Use of valbenazine for treating schizophrenia or schizoaffective disorder

Abstract

To provide use of valbenazine for treating schizophrenia or schizoaffective disorder.SOLUTION: The present invention provides a method of treating schizophrenia or schizoaffective disorder, by administering (S)-2-amino-3-methyl-butanoic acid(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinoline-2-yl ester, or an isotopic variant thereof, or a pharmaceutically acceptable salt or polymorph thereof to a subject in need thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] Provided herein is a method for treating schizophrenia or schizoaffective disorder by administering (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharma- ceutically acceptable salt or polymorph thereof to a subject in need thereof. [Background technology]

[0002] Schizophrenia affects approximately 1% of the adult population and reduces life expectancy by an average of 20 to 25 years through the impact of impairment on self-care and physical health, as well as through suicide. Currently, the pathogenic mechanisms underlying schizophrenia are not fully understood. Schizophrenia is clinically diagnosed based on the characteristic symptoms of psychosis, incoherence and so-called "negative" symptoms (representing reduced range of emotional expression, reduced speech production and lack of will / motivation); duration of illness; functional deficits; and exclusion of other disorders such as autism and bipolar disorder. For clinicians, identifying which psychotic patients have schizophrenia requires clinical acumen and familiarity with the DSM-IV or ICD-10 diagnostic manual (see, for example, Corvin, BMC Biol., 2011; 9:77).

[0003] Antipsychotic medication is the mainstay of schizophrenia treatment.These antipsychotic drugs, also known as neuroleptics, generally cause a reduction in the "positive" symptoms of schizophrenia, namely psychosis, thought disorder and disorganized behavior.Antipsychotics generally have little effect on cognition and on the "negative" symptoms of the disease, including lack of motivation and affect, social withdrawal, lack of interest in daily activities, and reduced ability to plan or carry out activities.

[0004] First generation or "typical" antipsychotics have been used for more than 50 years in the treatment of schizophrenia and other psychotic disorders. The first antipsychotic to be marketed was chlorpromazine; other typical antipsychotics include fluphenazine, haloperidol, loxapine, molindone, perphenazine, pimozide, sulpiride, thioridazine and trifluoperazine. All of these typical antipsychotics obtain their primary efficacy through D2 dopamine receptor antagonism and have a tendency to cause parkinsonism (tremor, rigidity, bradykinesia and gait unsteadiness), as well as movement disorders including dystonia, dyskinesia (e.g., tardive dyskinesia) and akathisia.

[0005] Second generation or "atypical" antipsychotics have been developed, which have a lower risk of causing TD and related behavior disorders with chronic administration. These drugs include aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. All of these atypical antipsychotics exert their primary efficacy through D2 dopamine receptor antagonism with additional effects on receptors for other neurotransmitters. These atypical antipsychotics are accompanied by metabolic side effects sufficient to affect life expectancy. These side effects include a tendency to induce weight gain, as well as associated metabolic disturbances such as hypertriglyceridemia and hyperglycemia. Although clozapine appears to be the most effective treatment for severe mental illness, it has additional serious medical side effects, including a significant incidence of agranulocytosis, which necessitates frequent monitoring of the patient's white blood cell count as a requirement for using the drug.

[0006] In addition to treating schizophrenia or schizoaffective disorder, certain antipsychotic medications have been approved for the treatment of bipolar disorder, major depressive disorder (MDD), and autism spectrum disorder. Atypical off-label uses are prevalent, including for the treatment of a variety of conditions, including anxiety, attention-deficit hyperactivity disorder (ADHD), dementia, depression, insomnia, obsessive-compulsive disorder (OCD), post-traumatic stress disorder, substance abuse, and Tourette's syndrome.

[0007] Because side effects associated with the administration of antipsychotic medications can significantly impact a patient's health and well-being, alternatives to current treatments are needed.

[0008] Reversible inhibition of vesicular monoamine transporter system 2 (VMAT2) by 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one, also known as tetrabenazine (TBZ), improves the treatment of various neurological disorders. However, drawbacks of such treatment are variable response, the need for frequent intake due to rapid metabolism of TBZ, and side effects. Side effects associated with TBZ include sedation, depression, akathisia, and parkinsonism.

[0009] TBZ, which has two chiral centers and is a racemic mix of two stereoisomers, is rapidly and extensively metabolized in vivo to its reduced form, 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, also known as dihydrotetrabenazine (DHTBZ). DHTBZ is believed to exist as four individual isomers: (±) alpha-DHTBZ and (±) beta-DHTBZ. (2R,3R,11bR) or (+) alpha-DHTBZ is believed to be the absolute configuration of the active metabolite (Kilbourn et al., Chirality, 1997, vol. 9, pp. 59-62). Tetrabenazine is a compound that has been shown to be effective in treating Huntington's disease. Regarding the treatment of chorea in patients with Hungtington's disease, certain European Tetrabenazine is approved in many countries. However, it is rapidly metabolized and must be administered frequently throughout the day. (Muller, Expert Opin. Investig. Drugs, 2015, Vol. 24, pp. 737-742). Therefore, in the art, There is an unmet need to develop effective therapeutic agents for the treatment of neurological disorders, including schizophrenia or schizoaffective disorder. Valbenazine, (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, a purified prodrug of the (+)-α-isomer of dihydrotetrabenazine, is also an inhibitor of the vesicular monoamine transporter system 2 (VMAT2). [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Corvin, BMC Biol., 2011; vol. 9: p. 77. [Non-Patent Document 2] Kilbourn et al., Chirality, 1997, 9, 59-62 [Non-Patent Document 3] Muller, Expert Opin. Investig. Drugs, 2015, vol. 24, pp. 737-742 Summary of the Invention [Means for solving the problem]

[0011] Provided herein is a method for treating schizophrenia or schizoaffective disorder by administering a VMAT2 inhibitor or a pharmaceutical composition comprising a VMAT2 inhibitor to a subject in need thereof.

[0012] Additionally, provided herein is a method of treating schizophrenia or schizoaffective disorder by administering (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant thereof, or a pharma- ceutically acceptable salt or polymorph thereof.

[0013] Further provided herein is a pharmaceutical composition comprising (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant thereof, or a pharma- ceutically acceptable salt or polymorph thereof, for use in treating schizophrenia or schizoaffective disorder. [Brief description of the drawings]

[0014] [Figure 1] Figure 1 depicts the mean change in score from baseline as measured by the Positive and Negative Syndrome Scale (PANSS) after chronic valbenazine treatment (week 48) and treatment withdrawal (week 52). The PANSS was administered only to subjects with schizophrenia / schizoaffective disorder (40 mg, n=154; 80 mg, n=155). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] definition To facilitate understanding of the disclosure described herein, a number of terms are defined below.

[0016] Generally, the names used herein and the laboratory procedures in organic chemistry, medicinal chemistry and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0017] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat or mouse. The terms "subject" and "patient" are used interchangeably herein in reference to a mammalian subject, such as a human subject, and in one embodiment, a human.

[0018] As used herein, "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

[0019] With respect to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D", it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. Positions designated as having deuterium typically have a minimum isotopic enrichment factor of at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position, in certain embodiments.

[0020] The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those of skill in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy and crystallography.

[0021] Isotopic enrichment (e.g., deuteration) of pharmaceuticals to improve pharmacokinetic ("PK"), pharmacodynamic ("PD") and toxicity profiles has been previously demonstrated for some classes of drugs. See, e.g., Lijinsky et al., Food Cosmet. Toxicol. 20:393 (1982). see, Lijinsky et al., J. Nat. Cancer Inst., 69:1127 (1982); Mangold et al., Mutation Res., 308:33 (1994); Gordon et al., Drug Metab. Dispos., 15:589 (1987); Zello et al., Metabolism, 43:487 (1994); Gately et al., J. Nucl. Med., 27:388 (1986); Wade D, Chem. Biol. Interact., 117:191 (1999).

[0022] Isotopic enrichment of drugs can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of dose needed to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and / or (6) decrease the production of harmful metabolites in specific tissues, and / or create more effective and / or safer drugs for combination therapy, whether or not combination therapy is contemplated.

[0023] The replacement of an atom with one of its isotopes often results in a change in the reaction rate of a chemical reaction. This phenomenon is known as the kinetic isotope effect ("KIE"). For example, if a C-H bond is broken during a rate-determining step in a chemical reaction (i.e., the step with the highest transition state energy), the replacement of that hydrogen with deuterium causes a decrease in the reaction rate and the process slows down. This phenomenon is known as the deuterium kinetic isotope effect ("DKIE"). (See, e.g., Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88) (1999)).

