Prevention or treatment of sleep disorders using dexmedetomidine formulation

Abstract

To provide a composition suitable for oral transmucosal administration (sublingual) comprising dexmedetomidine.SOLUTION: A composition is useful for the treatment of sleep disorders such as insomnia and capable of providing sleep on demand. The composition comprises an effective amount of dexmedetomidine or pharmaceutically acceptable salts thereof, solvates thereof, or derivatives thereof, formulated for delivery of dexmedetomidine across a subject's oral mucosa.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a sublingual formulation of dexmedetomidine. The present invention also relates to a method for treating a disease or condition (e.g., sleep disorder) in a patient in need thereof, which is sensitive to treatment with an α2 - adrenergic receptor agonist, comprising administering an effective amount of a sublingual dexmedetomidine formulation or a pharmaceutically acceptable salt, solvate or derivative thereof.

Background Art

[0002] Sleep disorders (e.g., insomnia) affect millions of people. Insomnia is estimated to affect about 60 - 70 million Americans. Insomnia disorder has a significant negative impact on quality of life and can impair the health, general well - being, and / or safety of people suffering from it.

[0003] Insomnia includes the inability to fall asleep persistently, or the persistent difficulty in falling asleep and / or maintaining sleep during normal sleep hours.

[0004] Four types of insomnia are recognized from medical literature and include onset insomnia (e.g., difficulty falling asleep at bedtime), maintenance insomnia (e.g., sleep disturbances during the night), early morning awakening, and transient insomnia (e.g., new environment, first night in hotel syndrome). Other types of insomnia include "mid - night" insomnia, "late - night" insomnia, "prolonged post - sleep awakening" insomnia, "maintenance insomnia", and insomnia following "mid - night" awakenings, each of which has an element of sleep disruption.

[0005] Insomnia can be caused by, for example, certain drugs and / or stimulants (e.g., caffeine), among other factors, hormonal fluctuations, stress, anxiety, depression, and / or neurological disorders.

[0006] Generally, hypnotic sedatives (such as benzodiazepines) have been used for many years in the treatment of insomnia. Examples of benzodiazepines include temazepam (e.g., Restoril®), flunitrazepam (e.g., Rohypnol®), triazolam (e.g., Halcion®), flurazepam (e.g., Dalmane®), nitrazepam (e.g., Mogadon®), and midazolam (e.g., Versed®). The long-term administration of benzodiazepines and opioids causes tolerance and physical dependence. Non-benzodiazepine agents are also used in the treatment of insomnia and include, for example, zolpidem, zaleplon, and eszopiclone. In some cases, the antihistaminic diphenhydramine (e.g., Benadryl®) has been used as a sleep aid. Diphenhydramine is available without a prescription and is not thought to induce dependence, but its effectiveness may decrease over time. In addition, it may cause sedation the next day.

[0007] Considering the prevalence of insomnia disorders in the world population and the serious drawbacks of current therapies, it would be desirable to provide new pharmaceutical compositions and methods for the treatment of insomnia.

[0008] Currently, dexmedetomidine is only commercially available as an injectable formulation for sedation, which should be administered intravenously by medical personnel. However, a dexmedetomidine formulation that can be used for the treatment of insomnia and other sleep disorders without a hospital setup and by self-administration is not commercially available.

[0009] The present invention relates to the overcoming of these and other deficiencies in the prior art.

Summary of the Invention

[0010] There is a need for pharmaceutical formulations for treating insomnia without drug abuse and without a calming effect.

[0011] The present invention discloses that dexmedetomidine (5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, a non-narcotic α2-adrenergic receptor agonist with sedative and analgesic properties) is very effective for the treatment of sleep disorders (such as insomnia).

[0012] Accordingly, to solve the above problems and with expectations, the present invention provides a composition comprising a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, a solvate thereof or a derivative thereof, formulated for the delivery of dexmedetomidine through the oral mucosa of a subject.

[0013] In one aspect, the composition is formulated as a sublingual formulation of dexmedetomidine, the unit dosage form of the formulation is placed sublingually, and the active ingredient is absorbed through the surrounding mucosa. Thereby, the action occurs very quickly.

[0014] In one aspect, the present invention provides a single-dose composition for sublingual administration, comprising a pharmacologically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, a solvate thereof or a derivative thereof.

