WO2016061554A1 - Composition synergique de produits pharmaceutiques connus et sans risque à utiliser dans l'insomnie, et sa méthode de traitement - Google Patents

Composition synergique de produits pharmaceutiques connus et sans risque à utiliser dans l'insomnie, et sa méthode de traitement Download PDF

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Publication number
WO2016061554A1
WO2016061554A1 PCT/US2015/056096 US2015056096W WO2016061554A1 WO 2016061554 A1 WO2016061554 A1 WO 2016061554A1 US 2015056096 W US2015056096 W US 2015056096W WO 2016061554 A1 WO2016061554 A1 WO 2016061554A1
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Prior art keywords
sleep
doxepin
insomnia
dexmedetomidine
pharmaceutically acceptable
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PCT/US2015/056096
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English (en)
Inventor
Harsh NEGI
Deepa Saini
Sameer Sharma
Krishnan Nandabalan
Frank Yocca
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Bioxcel Corporation
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Publication of WO2016061554A1 publication Critical patent/WO2016061554A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed

Definitions

  • the present invention is the field of formulation development and relates to a synergistic combination composition of dexmedetomidine with doxepin and a method of treatment of insomnia and related conditions. More particularly, the invention relates to treatment of patients suffering from insomnia by the administering a combination composition having no residual side effects.
  • a sleep disorder is a medical disorder of the sleep patterns of a person or animal. Disruptions in sleep can be caused by a variety of issues. Insomnia is a common sleep disorder that occurs when you have hard time initiating sleep, struggle to sleep maintenance, waking up frequently during night and you tend to wake up too early and are unable to go back to sleep. These symptoms of insomnia can be caused by a variety of biological, psychological and social factors.
  • insomnia is when the person cannot sleep through the night, but wakes several times for indeterminate periods. Sleep maintenance insomnia is also called as trouble staying asleep. Sleep onset insomnia (initiating sleep) is trouble falling asleep. Particularly, those patients having problem in both sleep initiation as well as sleep maintenance, require treatment intervention that would quickly initiate sleep and can maintain it for at least 7 to 8 hours without leaving residual sedative effects in the morning. Improved sleep can assist in keeping awake; keeping alert; keeping refreshed; and performing well the next day. While known sleeping pill compositions are effective for either treating sleep-onset insomnia, i.e. a subject's difficulty in falling asleep or treating sleep maintenance insomnia, i.e., maintaining a subject's sleep throughout a normal sleep period after falling asleep. However, there is no sleeping pill composition currently available which could treat both conditions simultaneously without residual side effect.
  • the present inventors are the first to realize the usefulness of low dose dexmedetomidine for sleep induction.
  • Dexmedetomidine formulation useful for treating sleep disorders is not commercially available.
  • Dexmedetomidine is only commercially available as an injectable formulation indicated for sedation, and it must be administered intravenously by a heath care professional.
  • the commercially available injectable formulation is not suitable for use in insomnia that can be self-administered.
  • Doxepin is very effective at addressing sleep maintenance aspects of insomnia and at reducing early morning awakenings that can occur in some cases of insomnia.
  • doxepin has poor sleep onset latency problem.
  • Doxepin binds with high specificity and affinity to the histamine HI receptor compared with other receptors. Therefore, at low doses, doxepin selectively antagonises HI receptors, which is believed to promote maintenance of sleep.
  • the present invention describes a combination composition comprising dexmedetomidine and doxepin that is effective for providing sleep onset and sleep maintenance, as well as methods of using the combination compositions thereof.
  • the invention provides a single sleeping pill comprising a combination of two pharmaceutical compounds, dexmedetomidine and doxepin, which have a synergistic effect when taken together than when taken alone.
  • the amount of each of the pharmaceutical compounds in the combination are lower than the amount of each individual compound that are required to consistently get seven to eight hours of sleep in night in comparison to pharmaceutical compounds are taken alone.
  • the invention provides a pill comprising a combination of a first compound and a second compound wherein, the first compound comprises dexmedetomidine and the second compound comprises doxepin.
