EP4536181A1 - Formes posologiques osmotiques comprenant de la deutétrabénazine et leurs procédés d'utilisation - Google Patents

Formes posologiques osmotiques comprenant de la deutétrabénazine et leurs procédés d'utilisation

Info

Publication number
EP4536181A1
EP4536181A1 EP23738387.2A EP23738387A EP4536181A1 EP 4536181 A1 EP4536181 A1 EP 4536181A1 EP 23738387 A EP23738387 A EP 23738387A EP 4536181 A1 EP4536181 A1 EP 4536181A1
Authority
EP
European Patent Office
Prior art keywords
deutetrabenazine
dosage form
amount
microparticles
total
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23738387.2A
Other languages
German (de)
English (en)
Inventor
Parag Shah
Mayank Joshi
Soumen PATTANAYEK
Divyang PATEL
Sandeep Pandita
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Auspex Pharmaceuticals Inc
Original Assignee
Auspex Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US17/835,435 external-priority patent/US12599598B2/en
Application filed by Auspex Pharmaceuticals Inc filed Critical Auspex Pharmaceuticals Inc
Publication of EP4536181A1 publication Critical patent/EP4536181A1/fr
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • TECHNICAL FIELD The present disclosure pertains to osmotic dosage forms and methods of use of those dosage forms for treating hyperkinetic movement disorders deriving from conditions such as Huntington’s disease, tardive dyskinesia, Tourette syndrome, levodopa-induced dyskinesia and dyskinesia in cerebral palsy.
  • BACKGROUND Deutetrabenazine (RR,SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2- methylpropyl)-2H-benzo[a]quinolizin-2-one) is a vesicular monoamine transporter type 2 (VMAT2).
  • deutetrabenazine alpha- dihydrodeutetrabenazine [ ⁇ -deuHTBZ] and beta-dihydrodeutetrabenazine [ ⁇ -deuHTBZ]
  • deuHTBZ beta-dihydrodeutetrabenazine
  • Deutetrabenazine exhibits an increased half-life of its active metabolites, relative to tetrabenazine (e.g., U.S. Patent No.8,524,733). Deutetrabenazine is approved by the U.S.
  • AUSTEDO® dosage forms are orally administered twice-daily (bid), for total daily doses of 12 mg or above of deutetrabenazine.
  • a factor affecting gastrointestinal absorption of orally administered drugs is the rate at which drug is released from the dosage form.
  • Drug release rates for oral dosage forms are typically measured as rate of dissolution in vitro, i.e., a quantity of drug released from the dosage form per unit time for example, in a FDA approved system.
  • Such systems include, for example, United States Pharmacopeia (USP) dissolution apparati I and II.
  • USP United States Pharmacopeia
  • the therapeutic window of a drug is the time period when the plasma drug concentration is within the therapeutically effective plasma drug concentration range. Because the plasma drug concentration declines over time, however, multiple doses of drug dosage form must be administered at appropriate intervals to ensure that the plasma drug concentration remains within or, again rises to, the therapeutic window. At the same time, however, there is a need to avoid or minimize plasma drug concentrations that result in undesirable side effects.
  • Several dosage forms comprising deutetrabenazine are disclosed in U.S. Patent No. 9,296,739.
  • FIG.1 provides an illustration of an osmotic dosage form in cross-section.
  • FIG. 2a and FIG. 2b provide flowcharts of the general manufacturing processes for osmotic dosage forms according to the present disclosure.
  • FIG.3a and FIG.3b are graphs showing concentration (pg/mL) of deutetrabenazine vs.
  • FIG. 3a shows direct scale for mean concentration
  • FIG.3b shows a log scale for mean concentration
  • FIG.4a and FIG.4B are graphs showing concentration (pg/mL) of ⁇ - and ⁇ - deuHTBZ (total deuHTBZ) vs. time (hours, “h”) in subjects administered 12 mg AUSTEDO® tablet bid (“R”) or an osmotic dosage form containing 24 mg deutetrabenazine qd (“T2A”).
  • FIG. 1 shows direct scale for mean concentration
  • FIG.3b shows a log scale for mean concentration
  • FIG.4a and FIG.4B are graphs showing concentration (pg/mL) of ⁇ - and ⁇ - deuHTBZ (total deuHTBZ) vs. time (hours, “h”) in subjects administered 12 mg AUSTEDO® tablet bid (“R”) or an osmotic dosage form containing 24 mg deutetrabenazine qd (“T2A”).
  • the terms “compound”, “drug”, “pharmacologically active agent”, “active agent”, or “medicament” are used interchangeably herein to refer to a compound or compounds or composition of matter which, when administered to a subject (human or animal) induces a desired pharmacological and/or physiologic effect by local and/or systemic action.
  • the active agent is preferably deutetrabenazine, as disclosed herein.
  • drug form refers to a drug form having osmotic properties and able to release active agent over an extended period, for example, the dosage form releases not more than 60 wt% of the active agent in the dosage form for 8 hours after administration.
  • the active - 3 - 4879-5033-3801.1 agent is preferably deutetrabenazine, as disclosed herein.
  • drug formulation refers to a solution or suspension of the drug, optionally with excipients, formed in situ under aqueous conditions of the dosage form.
  • the active agent is preferably deutetrabenazine, as disclosed herein.
  • port refers to means and methods suitable for exit of the drug or the drug formulation from the core of the dosage form, for example, any hole, passage, channel or similar opening though which the drug or the drug formulation in the core of the dosage form may exit. Other expressions of such term include, for example, exit means, orifice or hole.
  • treatment or “therapy” (as well as different forms thereof) include preventative (e.g., prophylactic), curative, or palliative treatment.
  • treating includes alleviating or reducing at least one adverse or negative effect or symptom of a condition, disease or disorder.
  • This condition, disease or disorder may refer to hyperkinetic movement disorder, such as, but not limited to, Huntington’s disease, tardive dyskinesia, Tourette syndrome, dystonia, dyskinesia in cerebral palsy and Parkinson's disease levodopa-induced dyskinesia.
  • administering means providing to a patient a pharmaceutical composition or dosage form (used interchangeably herein) disclosed herein.
  • subject means providing to a patient a pharmaceutical composition or dosage form (used interchangeably herein) disclosed herein.
  • subject “individual”, and “patient” are used interchangeably herein, and refer to a human, to whom treatment, including prophylactic treatment, with a dosage form disclosed herein, is provided.
  • a derivative in the case of cellulose, a derivative can refer to semi-synthetic cellulose products such as cellophane, rayon, and cellulose acetate, cellulose esters, and cellulose ethers.
  • “Microparticles” refers to particles, for example deutetrabenazine particles, with a particle size (i.e. diameter) below 1 mm.
  • the median diameter (D50) of the microparticles is from about 0.05 to about 100 ⁇ m. In another embodiment, D50 of the microparticles is from about 0.05 to about 50 ⁇ m.
  • the D 50 of the - 4 - 4879-5033-3801.1 microparticles is from about 1 ⁇ m to about 30 ⁇ m, or about 1 ⁇ m to about 25 ⁇ m, or about 5 ⁇ m to about 30 ⁇ m, or about 1 ⁇ m to about 20 ⁇ m, or about 5 ⁇ m to about 25 ⁇ m, or about 10 ⁇ m to about 20 ⁇ m.
  • the deutetrabenazine microparticles have a particle size distribution of about 1 ⁇ m to about 30 ⁇ m in diameter.
  • the deutetrabenazine microparticles have a D 90 of 15 ⁇ m (i.e.90% of the particles have a diameter less than or equal to 15 um).
  • the deutetrabenazine microparticles have a D 50 10 ⁇ m (i.e. 50% of the particles have a diameter greater than 10 um and 50% of the particles have a diameter less than or equal to 10 um). In yet another embodiment, the deutetrabenazine microparticles have a D10 of 3 ⁇ m (i.e.10% of the particles have a diameter less than 3 um).
  • the terms D 90 , D 50 or D 10 are well understood in the art.
  • the particle size distribution of the microparticles i.e. the diameters
  • osmotic systems may operate independently of pH and thus, operation continues at the osmotically-determined rate throughout an extended time period even as the dosage form transits the GI tract and encounters differing microenvironments having significantly different pH values.
  • An example of one type of osmotic device comprises two component layers within a compartment (herein referred to as, and used interchangeably with, a core) formed by a semipermeable wall.
  • One component layer (herein referred to as an active layer) comprises drug (i.e.
  • the second component layer (herein referred to as a push layer) comprises an osmotically active agent(s), optionally in a mixture with excipients but does not contain drug.
  • This core is further coated by the - 5 - 4879-5033-3801.1 semipermeable wall, which permits entry of aqueous fluid, i.e. from the GI system, into the core.
  • the active layer forms a drug formulation and the osmotic agent(s) in the push layer swell and push against the drug formulation to thereby facilitate release of the drug formulation at a substantially constant rate.
  • the presently disclosed osmotic dosage forms provide a pharmacokinetic profile when administered orally to a subject on a once daily basis (q.d.) that is comparable, e.g., bioequivalent, to that of the AUSTEDO® dosage forms administered b.i.d.
  • the osmotic dosage forms provide an in vivo plasma profile for total deuHTBZ at steady state that includes a mean AUC0-24 of about 410,000 to 800,000 h*pg/mL, and a mean Cmax of less than about 40,000 pg/mL.
  • the osmotic dosage forms of the present disclosure include a tablet core containing at least a push layer and an active layer, wherein the active layer includes deutetrabenazine and one or more excipient for forming a drug formulation when hydrated, and wherein the push layer includes at least one osmotic agent and one or more excipient.
  • Both the push layer and active layer are contained within a tablet core at least partially surrounded by a semipermeable layer having a port that functions as an exit means for drug formulation release from the tablet core.
  • the two layers are compressed into a bilayer tablet core surrounded by a semipermeable membrane and further having a suitable orifice for drug release there through.
  • the dosage form (2) comprises a bilayer tablet core.
  • the core comprises an active layer (4), containing drug, e.g. deutetrabenazine, and one or more active layer excipients, and a push layer (6), containing at least one osmotic agent along with one or more push layer excipients.
  • active layer and push layer excipients are known in the art and include diluents, carriers, binders, fillers, control release agents and processing aids.
  • a semipermeable membrane (8) surrounds the bi- layer tablet core and a suitably sized port (10) that extends from the semipermeable membrane into the active layer (4) is present to permit drug formulation to be released from within the tablet core.