[0015] In another aspect, the present invention relates to a pharmaceutical preparation for sublingual administration and a process for preparing such a preparation.

[0016] According to another aspect of the present invention, the pharmaceutical preparation comprises any one of a pharmaceutically effective amount of dexmedetomidine or a salt, solvate or derivative thereof, together with a pharmaceutically acceptable excipient(s).

[0017] In a further aspect, the composition of the present application is in the form of a sublingual tablet comprising dexmedetomidine together with a pharmaceutically acceptable excipient(s).

[0018] In another aspect, the composition of the present invention is in the form of a sublingual patch comprising dexmedetomidine together with a pharmaceutically acceptable excipient(s).

[0019] In another aspect, the composition of the present invention is in the form of an oral spray containing dexmedetomidine together with a pharmaceutically acceptable liquid vehicle.

[0020] In yet another aspect, the composition of the present invention is useful for the treatment of acute and chronic insomnia.

[0021] In another aspect of the present invention, the composition is used for the targeting of primary insomnia, where the main complaint is difficulty in sleep onset or maintenance.

[0022] In another aspect of the present invention, the composition is used for patients suffering from frontotemporal dementia (FTD).

[0023] In another aspect of the present invention, the composition is used for the treatment of insomnia associated with excitatory insomnia and / or hypersomnia.

[0024] A further aspect of the present invention relates to a method of treating or preventing a disease or condition sensitive to treatment with an α2 - adrenergic receptor agonist, comprising selecting a patient suffering from a disease or condition sensitive to treatment with an α2 - adrenergic receptor agonist, and administering to the patient a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt or derivative thereof.

[0025] A further aspect of the present invention is a method of treating or preventing a sleep disorder, comprising selecting a patient suffering from a sleep disorder, and administering to the patient a therapeutically effective amount of dexmedetomidine. In one embodiment, the administration is carried out sublingually.

[0026] Accordingly, the present technology discloses a sublingual formulation of dexmedetomidine that can be used for the treatment of insomnia by once - daily ingestion, and can be convenient for self - administration without significant sedative effects. This formulation acts very rapidly without the potential for drug abuse. BRIEF DESCRIPTION OF THE DRAWINGS

[0027]

Figure 1

Figure 2

Figure 3

Mode for Carrying Out the Invention

[0028] Dexmedetomidine is a specific α2 - adrenergic receptor agonist that causes sedation and anesthesia in mammals. In humans, dexmedetomidine is commercially available for sedation of intubated patients during treatment in intensive care settings and for sedation of non - intubated patients before or during surgical procedures and other procedures, in addition to its sedative effects during treatment of initially intubated mechanically ventilated patients. The present invention discloses that dexmedetomidine is very effective for the treatment of sleep disorders (such as insomnia) without causing sedation and without causing drug dependence.

[0029] Dexmedetomidine is commercially available as an injectable preparation. Injectables are not necessarily the preferred mode of treatment for insomnia.

[0030] Dexmedetomidine could be absorbed from the oral cavity. However, oral dexmedetomidine via the gastric route is not preferable due to high first-pass metabolism. The metabolism of this drug results in correspondingly low systemic bioavailability and high variability.

[0031] In particular, in oral administration via the gastric route, the drug must pass through the gastrointestinal system (portal circulation) to enter the bloodstream. The time to achieve a therapeutic effect may be quite long (typically more than about 45 minutes). Considering this, the onset of action is delayed in many patients, resulting in dissatisfaction from the lack of "on-demand" sleep and perhaps undesirable residual effects the next day.

[0032] Accordingly, the present invention provides herein a new composition of dexmedetomidine or a pharmaceutically acceptable salt, solvate or derivative thereof formulated for the delivery of dexmedetomidine through the oral mucosa of a subject, and in certain embodiments, methods of its use in the prevention, treatment and management of sleep disorders (such as insomnia). Delivery via the mucosa is very rapid and avoids first-pass metabolism. Minimal doses are effective for the treatment of insomnia and rapid onset of action. Furthermore, the oral mucosa is highly vascularized and well-supplied with lymphatic drainage sites.

[0033] Oral transmucosal administration of the drug also results in an accelerated absorption rate compared to oral ingestion (portal circulation), thereby resulting in a significantly increased bioavailability over a short period.