  • the combination comprises from 0.0001 mg to 10 mg of the first compound combined with from 0.000 lmg to 10 mg of the second compound.
  • the invention provides a method of promoting sleep in a human, the method comprises preparing a synergistic composition of first compound i.e. dexmedetomidine with second compound i.e. doxepin and administering the composition orally or parenterally to a human being prior to a sleep period.
  • first compound i.e. dexmedetomidine
  • second compound i.e. doxepin
  • the present invention relate to compounds, compositions and methods for treating sleep disorders using dexmedetomidine in combination with doxepin.
  • the present invention relate to a sublingual composition comprising of dexmedetomidine in combination with doxepin for treating sleep disorders.
  • this combinations surprisingly and unexpectedly have the ability to provide improved sleep, with additional advantage of a reduced dose (e.g., reduced when compared to the normal dose when used alone) of one or both of dexmedetomidine and doxepin.
  • the combination composition is very effective in treating sleep disorders without residual side effects.
  • the combination is devoid of side effects seen with the therapeutically effective dose of the known benzodiazepines and non-benzodiazepine drugs when used alone or when an approved mono treatment dosage is used.
  • Figure 1 Total sleep time of doxepin alone or in combination of dexmedetomidine with doxepin in comparison to the vehicle control in Wistar rats observed by video monitoring of home cage activity.
  • Figure 2 Percentage of total sleep time of doxepin alone or in combination of dexmedetomidine with doxepin in comparison to the vehicle control in Wistar rats observed by video monitoring of home cage activity.
  • Figure 3 Latency to sleep time of doxepin alone or in combination of dexmedetomidine with doxepin in comparison to the vehicle control in Wistar rats observed by video monitoring of home cage activity.
  • Figure 4 Number of sleep episodes of doxepin alone or in combination of dexmedetomidine with doxepin in comparison to the vehicle control in Wistar rats observed by video monitoring of home cage activity.
  • Doxepin is a non DEA schedule IV drug approved for the treatment of insomnia characterized by difficulty with sleep maintenance.
  • doxepin has poor sleep onset latency problem and has been reported in clinical studies to increase sleep onset latency.
  • doxepin in regular dose then it might increase the sleep onset time especially in those patients which have difficulty in both sleep onset and sleep maintenance.
  • the present inventor provided a solution wherein they reduced the dose of doxepin and combined it with sleep inducing drug in a low dose which has no reported residual side effect.
  • Dexmedetomidine the D-enantiomer of medetomidine, is among the most potent sedative drugs known. Dexmedetomidine is reported to induce arousable sedation and has quick onset and short acting nature. Its sedative effects are mediated by subtype A of the a2 adrenergic receptor, a G-protein-coupled receptor. Acting as an agonist at this receptor, dexmedetomidine causes numerous intracellular changes that lead, generally speaking, to reduce neuronal excitability. Dexmedetomidine is impact on the locus ceruleus- norepinephrine and other awakening pathway activity to regulate the body wakefulness.
  • Dexmedetomidine reduces the cerebral cortical hyper arousal level in patients with insomnia by changing the activity of locus ceruleus-noradrenergic system and other arousal pathways of ascending reticular activating system. It helps to restore the sleeping-awakening system and improve the symptoms of insomnia. Dexmedetomidine induces a qualitatively similar pattern of c-fos expression as seen during normal NREM sleep, a decrease in the locus ceruleus and tuberomammillary nucleus and an increase in the ventrolateral preoptic nucleus (VLPO).
  • VLPO ventrolateral preoptic nucleus
  • the present invention combined low dose dexmedetomidine with a non DEA schedule IV drug, with poor ability to decrease the sleep onset latency such as doxepin.
  • the combination of dexmedetomidine with doxepin when compared to BZD and Z drug has no residual side effect such as dependence, rebound insomnia, post dose day residual sedation.
  • the present invention discloses a synergistic pharmaceutical composition
  • a synergistic pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof in combination with doxepin or a pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof.
