premixed dexmedetomidine composition comprises dexmedetomidine at a concentration of about 4 ug/mL.

In certain non-limiting ments, the ed dexmedetomidine composition is formulated as a liquid. moaumm _ 1 1 _ 077350.0356 In certain non—limiting embodiments, the premixed dexmedetomidine composition is formulated at a pH of between about 1 and about 10, or between about 1 and about 8, or between about 1 and about 6, or between about 1. and about 4, or betWeen about 1 and about 2. In other nonwlimiting embodiments, the premixed UI dexmedetomidine composition is formulated at a pH of between about 2 and about 10, or between about 4 and about 8, or between about 4 and about 7. In other non— limiting embodiments, the ed dexmedetomidine composition is ated at a pH of between about 4.7 and about 6.2. In a preferred non-limiting embodiment, the premixed dexmedetomidine composition is formulated at a pH of n about 4.5 l0 and about 7.0. in other non—limiting ments, the premixed dexmedetomidine composition ses etomidine mixed or dissolved in a sodium. chloride saline solution: The saline solution can se sodium chloride present at a concentration of between about 0.05 weight percent and about 10 weight percent, or between about 0.05 weight percent and about 5 weight percent, or between about 0.05 weight percent and about 3 weight percent, or between about 0.05 weight percent and about 2 weight percent, or n about 0.05 weight percent and about 1 weight percent. In one preferred, non-limiting ment, the sodium chloride is present at a concentration of about 0.9 weight percent.

In certain embodiments, the weight percent of the saline solution is a percent weight/weight of the premix composition. In certain embodiments, the weight t of the saline solution is a percent weight/volume of the premix composition.

In certain non-limiting embodiments, the premixed dexmedetomidine K‘s) U| composition of the present invention comprises dexmedetomidine, or a phamiaceutically acceptable salt thereof, at a concentration of between about 0.05 ug/mL and about 15 pig/mic, and sodium chloride at a concentration of n about 0.0l and about 2.0 weight percent.

In other non—limiting ments, the premixed dexmedetomidine composition of the present invention comprises dexmedetomidine, or a pharmaceutically acceptable salt thereof, at a concentration of about 4 rig/ml; and sodium chloride at a concentration of about 0.90 weight percent.

In one non—limiting example, the 0.9% NaCl solution is formulated by mixing 9.0 g NaCl / 1000 mL of water. In certain embodiments, the premix NY02:746890.I _- 12 — 0773500356 compositions of the present ion are formulated by adding 0.118 g dexmedetomidine HCl plus 9.0 g NaCl into the same 1000 mL of water. The solution can. then be mixed with addition, 0.9% NaCl solution to achieve a desired concentration of dcxmedetomidine, for example, 4 ug/mL.

VI In certain miting embodiments, the premixed dexmedetomidine composition of the present invention is disposed in a container or vessel that can maintain the sterility of, or prevent the contamination of, a ed dexmedetomidine composition that is purified or substantially free of any inants. In certain non—limiting embodiments, the container or vessel is a sealed container or vessel. in certain non-limiting embodiments, the etomidine composition of the present invention is disposed in a container or vessel and is formulated as a premixture. in certain non-limiting embodiments, the premixed dexmedetomidine composition of the present ion. is disposed in a container or vessel and is formulated, as a single use dosage. In certain miting embodiments, the premixed dexmedetomidine composition of the present invention is disposed in a container or vessel and. is formulated as a dosage for multiple use.

In certain non—limiting ments, the container or vessel includes, but is not limited to, glass vials (for example, but not limited to, flint glass vials), ampoules, c flexible containers, for example, but not limited. to, PVC (polyvinyl chloride) containers, VisIVTM plastic containers (Hospira, Inc, Lake , IL), and CR3 elastomer copolyester ether containers ra, Inc, Lake , IL), CZ resin containers, poly propylene containers and syringes.

In certain non—limiting embodiments, the premixed dexmedetomidine composition of the present invention can be stored as a liquid in an aliquot having a total volume of between about 1 and 50011114, or between about 1 and 250 mL, or between about '1 and 200 mL, or between about 1 and 150 mL, or between about 1 and 125 mL, or. between about 1 and 120 mL, or between about 1 and 110 mL, or Lu 0 between about 1 and 100 mL, or between about 1 and 90 mL, or between about 1 and 80 mL, or between about 1 and 70 mL, or n about 1 and 60 mL, or between about 1 and 50 mL, or between about 1 and 40 mL, or between about 1 and 30 mL, or between about 1 and 20 mL, or between, about '1 and 10 mL, or between about 1 and 5 NY021746396. I _ 13 _ 0773500356 In certain non-limiting embodiments, the premixed dexmedetomidine composition of the t invention can be stored as a liquid in an t having a total volume of about 5 mL, or about 10 mL, or about 15 mL, or about 20 mL, or about 25 mL, or about 30 mL, or about 35 mL, or about 40 mL, or about 45 mL, or (Jr about 50 mL, or about 55 mL, or about 60 mL, or about 65 mL, or about 70 mL, or about 75 mL, or about 80 mL, or about 85 mL, or about .90 mL, or about 95 mL, or about 100 mL, or about 105 mL, or about 110 mL, or about 115 mL, or about 120 mL, or about 125 mL, or about 130 mL, or about 135 mL, or about l40 mL, or about 145 mL, or about 150 mL, or about 2.00 mL, or about 250 mL, or about 500 mL. in certain non—limiting embodiments, the premixed dexmedetomidine composition of the present invention can. be stored as a liquid in an aliquot having a totai voiume of about 20 mL. in certain non—limiting embodiments, the premixed dexmedctomidine composition of the present invention can. be stored as a liquid in an aliquot having a l5 total volume of about 50 mL. in certain. miting embodiments, the premixed dexmedetomidine composition of. the present invention can be stored. as a liquid in an t having a total voiume of about 100 mL. 4.3 Methods of Using ed Dexmedetomidine Compositions In accordance with the invention, there are provided methods of using a premixed dexmedetomidine composition. In certain non—limiting ments, the present invention provides for preoperative treatment of a patient to reduce the response of the autonomic nervous system to stimuli during an operation by administering a dexmedetomidine composition of the invention, as described in U .8.

Pat. No. 5,344,840. In other non~limiting embodiments, the dexmedetomidine compositions of the present invention can be stered as a sedative. In certain embodiments, the composition is administered preoperatively to potentiate the effect of an anesthetic, wherein administration of the composition reduces the amount of anesthetic required to achieve a desired level of anesthesia. In certain embodiments, the dexmedetomidine compositions of the present invention can be stered as an ytic analgesic premedication prior to the operation with or without administration. of an amount. of an, etic effective to achieve a desired level of local or general anesthesia. in certain embodiments, the dexmedetomidine NYO2:74(789().1 0773500356 compositions of the present invention are formulated as a pharmaceutical composition for use in a method of on, analgesia or treatment of anxiety or hypertension.

In certain non—limiting embodiments, the patient treated with the premixed dexmedetomidine composition of the invention is intubated. The patient Ur may be intubated prior to, during, or after administration of the ed dexmedetomidine composition. The patient may be ted by the nasotracheal, endotraclieal, direct oral laryngoscopy or by ptic routes, or via tracheotomy, for example, while being treated in an intensive care unit (ICU), which, as used herein refers to any setting that es intensive care, as described, for e, in US.

Pat. No. 867. For example, the compositions of the invention can be used for sedating a patient in an intensive care unit which means rendering a patient calm and treating conditions that affect patient comfort, such as pain and anxiety, in any setting that provides intensive care.

In other non-limiting embodiments, the premixed dexmedetomidine compositions of, the present ion can be administered to a patient as a perioperative treatment. in certain embodiments, the composition can be administered as a premedication prior to an operation. In certain embodiments, the premixed dexmedetomidine compositions of the present invention can. be used in the manufacture of a medicament for erative treatment of mammals to reduce the responses of the autonomic nervous system. to stressful. stimuli during an operation, for example, as described in US. Pat. No. 5,344,840.

In other non—limiting embodiments, the premixed etomidine compositions of the present invention can be administered. to a patient as an adjunct anesthesia. For example, the composition can be administered with or without an amount of an anesthetic effective to achieve a desired level of local or general. anesthesia, for example, as described. in US. Pat. No. 5,344,840. In certain embodiments, stration of the compositions of the present invention reduces the amount of anesthetic required to achieve a desired level of anesthesia.

In other non—limiting embodiments, the patient treated with the premixed dexmedetomidine composition is critically ill. In one embodiment, the patient suffers from one or more medical conditions. in certain embodiments, the medical condition is a lung m, brain problem, heart problem, liver problem, kidney problem, eye or car problem, gastrointestinal problem, or skin problem. Non— ng es of lung ms include atory distress syndrome, NY021746890. l - 15 _ 0773500356 nia, bronchopulmonary dysplasia, apnea of prematurity, and pneumothorax. miting examples of brain problems include intraventricularhemorrhage, and cerebral palsy. Non—limiting examples of liver problems includejaundice. Non- limiting examples of heart problems include patent ductus arteriosus. Non-limiting (J) examples of eye problems e retinopathy of prematurity, myopia, and strabismus. Non—limiting examples of other medical conditions includes heroin withdrawal, cocaine withdrawal, alcohol fetal syndrome, HIV-positive status, and Tay Sachs disease.

In. one ment, the patient has undergone surgery. The patient may undergo surgery prior to, , or after administration of the premixed dexmedetomidine composition. Non—limiting examples of y include cardiopulmonary bypass.

In other non—limiting embodiments, the premixed dexmedetomidine compositions of the present invention can be stered to a patient as an anxiolytic or sic agent, for example, as described in U.S. Pat. Nos. 5,344,840 and 6,716,867. In one non-limiting example, the method comprises local epidural. or intraspinal administration of the premixed dexmedetomidine composition of the invention. "in other miting embodiments, the premixed dexmedetomidine itions of the present invention can be administered to a patient to lower intraocular re, for example, in the treatment of glaucoma, as described in 15.8.

Pat. No. 5,304,569.

In certain embodiments, the premixed dexmedetomidine compositions of the present invention do not e any other active ingredient, or therapeutic agent, other than dexmedetomidine. in certain non-limiting embodiments of the present invention, the premixed dexmedetomidine composition can be administered as a single continuous dose over a period of time. For example, the premixed dexmedetomidine composition can be stered intravenously for a period of time of between about 1 and about minutes, or between about 1 and about 20 minutes, or between about 1 and about minutes, or between about 1 and about 2 hours, or n about 1 and about 3 hours, or between about 1 and about 4 hours, or between about 1 and about 5 hours, or between about l and about 6 hours, or between about i and about 7 hours, or between about 1. and about 8 hours, or between about i and about 9 hours, or between about 1 NY021746896.l ~16- 0773500356 and about 10 hours, or between about 1 and about 11 hours, or n about 1 and about 12 hours, or between about 1 and about 13 hours, or between about 1 and about 1 4 hours, or between about 1 and about 1.5 hours, or between about 1 and about 16 hours, or between. about I and about 17 hours, or between about I and about 18 hours, or between about 1 and about '19 hours, or between about 1 and about 20 hours, or between about 1 and about 21 hours, or between about 1 and about 22 hours, or between about 1 and about 23 hours, or between about 1 and about 24 hours, and administered at a dosage of between about 0.005 ug/kg/hr and about 5 hr, or between about 0.005 ttg/kg/lir and about 4.5 ug/kg/hr, or between about 0.005 ug/kg/hr and about 3 ug/kg/hr, or between about 0.005 hr and about 2.5 ug/kg/hr, or between about 0.005 hr and about 2 ug/kg/hr, or between about 0.005 ug/kg/hr and about 1.5 ug/kg/hr, or between about 0.005 ug/kg/hr and about 1 ug/kg/hr, or between about 0.005 ug/kg/hr and about 0.5 ug/kg/hr, or between about 0.005 ug/ltg/hr and about 0.25 ug/kg/hr.

In other non—limiting embodiments of the present invention, the ed dexmedetomidine composition can be administered as a loading dose followed by a maintenance dose over a period of time. For example, the loading dose can comprise administration of the premixed dexmedetomidine composition at a first dosage amount for a first period of time, followed by administration of the maintenance dose at a second dosage amount for a second period of time. The loading dose can be administered for a period of time of between about 1 and about 5 s, or between about 1 and about 1.0 s, or between about 1 and about 1.5 minutes, or between about 1 and about 20 minutes, or n about 1 and about 25 minutes, or n about 1, and about 30 minutes, or between about 1. and about 45 minutes, or between about 1 and about 60 minutes. ing the loading dose, the maintenance dose can be administered for a period of time as described above for a single continuous dose.

In certain non— limiting embodiments, the premixed dexmedetomidine composition, when administered as a single continuous, loading or maintenance dose, is administered for a period of time of about 1 hour to about 7 days, or about 1 hour to about 4 days, or about 1 hour to about 48 hours, or about 1 hour to about 36 hours, or about 1 hour to about 24 hours, or about 1 hour to about 12 hours.

In certain non—limiting ments, the premixed dexmedetomidine composition, when administered as a single continuous, loading or maintenance dose, NY02:74(1896.1 - 17 _ 0773500356 is stered for a period of time of about 24 hours to about 120 hours, or about 24 hours to about 108 hours, or about 24 hours to about 96 hours, or about 24 hours to about 72 hours, or about 24 hours to about 48 hours, or about 24 hours to about 36 U] When administered as a loading dose followed by a maintenance dose, the loading dose and/or maintenance dose can be a dose of between about 0.005 ug/kg/hr and about 5 ug/kg/hr, or between about 0.005 ug/kg/hr and about 4.5 ug/kg/hr, or between about 0.005 ug/kg/hr and about 3 ug/kg/hr, or between about 0.005 hr and about 2.5 ug/kg/hr, or between about 0.005 ug/kg/hr and about 2 ug/kg/hr, or between about 0.005 ug/kg/hr and about 1.5 ug/kg/hr, or between about 0.005 ug/kg/hr and about I. ug/kg/hr, or between about 0.005 ug/kg/hr and about 0.5 ug/kg/hr, or between about 0.005 ug/kg/hr and about 0.25 hr.

In a preferred non-limiting embodiment, the premixed dexmedetomidine composition is stered as a loading dose followed by a maintenance dose, wherein the loading dose is about 1 ug/kg/hr fora period of about minutes, followed by a nance dose of between about 0.2 hr to about 1. ug/kg/hr, more preferably, between about 0.2 ug/kg/hr to about 0.7 ug/kg/hr.

In other preferred non~limiting embodiments, the premixed dexmedetomidine composition is administered as a g dose followed by a maintenance dose, wherein the loading dose is about 0.5 ug/kg/hr for a period of about 1.0 minutes, followed by a maintenance dose of between about 0.2 ug/kg/hr to about i ug/kg/hr, more preferably, n about 0.2 ug/kg/hr to about 0.7 ug/kg/hr. in certain non-limiting embodiments, the dosage of ed etomidine composition administered as a single continuous, loading or [\J U: maintenance dose, is titrated until a desired effect is achieved. in some patients, the quaiity of the sedation achieved by stering the premixed dexmcdetomidine composition of the present invention can be unique.

In one non-limiting example, a patient sedated by the premixed dexmedetomidine composition is arousable and oriented. The patient can be awakened and is able to respond to questions. The patient is aware and can tolerate an endotracheal tube.

Should a deeper level of sedation be required or desired, an increase in dose of the composition of the invention can be administered to transit the patient into a deeper level of on.

NY021746896. I 0356 in certain. non—limiting embodiments, the itions of the invention can be administered to non-ventilated patients who require sedation, anxiolysis, analgesia, or hemodynamic stability in an amount to achieve a sedative, anxiolytic, analgesic or hemodynamic stabilizing effect in the patient.

. EXAMPLES The following examples are merely illustrative of the presently disclosed subject matter and they should not be considered as limiting the scope of the invention in any way.

EXAMPLE 1: Seiection of Packaging Components for the Premixed Dexmedetomidine Pharmaceutical Composition In order to identify suitable primary packaging components for the 4 ug/mL premixed dexmedeto‘midine composition in 0.9%NaCl, ity studies were conducted in. s configurations including glass vials, ampoules, plastic flexible containers (CR3 elastomer copolyester ether containers (Hospira, Inc, Lake Forest, IL), PVC and VisIVTM plastic containers (Hospira, Inc, Lake Forest, 119)), and Ansyr® syringes (Hospira, Inc, Lake Forest, IL). A batch of premixed dexmedetomidine composition was prepared at the premix concentration of 4 ug/mL, in 0.9% NaCl. Solution was filled into 20 mL ampoules, 50 :mL glass vials, 100 mL PVC flexible containers, 100 mL CR3 elastomer copolyester ether e containers (Hospira, Inc, Lake Forest, IL), 50 mL VisIVTM plastic (Hospira, Inc, Lake Forest, IL) flexible containers, and 10 mL Ansyr® syringes (Hospira, Inc, Lake Forest, IL), and all, configurations were autoclaved. The pH and potency (using HPLC method) of the sterilized samples were ined. The stability of the autoclaved samples under accelerated conditions (40°C/75%RH) was also evaluated over a period of 5 months (Table l)‘ Potency was evaluated using a HPLC method. Post sterilization L.) 0 potency values ranged from 73-88%. The solution pHs varied from 4.7—6.2 ing an iii-process result of 6.0. Two weeks samples stored under ambient conditions were tested for pH, y and. d substances. The two weeks potency results Were considered as time zero s because the 4 ; formulation remains stable at room temperature for more than 2 weeks. Comparison of potency results at time zero NY02:74689(),1 .0356 in different configurations indicated a drop in potency of premixed dexmedetomidine composition filled in CR3 elastomer copolyester ether bags (Hospira, Inc, Lake Forest, IL) and VislVTM c bags (Hospira, Inc, Lake Forest, IL), after sterilization (Table l).

U\ The stability of the autoclaved samples under accelerated conditions (40°C/75%RH) was also evaluated over a period of 5 months (Table 1). After five months under accelerated conditions the potency of the premixed dexmedetomidine composition in glass ampoules and vials remained at about 98% while that in the e was found to be about 90%. In PVC and CR3 elastomer copolyester ether bags (Hospira, Inc, Lake Forest, IL), after the initial potency loss no r loss of potency was ed during the five month period.

Table l: 4 pig/mt. Premixed Dexmedetomidine Composition in Normal Saline Formulation Stability i 2 t 1 $— 2 3 5 l ' Week/2 i i Month/ Month/ Month/ I I M'onth/ °C i 40"C ' 40°C 40°C 1 40°C i i Avg ‘ ~Avg i W? “1 Avg Avg Avg Potency i Potency Potency Potency Potency (%) pH (%) pH (%) (%) (%) i iAmpoule; i 99.0 5.0 99.0 5.6 . 97.7 98.3 987 ._ mm. + -< Vial 98.2 99.4 6.3 98.0 g 6.71 98.3 i 986 Syringe 95.0 5.5 94.6 5.7 92.2 a 89.5 90.8 % ' ‘ WW ............... i--- y a-..”....... i CR3 80.2 4.7 79.5 4.8 NT 75.3 792 x_.~_._.. _i¥ i ....

.. I PVC 79.9 4.8 § 81.4 4.6 NT 79.0 76.7 m.” 1______w i/is—tvmi 95.8 5.9 i 92.8 5.8 NT 940 NT ; i g ' a--- i NT — Not tested NY022746896. I 0773500356 The cause of potency loss in PVC bags and CR3 elastomcr copolyester ether bags (HOSpira, Inc., Lake Forest, IL) during autoclaving was investigated.

Related substances testing on autoclaved premixed dexmedetomidine composition filled in PVC and CR3 elastomer copolyester ether bags (Hospira, Inc, Lake Forest, UK IL) revealed that potency drop did not occur due to degradation, because the total percent of impurities was much less than 20% (Table 2). Loss of potency may be due to either adsorption (restricted to the surface of the flex bag) and /or absciption (not restricted to the surface) of the drug in to the flex bags. To confirm the absorption/adsorption phenomena, the CR3 elastomer copolyester ether bags (Hospira, inc, Lake Forest, IL) and PVC bags that showed 20% y loss were emptied and rinsed with. MeOH. The rinse solvent was tested, for dexmedetomidine.

Nearly all the drug was red from CR3 elastomer copoiyester ether bags (H’ospira, Inc, Lake Forest, IL) — ting adsorption and only 1 % of the drug was recovered from PVC bags — indicating absorption, since drug dissolves in DEHP.

The related nces s indicated that premixed etomidine composition in VisilVTM plastic bags (Hospira, Inc, Lake Forest, IL) had high impurity ievels (Table 2), higher than levels observed in ampoules, vials, syringes, PVC bags and CR3 elastomer copolyester ether bags (Hospira, Inc, Lake Forest, IL).

Table 2: Impurity Results for 4 pg/rnL Premixed Dexmedetomidine Composition 2 week/”250C i 40°C Iota] impurity (%) M _ Totaii‘gppurity (%) Ampoule 0.66% i 054% {Van 0.02% INT , a.“ , _ WWJ Syringe 0.49% “ _J 1.48% CR3 i.6‘l% 5.88% ;iPVC "mm ” ‘ .2.26% NT m 39.08% 7.02% i g EXAMPLE 2: Development in tage® PVC (Hospira, Inc, Lake Forest, IL) Admixture System In this study three 2501nL ADDVantage® PVC bags (Hospira, Inc, Lake Forest, IL) were spiked with 10 mL of dexmedetornidine concentrate (100 NYO2:746896.I 0773500356 ug/mL) to obtain a final concentration of 4 ug/mL. As a control, a glass bottle was spiked in the same manner. Upon thorough mixing of the samples, an t was withdrawn for subsequent y analysis. The bag was then allowed to sit on the bench top for various interval testing. The results showed that there is a drop in potency after the l, mixing period and a slight decrease thereafter (Table 3).

Table 3: 4 ug/mL Premixed Dexmedetomidine Composition ADDVantage® PVC bag (Hospira, inc, Lake Forest, IL) Admixture Study i Time Following Admixture 3%"ESAE'E'rm—l Tmmcdi ately 5 .3 4 Hours % 5.6 TWMW 8 Hours 6 0 24 Hours 5 5”" 1 _________ 48 Hours 5.8 ’ 72 Hours T??— 7 Days 6.1 § _i * Average of three spiked bags compared to glass bottle.

EXAMPLE 3: Modification of the Premixed Dexmedetomidine Composition Formulation The pH of the premixed dexmedetomidine composition formulation can affect the adsorptiOn of dexmedetomidine le. The free base form of dexmedetomidine is more adsorptive. At lower pH ~ 4.0, most of the dexmedetomidine is in the ionized form, which minimized adsorption and thereby loss in potency. Buffered formulations were tested to determine whether loss of potency in flex bags can be zed.

NY02:746896.1 0773500356 Buffered ations were prepared at different pHs 3.0, 3.4, 4.0, and 4.5 using acetate, citrate, lactate and ascorbate buffer. Since the pKa for dexmedetomidine is about 7.1, at this pH the molecule might be protonated sufficiently to retard adsorption. Post—autoclave potency values dropped approximately 10% in all ces; this was an. improvement from the 20% decrease observed. in the unbuffered formulation in Example 1.

In a second study, additives were formulated with the premixed dexmedetomidine composition to prevent adsorption of the dexmedetomidine to CR3 elastomer copolyester ether (Hospira, Inc., Lake Forest, IL). The following additives were tested: ethyl alcohol, benzyl alcohol, methyl parahen, propyl paraben, PEG 1000, rbate 20 and 80, propylene glycol. Formulations prepared included additives in both ed and unbuffered ed dexmedetomidine composition.

Both these reformulation. gies reduced potency loss. .4 k/I Stability testing of the 4 ug/mL premixed dexmedetomidine composition (unbuffered saline fonnulation), in glass vials and ampoules stored at °C, after 9 months was perfonned. Potency remained relatively unchanged from initial measurements. Additionally, the largest single impurity detected in the samples was present at a concentration of 0.06%.

EXAMPLE 4: ity of the Premixed etomidine Composition The stability of dexmedetomidine hydrochloride to acidic, basic, oxidative and photolytic stress was examined. In order to demonstrate the resiliency of dexmedetomidine, even when present in extremely low levels (ppm or ug/mL levels), dilute solutions of dexmedetomidine (approx. 13.3 ug/mL) were separately subjected to acidic, basic, oxidative and photolytic stress and then d with 0.9% Sodium Chloride to a final nominal concentration of 4 ug/mL and assayed by HPLC NY02:746896.1 _ 23 _ 0773500356 with a photodiode array (PDA) detector for spectral, peak purity analysis. Each sample was injected in duplicate. The stress conditions are listed in Table 4.

Table 4: Stress Conditions Stress i Condition Description .0 mL of a 40 ug/mL stock Dexmedetomidine Hydrochloride solution" and 10 rnL of 5N hloric Acid were added to 20 mL scintillation vial. The vial was placed in an oven at 60°C for 8 Acid hours. The on was then diluted with 0.9% NaCl to 4 gig/ml.“ .0 mL of a40 ug/mL stock Dexmedetomidine Hydrochloride solution* and 5 mL of 2N Sodim Hydroxide were added to 20 mL llation vial. The vial was placed in. an oven. at 60°C for 4 Base hours. The on was then diluted with 0.9% NaCl to 4 ug/mL. .0 mL of a 40 ug/rnL stock Dexrnedetornidine Hydrochloride solution* was added to 20 mL scintillation vial. The vial was placed in. an. oven at 60°C for 8 hours. The on was then diluted with Thermal. 0.9% NaCl to 4 ug/mL. solution“ and 5 rnL of 0.3% Hydrogen de were added to 20 inL scintillation vial. The vial was placed in an oven at 60°C for 8 H202 hours. The solution was then diluted with 0.9% NaCl to 4 ug/rnL. } 5.0 ml, of a 40 ug/mL stock, Dexmedetomidine Hydrochloride solution* were added to 20 mL scintillation vial and placed into a photochemical. reaction. unit for 24 hours. The solution was then Light diluted with 0.9% NaCl to 4 ug/mL. i 5.0 mL of a 40 ug/mL stock Dexmedetomidine Hydrochloride a solution" i was added to 20 mL scintillation vial. The vial was not 3 subjected to any stress condition. The solution was then diluted l Control with 0.9% NaCl to 4 ug/mL.

S * Stock solution of dexmedctornidine HCl was prepared in 0.9% NaCl solution.

NYO21746896.1 _ 24 - 077350.0356 The peak purity is shows that under all stress conditions the parent peak were spectrally pure, attesting to the assay being performed under conditions of specificity. See Table 5 for Potency Results.

Under oxidative conditions, the sample showed t amount of Ur degradation (12.7%) compared to the control sample. Appropriate precautions are taken during manufacturing and packaging to prevent ive stress.

Thermal stress studies indicate that the premixed dexmedetomidine composition is stable at high temperature. It is also ed by accelerated stability studies, n. potency values ed within shelf life cations over a period of 6 months. er the premixed dexmedetomidine composition. is a terminally sterilized product. Hence, it is expected that premixed dexmedetomidine composition would remain stable if exposed to temperature excursions during transportation or storage.

Table 5: Forced Degradation Results Samples ID Assay Control Sample 98.4% i .

Acid Sample 95.2% i BaseWSainple ________“Al 93.8% Heat Sample 98.4% ion Sample 85.7% Light Sample 92.0% EXAMPLE 5: Manufacture of the Premixed Dexmedetomidine Composition Formulation A 4 ug/mL premixed dexmedetomidine composition can be manufactured according to the following process: Water for injection is added to a mixing tank to approximately 110% of the final volume and heated to 80°C. Nitrogen sparging in the tank is started and maintained throughout the manufacturing process.

Water for lnj ection is then cooled and a sufficient amount of water is withdrawn from the tank, to leave approximately 90% of the final volume in the mix tank.

NYOZ:74689().l _ 25 _ 0773500356 etomidine HCl is then added to the tank and mixed for not less than 1.5 minutes. Sodium chloride is then added and mixed. The solution is then divided into batch size. An in~process sample is then evaluated for pH and potency. The nitrogen protection is maintained.

Filtering of dexmedetomidine composition The dexmedetomidine solution is filtered prior to filling in a clinician- useable container. For the 20 mL batches, solution is filtered through Pall Nylon 66, 0.45 pm filter ne with a pre filter. For 50 and 100 mL batches, solution is filtered through Nylon 66, 0.22 pm filter membrane with a pre filter. A filter compatibility study was med using Pall Nylon 66 0.45 pm filter. It was determined that filters had little to no impact on the ed dexmedetomidine composition product after 52 hours of recirculation. The prolonged exposure of these filter materials did not produce any significant potency or pH changes in the drug t (See Table 6). Additionally, there was no change in bubble point for the filters before and after exposure.

Table 6: Filter compatibility testing Time Sample Tested Pall Nylon 66 filter (Pall. Corp, Port Washington, ! NY) , .

Potency (%) pH E _! tration Tank (0 hr) ‘ 99.8 6.30 i S ! g minute static-filter hold 97.3 6.01 i sample one hour tank I 99.4 E 6.17 Six hour tank 99.1 7, 6.18 EMS?” "— 99.2 i 6.23 , hour tank 98.9 t 6.24 1:52 hour tank 99.3 J ‘617 ~flitrogen protection durinng The transfer line from solution manufacturing to filling is ally flushed with filtered nitrogen gas prior to filling. The filling equipment, including all lines are purged with nitrogen before starting to til} the product. An atmosphere of NY02:746896.l —26- 0773500356 filtered nitrogen gas is maintained in the headspace of the surge bottle. After filling, the headspace of the container is gassed with nitrogen to achieve not more than 5% of oxygen in the headspace.

Hold Time The following time limits will be applied to manufacture of the sub} ect drug product: Total time for filtration and filling: NMT (Not More Than.) 16 hours Total time for manufacturing (from compounding to end of filling): NMT 24 hours Sterilization The premixed etomidine composition is ally sterilized.

Vials filled with the composition are autoclaved using 15 30 minutes exposure at 12} — 124°C.

Container closure system The 4 ug/mL ed dexmedetomidine composition can be manufactured in three configurations: 20 mL fill in 20 mL vial, 50 mL fill in 50 mL vial and 100 mL fill in 100 mL vial. Examples of packaging components for the 20 mL, 50 mL and 100 mL configurations are listed in Tables 7, 8, and 9 below.

Table 7: Container Closure System for 4 tig/mL Premixed Dexmedetomidine Composition, 20 mL ! y Packaging Materials : Kimbic USP Type 1, Clear Tubing Glass Vial, Sulfur—TreatedTQO mm, i0 mL ; (Kimble Chase, Vineland, NJ) Westmmr‘ayrubber Closure er), 20 mm (West Pharmaceutical Services, Inc.) Lam“.._a,,tl...mmmm_._._m........

: Seal, Flip~0ff® (Blue or Cray) elastomer stoppers, 20 mm, (West Pharmaceutical es, Inc, Lionville, PA) Table 8: Container Closure System for 4 ug/mL ed Dexmedetomidine Composition, 50 mL Materials i 1 Primary Packaging I Gerresheirner USP Type 1, Glass Vial (Bottle), Sulfur—“Treated”, 28 mm, 50 mL NY0227468901 _ 27 _ 0773500356 """""" i (G-erresheimer Glass Inc, Vineland:Nl) l WWJ [Helvolet FM 259/0 Gray with OmniflexPlus® Fluoropolymer coating Rubber i Closure (Stopper), 28 mm et Pharma, Datwyler USA, Pennsauken, NJ) l r . S Table 9: Container Ciosure System for 4 ng/mL Premixed. Dexmedetomidine Composition, 100 mL Primary Packaging Materials Gerresheimer USP Type I, Glass Bottle, Sulfur-Treated, l00 mL—ZGen‘esheimer Glass Inc, Vineland, NJ) Closure er), 28 mm (Helvoet Pharma, Datwyler USA, Pennsauken, NJ) Aluminum Seal, Cverseal Assembly, 3 piece, 28 mm Mi .

U} Batch Formula Examples of qualitative and tative batch a for a ration batch and a commercial batch for a 4 pg/mL premixed dexmedetomidine (dexmedetomidine hydrochloride) composition, for a 20, 50, and. 1.00 mL presentation are presented in. Tables 10 and 11 below.

Table 10: Batch Formula for 4 ug/mL Premixed Dexmedetomidine Hydrochloride Composition, 20 mL 3 Registration Maximum ‘7 Component Stability Batch Commercial Batch Size: Size: {bexmedetomidine HCl 2.832 mg 25.96 mg :LgSodium. Chloride + .4 g "27:95 g Water for Injection USP q.s. to 600 Liters q.s. to 5500 Liters Jf - Nitrogen NF3 AR. i A.R. q.s. = Quantity sufficient NY0217468962 - 28 _ 0773500356 AR. = As required Factored to 100% basis.

The final pH range of the finished product is 4.5 vvvvvv 7.0.

Nitrogen is used. to displace air during manufacturing (ie. to blanket the formulation and to fill the Vial headspace).

Table l 1: Batch Formula for 4 pg/rnL Premixed Dexmedetomidine Hydrochloride Composition, 50 & 100 mL Registration Maiiiimuuih“““““w Component Stability Batch cial Batch.

Size: Size: Dexmedetomidine HCl i 4.72 mg 33.04 mg ' “M Sodium Chloride 9 g 63 g Water for ion .. é m USP (1.5. to 1000 Liters q.s. to 7000 Liters "my???“ AR. "U“R (1.5. =2 Quantity sufficient AR. = As required Factored to 100% basis.

The final pH range of the finished drug product is 4.5 —- 7.0. en is used. to displace air during manufacturing (i.e. to blanket the formulation and to fill the Vial headspace).

In-Process Specification Examples of in-process controls during the manufacturing process for the 4 pg/mL premixed dexmedetomidine ition are presented in Table 12.

N\’02:746896.l 0773500356 Table 12: Iii-Process Specification Iii-Process In~Process Unit Operation centrol/Test Procedures or Methods Limit pH """""" ' Solution Preparation USP <79l> 4 5—: 7.0 HHWW9?” (Compounding) Assay HPLC _ ._ _ _. i Perform fill Weight/volume weight/volume checks per Meets ' Filling Process control SOP requirements i An example of final product limits f6} physical, chemical, and biological testing of 4 ng/mL premixed dexmedetomidine composition are listed in the Table 13.

Table 1.3 Premixed Dexmedetomidine Composition Specifications Test 5 ance Criteria Clarity particles Visible upon attentive inspection “ll-”50.0% — 110.0% _ : Assay (9.00 mg/mL _. 1.10 mg/mL) Color wEMColorless : fabel Claim m able Range mL 20.5 -— 22.5 mL 50 mL 50.0 —- 54.5 mL Volume 100 mL 102.0 ~~ 10.8.0 mL figfififiifi?""""""W NMT 1.0% -. -.

Related Substances: A. Individual A. NMT 0.5% B. Total B. NMT 1.0% 90.0% — 110.0% Sodium Chloride f (8.1 mg/mL — 9.9 'mg/mL) E NMT 25/nii "710 mm Particulate Matter NMT 3/mL 3 25 mm ity — E Meets USP requirements § ial. Endotoxin J NMT 0.08 EU/mL NYO22740890.1 -30_ 0773500356 E 6: Stopper Selection for Glass Vials The objective was to have three presentations of ex® (dexmedetomidine hydrochloride, Hospira, Inc, Lake Forest, IL) premix Inj ection 4 ug/mL: 201131,, 50 mL and 100 mL. Precedex® concentrate Injection IOO ug/rnL is currently marketed in 2mL glass vial with West 4416 Teflon coated elastomer stopper (West Pharmaceutical Services, Inc, Lionville, PA).

Uncoated infusion stoppers, were evaluated. 28 mm Helvoet 5330 l() rubber stopper (Helvoet Phanna, er USA, Pennsauken, NJ), EDPM rubber stoppers (EPSI, Franksville, WE) and West 4432 elastomer stoppers (West Pharmaceutical Services, Inc.) were investigated. During feasibility testing loss of potency and stopper extractables were ed. The performance of coated. stoppers was compared with that of uncoated rs (West 4432 and Helvoet 5330) by conducting feasibility studies on West 4588/40 FluroTec® elastomer stoppers (West Pharmaceutical Services, Inc, Lionville, PA). Results showed a clear benefit to using a coated stopper vs. the ed stopper. The potency remained stable with the coated stopper. Hence for Precedex® Injection, it was d to implement coated stoppers in order to mimic the current product and prevent any drug adsorption.

Helvoet FM 259/0 xPlus® fluoropolymer coated rubber stoppers (Helvoet Pharma, Datwyler USA, Pennsauken, NJ) 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 OmniflexPl‘us® coated stopper from Helvoet, was examined for determining the self (K) U: sealing characteristics of the stopper when ated multiple times with hypodermic needle. This is a dye ingress test. The new stopper/vial/3-piece overseal combination passed this test. Helvoet OmnifiexPlus® coated r passed the Rocky Mount pressure test at the ed 80 psi criterion. These stoppers, vials and overseals were also evaluated by Tech Ops for functional testing to confirm that the stoppers can be d t being pushed into the vial. All testing indicated that the stoppers are acceptable for use.

Feasibility stability studies were conducted by preparing a batch of Precedex® injection 4 pg/mL and filling into 50 mL vials with the Helvoet OmniflexPlus® stoppers followed by autoclaving. Samples were stored under NYO2:746806.l 0773500356 accelerated (40°C/75% relative humidity, inverted) and long term (25°C/60% relative humidity) conditions. Initial testing showed no loss in potency, no change in pltl, and. virtually no measurable ties. The 1 month ity 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 ged as compared to that of 2 months, indicating 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 (250C/60% relative humidity) but the t drop was less. The total percent drop in potency over three months under long term conditions was 1.1%. Stability g 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 hatch 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 of c vials were used: CZ resin and poly propylene vials.

West 4432 Teflon coated 20 mm elastomer stopper (West Phannaceutical Services, lnc.) was used for both the plastic vials. The pH, potency and impurities of Precedex® ion 4 mcg/mL filled in plastic vials and stored under accelerated conditions over a period of 3 months was determined. r trend in potency drop was observed.

The total % impurities were found to se over a period of 3 months for both CZ resin vials and polypropylene 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 pg/mL, even ppb leVels of impurities would have a significant contribution toward the ty limit. Moreover the Precedex® related substances method was ped to detect organic impurities at ppb levels. This method. requires detection at scriminating low wavelength of 2l0 nm and high injection volume of 500 pl, which render it highly sensitive to detect any organic impurity, including stopper extractables.

NYO2:7468‘)6.1 _ 32 _ 0773500356 Extractables West 4432/50 Teflon 2 coated mer stoppers (West Pharmaceutical Services.

Inc.) The West 4432/50 Teflon 2 coated elastomer stopper, 20 mm is used for Precedex® Inj ection 4 ug/mL, 20 mL presentation. The stoppers have been qualified for use based on the results of compendial biological, physiochemical and other characterization tests. The related substance testing of Precedex® Injection has not shown any unidentified peaks that exceed the specification ofNMT 0.2%, l0 suggesting that extractables are not an issue for ex® Injection in this container closure system. t FM 25 9/0 Omniflex® fluoropolymer coated. rubber rs (Helvoet Pharma, er USA, Pennsauken, NJ) The Helvoet Omniflex® fluoropolymer coated FM259/O gray bromobutyi 28 mm rubber stoppers (Helvoet Pharma, Datwyler USA, Pennsauken, NJ) (ready—to-use) are used. for ex® Injection 4 ug/mL, 50 and 100 mL presentations. The stOppers have been qualified for use based on the results of dial biological, physioehemical and other characterization tests performed During related substances analysis of the exhibit. batches of Precedex® 4 ug/mL Injection, unidentified impurity peaks were observed in chromatograms of 50 and 1.00 mL presentation. samples. During investigation of the source of chemical constituents responsible for the ntified impurity peaks’. it was found that these peaks also appeared. in chromatograms of 0.9% NaCl placebo formulation filled into 50 mL vials with Helvoet FM25 9/0 rubber stoppers (Helvoet Pharma, Datwyler USA, Pennsa’uken, NJ), but were absent in those of 0.9% NaCl placebo formulation filled into glass es. Additionally identical, peaks were observed in chromatograms of Helvoet FM259/O rubber r (Helvoet Pharma, Datwyler USA, uken, NJ) extract solution analyzed by Precedex® related substances method. The extract was ed by autoclaving (121°C for 60 minutes) 30 rs 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. d, but were extractables from Helvoet rubber stoppers NY0227468961 0773500356 used in the container/closure system. It was expected that stopper extractables would be detected at such low limits of detection, i..e. ppb , as a highly sensitive 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 , Datwyler USA, Pennsauken, NJ), part of ner closure system for Precedex® lnj cation 50 and 1.00 1111.. Moreover no peaks were found in these specific relative retention times in tograms of forced l0 degradation samples of dexmedetomidine HCI or Precedex® Injection filled in arnpoules. Hence in the calculation of single largest related substance and total related substances, peaks in relative retention time ranges: 0.71—0.80, 1.10—1.30, .80 are excluded. ln an effort to quantify the highest levels of observed individual extractable and total extractable, dexmedetomidine H'Cl was used as a surrogate standard. for all. r extractables. Since, the Helvoet FM25 9/0 rubber stopper (Helvoet Pliarma, Datwyl er USA, Pennsauken, NJ) 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 Precedex® stability s stored. at 30°C/65%.relative humidity for 3 months. The largest individual extractable "/0 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 RR'l‘ 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, NJ") passed the ‘Elastomeric Closures for Injections’ testing. As per Helvoet technical documentation the total amount of extractables was determine to be 0.8 rag/1,00 mL or 8 ppm for a total e area of mo cmz. The surface area of a 28 mm t stopper is approximately 6.45 cm2 the total acceptable amount of extractable for each 28 mm. Helvoet FM259/O rubber stopper (Helvoet Phanna, er USA, Pennsauken, NJ) on an average would be 0.05 nag/100 mL or 500 ppb. onally as per USP the total organic content of purified water should not exceed 0.5 mg/L or 500 ppb. The highest levels of ed tables in Precedex® Injection are at least 5 times lower than the acceptable levels of NY02:746896.1 _ 34 _ 077350.0356 extractable in purified water and acceptable levels of extractable in the qualified Helvoet stOppers.