[0034] Pharmacologically, dexmedetomidine is an α2 - adrenergic receptor agonist. It can affect the locus coeruleus centralis of the brain, which synthesizes norepinephrine and other arousal pathway activities, and regulate the body's arousal. Dexmedetomidine reduces the high arousal level of the cerebral cortex in patients suffering from insomnia by changing the activities of the locus coeruleus noradrenergic system and other arousal pathways of the ascending reticular activating system. It supports the restoration of the sleep - wake system and the improvement of insomnia symptoms. Dexmedetomidine induces a pattern of c - fos expression (decrease in the locus coeruleus and the tuberomammillary nucleus, and increase in the ventrolateral preoptic nucleus (VLPO) of the ventral bilateral preoptic area) that is qualitatively similar to that observed during normal NREM sleep.

[0035] In another embodiment, the present invention discloses a pharmaceutical composition comprising a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt, solvate or derivative thereof and a pharmaceutically acceptable carrier(s) in a non - injectable formulation.

[0036] In one embodiment, the pharmaceutical composition is formulated as, for example, a tablet, capsule, patch or oral spray for the delivery of dexmedetomidine through the oral mucosa of a subject.

[0037] In one embodiment, the pharmaceutical composition comprises a sublingual composition of dexmedetomidine or a pharmaceutically acceptable salt, solvate or derivative thereof (e.g., prodrug) in an amount sufficient to treat insomnia, in addition to a pharmaceutically acceptable excipient, along with optional flavoring agents, preservatives, excipients, emulsifiers, buffers, coloring agents, and the like.

[0038] A further embodiment of the present invention relates to a method of treating or preventing a disease or condition sensitive to treatment with an α2 - adrenergic receptor agonist, comprising selecting a patient suffering from a disease or condition sensitive to treatment with an α2 - adrenergic receptor agonist, and administering to the patient a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, its solvate or its derivative.

[0039] Suitable diseases and conditions include, but are not limited to, sleep disorders (such as insomnia, snoring, sleep apnea, sleep disruption, and restless legs syndrome, etc.), central nervous system disorders and / or conditions (such as headache, pain, epilepsy, spasm, neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, ataxia, dystonia, movement disorders, memory impairment, depression, avoidant personality disorder, anxiety, panic disorder, obsessive-compulsive disorder, phobia, impulse disorder, cognitive impairment, mood disorder, psychosis, schizophrenia, drug abuse, drug dependence, drug tolerance or drug withdrawal, post-traumatic stress disorder, and eating disorders).

[0040] In yet another embodiment, the present invention relates to a method for treating or preventing a sleep disorder, comprising selecting a patient suffering from a sleep disorder, and administering to the patient a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, a solvate thereof, or a derivative thereof.

[0041] In one particular embodiment, the present invention provides a method for treating insomnia, comprising the steps of selecting a patient suffering from insomnia, and administering to the patient a sublingual pharmaceutical composition comprising a therapeutically effective dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof, a solvate thereof, or a derivative thereof, and a pharmaceutically acceptable excipient, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof, a solvate thereof, or a derivative thereof is absorbed via the sublingual route.

[0042] In another embodiment, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof is based on the serum concentration that induces sleep (i.e., approximately 0.5 - 1.2 ng / ml). The total required dose is estimated to be in the range of 0.02 - 5 mg. This dose is for humans having a body weight in the range of 40 - 100 kg. The detailed doses required for humans according to body weight are described in the following table.

Table A

[0043] In another embodiment, a systemically absorbed pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt, solvate or derivative thereof is administered to the oral mucosa of a mammal in an amount effective for the treatment or prevention of insomnia in the mammal upon administration, the pharmaceutical composition providing a physiologically active amount of dexmedetomidine into the systemic circulation of the mammal at a rate that causes insomnia without sedation within 3 to 30 minutes of administration, thereby providing a method for treatment.

[0044] In yet another embodiment, the pharmaceutical composition comprises dexmedetomidine or a pharmaceutically acceptable salt, solvate or derivative thereof together with a pharmaceutically acceptable excipient, and the pharmaceutical composition is configured and adapted for oral transmucosal administration to a mammal by application of the pharmaceutical composition to the mucosa of the mammal. Still further, the pharmaceutical composition can be configured and adapted for sublingual administration by application of the composition to the sublingual mucosa of the mammal.