  • the synergistic composition help to lower down the dose of combined drugs with comparison to their individual dose amount for treatment of insomnia patient which in turn, helps in minimizing the residual side effects associated with such drugs when taken in full dose.
  • composition according to the present invention is capable of providing levels of drug at an appropriate time after administration that do not give rise to the undesirable residual effects mentioned hereinbefore the following day.
  • the synergistic combination composition could also be used in other related central nervous system conditions such as but not limited to snoring, sleep apnoea, sleep deprivation, and restless legs syndrome
  • central nervous system disorders and/or states are not limited to headache, pain, epilepsy, convulsions, neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, ataxias, dystonia, movement disorders, memory disorders, depression, avoidant personality disorder, anxiety, panic disorder, obsessive-compulsive disorders, phobias, impulsive disorders, cognitive disorders, mood disorders, psychoses, schizophrenia, drug abuse, chemical dependencies, drugs tolerance or withdrawal, posttraumatic stress syndrome and eating disorders.
  • composition described herein may be administered to a subject in need of treatment by a variety of routes of administration, including orally and parenterally, (e.g., intravenously, subcutaneously or intramedullary), intranasally or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water, topically, intradermally, subcutaneously and/or administration via mucosal routes in liquid or solid form.
  • the composition can be formulated into a variety of dosage forms, e.g., extract, pills, tablets, microparticles, capsules, oral liquid.
  • composition pharmaceutically or physiologically acceptable compatible binding agents, and/or adjuvant materials.
  • the mode of administration of the composition described herein is oral composition.
  • Oral compositions generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the aforesaid compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • the present invention discloses an oral composition for the treatment of insomnia in a subject comprising dexmedetomidine or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof and doxepin or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof, wherein said insomnia treatment obtainable from the said combination exceeds the degree of insomnia treatment obtainable from doxepin alone or dexmedetomidine alone.
  • Preferred route for delivery of pharmaceutical composition is an oral route.
  • an orally disintegrating synergistic pharmaceutical composition comprising doxepin or a pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative for shortening the time to sleep onset in a patient being treated for insomnia in combination with a sleep maintenance drug such as dexmedetomidine or a pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof.
  • the present invention discloses a pharmaceutical composition for treatment of sleep disorders comprising a pharmaceutically effective amount of a combination of (a) dexmedetomidine or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof in combination with (b) doxepin or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof, wherein the weight ratio of dexmedetomidine to doxepin is in a range of 120: 1 to 1 : 120.
  • the present invention discloses a pharmaceutical composition for treatment of sleep disorders comprising a pharmaceutically effective amount of a combination of (a) dexmedetomidine or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof in combination with (b) doxepin or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof, wherein the weight ratio of dexmedetomidine to doxepin of about 1 :60.
  • the present invention discloses a pharmaceutical composition for inducing sleep comprising effective amount of a sleep onset shortening drug in combination of a sleep maintenance drug.
  • the present invention discloses a composition
  • a composition comprising a first compound and a second compound, wherein: said first compound comprises dexmedetomidine and said second compound comprises doxepin; and wherein said composition comprises from 0.0001 mg to 10 mg of said dexmedetomidine combined with from 0.0001 mg to 10 mg of said doxepin.
  • the present invention discloses a sleeping pill of a composition comprising dexmedetomidine and doxepin as disclosed in description.
  • the dexmedetomidine and doxepin in the composition are complementing each other for treatment of sleep disorder.
  • sleep disorder is insomnia.
  • Oral pharmaceutical composition of dexmedetomidine and doxepin could also be as liquid form preparations include solutions, suspensions and emulsions, for example, water or certain glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solutions.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, and stabilizing and thickening agents as desired.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions.
  • preparations may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the present invention discloses a mucoadhesive drug delivery system.
