NZ626999B2

NZ626999B2 - Intranasal dexmedetomidine compositions and methods of use thereof

Info

Publication number: NZ626999B2
Application number: NZ626999A
Authority: NZ
Inventors: Charles Alexander Freyer; Geraldine A Henwood; Jr John Joseph Koleng; Randall J Mack; Christopher T Sharr
Original assignee: Baudax Bio Inc
Priority date: 2011-12-11
Filing date: 2012-12-11
Publication date: 2016-11-01

Abstract

Provided is the use of dexmedetomidine in the preparation of a pharmaceutical composition for treating or preventing pain without significant sedation in a subject, wherein said pharmaceutical composition is formulated to be administered intranasally as a unit dosage comprising about 10 µg, about 15 µg, about 20 µg, about 25 µg, about 30 µg, about 35 µg, about 40 µg, about 45 µg or about 50 µg dexmedetomidine. Further provided are intranasal formulations comprising dexmedetomidine and metered dose devices comprising such formulations. µg, about 20 µg, about 25 µg, about 30 µg, about 35 µg, about 40 µg, about 45 µg or about 50 µg dexmedetomidine. Further provided are intranasal formulations comprising dexmedetomidine and metered dose devices comprising such formulations.

Description

Intranasal Dexmedetomidine Compositions And Methods Of Use Thereof Field Of The Invention The present invention is directed, in part, to intranasal formulations of dexmedetomidine, or a pharmaceutically acceptable salt thereof, that are analgesic but without significant sedation, as well as methods of use thereof.

Background Dexmedetomidine, 5-[(l S)(2,3-dimethylphenyl)ethyl]-lH-imidazole, is a non-narcotic a2-adrenoceptor agonist with sedative and analgesic properties.

Currently, dexmedetomidine is only commercially available as an injectable formulation indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting and sedation of non-intubated patients prior to and/or during surgical and other procedures, and it must be administered intravenously by an experienced and licensed health care professional.

Although dexrnedetomidine has analgesic properties, an intranasal formulation useful as an analgesic without sedation, however, is not commercially available. Moreover, for a variety ofreasons, the commercially available injectable formulation is not suitable for use as an analgesic that can be self-administered. A continuing and unmet need exists for a dexmedetomidine-based analgesic medicine that, for example, may be self-administered by the patient intranasally to produce analgesia (or otherwise treat or prevent pain) without significant sedation.

Brief Description of Drawings: Figure l shows intranasal dexmedetomidine pharmacokinetics for some embodiments.

Figure 2 shows mean dexmedetomidine plasma concentrations (ng/mL) for some embodiments.

Summary of the Invention In one aspect of the invention there is provided use of an intranasally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating or preventing pain without significant sedation in a subject, wherein said pharmaceutical composition is formulated to be administered intranasally to the subject as a unit dosage comprising about 10 μg, about 25 μg, or about 35 μg, and wherein said intranasally effective amount of dexmedetomidine or salt thereof is sufficient to produce a C of plasma dexmedetomidine of about 0.1 ng/ml within about 15 minutes to about 20 minutes of administration of said pharmaceutical composition to the subject.

In another aspect of the invention there is provided a metered dose device comprising a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereofwhen used the metered dose devicedelivers a metered dose spray of the pharmaceutical composition intranasally to a mammal and the pharmaceutical composition provides an analgesic effect to the mammal without significant sedation wherein the metered dose spray produced by the device comprises a metered dose of about 10 µg, about 25 µg, about 35 µg, about 40 µg, about 50 µg, about 75 µg, or about 100 µg of the dexmedetomidine or the pharmaceutically acceptable salt thereof.

The present invention provides methods of treating or preventing pain without significant sedation in a mammal comprising intranasally administering an intranasally effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, to the mammal whereby the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, produces a C of about 0.1 ng/ml within plasma about 15 minutes to about 20 minutes of administration and has an analgesic effect without significant sedation.

The present invention also provides methods of treating or preventi ng pain w ithout significant sedation in an adult hum an comprising intranasally administering an in tranasally effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, to the adult human whereby the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, does not produce significant sedation in the adult within a period of time of about two hours after admi nistration and has an anal gesic effect within the period oftime.

The present invention also provides methods of treating or preventing pain without significant sedation in a mammal comprising intranasally administering dexmedetomidine, or a pharmaceutically acceptable salt thereof, to a single nostril of the mamm al, particularly a human.

The present invention also provides methods of treatin g or preventing pain without significant sedation in a mammal comprising intranasally spraying in the mammal a pharmaceutical compo. ition comprising dexmedetomid ine, or a pharmaceutically acceptable salt thereof, wherein the spray comprises droplets which have a Dv90 of less than about l 50 µm.

The present invention also provides metered dose devices comprising a pharmaceutical composition comp ris ing dexmedetomidine, or a pharmaceutically acceptable salt thereof, wherein the metered dose device del ivers a metered dose spray of the pha1maceutical composition intranasally that is analgesic in a mammal w ithout signi ficant sedation.

Description Of Embodiments Unless defined otherwise, all technical and scientific te1ms have the same meaning as is commonly understood by one of ordinary skill in the art to which the embodiments disclosed belongs.

As used herein, the terms "a" or "an" means that "at least one" or "one or more" unless the context clearly indicates otherwise.

As used herei n, the term "about" means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, "about" means the numerical value can vary by± 10% and remai n within the scope of the disclosed embod iments.

As used herein, the term "analges ia" refers to the alleviation (partial or complete) or elimination of the sensation of pain.

As used herein, the term "carri er" means a diluent, adjuvant, or excipient with wh ich a compound is administered. Pharmaceutical caniers can be liquids, such as water and oils, including those of petroleum, animal , vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The phannaceutical carriers can also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal s il ica, urea, and the lik e. ln addition, auxiliary, tabilizing, thickening, lubricating and coloring agents can be used.

As used herein, the term, "compound" means all stereoisomers, tautomers, and isotopes of the compounds, or phannaccutically acceptable salts thereof, including any and all metabolites described herein.

As used herein, the terms "comprising" (and any form of comprising, such as "comprise", "comprises", and "comprised"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and " include"), or "containing" (and any form of containing, such as "contains" and "contain"), are inclus ive or IO open-ended and do not exclude additional, unrecited elements or method steps.

As used herein, the term "conta.cting" means bringing together of two elements in an in vitro system or an in vivo system. For example, "contacting" a compound or composition described herein with an individual or patient or cell includes the administration of the compound to an individual or patient, such as a human.

As used herein, the term "Dv90" means the value which represents the particle size below which 90% of the volume of a plurality of droplets exist (e.g., such as in a spray mist; in contrast to a nasal drop comprising one or two drops).

As used herein, the term "individual" or "patient," used interchangeably, means any animal, including mammals, such as mice, rats , other rodents, rabbits, dogs, cats, swine, cattle, sheep, horse~, or primates, such as hum ans.

As used herein, the phrase "in need thereof' means that the animal or mammal has been identified as having a need for the particular method or treatment. In some embodiments, the identification can be by any means of diagnosis. In any of the methods and treatments described herein, the animal or mammal can be in need thereof. In some embodiments, the animal or mamm al is in an environment or will be traveling to an environment in which a particular disease, disorder, or condition is prevalent. For example, a mammal or animal may be in need of treatment or prevention of pain without sedation or without significant sedation.

As used herein, the phrase "metered dose device" refers to a device th at provides a specified dose.

As used herein, the phrase "X to Y" means any number between X and Y and includes the endpoints. For example, the phrase "l to 5" means I, 2, 3, 4, or 5.

As used herein, "pain" refers to a wide range of clinical manifestations, and it has a broad meaning. Pain perception is highly subjective, and different individuals experience pain in different ways and with greatly different intensities. The International Association for the Study of Pain defines pain as "an unpleasant senso1y and emotional experience associated with actual or potential tissue damage, or described in terms of such damage." More simply stated, pain includes any sensory experience that causes suffering and is associated with an unpleasant awareness of one's own body. Non-limiting types and causes of pain include neuralgia, myalgia, hyperalgesia, hyperpathia, neuiitis, and neuropathy. Pain is often a symptom of an underlying physiological abnormality, such as cancer or arthritis. Some types of pain have no clearly identifi ed causes, such as migraine headache pain. Pain may also be caused by physical trauma, such as burns or surgery. Viral infections, such as Herpes zoster (chicken pox and shingles), can also cause pain. Withdrawal from chemical dependence on alcohol or drugs of abuse is also often IO associated with pain symptoms. Accordingly, "pain" is understood herein to have a very broad meaning.

As used herein, the phrase "pharmaceutically acceptable" means those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with tissues of humans and animals. In some embodiments, J 5 "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

As used herein, the phrase "pharmaceutically acceptable salt(s)," includes, but is not limited to, salts of acidic or basic groups. Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable an ions including, but not limited to, sulfuric, thiosulfuric, citric, rnaleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, bisulfite, phosphate, acid phosphate, isonicotinate, borate, acetate, lactate, sal icylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisi nate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesu lfonate, ethanesu lfonate, benzenesulfon ate, p-toluenesulfonate, bicarbonate, malonate, mesylate, esylate, napsydisylate, tosylate, besylate, orthophoshate, tritluoroacetate, and pamoate (i.e. , l,l '-methylene-bis-(2- hydroxynaphthoate)) salts. Compounds that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include, but are not limited to, alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, ammonium, sodium, lithium , zinc, potassium, and iron salts. The present invention can also include quaterna1y ammonium salts of the compounds.

As used herein, the terms "prevention" or "preventing" mean a reduction of the risk of acquiring a paiiicular disease, condition, or disorder.

As used herein, the term "prodrug" means a derivative of a known direct acting drug, which derivative has enhanced delive1y characteristics and therapeutic value as compared to the drug, and is transformed into the active dru g by an enzymatic or chemical process.

As used herein, the term "sedation" means depressed consciousness in which a patient or subject retains the ability to independently and continuously maintain an open airway and a regular breathing pattern, and to respond appropriately and rationally to physical stimulation and verbal commands.

As used herein, the phrase "significant sedation" is consistent with a patient's self evaluation on the Stanford Sleepiness Scale, with Subject patients rating their degree of sedation as greater than or equal to Level 3, wherein: Level 1 = Feeling active, vital, ale1i, or wide awake; Level 2 = Functioning at high levels, but not at peak; able to concentrate; Level 3 =Awake, but relaxed; responsive but not fully aleri; Level 4 = Somewhat foggy, Jet down; Level 5 = Foggy; losing interest in remaining awake; slowed down; Level 6 = Sleepy, woozy, fighting sleep; prefer to lie down; or Level 7 = No longer fighting sleep, sleep onset soon; having dream-like thoughts. "Significant sedation" also means that the patient or subject experiences sedation of Level 4 or greater on the Ramsay Sedation Scale, wherein: Level I = Patient is anxious and agitated or restless, or both; Level 2 = Patient is co-operative, oriented, and tranquil; Level 3 = Patient responds to commands only; Level 4 = Asleep; brisk response to light glabellar tap or loud auditory stimulus; Level 5 = asleep; sluggish response to light glabellar tap or loud auditory stimu lus; Level 6 = asleep; no response to painful stimulus. "Significant sedation" also means that the patient or subject experiences sedation of Level 5 or less on the Modified Observer's Assessment of Alertness/Sedation Scale, wherein: Level 6 = Appears alert and awake, responds readily to name spoken in normal tone; Level 5 = Appears asleep but responds readily to name spoken in normal tone; Level 4 = lethargic response to nam e spoken in norm al tone; Level 3 = responds only after name is called loudly or repeatedly; Level 2 = responds only after mild prodding or shaking; Level 1 = does not respond to mild prodding or shaking; and Level O = does not respond to noxious stimulus.

As used herein, the phrase "solubilizing agent" means agents that result in formation of a micellar solution or a true solution of the drug.

As used herein, the term "solution/suspension" means a liquid composition wherein a first po1iion of the active agent is present in solution and a second po1iion of the active agent is present in pa1iiculate form, in suspension in a liquid matrix.

As used herein, the phra~e "substantially isolated" means a compound that is at least partially or substantially separated from the environment in which it is formed or detected.

As used herein, the phrase "therapeutically effective amount" generally means the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, an imal, individual or human by a researcher, veterinarian, medical doctor or other clinician. The therapeutic effect is dependent upon the disorder being treated or the biological effect desired. As such, the therapeutic effect can be a decrease in the severity of symptoms associated with the disorder and/or inhibition (partial or complete) of progression of the disorder, or improved treatment, healing, prevention or elimination of a disorder, or side-effects. The amount needed to elicit the therapeutic response can be determi ned based on the age, health, size and sex of the subject. Optimal amounts can also be determined based on monitoring of the subject's response to treatment. In some embodiments, the therapeutically effective amount is a specific amount or range described herein.

As used herein, the terms "treat," "treated," or "treating" mean both therapeutic treatment or prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired phy iological condition, disorder or disease, or obtain beneficial or desired clinical resu lts. For purposes of this invention, beneficial or desired clinical results include, but are not limi ted to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e., not worsening) state of cond ition, disorder or disease; delay in onset or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder or disease. Treatment includes eliciting a clinically significant analgesic response without excessive levels of side effects, such as, but not limited to, significant sedation. Thus, "treatment of pain" or "treating pain" means an activity that prevents, alleviates or ameliorates any of the primary phenomena or seconda1y symptoms associated with pain.

As used herein "without significant sedation" means that the patient experiences a level of sedation not greater than Level 3 on the Ramsay Sedation Scale, not greater than Level 2 on the Stanford Sleepiness Scale, and/or not less than Level 6 on the Modified Observer's Assessment Of Alertness/Sedation Scale.

It is fwiher appreciated that certain features descri bed herein, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a si ngle embodiment. Conversely, various features which arc, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination .

Dexmedetomidine is a specific alphaadrenergic receptor agonist that causes sedation, anesthesia, and analgesia in mammals. In humans, dexmedetomidine is commercially available for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting, as well as sedation of non-intubated patients prior to or during surgical and other procedures. See, e.g., U.S. Patent Nos. 6,7 16,867 and 6,3 13,3 11 , each of which are hereby incorporated by reference in their entirety.

Dexmcdctomidinc contains a basic nitrogen atom capable of formin g a pharmaceutically acceptable salt with a pharmaceutically acceptable acid. Pharmaceutically acceptabl e salts, in this respect, refers to the relatively non-toxic, inorganic, and organ ic aci d ad dition salts of dexmedetomidi ne. These salts may be prepared in siiu during fi nal isolation and purification of dexmedetomidine or by separately reacting pu1ified dexmedetomidine in its free base form with a suitable organic or inorganic acid, and thereafter isolati ng the salt thus formed.

Fu1ihermore, the salt may be formed during a manufacturing process to produce the spray formulation. Representative pharmaceutically acceptable salts include, but are not li mited to, th e hydrohali dc (including hydrobromidc and hydrochloride), sulfate, bisulfatc, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, ta1 1rate, napthylate, mesylate, glucoheptonate, lactobionate, 2- hyd roxyethylsulfonate, and laurylsulphonate salts, and the like. See, e.g., " Ph armaceutical Salts," Berge et al. , .T. Pharm. Sci., 1977, 66, 1- 19. Dexmedetomidine hydrochlori de is an example of a pharmaceutically acceptable salt. Use of dexmedetomidine hydrochloride may be used, in part because, in some cases, the hydrochloride salt has greater water solubi lity and stabi lity agai nst oxidation by ambient oxygen.

Dexmedetomidine deri vatives include covalent modifications that create a prodrug.

Upon administration, the prodrug derivative undergoes chemical modification by the mammal that yields dexmedetomidine. Prodrugs may be used to favorably alter th e biodistribution or the pharmacokinetics of dexmedetomidine or to produce other desirable characteristics. For example, a reactive nitrogen of dexmedetomidine may be derivatized with a fu nctional group that is cleaved, enzymatica 11y or non-enzymatically, reductively, ox idatively, or hydrolytically , to reveal the active pharmaceutical ingredient. Uses of certain types of prodrugs are known (see, e.g., R. B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action," Academic Press, Chp. 8). For example, prodrugs may be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free base form with a sui table dcrivatizing agent.

The present disclosure describes the surprising and unexpected result(s) that an intranasal formulation of dexmedetomidine, or a pharmaceutically acceptable salt thereof, can be developed for the treatment of pain that has a reduced time to the onset of pain relief to Ci,1 asm a, a Cmax, and a reduced time to T max, that can lead to pain relief or corresponding prevention without sedation or significant sedation in a mammal.