[0045] In yet another embodiment of the present invention, a method of administering dexmedetomidine or a pharmaceutically acceptable salt, solvate or derivative thereof to a mammal includes spraying a spray composition comprising dexmedetomidine or a pharmaceutically acceptable salt, solvate or derivative thereof in a pharmaceutically acceptable liquid vehicle onto the oral mucosa of the mammal.

[0046] In certain embodiments, the dexmedetomidine products described herein are pharmaceutical formulations for the treatment of sleep disorders (such as insomnia).

[0047] As used herein, the term "pharmaceutically acceptable" includes compounds, materials, compositions, dosage forms, and methods of use thereof that are suitable for contact with the tissues of humans and animals within the scope of sound medical judgment, and that are without excessive toxicity, irritation, allergic reaction, or other problems or complications, but that are commensurate with a reasonable benefit / risk ratio and that elicit the desired pharmacological response.

[0048] In certain other embodiments, the pharmaceutical formulation of the present invention is also useful for patients suffering from chronic pain who have additional difficulties due to insomnia and sleep disorders. Back pain is the most common type of chronic pain problem and the most frequently seen medical disorder in industrialized societies. Not surprisingly, individuals with chronic back pain problems often report significant interference with sleep. Two-thirds of patients suffering from chronic back pain have been reported to be troubled by sleep disorders. It has been demonstrated from research that the interruption of sleep will in turn exacerbate the chronic back pain problem. Thus, a vicious cycle occurs where back pain interrupts the patient's sleep, sleep difficulties worsen the pain, which in turn makes sleep more difficult.

[0049] In yet another embodiment, the pharmaceutical formulation of the present invention is also useful for patients who have difficulty falling asleep at night and who wake up frequently.

[0050] In some embodiments, the pain can be neuralgia, myalgia, hyperalgesia, allodynia, 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, burns, blunt trauma, or other trauma (such as being in an accident) that can cause pain.

[0051] In another embodiment, the pharmaceutical formulation of the present invention is also useful for patients suffering from insomnia. A plurality of mental and physiological factors contribute to the onset and persistence of insomnia, and they include worry-prone and brooding personality traits, stressful events, mechanisms that weaken sleep homeostasis associated with aging, menopause, and genetic predispositions to central nervous system overarousal, etc.

[0052] In another embodiment, the pharmaceutical preparation of the present invention is also useful for patients suffering from frontotemporal dementia (FTD). Frontotemporal dementia or frontotemporal lobar degeneration refers to a group of disorders caused by progressive neuronal loss in the frontal lobe (the area behind the forehead) or the temporal lobe (the area behind the ear) of the brain. The neuronal damage caused by frontotemporal dementia results in loss of function in these brain regions, which variably causes deterioration of behavior and personality, language disorders, or changes in muscle or motor function.

[0053] In another embodiment, the pharmaceutical preparation of the present invention is useful for patients suffering from insomnia with excitatory insomnia and / or hyperarousal disorder in indications selected from the group consisting of multiple system atrophy, Creutzfeldt-Jakob disease, corticobasal degeneration, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, fatal familial insomnia, Cushing's syndrome, hypercortisolism, neurofibromatosis type 1, Norrie disease, progressive supranuclear palsy, hereditary spastic paraplegia, Alpers syndrome, Smith-Lemli-Opitz syndrome (Slos), fragile X syndrome, Mulvihill-Smith syndrome, transmissible spongiform encephalopathy, Morvan's syndrome, Morvan's fibrillary chorea, peripheral nerve hyperexcitability, CAPS and PTSD.

[0054] Dexmedetomidine forms pharmaceutically acceptable salts with pharmaceutically acceptable acids It contains a basic nitrogen atom that can be present. In this regard, the term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic acid addition salts and organic acid addition salts of dexmedetomidine. These salts can be prepared by insights during the final isolation and purification of dexmedetomidine, or by reacting purified dexmedetomidine in its free base form separately with a suitable organic or inorganic acid and then isolating the salt thus formed. Further, salts can be formed during the manufacturing process to produce a formulation. Salts of dexmedetomidine include, but are not limited to, hydrohalides (including hydrobromide and hydrochloride), sulfates, bisulfates, phosphates, nitrates, acetates, valerates, oleates, palmitates, stearates, laurates, benzoates, lactates, phosphates, tosylates, citrates, maleates, fumarates, succinates, tartrates, napthylates, mesylates, glucoheptonates, lactobionates, 2-hydroxyethylsulfonates and laurylsulfonates, and the like.