  • the combination composition is delivered through controlled release drug delivery system. It has been further disclosed that mucoadhesive properties of a tablet has additional advantages, e.g. efficient absorption and enhanced bioavailability of the drugs due to a high surface to volume ratio, a much more intimate contact with the mucus layer. Mucoadhesive tablets can be tailored to adhere to any mucosal tissue including those found in stomach, thus offering the possibilities of localized as well as systemic controlled release of drugs. Mucoadhesive tablets are widely used because they release the drug for prolong period, reduce frequency of drug administration and improve the patient compliance.
  • the pharmaceutical composition of the present invention is absorbed through oral mucosa.
  • Drug delivery via the mucous membranes of the oral cavity has certain advantages, due to the properties of the oral mucosa itself.
  • the mucous membranes of the oral cavity are highly vascularized and well supplied with lymphatic drainage sites
  • composition according to the present invention is provided as a pharmaceutical composition
  • the pharmaceutical composition includes pharmaceutically acceptable carriers.
  • the pharmaceutically acceptable carrier included in the pharmaceutical composition according to the present invention are those used generally in pharmaceutical formulation, and particular examples thereof include, but not limited to: lactose monohydrate, cellulose, crospovidone, magnesium stearate, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the pharmaceutical composition according to the present invention may further include a lubricant, wetting agent, sweetener, fragrance, emulsifier, suspending agent, preservative, or the like.
  • a lubricant wetting agent, sweetener, fragrance, emulsifier, suspending agent, preservative, or the like.
  • suitable pharmaceutically acceptable carriers and formulation thereof are described in detail in Remington's Pharmaceutical Sciences (19th edition, 1995).
  • Adequate dose of the pharmaceutical composition of the present invention may be determined according to various factors, including methods of formulation, administration modes, ages, weights, sex, pathological conditions and diet of patients, administration periods, administration routes, excretion rates and reaction sensitivity.
  • General dose of the pharmaceutical composition of the present invention is 0.01-1000 mg/kg weight in the case of adult patients.
  • the pharmaceutical composition of the present invention may be formulated by using pharmaceutically acceptable carriers and/or excipients so that it may be provided as a unit dosage form or may be packed in a multi-dose container in a manner generally known to those skilled in the art.
  • dosage forms include solutions or suspensions in oil or aqueous media, syrup, emulsion, elixir, powder, flour, granules, tablets, capsules, etc., and may further include a dispersant or stabilizer.
  • the composition can comprise a carrier or excipient such as a gum base, a pH-adjusting agent or buffer system, and optionally a protecting agent.
  • the present invention discloses that the composition of present invention could be formulated as sublingual/or an oral tablet by a method like direct compression, wet granulation or dry granulation.
  • direct compression method all materials including said drug substances are sifted in a specific sequence as per process optimized and then blended in V-blender or any other suitable blender sequentially to achieve uniform mixing of drug substances in the blend. The blend is then further compressed into tablets using appropriate tooling.
  • wet granulation method the drug substance alone or with other excipients such as binder, sweetener and others are dissolved or dispersed into pharmaceutically acceptable solvents and granulated. The same are used to granulate the sifted blend of other ingredients. The granules are then dried and sized appropriately. The granules are then lubricated in a suitable blender and compressed into tablets of specific dimensions using appropriate tooling. For dry granulation method, the granules are prepared either by compaction (e.g. Roller compactor) or slugging or any other suitable technique and tablets are prepared in a similar manner to that of wet granulation technique.
  • compaction e.g. Roller compactor
  • sublingual dosage forms such as films, buccal patches or spray formulations
  • the synergistic composition of present invention is effective for the treatment of sleep disorder.
  • Therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of doxepin or a pharmaceutically acceptable salt thereof is administrated to a patient for treatment of sleep disorders. More preferably, it is used for the treatment of insomnia.
  • the appropriate effective dosage to be administered to a subject can be evaluated in an appropriate patient population that has been selected based on factors such as age, weight, the number of hours of time in bed remaining.
  • the composition of present invention can be administered in a quick-dissolving tablet or lozenge.
  • the administration of the compositions of the present invention could be carried out via any of the accepted modes of administration to the mucous membranes of the oral cavity.