[0024] The magnitude of the DKIE can be expressed as the ratio between the rate of a given reaction in which a C-H bond is broken and the rate of the same reaction when deuterium is substituted for hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that a reaction can be 50 times slower or more when deuterium is substituted for hydrogen. High DKIE values ​​can be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is due to the small mass of hydrogen atoms, which occurs because transition states involving protons can form in the absence of the required activation energy. Deuterium is more massive than hydrogen, so statistically it is much less likely to undergo this phenomenon.

[0025] Tritium ("T") is a radioactive isotope of hydrogen used in research studies, fusion reactors, neutron generators and radiopharmaceuticals. Tritium is a hydrogen atom with two neutrons in its nucleus and has an atomic mass close to 3. It occurs naturally in the environment in very low concentrations, most commonly found as TO. Tritium decay is slow (half-life = 12.3 years) and emits low-energy beta particles that cannot penetrate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope, but it should pose a significant health risk if ingested orally in large amounts. Compared to deuterium, a smaller amount of tritium needs to be consumed before it reaches dangerous levels. Substitution of hydrogen for tritium ("T") still results in stronger binding than deuterium, giving a numerically larger isotope effect. Similarly, but not limited to, for carbon: 13 C or 14 C. For sulfur 33 S, 34 S or 36 S and nitrogen 15 For N and oxygen, 17 O or 18 Substitution of isotopes from other elements, including O, can result in similar kinetic isotope effects.

[0026] For example, DKIEs were used to reduce the hepatotoxicity of halothane, presumably by limiting the generation of reactive species such as trifluoroacetyl chloride. However, this method may not be applicable to all drug classes. For example, deuterium incorporation can result in metabolic switching. The concept of metabolic switching asserts that a foreign substance, when sequestered by a phase I enzyme, can bind transiently and rebind in various conformations before chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively enormous size of the binding pockets in many phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can potentially result in different ratios of known and entirely new metabolites. This new metabolic profile may confer more or less toxicity.

[0027] The animal body expresses various enzymes for the purpose of removing foreign substances, such as therapeutic agents, from its circulatory system. Examples of such enzymes include cytochrome P450 enzymes ("CYP"), esterases, proteases, reductases, dehydrogenases and monoamine oxidases, which react with these foreign substances and convert them into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of carbon-hydrogen (CH) bonds to either carbon-oxygen (CO) or carbon-carbon (CC) pi-bonds. The resulting metabolites may be stable or unstable under physiological conditions and may have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles relative to the parent compound. For many drugs, such oxidation is rapid. These drugs therefore often require administration of multiple or high daily doses.

[0028] As such, isotopic enrichment at certain positions of the compounds provided herein can produce detectable KIEs that affect the pharmacokinetic, pharmacological and / or toxicological profiles of the compounds provided herein in comparison to similar compounds having natural isotopic composition.

[0029] The term "isotopic variant" refers to a therapeutic agent that contains unnatural proportions of isotopes at one or more of the atoms that constitute such therapeutic agent. In certain embodiments, an "isotopic variant" of a therapeutic agent includes, but is not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), Carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), Fluorine-17( 17 F), Fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-32( 32 S), Sulfur-33( 33 S), Sulfur-34( 34 S), Sulfur-35( 35 S), Sulfur-36( 36 S), Chlorine-35( 35 Cl), Chlorine-36( 36 Cl), Chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), Iodine-123 ( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I), and iodine-131( 131 In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2H), tritium ( 3 H), Carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), Fluorine-17( 17 F), Fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-32( 32 S), Sulfur-33( 33 S), Sulfur-34( 34 S), Sulfur-35( 35 S), Sulfur-36( 36 S), Chlorine-35( 35 Cl), Chlorine-36( 36 Cl), Chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), Iodine-123 ( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I), and iodine-131( 131 I) contain unnatural proportions of one or more isotopes.

[0030] Where feasible according to the judgment of one of skill in the art, any hydrogen in the therapeutic agent may be, for example, 2 H, or any carbon can be, for example 13 C, or any nitrogen can be, e.g. 15 N or any oxygen can be, for example 18It is understood that the isotopic variant can be O. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of deuterium (D).

[0031] The terms "treat," "treating," and "treatment" are meant to include alleviating or arresting one or more of the symptoms associated with a disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0032] The terms "prevent," "preventing," and "prevention" are meant to include methods of delaying and / or eliminating the onset of a disorder, disease or condition and / or its attendant symptoms; precluding a subject from acquiring a disorder, disease or condition; or reducing a subject's risk of acquiring a disorder, disease or condition.

[0033] As used herein, and unless otherwise specified, the terms "manage", "managing" and "management" refer to preventing or slowing the progression, spread or worsening of a disease or disorder or one or more symptoms thereof. Often, the beneficial effects that a subject obtains from a prophylactic and / or therapeutic agent do not result in a cure of the disease or disorder. In this regard, the term "managing" encompasses treating a subject who has suffered from a particular disease in an attempt to prevent or minimize the recurrence of the disease.

[0034] As used herein, amelioration of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any reduction, whether permanent or temporary, persistent or transient, that may result from or be associated with administration of the composition.

[0035] The term "disorder", as used herein, is intended to be generally synonymous with, and is used interchangeably with, the terms "disease", "syndrome" and "condition" (in medical terms), in that all of these terms reflect an abnormal condition of the human or animal body or parts thereof that impairs normal function and is typically manifested by distinct signs and symptoms.

[0036] The term "therapeutically effective amount" is meant to include an amount of a compound that, when administered, is sufficient to prevent or alleviate to some extent one or more of the symptoms of the disorder, disease or condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA or DNA), cell, tissue, system, animal or human that is being sought by a researcher, veterinarian, physician or clinician.

[0037] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or disorder or prevent its recurrence. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with one or more other agents, that provides a prophylactic benefit in preventing disease. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0038] The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 22nd ed.; Pharmaceutical Press: 2012; Handbook of Pharmaceutical Excipients, 7th ed.; Rowe et al., eds.; The Pharmaceutical Press: 2012; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash, eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson, ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0039] The terms "dosage," "dosage unit," and "dosage level" are used interchangeably throughout this disclosure, unless the context clearly dictates otherwise.

[0040] As used in this specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents, unless the context clearly dictates otherwise.

[0041] The term "about" or "approximately" refers to an allowable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0042] The terms "active ingredient" and "active substance" refer to a compound administered alone or in combination with one or more pharma- ceutically acceptable excipients to a subject to treat, prevent, or ameliorate one or more symptoms of a disorder, disease, or condition. As used herein, "active ingredient" and "active substance" may be an optically active isomer or isotopic variant of a compound described herein.

[0043] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a chemical compound or pharmaceutical composition thereof that is administered to a subject to treat, prevent, or ameliorate one or more symptoms of a disorder, disease, or condition.

[0044] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, such as a compound provided herein, and one or more molecules of a solvent present in stoichiometric or non-stoichiometric amounts. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharma-ceutically acceptable. In one embodiment, the complex or aggregate is in crystalline form. In another embodiment, the complex or aggregate is in non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0045] As used herein and unless otherwise indicated, the terms "polymorph" and "polymorphic form" refer to solid crystalline forms of a compound or complex. Different polymorphs of the same compound can exhibit different physical, chemical and / or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., against heat or light), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). Differences in stability may be due to changes in chemical reactivity (e.g., differential oxidation, such as a dosage form discoloring more rapidly when composed of one polymorph than when composed of another polymorph) or mechanical characteristics (e.g., tablets crumble on storage when a kinetically favored polymorph transforms into a thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to degradation at high humidity). Different physical properties of polymorphs may affect their processing. For example, one polymorph may be more likely to form solvates or more difficult to filter or wash free of impurities than another polymorph, e.g., due to its particle shape or size distribution.

[0046] Polymorphs of molecules can be obtained by many methods known in the art. These methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, quenching, slow cooling, vapor diffusion and sublimation. Polymorphs can be detected, identified, classified and characterized using well-known techniques, such as, but not limited to, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffractometry (XRPD), single crystal X-ray diffraction, vibrational spectroscopy, solution calorimetry, solid-state nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, Raman spectroscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility and rate of dissolution.