[0055] Dexmedetomidine derivatives may include covalent modifications that produce a prodrug. Upon administration, the prodrug derivative is chemically modified by a mammal to produce dexmedetomidine.

[0056] The sublingual formulations of dexmedetomidine described herein are intended for direct administration to a mucosa (e.g., the oral mucosa of a mammal). Drug delivery occurs substantially via an oral transmucosal route rather than via absorption through the gastrointestinal tract following swallowing. The term "transmucosal" refers to delivery through or across a mucosa. In particular, "oral transmucosal" drug delivery includes delivery through any tissue of the mouth, pharynx, larynx, trachea or upper gastrointestinal tract, particularly through the mucosal tissues of the sublingual, buccal, gingival and palatal regions.

[0057] The term "sublingual" literally means "under the tongue" and refers to a method of administering a substance orally in such a way that the substance is rapidly absorbed via the blood vessels under the tongue rather than via the gastrointestinal tract. Sublingual absorption occurs through the highly vascularized sublingual mucosa, which allows for direct access of the substance to the blood circulation, thereby providing direct systemic administration independent of gastrointestinal effects and avoiding undesired first-pass hepatic metabolism. Compared to other routes of administration, the transmucosal absorption of dexmedetomidine in the present formulation can have a significantly faster onset due to higher bioavailability, which is required for the treatment of different types of insomnia as described above. Furthermore, the total amount of the active pharmaceutical ingredient in the formulation is reduced, thereby reducing the potential for sedative effects.

[0058] The pharmaceutical formulation of the present invention can be administered to mammals including humans, as well as to pet animals (e.g., rats, cats, and dogs), agricultural livestock, and other animals in need thereof.

[0059] The sublingual formulation of dexmedetomidine described herein can be co-administered with other pharmaceuticals, including NSAIDs (such as aspirin, ibuprofen, naproxen, celecoxib, acetaminophen, and other cyclooxygenase inhibitors); opioids (such as codeine, oxycodone, morphine, methadone, and fentanyl); antispasmodics and antiarrhythmics (such as phenytoin and carbamazepine); and antidepressants (such as amitriptyline, imipramine, venlafaxine, clonidine, and other active α-2 receptor agonist compounds). In particular, dexmedetomidine can significantly enhance the effectiveness of opioids and allow for a reduction in the required opioid dosage while maintaining equivalent therapeutic usefulness.

[0060] By "sleep on demand", it is meant that the formulation consistently, i.e., in at least 90% of cases (on an intra-patient and / or inter-patient basis), induces sleep within 60 minutes, preferably within 45 minutes, more preferably within 3 minutes.

[0061] In another embodiment of the present invention, the drug level is maintained at about 0.3 micrograms / ml for 2 to 6 hours.

[0062] The disclosed embodiments are not intended as limitations. In the practice of the present invention, formulations containing dexmedetomidine may be provided as, or in addition to, other sublingual and / or buccally compatible dosage forms.

[0063] Definitions

[0064] The terms "composition of the present invention", "pharmaceutical formulation", and equivalent expressions are meant to include the compounds as described above, and where the context permits, such expressions include, in addition to the prodrugs, pharmaceutically acceptable salts, oxides, solvates (e.g., hydrates) and inclusion complexes of such compounds, any mixture of any such forms of the compound in any ratio. Inclusion complexes are described in Remington, The Science and Practice of Pharmacy, 19th Ed. 1:176 - 177 (1995), which is hereby incorporated by reference in its entirety. The most commonly used inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes (natural and synthetic) are specifically included within the claims. Thus, according to some embodiments of the present invention, the compounds as described herein (including those in the context of pharmaceutical compositions, methods of treatment, and the compounds themselves) are provided in salt form. Similarly, references to intermediates are meant to include their salts and solvates where the context permits, whether or not they are themselves recited in the claims. For clarity, specific instances where the context permits are sometimes shown in the text, but these instances are purely illustrative and are not intended to exclude other instances where the context permits.