  • the synergistic composition is administered orally to human for the treatment of insomnia which comprises a combination formulation consisting essentially of 0.0001 to 10 mg of dexmedetomidme and 0.0001 to 10 mg of doxepin.
  • Insomnia which could be treated using this method is not limited to sleep onset insomnia, sleep maintenance insomnia, early morning awakening insomnia, transient insomnia, middle-of-the-night insomnia, late night insomnia, prolonged awakening after sleep onset insomnia.
  • the present invention discloses a preferred oral dose of dexmedetomidme in range of 0.005 mg to 5 mg with doxepin and dose of doxepin in combination composition is preferably between about 0.01 mg and 6 mg.
  • the one or more drugs used in combination with doxepin can be utilized in a dosage that is the same as the approved dosage for the drug, the clinical or literature test dosage of the drug, or the dosage used for the drug as a monotherapy for a sleep disorder.
  • both the doxepin and the one or more combination drugs can be used at a dosage that is same as or lower than the approved dosage for the drug, the clinical or literature test dosage or the dosage used for the drug as a monotherapy, preferably at a dosage that is lower than when used in their respective monotherapies
  • the dosage of dexmedetomidme is based on the serum concentration which induces sleep which is preferably 0.5 to 1.2ng/ml.
  • the total dose required is estimated to be in a range of 0.005 to 5 mg. This dose is for a human having weight ranging from of 40 to 100 kg.
  • the present invention discloses a synergistic composition of therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof in combination with a therapeutically effective amount of doxepin or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof for treating sleep disorder in an obese patient.
  • insomnia pharmaceutical composition means treatment of insomnia by combination of chemicals that is greater than would be expected if the chemicals were used individually.
  • next-day residual sedative effect after administration of an over-the- counter antihistamine or other sleeping aid is a major problem. It is very uncomfortable to patient do normal activities on next day.
  • the present invention provides a method of treatment of insomnia which minimizes next day residual sedation caused by standard sleep therapy, comprising providing a pharmaceutical composition of dexmedetomidine or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof in combination with a doxepin or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof to a patient.
  • the composition enhances onset of sleep as well as maintain 7 to 8 hour of uninterrupted sleep in individual in need of such enhancement.
  • the present invention discloses that the time range for sleep induction is less than 30 minutes, which is attributed to short acting nature of dexmedetomidine and it very effective when combined with doxepin, which is a poor in sleep induction and used only for sleep maintenance.
  • the two drugs do not come under the DEA schedule IV list as well.
  • sleep disorder refers to a disruptive pattern of sleep arising from many causes including, without limitation, dysfunctional sleep mechanisms, abnormalities in physiological functions during sleep, abnormalities of the biological clock, and sleep disturbances that are induced by factors extrinsic to the sleep process.
  • the term encompasses disorders associated with difficulties in staying asleep and/or falling asleep such as insomnia (e.g., transient, short-term, and chronic), delayed sleep phase syndrome, hypnotic-dependent sleep disorder, and stimulant-dependent sleep disorder; disorders associated with difficulties in staying awake such as sleep apnoea, narcolepsy, restless leg syndrome, obstructive sleep apnoea, central sleep apnoea, idiopathic hypersomnia, respiratory muscle weakness-associated sleep disorder; disorders associated with difficulties in adhering to a regular sleep schedule such as sleep state misperception, shift work sleep disorder, chronic time zone change syndrome, and irregular sleep-wake syndrome; disorders associated with abnormal behaviours such as sleep terror disorder (i.e., parasomnia) and sleepwalking (i.e., somnambulism); and other disorders such as sleep bruxism, fibromyalgia, and nightmares.
  • insomnia e.g., transient, short-term, and chronic
  • insomnia refers to a sleep disorder characterized by symptoms including, without limitation, difficulty in falling asleep, difficulty in staying asleep, intermittent wakefulness, and/or waking up too early.
  • the term also encompasses daytime symptoms such as sleepiness, anxiety, impaired concentration, impaired memory, and irritability.