[0047] The term "crystalline form" of a compound can refer to any crystalline form of the compound as a free acid, as a free base, as an acid addition salt of the compound, as a base addition salt of the compound, as a complex of the compound, as a solvate (including hydrates) of the compound, or as a co-crystal of the compound. The term "solid form" of a compound can refer to any crystalline form of the compound, or any amorphous form of the compound as a free acid, as a free base, as an acid addition salt of the compound, as a base addition salt of the compound, as a complex of the compound, or as a solvate (including hydrates) of the compound, or as a co-precipitate of the compound. In many instances, the terms "crystalline form" and "solid form" can refer to pharma- ceutically acceptable, including, for example, pharma- ceutically acceptable addition salts, pharma-ceutically acceptable complexes, pharma-ceutically acceptable solvates, pharma-ceutically acceptable co-crystals, and pharma-ceutically acceptable co-precipitates.

[0048] The term "schizophrenia or schizoaffective disorder" includes, but is not limited to, illnesses that manifest as abnormal social behavior and an inability to understand reality. Schizophrenia is described in terms of positive and negative (or deficit) symptoms. Positive symptoms are those that are not normally experienced by most individuals but are present in people with schizophrenia. They can include delusions, disorders of thought and speech, as well as tactile, auditory, visual, olfactory and taste hallucinations, and are typically considered manifestations of psychosis. Hallucinations are also typically related to thematic content of delusions. Negative symptoms are deficits in normal emotional responses or other thought processes. They generally include flat expression or poor affect, lack of speech, inability to experience pleasure, lack of desire to form relationships, and lack of motivation.

[0049] The term "VMAT2" refers to human vesicular monoamine transporter isoform 2, an integral membrane protein that acts to transport monoamines, particularly neurotransmitters such as dopamine, norepinephrine, serotonin and histamine, from the cell cytosol to synaptic vesicles.

[0050] The term "VMAT2 inhibitor", "inhibit VMAT2" or "inhibit VMAT2" refers to the ability of the compounds disclosed herein to modify the function of VMAT2. VMAT2 inhibitors can block or reduce the activity of VMAT2 by forming a reversible or irreversible covalent bond between the inhibitor and VMAT2, or through the formation of a non-covalent complex. Such inhibition may only be evident in a particular cell type, or may be associated with a particular biological event. The term "VMAT2 inhibitor", "inhibit VMAT2" or "inhibit VMAT2" also refers to modifying the function of VMAT2 by decreasing the probability that a complex forms between VMAT2 and a natural substrate. In some embodiments, modulation of VMAT2 is as described in WO2005077946; WO2008 / 058261; EP1716145; Kilbourn et al., European Journal of Pharmacology, 1995, (Vol. 278), pp. 249-252; Lee et al., J. Med. Chem., 1996, (Vol. 39), pp. 191-196; Scherman et al., Journal of Neurochemistry, 1988, Vol. 50(4), pp. 1131-36; Kilbourn et al., Synapse, 20 02, 43(3), 188-194; Kilbourn et al., European Journal of Pharmacology, 1997, 331(2-3), 161-68; and Erickson et al., Journal of Molecular Neuroscience, 1995, 6(4), 277-87. It can be assessed using the methods described.

[0051] "Pharmaceutically acceptable salt" refers to any salt of a compound provided herein that retains biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts can be derived from a variety of organic and inorganic counterions well known in the art.Such salts include, but are not limited to, the following: (1) salts of organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, benzo ... Acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthalenesulfonic acid, or (2) when an acidic proton present in the parent compound is replaced by (a) a metal ion, e.g., an alkali metal ion, an alkaline earth ion or an aluminum ion, or an alkali metal hydroxide or an alkaline earth metal hydroxide, e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, ammonia, or (b) an organic base, e.g., an aliphatic, alicyclic or aromatic organic amine, e.g., ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine. Salts formed when coordinated with piperazine, tris(hydroxymethyl)-aminomethane, and tetramethylammonium hydroxide, among others.

[0052] Pharmaceutically acceptable salts include, by way of example only and without limitation, salts of sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and the like, as well as, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g., hydrochlorides and hydrobromides, sulfates, phosphates, sulfamate, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, picrates, cinnamates, phenylalanides ... and the like.

[0053] The term "amino acid" refers to naturally occurring and synthetic alpha, beta, gamma or delta amino acids, including, but not limited to, those amino acids found in proteins, namely glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In one embodiment, the amino acid is in the L-configuration. Alternatively, the amino acid is alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl. , threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histyl In some embodiments, the amino acid may be a derivative of β-amino-, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl, or β-histidinyl. Methods of Treatment and Pharmaceutical Preparations and Compositions

[0054] VMAT2 inhibitors (and their physiologically acceptable salts) can reduce the supply of monoamines in the central nervous system by inhibiting vesicular monoamine transporter isoform 2 (VMAT2). VMAT2 inhibition leads to the regulation of neurotransmitter systems (e.g., dopamine and serotonin).

[0055] In one embodiment, described herein is the use of VMAT2 inhibitor for treating schizophrenia or schizoaffective disorder.In another embodiment, the VMAT2 inhibitor comprises (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or its isotopic variant; or its pharmaceutically acceptable salt or polymorph. In some embodiments, provided herein is the use of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or its isotopic variant, or its polymorph, for treating schizophrenia or schizoaffective disorder.In certain embodiments, the VMAT2 inhibitor is tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one).In other embodiments, the VMAT2 inhibitor is deuterated.In other embodiments, the VMAT2 inhibitor is deuterated tetrabenazine (TBZ). Deuterated tetrabenazine includes 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ). In some embodiments, the VMAT2 inhibitor is deuterated (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester. In certain embodiments, the VMAT2 inhibitor is deuterated (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate).In other embodiments, the VMAT2 inhibitor is (+)α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ((+)α-HTBZ); or (+)α-3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (deuterated (+)α-HTBZ). In other embodiments, the VMAT2 inhibitor is (+)β-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ((+)β-HTBZ); or (+)β-3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (deuterated (+)β-HTBZ).

[0056] In some embodiments, schizophrenia or schizoaffective disorder includes, but is not limited to, disorders associated with positive and negative symptoms.

[0057] In some embodiments, provided herein is a method for treating, preventing or ameliorating one or more symptoms of schizophrenia or schizoaffective disorder, comprising administering to a subject a VMAT2 inhibitor or a pharmaceutical composition comprising a VMAT2 inhibitor as described herein.In certain embodiments, the VMAT2 inhibitor comprises (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or its isotopic variant; or its pharmaceutically acceptable salt or polymorph.

[0058] In some embodiments, provided herein is a method for treating, preventing, or ameliorating one or more symptoms of schizophrenia or schizoaffective disorder, comprising administering to a subject (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant thereof, or a pharma- ceutically acceptable salt or polymorph thereof; or a pharmaceutical composition described herein. In some embodiments, the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate).In certain embodiments, the VMAT2 inhibitor is tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one).In other embodiments, the VMAT2 inhibitor is deuterated.In some embodiments, the VMAT2 inhibitor is deuterated tetrabenazine (TBZ). Deuterated tetrabenazine includes 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ). In some embodiments, the VMAT2 inhibitor is deuterated (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester. In certain embodiments, the VMAT2 inhibitor is deuterated (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate).In other embodiments, the VMAT2 inhibitor is (+)α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ((+)α-HTBZ); or (+)α-3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (deuterated (+)α-HTBZ). In other embodiments, the VMAT2 inhibitor is (+)β-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ((+)β-HTBZ); or (+)β-3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (deuterated (+)β-HTBZ).

[0059] In other embodiments, (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant thereof; or a pharma- ceutically acceptable salt or polymorph thereof, can prevent, reduce the likelihood of occurrence, slow the progression, delay the manifestation of, or treat symptoms associated with schizophrenia or schizoaffective disorder. In some embodiments, the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate).In certain embodiments, the VMAT2 inhibitor is tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one).In other embodiments, the VMAT2 inhibitor is deuterated.In some embodiments, the VMAT2 inhibitor is deuterated tetrabenazine (TBZ). Deuterated tetrabenazine includes 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ). In some embodiments, the VMAT2 inhibitor is deuterated (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester. In certain embodiments, the VMAT2 inhibitor is deuterated (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate).In other embodiments, the VMAT2 inhibitor is (+)α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ((+)α-HTBZ); or (+)α-3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (deuterated (+)α-HTBZ). In other embodiments, the VMAT2 inhibitor is (+)β-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ((+)β-HTBZ); or (+)β-3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (deuterated (+)β-HTBZ).