  • the dosage form may be longitudinally compressed and the port (10) present on the side of the dosage form comprising the active layer.
  • the dosage form is compressed along the lateral axis of the dosage form, and the port is present on one end of the dosage form. In all embodiments, more than one port may be present.
  • an optional immediate-release layer (immediate release coating), external to the semipermeable layer, including further drug (ie deutetrabenazine microparticles) may be further provided, if desired, as described elsewhere herein.
  • the invention provides an osmotic dosage form for once daily administration to a subject in need thereof comprising: a. a tablet core comprising an active layer comprising an amount of deutetrabenazine microparticles and a push layer; b. a semipermeable layer surrounding the tablet core; and c. a port in the semipermeable layer extending to the tablet core.
  • the active layer contained within the tablet core includes deutetrabenazine and pharmaceutically acceptable active layer excipients.
  • the deutetrabenazine is provided as deutetrabenazine microparticles.
  • the deutetrabenazine microparticles may be present in the active layer in an amount of about 2% to 20% (i.e., about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%), by weight (%w/%w) based on the total weight of the active layer.
  • the active layer excipient comprises an active layer control release agent.
  • the active layer control release agent has a viscosity of about 50-150 mPa s.
  • the active layer control release agent has a viscosity of about 55-90 mPa s.
  • the active layer control release agent comprises a polyoxyethylene polymer, an ionic hydrogel, a hydrophilic polymer, a hydrophobic polymer or any mixture thereof.
  • the active layer control - 7 - 4879-5033-3801.1 release agent comprises a polyoxyethylene polymer, which is polyethylene oxide.
  • the polyethylene oxide within the active layer has an average molecular weight of 100,000 daltons to 500,000 daltons. In some embodiments, the polyethylene oxide within the active layer has an average molecular weight of about 200,000 daltons.
  • the active layer control release agent is present in the active layer in an amount of about 60% to about 98% by weight, based on the total weight of the active layer. In one specific embodiment, the active layer control release agent is present in the active layer in an amount of about 70% to about 85% by weight, based on the total weight of the active layer. In one specific embodiment, the active layer control release agent is present in the active layer in an amount of about 80% to about 90% by weight, based on the total weight of the active layer. In one specific embodiment, the active layer control release agent is present in the active layer in an amount of about 85% to about 95% by weight, based on the total weight of the active layer.
  • the weight ratio of the amount of deutetrabenazine microparticles and the amount of active layer control release agent in the active layer is 2:3 – 1:50. In one specific embodiment, the weight ratio of the amount of deutetrabenazine microparticles and the amount of active layer control release agent in the active layer is 2:5 – 1:5. In one specific embodiment, the weight ratio of the amount of deutetrabenazine microparticles and the amount of active layer control release agent in the active layer is 1:4 – 1:9. In one specific embodiment, the weight ratio of the amount of deutetrabenazine microparticles and the amount of active layer control release agent in the active layer is 1:5 – 1:19.
  • the weight ratio of the amount of deutetrabenazine microparticles and the amount of active layer control release agent in the active layer is 1:5 – 1:10. In one specific embodiment, the weight ratio of the amount of deutetrabenazine microparticles and the amount of active layer control release agent in the active layer is 1:5 – 1:7. In one specific embodiment, the weight ratio of the amount of deutetrabenazine microparticles and the amount of active layer control release agent in the active layer is 1:12 – 1:15. In one specific embodiment, the weight ratio of the amount of deutetrabenazine microparticles and the amount of active layer control release agent in the active layer is 1:20 – 1:30.
  • Optional excipients within the active layer include antioxidants, binders, lubricants, colorants, and the like. Such excipients are well known among those of ordinary skill in the art.
  • the active layer comprises deutetrabenazine microparticles, an active layer excipient and optionally one or more of an antioxidant, a binder, a lubricant, a colorant, or any combination thereof. - 8 - 4879-5033-3801.1
  • the active layer further comprises at least one active layer antioxidant.
  • the active layer antioxidant comprises: tertiary butyl-4-methoxyphenol (mixture of 2 and 3-isomers), 2,6-ditertiary butyl-p-cresol, propyl gallate, 6-ethoxy-1,2- digydro-2,2,4-trimethylquinoline (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene or any mixture thereof.
  • the active layer comprises a mixture of butylated hydroxyanisole and butylated hydroxytoluene.
  • the active layer antioxidant may be present in the active layer in an amount of about 0.001% to about 1% by weight, based on the total weight of the active layer.
  • the active layer further comprises an active layer binder.
  • the active layer binder comprises hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural and synthetic gums and any mixture thereof.
  • the active layer binder comprises hypromellose.
  • the active layer binder may be present in the active layer in an amount of about 2% to about 20% by weight, based on the total weight of the active layer.
  • the active layer further comprises one or more pharmaceutically acceptable lubricant.
  • Suitable lubricants include, without limitation, talc, starch, zinc stearate, aluminum stearate, magnesium stearate, calcium stearate, boric acid, sodium chloride, paraffin, stearic acid, low melting point waxes, hydrogenated vegetable oils and saturated fatty acid esters.
  • one or more lubricants may be present in the active layer in an amount of about 0.001% to about 0.2% by weight, based on the total weight of the active layer.
  • the active layer comprises deutetrabenazine microparticles, and an active layer control release agent having a viscosity of about 55-90 mPa s.
  • the active layer control release agent comprises polyethylene oxide.
  • the active layer comprises deutetrabenazine microparticles, polyethylene oxide and further comprises butylated hydroxyanisole, butylated hydroxytoluene, hypromellose and magnesium stearate.
  • the push layer contained within the tablet core comprises an osmotic agent which, without being bound to theory, acts as a fluid-attracting agent which swells when exposed to an aqueous milieu and pushes against the active layer enabling the flow of the drug formulation from within the dosage form out into an external environment.
  • the osmotic agent is defined as, for example, a non-volatile species which is generally soluble in water and create the osmotic gradient thereby enabling the osmotic inflow of water.
  • osmotic agent examples include inorganic salts or carbohydrates.
  • osmotic agents include magnesium sulfate, magnesium chloride, potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, d-mannitol, sorbitol, inositol, urea, magnesium succinate, tartaric acid, raffinose, and various monosaccharides, oligosaccharides and polysaccharides such as sucrose, glucose, lactose, fructose, and dextran, as well as mixtures of any one of these various species.
  • the osmotic agent is present in the push layer in an amount of about 5% to about 50% by weight, based on the total weight of the dosage form. In an embodiment, the osmotic agent is present in the push layer in an amount of about 5% to about 20% by weight, based on the total weight of the dosage form. In another embodiment, the osmotic agent is present in the push layer in an amount of about 8% to about 10% by weight, based on the total weight of the dosage form. In one embodiment, the osmotic agent is present in the push layer in an amount of about 20% to about 40% by weight, based on the total weight of the push layer. In an embodiment, the osmotic agent is about 30% by weight, based on the total weight of the push layer.
  • the push layer further comprises one or more excipients, such as a control release agent.
  • the push layer comprises an osmotic agent and a push layer control release agent.
  • Push layer control release agents include polymers providing a swellable matrix upon contact with water.
  • the push layer control release agent has a viscosity of about 5500-7500 mPa s.
  • Examples of a push layer control release agent include polyoxyethylene polymers, ionic hydrogels, hydrophilic polymers, hydrophobic polymers and any mixture thereof.
  • the push layer control release agent comprises a polyoxyethylene polymer, which is polyethylene oxide.
  • the polyethylene oxide within the push layer has an average molecular weight of 1,000,000 daltons to 7,000,000 daltons.
  • the polyethylene oxide within the push layer has an average molecular weight of 5,000,000 daltons.
  • the push layer control release agent is present in the push layer in an amount of about 50% to about 80% by weight, based on the total weight of the push layer.
  • the push layer control release agent is present in the push layer in an amount of about 60% to about 70% by weight, based on the total weight of the push layer.
  • the weight ratio of the osmotic agent and the push layer control release agent in the push layer is 1:2 – 1:3.5 or about 1:2 to 1:2.5.
  • the push layer optionally further contains other pharmaceutically acceptable - 10 - 4879-5033-3801.1 excipients, e.g., for stabilizing the layer, providing color for tablet orientation, or the like.
  • excipients include binders, colorants, and lubricants, and suitable examples of these types of excipients are well known among those of ordinary skill in the art.
  • the push layer further comprises a push layer binder.
  • the push layer binder can be selected from hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural and synthetic gums, and any mixture thereof.
  • the push layer binder is hypromellose.
  • the push layer binder is present in the push layer in an amount of about 2% to about 10% by weight, based on the total weight of the push layer. In another embodiment, the push layer binder is present in the push layer in an amount of about 3% to about 6% by weight, based on the total weight of the push layer.
  • Lubricants within the push layer can include any of the exemplary materials described supra in connection with the active layer.
  • the push layer may also include a disintegrant such as cross-linked polyvinylpyrrolidone, corn starch, potato starch, smectite clay (e.g magnesium aluminum silicate such as Veegum®), bentonite and citrus pulp. It may also be desirable to include stabilizers for the drug.