  • pharmaceutically acceptable includes those compounds, materials, compositions, dosage forms, and methods of use thereof that are within the scope of sound medical judgment and suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, while being commensurate with a reasonable benefit/risk ratio and eliciting a desired pharmacological response.
  • Dexmedetomidme contains a basic nitrogen atom capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic, and organic acid addition salts of dexmedetomidme. These salts may be prepared in situ during final isolation and purification of dexmedetomidme or by separately reacting purified dexmedetomidme in its free base form with a suitable organic or inorganic acid, and thereafter isolating the salt thus formed. Furthermore, the salt may be formed during a manufacturing process to produce formulation.
  • the salts of dexmedetomidme comprises and are not limited to the hydrohalide (including hydrobromide and hydrochloride), sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, 2-hydroxyethylsulfonate, and laurylsulphonate salts, and the like.
  • hydrohalide including hydrobromide and hydrochloride
  • sulfate bisulfate
  • phosphate nitrate
  • acetate valerate
  • oleate palmitate
  • stearate laurate
  • benzoate lactate
  • phosphate tosylate
  • citrate maleate
  • fumarate succinate
  • tartrate nap
  • Dexmedetomidine derivatives may include covalent modifications that create a pro-drug. Upon administration, the pro-drug derivative undergoes chemical modification by the mammal that yields dexmedetomidine.
  • the formulation may be administered to mammals, including humans, as well as human companion animals (e.g., cats, dogs), agricultural livestock, and other animals in need thereof.
  • mammals including humans, as well as human companion animals (e.g., cats, dogs), agricultural livestock, and other animals in need thereof.
  • composition of the invention includes the prodrugs, the pharmaceutically acceptable salts, the oxides, the solvates, e.g. hydrates, and inclusion complexes of that compound, where the context so permits, as well as a mixture of any such forms of that 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.
  • inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims.
  • a compound as described herein including in the contexts of pharmaceutical compositions, methods of treatment, and compounds per se, is provided as the salt form.
  • reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
  • particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
  • a "pharmaceutically acceptable" carrier or excipient means approved by a regulatory agency of the Federal or a state government, or as listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in mammals, and more particularly in humans.
  • the term "pharmaceutical composition” as used in accordance with the present invention relates to compositions that can be formulated in any conventional manner using one or more pharmaceutically acceptable carriers or excipients.
  • solvate refers to a composition of the present technology in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered.
  • suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate.
  • solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions.
  • the term “derivative” refers, for example, to crystal forms, polymorphs, or prodrugs of the compositions useful according to the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitter ionic forms, where possible, of the compositions of the invention.
  • prodrug means compounds that are rapidly transformed in vivo to yield the parent compound, for example by hydrolysis in blood. Commonly, the conversion of prodrug to drug occurs by enzymatic processes in the liver or blood of the mammal.
  • compositions of the invention may be chemically modified without absorption into the systemic circulation, and in those cases, activation in vivo may come about by chemical action (as in the acid-catalyzed cleavage in the stomach) or through the intermediacy of enzymes and microflora in the gastrointestinal GI tract.
  • the composition may bear metabolically cleavable groups, which have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group.
  • prodrugs is provided in the following: 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.
  • human or “patient,” used interchangeably, means any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, such as humans.
  • 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.
  • the term "dosage” is intended to encompass a formulation expressed in terms of ⁇ g/kg/hr, ⁇ g/kg/day, mg/kg/day, or mg/kg/hr.
  • a “dose” is an amount of an agent administered to a patient in a unit volume or mass, e.g., an absolute unit dose expressed in mg of the agent.
  • the dose depends on the concentration of the agent in the formulation, e.g., in moles per litre (M), mass per volume (m/v), or mass per mass (m/m).
  • drug addiction means dependence on an illegal drug, controlled substance or a medication. When you're addicted, you may not be able to control your drug use and you may continue using the drug despite the harm it causes. Drug addiction can cause an intense craving for the drug. You may want to quit, but most people find they can't do it on their own.