[0065] Pharmaceutical preparation: The pharmaceutical preparation for the administration of the dexmedetomidine preparation for treating insomnia by the method of the present invention can take the form of a transdermal patch, a buccal patch, a nasal inhalation form, a mucosal spray, tablets and capsules for oral administration, and tablets or lozenges, or a "candy with stick" preparation for administration through the oral mucosal tissue. The latter preparations include tablets, lozenges and the like that are dissolved while being held on or under the tongue or in the buccal pouch.

[0066] A "pharmaceutically acceptable" carrier or excipient, as used herein, means being approved by a regulatory agency of the federal or state government or being listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in mammals and particularly humans.

[0067] The term "pharmaceutical composition" as used in accordance with the present invention relates to a composition that can be formulated in any conventional manner using one or more pharmaceutically acceptable carriers or excipients.

[0068] The term "solvate" refers to a composition of the present technology in the solid state in which molecules of a suitable solvent are incorporated into the crystal lattice. Solvents suitable for therapeutic administration are physiologically tolerable at the dosage administered. Examples of solvents suitable for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. Generally, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using an antisolvent. Solvates are typically dried or azeotroped under ambient conditions.

[0069] The term "derivative" refers to, for example, within the scope of sound medical judgment, the crystalline form, polymorph or prodrug of the useful composition according to the invention that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, and the like, is balanced with a reasonable benefit / risk ratio, and is effective for their intended use, and additionally, where possible, the zwitterionic form of the composition according to the invention. The term "prodrug" means, for example, a compound that is rapidly converted in vivo by hydrolysis in the blood to give the parent compound. In general, the conversion of a prodrug to a drug occurs by an enzymatic process in the mammalian liver or blood. The compositions of the present invention can be chemically modified so as not to be absorbed in the systemic circulation, and in those cases, in vivo activation can occur by chemical action (such as acid-catalyzed cleavage in the stomach) or through the mediation of enzymes and the microbiota in the gastrointestinal tract. The compositions can have metabolically cleavable groups and have the advantage that, as a result of the promotion of solubility and / or absorption rate conferred on the parent compound by the presence of the metabolically cleavable groups, they can exhibit improved bioavailability.A detailed discussion of prodrugs is provided in Design of Prodrugs, H. Bundgaard, ed., Elsevier (1985); Methods in Enzymology, K. Widder et al., Ed., Academic Press, 42, p. 309-396 (1985); A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; “Design and Applications of Prodrugs,” p. 113-191 (1991); Advanced Drug Delivery Reviews, H. Bundgaard, 8, p. 1-38 (1992); Journal of Pharmaceutical Sciences, 77:285 (1988); Nakeya et al, Chem. Pharm. Bull., 32:692 (1984); Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press (1987) (the entireties of which are incorporated herein by reference). Examples of prodrugs include, but are not limited to, acetate derivatives, formate derivatives, and benzoate derivatives of amine functional groups in the compositions of the present invention.

[0070] As used herein, the terms “human” or “patient,” used interchangeably, mean any animal, including mammals (such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, etc.) or primates (such as humans, etc.).

[0071] As used herein, the term "sedation" means suppression of consciousness such that a patient or subject is able to independently and continuously maintain airway patency and a regular breathing pattern and retain the ability to respond appropriately and rationally to physical stimuli and verbal commands.

[0072] The term "dosage" is intended to encompass formulations expressed in terms of μg / kg / hour, μg / kg / day, mg / kg / day, or mg / kg / hour.

[0073] "Dose" is the amount of drug administered to a patient per unit volume or unit mass (e.g., the absolute unit dose of a drug expressed in mg). The dose depends on the concentration of the drug in the formulation (e.g., in moles per liter (M), mass per volume (m / v), or mass per mass (m / m)).

[0074] The term "drug addiction" means dependence on an illegal drug, a controlled substance, or a pharmaceutical drug. In the case of addiction, a person will no longer be able to control drug use and will continue to use the drug despite the harm it causes. Drug addiction can cause a strong craving for the drug. It has been found that most people want to stop but are unable to do so on their own.

[0075] The term "method of treating" means remission or alleviation from symptoms and / or effects associated with the disorders described herein. When used herein, reference to "treatment" of a patient is intended to include prevention.