  • the selectively permeable materials forming the semipermeable layer are insoluble in body fluids, and are non-erodible or are bioerodible after a predetermined period with bioerosion corresponding to the end of the drug formulation release period.
  • semipermeable layer “semipermeable wall” and “semipermeable membrane” are interchangeable.
  • semipermeable materials useful for forming the semipermeable layer may have a fluid permeability of 10 -5 to 10 -1 (cc mil/cm 2 hr atm) expressed per atmosphere of hydrostatic or osmotic pressure difference across the wall at the temperature of use. Suitable materials are known in the art, see, e.g., U.S.
  • Typical materials useful for forming the semipermeable layer include materials known in the art including cellulose acetate, cellulose triacetate, agar acetate, amylose triacetate, beta - 11 - 4879-5033-3801.1 glucan acetate, cellulose diacetate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, polyamides, polyurethane, sulfonated polystyrenes, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbamate, cellulose acetate chloroacetate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanlate, cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succ
  • the semipermeable layer comprises water soluble polymers or water insoluble polymers including cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate; cellulose ethers including ethyl cellulose, agar acetate, amylose triacetate, betaglucan acetate, poly(vinyl methyl) ether copolymers, poly(orthoesters), poly acetals and selectively permeable poly(glycolic acid), poly(lactic acid) derivatives and any mixture thereof.
  • water soluble polymers or water insoluble polymers including cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate; cellulose ethers including ethyl cellulose, agar acetate, amylose triacetate, betaglucan acetate, poly(vinyl methyl) ether copolymers, poly(orthoesters), poly acetals and selectively
  • Cellulose acetate includes cellulose acetate polymers (e.g. Eudragit®).
  • the semipermeable layer comprises a water insoluble polymer, which is present in an amount of about 80% to about 99.9% by weight, based on the weight of the semipermeable layer. In another embodiment, the water insoluble polymer is about 85% to about 95% by weight, based on the weight of the semipermeable layer.
  • the semipermeable layer comprises a water insoluble polymer which is cellulose acetate, comprising about 32% - 40% acetyl content.
  • the semipermeable layer may further include a pore-forming agent or “pore former”.
  • Pore forming agents include biocompatible materials that when contacted with body fluids dissolve, disperse or degrade to create pores or channels in the semipermeable layer material.
  • water soluble organic and non-organic materials such as sugars (e.g., sucrose, dextrose), water soluble salts (e.g., sodium chloride, sodium phosphate, potassium chloride, and sodium carbonate), water soluble solvents such as N-methyl-2-pyrrolidone and polyethylene glycol and water soluble polymers (e.g., carboxymethylcellulose, hydroxypropylcellulose, and the like) can conveniently be used as pore formers.
  • the semipermeable layer comprises, in addition to the water soluble polymer or water insoluble polymer, a pore-forming agent, which is selected from water soluble sugars, water soluble salts, water soluble solvents and water soluble polymers or any mixture thereof.
  • the pore-forming agent is a water soluble solvent, which is polyethylene glycol.
  • the pore-forming agent comprises about 0.1% to - 12 - 4879-5033-3801.1 about 20% by weight of the semipermeable layer.
  • the pore-forming agent comprises about 8% to about 15% by weight of the semipermeable layer.
  • the weight ratio of the semipermeable layer and the tablet core is 1:8-1:10.
  • the semipermeable layer comprises cellulose acetate and polyethylene glycol.
  • the present dosage forms include a port(s), independently of or in addition to the pore- forming agent.
  • the port is present within the semipermeable layer and extends from external to the semipermeable layer into the tablet core providing an exit means for the drug formulation from the active layer within the tablet core into the environment external to the dosage form.
  • the exit port(s) are formed by any means known in the art including mechanical drilling, laser drilling, eroding an erodible element, extracting, dissolving, bursting, or by leaching.
  • the port(s) may be formed by post-coating mechanical or thermal means or with a beam of light (e.g., a laser), a beam of particles, or other high-energy source, or may be formed in situ by rupture of a small portion of the coating. Such rupture may be controlled by intentionally incorporating a relatively small weak portion into the coating. Exit port(s) may also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the coating over an indentation in the core. Exit port(s) may be formed by coating the core such that one or more small regions remains uncoated. In addition, the exit port(s) can be a large number of holes or pores that may be formed during coating.
  • a beam of light e.g., a laser
  • a beam of particles e.g., a beam of particles, or other high-energy source
  • Exit port(s) may also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the coating
  • the exit port(s) can be a pore formed by leaching sorbitol, lactose or the like from a wall or layer as disclosed in U.S. Pat. No. 4,200,098.
  • This patent discloses pores of controlled-size porosity formed by dissolving, extracting, or leaching a material from a wall, such as sorbitol from cellulose acetate.
  • a preferred form of laser drilling is the use of a pulsed laser that incrementally removes material from the semipermeable layer to the desired depth to form the exit port.
  • a port or a plurality of ports, can be formed, for example, by leaching a member selected from the group consisting of sorbitol, lactose, fructose, glucose, mannose, galactose, talose, sodium chloride, potassium chloride, sodium citrate and mannitol to provide a uniform- release dimensioned exit port.
  • the exit means can have any shape, such as round, triangular, square, elliptical and the like for the uniform metered dose release of a drug formulation from the dosage form.
  • the osmotic dosage form can be constructed with one or more exits ports in spaced-apart relation or one or more surfaces of the osmotic dosage form.
  • the port has a diameter of from about 0.1 mm to about 1 mm. In - 13 - 4879-5033-3801.1 another embodiment, the port has a diameter of from about 0.4 mm to about 0.8 mm.
  • the dosage form further includes one or more seal coatings for example, in order to ensure integrity of one or more subparts of the present dosage forms.
  • the tablet core comprises a seal coating immediately external to the tablet core. For example, a tablet core seal coating may be applied to the outer surface of the compressed, layered tablet core prior to application of the semipermeable layer.
  • the tablet core comprises a semipermeable layer immediately external to the tablet core and a seal coating immediately external to the semipermeable layer.
  • a semipermeable layer seal coating may be applied to the outer surface of the dosage form following application of the semipermeable membrane to the tablet core.
  • Seal coating materials can include binders, numerous types of which are disclosed supra.
  • the port will extend from external to the seal coating through all layers and into the core.
  • a tablet core seal coat is applied to the outer surface of the tablet core.
  • a semipermeable layer seal coat applied to the outer surface of the semipermeable layer.
  • the tablet core seal coat and or the semipermeable layer seal coat comprises a binder which can be selected from: hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural and synthetic gums and any mixture thereof.
  • the tablet core seal coat binder and or the semipermeable layer seal coat binder is hypromellose.
  • the total amount of the binder within the dosage form is from about 0 to about 20% by weight, based on the total weight of the dosage form. In another embodiment, the total amount of the binder within the dosage form is form about 5% to about 20% by weight, based on the total weight of the dosage form.
  • the total amount of the binder within the dosage form is about 8% to about 10% by weight, based on the total weight of the dosage form or about 10% to about 20% by weight, based on the total weight of the dosage form.
  • the absolute amount of deutetrabenazine in the active layer of the present osmotic dosage forms will depend on the dosage strength of the particular embodiment.
  • the dosage forms may further include an immediate release amount of deutetrabenazine microparticles that is external to the active layer, preferably external to the - 14 - 4879-5033-3801.1 semipermeable membrane layer.
  • the immediate release coating comprises about 0.3% to about 2% by weight deutetrabenazine microparticles, based on the total weight of the dosage form In another embodiment, wherein the dosage form comprises a total of 24 mg of deutetrabenazine microparticles, the immediate release coating comprises about 1% to about 2% by weight deutetrabenazine microparticles, based on the total weight of the dosage form. In another embodiment, wherein the dosage form comprises a total of 12 mg of deutetrabenazine microparticles, the immediate release coating comprises about 0.5% to about 1% by weight deutetrabenazine microparticles, based on the total weight of the dosage form.
  • the immediate release coating comprises about 0.1% to about 0.5% by weight deutetrabenazine microparticles, based on the total weight of the dosage form. In one embodiment, at least 70% of the total amount of deutetrabenazine microparticles in the dosage form is present within the active layer. In another embodiment, 70% to 100% of the total amount of deutetrabenazine microparticles in the dosage form, is present within the active layer. In yet another embodiment, about 70% to 80% of the total amount of deutetrabenazine microparticles in the present dosage forms is present within the active layer.
  • deutetrabenazine is present solely in the active layer.
  • the osmotic dosage forms comprise an immediate release coating, comprising up to about 30% of the total amount of deutetrabenazine microparticles in the dosage form. In one embodiment, about 8% to 30% of the total amount of deutetrabenazine microparticles in the dosage form is present within an immediate release coating.
  • the total amount of deutetrabenazine microparticles in the dosage form is about 24 mg. In yet another embodiment, the total amount of deutetrabenazine microparticles in the dosage form is about 36 mg. Yet in another embodiment, the total amount of deutetrabenazine microparticles in the dosage form is about 48 mg.