  • method of treating means amelioration or relief from the symptoms and/or effects associated with the disorders described herein.
  • treatment means amelioration or relief from the symptoms and/or effects associated with the disorders described herein.
  • reference to “treatment” of a patient is intended to include prophylaxis.
  • Winstar rats were randomly divided into different groups, each containing six animals.
  • the study groups were divided as vehicle control group, test compound groups and combination of dexmedetomidine and doxepin groups.
  • mice were administered with test compound (doxepin) and combination of dexmedetomidine and doxepin and motor coordination was tested on the rotarod at 3, 10, 17, 24 and 30 minutes post administration to establish a temporal scale of loss of motor activity and drowsiness.
  • animals were dosed with test compound (doxepin) and combination of dexmedetomidine and doxepin and respiratory parameters (tidal volume & frequency of respiration) and non-invasive measurement of heart rate and blood pressure was performed. A 10 minute baseline was recorded, test compound (doxepin) and combination of dexmedetomidine and doxepin was administered and the physiological parameters were recorded for up to 60 minutes after administration.
  • mice were dosed with test compounds and blood was collected at 30, 60 and 120 min post sublingual dosing to estimate plasma drug concentration of combination of dexmedetomidine and doxepin.
  • Plasma was separated into a fresh tube (75-100 ⁇ 1 per time point) and stored at -80°C until analysis/ shipment of samples to client location. All the animals were euthanized by C0 2 inhalation on day 10.
  • the vehicle control group received 0.9% saline water; test compound groups (doxepin dose (1) - O.lmg/kg, dose (2) - 0.3mg/kg and dose (3) - 0.6mg/kg), combination of dexmedetomidine and doxepin groups administered sublingually (dexmedetomidine dose (1) - 5 ⁇ g/kg and dose (2) -10 ⁇ g/kg); and doxepin dose (1) - 0.3mg/kg, dose (2) - 0.6mg/kg) were administered per oral in dose of 30 mg/kg.
  • the treatment was given such that no rat receives the same treatment twice. Total sleep time, latency to sleep and number of sleep episodes was measured:
  • Total sleep time (total duration of sleep in 180min): Total sleep time significantly increased at 0.1, 0.3 & 0.6 mg/kg (sublingual) for doxepin as compared to vehicle control. All the combinations tested for dexmedetomidme and doxepin also showed significant improvement in the total sleep time as compared to vehicle control with the maximum sleep time in combination of 10 ⁇ g/kg of dexmedetomidme and 0.6 mg/kg of doxepin. Similar data is also represented as percentage of total sleep time.
  • Latency to sleep (time of sleep onset): Latency to sleep was reduced with doxepin (0.1, 0.3 & 0.6 mg/kg (sublingual)) as compared to the vehicle control. All the combinations tested for dexmedetomidme and doxepin also showed improvement in the latency to sleep as compared to vehicle control. A significant effect in combination was found with combination of 10 ⁇ g/kg of dexmedetomidme and 0.3 mg/kg of doxepin and combination of 10 ⁇ g/kg of dexmedetomidme and 0.6 mg/kg of doxepin. However, the minimum latency to sleep (significant) in combination of 10 ⁇ g/kg of dexmedetomidme and 0.6 mg/kg of doxepin was observed. Additionally, the combination of 10 ⁇ g/kg of dexmedetomidme and 0.6 mg/kg of doxepin; also showed significant effect (p ⁇ 0.05) as compared to doxepin 0.6 mg/kg standalone.
  • Buccal delivery may require an additional back-liner if specified.
  • Example 3 Composition for a tablet formulation intended for oral administration (immediate release or extended release type.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une composition pharmaceutique de dexmédétomidine combinée à de la doxépine, destinée à être utilisée dans le traitement de troubles du sommeil tels que l'insomnie. Ladite composition fournit un modèle de sommeil sain permettant à l'utilisateur de dormir sept ou huit heures. L'invention concerne également une méthode de traitement ou d'amélioration du début du sommeil et du maintien du sommeil, qui consiste à identifier un patient nécessitant une telle amélioration, et à administrer ladite composition pharmaceutique.