The present invention provides methods of treating or preventing pain without significant sedation in a mammal comprisi ng intranasal ly admi nistering an intranasally effective amount of dex mcdetomidinc, or a pharmaceutically acceptable salt thereof, to the mammal. The dexmedetomidine, or a pharmaceutically acceptable salt thereof, or compositions comp1ising the same, can be administered in any conventional manner such that the composition is administered intranasally. That is, the composition is contacted with the nasal cavity. The compositions can also be administered, for example, by implanting the composition so that it is absorbed intranasally.

In some embodiments, the dexmedetomidine, or pharmaceutically acceptable salt thereof, is absorbed through the nasal mucosa. In some embodiments, at least l 0%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the composition is absorbed through the nasal mucosa. ln some embodiments, dexmedetomidine, or a pharmaceutically acceptable salt thereof, is not absorbed through the oral mucosa.

In some embodiments, the method comprises treating or preventing pain relief without sedation or ignificant sedation. In some embodiments, the level of sedati on is no greater than Level l on the Ramsay Sedation Scale. In some embodiments, the level of sedation is no greater than Level 2 on the Ramsay Sedation Scale. In some embodiments, the level of sedation is no greater than Level 3 on the Ramsay Sedation Scale. In some embodiments, the level of sedation is no greater than Level 1 on the Stanford Sleepiness Scale. In ome embodiments, the level of sedation is no greater than Level 2 on the Stanford Sleepiness Scale. In some embodiments, the level of sedation is no less than Level 6 on the Modified Ob~erver's Assessment of Alertness/Sedation Scale. In some embodiments, during the hour immediately after administration of the dexrnedetomidine, or pharmaceutically acceptable salt thereof, to the mammal or human, the level of sedation is not greater than Level 3 on the Ramsay Sedation Scale. In some embodiments, during the hour immediately after administration of the dexmedetomidine, or pharmaceutically acceptable salt thereof, to the mammal or human, the level of sedation is not greater than Level 2 on the Ramsay Sedation Scale. In some embodiments, during the hour immediately after administration of the dexmedetomidinc, or pharmaceutically acceptable salt thereof, to the mammal or human, the level of sedation is not greater than Level l on the Ramsay Sedation Scale. In some embodiments, during the hour immediately after administration of the dexmedetomidine, or pharmaceutically acceptable salt thereof, to the mammal or human, the level of sedation is not greater than Level 2 on the Stanford Sleepiness Scale. In some embodiments, during the hour immediately after administration of the dexmedetomidine, or pharmaceutically acceptable salt thereof, to the mammal or human, the level of sedation is not greater than Level l on the Stanford Sleepiness Scale. In some embodiments, during the hour immediately after administration of the dexmedetomidine, or pharmaceutically acceptable salt thereof, to the mammal or human, the level of sedation is not less than Level 6 on the Modified Observer's Assessment Of Ale1iness/Sedation Scale.

In some embodiments, the pain is idiopathic pain. In some embodiments, the idiopathic pai n is neuralgia, myalgia, hyperalgia, hyperpathia, neuritis, or neuropathy. In some embodiments, the pain is associated with or caused by cancer, viral infection, physical trauma, arthritis, headache, migraine, or lower back pain. In some embodiments, the physical trauma is associated with or caused by surgery, a burn, blunt force trauma, or other trauma that can cause pain, such as being in an accident.

In some embodiments., the means and methods of administe1ing the compositions described herein are known . The means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance (see, for example, Modern Pharmaceutics, Banker & Rhode , Marcel Dekker, Inc. (1979); and Goodman & Gilman 's The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York ( 1980)).

T n some embodiments, the amount of compound to be administered is that amount which is therapeutically effective or intranasally effective. The dosage to be administered can depend on the characteristics of the subject being treated, e.g., the pa1iicular animal treated, age, weight, health, types of concurrent treatment, if any, and frequency of treatments, and can be eas ily detennined by one of skill in the art (e.g., by the clinician). The selection of the specific dose regimen can be selected or adjusted or titrated by the clinician according to methods known to the clinician to obtain the des ired clinical response or as they are described herein. Further, the amount of a compound described herein that will be effective in the treatment and/or prevention of a particular disease, condition, or disorder will depend on the nature and extent of the disease, condition, or disorder, and can be determined by standard clinical techniques. In addition, in vitro or in vivo ai.;says may optionally be employed to help identify optimal dosage ranges. The dosages can be, for example, the doses described herein.

The compounds, or composition comprising the same, can be administered in various dosage forms suitable for intranasal administration. The dosage amount present in the dosage form can be a pharmaceutically or intranasally effective amount. In some embodiments, the effective amount is an amount sufficient to treat or prevent pai n. In some embodiments, the effective amount is an amount that does not produce sedation. In some embodiments, the effective amount does not produce significant sedation. In some embodiments, the effective amount is an amount sufficient to treat or prevent pain, yet docs not produce sedation or significant sedation.

Cp1asma is the concentration of dexmedetomidine in the plasma of a mammal or human at a pariicu lar time after administration. In some embodiments, the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, produces a Cplasma of about 0.1 nglml within about 15 minutes to about 20 minutes of administration and has an analgesic effect without significant sedation. Thus, in some embodiments, within about 15 minutes to about 20 minutes of administration of dexmedetomidine, or pharmaceutically acceptable salt thereof, to a mammal or human , the mammal or human will have a Cplasma of about 0. 1 ng/m 1. T n some embodiments, the Cp1asma is from about 0.09 ng/ml to about 0.11 ng/ml, from about 0.08 ng/ml to about 0.12 nglml, from about 0.06 ng/ml to about 0.09 ng/ml, from about 0.07 nglm l to about 0.09 nglml, or from about 0.08 nglml to about 0.09 ng/ml. 1n some embodiments, the targeted Cp1a, ma is reached within about 8 minutes to about 30 minutes, with in about l O minutes to about 30 minutes, within about 12 minutes to about 30 minutes, within about 8 minutes to about 20 minutes, within about IO minutes to about 20 minutes, within about 12 minutes to about 20 minutes, within about 8 minutes to about 15 minutes, within about 10 minutes to about 15 minutes, within about 12 minutes to about 15 minutes, within about 8 minutes to about 10 minutes, within about 8 minutes to about 12 minutes, within about 15 minutes to about 20 minutes, within about 15 minutes to about 20 minutes, within about 15 minutes, within about 12 minutes, within about 10 minutes, or within about 8 minutes of administration and has an analgesic effect without significant sedation. This time point can reflect the onset of pain relief (i.e., an analgesic effect).

Tn some embodiments, the onset of pain relief is less than about 60 minutes, less than about 55 minutes, less than about 50 minutes, less than about 45 minutes, less than about 40 minutes, less than about 35 minutes, less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about l 5 minutes, less than about 12 minutes, less than about 10 minutes, about 12 minutes, about IO minutes, or abou t 8 minutes. The onset of minutes, about pain relief is the time w hen a mammal feels that th e pain is less than prior to the administration of a compoun d or composition described herein. In some embod iments, the pain rel ief is complete and th e mammal no longer feels the pain that was being relieved.

The present invention also provides methods of treating or preventing pain without significant sedation in an adult human comprisin g intranasally adm inistering an intranasally effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, to the adult human whereby the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, does not produce significant sedation in the adult within a pc1iod of time of about two hours after administration and has an analgesic effect within the period of time. ln some embodiments, significant sedation in the adult is not produced within a period of time of about 1.5 hours after administration, but yet has an analgesic effect within the period of time. In 'ome embodiments, significant sedation in the adult is not produced within a period of time of about 1.0 hours after administration, but yet has an analgesic effect w ithin the period of time. In some embodiment , significant sedation in the adult is not produced within a period of time of about 45 minutes after administration, but yet has an analges ic effect within the peri od of time.

In some embodiments, significant sedation in th e adult is not produced within a period of time from about 30 minutes to about of about 1.5 hours after administration, but yet has an analgesic effect within the period of time. In some embodiments, significant sedati on in th e adult is not produced within a period of time from about 40 minutes to about 75 minutes after administration, but yet has an analgesic effect within the period of time. In some embodiments, significant sedati on in the adult is not produced within a period of time from about 45 minutes to about 70 minutes after admi nistration, but yet has an analgesic effect within the period of time.

In some embodiments, significant sedation in the adult is not produced within a pe1iod of time from about 50 minutes to about 65 minutes after administration, but yet has an analgesic effect within the pe1iod of time. In some embodiments, significant sedation in the adult is not produced within a period of time from about 55 minutes to about 60 minutes after administration, but yet has an analgesic effect within the period of time.

The present invention also provides methods of treating or preventing pain without significant sedation in a mammal comprising intranasally administering dexmedetomidine, or a pharmaceutically acceptable salt thereof, to a single nostril of the mamm al, patiicularly a human.

Administration to a single nostril means that the entire unit dose is administered to a single of the unit dose being administered to both nostrils. In some nostril as compared to a portion embodiments, the unit dose is only administered to a single nostril. That is, if a dosage is given every 4 hours, the dosage iR administered to only a single nostril every 4 hours. The single nostril to which the compositions are administered may alternate between the two nostril s, however. In some embodiments, the methods comprise not administering dexmedetomidine or a pharmaceutically acceptable salt thereof or a composition described herein to more than one nostril (e.g., two nostrils).

The present invention also provides methods of treating or preventing pain without l O significant sedation in a mammal comprising intranasally spraying in the mammal a pharmaceutical composition comprising dexmedetomidine, or a pharmaceutically acceptable salt thereof, wherein the spray comprises droplets which have a Dv90 of less than about 150 µm. In some embodiments, the spray comprises droplets which have a Dv90 of less than about 125 µm.

In some embodiments, the spray comprises droplets which have a Dv90 of less than about 100 µm. In some embodiments, the spray comprises droplets which have a Dv90 from about 60 µm to about 150 µm, from about 60 µm to about 125 µm , or from about 60 µm to about 100 µm. In some embod iments, the spray comprises droplets w hich have a Dv90 of more than about 40 µm .

In some embodiments, the spray comprises droplets which have a Dv90 of more than about 50 µm. In some embodiments, the spray comprises droplets which have a Dv90 of more than about 60 µm. Tn some embodiments, the spray comprises droplets which have a Dv90 of more than about 70 µm.

In some embodiments, the present invention provides methods of treating or preventin g pain without significant sedation in a mammal comprising intranasally administering an intranasally effective amount of dexmedetomidine, or a pha1maceutically acceptable salt thereof, to the mammal whereby the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, produces a Cplasma of about 0.1 nglrnl within about 15 minutes to about 20 minutes of administration and has an analgesic effect without significant sedation, and whereby the intranasally effective amount of dexrnedetomidine, or pharmaceutically acceptable salt thereof, docs not produce significant sedation within a period of time of about two hours after administration and has an analgesic effect within the period of time.

In some embodiments, the present invention provides methods of treating or preventing pain without significant sedation in a mammal comprising intranasally administeri ng an intranasally effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, to a single nostril of the mammal, particularly a human, whereby the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, produces a Cp1asma of about 0.1 ng/ml within about 15 minutes to about 20 minutes of administration and has an analgesic effect without significant sedation.

In some em bodiments, the present invention provides methods of treating or preventing pain without significant sedation in a mammal comprising intranasally spraying an intranasally effective amount of dexmedetomidine, or a pha1111aceutically acceptable salt thereof, to the mammal whereby the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, produces a C plasma of about 0.1 ng/ml within about 15 minutes to about 20 IO minutes of administration and has an analgesic effect without significant sedation, and wherein the spray comprise droplets which have a Dv90 of less than about 150 µm.

In some embodiments, the present invention also provides methods of treating or preventing pain without significant sedation in an adult human comprising intranasally administering an intranasally effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, to a single nostril of the adult human, whereby the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, does not produce significant sedation in the adult within a period of time of about two hour after administration and has an analgesic effect within the period of time.

In some embodiments, the present invention also provides methods of treating or preventing pain without significant sedation in an adult human comprising intranasally spraying an intranasally effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, to the adult human whereby the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, does not produce significant sedation in the ad ult within a period of time of about two hours after administration and has an analgesic effect within the period of time, and wherein the spray comprises droplets which have a Dv90 of less than about 150 µm .

In some embodiments, the present invention also provides methods of treating or preventing pain without significant sedation in a mammal comprising intranasally spraying dex medetornidine, or a pharmaceutically acceptable salt thereof, to a single nostril of the mammal, particularly a human , wherein the spray comprises droplets which have a Dv90 of less than about 150 µm.

In some embodiments, the present invention provides methods of treating or preventing pain without significant sedation in a human comprising intranasally administering an intranasally effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, to a single nostril of the human whereby the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, produces a Cp1asma of about 0. I ng/ml within about 15 minutes to about 20 minutes of administration and has an analgesic effect without significant sedation, whereby the intranasally effective amount of dcxmcdctomid ine, or pharmaceutically acceptable salt thereof, does not produce significant sedation in the human within a period of time of about two hours after administration and has an analgesic effect within the period of time.

In some embodiments, the present inven tion provides methods of treating or preventing pain without significant sedation in a mammal comprising intranasally spraying an intranasally effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, to the mammal whereby the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, produces a Cp1asma of about 0.1 ng/ml within about 15 minutes to about 20 minutes of administration and has an analgesic effect without significant sedation, whereby the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, doe · not produce significant sedation in the mammal within a period of time of about two hours after administration and has an analgesic effect within the petiod of time, and wherein the spray comprises droplets which have a Dv90 of less than about 150 µm.

Tn some embodiments, the present invention provides methods of treating or preventing pain without significant sedation in a human comprising intranasally spraying an intranasally effective amount of dcxmcdctomidinc, or a phannaccutically acceptable salt thereof, to a single nostril of the human whereby the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, produces a Cplasma of about 0. l ng/ml within about 15 minutes to about 20 minutes of administration and has an analgesic effect without significant sedation, wherein the spray comprises droplets which have a Dv90 of less than about 150 µm.

In some embodiments, the present invention also provides methods of treating or preventing pain without significant sedation in a human comprising intranasally spraying an intranasally effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, to a single nostril of the human whereby the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, does not produce significant sedati on in the human within a period of time of about two hours after administration and has an analgesic effect withi n the period of time, wherein the spray comprises droplets which have a Dv90 of less than about 150 µm.

In some embodiments, the present invention provides methods of treating or preventing pain without significant sedation in a human comprising intranasally spraying an intranasally effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, to a single nostril of the human whereby the intranasally effective amou nt of dexmedetomidine, or pharmaceutically acceptable salt thereof, produces a Ci>1asma of about 0.1 nglml within about 15 minutes to about 20 minutes of administration and has an analgesic effect without significant sedation, whereby the intranasally effective amount of dexmedetomidine, or pharmaceutically acceptable salt thereof, does not produce significant sedation in the human within a period of time of about two hours after administration and has an analgesic effect within the period of time, and wherein the spray comprises droplets which have a Dv90 of less than about 150 µm.

In any of the methods described herein, the plasma Cmax of dexmedetomid ine is from about 0.08 nglml to about 0.25 nglml, about 0.08 ng/ml to about 0.2 nglml, from about 0.1 ng/ml to about 0.2 nglml, from about 0.08 ng/ml to about 0.15 ng/ml, from about 0.1 nglml to about 0.15 nglml, or from about 0.15 ng/ml to about 0.2 ng/ml. In some embodiments, the plasma Cmax of dexmedetomidine is from about 0.08 ng/ml to about 0.2 ng/ml. In some embodiments, the plasma Cmax of dexmedetomidine is about 0.15 nglml. In some embodiments, the plasma Cmax of dexmedetomidine is about 0.2 ng/111!. In some embodiments, the plasma Cmax of dexmedetomidine is about 0.25 nglm l.

In any of the methods desc1ibed herein, the Tnrnx is less than about 60 minutes, less than about 50 minutes, less than about 40 minutes, less than about 35 minutes, or less than about 30 minutes. In some embodiments, the Tmax is from about 20 minutes to about 60 minutes, from about 20 minutes to about 50 minutes, from about 20 minutes to about 40 minutes, from about 20 minutes to about 30 minutes, from about 30 minutes to about 60 minutes, from about 30 minutes to about 50 minutes, from about 30 minutes to about 40 minutes, from about 40 minutes to about 60 minutes, from about 40 minutes to about 50 minutes, or from about 50 minutes to about 60 minutes. In some embodiments, the T ,,x of dexmedetomidine is less than about 1 hour. In some embodiments, the T max is less than about 50 minutes.