  • the total amount of deutetrabenazine or the total daily dose of deutetrabenazine, used herein interchangeably is administered to a subject as a one dose a day (QD). Depending on the total daily dose, one or more than one (multiple) dosage forms may be administered to a subject at one dose. Preferably, a single dosage form is administered at one dose.
  • the total daily dose of deutetrabenazine is from 12 mg to 48 mg. In one embodiment, the total daily dose of deutetrabenazine is 12 mg. In one embodiment, the total daily dose of deutetrabenazine is 18 mg. In one embodiment, the total daily dose of deutetrabenazine is 24 mg. In one embodiment, the total daily dose of deutetrabenazine is 30 mg. In one embodiment, the total daily dose of deutetrabenazine is 36 mg. In one embodiment, the total daily dose of deutetrabenazine is 42 mg. In one embodiment, the total daily dose of deutetrabenazine is 48 mg.
  • Patients being treated with deutetrabenazine twice daily may be switched to deutetrabenazine once daily (qd), at the same total daily dose, the day following a last dose of deutetrabenazine bid.
  • Patients being treated with deutetrabenazine once daily (qd) may be switched to deutetrabenazine twice daily (bid), at the same total daily dose, the day following a last dose of deutetrabenazine qd.
  • Patients being treated with tetrabenazine may be switched to deutetrabenazine once daily osmotic dosage form disclosed herein (qd), the day following a last dose of tetrabenazine.
  • the dosage form comprises a total of 12 mg of deutetrabenazine microparticles
  • the total amount of deutetrabenazine microparticles present within the dosage form is about 1% to about 5% by weight, based on the total weight of the dosage form.
  • the dosage form comprises a total of 24 mg of deutetrabenazine microparticles
  • the total amount of deutetrabenazine microparticles present within the dosage form is about 5% to about 10% by weight, based on the total weight of the dosage form.
  • the immediate release coating may further include one or more pharmaceutically acceptable excipients such as an antioxidant, a binder, and a surfactant or any combination thereof.
  • Antioxidants, binders, and surfactants may be selected from a wide variety of choices known among those skilled in the art. Exemplary antioxidants and binders are disclosed supra in connection with the other components of the present dosage forms.
  • Surfactants may include, but are not limited to, esters of polyhydric alcohols such as glycerol monolaurate, ethoxylated castor oil, polysorbates, esters or ethers of saturated alcohols such as myristyl lactate (e.g.
  • the immediate release coating further comprises an antioxidant which can be selected from: tertiary butyl-4-methoxyphenol (mixture of 2 and 3-isomers), 2,6- ditertiary butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-digydro-2,2,4-trimethylquinoline (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene and any mixture thereof.
  • an antioxidant which can be selected from: tertiary butyl-4-methoxyphenol (mixture of 2 and 3-isomers), 2,6- ditertiary butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-digydro-2,2,4-trimethylquinoline (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene and any mixture thereof.
  • the immediate release coating comprises a mixture of butylated hydroxyanisole, and butylated hydroxytoluene.
  • the immediate release coating comprises deutetrabenazine microparticles, butylated hydroxyanisole, butylated hydroxytoluene, hypromellose and polysorbate 80.
  • an osmotic dosage form for once daily administration of deutetrabenazine to a subject in need thereof comprising: a. a tablet core comprising: i.
  • an active layer comprising an amount of deutetrabenazine microparticles and an active layer control release agent comprising a polymer having a viscosity of about 55-90 mPa s, an active layer antioxidant, an active layer binder; ii. a push layer comprising an osmotic agent and a push layer control release agent comprising a polymer having a viscosity of about 5500-7500 mPa s and a push layer binder; - 17 - 4879-5033-3801.1 b. a tablet core seal coat comprising a binder on the outer surface of the tablet core; c.
  • a semipermeable layer comprising a water insoluble polymer and a pore-forming agent surrounding the tablet core seal coat; d. a semipermeable layer seal coat comprising a binder on the outer surface of the semipermeable layer; e. an immediate release coating comprising a second amount of deutetrabenazine microparticles and an immediate release coating antioxidant on the outer surface of the semipermeable layer seal coat; and f. a port in the semipermeable layer seal coat reaching the tablet core.
  • an osmotic dosage form according to any one of the embodiments of the invention, wherein not more than 15% of the drug formulation is released within 2 hours and/or wherein not more than 60% of the drug formulation is released within 8 hours, when the dosage form is tested in 500 mL acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus.
  • a method of treating a hyperkinetic movement disorder in a subject comprising orally administering, on a once daily basis to the subject, an osmotic dosage form according to any one of the embodiments of the invention.
  • the movement disorder is selected from chorea, akathisia, dyskinesia, tremor, or tic. In some embodiments, the movement disorder is selected from chorea associated with Huntington’s disease, tardive dyskinesia, a tic associated with Tourette syndrome, Parkinson's disease levodopa-induced dyskinesia or dyskinesia in cerebral palsy.
  • the osmotic dosage form according to any one of the embodiments disclosed herein is administered with food. In certain embodiments, the osmotic dosage form according to any one of the embodiments disclosed herein, is administered under fasting conditions.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein single dose administration of the osmotic dosage form, which comprises a total amount of 6mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean AUC0-inf of about 91,250 to 142,750 h*pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein single dose administration of the osmotic dosage form, which comprises a total amount of 6mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean Cmax of less than about 4,600 pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein single dose administration of the osmotic dosage form, which comprises a total amount of 12mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean AUC0-inf of about 182,500 to 285,500 h*pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein single dose administration of the osmotic dosage form, which comprises a total amount of 12mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean Cmax of less than about 9,200 pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein single dose administration of the osmotic dosage form, which comprises a total amount of 24mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean AUC0-inf of about 365,000 to 571,000 h*pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein single dose administration of the osmotic dosage form, which comprises a total amount of 24mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean C max of less than about 18,400 - 19 - 4879-5033-3801.1 pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein single dose administration of the osmotic dosage form, which comprises a total amount of 36mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean AUC 0-inf of about 547,500 to 856,500 h*pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein single dose administration of the osmotic dosage form, which comprises a total amount of 36mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean C max of less than about 27,600 pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein single dose administration of the osmotic dosage form, which comprises a total amount of 48mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean AUC 0-inf of about 730,000 to 1,142,000 h*pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein single dose administration of the osmotic dosage form, which comprises a total amount of 48mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean C max of less than about 36,800 pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein the osmotic dosage form which comprises a total amount of 6mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine at steady state that includes a mean C max of less than about 10,000 pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein the osmotic dosage form which comprises a total amount of 12mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine at steady state that includes a mean AUC0-24 of about 205,000 to 400,000 h*pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein the osmotic dosage form which comprises a total amount of 12mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine at steady state that includes a mean Cmax of less than about 20,000 pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein the osmotic dosage form which comprises a total amount of 24mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine at steady state that includes a mean AUC 0-24 of about 410,000 to 800,000 h*pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein the osmotic dosage form which comprises a total amount of 24mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine at steady state that includes a mean C max of less than about 40,000 pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention - 21 - 4879-5033-3801.1 wherein the osmotic dosage form which comprises a total amount of 36mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine at steady state that includes a mean AUC0-24 of about 615,000 to 1,200,000 h*pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein the osmotic dosage form which comprises a total amount of 36mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine at steady state that includes a mean Cmax of less than about 60,000 pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein the osmotic dosage form which comprises a total amount of 48mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine at steady state that includes a mean AUC 0-24 of about 820,000 to 1,600,000 h*pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering to the subject a once daily osmotic dosage form according to any one of the embodiments of the invention wherein the osmotic dosage form which comprises a total amount of 48mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine at steady state that includes a mean C max of less than about 80,000 pg/mL.
  • the invention provides a method of treating a hyperkinetic movement disorder comprising: administering an osmotic dosage form according to any one of the embodiments of the invention, wherein not more than 15% of the drug formulation is released - 22 - 4879-5033-3801.1 after 2 hours and wherein not more than 60% of the drug formulation is released within 8 hours when tested in 500 mL acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus.