PCT/US2015/056096 2014-10-16 2015-10-16 Composition synergique de produits pharmaceutiques connus et sans risque à utiliser dans l'insomnie, et sa méthode de traitement WO2016061554A1 (fr)

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Cited By (4)

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WO2018126182A1 (fr) * 2016-12-31 2018-07-05 Bioxcel Therapeutics, Inc. Utilisation de dexmédétomidine sublinguale permettant le traitement de l'agitation
US10792246B2 (en) 2018-06-27 2020-10-06 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them
US11806334B1 (en) 2023-01-12 2023-11-07 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens
US11890272B2 (en) 2019-07-19 2024-02-06 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens

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US20110077200A1 (en) * 2006-12-06 2011-03-31 Somaxon Pharmaceuticals, Inc. Combination therapy using low-dose doxepin for the improvement of sleep

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US20080058408A1 (en) * 2006-05-19 2008-03-06 Rogowski Roberta L Low-dose doxepin for treatment of sleep disorders in elderly patients
US20110077200A1 (en) * 2006-12-06 2011-03-31 Somaxon Pharmaceuticals, Inc. Combination therapy using low-dose doxepin for the improvement of sleep
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Cited By (20)

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Publication number Priority date Publication date Assignee Title
US11839604B2 (en) 2016-12-31 2023-12-12 Bioxcel Therapeutics, Inc. Use of sublingual dexmedetomidine for the treatment of agitation
US11931340B2 (en) 2016-12-31 2024-03-19 Bioxcel Therapeutics, Inc. Use of sublingual dexmedetomidine for the treatment of agitation
JP2020503323A (ja) * 2016-12-31 2020-01-30 バイオエクセル セラピューティクス，インコーポレイテッド 激越の治療のための舌下デクスメデトミジンの使用
WO2018126182A1 (fr) * 2016-12-31 2018-07-05 Bioxcel Therapeutics, Inc. Utilisation de dexmédétomidine sublinguale permettant le traitement de l'agitation
JP2021102654A (ja) * 2016-12-31 2021-07-15 バイオエクセル セラピューティクス，インコーポレイテッド 激越の治療のための舌下デクスメデトミジンの使用
JP2021113203A (ja) * 2016-12-31 2021-08-05 バイオエクセル セラピューティクス，インコーポレイテッド 激越の治療のための舌下デクスメデトミジンの使用
JP7008153B2 (ja) 2016-12-31 2022-02-10 バイオエクセル セラピューティクス，インコーポレイテッド 激越の治療のための舌下デクスメデトミジンの使用
US11786508B2 (en) 2016-12-31 2023-10-17 Bioxcel Therapeutics, Inc. Use of sublingual dexmedetomidine for the treatment of agitation
JP2022040229A (ja) * 2016-12-31 2022-03-10 バイオエクセル セラピューティクス，インコーポレイテッド 激越の治療のための舌下デクスメデトミジンの使用
CN110337290A (zh) * 2016-12-31 2019-10-15 比奥克斯塞尔医疗股份有限公司 舌下右旋美托咪啶用于治疗激越的用途
US11559484B2 (en) 2018-06-27 2023-01-24 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them
US11517524B2 (en) 2018-06-27 2022-12-06 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them
US11806429B2 (en) 2018-06-27 2023-11-07 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them
US10792246B2 (en) 2018-06-27 2020-10-06 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them
US11497711B2 (en) 2018-06-27 2022-11-15 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them
US11478422B2 (en) 2018-06-27 2022-10-25 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them
US11890272B2 (en) 2019-07-19 2024-02-06 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens
US11998529B2 (en) 2019-07-19 2024-06-04 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens
US11998528B1 (en) 2023-01-12 2024-06-04 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens
US11806334B1 (en) 2023-01-12 2023-11-07 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens

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