In any of th e methods described herein, the compound or composition can be administered according to a specific schedule. In some embodiments, the composition is administered about every 2 hours, about every 4 hours, about every 6 hours, about every 8 hours, about eve1y 10 hours, about eve1y 12 hours, or about every 24 hours. The composition can also be administered as needed. In some embodiments, dexmedetomidine, or pharmaceutically acceptable salt thereof, or composition comprising the same, is administered about every 6 hours.

In any of the methods described herein, the dexmedetomidine, or pharmaceutically acceptable salt thereof, is administered as a unit dose of about l O µg to about l 00 µg, from about µg to about 90 µg, from about IO µg to about 80 µg, from about 10 µg to about 70 µ.g, from about IO µg to about 60 µg, from about 10 µg to about 50 µg, from about IO µg to about 40 µg, from about 10 µg to about 30 µ.g, from about IO µg to about 20 µg , from about 25 µg to about 100, from about 25 µg to about 90 µg, from about 25 µg to about 80 µg, from about 25 µ.g to about 70 µg , from about 25 µg to about 60 µg, from about 25 µg to about 50 µg, from about 25 µg to about 40 µg, from about 25 µg to about 35 µg, from about 25 µg to about 30 µg, from about 30 µg to about 45 µg , from about 35 µg to about 45 µg, from about 30 µg to about 40 µg, or from about 25 µg to about 45 µg. In some embodiments, the dexmedetomidine, or pharmaceutically acceptable salt thereof, is administered as a unit dose of about IO µg, about 15 µg, about 20 µ g, about 25 µg, about 30 µg, about 35 µg, about 40 µg, about 45 µg, about 50 µg, about 55 µg , about 60 µg, about 70 µ.g, about 75 µg, about 80 µg, about 85 µg, about 90 µg, about 95 µ g, or about l 00 µg. In some embodiments, the dexmedetomidine, or pharmaceutically acceptable salt thereof, is administered as a unit dose of less than about 100 µg, less than about 90 µ.g, less than about 80 µg, less than about 70 µg, less than about 60 µg, les than about 50 µg, less than about 40 µg , less than about 3 0 µg , less than about 20 µg, or less than about IO µ.g. In some embodiments, the dexmedetomidine, or pharmaceutical ly acceptable salt thereof, is administered as a unit dose of about 10 µ.g, about 25 µ.g, about 30 µg, about 35 µg, about 40 ~ Lg, about 50 µ g, about 75 µg , or about 100 µg. As discussed herein, the unit dose can be administered in many different manners. In some embodiments the unit dose is administered by a single nasal spray. In some embodiments th e unit dose is administered by a single nasal spray using a single dose spray device requiring no priming. The single dose can be administered through a single actuation of a nasal spray device. An examples of spray device that does not require priming includes, but is not limited to, Aptar Unitdose Intranasal Systems. The spray device can, in some embodiments, deliver a volume of about 100 µ1. In some embodiments, the volume is about I 0, 20, 30, 40, 50, 60, 70, 80, or 90 µ1. In some embodiments, the volume is from about 10-100, about 20-1 00, about 30-100, a.bout 40-100, about 50-100, about 60-100, about 70- 100, about 80-100, about 90-100 µI.

In any of the methods described herein, the method comprises having no effect or having minimal effect on blood pressure after administration. In some embodiments, there is no effect on blood pressure within the hour immediately after a compound described herein is administered. In some embodiments, there is only minimal effect on blood pressure within the hour immediately after a compound described herein is admin istered. In some embodiments, the resting mean arterial blood pressure of the mammal is not effected by more than about 5 mmHg, more than about l O mmHg, more than about 15 mm Hg, more than about 20 mmHg, more than about 25 mmHg, or more than about 30 mmHg. The mean a1terial blood pressure can be measured by any method known to one of skill in the a1t. ln some embod iments, there is no or minimal effect on blood pressure after administration of the dexmedetomidine, or pharmaceutically acceptable salt thereof.

In any of the methods described herein, the method fmther comprises administering in simultaneous, alternating, or sequential combination to the human or mammal one or more additional therapeutic agents. The one or more additional therapeutic agents is chosen from an analgesic, such as an opioid analgesic (e.g. morphine, oxycodone, hydromorphon e, etc.), a synthetic opioid-like analges ic (e.g. meperidine, fentanyl, pentazocine, butorphanol , etc.), or a non-opioid analgesic (e.g. NSAlDs, ketamine, sal icylates, steroids, etc.); a vitamin; a vasodilator; a benzodiazepine (e.g. clonazepam, alprazolam, lorazepam, etc. ); a triptan (and other compounds for migraine headaches); an anti-convulsant (e.g. pregabalin, valproic acid, gabapentin, etc.); an anti-depressant (e.g. tricyclics such as amitriptyline, nortriptyl ine, etc.; serotonin and norepinephrine reuptake inhibitors such as duloxeti ne, fluoxetine, venlafaxine, etc.); an anti-nausea medication (e.g. metoclopramide, proch lorperazine, ondansetron, granisetron, etc.); and an anti-hypertensive (e.g. beta blockers such as propranol ol and calcium channel blockers such as verapamil, etc. ).

The present invention also provides any one or more of the compositions described herein for treating pain in a mammal without significant sedation.

The present invention also provides any one or more of the compositions described herein for use in the manufacture of a medicament fo r treating pain in a mammal without significant sedation.

In any of the methods described herein, the dexmedetomidine, or pharmaceutically acceptable salt thereof, can be administered intranasally with a device. In some embodiments, the dev ice is a metered dose device. In some embodiments, the metered dose device is a multi-dose, unit dose, or bi-dose device.

Tn some embodiments , the device is suitab le for intranasal admi nistration. Any device that is suitable for intranasal administration can be used. In some embodiments, the device is a metered dose device. The metered dose device can deliver a specific dosage amount of the composition. The metered dose device can be a unit-dose, bi-dose, or a multi-dose device. The pharmaceutically effective amount that can be administered using a metered dose device can be a unit dose device. The metered dose can, in some embodiments, be a device that can deliver a pharmaceutical composition intranasally. Examples of metered dose devices include, but are not li mi ted to, devices that are pump devices, mechanical devices, pressurized devices, and/or electro mechanical devices. Examples of a metered dose device include, but are not limited to, a spray pump, a pre-compression nasal spray pump, a metered valve device, an actuated spray device, a sid e actuated spray device, a syrin ge nasal spray device ( e.g. a syringe that has an atomizer to deliver a spray to the nasal cavity), a mucosa) atomization device, an electromechanical pump device (with and without a counter), and the like. Examples of metered dose devices also include, but are not limited to, devices manufactured by Aptar Pharma (Congers, NY) and are commercially available. Examples of metered dose dev ices also include, but are not limited to, UDS (Aptar Pharma), BDS (Aptar Pharma), eDevices (Aptar Pharma), Equadel (Aptar Pharma), Latitude (Aptar Pharma), DF30 (Aptar Pharma), VP7 (Aptar Pharma), l O Class ic Nasal Device (Aptar Pharma), MAD Nasal Drug Device (Wolf Tory Medical, Inc. ), BD Accuspray SCfTM (Becton Dickinson), and the like. Another example includes, but is not limited to, an Aptar Unitdosc Intranasal System.

Analgesic, intranasal fo rmulations of dexmedetomidine, or a pharmaceutically acceptable salt or derivative thereof, can be administered in metered dosages so that a predetermined amount of the active pharmaceutical ingredient is properly administered to the subject in a pharmaceutically effective amount. For example, the intranasal form ulation may be packaged as a bulk liquid containing multiple doses in a pump spray system comprisi ng a sealed container fitted with a metering pump. In some embod iments, a subject is treated by intranasal self-administration, such as by one or more actuations from a spray pump. An advantage of intranasal delivery examples herein is the ability to titrate subjects by si ngle doses as suppl ied by single, discrete actuations. This advantage is typically absent from other forms of drug delivery (e.g., patches, lozenges, tablets, and suppositories) in which a one-size-fits-all dosage is admi nistered in a standard regimen. Additional advantages of intranasal formulations include its ease of use, especially when self-administered absent an attending health care professional.

In some embodiments, the metered dose device is a spray delive1 y device, which includes a base unit, a discharge actuator, an orifice for the formulation to be release from the device, and a reservoir. The reservoi r can be filled with dexmedetomidine, or pharmaceutically acceptable salt thereof, and opti onally other excipients, such as those described throughout the present app licati on, prior to dispen1-1ing to the patient, e.g., at the manufacturing site. The reservoir can contain a measured amou nt of dexmedetornidine, or pharmaceutically acceptable salt thereof, or derivative thereof, to be discharged upon activation. The reservoir body may be any acceptable material, for example, fo rmed simply by a section of a cylindrical hollow of a plastic, steel, such as stainless steel, transparent material, or the like so that its production is very sim ple. An actuator, which is movable relative to the orifice for activating discharge, may be provided on or with the device. In the course of the actuating movement, the reservoir opens, e.g. by puncturing, to administer a single dosage through an orifice. During a part of the actuating travel fo llowing the sta1iing position an elevated pressure is built up. In a subsequent portion of the actuating movement continuing in the same direction, the medium may be relieved of the pressure at one of the sides and communicated to an 01ifice. In such a manner, the medium is pushed from the reservoir and through the orifice by the action of pressure.

In some embodiments, as the liquid formu lation leaves the orifice, the liquid droplets follow a trajectory which is influenced by the orifice shape, as well as by pressure asse1ied. In some embodiments, the droplet size, spray geometry, and the sp ray pattern are dependent on the IO design of the pump and/or the properties of the fo rmulation. ln some embodiments, the 01ientation of the actuator, pump design, and the prope1iies of the formulation wi ll influence the spray symmet1 y and the shape. The spray pattern may also be optimi zed to disperse the droplets over a wider pathway thereby increasi ng the surface area through which the compound can be absorbed. The device may fu1iher be designed to faci litate ease of patient use and placement of the administered spray to specific regions of the nasal mucosa.

Pump action sprays can be characterized by the application of external pressure for actuation, for example, external manual, mechanical or electrically initiated pressure. This is in contrast to pressmized systems, e.g., propellant-driven aerosol or compressed gas sprays, where actuation is typically achieved by controlled release of pressure, such as by controlled openi ng of a valve. In some embodiments, pump sprays are used. Use of a pump spray with the formulations herein allows for the administration of droplets or pa1iicles having a small mean diameter and a controllable size distribution of droplets. In some embodiments, pressurized systems containing a reservoir of pressu1ized propellant gas (e.g., carbon dioxide, nitrogen, chlorofluorocarbons, hydrofluoroalkanes, etc.) may produce suitable particles or droplets. Liquid droplets or pa1iicles having a diameter that is too small have the potential to enter into the lungs of a subject upon administration. ln some embodiments, the droplet size of the delivered formulations further provides for an increase in surface area by being sprayed intranasally as opposed to being placed in a nostril, fo r example, with a dropper. The size of the spray particles and shape of the spray pattern also may contribute to whether the active ingredient is absorbed into body systems in addition to the na al mucosa (e.g., lu ngs).

As described herein, the spray pump device may be pre-metered or, alternately, the device may be device-metered. Pre-metered dose devices may contain previously measured doses or a dose fraction in some type of units ( e.g., single unit dose amount of solution, single or mu ltip le blisters or other cavities) that may be included in the device during manufacture or by the patient before use. Typical device-metered units have a reservoir containing a formulation sufficient for mu ltiple doses that are de livered as metered prays by the device itself when activated by the patient. The device may be metered both in the amount of drng substance delivered (i.e., the dosage per actuation), as well as the length of time between each dosage.

Limiting the time between each dosage can prevent over-use by limiting how often a dosage can be delivered to the patient.

The embodiments of the device1s described herein, is not intended as limiting. In some embodiments, the formulations containing dexmedetomidine may alternately or additionally be provided as other intranasal dosage forms. For example, the intranasal composition may be provided as a liquid compatible with administration by a dropper or similar device. The intranasal formulation can also be provided as a powder to be administered into the nasal cavity.

The formu lations can be, for example, packaged in pharmaceutically acceptable u nit dose ampules with snap-off tops to permit the opened ampule to be inserted into the patient's nasal cavity to dispense a single dose of the formulation.

In yet another embodiment, the compounds can be delivered in a contro lled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref.

Biomed. Eng., 1987, 14,201 ; Buchwald et al., Surgery, 1980, 88,507 Saudek et al. , N. Engl. J.

Med., 1989, 321,574). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailabi lity, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger et al., J. Macromol. Sci. Rev. Macromol. Chem. , 1983 , 23, 61; see, also Levy et al., Science, 1985, 228, 190; During et al. , Ann. Neurol., 1989, , 351; Howard et al. J. Neurosurg., 19 89 , 71, l 05). Other controlled-release systems discussed in the review by Langer, Science, 1990, 249, 1527-1533 may be used and can be adapted for intranasal administration.

In some em bodiments, the aqueous dexmedetomidine intranasal compositions may be administered as drops or as a fine mist. Administration as a fine mist can improve the reproducibility of dosing by facilitating even deposition of the composition on the nasal mucosa.

In some embodiments, a pump device is used to generate a fine mist from the bulk nasal solution composition. Unit-dose and bi-dose devices may be used for dexmedetomidine nasal spray compositions since these devices can limit the total dose and/or number of doses that can be delivered from a single device thu reducing the potential fo r over-dos ing/abu e. Fu1ihermore, the unit-dose and/or bi-dose devices may require less packaged volume to deliver the spray vo lume by reducing the required amount of solution lost to pump priming. In some embodiments, multi-dose devices are used due to their lower cost of manufacturing and less packaging waste.

The present invention also provides metered dose devices comprising a pharmaceutical composition comprising dcxmcdctomidine, or a pharmaceutically acceptable salt thereof, wherein the metered dose device delivers a metered dose pray of the pharmaceutical composition intranasally that is analgesic in a mammal without significant sedation.

In some embodiments, the metered dose spray produced by the device comprises droplets comprising dexmedetomidine, or a pharmaceutically acceptable salt thereof, that have a Dv90 of less than about 150 µm. In ome embod iments, the spray comprises droplets which have a Dv90 of less than about 125 µm. In some embodiments, the spray comprises droplets which have a Dv90 of less than about 100 µm . In some embod iments, the spray comprises droplets which have a Dv90 from about 60 µm to about 150 µm, from about 60 µm to about L 25 µm, or from about 60 µm to about l 00 µm.

In some embodiments, the metered dose spray produced by the device comprises a metered dose of dexrnedetomidine, or a pharmaceutically acceptable salt thereof, from about 10 µg to about JOO ~Lg, from about 10 µg to about 90 µg, from about 10 µ g to about 80 µg, from about 10 µg to about 70 µg, from about 10 µg to about 60 µg, from about 10 µg to about 50 µg, from about 10 µg to about 40 µg, from about 10 µg to about 30 µg, from about 10 µg to about 20 µg, from about 25 µg to about 100, from about 25 µg to about 90 µg, from about 25 µg to about 80 µg, from about 25 µg to about 70 µg, from about 25 µ g to about 60 µ.g, from about 25 µg to about 50 µg, from about 25 µ.g to about 40 µg , from about 25 µ.g to about 35 µg, from about 25 µg to about 30 µg, or from about 25 µg to about 45 µg. In some embod iments, the metered dose spray produced by the device comprises a metered dose of about IO µg , about 15 µg, about 20 µg, about 25 µg, about 30 µ g, about 35 µg, about 40 µg, about 50 µg, about 55 µg, about 60 µg, about 70 µg , about 75 µg , about 80 µg, about 85 µ.g, about 90 µg, about 95 µg, or about 100 µ.g.

Tn some embodiments, the metered dose spray produced by the device comprises a metered dose of less than about I 00 µ.g, less than about 90 ~Lg, less than about 80 ~Lg, less than about 70 µg, less than about 60 µg, less than about 50 µg , less than about 40 µg , less than about 30 µg , less than about 20 µg, or less than about l O µg. In some embodiments, the metered dose spray produced by the device comprises a metered dose of about IO µg, about 25 µg, about 35 µg, about 50 µg, about 75 µg , or about I 00 ~Lg.

In some embodiments, the metered dose spray produced by the device comprises a volume of less than about 150 µl, less than about 140 µI, less than about 130 µ.l, less than about 120 µI , less than about 110 µl, less than about 100 µ1 , less than about 75 µI, or less than about 50 µI. In some embodiments, the metered dose spray produced by the device comprises a volume of about 150 µI, about 140 µl, about 130 µJ, about 120 µl, about 110 µl , about 100 µJ, about 75 µ.I, or about 50 µI.

In some embodiments, the metered dose spray produced by the device produces a Cpl asma in the mammal of from about 0.09 ng/ml to about 0.1 l ng/ml, from about 0.08 ng/ml to about 0.12 ng/ml, or about 0.1 ng/ml within about 12 minu tes to about 30 minutes, from about 12 minutes to about 20 minutes, from about 15 minutes to about 20 minutes, or within about 15 minutes of administration and has an analgesic effect without significant sedation. Tn some IO embodiments, the metered dose . pray produced by the device produces a C p1 asma in the mammal of about 0.1 ng/ml within about 15 minutes to about 20 minutes of administration.

In some embodiments, the metered do e spray produces an onset of pain relief less than about 60 minutes, less than about 55 minutes, less than about 50 minutes, less than about 45 minutes, less than about 40 minutes, less than about 35 minutes, less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, or about 15 minutes .

Tn some embodiments, the metered dose spray produced by the device does not produce in an adult within a period of time of about two hours after administration significant sedation and has an analgesic effect within the period of time. In some embodiments, significant sedation in the adult is not produced within a peiiod of time of about 1.5 hours after administration, but yet has an analgesic effect within the period of time. In some embodiments, significant sedation in the adult is not produced within a period of time of about 1.0 hours after administration, but yet has an analgesic effect within the period of time. ln some embodiments, significant sedation in the adult is not produced within a pe1iod of time of about 45 minutes after administration, but yet has an analgesic effect within the period of time. Tn some embod iments, significant sedation in the adult is not produced within a period of time from about 30 minutes to about of about 1.5 hours after administration, but yet has an analgesic effect within the period of time. In some embodiments, signi ficant sedation in the adult is not produced within a period of time from about 40 minutes to about 75 minutes after administration , but yet has an analgesic effect within the period of time. In some embodiments, significant sedation in the adult is not produced within a period of time from about 45 minutes to about 70 minutes after adm inistration, but yet has an analgesic effect within the period of time. In some embodiments, significant sedation in the adult is not produced within a period of time from about 50 minutes to about 65 minutes after administration, but yet ha~ an analgesic effect within the peiiod of time. In some embodiment , significant sedation in the adult i not produced within a period of time from about 55 minutes to about 60 minutes after administration, but yet has an analgesic effect within the period of time.

In some embodiments, the metered dose spray produced by the device produces a plasma Cmax in the mammal from about 0.08 ng/ml to about 0.25 ng/ml, from about 0.08 ng/ml to about 0.2 ng/ml, from about 0. 1 ng/ml to about 0.25 ng/ml , from about O. l ng/ml to about 0.2 ng/ml, from about 0.08 ng/rnl to about 0. 15 ng/ml, from about 0.1 ng/m l to about 0. 15 ng/ml , from about 0.15 ng/ ml to about 0.2 ng/ml , or from about 0. 15 ng/ml to about 0.25 ng/ml. In some embod iments, the metered dose spray produced by the device produces a plasma Cmax in the mammal of about 0.08 ng/ml to about 0.25 ng/ml. In some embodiments, the metered dose spray produced by the device produces a plasma Cmax in the mammal of abou t 0.08 ng/ml to about 0.2 JO ng/ml. In some embodiments, the metered dose spray produced by the dev ice produces a plasma Cmax in the mammal of about 0. J 5 ng/ml. In some embodiments, the metered dose spray produced by the device produces a plasma Cmax in the mammal of about 0.08 ng/ml, about 0.1 ng/ml, about 0.2 ng/ml, or about 0.25 ng/ml.

In some embodiments, the metered dose spray produced by the device produces a Tmax in the mammal of less than about 60 minutes, less than about 50 minutes, less than about 40 minutes, less than about 35 minutes, or less than about 30 minutes. In some embodiments, the metered dose spray produced by the device produces a T max in the mammal fro m about 20 minutes to about 60 minutes, from about 20 minutes to about 50 minutes, from about 20 minutes to about 40 mi nutes, from about 20 minutes to about 30 minutes, from about 30 minutes to about 60 minutes, from about 30 minutes to about 50 minutes, fro m about 30 minute to about 40 minutes, from about 40 minutes to about 60 minutes, from about 40 minutes to about 50 minutes, or from about 50 minutes to about 60 minutes. Jn some embod iments, the metered dose spray produced by the device produces a T max in th e mammal of less than about 1 hour. In ome embodiments, the metered dose spray produced by the device produces a T max in the mammal of less than about 50 minutes.

In some embodiments, the metered dose spray produced by the device during the hour immediately after administration to the mammal produces a level of sedation not greater than Level I, Level 2, or Level 3 on the Ramsay Sedation Scale. Tn some embodiments, the metered dose spray produced by the device during the hour immediately after administration to the mammal produces a level of sedation not greater than Level 3 on the Ramsay Sedation Scale. In some embodiments, the metered dose spray produced by the device during the hour immediately after administration to the mammal produces a level of sedation not greater than Level 2 on the Ramsay Sedation Scale.

In some embodiments, the metered dose spray produced by the device during the hour immediately after administration to tl1e mammal produces a level of sedation not greater than Level l or Level 2 on the Stanford Sleepiness Scale. In some embodiments, the metered dose spray produced by the device during the hour immediately after administration to the mammal produces a level of sedation not greater than Level 2 on the Stanford Sleepiness Scale.

In some embodiments, the metered dose spray produced by the device during the hour immediately after administration to the mammal produc es a level of sedation not less than Level 6 on the Modified Observer's Assessment Of Ale1ine s/Sedation Scale.

In some em bodiments, the metered dose sp ray produced by the device ha<; no or l O minimal effect on th e blood pressure of the mammal after administration. In some embodiments, the metered dose spray produced by the device has no effect on blood pressure withi n the hour im mediately after a compound described herein is administered. In some embodiments, the metered dose spray produced by the device has only minimal effect on blood pressure within the hour immediately after a compound described hereiu is administered. In some embodiments, the resti ng mean arterial blood pressure of th e mammal is not effected by more than about 5 mmH g, more than about 10 mmHg, more than about 15 mmHg, more than about 20 mmHg, more than about 25 mmHg, or more than about 30 mmHg.

In some embodiments, any of the compositions described herein can further comprise one or more other therapeutic agents. The one or more additional therapeutic agents is chosen from an analgesic, such as an opioid analgesic (e.g. morph ine, oxycodonc, hydromorphone, etc.), a synthetic opioid-like analgesic (e.g. meperidine, fentanyl, pentazocine, buto rphanol, etc. ), or a non-opioid analgesic (e.g. NSAIDs, ketamine, salicylates, steroids, etc.); a vitamin; a vasodi lator; a benzodiazepine (e.g. clonazepam, alprazolam , lorazepam, etc.); a triptan (and other compounds for mi graine headaches); an anti-con vulsant (e.g. pregabalin, valproic acid, gabapentin, etc. ); an anti-depressant (e.g. tricyclics such as amitriptyline, nortriptyline, etc.; serotonin and norepinephrine reuptake inhibito rs such as duloxetine, fluoxetine, venlafaxine, etc.); an anti-nausea medication (e.g. metoclopramide, prochlorperazine, ondansetron, granisetron, etc.); and an anti-hype1iensive (e.g. beta blockers such as propranolol and calcium channel blockers such as verapamil , etc.).

Examples of other analgesic agents include, but are not li mited to, narcotics, NS AIDs, Cox-2 inhibitors, steroids, and the like. Other examples include, but are not limited to, aspirin , codeine, oxycodone, ibuprofen, butalbital, acetaminophen (APAP), caffein e, aspirin, hydrocodone, acetaminophen, propoxyphene n-apap, propoxyphene HCI, butorphanol tartrate, pentazocine-apap, pentazocine-naloxone, tramadol, tramadol extended release, fentany l, morphine, meperidine HCI, hydromorphone HCI, methadone, levorphanol tartrate, oxymorphone, buprenorphine, celecoxib, rofecoxib, naltrexone, naproxen, flurbiprofen, diclofenac, sulindac, oxaprozin, piroxicam, indomethacin, etodolac, meclofenamate, meloxicam, fenoprofen , ketoprofcn, nabumctone, tolmetin, kctorolac tromethamine, salsalatc, difluniiml, cho line and magnesium salicylates, or any combination thereof. The compounds or salts thereof, and compositions comprising the same, described herein can be admini. tered either alone or in combination (concunently or serially) with the other pharmaceutical agents. Tn some embod iments, the compositions described herein can be administered with one or more other analgesic agents.

JO ln some embodiments, the compo ition further comprises a canier vehicle. In some embod iments, the pharmaceutical composition further comprises sodium phosphate and/o r sodium citrate. In some embodiments, the pharmaceutical composition further comprises sodium citrate, citric acid, and sodium chlorid e. In some embodi ments, the pharmaceutical composition further comprises about 0.2% to about 0.3% (w/w) sodium citrate and about 0.005% to about 0.015% (w/w) cit1ic acid.

In some embodiments, the composition comprises a salt, such as a pharmaceutically acceptable salt. In some embodiments, the composition comprises sodium chloride, potassium chloride, or any combination thereof. ln some embodiments, the composition comp1ises citric acid. Tn some embodiments, the composition comprises sodium citrate, citric acid, and a salt, including, but not limited to , sodium chloride. In some embodiments, the composition comprises about 0.1% to about 0.5%, from about 0.1% to about 0.4%, from about 0.2% to about 0.5%, from about 0.2% to about 0.4%, from about 0.2% to about 0.3 % (w/w) of . odium citrate. In some embodiments, the composition comprises from about 0.005% to about 0.015%, from about 0.005% to about 0.05%, from about 0.005% to about 0.004%, from about 0.005% to about 0.03%, from about 0.005% to about 0.02%, or from about 0.005% to about 0.0175 % (w/w) of citric acid.

In some embodiments, the pharmaceutical composition further comprises a chelator or stabilizer that can be used to enhance chemical stability where requ ired. Suitable stabilizers include, but are not limited to, chelating agents or complexing agents, such as, for example, the calcium complexing agent ethylene di amine tetraacetic acid (EDTA), a salt of EDT A, citric acid, chitosan, sorbitol, and tartaric acid. For example, an appropriate amount of EDT A or a salt thereof, e.g. , the disodi um salt, can be included in the composition to complex excess calcium ions and prevent gel format ion during storage. EDTA or a salt thereof can suitably be included in an amount of about 0.01% to about 0.5%. In those embodiments containing a preservative other than EDTA, the EDTA or a salt thereof, more particularly disodium EDTA, can be present in an amount of about 0.025% to about 0.1 % by weight. Without being bound by any theory, the chelating agents can prevent multivalent cationic degradation of dcxmedetomidine or other components in the composition.

In some embodiments, the intranasal compositions described herein may optionally include a buffering system comprised of an acid/base pair that resis ts changes in pH. The pH of the compositions can be controlled to limit irritation of the nasal sp ray. In some embodiments, a sol ution pH of about 6.0 to about 6.5 can be used to be compatible with the pH of nasal secretions while maintaining the drug in solu tion. Pharmaceutically acceptable buffers that provide a pH compatible with the nasal mucosa include citrate, phosphate, and the like. In some embodiments, the pH of the composition is less than 7, less than 6.9, less than 6.8, less than 6.7. less than 6.6, less than 6.5, less than 6.4, less than 6.2, or less than 6.1. In some embodiments, the pH of the composition is from about 6 to about 6.1, from about 6 to about 6.2, from about 6 to about 6.3, from about 6 to about 6.4, from about 6 to about 6.5, fro m about 6 to about 6.6, from about 6 to about 6. 7, from about 6 to about 6. 8, from about 6 to about 6.9, or from about 6 to about 7 .0. In some embodiments, the pH of the composition is such that the composition does not iJTitate the nasal cav ity.

In some embodiments, the pharmaceutical composition further comprises one or more anti-microbial preservatives. Examples of preservatives include, but are not limited to, mercuiy- containing substances such as phcnylmercuric salts (e.g., phcnylmcrcuric acetate, borate and nitrate) and thimerosal; stabilized chlorine dioxide; quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride; irnidazolidinyl urea; parabens such as methylparaben, ethylparaben, propylparaben and butylparaben, and salts thereof; phenoxyethanol; chlorophenoxyethanol; phenoxypropanol; chlorobutanol; chlorocresol; phenylethyl alcohol; disodium EDT A; and sorbic acid and salts thereof. Preservatives may precipitate in the presence of other excipients in the composition. For example, benzal.konium chloride can precipitate. T hu s, in some embodiments in which a one that does not precipitate but remains in solution in preservative is present, the preservative is the composition. A suitable preservative is phenylethyl alcohol. The one or more anti-microbial preservatives can be included, for example, to suppress microbial and fungal growth in the final delive1y systems.

In some embodiments, the pharmaceutical composition further comprises one or more antioxidants. Suitable antioxidants may optionally be included in the nasal composition, for example, to stabilize the formulation against long term effects of oxidation. Examples of antioxidants include, but are not limited to, V itamin E (and derivatives thereof), Vitamin C (and derivatives thereof), BHT, BHA, propyl gallate, citric acid, erythorbic acid, monothioglycerol, a metabisulfite (sodium or potassium), propionic acid, sodium sulfite, and thymol.

In some embodiment,;, the pharmaceutical composition further comprises one or more dose confinnation excipients, which help faci litate proper usage and/or avoid overdosage. For medications that are administered intranasally, it can be difficult for the subject to determine whether the medication has been properly administered. The inclusion of a dose confirmation excipient can provide positive feedback to the subject after administration, confirming that the dose has been adm in istered intranasally. In some embodiments, the dose confirming excipient l O has an odor that can allow the subject to confirm that the dose was administered and taken or deposited into the nose. Other feedback mechanisms can be used to confirm that the dose has been administered appropriately. Odor is one non limiting example. In some embodiments, the dose confim1ation excipient is phenylethyl alcohol. Without being bound by theory, dose confirmation excipients provide sensory feedback to the patient to confirm that a dose has been delivered, thereby increasing compliance with the prescribed dosing regimen and reducing the potential for overdosing. Phenylethyl alcohol has a distinct odor and may serve as both an antimicrobial and dose confirmation excipient in the compositions previously described.

In some embodiments, the pharmaceutical composition futiher comprises one or more humectants. Examp les of humectants include, but are not limited to, glycerin, propylene glycol, polyethylene glycol, and a sugar/sugar alcohol, or any combi nation thereof. Humcctants can provide moisturi zing effects and reduce nasal irritation.

In some embodiments, the pharmaceutical composition fmiher comprises one or more osmolality adjusting agents . The osmality of the intranasal composition can also be relevant to the uptake of the medication intranasally. Suitable osmolali ty adjusting agents include, but not limited to, sodium chlorid e, dextrose, sugars, or any combination thereof. The osmolality adjusting agents can also be included in the composition to produce solutions that are less itTitating to the nasal mucosa by aligning the osmolality of the administered solution with the nasal mucosa.

In some embodiments, the pharmaceutical composition is free of a viscosity enhancing agent. Viscosity enhancing agents including, but not limited to, Methocel E4M can optionally be added to increase residence time of the instilled or spray solution with the nasal mucosa.

However, in the case of dexmedetomidine, the use of a viscosity increasing agent may result in dimi nished dexmedetomidine plasma levels and may therefore be omitted under certain conditions, such as when the dexmedetomidine composition is intended for rapid uptake.

Therefore, it wa5 surprisingly found that the viscosity of the intranasal composition can affect the uptake of the active ingredient. Thus, in some embodiments, an increase in viscosity can decrease the uptake of dexmedetomidine. Accordingly, in some embodiments, the composition is free of a roly mer that increases the viscosity of a liquid vehicle or composition. In some embod iments, the polymer is a water-soluble polymer. Examples of a soluble polymer include, but are not limited to, a cellulose ether (e.g. hydroxypropyl methylcellulose), other cellulose based polymers (methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), povidone, polyvinyl alcohol, gums (e.g. xanthum gum), polyethylene glycol (PEG), polyethylene oxide (PEO), hyaluronic acid (and derivates and salts thereof), carrageenan, dextran, and IO poloxamer. In some embodiments, the cellulose ether is hydroxypropyl methylcellulose (HPMC). Thus, in some embodiments, the composition is free of HPMC. In some embodiments, the viscosity of the intrana-;al composition is no greater than the viscos ity of water.