[0060] In some embodiments, in a subject with schizophrenia or schizoaffective disorder, treatment with (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or its isotopic variant, or its pharma- ceutically acceptable salt or polymorph, can improve or effectively reduce one or more symptoms associated with schizophrenia or schizoaffective disorder. In some embodiments, symptoms include, but are not limited to, positive symptoms and negative symptoms. In some embodiments, symptoms include, by way of example, positive symptoms, such as delusions, disorders of thought and speech, and tactile, auditory, visual, olfactory and gustatory hallucinations, which are typically considered to be manifestations of psychosis. Hallucinations are also typically associated with thematic content of delusions. In some embodiments, symptoms include negative symptoms such as, by way of example, flat expression or poor affect, lack of speech, inability to experience pleasure, lack of desire to form relationships, and lack of motivation, in some embodiments, negative symptoms include those that appear to contribute to poor quality of life, functional ability, and burden on others.

[0061] In some embodiments, in a subject with schizophrenia or schizoaffective disorder, treatment with (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant thereof, or a pharma- ceutically acceptable salt or polymorph thereof, can manage behavioral problems associated with schizophrenia or schizoaffective disorder, including, but not limited to, those associated with positive and negative (or deficit) symptoms.

[0062] Causes of schizophrenia or schizoaffective disorder include environmental and genetic factors. Possible environmental factors include urban upbringing, cannabis use, certain infections, parental age, and poor nutrition during pregnancy. Genetic factors include a variety of common and rare gene variants. Diagnosis is based on observation of behavior, the person's reported experiences, and the reports of others who know the person well. A person's culture must also be taken into consideration during diagnosis. Schizophrenia does not mean "split personality" or "multiple personality disorder," conditions with which it is often confused in conventional wisdom.

[0063] The mainstay of treatment is antipsychotic pharmacotherapy, along with counseling, vocational training, and social rehabilitation. It is unclear whether typical or atypical antipsychotics are better. In more severe situations where there is a risk to self or others, involuntary hospitalization may be necessary, but hospitalization periods are now shorter and less frequent than in the past.

[0064] Psychotic symptoms may be present in several other psychiatric disorders, including bipolar disorder, borderline personality disorder, drug addiction, and drug-induced psychosis. Delusions ("non-bizarre") are found in delusional disorder, and withdrawal is also found in social anxiety disorder, avoidant personality disorder, and schizotypal personality disorder. Schizotypal personality disorder has symptoms similar to, but less severe than, those of schizophrenia. Schizophrenia occurs in conjunction with obsessive-compulsive disorder (OCD) more often than can be accounted for, by chance, but the obsessions that occur in OCD can be difficult to distinguish from the delusions of schizophrenia. Some people who withdraw from benzodiazepines experience a severe withdrawal syndrome that can last for a long time. It can resemble schizophrenia and can be misdiagnosed as such.

[0065] A more general medical and neurological examination may be required to rule out medical illnesses that may rarely produce psychotic schizophrenia-like symptoms, such as metabolic disturbances, systemic infections, syphilis, HIV / AIDS, epilepsy, limbic encephalitis, and brain lesions. Stroke, multiple sclerosis, hyperthyroidism, hypothyroidism, and dementia, such as Alzheimer's disease, Huntington's disease, frontotemporal dementia, and dementia with Lewy bodies, may also be associated with schizophrenia-like psychotic symptoms. It may be necessary to rule out delirium, which can be differentiated by visual hallucinations, acute onset, and fluctuating levels of consciousness and indicates an underlying medical illness. In children, hallucinations must be separated from typical childhood daydreams.

[0066] Schizophrenia is associated with subtle differences in brain structure found in 40 to 50 percent of cases, and in brain chemistry during acute psychotic states. Studies using neuropsychological tests and brain imaging techniques, such as fMRI (functional magnetic resonance imaging) and PET, to examine functional differences in brain activity, have shown that the differences appear to occur most commonly in the frontal lobe, hippocampus, and temporal lobe. Reductions in brain volume, smaller than those found in Alzheimer's disease, have been reported in areas of the frontal cortex and temporal lobe. It is unclear whether these volumetric changes are progressive or present before the onset of the disease. These differences have been linked to the neurocognitive deficits often associated with schizophrenia.

[0067] Schizophrenia is classified as a mental disorder by the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM Schizophrenia is diagnosed based on criteria in either the International Statistical Classification of Diseases and Related Health Problems (ICD-10) or the World Health Organization's International Statistical Classification of Diseases and Related Health Problems (ICD-10). These criteria use the individual's self-reported experiences and abnormalities in reported behavior, followed by clinical evaluation by a mental health professional. Symptoms associated with schizophrenia occur on a continuum in the population and must reach a certain severity before a diagnosis is made. The Positive and Negative Syndrome Scale (PANSS) is a 30-item, 7-point rating instrument used in measuring the severity of symptoms in subjects with schizophrenia. The ratings are made by trained interviewers over a period of approximately 45 minutes. Each item on the PANSS is accompanied by a complete definition, as well as detailed fixed criteria for all seven rating points (Stanley R. Kay, The Positive and Negative Syndrome Scale (PANSS) for Schizophrenia, Scizophrenia Bulletin, 1987, vol. 13, pp. 262-276). The 30 items are divided into three subscales - positive symptoms (delusions and hallucinations), negative symptoms (social withdrawal, flat affect / blunted affect), and general psychopathology. These three subscales can be summed to give a total score.

[0068] In certain embodiments, in a subject having schizophrenia or schizoaffective disorder, treatment with (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant thereof, or a pharma- ceutically acceptable salt or polymorph thereof, can improve or effectively reduce one or more symptoms associated with schizophrenia or schizoaffective disorder. In some embodiments, the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate).In certain embodiments, the VMAT2 inhibitor is tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one).In other embodiments, the VMAT2 inhibitor is deuterated.In some embodiments, the VMAT2 inhibitor is deuterated tetrabenazine (TBZ). Deuterated tetrabenazine includes 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ). In some embodiments, the VMAT2 inhibitor is deuterated (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester. In certain embodiments, the VMAT2 inhibitor is deuterated (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate).In other embodiments, the VMAT2 inhibitor is (+)α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ((+)α-HTBZ); or (+)α-3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (deuterated (+)α-HTBZ). In other embodiments, the VMAT2 inhibitor is (+)β-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ((+)β-HTBZ); or (+)β-3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (deuterated (+)β-HTBZ).

[0069] In some embodiments, the subject includes a subject who has been diagnosed by a medical practitioner. Symptoms associated with schizophrenia or schizoaffective disorder include, but are not limited to, positive and negative symptoms. In some embodiments, individuals with schizophrenia may experience hallucinations (most reportedly hearing voices), delusions (often bizarre or paranoid in nature), and incoherent thoughts and speech. The latter may range from a loss of train of thought to sentences that are merely vaguely related in meaning, an incomprehensible speech known as word salad. Social withdrawal, poor grooming and hygiene, and loss of motivation and judgment are all common in schizophrenia. Distorting one's self-experience, such as feeling as if one's thoughts or feelings are not actually one's own, to believe that thoughts are placed in one's head, sometimes referred to as a passivity phenomenon, is also common. There is often an observable pattern of emotional difficulties, such as lack of responsiveness. Deficits in social cognition are associated with schizophrenia, as is the symptom of paranoia. Social isolation commonly occurs. Difficulties in working and long-term memory, attention, executive function, and speed of processing also commonly occur. In one uncommon subtype, the person may be nearly mute, sit in bizarre positions, or exhibit aimless agitation, all signs of catatonia. Approximately 30 to 50 percent of people with schizophrenia cannot accept that they have the illness or follow their recommended treatment. Treatment may have some effect on awareness. People with schizophrenia often find that they have difficulty with facial emotion perception.

[0070] Valbenazine can be prepared according to US Patent Nos. 8,039,627 and 8,357,697, the disclosures of each of which are incorporated herein by reference in their entirety.Tetrabenazine can be administered by various methods, including the formulations disclosed in PCT Publications WO2010 / 018408, WO2011 / 019956 and WO2014 / 047167, the disclosures of each of which are incorporated herein by reference in their entirety.In another embodiment, the valbenazine for use in the compositions and methods provided herein is polymorphic Form I as disclosed in US Application No. 15 / 338,214, the disclosures of which are incorporated herein by reference in their entirety.