  • Deutetrabenazine twice daily may refer to, for example, AUSTEDO® bid tablets or any equivalent thereof.
  • the term "last dose" refers to discontinuation of current treatment, for example, discontinuing treatment with deutetrabenazine twice daily.
  • last dose of the deutetrabenazine twice daily may refer to the second daily dose of deutetrabenazine twice daily, administered to the human subject, for example, in the afternoon or evening.
  • the human subject is being treated with deutetrabenazine twice daily tablets at a total daily dose of 12 mg, and is transitioned to a total daily dose of 12 mg deutetrabenazine once daily.
  • the human subject is being treated with deutetrabenazine twice daily tablets at a total daily dose of 18 mg, and is transitioned to a total daily dose of 18 mg deutetrabenazine once daily.
  • the human subject is being treated with deutetrabenazine twice daily tablets at a total daily dose of 24 mg, and is transitioned to a total daily dose of 24 mg deutetrabenazine once daily.
  • the human subject is being treated deutetrabenazine twice daily tablets at a total daily dose of 30 mg, and is transitioned to a total daily dose of 30 mg deutetrabenazine once daily.
  • the human subject is being treated with deutetrabenazine twice daily tablets at a total daily dose of 36 mg, and is transitioned to a total daily dose of 36 mg deutetrabenazine once daily.
  • the human subject is being treated with deutetrabenazine twice daily tablets at a total daily dose of 42 mg, and is transitioned to a total daily dose of 42 mg - 23 - 4879-5033-3801.1 deutetrabenazine once daily.
  • the human subject is being treated with deutetrabenazine twice daily tablets at a total daily dose of 48 mg, and is transitioned to a total daily dose of 48 mg deutetrabenazine once daily.
  • the deutetrabenazine once daily is an extended-release osmotic dosage form, preferably, a deutetrabenazine osmotic dosage form according to any one of the embodiments of the invention.
  • the deutetrabenazine once daily osmotic dosage form comprises: a.
  • a tablet core comprising an active layer and a push layer, wherein the active layer comprises an amount of deutetrabenazine microparticles and an active layer control release agent, and wherein the push layer comprises an osmotic agent and a push layer control release agent, and an optional tablet seal coat on the outer surface of the tablet core, wherein about 70%-80% of the total amount of deutetrabenazine microparticles present in the dosage form is present within the active layer and wherein about 20%-30% of the total amount of deutetrabenazine microparticles present in the dosage form, is present within the immediate release coating and wherein the deutetrabenazine microparticles have a particle size with D 90 of 15 ⁇ m, a D5010 ⁇ m, and/or a D10 of 3 ⁇ m; b.
  • the deutetrabenazine once daily extended-release dosage form is administered with food or without food.
  • the abnormal involuntary movement being controlled during the transition from the deutetrabenazine twice daily to the deutetrabenazine once daily dose is chorea, akathisia, dyskinesia, tremor, tic, chorea associated with Huntington’s disease, tardive dyskinesia, a tic associated with Tourette syndrome, Parkinson's disease levodopa-induced dyskinesia or dyskinesia in cerebral palsy.
  • the abnormal involuntary movement being controlled is chorea associated with Huntington’s disease.
  • the abnormal involuntary movement being controlled is tardive dyskinesia.
  • a method of transitioning a human subject being treated with a total - 24 - 4879-5033-3801.1 daily dose of deutetrabenazine once daily to deutetrabenazine twice daily (bid) tablets at the same total daily dose, for control of abnormal involuntary movement comprising: a) administering a last dose of the deutetrabenazine once daily; and b) the next day, administering to the human subject the total daily dose of deutetrabenazine twice daily.
  • a human subject is transitioned to the same total daily dose, for example, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg or 48 mg.
  • the human subject is being treated with a dose of a deutetrabenazine once daily at a total daily dose of 12 mg, and is transitioned to a total daily dose of 12 mg of deutetrabenazine twice daily tablets.
  • the human subject is being treated with a dose of a deutetrabenazine once daily at a total daily dose of 18 mg, and is transitioned to a total daily dose of 18 mg of deutetrabenazine twice daily tablets.
  • the human subject is being treated with a dose of a deutetrabenazine once daily at a total daily dose of 24 mg, and is transitioned to a total daily dose of 24 mg of deutetrabenazine twice daily tablets.
  • the human subject is being treated with a dose of a deutetrabenazine once daily at a total daily dose of 30 mg, and is transitioned to a total daily dose of 30 mg of deutetrabenazine twice daily tablets.
  • the human subject is being treated with a dose of a deutetrabenazine once daily at a total daily dose of 36 mg, and is transitioned to a total daily dose of 36 mg of deutetrabenazine twice daily tablets.
  • the human subject is being treated with a dose of a deutetrabenazine once daily at a total daily dose of 42 mg, and is transitioned to a total daily dose of 42 mg of deutetrabenazine twice daily tablets.
  • the human subject is being treated with a dose of a deutetrabenazine once daily at a total daily dose of 48 mg, and is transitioned to a total daily dose of 48 mg of deutetrabenazine twice daily tablets.
  • the deutetrabenazine once daily is an extended-release dosage form, preferably, an osmotic dosage form according to any one of the embodiments of the invention.
  • the deutetrabenazine once daily extended-release dosage form is administered with food or without food.
  • a human subject is treated with a deutetrabenazine once daily osmotic dosage form and is transitioned to a deutetrabenazine twice daily dosage form.
  • the abnormal involuntary movement being controlled during the transition from the once daily deutetrabenazine dosage form to the twice daily deutetrabenazine tablet is chorea, akathisia, dyskinesia, tremor, tic, chorea associated with Huntington’s disease, tardive dyskinesia, a tic associated with Tourette syndrome, Parkinson's disease levodopa- induced dyskinesia or dyskinesia in cerebral palsy.
  • the abnormal involuntary movement being controlled is chorea associated with Huntington’s disease.
  • the abnormal involuntary movement being controlled is tardive dyskinesia.
  • a method of transitioning a human subject being treating with a daily amount of tetrabenazine to a once daily amount of deutetrabenazine, for control of abnormal involuntary movement from comprising: a) administering the last dose of tetrabenazine; and b) the next day, administering to the human subject a once daily deutetrabenazine osmotic dosage form wherein: the daily amount of tetrabenazine is 12.5 mg and the once daily amount of deutetrabenazine is 6 mg; or wherein the daily amount of tetrabenazine is 25 mg and the once daily amount of deutetrabenazine is 12 mg; or wherein the daily amount of tetrabenazine is 37.5 mg and the once daily amount of deutetrabenazine is 18 mg; or wherein the daily amount of tetrabenazine is 50 mg and the once daily amount of deutetraben
  • the daily amount of tetrabenazine is administered in divided doses, for example, in two, three, or more divided doses.
  • the abnormal involuntary movement being controlled during the transition from tetrabenazine to once-daily dose of deutetrabenazine is chorea, akathisia, dyskinesia, tremor, tic, chorea associated with Huntington’s disease, tardive dyskinesia, a tic - 26 - 4879-5033-3801.1 associated with Tourette syndrome, Parkinson's disease levodopa-induced dyskinesia or dyskinesia in cerebral palsy.
  • the abnormal involuntary movement being controlled is chorea associated with Huntington’s disease. In one embodiment, the abnormal involuntary movement being controlled is tardive dyskinesia. In one embodiment, the once daily deutetrabenazine extended-release dosage form is administered with food or without food.
  • the present disclosure provides oral dosage forms and methods, according to any of the following aspects: Aspects 1.
  • An osmotic dosage form for once daily administration to a subject in need thereof comprising: a. a tablet core comprising an active layer comprising an amount of deutetrabenazine microparticles and a push layer; b. a semipermeable layer surrounding the tablet core; and c. a port extending from the periphery of the dosage form into the tablet core.
  • the dosage form of Aspect 5 wherein the polyethylene oxide within the active layer has an average molecular weight of 100,000 daltons to 500,000 daltons. 7.
  • the active layer further comprises at least one active layer antioxidant.
  • the active layer antioxidant comprises at least one of tertiary butyl-4-methoxyphenol (mixture of 2 and 3-isomers), 2,6-ditertiary butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-digydro-2,2,4-trimethylquinoline (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene or any mixture thereof. 13.
  • the dosage form of Aspect 16 wherein the active layer binder comprises hypromellose. 18.
  • the active layer further comprises one or more pharmaceutically acceptable excipients.
  • the active layer comprises deutetrabenazine microparticles, and an active layer control release agent which is a polymer having a viscosity of about 55-90 mPa s and an antioxidant. 21.
  • the dosage form of Aspect 20 wherein the active layer comprises deutetrabenazine - 28 - 4879-5033-3801.1 microparticles, butylated hydroxyanisole, butylated hydroxytoluene, polyethylene oxide, hypromellose and magnesium stearate. 22.
  • the osmotic agent comprises an inorganic salt that is magnesium sulfate, magnesium chloride, potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, or any mixture thereof. 26.
  • 28. The dosage form of Aspect 27, wherein the osmotic agent is present in the dosage form in an amount of about 5% to about 20% by weight, based on the total weight of the dosage form.
  • 29. The dosage form of Aspect 27 or Aspect 28, wherein the osmotic agent is present in the dosage form in an amount of about 8% to about 10% by weight, based on the total weight of the dosage form.
  • the dosage form of any one of Aspects 22-31, wherein the push layer control release agent comprises a polymer having a viscosity of about 5500-7500 mPa s. 33.
  • the dosage form of Aspect 32 wherein the polymer having a viscosity of about 5500- 7500 mPa s is selected from a polyoxyethylene polymer, an ionic hydrogel, a hydrophilic polymer, a hydrophobic polymer or any mixture thereof. - 29 - 4879-5033-3801.1 34.
  • the dosage form of Aspect 33 wherein the push layer control release agent is a polyethylene oxide.
  • the dosage form of Aspect 34, wherein the polyethylene oxide within the push layer has an average molecular weight of 1,000,000 daltons to 7,000,000 daltons.