In some embodiments, the viscosity of the intranasal composition is no greater than 110%, no greater than 120%, no greater than 130%, no greater than 140%, no greater than 150%, no greater than 160%, no greater than 170%, no greater than 180%, no greater than 190%, or no greater than 200% of the viscosity of water. In some embodiments, the viscosity of the intranasal formulation is about 1 mPa*s, 2 mPa*s, 3 mPa*s, 4 mPa*s, or 5 mPa*s. In some embodiments, the viscosity of the intranasal formulation is less than about 1 mPa*s, 2 mPa*s, 3 mPa*s, 4 mPa*s, or 5 mPa.*s. In some embodiments, the viscosity of the intra.nasal formulation is from about 1 mPa*s to about 2 mPa*s, from about 1 mPa*s to about 3 rnP a*s, from about 1 mPa*s to about 4 mPa*s, from about l mPa*s to about 5 mPa*s, from about 1.5 mPa*s to about 2.5 rnPa*s, from about 2 mPa*s to about 3 mPa*s, from about 2 mPa*s to about 4 mPa*s, or from about 2 mPa*s to about 5 mPa*s.

The viscosity of a composition can be calculated by various methods. The viscosity can also be directly measured u. ing various techniques. For example, the viscosity of a composition can be calculated according to the fo llowing equation. The equation expresses the illustrated approximate relationship between soluti on viscosity and polymer concentration is 11 =(C*a.) + 1, where 11 is the soluti on viscosity in millipascal-seconds, C is the polymer concentration in solution (expressed in percent), and a is a constant specific to the molecular weight. For example, the value of a can be calculated by substitution and may then be used to calculate the approximate viscosity at the desired concentration.

It is also known in the art that the compounds and compositions comprising the same can be contained in formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, em ulsifiers, buffers, humectants, moistu,i zers, solubilizers, preservatives and the like. In some embodime nts, the compounds and compositions comprising the same can be contained in formulations that do not comprise pharmaceutically acceptable diluents, fillers, disintegrants, bin ders, lubricants, surfactant\ hydrophobic vehicles, water soluble vehicles, emu lsifiers, buffers, humcctants, moistu1izers, solubilizers, preservatives and the like. In some embodiment , the compounds and compositions comprising the same can be contained in form ul ations that do not comprise a su,factant. The pharmaceutical compositions can also comprise suitable sol id or gel phase carriers or excipients. In addition to other excipients desc1ibed herein, exampl es of such caniers or excipients include, but are not li mited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethy Jene glycols. In some embodiments, the compounds described herei n can be used with agents including, but not limited to, topical analgesics (e.g., lidocainc), banier devices (e.g., GelClair), or 1inscs (e.g., Caphosol).

In some embodiments, when administered to a human, the compounds can be sterile.

Water can be a suitable earlier when the compound is administered intranasally. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers. Suitable pharmaceutical carriers also include excipients such as, but not limited to, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, si lica gel, sod ium stearate, glycerol monostearate, talc, sodium chloride, dri ed skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetti ng or emulsifying agents, or pH buffering agents.

The composition described herei n can take the fo rm of a so lution, suspension, emulsion, powder, sustained-release formulation, aerosol, spray, or any other fo rm suitable for the uses described herein. Examples of suitable pharmaceutical carriers are described in Rem in gton's Pharmaceutical Sciences, A.R. Gennaro (Editor) Mack Publishing Co.

In some embodiments, the compounds are formulated in accordance with routine procedures as a pharmaceutical composition adapted fo r administration to humans. In some embodiments, compounds are solutions in steril e isotonic aqueous buffer and , for example, with the other components described herein. Where necessary, the compositions can also include a solubi lizing agent. Compositions may optionally include a local anesthetic such as lidocai ne to ease pain at the site of the ad ministration that can be due to , fo r example, irritation from the composition.

In some embodiments, the present invention also provides pharmaceutical packs or kits comprisi ng one or more containers containing one or more compounds described herein.

Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regu lating the manufacture, use or sale of pharmaceuticals or biological products , which notice reflects approval by the agency of manufacture, use or sale for human administration fo r treating a cond ition, disease, or disorder described herein. In some embodiments. the kit contains more than one compound described herein. In some embodiments, the kit comprises a compound described herei n in a single unit dosage form, such as a single dose withi n an intranasal admini strable device such as a metered dose device that admi nisters a spray or a powder to a nasal activity.

In some embodiments, the components described herein are supp lied either separately or mixed together in unit dosage form, for example, the components can be combined to create an intranasal formulation. Examp les of making the formulations are described herein and can be modified to yield any suitable intranasal formulation.

The pharmaceutical compositions can be in unit dosage form . In such form, the composition can be divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quanti ties of the preparations. The dosage form can be any form including, but not limited to, the fo rms described herei n. ln some embodiments, a composition of the present invention is in the form of a liquid wherein the active agent is present in solutio n, in suspension, as an emulsion, or a a solution/suspension. 1n some embodiment<;, the liquid composition is in the fo rm of a gel. In other embodiments, the liquid composition is aqueous. In other embodiments, the composition is in the form of an ointment. The liquid composition can also be a spray.

Th e I iquid vehicle refers to the liquid in which dexmedetomidine is suspended or dissolved. Examples of the liquid vehicles include, but are not limited to, water, saline, an aqueous solution, DMSO, and the like.

In some embodiments, the pl1armaceutical composition comprises, in addition to dexmedetomidine, the following (all based on% w/w): about 0.245% anhydrous odium citrate, about 0.0 l % anhydrous citric acid, about 0.7% sodium chloride, about 99.045% purified water, at an initial pH of 6.31 adjusted to a final pH of about 6. 78 with 2N sodium hydrox ide. In some embodiments, the pharmaceutical composition comprises, in addition to dexmedetomidine, the followi ng (all based on % w/w): about 0.245% anhydrous sodium citrate, about 0.0 1 % anhydrous citric acid, about 0.1 % Methocel E4M, about 0. 7% sodiu m ch loride, about 98. 945% purifi ed water, at an initial pH of 6.36 adjusted to a final pH of about 6.83 with 2N sodium hydroxide. In some embodiments, the pharmaceutical composition comprises, in addition to dexmedetomidine, the following (all based on% w/w): about 0.193% sodium phosphate monobasic (monohydrate), about 0.162% sodium phosphate di basic (heptahyd rate), about 0. 7%, sodium chloride, about 98.946% purified water, at an initial pH of 6.37 adjusted to a final pH of about 6.53 with 2N sodium hydroxide. In some embodiments, the pharmaceutical composition comprises, in addition to dexmedetomidine, the following (all based on% w/w): about 0.193% odium phosphate monobasic (monohydrate), about 0.162% sodium phosphate diba<;ic (heptahydrate), about 0.75% sodium chloride, about 98.896% purified water, at an initial pH of 6.3 7 adjusted to a final pH of about 6.53 with 2N sodium hydroxide. In some embodiments, the pharmaceutical composition comprises, in addition to dexmedetomidine, the following (all based on% w/w): about 0.193% sodium phosphate monobasic (monohydrate), about 0.162% sodium phosphate dibasic (heptahydrate), about 0.25% phenylethyl alcohol, about 0.68% sodium chloride, about 98.616% purified water, at an initial pH of 6.15 adjusted to a final pH of about 6.51 with 2N sodium hydroxide. In some embodiments, the pharmaceutical composition comprises, in addition to dexmedetomidin e, the following (all based on% w/w): about 0.226% anhydrous sodium citrate, about 0.024% anhydrous citric acid, about 0.25% phenylethyl alcohol, about 0.76% sodium chloride, about 98.64% purified water, at an initial pH of 5.68 adjusted to a final pH of about 6.04 with 2N sodium hydroxide.

The compos iti ons comprising dexmedetomidine described he rei n are stable. For a 0.035% dexmedetomidine hydrochloride intranasal spray formulation, for example, the stability is at least 3 months, at least 6 months, at least 9 months, or at least one year wherein the storage conditions are 25°C at 60% relative humidity, and at least 1 month , at least 3 months, at least 6 months wherein the storage conditions are 40°C at 75% relative humidity.

Where dexmedetomidine, or a pharmaceutically acceptable salt thereof, is u, ed in any method or device described herein, it is understood that any and all metabolites of dexmedetomidine, or a pharmaceutically acceptable salt thereof, can also be used likewise.

In order that the invention disclosed herein may be more efficiently understood, examples are provided below. It should be under tood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any manner.

Exam1Jles Example 1: Preparation oflntranasal Formulations To a container, purified water, USP was added. To the water, anhydrous citric acid, sod iu m citrate dihydrate, sodium chloride, phenylethyl alcohol, and disodium EDTA was mi xed until dissolved. The pH of the solution was modified, ifnecessary, to be in the range of 6.0 and 6.5. With continued mixing, dexmedetomidine HCI was added until di solved. Water was added to adjust the dexmedetomidine HCl to a final selected concentration.

Example 2: Intranasal Formulations of Dexmedetomidine Nasal delivery of dexrnedetornidine HCI (DEX) was evaluated from aqueous sprays to provide pharmacokinetic profiles that provide analgesia without significant sedation. The nasal ·route of delivery is often desired by patients in pain that may be unable or unwilling to tolerate the treatment by an oral route (e.g., buccal, sublingual, swallowing), by a rectal route (e.g. foams , suppositories, etc.), or an injection route. In addition to the aqueous nasal sprays initially developed for evaluation of intranasally administered DEX, the formulations can be modified to include dry powders, suspensions, and/or vapors as would be apparent from the description contained herein.

An initial screening of DEX aqueous nasal compositions ad mini tered a<; nasal drops was evaluated in a canine model. The influence of buffer species and viscosity was evaluated in the fo llowing base compositions.

First Placebo Base Composition(% w/w) Component Formulation F orrnulation Formulation Sodium Citrate, Anhydrous 0.245 0.245 -- Citric Acid, Anhydrous 0.010 0.010 -- Methocel E4M -- 0.100 -- Sodium Phosphate Monobasic, -- 0.193 Monohydrate Sodium Phosphate Dibasic, Heptahydrate -- -- 0.162 0.700 0.700 Sodium Chloride 0.700 Purified Water 99.045 98.945 98.946 Total 100.000 100.000 100.000 6.37 Initial pH 6.31 6.36 Final pH 6.78 6.83 6.53 Adjusted with 2N Sodium Hydroxide.

DEX was dissolved into the Placebo Base Compositions to prepare Formulation solutions that would deliver 50 µg DEX in 100 µL volume. The DEX compositions were expressed as follows.

DEX Na5al Drop Composition(% w/v) Component Formu lation Formulation Formul ation 1-DEX 2-DEX 3-DEX Dexmedeto midine HCI 0.059 0.059 0.059 -- -- Formulation I 99.94 1 Formulation 2 99.941 -- Formulation 3 -- -- 99.94 1 Total 100.000 100.000 100.000 The density of the DEX nasal drop compositions was approx imately l g/mL at room temperahire and aJlowed for weight and volume to be used interchangeably. The three DEX Nasal Drop Compositions were administered to canines. Surprisingly, compositi ons without a cellulose ether, which is a viscos ity enhancing agent, such as Formulation I -Dex and Form ul ation 3-Dex, provided significant plasma levels in less than 15 minutes after administration. Also surprisingly, Formulation 2-Dex, which contained 0.1 % Methocel E4M and had the highest solution viscosity, resulted in negligible plasma levels of DEX. indicating that increased sol ution viscos ity dim inished the effectiveness of DEX delivered intranasally. This result was unexpected.

The influence of additional fomrn lation add itives was fu1iher investigated from aqueous DEX solutions that were delivered as fine mists from mu ltiple-use aqueous spray pumps. The following placebo base compositions were prepared.

Second Placebo Base Composition (% w/w) Component F orrnulation Formulation Formulation 4 5 6 Sodium Citrate, Anhydrous 0.226 Citric Acid, Anhydrous -- 0.024 Sodium Phosphate Monobasic, 0.1 93 0.193 -- Monohydrate Sod ium Phosphate Dibasic, Heptahydrate 0.162 0.162 -- Phenylethyl Alcohol 0.250 -- 0.250 Disodium Edetate Dihydrate -- 0.100 0.100 Sodium Chloride 0.750 0.680 0.760 Purified Water 98.896 98.616 98.640 Total 100.000 100.000 100.000 Initial pH 6.37 6. 15 5.68 Final pH 6.53 6.51 6.04 Adjusted wi th 2N Sodium Hydroxide.

DEX was dissolved into the second set of Placebo Base Compos itions to prepare solutions that would deliver 50 µg DEX in 100 µL volume. The DEX compositions are expressed as fo llows.

DEX Nasal Spray Compos ition(% w/v) Component Formulation F01m ulation Formu lation 4-Dex 5-Dex 6-Dex Dexmedetomidine HCI 0.059 0.059 0.059 Formulation 4 99.941 -- -- Formul ation 5 -- 99.941 -- Formul ation 6 -- 99.941 Total 100.000 100.000 100.000 Calculated Osmolality (mOsm/kg) 288 368 306 The density of the DEX nasal spray compositions wa approximately l g/mL at room temperature and allowed for weight and volume to be used interchangeably. The th ree DEX Nasal Spray Compositions were administered to canines using a manually actuated nasal pump.

The results of the canine study indicated measurable plasma levels as early as 5 minutes and decreasing plasma levels according to Formulation 4-Dex> Formulation 5-Dex > Formulation 6- Dex.

An add itional placebo base composition wa-; prepared as defined below.

Thi rd Placebo Base Composition (% w/w) Component Formulation 7 Sod ium Citrate, Anhydrous 0. 230 Citric Acid, Anhydrous 0.020 Phenylethyl Alcohol 0.250 Disodium Edetate Dihydrate 0.100 Sodium Chloride 0.760 Purified Water 98.640 Total 100.000 Initial pH 5.79 Final pH 6.27 Adjusted with 2N Sodium Hydroxide.

DEX was dissolved into the third Placebo Base Composition to prepare a solution that would deliver 25 µg DEX in 100 µL volume. The DEX composition is expressed as follows.

DEX Nasal Spray Composition(% w/v) Component Formulation 7-Dex Dexmedetomidine HCI 0.0295 Formulation 7 99.9705 Total 100.0000 Final pH 6.20 The density of the DEX nasal spray composition was approximately l g/mL at room S temperature and allowed for weight and volume to be used interchangeably. The DEX nasal compositions were developed as an aqueous solution that could be delivered as nasal drop or as a fine mist from a nasal spray device. The DEX nasal compositions min imally contained DEX dissolved in purified water at a suitable concentration to deliver the intended DEX dose in 25 µL to 200 µL. Dose volumes less than 25 µL can result in variable delive1y while dose volumes JO greater than 200 µL can result in excess run off from the nasal cavity. The aqueous nasal compo itions can optionally contain additional materials to facilitate the intranasal delivety of DEX.

Example 3: Droplet Particle Size Determination Tn vitro spray pump performance of the Drug Product (DEX-TN.02 50µg APT/I 00 µL Intranasal Spray and DEX-IN.03 25µg API/50 µL Intranasal Spray) and Placebo (DEX-IN.02P 100 µL Intranasal Spray) was based on droplet size distribution a measured by laser diffraction using a Malvern Spraytec. The Malvern Spraytec operates based on a laser diffraction principle and is a commonly used technique to characterize droplet size distributions from nasal sprays.

The droplet size distribution was characterized by the following metrics: volume distribution (Dvl 0, Dv50, Dv90), Span and percentage(%) less than 10 µm per the FDA CMC Guidance for Nasal Sprays (2002) and FDA Draft Guidance for Industry: Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action, April 2003 .

Example 4: Pharmacokinetic Study of Dexmedetomidine Formulations Following Intranasal or Sublingual Adm inistration in Dogs One objecti ve of the present study was to compare the pharmacokinetics of multiple experimental dcxmcdctornidine formulations to the pharmacokinctics of a commercial formu lation of dexmedetomidine when administered intranasally or sub lingually in dogs. For each dosing event, five male dogs were dosed intranasally or sublingually with 50 µg of dexmedetomidine free-base (equivalent to 59 µg of dexmedetomidine HCl) in 100 µL of formulation, except for Formulation 7-Dex, where the dogs were dosed with 25 µg of dexmedetomid ine free-base (equivalent to 29.5 µg of dexmedetomidine HCI) in 100 µL, and the PRECEDEX® formulatio n, which contained 50 µg dcxmcdetomidinc base equivalent in 500 µL of solutio n. Dosing was performed in 10 dosing events in th ree segments with the fonnulation s, with a minimum 2-day interval between the dosing events, as shown in the table below: Segment Dosing Event Fo rmulation Dose Route l Formulation 1-Dex* Intranasal 2 Formulati on 3-Dex* Intranasal 3 Formulation 2-Dex* Intranasal PRECEDEX'lll* 4 Intranasal Formulation 4-Dex* Intranasal 6 Formulation 5-Dex* Intranasal Intranasal 7 Formulation 6-Dex* 3 Formulation 6-Dex* Intranasal Intrana.-;;al 9 Formu lation 7-Dex*** DEX-SL.01 * Sub lingual *Dose= 50 ~Lg of dexmedetomidine free-base (equiv. to 59 µg of dexmedetomidine HCl).

**Redose of Formulation 6-Dex using a new sprayer.

***Dose = 25 µg of dexmedetomidi ne free-base (equiv. to 29.5 µg of dexmedetomidine HCI).

Mean pharmacokinetic parameters for dexmedetomidine are summarized below.

Formul ation !1 12 (hr) AUCtat AUCo. oo Tmax Cmax g/ml) (Dosi ng Event) (hr) (ng/ml) (hr*ng/ml) (hr*n Formulation 1-DEX(l) 0.7 7.72 7.18 0.93 8.88 Formulation 2-DEX (2) 0.7 NCl 16.9 12.3 NCI Formulation 3-DEX (3) 0.42 1.30 1.10 1.1 6 0.43 PRECEDEX® (4) 0.38 0.52 12.2 6.68 6.69 Formul ation 4-DEX (5) 0.47 0.4 1.35 1.1 2 0.984 Formulation 5-DEX (6) 2.44 0.80 0.50 2.46 2.62 Formulation 6-DEX (7) 0.42 0.56 9.05 6.57 2. 18 Formulation 6-DEX (8)* 0.27 0.79 5.92 3.61 6.06 Formulation 7-DEX (9) 0.32 0.63 1.33 1. 18 1.09 DEX-SL.0 1 (LO) 0. 60 1. 72 2. 15 2.27 4.75 NC 1 = Value could not be calculated by Wi nNonlin due to insufficient data points for the eli mi nation phase.

*Redose of Formulation 6-DEX using a new sprayer.

For intranasal administration (dose events 1 to 9), Tmax and elimination half- life for dexmedetomidine were si milar between the PRECEDEX 'Ki formu lation and the experimental doses 1-3 and 5-9. The mean T max for dexmedetomidine for the PRECEDEX® fo rmulation was 0.3 8 hours, and the mean T max fo r dexmedetomidine for the experimental fo rmulations that were administered intranasally (doses 1-3, 5-9) ranged from 0.32 hours to 0.80 hours. The mean elimination half-life for dexmedeto mi dine for the PRECEDEX® formulation was 0.52 hours, and the mean elimination half-life for dexmedetomidine for the experimental formulations admi nistered intranasally (doses 1-3, 5-9) ranged from 0.43 hours to 0.93 hours. For subl ingual adm inistration (dos ing event 10, fo rmulation DEX-SL. OJ ), the mean T max was 0.60 hours similar to the T max obtain ed following intranasal administration of PRECEDEX® and experimental doses 1-9, while the mean el im ination half-l ife for the DEX-SL.0 1 formulation was 1.72 hours, longer than the eli mination half- li fe obtained fol low ing intranasal administration of PRECEDEX® and experi mental doses 1-3 and 5-9.

Based on Cmax and AUC1 ast, dexmedetomidine exposure follow ing intranasal administration was highest for the Formulation 3-DEX formulation. The mean Cmax fo r Formul ation 3-DEX formulation was approximately 140% of the mean Cmax for PRECEDEX®, wh ile mean AUC1as1 for the Formulation 3-DEX formul ation was approximately 180% of the mean AUC1ast for PRECEDEX®. The mean AUC1 ast for the Formu lation 6-Dex and Formul ation I-DEX fo rmulations were similar to that of PRECEDEX®, while the mean Cmax for these fo rmulations were approximately 70% of the mean Cmax fo r PRECEDEX®. The mean Cmax and AUC1 as1 for all other experimental formulations dosed intranasally were lower than that for PRECEDEX®. Dexmedetomidine exposme foll owing intranasal administration was lowest for the Formulation 2-DEX and Formulation 7-DEX fo rmulations. Surpris ingly, dexmedeto mi di ne exposure fo llowing sublingual ad ministration of formulation DEX-SL.O J was substantially lower than for intrana al ad ministration of PRECEDEX®; the mean Cmax for the DEX-SL.01 formulation was 18% of the mean Cmax for PRECEDEX®, and mean A UC1 ast for the DEX-SL.O I formulation was 34% of the mean AUC1 as1 for PRECEDEX®.

Formulati on (Dos ing Event) AUC1 as1 AUCo-ro Tmax t112 Cm:1x (hr) (hr) (ng/rnL) (hr*ng/rnL) (hr*ng/mL) Formulation I-DEX (1) 1.75 NC 0.272 0.355 Formulation 2-DEX (2) 1. 80 NC' 0.29 1 0.386 NC' Formulation 3-DEX (3) 0.65 NC 0.285 0.203 NC PRECEDEXo, (4) 1.55 NC 0.248 0.358 NC Formul ation 4-DEX (5) 1.00 NC 0.0847 0.1 11 NC Formul ation 5-DEX (6) 1.35 1.28 0. 11 6 0.1 69 0.233 Formul ation 6-DEX (7) NC 0.221 0.319 NC 0.90 Formulation 6-DEX (8)* 1. 15 7.29 0.168 0.265 2.3 8 Formulation 7-DEX (9) 1. 15 1.25 8.70 0.0999 0.109 DEX-SL.0 1 (1 0) I .80 NC 0. 152 0.204 NC' NCI = Value could not be calculated by WinNonlin due to insufficient data points for the elimi nation phase. *Redose of Formulation 6-Dex using a sprayer.

For intranasal administration (dose events 1 to 9), the Tmax fo r this table was generally si milar between the PRECEDEX® formul ation and the experimental doses 1 .-3 and 5-9. The mean T max for the PRECEDEX® fo rmulation was 1.55 hours, and the mean T max for the expetimental formul ations administered intranasally (doses 1-3, 5-9) ranged fro m 0.65 hours to l.80 hours. For most fo rmulations, the elimination half-life was either not calcu lated or not repotied due to insufficient data poin ts for the elimination phase or poor goodness-of-fi t (R2<0.8) for the elimi nation phase. Where calculable, the half-life ranged from l. 3 hours to 8.7 hours. For sublingual admi nistration (dosing event I 0, form ulation DEX-SL.01 ), the mean T max was l.80 hours, similar to the Tmax obtained fo llowing intranasal administration of PRECEDEX® and the experimental doses 1-3 and 5-9.

Based on Cmax and AUC1ast, exposure fo llowing intranasal ad ministration was highest for the Formulation 3-Dex formulation. The mean Cmax for the Form ulation 3-Dex formulation was app roximately 11 7% of the mean Cmax for PRECEDEX®, while the mean AUC1 ast fo r the Formulation 3-Dex formulation was approximately 108% of the mean AUC1 as1 for PRECEDEX®.

Mean Cmax and AUC1ast for all other experimental fo rmulations dosed intra.nasally were si mil ar to that for PRECEDEX®, except for Formul ation 4-DEX and Formulation 7-DEX (the amount of dexmedetomidine dosed with Formulation 7-DEX was half that of the other fo rmulations).

Exposure following sublingual admi nistration of formulation DEX-SL.Ol was lower than for intranasal administration of PRECEDEX®; mean Cmax for the DEX-SL.01 formulation was approximately 61% of the mean Cmax for PRECEDEX®, and mean AUC1 ast for the DEX-SL.01 form ul ation was approximately 57% of the mean AUC1ast for PRECEDEX®.

The results presented herein, surprisingly show that when compared to the previously studied sublingually administered fonnulation DEX-SL. 0 1, absorption occurs more quickly via the nasal route. Therefore, intranasal administration of DEX surprisingly may provide faster pain relief and/or prevention of pain in subject as compared to sub lingual or methods of adrnini tering DEX across the oral mucosa, without significant sedation, and with little or no IO effect on blood pressure.

Dosing Doses 1-3 were administered intranasally with a micropipette with the head inverted fo r dosing. The dosage was 50 µ.g of dex medetomidine free-base (equiv alent to 59 µg of dexmedetomidine HCl) in 100 µL of formulation. Dose 4 was administered using a commercial nasal spray bottle. Spray doses were administered with the head upright, alternating nostrils for each spray. The head was inverted fo r 30 seconds to 1 minute after spray administration . The spray bottle adm inisters 100 µL per spray, and five sprays were required to deliver the dosage of 50 µg of dexmedetomidine free-base (equivalent to 59 µg of dexmedetomidine HCl). The spray bottle was primed in an area remote from dos ing prior to dose administration to prevent possible cross-contamination. Additionally, dosing wa,;; performed in an area remote from blood collection to prevent possible contamination of blood samples wi th aerosolized test article.

Doses 5-7 were administered usin g a commercial nasal spray bottle. Spray doses were ad ministered with the head upright. The head was inverted for 30 seconds to 1 minute after spray administration. The spray bottle administers I 00 µL per spray, and one spray was required to deliver the dosage of 50 µg of dexmedetomi dine free base (equi valent to 59 µg o f dexmedetomidine HCI). The spray bottle was primed using five spray actuations in an area remote from dosing prior to dose adm inistration to prevent possible cross-contamination.

Additionally, dosing was performed in an area remote from blood collection to prevent possible contamination of blood samples with aerosolized test a1iicle.

Dose 8 was ad mini tcrcd using a commercial nasal spray bottle. Spray doses were administered with the head upright. The bead was inverted for 30 seconds to 1 minute after spray administration. The spray bottle administered 100 µL per spray, and one spray was required to deliver the dosage of 50 ~Lg of dexmedetomidine free base (equivalent to 59 µg of dexmedetomid ine HCl). The spray bottle was primed using five spray actuations in an area remote from dosing prior to dose admi nistration to prevent possibl e cross-contaminati on.

Additionally, dosing was performed in an area remote from blood collection to prevent possible contamination of bl ood samples wi th aeroso li zed test article.

Dose 9 was ad ministered us ing a commercial nasal spray bottle. Spray doses were administered with the head upright. The head was inve1ied for 30 seconds to I minute after spray administration . The spray bottle administered I 00 µL per spray, and one spray wa requi red to deliver the dosage of 25 µg of dexmedetomidine free ba e ( equivalent to 29.5 µ.g of dexmedetomidine HCl). The spray bottle was primed using five spray actuations in an area remote from dosing prior to dose adm inistration to prevent poss ible cross-contamination.

Additionally, dos ing was pe1 formed in an area remote from blood collection to prevent possible contami nation of blood samples with aerosolized test article.

Dose IO was admin istered sub lingually with a micropipette. The dosage was 50 µg of dex medetomidine free base (equivalent to 59 µg of dexmedetomidine HCl) in 100 µL of formulation.

For intranasal ad ministrations, the formulations were administered intranasally.

Fo ll owing dosing, the dog's nares were held shut and the head inverted for approx imately I minute. Each dosing event was separated by a min imum of 2 days to allow an appropriate washout.

After dosing, blood samples were obtained and tested fo r DEX plasma levels.

Example 5: Pharmacokinetics Of Intranasally Administered Dexmedetomidine in Humans Four different fo rmulations of DEX were used. PRECEDEX® (Treatment A) at a dose of 25 µ.g which was admi nistered intravenously over 10 minutes and 3 different intranasal dosages or formulations. Fo rm ulation B (35 µ.g administered in 100 µI in one nostril via I spray); Formulation C (35 µg total administered via 2 nostrils); and Formulation D (17.5 µg administered in 50 µI in one nostril via I spray).

Treatment A Treatment B DEX- Treatment C Treatment D Precedex 1V IN.O I 35 µg l 00 1 1! DEX-IN.0 1 35 ,ttg DEX-IN.01 17.5 !Lg µg in one nostril 50 µl in each nostril 50 µ! in one nostril 0.08 (31.9%) Cmax (ng/ ml) 0. 61 (58.7%) 0.17 (2 1.7%) 0.14 (34.0%) AUC0- 4(hr ng/ml) 0.71 (27.7%) 0.83 (23 .6%) 0.75 (22.5%) 0.38 (16.6%) 0.1 7 (0. 17, 0.25) l.00 (0.3 3, 4.00)T 1.13 (0.33, 2.00) T m, (hrs) 1.25 (0.33, 4.00) t, n (hrs) 2.43 ± 0.825~ l.60 (NA)~ 2.04 ± 0.200' 2.64± o.nt Geometric means (CV%) for Cm ax and AUC 0- a median (min, max) for T , ix; and arithmetic mean± SD 2 11 fortt12; t n=l l ; t n= lO; § n=4; ¥ n= I The pharmacokinetic obse1ved showed the surprising result that the administration of the dose in single spray to a single nostril (Treatment B) provided a better Cmax and a sho1ier T max as compared to the same total dose administered in two nostrils via 2 sprays (half the dose being administered into each nostril). This result could not have been predicted and is opposite of what wou Id have been expected by the skilled a1iisan, in part, due to a surface area comparison. The mean plasma concentrations produced by Treatment Breached a minimum target concentration (0 .1 ng/ml) with in 20 minutes after dosing. This su1vrising result of administering to a single nostril can facilitate the more rapid onset of activity (e.g., pain relief) in target patient populations. The rate of absoll)tion obse1ved in Treatment B was more rapid than previously studied non-lV fomm lations or routes of administration. This unexpected more rapid absorption set of analges ic effects. Tn fact, the analges ic effects can begin in less can allow for the fast on than 20 minutes. Plasma concentrations achieved with the 17.5 and 35 ~tg intranasal administration are provided in Figure l.

Dosing Healthy volunteers were administered the selected dose intranasally or, if indicated, another route of administration. A single nostril was administered to at a time with the untreated nostri l covered by a finger. B lood samples were taken and measured for DEX concentrations as indicated.

Example 6: Phase l, Two Period, Open Label, Multiple-Dose Evaluation of the Safety, Tolerability, and Pharmacokinetics oflntranasal Dexmecletomidine in Healthy Volunteers The p1ima1y objective of thi s study was to evaluate the pharmacokinetic profile of multiple doses of intranasal dexmedetomidine in healthy male and female subjects. Seconda1y endpoints of this study were to evaluate the safety and tolerability of intranasal dexrnedetomidine in healthy volunteers.

Methodology This was a Phase 1, open-label , two period, repeated dose study in healthy subj ects to investigate the safety, tolerability, and pharmacokinetics of intranasal dexmedetomidine. A total of 12 subjects (6 male and 6 female) were planned and enrolled. Healthy subjects between the ages of 18 and 50 years, inclusive, were screened for participation at one study site in the United States within 28 days before study drug administration. Medical history, physical examination, baseline laboratory testing, 12 lead electrocardiogram (ECG), pregnancy testing, vital s ign mea urements, and infonned consent were completed du1ing the screening visit.

All study doses were a 35 µg dose of DEX IN .0 1 administered as a single 100 µL spray into the left nostril. DEX-IN .OJ contained 35 µg dexmedetomidine in each 100 µL of olution, as well a5 excipients including: citric acid, sodium citrate, sodium ch lorid e, phenylethyl alcohol, disodium EDTA, and pu 1ified water. Doses ofDEX-IN.0 1 utilized a 100 µL spray nozzle for administrati on into the nostril according to the treatment assignment.

During Period 1, subjects received two doses of study medication, separated by six hours. During Period 2, study pa1iicipants received seven doses of study medicati on administered at six hour intervals. Study Periods were separated by not less than 24 hours between the last dose in Peri od I and the first dose in Period 2.

During Peri od l , subjects were confi ned from the evenin g before dos ing ( Day -I ) to l O approximately 18 hours after Dose 2 (Day 2). During Period 2, subjects were confined from the eveni ng before dosing (Day - I) to approximately 24 hours after the last study dose (Day 3).

W11ile confined, subjects received a standardized daily diet.

Serial blood samples were collected at defined intervals du1ing each study period in order to evaluate the pharmacokinetic properties of intranasally administered dexmedetomid ine, and its metabolite. W11ole blood was collected in 6 mL evacuated collection tubes treated with K2EDTA.

Plasma amples were to be collected w ithin ±2 minutes of the scheduled pos t-dose time through 60 minutes after dosing, samp les collected 75 minutes to 6 hours after dosing were able to be collected within ±5 minutes, and samples collected at and beyond 12 hours after dosing were able to be collected within ± 15 minutes of scheduled post-dose time. Actual times were to be recorded for all events, and any deviation outside the specified ranges were required to be clearly documented in the subject's study reco rds.

Immediately after the collection of each sample, the collection tube was to be gently inverted and then placed in wet ice. Within 30 minutes of withdrawal, th e tub es were centrifuged at about 2,000 x gravity fo r 10- 15 minutes to separate the cells from the plasma. No aids for separation were to be used. Two aliquots (2:0 .5 mL each) of plasma were transferred from each sample w ith clean pipette and placed in 2 polypropylene storage tubes in equal volumes. The storage tubes were labeled with the following information: protocol number, subject number, study day and relative time of sample (e.g., Period l , Dose 1, 10 Minutes after dosi ng), and biologic matrix to be analyzed (e.g., plasma). Within 60 minutes of the collection time, the storage tubes were to be placed into a freezer at - 20°C or below; they remain ed in the freezer until shipment for analysis.

For pharmacoki netic analyses in Period 1, up to 12 blood samples were collected from each subject prior to an d following admi nistration of each study dose. These were collected at predose (Time 0) and at the fol lowing approximate times after each dose of study medication: , 20, 30, 45, 60, and 90 minutes and 2 and 4 hours; additional blood samp les were collected at 6, 12 and 18 hours after Dose 2. In Period 2, up to 13 blood samples were co llected from each subject prior to and fo llowing admin istration of Dose 1 and Dose 7. These were collected at predose (Ti me 0) and at the followi ng approximate times after dosi ng with study medication: 10, , 30, 45, 60, and 90 minutes and 2 and 4 hours; additional blood samples were collected at 6, 12, 18 and 24 hours after Dose 7. Blood samples for Dose 2 through Dose 6 were collected at predose (Time 0) only.

A summary tabl e of study visits, and the assigned time points, is prov ided for the overa ll study, Period 1, Period 2 Doses 1 and 7, and Period 2 Doses 2 throu gh 6 in the table below.

Table: Summary of Study Visits Period l Period 2 Day 1 Day 3 Study Event Day 1 (hr) Day 2 (hr) Day Day (hr) (hr) -1 -1 6 24 18 24 36 60 o I o I 6 1 12 I 3 o I Washout <--- --- ---- -- ----- --- ------ ------- ----- - <----- - - - - - -x- Confinement x-- --- - ----- ------- -- --- - ------- ------- - ---- ----- - > Study X X X X X Dos i ng X I X I X I X I I I I Inclusion Criteria: Subjects met the fo llowing criteria to pa1 t icipate in the study: 1) was a man or woman between 18 and 50 years of age, inclusive; 2) for female subjects of childbearing potential, be surgically sterile, use double-barrier contraception, practice abstinence (must agree to use double-barrier contraception in the event of sexual activity) or using an insertable, injectable, transdermal, or combination oral contraceptive approved by the FDA through completion of the study and have negative results on a sernm pregnancy test done before administration of study medication, and have negative results on subsequent urine pregnancy tests (women who are postmenopausal [no menses for at least 2 years] are also eligible to participate); 3) had a body mass index (BMI) :S32 kg/111 and a body weight between 50 and 95 kg, inclusive; and 4) was able to understand the study procedures, agree to pa1ticipate in the study program, and voluntarily provide written informed consent.

Treatments Administered Study personnel administered al l doses of study medication according to the treatment schedule. Doses of dexmedetomidine were administered using the intranasal delivery device into the left nostril. Doses were administered into the assigned nostril with the untreated nostril covered with a finger. The subject's head was held in an upright position with the spray applicator inse1ied approximately Y:z" into the treated nostril. The subject inhaled through the treated nostril as the pump wa<s squeezed and the dose was delivered.

After administration of study medication. pa1iicipants were allowed to move around the study facility, and perform non-strenuous activities. Subjects may have been required to remain seated for a period of time by the study investigator if it was deemed unsafe for the subject to move around the study site without the accompaniment of study personnel.

Doses were subsequently evaluated in a single dose study in healthy volunteers where JO DEX-[N was evaluated us ing single and paired spray adm inistration at doses of 17.5 and 35 ~tg.

Based on the observed pharmacokinetics, it was determined that the 35 µ g dose level administered in to a single nostril woul d be most appropriate to explore fu1th er to achieve th e targeted plasma concentrations. Plasma concentrations achieved with the 17.5 and 35 µg intranasal doses are provided in Figure 1.

Ramsay Sedation Scale The investigator, or designee, used the Ramsay Sedation Scale to assess each subject's degree of sedation. For each subject at each time point, the degree of sedati on was assessed according to the Ramsay ratin g catego1ies. The Ramsay Sedation Scale was performed 'pre-dose (Time 0), and at 30, 60 and 90 minutes after each study dose. All scores returned to their baseline level (Score 2) within six hours after dosin g. Although an RSS score of 5 was assigned to two subjects during the course of the study, the majority of subjects did not experience significant sedation. Subjects were administered study doses eve,y six hours, and completed safety monitoring activities subsequent to each dose, around the clock for seven doses durin g Period 2; the confounding effect of this schedule is not addressed in th e assessment tool/result .

Criteria/or evaluation.: Pharmacokinetic parameters fo r the concentrations of dexmedetomidi ne and its major metabolite (ORM-14305) in plasma were calculated for Dose 1 and 2 during Peri od 1, and for Dose l and 7 during Period 2. The calculated parameters included peak (max imum) observed plas ma drug concentration (Cmax), time to Cmax (T max), area under th e concentration time curve (AUC) from Time Oto last sampling time (t) with a quantifiable plas ma drug concentration (AUCo-t), AUC from Time Oto 6 hours after dosing (AUCo-6), AUC from Time Oto infi ni ty (AUCo-oo, for Period l Dose 2, and Peri od 2 Dose 7), and terminal phase el im ination half life (t h, fo r Period 1 Dose 2, and Pe1iod 2 Dose 7).

Results : Observed pharmacokinetic parameten,, Cmax, Tmax, and AUCo-6 of dexmedetomidine are presented in the table below.

Pharmacokinetic Parameters of Dexmedetomidine Period 1 Period 1 Period 2 Period 2 Parameters [lj Dose 1 Dose 2 Dose 1 Dose 7 Cmax (ng/mL) 0.09 (30.6)' 0.16 (22.8Y 0.12 (3 5.8i O. l3 (3 l.3i Trn ax (hr~) 1.26 (0.33, 4.00/ 0.88 (0.33, 2.02)t 1.01 co.5o, 2.ooi 1.50 (0.33, 2.oo)t 0.39 (31.7) t 0.61 (19.2) t 0.47 (3 2.6) t 0.50 (31 .1) t AUCo.G 0.63 (22.2) t 0.47 (3 2.6) t AUC1 asi 0.38 (35.2) t 0.5 1 (55.0)t (hr·ng/rnL) (1] Geomet1ic means (CV%) for Cmax , AUC0-6, and AUC1 ast ; median (mi n, mi x) for Tmax t n= l 2; t n= IO Compa1ison of Pharmacokinetic Parameters Between Doses Doses Crns, (ng/mL) AUC1 a,1 (hr·ng/mL) AUCo-6 (hr·ng/mL) Period 1 Dose 2: 164.1 (l 38.0, 195.0) 164.2 (l34. l, 20 1. 0) 156.9 (134.7, 182.8) Period 1 Dose 1 Period 2 Dose 106.3 (82 .5, 136.9) 108.4 (77.8, 151.0) 05.5 (8 l. 1, 137.3) Period 2 Dose I Period 2 Dose I : 127.7 (l l2.4, [45.2) 125.1 (l 05.4, 148.6) 122.8 (106.5, 141.7) Period 1 Dose I Period 2 Dose 7: 86.8 (71. 0, 106.1 ) 84.4 (66.5, 107 .2) 85.2 (72.0, 100. 9) Period 1 Dose 2 Data presented is Ratio % (90% CI) Observed Mean Dexmedetomidine Plasma Concentrations (ng/mL) Period 1 (N=l2) Period 2 (N=IO) Time Post-Dose ,__------ -------+-------~--------1 Dose 7 Dose 1 Dose 2 Dose 1 0.033 ± 0.014 0 0.037 ± 0.0 16 Om in 0 0.028 ± 0.035 0.059 ± 0.028 min 0.008 ± 0.014 0.077 ±0.033 min 0.060 ± 0.028 0.1 18 ± 0.054 0.073 ± 0.050 0.09 1 ± 0.033 min 0.059 ± 0.020 0.134 ± 0.044 0.085 ± 0.041 0. 101 ± 0.034 0.083 ±0.028 0.145 ± 0.040 0. 112 ± 0.046 0. 113 ±0.032 45 min 0.088 ± 0.024 0.145 ± 0.023 0.1 16±0.041 0. J 19 ± 0.031 60 min 90 min 0.090 ±0.025 0. 134 ± 0.0 14 0. 11 6±0.036 O. l l 9 ±0.03 l 0.117±().039 2 hr s 0.092 ± 0.026 0. 135 ± 0.019 0.126 ± 0.033 4 hr.s 0.067 ± 0.024 0.090 ± 0.023 0.073 ± 0.026 0.072 ± 0.072 6 hrs 0.036 ±0.010 0.050 ± 0.018 0.037 ± 0.0 12 0.048 ± 0.0 I 3 12 hrs 0.022 ± 0 0.024 ± 0 18 hrs 0 0 24 hrs 0 Observed Mean ORM-1 4305 Plasma Concentrations (ng/mL) Period 1 (N=l2) Period 2 (N=lO) Time Post-Dose Dose J Dose 2 Dose 1 Dose 7 Om in 0 0.032 ± 0.019 0 0.085 ± 0.03 7 LO min 0 0.032 ± 0.019 0 0.085 ± 0.036 min 0 0.035 ± 0.0 15 0 0.083 ± 0.036 min 0 0.042 ± 0.0 13 0 0.08 1 ± 0.032 45 min 0 0.039± 0.0 14 0 0.078 ± 0.029 0.084 ± 0.034 60 min 0 0.042 ± 0.0 13 0 90 min 0 0.045 ± 0.0 14 0.002 ± 0.006 0.080 ± 0.034 2 hrs 0.01 0 ± 0.0 13 0.053 ± 0.0 14 0.017 ± 0.015 0.088 ± 0.038 4 hrs 0.032 ± 0.019 0.064 ± 0.0 19 0.039 ± 0.014 0.087 ± 0.035 6 hrs 0.038 ± 0.013 0.062 ± 0.021 0.043 ± 0.016 0.079 ± 0.035 . .r :•....... : :JL!\: .... 12 hrs 0.048 ± 0.0 I I 0.061 ± 0.027 i= ·· t}i: Jf>>t:/')): : .. •:·, ,' ... ., ··•·:" .> 0.032 ± 0.01 1 0.045 ± 0.02 L 18 hrs .:.) ... : ':::\.· :: :::: ; .. ,: :>••·· .. ·, ...... : \.::=::: :U:i.•: :• .. ····'· •' .)::.·•.::.:, :;··· . ? ··. Lt t t•· ·:r<• : 24 hrs ·····::· ·:·: /•.r ·rt· 0.03 1 ±0.0 11 . : : .· • .. · ·.·.··· .. ·.·.•.·.·-· ·: These results are illustrated in Figu re 2.

This study supported the safety and tolerability of repeated dosing with intranasal administration. When administered at the six hour dosing interval, there was little evidence of accumul ation of dexmedetomidine when comparing the AUC for Dose 1 to Dose 7. DEX-IN.O J was demonstrated to be well tolerated upon repeated dosi ng with up to seven doses administered on a six hour interval. There was no apparent increase in adver e events, changes in vital signs, or nasal irritation severity with repeated dosing. When administered as an initial 35 µg dose, DEX-IN.O 1 reached peak plasma concentrations after 1.01- 1.26 hours (median) with an average Cnrnx of0.09-0.12 ng/mL. No significant sedation was observed in subject at various time points during the tudy.

Exampl e 7: A Randomized, Double-Blind, Placebo-Controlled, Three Period Crossover Evaluation of the Efficacy, Safety, and Pharmacokinetics of Intranasal Dexmedetomidine in Chronic Low Back Pain Subjects A study was performed to to evaluate the efficacy, safety, and pharmacokinetics of two dose levels of intranasal dexmedetomidine (DEX-IN.02 and DEX-IN.03) compared with placebo in subj ects with chronic low back pain .

Methods: Adult s ubjects with chro nic low back pain symptoms present fo r greater than three months, and a baseline 24-hour pain intensity ~4 (0-10 scale) were eligible to participate.

Subjects were randomly assigned to a treatment sequence with DEX-IN.02 (50 µg; 50 µg/100 µL ), DEX-1 .03 (25 µg; 25 µg/50 µL) and matching placebo. Study doses were administered as an in tranasal spray usin g a si ngle dose spray device requirin g no p1iming. Doses were administered to a single nostril. Dosing devices were fill ed with the appropriate volume of drug solution to deliver the designated 25 or 50 µg dose of dexmedetomid ine. Study doses were administered on consecutive days, with a minimum 24-hour washout between doses. Subjects with baseline chronic analgesic therapy were allowed to continue their regimen throughout study, but no doses were to be administered within 2 hours of study treatment (unless analgesic rescue was required ). Rescue analgesia was available upon subject request according to the individual's baseline pain regimen.

Efficacy assessments included measures of pain intensity (PI), pain relief (PR), and global medication performance (GMP). Efficacy measures were used to calculate the pain intensity difference (PID), su mmed pain intensity difference (SPID) and total pain relief (TOTPAR) at multiple post-dose time points, and to determine the number of subjects with pa1iial and complete responses to therapy. Safety assessments included collection of vital signs, nasal ~ymptom assessment, sedation, and adverse events. Plasma samples were collected at intervals over the first 12 hours post-dose fo r pharmacokinetic analysis.

Results: The study enrolled and treated 24 subjects with DEX-IN.02, DEX-IN.03, and placebo; all enrolled ubjects completed all scheduled study doses. Subjects were primarily white (9 I. 7%) and male (58.3% ), with a mean age of 33. 7 ± 10.1 9 years. Subjects had primaii ly visceral pain (9 1.7%) with a mean history of pain symptoms lasting 6.75 ± 6.85 years. One third of subjects uti lized opioid analgesicf'. for their pain symptoms.

Mean improvement in subject PID values were significantly greater for the 50 µg dose (DEX-JN.02) compared with placebo from 45 minutes through 2 hours post-dose (45 min: 2.2 vs. 1.2, p=0.029 I; 1 hr: 2.2 vs . 0.8, p=0.0082; 1.5 hr: 2.2 vs. 0.7, p=0.0028 ; 2 hr: 2 vs. 0.9, p=0.0126). The mean SPID value was significantly greater for the 50 µg dose th an placebo at 60 minutes after dose (7. l vs. 3.6; p=0.0352). Mean TOTPAR was significantly higher for the 50 ~tg dose than placebo at both 45 and 60 minutes after dose (4.3 vs. 2.5; p=0.0298 and 6.2 vs. 3.3; p=0.0097, respectively). The results for the study are shown in the fo llowing tables.

Table: Summary of Mean±SD PIO Values for All Post-Dose Time Points Time Point Placebo (N=24) DEX-JN.03 (N=24) DEX-IN.02 (N=24) min 0.2 ± 0.48 0.3 ± 0.53 0.5 ± 0.93 min 0.6 ± 0.93 0.7 ± 1.09 0.8±1.18 min 1.0 ± 1.33 0.9± 1. 25 1.5 ± 1.32 min 1.0 ± 1.44 1.3 ± 1.36 1.9 ± 1.85 2.2~± 1.72 45 min 1.2 ± l .63 1.4 ± 1.44 2.2'~ ± 1.82 60 min 0.8 ± 1.49 1.5± 1.47 90 min 0.7 ± 1.16 1.4±1.41 2.i" ± l.81 2 hourn 0.9 ± 1.28 1.3 ± 1.23 2.0 ± 1.76 4 hours 1.1 ± 1.75 1.5 ± 1.38 l.8 ± 1.81 6 hours J.5 ± 1.56 1.5 ± 1.10 l.6±1.71 § p < 0.05; ¥ p < 0.01 Table: Summary of Mean±SE SPID Values Time Point Placebo (N=24) DEX-IN.03 (N==24) DEX-JN.02 (N=24) min 0.6 ± 0.19 0.7 ± 0.22 0.8 ± 0.24 min 1.6 ± 0.47 1.9 ± 0.48 2.7 ± 0.59 45 min 2.8 ± 0.78 3.3± 0.75 4.9 ± 0.90 60 min 3.6 ± 1.05 4.8 ± 1.03 7. 1* ± 1.24 *p = 0.0352 Table: Summary of Mean±SE TOTPAR Values Time Point Placebo (N=24) DEX-IN.03 (N=24) DEX-I N.02 (N=24) min 0.8 ± 0.20 0.6 ± 0. 15 0.5 ± 0.1 5 mi n 1.5 ± 0.35 1.3 ± 0.32 2.4 ± 0.39 45 min 2.5 ± 0.56 2.4 ± 0.48 4.3 ± 0.59 60 min 3.3 ± 0.74 3.5 ± 0.68 6.2'' ± 0.81 § p < 0.05; ¥ p < 0 .01 Mean GMP scores were similar among all 3 treatment groups during both 30- and 60- minute post-dose time points. The 50 µg dexmedetomidine treated group had more subjects with improvement ~ 33% and~ 50% at all time points after 15 minutes post dose; 11 DEX-IN.02 treated subjects repo1ied ~ 50% improvement at 90 minutes (95% CI, J .02-7.44) and 10 subjects at 2 hours (95% CI, 1.05-10.63), compared with 4 subjects at 90 minutes and 3 subjects at 2 hours in placebo group. No subjects in any of the treatment groups required rescue medications.

Adverse reactions were generally mild in DEX-IN treated subjects, w ith 5 events IO determined to be moderate in severity (2 BP decreased, l dizziness, 1 somnolence and 1 hypotension ). No SAEs, deaths , or withdrawals due to an AE occu n-ed during the conduct of th e study. Changes in systolic and diastolic blood pressure (SBP and DBP respectively) were greater with DEX-IN. 02 treated subjects than DEX-IN.03 and placebo treated subjects. Changes in heart rate (HR) were similar following DEX-IN.03 and placebo, while DEX-IN.02 treated subjects had a greater decrease in heart rate; the greatest mean percent change below ba eline was -1 % for placebo and -9% for DEX-TN.02, while the mean HRs for DEX-IN.03 never decreased below baseline. Results of the nasal assessment of nasal irritation were similar among all treatment groups at all time points with the mean core not exceeding I in DEX-IN.02 treated subjects at one hour post-dose (scale of 0-10). Subjects in the DEX-IN.02 treatment group experienced the hi ghest Stanford Sleepiness Scale values 60 minute post-dose w ith 17 subjects repo 11ing a score ~ 5.

A single dose of DEX-IN.03 (25 µg) yielded a mean Cmax of 0.1 l nglmL with a median Tmax of 0.75 hrs, while a single dose of DEX-IN.02 (50 µg) yielded a mean Cmax of0.25 ng/mL with a median T max of 0.51 hrs . The following tables summarize these results Table: Observed Mean Dexmedetomidine Plasma Concentrations (ng/rnL) Time Post- DEX-IN.03 (25 µg) DEX-IN .02 (50 ~1g) Dose 0 min 0 0 min 0.047 0.098 min 0.081 0.182 min 0.096 0.2 15 0. l 11 min 0.212 45 min 0.110 0.228 60 min 0.102 0.196 75 min 0.094 0.183 90 min 0.085 0.169 2 hrs 0.077 0.1 49 4 hrs 0.048 0.101 0.030 0.050 6 hrs 12 hrs 0 0.027 Table: Observed Pharmacokinetic Properties of Dexmedetomidine Parameter D.EX-lN.03 (25 µg) DEX-JN.02 (50 µg) Cmax (ng/mL) 0.11 (71.4) 0.25 (38.3) 0. 75 (0.25, 4.00) 0.5 l (0.25 , 4.00) T max (hrs) AUCnr (hr-ng/mL) 0.48 ( 13 .7) 0.92 (26.0) AUCo-1 (hr-ng/mL) 0.08 (110.4) 0.16 (64.1) AUC1 ast (hn1g/mL) 0.24 (182.4) 0.75 (2 1.6) 2.24 (1.60, 2.45) t Yi (hrs) 2.05 (1.52, 3.07) [I ] Geometric means (CV%) for Cmax, AUC0-1, AUC1ast, and AUCinf, median (min, mix) for T m ax; and arithmetic mean ± SD fort, ;, This study shows that the intranasal route is a viable non-invasive means of administering dexmedetomidine. Dos ing with DEX-IN.02 and DEX-IN.03 produced more rapid absorption with higher dexmedetornidine peak plasma concentrations than previously explored fo rmul ations. Analysis of SPTD and TOTPAR values demonstrates the significant analgesic effects of a 50 ~ig dose of intranasal dcxmcdetomidinc compared with a 25 µg dose or placebo in subjects with CLBP starting 45 minutes post dose. Overall, DEX-IN was well tolerated; the AEs reported were generally mil d in severi ty, while no SAE were repo1ied.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. Use of an intranasally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating or preventing pain without significant sedation in a subject, wherein said pharmaceutical composition is formulated to be administered intranasally to the subject as a unit dosage comprising about 10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg or about 50 μg and wherein said intranasally effective amount of dexmedetomidine or salt thereof is sufficient to produce a C of dexmedetomidine plasma of about 0.1 ng/ml within about 15 minutes to about 20 minutes of administration of said pharmaceutical composition to the subject.

2. Use of an intranasally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating or preventing pain without significant sedation in an adult human subject, wherein said pharmaceutical composition is formulated to be administered intranasally to the adult human subject as a unit dosage comprising about 10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg or about 50 μg and wherein said intranasally effective amount of dexmedetomidine or salt thereof is sufficient to produce an analgesic effect with no significant sedation in the adult human subject within a period of time of about two hours after administration of the pharmaceutical composition to the subject.

3. Use of dexmedetomidine or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating or preventing pain without significant sedation in a subject, wherein said pharmaceutical composition is formulated to be administered intranasally to a single nostril of the subject as a unit dosage comprising about 10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg or about 50 μg.

4. Use of dexmedetomidine or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating or preventing pain without significant sedation in a subject, wherein said pharmaceutical composition is formulated to be administered to the subject by intranasal spray wherein said spray comprises droplets which have a Dv90 of less than about 150 µm, wherein the intranasal spray has a unit dosage of about 10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg or about 50 μg.

5. The use of any one of claims 1 to 4, wherein the pharmaceutical composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof in an amount sufficient to produce a plasma C of dexmedetomidine of up to about 0.2 ng/ml following administration of the pharmaceutical composition.

6. The use of any one of claims 1 to 4, wherein the pharmaceutical composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof in an amount sufficient to produce a plasma C of dexmedetomidine of about 0.15 ng/ml following administration of the pharmaceutical composition.

7. The use of any one of claims 1 to 4, wherein the pharmaceutical composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof in an amount sufficient to produce a plasma C of dexmedetomidine of about 0.2 ng/ml following administration of the pharmaceutical composition.

8. The use of any one of claims 1 to 7, wherein the pharmaceutical composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof in an amount sufficient to provide a T of dexmedetomidine of less than about 1 hour.

9. The use of any one of claims 1 to 7, wherein the pharmaceutical composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof in an amount sufficient to provide a T of dexmedetomidine of less than about 50 minutes.

10. The use of any one of claims 1 to 9, wherein the pharmaceutical composition provides a level of sedation that is not greater than Level 2 on the Ramsay Sedation Scale during a period of one hour immediately after administration of the dexmedetomidine or pharmaceutically acceptable salt thereof to the subject.

11. The use of any one of claims 1 to 9, wherein the pharmaceutical composition provides a level of sedation that is not greater than Level 1 on the Stanford Sleepiness Scale during a period of one hour immediately after administration of the dexmedetomidine or pharmaceutically acceptable salt thereof to the subject.

12. The use of any one of claims 1 to 9, wherein the pharmaceutical composition provides a level of sedation that is not less than Level 6 on the Modified Observer’s Assessment Of Alertness/Sedation Scale during a period of one hour immediately after administration of the dexmedetomidine or pharmaceutically acceptable salt thereof to the subject.

13. The use of any one of claims 1 to 12, wherein the pharmaceutical composition provides no or minimal effect on blood pressure of the subject after administration of the dexmedetomidine or pharmaceutically acceptable salt thereof to the subject.

14. The use of any one of claims 1 to 13, wherein the pharmaceutical composition is formulated to be administered to the subject in combination with one or more therapeutic agents other than the dexmedetomidine or pharmaceutically acceptable salt thereof.

15. The use according to any one of claims 1 to 13, wherein the pharmaceutical composition comprises one or more therapeutic agents other than the dexmedetomidine or pharmaceutically acceptable salt thereof.

16. The use of claim 15, wherein each of the one or more additional therapeutic agents is chosen from an opioid analgesic, a synthetic opioid-like analgesic, a non-opioid analgesic, a vitamin, a vasodilator, a benzodiazepine, a triptan, an anti-convulsant, an anti-depressant, an anti-nausea medication, and an anti-hypertensive.

17. The use of any one of claims 1 to 16, wherein the pharmaceutical composition is formulated to be administered to the subject about every 6 hours.

18. The use of any one of claims 1 to 17, wherein the pain is idiopathic pain.

19. The use of claim 18, wherein the idiopathic pain is neuralgia, myalgia, hyperalgia, hyperpathia, neuritis, or neuropathy.

20. The use of any one of claims 1 to 19, wherein the pain is associated with or caused by cancer, viral infection, physical trauma, arthritis, headache, migraine, or lower back pain.

21. The use of claim 20, wherein the physical trauma is associated with or caused by surgery, a burn, or blunt force trauma.

22. The use of any one of claims 1 to 21, wherein the pharmaceutical composition is formulated to be administered to the subject intranasally with a metered dose device.

23. The use of claim 22, wherein the metered dose device is a multi-dose, unit dose, or bi-dose device.

24. A metered dose device comprising an intranasal pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, the metered dose device being adapted to deliver the pharmaceutical composition to a mammal in a manner so as to provide an analgesic effect to the mammal without significant sedation wherein the metered dose spray produced by the device comprises a metered dose of about 10 µg, about 25 µg, about 35 µg, about 40 µg, about 50 µg, about 75 µg, or about 100 µg of the dexmedetomidine or the pharmaceutically acceptable salt thereof.

25. The metered dose device of claim 24, wherein the metered dose spray produced by the device comprises droplets comprising dexmedetomidine or a pharmaceutically acceptable salt thereof that have a Dv90 of less than about 150 µm.

26. The metered dose device of claim 24 or claim 25, wherein the metered dose spray produced by the device comprises a volume of less than about 150 µl, less than about 140 µl, less than about 130 µl, less than about 120 µl, less than about 110 µl, less than about 100 µl, less than about 75 µl, or less than about 50 µl.

27. The metered dose device of any one of claims 24 to 26, wherein the metered dose spray produced by the device produces a C of dexmedetomidine in the mammal of plasma about 0.1 ng/ml within about 15 minutes to about 20 minutes of administration of the metered dose to the mammal.

28. The metered dose device of any one of claims 24 to 26, wherein the metered dose spray produced by the device produces an analgesic effect with no significant sedation in an adult mammal within a period of time of about two hours after administration of the metered dose spray to the subject.

29. The metered dose device of any one of claims 24 to 28, wherein the metered dose spray produced by the device produces a plasma C of dexmedetomidine in the mammal up to about 0.2 ng/ml.

30. The metered dose device of any one of claims 24 to 28, wherein the metered dose spray produced by the device produces a plasma C of dexmedetomidine in the mammal of about 0.15 ng/ml.

31. The metered dose device of any one of claims 24 to 28, wherein the metered dose spray produced by the device produces a plasma C of dexmedetomidine in the mammal of about 0.2 ng/ml.

32. The metered dose device of any one of claims 24 to 31, wherein the metered dose spray produced by the device produces a T of dexmedetomidine in the mammal of less than about 1 hour.

33. The metered dose device of any one of claims 24 to 31, wherein the metered dose spray produced by the device produces a T of dexmedetomidine in the mammal of less than about 50 minutes.

34. The metered dose device of any one of claims 24 to 33, wherein the metered dose spray produced by the device is for producing in the mammal a level of sedation not greater than Level 3 on the Ramsay Sedation Scale during a period of one hour immediately after administration of said metered dose spray.

35. The metered dose device of any one of claims 24 to 34, wherein the metered dose spray produced by the device produces in the mammal a level of sedation not greater than Level 2 on the Stanford Sleepiness Scale during a period of one hour immediately after administration of said metered dose spray.

36. The metered dose device of any one of claims 24 to 35, wherein the metered dose spray produced by the device produces in the mammal a level of sedation not less than Level 6 on the Modified Observer’s Assessment Of Alertness/Sedation Scale during a period of one hour immediately after administration of said metered dose spray.

37. The metered dose device of any one of claims 24 to 36, wherein the metered dose spray produced by the device provides no or minimal effect on the blood pressure of the mammal after administration of said metered dose spray.

38. The metered dose device of any one of claims 24 to 37, wherein the pharmaceutical composition further comprises one or more therapeutic agents other than the dexmedetomidine or the pharmaceutically acceptable salt thereof.

39. The metered dose device of claim 38, wherein each of the one or more additional therapeutic agents is chosen from an opioid analgesic, a synthetic opioid-like analgesic, a non-opioid analgesic, a vitamin, a vasodilator, a benzodiazepine, a triptan, an anti- convulsant, an anti-depressant, an anti-nausea medication, and an anti-hypertensive.

40. The metered dose device of any one of claims 24 to 39, which is a multi-dose, unit dose, or bi-dose device.

41. The metered dose device of any one of claims 24 to 40, wherein the pharmaceutical composition further comprises a carrier vehicle.

42. The metered dose device of any one of claims 24 to 41, wherein the pharmaceutical composition further comprises sodium phosphate and/or sodium citrate.

43. The metered dose device of any one of claims 24 to 42, wherein the pharmaceutical composition further comprises a chelator.

44. The metered dose device of any one of claims 24 to 43, wherein the pharmaceutical composition is free of a viscosity enhancing agent.

45. The metered dose device of any one of claims 24 to 44, wherein the pharmaceutical composition further comprises sodium citrate, citric acid, and sodium chloride.

46. The metered dose device of claim 45, wherein the pharmaceutical composition further comprises about 0.2% to about 0.3% (w/w) sodium citrate and about 0.005% to about 0.015% (w/w) citric acid.

47. The metered dose device of any one of claims 24 to 46, wherein the pH of the pharmaceutical composition is from about 6 to about 6.5.

48. The metered dose device of any one of claims 24 to 47, wherein the pharmaceutical composition further comprises one or more anti-microbial preservatives.

49. The metered dose device of claim 48, wherein the preservative is phenylethyl alcohol.

50. The metered dose device of any one of claims 24 to 49, wherein the pharmaceutical composition further comprises one or more antioxidants.

51. The metered dose device of any one of claims 24 to 50, wherein the pharmaceutical composition further comprises one or more dose confirmation excipients.

52. The metered dose device of claim 51, wherein the one or more dose confirmation excipients is phenylethyl alcohol.

53. The metered dose device of any one of claims 24 to 52, wherein the pharmaceutical composition further comprises one or more humectants.

54. The metered dose device of claim 53, wherein the one or more humectants is glycerin, propylene glycol, polyethylene glycol, or a sugar/sugar alcohol, or any combination thereof.

55. The metered dose device of any one of claims 24 to 54, wherein the pharmaceutical composition further comprises one or more osmolality adjusting agents.

56. The metered dose device of claim 55 wherein the one or more osmolality adjusting agents is sodium chloride, dextrose, or another sugar, or any combination thereof.

57. The use according to any one of claims 1 to 23 as described in any example hereof.

58. The metered dose device according to any one of claims 24 to 56 as described in any example hereof. 0.18 0.16 ...... S 0.14 ~ 0.12 'c 0.08 .... .. T T T ,:, T _.~----==-- _.:_ ~ - - E 0.06 1 0.04 ~ -+- 35 µgin One Nostril ., -+- 35 µgin Divided Nostrils 0.02 I l 17.5 µgin One Nostril 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Time (hr)