[0071] In another embodiment, d6-tetrabenazine is administered as disclosed in U.S. Patent No. 8,524,733 to provide an adequate concentration of the metabolite (+)α-3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (deuterated (+)α-HTBZ) or deuterated (+)β-HTBZ) in plasma over a specified period of time. d6-tetrabenazine can be administered by a variety of methods, including formulations as disclosed in PCT Publication WO2014 / 047167, the disclosure of which is incorporated herein by reference in its entirety. Pharmaceutical Compositions

[0072] Further provided herein is a pharmaceutical composition for use in treating schizophrenia or schizoaffective disorder comprising as an active pharmaceutical ingredient (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant thereof; or a pharma-ceutically acceptable salt or polymorph thereof, in combination with one or more pharma-ceutically acceptable carriers or excipients. In some embodiments, the pharmaceutical composition comprises (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate). In certain embodiments, the pharmaceutical composition comprises a VMAT2 inhibitor. In certain embodiments, the VMAT2 inhibitor is tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one). In other embodiments, the pharmaceutical composition comprises a deuterated VMAT2 inhibitor. In some embodiments, the VMAT2 inhibitor is deuterated tetrabenazine (TBZ). Deuterated tetrabenazine includes 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ). In some embodiments, the VMAT2 inhibitor is deuterated (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester. In certain embodiments, the VMAT2 inhibitor is deuterated (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate).In other embodiments, the VMAT2 inhibitor is (+)α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ((+)α-HTBZ); or (+)α-3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (deuterated (+)α-HTBZ). In other embodiments, the VMAT2 inhibitor is (+)β-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ((+)β-HTBZ); or (+)β-3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (deuterated (+)β-HTBZ).

[0073] The choice of excipient will, to a large extent, depend on factors such as the particular mode of administration, the effect of the excipient on the solubility and stability of the active ingredient, and the nature of the dosage form.

[0074] The pharmaceutical compositions provided herein can be provided in unit dosage form or multiple dosage form. Unit dosage form, as used herein, refers to a physically discrete unit that is suitable for administration to human and animal subjects and is individually packaged, as known in the art. Each unit dose contains a predetermined amount of active ingredient(s) sufficient to produce the desired therapeutic effect in association with the required pharmaceutical carrier or excipient. Examples of unit dosage forms include ampoules, syringes, and individually packaged tablets and capsules. A unit dosage form can be administered in fractions or multiples thereof. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container to be administered in segregated unit dosage form. Examples of multiple dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.

[0075] The pharmaceutical compositions provided herein can be administered alone or in combination with one or more other compounds provided herein, one or more other active ingredients. The pharmaceutical compositions provided herein can be formulated in various dosage forms for oral, parenteral and topical administration. The pharmaceutical compositions can be administered in delayed release dosage forms, extended release dosage forms, prolonged release dosage forms, sustained release dosage forms, pulsatile release dosage forms, and the like. release dosage form, controlled release dosage form, accelerated and fast release dosage form, targeted release dosage form These dosage forms can also be formulated as modified release dosage forms, including programmed-release dosage forms, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those of skill in the art (Remington: The Science and Practice of Pharmacy, see above; Modified-Release Drug Delivery Technology, Rathbone et al., eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; see vol. 126).

[0076] The pharmaceutical composition provided herein can be administered once or multiple times at intervals.It is understood that the exact dosage and duration of treatment can vary according to the age, weight and condition of the patient being treated, and can be empirically determined using known test protocols or by extrapolation from in vivo or in vitro test or diagnostic data.It is further understood that for any particular individual, specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person who administers or supervises the administration of the formulation. Oral route

[0077] The pharmaceutical compositions provided herein can be provided in solid, semi-solid or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, liquids, emulsions, suspensions, solutions, wafers, sprinkles, elixirs and syrups. In addition to the active ingredient(s), the pharmaceutical compositions can contain one or more pharma- ceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye-migration inhibitors, sweeteners and flavoring agents.

[0078] Binders or granulators provide cohesiveness to the tablet, ensuring that it remains intact after compression. Suitable binders or granulators include, but are not limited to, starches such as corn starch, potato starch and pregelatinized starch (e.g., Starch 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of Isabgol shell, carboxymethylcellulose, methylcellulose, cellulose acetate ... Suitable fillers include cellulose, polyvinylpyrrolidone (PVP), veegum, larch arabogalactan, powdered tragacanth, and guar gum; cellulose, such as ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC); microcrystalline cellulose, such as Avicel-PH-101, Avicel-PH-103, Avicel RC-581, Avicel-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler can be present in the pharmaceutical compositions provided herein at about 50% to about 99% by weight.

[0079] Suitable diluents include, but are not limited to, dibasic calcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient amounts, can impart properties to some compressed tablets that allow them to disintegrate in the mouth by chewing. These compressed tablets can be used as chewable tablets.

[0080] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and Veegum HV; citrus pulp; crosslinked celluloses such as croscarmellose; crosslinked polymers such as crospovidone; crosslinked starch; calcium carbonate; microcrystalline celluloses such as sodium starch glycolate; polacrilin potassium; starches such as com starch. , potato starch, tapioca starch and pregelatinized starch; clay; align; and mixtures thereof. The amount of disintegrant in the formulation varies with the type of formulation and is readily discernible to one of ordinary skill in the art. The pharmaceutical compositions provided herein can contain from about 0.5% to about 15% by weight, or from about 1% to about 5% by weight of disintegrant.

[0081] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or lubricants include silica gels, such as AEROSIL® 200 (WR Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co., Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain from about 0.1% to about 5% by weight of a lubricant.

[0082] Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co., Boston, MA), and asbestos-free talc. Coloring agents include any of the approved certified water soluble and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. Color lakes are the combination of water-soluble dyes by adsorption onto hydrous oxides of heavy metals, resulting in an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propyl parabens, benzoic add, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

[0083] It should be understood that many carriers and excipients may serve several functions, even within the same formulation. The pharmaceutical compositions provided herein may be in the form of compressed tablets, tablet triturates, chewable lozenges, quick dissolve tablets, multiple compressed tablets, or enteric tablets. They can be provided as enteric-coated tablets, sugar-coated tablets or film-coated tablets. Enteric-coated tablets are tablets that are protected from the action of stomach acid. Compressed tablets are tablets that are coated with a substance that resists dissolving or disintegrating in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets that are surrounded by a sugar coating, which may be beneficial in masking unpleasant tastes or odors and protecting the tablet from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of water-soluble material. Film-coated agents include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general characteristics as sugar coatings. Multiple compressed tablets are compressed tablets that are made by more than one compression cycle, including layered tablets, and pressure-coated or dry-coated tablets.

[0084] Tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents, and / or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

[0085] The pharmaceutical compositions provided herein can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.Hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two sections, one slipping over the other, thus completely enclosing the active ingredient.Soft Elastic Capsule (SEC) is a soft globular shell, such as a gelatin shell that is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shell can contain a preservative to prevent microbial growth. Suitable preservatives are as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsule can also be coated as known by those skilled in the art to modify or sustain the dissolution of the active ingredient.

[0086] The pharmaceutical compositions provided herein can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems, in which one liquid is dispersed throughout another liquid in the form of small globules, which may be oil-in-water or water-in-oil. Emulsions can include pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions can include pharmaceutically acceptable acetals, such as di(lower alkyl)acetals of lower alkyl aldehydes (the term "lower" means alkyl having between 1 and 6 carbon atoms), such as acetaldehyde diethyl acetal; and water-miscible solvents with one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear sweetened and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and can also contain preservatives. For a liquid dosage form, a solution, for example, in a polyethylene glycol, can be conveniently measured for administration by dilution with a sufficient quantity of a pharma- ceutically acceptable liquid carrier, for example water.

[0087] Other useful liquid and semi-solid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein and dialkylated mono- or polyalkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations can further include one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0088] For oral administration, the pharmaceutical compositions provided herein can also be provided in the form of liposomes, micelles, microspheres or nanosystems.Micelle dosage forms can be prepared as described in U.S. Patent No. 6,350,458.

[0089] The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders to be reconstituted into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders can include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders can include organic acids and a source of carbon dioxide.

[0090] Coloring and flavoring agents can be used in all of the above dosage forms.The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed, sustained, pulsed, controlled, targeted and programmed release forms.