  • the dosage form of Aspect 35 wherein the polyethylene oxide within the push layer has an average molecular weight of 5,000,000 daltons. 37.
  • 39. The dosage form of any one of Aspects 22-38, wherein the weight ratio of the osmotic agent and the push layer control release agent in the push layer is 1:2 – 1:3.5 or 1:2 – 1:2.5.
  • 40. The dosage form of any one of Aspects 22-39, wherein the push layer further comprises a push layer binder. 41.
  • the dosage form of Aspect 40 wherein the push layer binder comprises hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar, natural or synthetic gums, or any mixture thereof. 42. The dosage form of Aspect 41, wherein the push layer binder comprises hypromellose. 43. The dosage form of any one of Aspects 40-42, wherein the push layer binder is present in the push layer in an amount of about 2% to about 10% by weight, based on the total weight of the push layer. 44.
  • hypromellose hydroxypropyl methylcellulose
  • the dosage form of Aspect 43 wherein the push layer binder is present in the push layer in an amount of about 4% to about 6% by weight, based on the total weight of the push layer or about 3% to about 6% by weight, based on the total weight of the push layer.
  • the push layer comprises sodium chloride and a polymer having a viscosity of about 5500-7500 mPa s. 47.
  • the semipermeable layer comprises a water soluble polymer, a water insoluble polymer or any mixture thereof.
  • the dosage form of Aspect 49 wherein the water insoluble polymer is cellulose acetate, comprising 32% - 39.8% acetyl content.
  • 51. The dosage form of any preceding Aspect, wherein the semipermeable layer comprises cellulose acetate and polyethylene glycol.
  • 52. The dosage form of any one of Aspects 48-51, wherein the water insoluble polymer is present in the semipermeable layer in an amount of about 80% to about 99.9% by weight, based on the weight of the semipermeable layer or about 85% to about 95% by weight, based on the weight of the semipermeable layer.
  • 53. The dosage form of any preceding Aspect, wherein the semipermeable layer comprises a pore-forming agent. 54.
  • the dosage form of Aspect 53 wherein the pore-forming comprises a water soluble sugar, a water soluble salt, a water soluble solvent, a water soluble polymer or any mixture thereof.
  • the dosage form of Aspect 54 wherein the pore-forming agent is a water soluble solvent which is polyethylene glycol.
  • 56 The dosage form of any one of Aspects 53-55, wherein the pore-forming agent is present in the semipermeable layer in an amount of about 0.1% to about 20% by weight of the semipermeable layer.
  • the dosage form of Aspect m 56 wherein the pore-forming agent is present in the semipermeable layer in an amount of about 8% to about 15% by weight of the semipermeable layer. 58.
  • the dosage form of any preceding Aspect wherein the weight ratio of the semipermeable layer and the tablet core is 1:8-1:10. - 31 - 4879-5033-3801.1 59.
  • the dosage form of any preceding Aspect wherein the port has a diameter of from about 0.1 mm to about 1 mm. 60.
  • the dosage form of any preceding Aspect further comprising a tablet core seal coat on the outer surface of the tablet core.
  • the dosage form of any preceding Aspect further comprising a semipermeable layer seal coat on the outer surface of the semipermeable layer. 63.
  • the dosage form of Aspect 64, wherein the tablet core seal coat binder and or the semipermeable layer seal coat binder is hypromellose.
  • the dosage form of any preceding Aspect further comprising an immediate release coating external to the semipermeable membrane, the immediate release coating comprising a second amount of deutetrabenazine microparticles.
  • the immediate release coating comprises about 0.1% to about 25% by weight deutetrabenazine microparticles, based on the total weight of the dosage form or about 0.2% to about 5% by weight deutetrabenazine microparticles, based on the total weight of the dosage form or about 0.3% to about 2% by weight deutetrabenazine microparticles, based on the total - 32 - 4879-5033-3801.1 weight of the dosage form.
  • the dosage form of Aspect 69 wherein the dosage form comprises a total of 24 mg of deutetrabenazine microparticles and the immediate release coating comprises about 1% to about 2% by weight deutetrabenazine microparticles, based on the total weight of the dosage form or wherein the dosage form comprises a total of 12 mg of deutetrabenazine microparticles and the immediate release coating comprises about 0.5% to about 1% by weight deutetrabenazine microparticles, based on the total weight of the dosage form or wherein the dosage form comprises a total of 6 mg of deutetrabenazine microparticles and the immediate release coating comprises about 0.1% to about 0.5% by weight deutetrabenazine microparticles, based on the total weight of the dosage form.
  • any preceding Aspect wherein about 70% to 99% of the total amount of deutetrabenazine microparticles in the dosage form, is within the active layer.
  • 72. The dosage form of any preceding Aspect, wherein about 5% to 30% of the total amount of deutetrabenazine microparticles in the dosage form, is within immediate release coating.
  • 73. The dosage form of any preceding Aspect, wherein about 70%-80% of the total amount of deutetrabenazine microparticles in the dosage form, is within the active layer and wherein about 20%-30% of the total amount of deutetrabenazine microparticles in the dosage form, is within immediate release coating. 74.
  • the immediate release coating antioxidant comprises: tertiary butyl-4-methoxyphenol (mixture of 2 and 3-isomers), 2,6- ditertiary butyl-p-cresol, propyl gallate, 6-ethoxy-1,2-digydro-2,2,4- trimethylquinoline (ethoxyquin), nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylated hydroxytoluene and any mixture thereof.
  • NDGA nordihydroguaiaretic acid
  • the immediate release coating comprises: deutetrabenazine microparticles, butylated hydroxyanisole, butylated - 33 - 4879-5033-3801.1 hydroxytoluene, hypromellose and polysorbate 80. 79.
  • the dosage form of any preceding Aspect wherein the total amount of deutetrabenazine microparticles in the dosage form is from about 6 mg to about 48 mg. 80.
  • the dosage form of any preceding Aspect wherein the total amount of deutetrabenazine microparticles in the dosage form is about 6 mg.
  • the dosage form of any preceding Aspect wherein the total amount of deutetrabenazine microparticles in the dosage form is about 12 mg.
  • the dosage form of any preceding Aspect, wherein the total amount of deutetrabenazine microparticles in the dosage form is about 24 mg. 83.
  • the dosage form of any preceding Aspect, wherein the total amount of deutetrabenazine microparticles in the dosage form is about 48 mg.
  • the dosage form of any preceding Aspect, wherein the total amount of deutetrabenazine microparticles is about 0.5% to about 15% by weight, based on the total weight of the dosage form.
  • the dosage form of Aspect 84, wherein the total amount of deutetrabenazine microparticles is about 1% to about 10% by weight, based on the total weight of the dosage form. 86.
  • the dosage form of Aspect 85 comprising a total of 6 mg of deutetrabenazine microparticles, wherein the total amount of deutetrabenazine microparticles is about 0.5% to about 3% by weight, based on the total weight of the dosage form or a dosage form comprising a total of 12 mg of deutetrabenazine microparticles, wherein the total amount of deutetrabenazine microparticles is about 1% to about 5% by weight, based on the total weight of the dosage form or a dosage form comprising a total of 24 mg of deutetrabenazine microparticles, wherein the total amount of deutetrabenazine microparticles is about 5% to about 10% by weight, based on the total weight of the dosage form.
  • a method of treating a hyperkinetic movement disorder in a subject in need thereof comprising orally administering, on a once daily basis to the subject, an osmotic dosage form according to any one of the preceding Aspects.
  • the method of Aspect 91, wherein the movement disorder is selected from chorea, akathisia, dyskinesia, tremor, and tic. 93.
  • any one of Aspects 91-94 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90, wherein single dose administration of the osmotic dosage form, which comprises a total amount of 6mg of deutetrabenazine microparticles provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean C max of less than about 4,600 pg/mL. 96.
  • any one of Aspects 91-93 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90, wherein single dose administration of the osmotic dosage form, which comprises a total amount of 12mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean AUC 0-inf of about 182,500 to 285,500 h*pg/mL. 97.
  • any one of Aspects 91-93 or 96 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90, wherein single dose administration of the osmotic dosage form, which comprises a total amount of 12mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean Cmax of less than about 9,200 pg/mL. - 35 - 4879-5033-3801.1 98.
  • any one of Aspects 91-93 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90, wherein single dose administration of the osmotic dosage form, which comprises a total amount of 24mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean AUC0-inf of about 365,000 to 571,000 h*pg/mL. 99.
  • any one of Aspects 91-93 or Aspect 98 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90, wherein single dose administration of the osmotic dosage form, which comprises a total amount of 24mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean Cmax of less than about 18,400 pg/mL. 100.
  • any one of Aspects 91-93 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90, wherein single dose administration of the osmotic dosage form, which comprises a total amount of 36mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean AUC 0-inf of about 547,500 to 856,500 h*pg/mL. 101.
  • any one of Aspects 91-93 or Aspect 102 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90, wherein single dose administration of the osmotic dosage form, which comprises a total amount of 48mg of deutetrabenazine microparticles, provides an in - 36 - 4879-5033-3801.1 vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine that includes a geometric mean Cmax of less than about 36,800 pg/mL. 104.
  • any one of Aspects 91-93 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90 wherein the osmotic dosage form which comprises a total amount of 6mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ - dihydrodeutetrabenazine at steady state that includes a mean AUC 0-24 of about 102,500 to 200,000 h*pg/mL. 105.
  • any one of Aspects 91-93 or Aspect 104 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90 wherein the osmotic dosage form which comprises a total amount of 6mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine at steady state that includes a mean Cmax of less than about 10,000 pg/mL. 106.