[0076] In another embodiment, the present invention unexpectedly discloses that a sublingual formulation of dexmedetomidine or a pharmaceutically acceptable salt and / or derivative thereof can be developed for the rapid alleviation of insomnia corresponding to a reduction in time to Cplasma, Cmax, and Tmax.

[0077] Methods for formulating compositions for sublingual administration in tablet form are well known to those skilled in the art. Any such method can be used to formulate the compositions of the present invention. For example, dexmedetomidine can be formulated as a blend of drug powder with other ingredients as granules or tablets or microspheres.

[0078] The term "sedative" means a drug that relieves emotional agitation, enables sleep, and calms the patient. Sedatives generally act by modifying signals within the central nervous system.

[0079] The following examples are illustrative and are not intended to be limiting.

Example

[0080] Example 1: Composition for a typical tablet formulation for sublingual or buccal delivery. If specified, buccal delivery may require a backing.

Table B

[0081] Manufacturing process for sublingual dexmedetomidine tablets:

[0082] Any conventional tablet manufacturing method such as direct compression, wet granulation or dry granulation can be used.

[0083] In the direct compression method, all materials containing the drug substance should be sieved in a specific order according to an optimized process and then continuously blended in a V blender or other suitable blender to achieve uniform mixing of the drug substance in the blend. The blend is then further compressed into tablets using an appropriate tableting.

[0084] In the wet granulation method, the drug substance should be dissolved / dispersed alone or together with other excipients (binders, sweeteners, and others) in a suitable solvent (water or other acceptable ones). Using this, a blend of other sieved components is granulated. Then, the granules are appropriately dried and sized. Next, the granules are smoothed in a suitable blender and compressed into tablets of specific dimensions using appropriate tableting.

[0085] In the dry granulation method, the granules are prepared by either compression (e.g., roller compactor) or slugging or other suitable techniques, and the tablets would be prepared in a manner similar to the wet granulation technique.

[0086] Other sublingual dosage forms (films, buccal patches, spray formulations, etc.) would involve the use of a film casting apparatus for the preparation of the film dosage form, or an impermeable or semi - permeable backing for the buccal patch dosage form or filling into a canister for the spray dosage form using appropriate manufacturing techniques such as those described.

[0087] Example 2:

[0088] Evaluation of the sleep - promoting properties of sublingual dexmedetomidine in Wistar rats

[0089] The sublingual dexmedetomidine formulation of the present invention was tested in rats for its ability to increase the amount of sleep or decrease sleep interruption or both, without unwanted effects. The activity of the test animals was continuously monitored by using an overhead video camera, and data were analyzed for sleep latency, total sleep time, and the number of sleep episodes using Noldus Ethovision - XT 11.

[0090] Male Wistar rats weighed approximately 180 g to 220 g and were about 5 to 7 weeks old. The animals were numbered and acclimatized for a period of 5 to 7 days before the start of the experiment. All experiments on animals were conducted in accordance with the guidelines of the Committee for the Purpose of Control (CPCSEA) and Supervision of Experiments on Animals, and the Association for Assessment and Accreditation of Laboratory Animal Care international (AAALAC) by the Government of India.

[0091] Housing environment: The animals were housed in a group manner (3 animals per cage) in a micro-isolator cage modified with a polycarbonate filter top riser that allowed more overhead space in the vertical direction. The animals were fed ad libitum with a normal rodent solid diet and had free access to fresh autoclaved drinking water suitable for drinking. The animals were maintained under controlled environmental conditions of a temperature of 22 ± 3°C, a humidity of 50 ± 20%, a 12-hour light-dark cycle each, and 15 to 20 exchanges of fresh air per hour.

[0092] Animal groups: Wistar rats were randomly divided into different groups (each containing 6 animals). The test groups were divided into a normal control group, a vehicle control group, a test compound group, and a reference compound group.

[0093] Test drugs and reference drugs: The test drug dexmedetomidine was obtained from Neon Laboratories (India), and the reference drug zolpidem was obtained from Sigma Aldrich (catalog number Z103 Sigma).

[0094] Test design and dosage:

[0095] Animals were weighed once at randomization and then daily. Animals were examined from day 1 to day 9. On day 1, the test compound and reference compound were administered, activity was recorded for 180 minutes using an overhead video camera, and data were analyzed by Noldus Ethovision-XT 11. On day 3, animals were dosed with the test compound, and respiratory parameters (tidal volume, respiratory rate, etc.); heart rate and blood pressure were recorded. On days 5 and 6, animals were trained on a rotarod apparatus (4 - 40 rpm in 300 seconds). On day 7, animals were administered the test compound, and motor coordination was tested on the rotarod at 3, 10, 17, 24, and 30 minutes after administration to establish a time scale for loss of motor activity and onset of sedation. On day 9, animals were dosed with the test compound, blood was collected at 15, 30, 60, and 120 minutes after sublingual dosing to estimate the plasma drug concentration of dexmedetomidine. All animals were euthanized by CO2 inhalation on day 9. Animals in the satellite group were dosed with the test compound, and blood was collected at 15, 30, 6 0, and 120 minutes after sublingual dosing to estimate the plasma drug concentration of dexmedetomidine after the first drug exposure. [Chemical formula]

[0096] The normal control group received no treatment; the vehicle control group received 0.9% saline; the test groups received the compound (dexmedetomidine), with different doses (dose 1, 5.14 μg / kg body weight, dose 2, 10 μg / kg body weight, dose 3, 20 μg / kg body weight, dose 4, 30 μg / kg body weight, and dose 5, 40 μg / kg body weight) administered sublingually and also parenterally (dose 6, 1.5 μg / kg body weight); the reference compound (zolpidem) was administered orally at a dose of 30 mg / kg body weight. Treatments were given such that rats did not receive the same treatment twice.

[0097] Total sleep time, sleep latency, and number of sleep episodes were measured. Sleep latency, total sleep time, and sleep episodes were recorded after administration of each dose to each group of animals.

[0098] Results:

[0099] Comparisons of total sleep time, sleep latency, and sleep episodes were performed for different groups (normal control, vehicle control, and different doses of dexmedetomidine and zolpidem) and are shown as tabulated in Tables 1 and 2.

[0100] One-way analysis of variance tests were applied for comparison of data from different groups for total sleep time, sleep latency, and number of sleep episodes.

Table 1-1

Table 1-2

Table 2

[0101] Conclusion:

[0102] Total sleep time (total duration of sleep over 180 minutes): A significant increase in total sleep time was observed for the sublingual dexmedetomidine treatment group, with a significant effect at 40 μg / kg. The reference compound zolpidem, tested at standard doses, also showed a significant increase in sleep time compared to normal control and vehicle control.

[0103] Sleep latency (time to fall asleep): Sleep latency was significantly decreased for sublingual dexmedetomidine at doses of 10, 20, 30, and 40 μg / kg, as well as for intramuscular dexmedetomidine (1.5 μg / kg, oral), compared to vehicle control. A significant decrease in sleep latency was observed for dexmedetomidine at 10, 20, 30, and 40 μg / kg doses, but a significant increase in sleep time was not observed at these doses. The reference compound zolpidem also showed a reduction in sleep latency when compared to normal control and vehicle control.

[0104] Number of sleep episodes: The number of sleep episodes was gradually reduced with sublingual dexmedetomidine at doses of 10, 20, 30 and 40 μg / kg, as well as with parenteral dexmedetomidine (1.5 μg / kg, oral), compared to vehicle control. The reference compound zolpidem showed a similar number of sleep episodes as the vehicle control.

[0105] Therefore, it can be concluded that dexmedetomidine delivered sublingually in the dose range of 10 - 40 micrograms / kg significantly reduces sleep latency, although it does not significantly affect total sleep time. The number of sleep episodes gradually decreased in response to increasing doses of sublingual dexmedetomidine. A dose of 40 micrograms / kg of sublingual dexmedetomidine also showed a significant increase in total sleep time. Therefore, sublingually delivered dexmedetomidine significantly reduces sleep latency.

Claims

1. A sublingual film formulation for use in the treatment of sleep disorders, comprising approximately 0.1 mg to approximately 0.5 mg of dexmedetomidine or a pharmaceutically acceptable salt thereof formulated to deliver dexmedetomidine through the oral mucosa of a subject.

2. A formulation for use as described in claim 1, wherein the sleep disorder is insomnia.

3. A formulation for use as described in claim 1 or 2, wherein the effective time for treatment is in the range of about 3 to about 30 minutes.

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