[0091] The pharmaceutical compositions provided herein can be co-formulated with other active ingredients that do not detract from the desired therapeutic action, or with substances that supplement the desired action, such as antacids, proton pump inhibitors, and H2 receptor antagonists.

[0092] The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration, as used herein, includes intravenous administration, intraarterial administration, intraperitoneal administration, intrathecal administration, Includes intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration. Parenteral Administration

[0093] The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solution or suspension in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmacy (see Remington: The Science and Practice of Pharmacy, supra). sea ​​bream).

[0094] Pharmaceutical compositions intended for parenteral administration can contain one or more pharma- ceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.

[0095] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and medium chain triglycerides of coconut oil and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide.

[0096] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzates, thimerosin, ethyl esters ... Suitable isotonicity agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants include those as described herein, including bisulfites and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those as described herein, including sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those as described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include cyclodextrins, including, but not limited to, alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, and sulfobutylether 7-beta-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

[0097] The pharmaceutical compositions provided herein can be formulated for single or multiple dose administration.Single dose formulations are packaged in ampoules, vials or syringes.Multiple dose parenteral formulations must contain antimicrobial agents at bacteriostatic or fungistatic concentrations.All parenteral formulations must be sterile, as known and practiced in the art.

[0098] In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile liquid formulation. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, including lyophilized powders and hypodermic tablets, which are reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product, which is reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

[0099] The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0100] The pharmaceutical composition can be formulated as a suspension, solid, semi-solid or thixotropic liquid for administration as an implanted depot. In one embodiment, the pharmaceutical composition provided herein is dispersed in a solid internal matrix surrounded by an external polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse.

[0101] Suitable inner matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate.

[0102] Suitable outer polymeric membranes include polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers. Topical administration

[0103] The pharmaceutical compositions provided herein can be administered topically to the skin, orifices, or mucosa. Topical administration, as used herein, includes dermal, conjunctival, corneal, ocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, ​​respiratory, and transdermal administration. This includes intravenous and rectal administration.

[0104] The pharmaceutical compositions provided herein can be formulated in any form suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dustable powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, enemas, sprays, suppositories, bandages, skin patches, etc. Topical formulations of the pharmaceutical compositions provided herein can also include liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

[0105] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryopretectants, lyoprotectants, thickening agents, and inert gases.

[0106] The pharmaceutical compositions can be used in a variety of applications including electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp., Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, Oreg.).

[0107] The pharmaceutical compositions provided herein can be provided in the form of ointments, creams and gels.Suitable ointment vehicles include oily or hydrocarbon bases, including lard, benzoic lard, olive oil, cottonseed oil and other oils, white petrolatum, etc.; emulsifying or absorbing bases, such as hydrophilic petrolatum, hydroxystearin sulfate and anhydrous lanolin; water-removable bases, such as hydrophilic ointments; polyethylene glycol of various molecular weights; water-soluble ointment bases, including glycol; emulsion bases, either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (Remington: The Science and Practice of Pharmacy, supra). Although these are chemicals, they generally require the addition of antioxidants and preservatives.

[0108] Suitable cream bases may be oil-in-water or water-in-oil. Cream vehicles may be water-washable and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the "internal" phase, is generally composed of petrolatum and a fatty alcohol, such as cetyl alcohol or stearyl alcohol. The aqueous phase usually, but not necessarily, exceeds the oil phase in volume and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic, anionic, cationic or amphoteric surfactant.

[0109] Gels are semi-solid suspension-type systems. Single-phase gels contain organic macromolecules that are substantially uniformly distributed throughout the liquid carrier. Suitable gelling agents include cross-linked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, Carbopol®; hydrophilic polymers, such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol; cellulosic polymers, such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a homogeneous gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by grinding, mechanical mixing and / or stirring.

[0110] The pharmaceutical compositions provided herein may be administered rectally, urethrally, vaginally, or perivaginally in the form of a suppository, pessary, bougie, poultice or cataplasm, paste, powder, dressing, cream, plaster, contraceptive, ointment, solution, emulsion, suspension, tampon, gel, foam, spray, or enema. These dosage forms are described in Remington: The Science and Practice of Pharmacy (see above). It can be manufactured using conventional processes as shown.

[0111] Rectal, urethral and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at normal temperatures but melt or soften at body temperature, releasing the active ingredient inside the orifice. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include vehicles such as hardeners that produce a melting point near body temperature when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and suitable mixtures of mono-, di- and triglycerides of fatty acids, hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; glycerinated gelatin. Combinations of various vehicles may be used. Rectal and vaginal suppositories can be prepared by the compressed method or by molding. The typical weight of a rectal and vaginal suppository is about 2 g to 3 g.

[0112] The pharmaceutical compositions provided herein may be in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts and implants. The compound can be administered ophthalmologically in such a form.

[0113] The pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions can be provided in the form of aerosols or liquids for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to generate a fine mist, or a nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions can also be provided as dry powders for insufflation, alone or in combination with an inert carrier, such as lactose or phospholipids; and nasal drops. For intranasal use, the powders can include bioadhesives, including chitosan or cyclodextrin.

[0114] Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers or nebulizers can be formulated to contain ethanol, aqueous ethanol or a suitable alternative to disperse, solubilize or extend the release of the active ingredients provided herein, a propellant as a solvent; and / or a surfactant, such as sorbitan trioleate, oleic acid or oligolactic acid.

[0115] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as 50 micrometers or less, or 10 micrometers or less.Particles of such size can be prepared using comminution methods known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0116] Capsules, blisters and cartridges for use in an inhaler or insufflator may contain a powder mix of the pharmaceutical composition provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as l- It can be formulated to contain leucine, mannitol or magnesium stearate. Lactose can be anhydrous or in the form of monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. The pharmaceutical composition provided herein for inhalation / intranasal administration can further contain suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.

[0117] The pharmaceutical compositions provided herein for topical administration can be formulated to be immediate or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release. modified release

[0118] The pharmaceutical compositions provided herein can be formulated as modified release dosage forms. As used herein, the term "modified release" refers to a dosage form in which the rate or location of release of active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include delayed release dosage forms, extended release dosage forms, prolonged release dosage forms, sustained release dosage forms, pulsatile or pulsed release dosage forms, controlled release dosage forms, accelerated and fast release dosage forms, targeted release dosage forms, programmed release dosage forms and gastric retention dosage forms. The pharmaceutical compositions in modified release dosage forms can be prepared using various modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of active ingredient(s) can also be modified by changing the particle size and polymorphorism of active ingredient(s).

[0119] Examples of modified release are described in, but not limited to, U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,47 4; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500. Matrix Controlled Release Device

[0120] The pharmaceutical compositions provided herein in modified release dosage forms can be fabricated using matrix controlled release devices known to those skilled in the art (Takada et al., "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz, Ed., Wiley, 1999). (see, e.g.,

[0121] In one embodiment, the pharmaceutical compositions provided herein in modified release dosage forms are formulated using erodible matrix devices that are water-swellable, erodible or soluble polymers, including synthetic polymers, and naturally occurring polymers and derivatives such as polysaccharides and proteins.

[0122] Materials useful in forming the erodible matrix include, but are not limited to, chitin, chitosan, dextran and pullulan; agar gum, gum arabic, gum karaya, locust bean gum, tragacanth gum, carrageenan, gum ghatti, guar gum, xanthan gum and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulosics, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydrogels, and the like. Hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT) and ethyl hydroxyethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic or methacrylic acid (EUDRAGIT®, Rohm copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acidglycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

[0123] In another embodiment, the pharmaceutical composition is formulated with a non-erodible matrix device: the active ingredient is dissolved or dispersed in an inert matrix and, once administered, is released primarily by diffusion through the inert matrix. Materials suitable for use as non-erodible matrix devices include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, and; hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone, and crosslinked partially hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax. wax), microcrystalline wax and triglycerides.

[0124] In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the type of polymer used, the polymer viscosity, the particle size of the polymer and / or the active ingredient(s), the ratio of active ingredient(s) to polymer, and other excipients in the composition.

[0125] Pharmaceutical compositions provided herein in modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt-granulation followed by compression. Osmotic Controlled Release Devices

[0126] The pharmaceutical composition provided herein in modified release dosage form can be fabricated using osmotic controlled release devices, including one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruded core system (ECS).In general, such devices have at least two components: (a) a core that contains active ingredient(s); and (b) a semipermeable membrane that encapsulates the core and has at least one delivery port.The semipermeable membrane controls the influx of water from the aqueous environment of use into the core to cause drug release by extrusion through delivery port(s).

[0127] In addition to the active ingredient(s), the core of the osmotic device optionally contains an osmotic agent that creates a driving force for the transport of water from the environment of use to the core of the device. One class of osmotic agents are water-swellable hydrophilic polymers, also referred to as "osmopolymers" and "hydrogels," including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, copolymers of PVA / PVP with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0128] Another class of osmotic agents are osmogens, which can absorb water and thus affect the osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride and sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid and tartaric acid; urea; and mixtures thereof.

[0129] Osmotic agents with different dissolution rates can be used to affect how rapidly the active ingredient(s) is initially delivered from the dosage form. Amorphous sugars such as EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first two hours to rapidly produce the desired therapeutic effect, and to provide a gradual and continuous release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time, in which the active ingredient(s) are released at a rate to replace the amount of active ingredient metabolized and excreted.

[0130] The core can also contain a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to facilitate stability or processing.

[0131] Materials useful in forming semipermeable membranes include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water permeable and water insoluble at physiologically relevant pH or are susceptible to being rendered water insoluble by chemical modification such as crosslinking. Examples of suitable polymers useful in forming coatings include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylamino acetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, triacetate, cellulose acetate ... Amylose acetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, hydroxlated ethylene vinyl acetate, EC, PEG, PPG, PEG / PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0132] The semipermeable membrane may be a hydrophobic microporous membrane, in which the pores are substantially filled with gas and are not wetted by aqueous media but are permeable to water, as disclosed in U.S. Patent No. 5,798,119. Such hydrophobic but water-permeable membranes are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinylidene fluorides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0133] The delivery port(s) on the semipermeable membrane can be formed after coating by mechanical or laser drilling. The delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over a notch in the core. In addition, the delivery port can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patents 5,612,059 and 5,698,220.

[0134] The total amount and release rate of the active ingredient(s) released can be substantially controlled via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size and location of the delivery ports.

[0135] The pharmaceutical composition in an osmotic controlled release dosage form may further comprise additional conventional excipients as described herein to facilitate performance or processing of the formulation.

[0136] Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release, 1995, Vol. 35, pp. 1-21; Verma et al., Drug Development and Industrial Pharmacy, 2000, Vol. 26, pp. 695-708; Verma et al., J. Controlled Release, 2002, Vol. 79, pp. 7-27).

[0137] In certain embodiments, the pharmaceutical composition provided herein is formulated as an AMT controlled release dosage form comprising an asymmetric osmotic membrane that coats the core that comprises active ingredient(s) and other pharmaceutical acceptable excipients.See US Patent No. 5,612,059 and WO2002 / 17918.AMT controlled release dosage form can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation and dip-coating method.

[0138] In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled release dosage forms comprising an osmotic membrane coating a core comprising the active ingredient(s), hydroxyethyl cellulose and other pharmaceutically acceptable excipients. Multiparticulate controlled release devices

[0139] The pharmaceutical composition provided herein in modified release dosage form can be fabricated as a multiparticulate controlled release device, comprising a variety of particles, granules or pellets with diameters ranging from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or about 100 μm to 1 mm.Such multiparticulates can be produced by processes known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compaction, melt congealing, and by spray coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

[0140] Other excipients as described herein can be blended with the pharmaceutical composition to aid in processing and forming the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated with various film-forming materials such as enteric polymers, water-swellable polymers and water-soluble polymers. The multiparticulates can be further processed into capsules or tablets. targeted delivery

[0141] The pharmaceutical compositions provided herein can also be formulated to be targeted to particular tissues, receptors or other areas of the subject's body to be treated, including using liposome-based delivery systems, resealed erythrocyte-based delivery systems, and antibody-based delivery systems. Examples include, but are not limited to, U.S. Patent Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874. Dosage

[0142] In the treatment, prevention or amelioration of one or more symptoms of schizophrenia or schizoaffective disorder or other conditions, disorders or diseases associated with VMAT2 inhibition, suitable dosage levels are generally about 0.001 mg to 100 mg per kg of patient body weight per day (mg / kg per day), about 0.01 mg / kg to about 80 mg / kg per day, about 0.1 mg / kg to about 50 mg / kg per day, about 0.5 mg / kg to about 25 mg / kg per day, or about 1 mg / kg to about 20 mg / kg per day, which can be administered in single or multiple doses. Within this range, dosages may be from 0.005 mg / kg to 0.05 mg / kg, 0.05 mg / kg to 0.5 mg / kg, or 0.5 mg / kg to 5.0 mg / kg, 1 mg / kg to 15 mg / kg, 1 mg / kg to 20 mg / kg, or 1 mg / kg to 50 mg / kg per day. In certain embodiments, dosage levels are from about 0.001 mg / kg to 100 mg / kg per day. In certain embodiments, dosage levels are from about 5.0 mg to 150 mg per day, and in certain embodiments, from 10 mg to 100 mg per day. In other embodiments, dosage levels are from about 25 mg / kg to about 100 mg / kg per day. In certain embodiments, dosage levels are from about 0.01 mg / kg to about 40 mg / kg per day. In certain embodiments, the dosage level is about 0.1 mg / kg to about 80 mg / kg per day. In certain embodiments, the dosage level is about 0.1 mg / kg to about 50 mg / kg per day. In certain embodiments, the dosage level is about 0.1 mg / kg to about 40 mg / kg per day. In certain embodiments, the dosage level is about 0.5 mg / kg to about 80 mg / kg per day. In certain embodiments, the dosage level is about 0.5 mg / kg to about 40 mg / kg per day. In certain embodiments, the dosage level is about 0.5 mg / kg to about 25 mg / kg per day. In certain embodiments, the dosage level is about 1 mg / kg to about 80 mg / kg per day. In certain embodiments, the dosage level is about 1 mg / kg to about 75 mg / kg per day.In certain embodiments, the dosage level is about 1 mg / kg to about 50 mg / kg per day. In certain embodiments, the dosage level is about 1 mg / kg to about 40 mg / kg per day. In certain embodiments, the dosage level is about 1 mg / kg to about 25 mg / kg per day. In certain embodiments, the dosage level is about 80 mg per day. In certain embodiments, the dosage level is about 40 mg per day.

[0143] For oral administration, the pharmaceutical composition can be provided in the form of a tablet containing 1.0 mg to 1,000 mg of active ingredient, in particular about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, about 75 mg, about 80 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 750 mg, about 800 mg, about 900 mg and about 1,000 mg of active ingredient, for symptomatic adjustment of dosage to the patient to be treated.In certain embodiments, the pharmaceutical composition can be provided in the form of a tablet containing about 100 mg of active ingredient.In certain embodiments, the pharmaceutical composition can be provided in the form of a tablet containing about 80 mg of active ingredient.In certain embodiments, the pharmaceutical composition can be provided in the form of a tablet containing about 75 mg of active ingredient. In certain embodiments, the pharmaceutical composition can be provided in the form of a tablet containing about 50 mg of active ingredient.In certain embodiments, the pharmaceutical composition can be provided in the form of a tablet containing about 40 mg of active ingredient.In certain embodiments, the pharmaceutical composition can be provided in the form of a tablet containing about 25 mg of active ingredient.The composition can be administered in a regimen of 1 to 4 times per day, including 1, 2, 3 and 4 times per day.

[0144] It will be understood, however, that the specific dose level and frequency of administration for any particular patient may vary and will depend upon a variety of factors, including the activity of the particular compound employed, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host being treated.

[0145] Also provided herein is a method for regulating VMAT2 activity, comprising contacting one or more solid form compounds as provided herein with transporter.In one embodiment, transporter is expressed by cell.

[0146] The compounds provided herein can also be combined or used in combination with other agents useful in the treatment, prevention, or amelioration of one or more symptoms of the diseases or conditions for which the compounds provided herein are useful, including schizophrenia or schizoaffective disorder, and other conditions commonly treated with antipsychotic medication.

[0147] In one embodiment, the compounds provided herein can also be combined or used in combination with typical antipsychotic drugs.In a specific embodiment, the typical antipsychotic drug is fluphenazine, haloperidol, loxapine, molindone, perphenazine, pimozide, sulpiride, thioridazine or trifluoperazine.In another specific embodiment, the antipsychotic drug is an atypical antipsychotic drug.In a more specific embodiment, the atypical antipsychotic drug is aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone or ziprasidone.In a specific embodiment, the atypical antipsychotic drug is clozapine.

[0148] These other agents or drugs can be administered simultaneously or sequentially with the compounds provided herein by their commonly used route and amount.When the microparticles provided herein are used simultaneously with one or more other drugs, the pharmaceutical composition containing these other drugs in addition to the compounds provided herein can be utilized, but is not necessary.Therefore, the pharmaceutical compositions provided herein include those that contain one or more other active ingredients or therapeutic agents in addition to the compounds provided herein.

[0149] The weight ratio of the compound provided herein to the second active ingredient can vary and depends on the effective dose of each ingredient.In general, each effective dose is used.Thus, for example, when the compound provided herein is used in combination with a second drug or a pharmaceutical composition containing such other drug, the weight ratio of microparticles to the second drug can range from about 1,000:1 to about 1:1,000, or from about 200:1 to about 1:200.The combination of the microparticles provided herein and other active ingredients is also generally within the above range, but in each case, the effective dose of each active ingredient should be used. Pharmacokinetic properties

[0150] In certain embodiments, (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant, or a pharma- ceutically acceptable salt or polymorph thereof, is metabolized in vivo to its active form, (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, also known as dihydrotetrabenazine: (+)α-DHTBZ, which is believed to be the most active metabolite (see, e.g., Kilbourn et al., Chirality, 1997, (See Volume 9, pages 59-62.)

[0151] In one embodiment, (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant thereof, or a pharma- ceutically acceptable salt or polymorph thereof, is administered at a maximum blood plasma concentration (C) of between about 15 ng and about 60 ng of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) per mL of plasma. max ) and a minimum blood plasma concentration (C) of at least 15 ng of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) per mL of plasma. min Provided herein is a method for treating schizophrenia or schizoaffective disorder, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising:

[0152] In other embodiments, references in the methods described herein to plasma concentrations of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) include deuterated (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) and non-deuterated (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R Deuterated VMAT2 inhibitors as described herein (e.g., deuterated (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or deuterated (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester) are also included. It will be apparent to one skilled in the art that if deuterated (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol) is administered to a subject, deuterated (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol will appear in the blood plasma of the subject and be measured.A non-deuterated VMAT2 inhibitor as described herein (e.g., non-deuterated (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or non-deuterated (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester) If deuterated (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol is administered to a subject, undeuterated (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol will appear in the blood plasma of the subject and be measured. If a combination of deuterated and non-deuterated VMAT2 inhibitors as described herein is administered to a subject, both deuterated and non-deuterated (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol will appear in the blood plasma of the subject and both will be measured.

[0153] In certain embodiments, the C of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) max is about 15 ng / mL, about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL or about 60 ng / mL plasma. In certain embodiments, the C of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) minis at least 15 ng / mL, at least 20 ng / mL, at least 25 ng / mL, at least 30 ng / mL, or at least 35 ng / mL plasma over a period of 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, 28 hours, or 32 hours. In certain embodiments, the C of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) min is between about 15 ng / mL and about 35 ng / mL.

[0154] In one embodiment, the pharmaceutical composition comprises a C of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) of about 15 ng / mL to about 60 ng / mL plasma. max and C max Approximately at least 33% of C min In another embodiment, the pharmaceutical composition is administered in an amount sufficient to provide about 15 ng / mL to about 60 ng / mL plasma C of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ). max and C max Approximately at least 50% of C min In certain particular embodiments, the pharmaceutical composition provides a C of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) of about 15 ng / mL to about 60 ng / mL plasma. max and C max Approximately at least 33%~50% C min is administered in an amount sufficient to provide

[0155] In certain embodiments, the pharmaceutical composition has a C of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) of about 15 ng / mL to about 60 ng / mL plasma. max and C max Approximately at least 33% of C min In yet another specific embodiment, the pharmaceutical composition is administered in an amount sufficient to provide a C of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) of about 15 ng / mL to about 60 ng / mL plasma. max and C max Approximately at least 50% of C min In certain particular embodiments, the pharmaceutical composition provides a C of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) of about 15 ng / mL to about 60 ng / mL plasma. max and C max Approximately at least 33%~50% C min is administered in an amount sufficient to provide

[0156] In another embodiment, the pharmaceutical composition provides to a subject in need thereof about 15 ng / mL to about 60 ng / mL plasma C of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ). max and C between about 5 ng / mL and about 30 ng / mL plasma minIn yet another embodiment, the pharmaceutical composition is administered to a subject in need thereof in an amount that provides about 15 ng / mL to about 60 ng / mL plasma C of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ). max and C between about 7.5 ng / mL and about 30 ng / mL plasma min is administered in an amount that provides

[0157] In another embodiment, (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant thereof; or a pharma- ceutically acceptable salt or polymorph thereof, is administered in a dose-dependent manner in the presence of: (i) about 15 ng to about 60 ng of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R Provided herein is a method for treating schizophrenia or schizoaffective disorder, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising: (i) a therapeutic concentration range of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ); and (ii) a threshold concentration of at least 15 ng per mL of plasma of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) over a period of about 8 to about 24 hours.

[0158] In certain embodiments, the therapeutic concentration range is from about 15 ng to about 35 ng, about 40 ng, about 45 ng, about 50 ng or about 55 ng of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) per mL of plasma.

[0159] In certain embodiments, the threshold concentration of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) is about 15 ng / mL, about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL or about 60 ng / mL plasma for a period of about 8 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours or about 32 hours. In certain embodiments, the threshold concentration of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) is between about 15 ng / mL and about 35 ng / mL for a period of about 8 hours to about 24 hours.

[0160] Plasma concentrations of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, and compounds as disclosed herein, can be measured by methods as described in Derangula et al., Biomedical Chromatography, 2013, 27(6):792-801; Mehvar et al., Drug Metabolism and Distribution, 1987, 15(2):250-55, and generally by tandem mass spectrometry.

[0161] These and other changes can be made to the embodiments in light of the above detailed description. While specific embodiments have been described herein for illustrative purposes, various modifications of the above modes for carrying out the disclosure that are obvious to those skilled in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated by reference into this specification as if each such publication, patent, or patent application was specifically and individually indicated to be incorporated by reference into this specification. In certain embodiments, for example, the following items are provided: (Item 1) 1. A method of treating schizophrenia or schizoaffective disorder comprising administering (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant thereof, or a pharma- ceutically acceptable salt or polymorph thereof. (Item 2) 1. A method for treating behavioral problems associated with schizophrenia or schizoaffective disorder comprising administering (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant thereof, or a pharma- ceutically acceptable salt or polymorph thereof. (Item 3) The method according to item 1 or 2, wherein the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant thereof, or a pharma- ceutically acceptable salt or polymorph thereof, is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or a polymorph thereof. (Item 4) 4. The method according to any of items 1 to 3, for treating positive symptoms. (Item 5) 4. The method according to any of items 1 to 3, for treating negative symptoms. (Item 6) 6. The method according to any of items 1 to 5, wherein the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant thereof, or a pharma- ceutically acceptable salt or polymorph thereof, is in the form of a dosage unit. (Item 7) 7. The method of claim 6, wherein the dosage unit contains 25 mg to 100 mg of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant or polymorph thereof. (Item 8) 8. The method of claim 7, wherein the dosage unit contains 40 mg of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant or polymorph thereof. (Item 9) 9. The method of claim 8, wherein the dosage unit contains 80 mg of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant or polymorph thereof. (Item 10) 9. The method according to any of items 6 to 8, wherein the dosage unit is a tablet or a capsule. (Item 11) The compound (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or an isotopic variant thereof, or a pharma- ceutically acceptable salt or polymorph thereof, for use in treating schizophrenia or schizoaffective disorder. (Item 12) 12. The compound for use according to item 11, wherein said compound is formulated for oral administration. (Item 13) 13. The compound for use according to item 11 or 12, wherein said compound is formulated as a single dosage form. (Item 14) 14. The compound for use according to item 13, wherein said dosage form is a tablet or a capsule. (Item 15) 15. The compound for use according to item 13 or 14, wherein the dosage form contains 40 mg of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or a polymorph thereof. (Item 16) 15. The compound for use according to item 13 or 14, wherein the dosage form contains 80 mg of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or a polymorph thereof.

Claims

[Claim 1] An object, method or system as described in the present specification and drawings.

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