  • any one of Aspects 91-93 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90 wherein the osmotic dosage form which comprises a total amount of 12mg of deutetrabenazine microparticles provides an in vivo plasma profile for total ⁇ - and ⁇ - dihydrodeutetrabenazine at steady state that includes a mean AUC0-24 of about 205,000 to 400,000 h*pg/mL. 107.
  • any one of Aspects 91-93 or Aspect 106 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90 wherein the osmotic dosage form which comprises a total amount of 12mg of deutetrabenazine microparticles provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine at steady state that includes a mean C max of less than about 20,000 pg/mL. 108.
  • any one of Aspects 91-93 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90 wherein the osmotic dosage form which comprises a total amount of 24mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ - dihydrodeutetrabenazine at steady state that includes a mean AUC 0-24 of about 410,000 to 800,000 h*pg/mL. 109.
  • any one of Aspects 91-93 or Aspect 108 comprising orally administering to the subject a once daily osmotic dosage form according to any one of - 37 - 4879-5033-3801.1 Aspects 1-90 wherein the osmotic dosage form which comprises a total amount of 24mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine at steady state that includes a mean Cmax of less than about 40,000 pg/mL. 110.
  • any one of Aspects 91-93 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90 wherein the osmotic dosage form which comprises a total amount of 36mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ - dihydrodeutetrabenazine at steady state that includes a mean AUC0-24 of about 615,000 to 1,200,000 h*pg/mL. 111.
  • any one of Aspects 91-93 or Aspect 110 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90 wherein the osmotic dosage form which comprises a total amount of 36mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine at steady state that includes a mean C max of less than about 60,000 pg/mL. 112.
  • any one of Aspects 91-93 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90 wherein the osmotic dosage form which comprises a total amount of 48mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ - dihydrodeutetrabenazine at steady state that includes a mean AUC 0-24 of about 820,000 to 1,600,000 h*pg/mL. 113.
  • any one of Aspects 91-93 or Aspect 112 comprising orally administering to the subject a once daily osmotic dosage form according to any one of Aspects 1-90 wherein the osmotic dosage form which comprises a total amount of 48mg of deutetrabenazine microparticles, provides an in vivo plasma profile for total ⁇ - and ⁇ -dihydrodeutetrabenazine at steady state that includes a mean Cmax of less than about 80,000 pg/mL. 114.
  • any one of Aspects 91-113 comprising administering an osmotic dosage form according to any one of Aspects 1-90, wherein not more than 15% of the drug formulation is released after 2 hours when tested in 500 mL acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus.
  • the method of any one of Aspects 91-113 comprising administering an osmotic dosage form according to any one of Aspects 1-90, wherein not more than 60% of the - 38 - 4879-5033-3801.1 drug formulation is released after 8 hours when tested in 500 mL acid phosphate buffer at pH 3.0 using a USP II dissolution apparatus.
  • FIG. 2a and FIG. 2b provide flowcharts of the general manufacturing processes for osmotic dosage forms according to the present disclosure.
  • Tables 1-13, below, provide non- - 39 - 4879-5033-3801.1 limiting examples of the materials and their relative amounts used to produce the dosage forms described herein.
  • the preparation method was as follows: A: Active layer materials processing: deutetrabenazine (micronized) and the active layer control release agent were passed through a #30 mesh screen and combined with a binder (previously passed through a #20 mesh screen). The mixture was introduced into a high shear granulator and dry mixed for about 5 minutes. While mixing, antioxidant (pre dissolved in alcohol) was added to the mixing powders to granulate the material. Additional mixing continued until the desired granulation end-point was achieved. The resulting granulation is wet screened to break up any oversized agglomerates. The material was fed into a diffusive mixer (V-Blender) where it was blended for about 15 minutes.
  • V-Blender diffusive mixer
  • Lubricant that had been passed through a #30 mesh screen was added to the blended material in the V- Blender. The contents were lubricated for about 5 minutes.
  • C Optional tablet core seal coat: A tablet core seal coat comprising a binder solution was applied on the tablet core.
  • D Semipermeable layer: Semipermeable layer comprising a solution of cellulose acetate and an optional pore-forming agent was applied to the tablet core, or sealed tablet core, using a pan coater.
  • E Optional Semipermeable layer seal coat: Semipermeable layer seal coat comprising a binder solution was applied on the tablet compromising the semipermeable wall.
  • F Creating an exit means: a pore was laser-drilled through the layers into the active layer. A final immediate release coating comprising deutetrabenazine is optionally applied, using similar materials and following the processing steps as detailed above for active layer.
  • the primary objective was to assess the comparative bioavailability (BA) of deutetrabenazine and deuterated ⁇ - and ⁇ -dihydrotetrabenazine (deuHTBZ) metabolites following a single administration of 24 mg, once daily (q.d.) osmotic formulation (Test) compared to a single 12 mg AUSTEDO® tablet administered twice, 12 hours apart (b.i.d), under fasted conditions.
  • Study Population and Number of Subjects The study included healthy male and female non-smoking subjects, aged 18 through 45 years. A total of 8 healthy subjects (4 per sequence) were enrolled in this study.
  • Treatments Treatment sequence A: Day 1 - administration of Test2A. Days 2-3 - at least 6 hours wash out of Test2A followed by administration of R. Treatment sequence B: Day 1 - administration of R Days 2-3 - at least 6 hours wash out of R, followed by administration of Test2A.
  • Comparisons of Cmax, AUC0-t, AUC0- ⁇ , and AUC0-24h between treatments was be carried out using a separate parametric analysis of variance (ANOVA) model with fixed effect terms for sequence, period, treatment group, and a random effect of subject within sequence.
  • the difference between the reference formulation (R) and the test formulation (Test2A) was evaluated by constructing 90% confidence intervals for the Test/Reference ratios, based on the least-square means from the ANOVA for the log- transformed Cmax, AUC0-t, AUC0- ⁇ and AUC0-24h.
  • the treatment difference and the associated 90% confidence interval estimated from the ANOVA on the log scale was back- transformed to obtain the estimated ratio of geometric means between treatment groups and the 90% confidence interval for this ratio.
  • FIG 3a and FIG 3b show the results of the R treatment compared to Test2A treatment (mean concentration of deutetrabenazine vs. time) direct scale and log scale, respectively.
  • Table 14 below, provides the specified pK parameters observed for deutetrabenazine with respect to Test2A compared to R.
  • FIG. 4a and FIG 4b show the metabolite data for the treatment using R compared to Test2A (mean concentration of total deuHTBZ vs. time), direct scale and log scale, respectively.
  • Table 15, below, provides the specified pK parameters observed for total deuHTBZ for the Test2A compared to R.
  • Table 15 As shown in Tables 14 and 15, a once-daily dose of Test2A provided acceptable deuHTBZ plasma concentrations observed for the reference.
  • the osmotic dosage forms disclosed herein are administered once daily and provide acceptable treatment effects to that of AUSTEDO® and also have no safety concerns. - 57 - 4879-5033-3801.1
  • the results of this study, having a crossover design, further show that a patient can be safely and effectively transitioned from a twice daily (two divided doses) administration of deutetrabenazine tablets, to a once daily osmotic dosage form.
  • Example 3 Multiple Dose Bioavailability Assessment Osmotic dosage form containing 24mg of deutetrabenazine were produced as disclosed in Example 1 and studied in an open label, randomized, multiple-dose, 2-way crossover study in healthy volunteers. The primary objective was to assess the bioequivalence (BE) of administration of Test2A, once daily (qd) compared to bid administration of R, under fasted or fed conditions.
  • BE bioequivalence
  • Treatment included 7 days repeated dosing of Test2A once daily versus 7 days repeated dosing of R, bid. Qualified models were used to predict the steady state, AUCt, Cmax, tmax, Cmin, Cav for deutetrabenazine and deuHTBZ concentrations.
  • Table 16, below provides simulation results for steady state pK parameters for deutetrabenazine with respect to Test2A compared to R as well as pK parameters for total deuHTBZ for the Test2A compared to R.
  • Example 4 Food effect study Osmotic dosage forms containing 24mg deutetrabenazine were produced as disclosed in Example 1 and studied in an open label, randomized, 3-period, 3-treatment, 6-sequence, crossover study, to assess the comparative bioavailability of deutetrabenazine and deuHTBZ in the fed compared to the fasted state, following a single administration of 24 mg, once daily (qd) osmotic formulation.
  • a standardized high-calorie, high-fat breakfast (containing 800 to 1000 kilocalories [kcal] with 50% fat) was served 30 minutes before the first dose to subjects receiving R BID fed or Test2A tablet fed.
  • a standardized dinner was served 30 minutes before the second dose for R BID fed or the corresponding time for Test2A tablet fed.
  • - 59 - 4879-5033-3801.1 Blood samples for pharmacokinetic analysis were collected prior to dosing and up to 96 hours after dosing in all treatment periods AUCt, Cmax, tmax, Cmin, Cav for deutetrabenazine and deuHTBZ were analyzed.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychology (AREA)
  • Psychiatry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des formes posologiques osmotiques contenant de la deutétrabénazine destinées à être utilisées dans le traitement, par ex., de troubles du mouvement hyperkinétique. Lorsqu'elles sont administrées par voie orale à un sujet une fois par jour, les formes posologiques assurent un profil pharmacocinétique favorable pour l'agent actif indiquant une efficacité de traitement sur une période de temps prolongée.
EP23738387.2A 2022-06-08 2023-06-08 Formes posologiques osmotiques comprenant de la deutétrabénazine et leurs procédés d'utilisation Pending EP4536181A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17/835,435 US12599598B2 (en) 2020-06-10 2022-06-08 Osmotic dosage forms comprising deutetrabenazine and methods of use thereof
PCT/US2023/068129 WO2023240186A1 (fr) 2022-06-08 2023-06-08 Formes posologiques osmotiques comprenant de la deutétrabénazine et leurs procédés d'utilisation