USP ‘ln vitro cytotoxicity test’ and USP ‘Intracutaneous test and systemic injection test’ were performed on Helvoet stopper ts. The results show that rs meet the requirements of these tests, confirming the safety of the stoppers and any r related extractables. The ‘In vitro xicity 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 t of 2 l0 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 . Precedex® injection is formulated in 0.9% NaCl and the final t Le. Precedex® Injection in container— closure .is autoclaved at 121°C for 20 — 40 minutes. Additionally while investigating the source of ‘unidentified impurity peaks’ Helvoet FM259/O rubber stopper (Helvoet , Datwyler USA, Pennsauken, NJ) aqueous extracts were prepared by autoclaving the stoppers at 121°C for one hour and then tested by the Precedex® related substances method. The results demonstrated that the chemical constituents responsible for the peaks were also present in. the Helvoet FM259/O rubber stopper (Helvoet Pharma, Datwyler USA, Pennsauken, NJ) aqueous extracts. The stoppers passed the USP 87 testing indicating that the stopper extractables are non xic.

According to Helvoet Pharma, Helvoet O Omniflex® polymer coated rubber stoppers (Helvoet Pharma, Datwyler USA, Pennsauken, NJ) 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 s were made to terize and. identify the DJ (3 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 ex® chromatograms were selected: - BHT - lrganox~ l 076 mozmewm _ 35 _ 0773500356 - x‘—l 01 0 ' Stearic Acid - Palmitic Acid - Sulphur Samples of these compounds were obtained, and solutions were prepared and injected into an HPLC using the Precedex® 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.

Claims (21)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A ready to use liquid pharmaceutical composition for parenteral administration to a subject, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a concentration of about 0.005 to about 50 µg/mL disposed within a sealed glass container, wherein, the ready to use liquid pharmaceutical composition is administered to the subject without dilution.

2. The ready to use liquid pharmaceutical composition of claim 1, wherein the liquid pharmaceutical composition when stored in the glass container for at least five months exhibits no more than about 2% decrease in the concentration of dexmedetomidine.

3. The ready to use liquid pharmaceutical composition of claim 1 or 2, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is at a concentration of about 0.05 to about 15 µg/mL.

4. The ready to use liquid pharmaceutical composition of any one of claims 1 to 3, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is at a concentration of about 0.5 to about 10 µg/mL.

5. The ready to use liquid pharmaceutical composition of any one of claims 1 to 4, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is at a concentration of about 1 to about 7 µg/mL.

6. The ready to use liquid pharmaceutical composition of any one of claims 1 to 5, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is at a concentration of about 4 µg/mL.

7. The ready to use liquid pharmaceutical composition of any one of claims 1 to 6, further comprising sodium chloride at a concentration of between about 0.01 and about 2.0 weight percent. 40

8. The ready to use liquid pharmaceutical composition of claim 7, wherein the sodium chloride is present at a concentration of about 0.9 weight percent.

9. The ready to use liquid pharmaceutical composition of any one of claims 1 to 8, wherein the composition is formulated as a total volume selected from the group consisting of 20 mL, 50 mL and 100 mL.

10. Use of a composition according to any one of claims 1 to 9 in the preparation of a medicament for providing sedation or analgesia.

11. The use according to claim 10, wherein the medicament is formulated for perioperative administration.

12. The use according to claim 11, wherein the medicament is formulated for administration before or after surgery.

13. The use according to claim 10, wherein the medicament is formulated for administration to a patient in an intensive care unit.

14. The use according to claim 10, wherein the medicament is formulated for administration to a non-ventilated or intubated patient.

15. The use according to claim 10, wherein the medicament is formulated for administration to a patient that is critically ill.

16. The use according to claim 10, wherein the medicament is formulated for administration by intravenous infusion. 41

17. The use according to any one of claims 10 to 16, wherein the medicament is formulated for administration as an anxiolytic, anti-hypertensive agent, or adjunct to an anesthetic.

18. The use according to any one of claims 10 to 16, wherein the medicament is formulated for administration as an analgesic.

19. The use according to any one of claims 10 to 16, wherein the medicament is formulated for administration as a sedative.

20. A ready to use liquid pharmaceutical composition according to claim 1, substantially as hereinbefore described with reference to any one of the Examples.

21. The ready to use liquid pharmaceutical composition of any one of claims 1-9 and 20, or use according to any one of claims 10-19, wherein the dexmedetomidine is formulated as a hydrochloride salt.