Publications (1)

Publication Number Publication Date
EP4536181A1 true EP4536181A1 (fr) 2025-04-16

Family

ID=87136419

Family Applications (1)

Application Number Title Priority Date Filing Date
EP23738387.2A Pending EP4536181A1 (fr) 2022-06-08 2023-06-08 Formes posologiques osmotiques comprenant de la deutétrabénazine et leurs procédés d'utilisation

Country Status (9)

Country Link
EP (1) EP4536181A1 (fr)
JP (1) JP2025519517A (fr)
KR (1) KR20250019144A (fr)
CN (1) CN119384270A (fr)
CA (1) CA3257711A1 (fr)
CL (1) CL2024003740A1 (fr)
IL (1) IL317235A (fr)
MX (1) MX2024015020A (fr)
WO (1) WO2023240186A1 (fr)

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3173876A (en) 1960-05-27 1965-03-16 John C Zobrist Cleaning methods and compositions
US3276586A (en) 1963-08-30 1966-10-04 Rosaen Filter Co Indicating means for fluid filters
US3546142A (en) 1967-01-19 1970-12-08 Amicon Corp Polyelectrolyte structures
US3541006A (en) 1968-07-03 1970-11-17 Amicon Corp Ultrafiltration process
US3541005A (en) 1969-02-05 1970-11-17 Amicon Corp Continuous ultrafiltration of macromolecular solutions
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
GB1478759A (en) 1974-11-18 1977-07-06 Alza Corp Process for forming outlet passageways in pills using a laser
US4200098A (en) 1978-10-23 1980-04-29 Alza Corporation Osmotic system with distribution zone for dispensing beneficial agent
US4327725A (en) 1980-11-25 1982-05-04 Alza Corporation Osmotic device with hydrogel driving member
US4612008A (en) 1983-05-11 1986-09-16 Alza Corporation Osmotic device with dual thermodynamic activity
US4783337A (en) 1983-05-11 1988-11-08 Alza Corporation Osmotic system comprising plurality of members for dispensing drug
US5082668A (en) 1983-05-11 1992-01-21 Alza Corporation Controlled-release system with constant pushing source
WO2010044981A2 (fr) 2008-09-18 2010-04-22 Auspex Pharmaceutical ,Inc. Inhibiteurs benzoquinoline du transporteur de monoamines vésiculaire 2
CA2771539A1 (fr) * 2009-08-12 2011-02-17 Valeant International (Barbados) Srl Compositions pharmaceutiques
CN104684555A (zh) 2012-09-18 2015-06-03 奥斯拜客斯制药有限公司 囊泡单胺转运体2的氘化苯并喹啉抑制剂的制剂药代动力学
US11311488B2 (en) * 2020-06-10 2022-04-26 Auspex Pharmaceuticals, Inc. Osmotic dosage forms comprising deutetrabenazine and methods of use thereof

Also Published As

Publication number Publication date
IL317235A (en) 2025-01-01
WO2023240186A1 (fr) 2023-12-14
KR20250019144A (ko) 2025-02-07
MX2024015020A (es) 2025-01-09
CN119384270A (zh) 2025-01-28
CA3257711A1 (fr) 2023-12-14
CL2024003740A1 (es) 2025-05-02
JP2025519517A (ja) 2025-06-26

Similar Documents

Publication Publication Date Title
US12589075B2 (en) Osmotic dosage forms comprising deutetrabenazine and methods of use thereof
JP4500679B2 (ja) パリペリドンを制御送達する方法および投薬形態物
DE69524214T3 (de) Azithromycin enthaltende arzneiverabreichungsformen mit gesteuerter wirkstoffabgabe
JPH07119171B2 (ja) ヒドロゲルを用いた徐放製剤
MXPA06002067A (es) Suministro gradual de topiramato durante periodo prolongado.
JP5325421B2 (ja) アマンタジンおよび浸透塩を含有する浸透デバイス
US12599598B2 (en) Osmotic dosage forms comprising deutetrabenazine and methods of use thereof
EP4536181A1 (fr) Formes posologiques osmotiques comprenant de la deutétrabénazine et leurs procédés d'utilisation
HK40109452A (en) Osmotic dosage forms comprising deutetrabenazine and methods of use thereof
HK40087427B (en) Osmotic dosage forms comprising deutetrabenazine and methods of use thereof
HK40087427A (en) Osmotic dosage forms comprising deutetrabenazine and methods of use thereof
EA047365B1 (ru) Осмотические дозированные лекарственные формы, включающие деутетрабеназин, и способы их применения
HK40120984A (zh) 包含氘代丁苯那嗪的渗透剂型及其使用方法
WO2005102272A2 (fr) Formes posologiques a liberation prolongee de cabergoline

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20241219

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40123899

Country of ref document: HK

RAP3 Party data changed (applicant data changed or rights of an application transferred)

Owner name: AUSPEX PHARMACEUTICALS LLC

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS