Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
  • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
  • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
  • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

• Dysregulation of dopaminergic systems is integral to several central nervous system (CNS) disorders, including neurological and psychiatric diseases and disorders. These neurological and psychiatric diseases and disorders include hyperkinetic movement disorders, and conditions such as schizophrenia and mood disorders.
• the transporter protein vesicular monoamine transporter-2 (VMAT2) plays an important role in presynaptic dopamine release and regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release.
• valbenazine which has the following chemical structure:
• valbenazine ditosylate A formulation of valbenazine:4-toluenesulfonate (1:2) (referred to herein as “valbenazine ditosylate”) has been previously reported in the FDA approved drug label Ingrezza®.
• VMAT2 inhibitor such as valbenazine or (+)- ⁇ -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof, wherein the patient is also being treated with another substance which may interact with the VMAT2 inhibitor, such as digoxin.
• a VMAT2 inhibitor such as valbenazine or (+)- ⁇ -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof
• VMAT2 vesicular monoamine transport 2
• VMAT2 inhibitor chosen from valbenazine and (+)- ⁇ -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof
• VMAT2 vesicular monoamine transport 2
• a method of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)- ⁇ -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof comprising: administering to the patient a therapeutically effective amount of the VMAT2 inhibitor, subsequently determining that the patient is to begin treatment with digoxin, and continuing administration of the therapeutically effective amount of the VMAT2 inhibitor to the patient.
• VMAT2 vesicular monoamine transport 2
• VMAT2 vesicular monoamine transport 2
• valbenazine may be referred to as (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 as L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester or as NBI-98854.
• (+)- ⁇ -HTBZ means the compound which is an active metabolite of valbenazine having the structure:
• NBI-136110 means the compound which is a metabolite of valbenazine having the structure:
• isotopic variant means a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound.
• an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but 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
• an “isotopic variant” of a compound is in a stable form, that is, non-radioactive.
• an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13 ( 13 C), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-16 ( 16 O), oxygen-17 ( 17 O), and oxygen-18 ( 18 O).
• an “isotopic variant” of a compound is in an unstable form, that is, radioactive.
• an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3 H), carbon-11 ( 14 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), oxygen-14 ( 14 O), and oxygen-15 ( 15 O).
• any hydrogen can be 2 H, as example, or any carbon can be 13 C, as example, or any nitrogen can be 15 N, as example, and any oxygen can be 18 O, as example, where feasible according to the judgment of one of skill in the art.
• an “isotopic variant” of a compound contains an unnatural proportion of deuterium.
• a position designated as having deuterium typically has a minimum isotopic enrichment factor of, in certain embodiments, 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)
• hypokinetic disorder or “hyperkinetic movement disorder” or “hyperkinesias” refers to disorders or diseases characterized by excessive, abnormal, involuntary movements. These neurological disorders include tremor, dystonia, myoclonus, athetosis, Huntington's disease, tardive dyskinesia, Tourette syndrome, dystonia, hemiballismus, chorea, senile chorea, or tics.
• Tardive dyskinesia is characterized by rapid, repetitive, stereotypic, involuntary movements of the face, limbs, or trunk.
• AUC refers to the area under the curve, or the integral, of the plasma concentration of an active pharmaceutical ingredient or metabolite over time following a dosing event.
• AUC 0-t is the integral under the plasma concentration curve from time 0 (dosing) to time “t”.
• AUC 0-t is the AUC from time 0 (dosing) to time infinity. Unless otherwise stated, AUC refers to AUC 0- ⁇ .
• a drug is packaged in a salt form, for example valbenazine ditosylate, and the dosage form strength refers to the mass of this salt form or the equivalent mass of the corresponding free base, valbenazine.
• C max is a pharmacokinetic parameter denoting the maximum observed blood plasma concentration following delivery of an active pharmaceutical ingredient. C max occurs at the time of maximum plasma concentration, t max .
• adjusting administration As used herein, “adjusting administration”, “altering administration”, “adjusting dosing”, or “altering dosing” are all equivalent and mean tapering off, reducing or increasing the dose of the substance, ceasing to administer the substance to the patient, or substituting a different active agent for the substance.
• administering to a patient refers to the process of introducing a composition or dosage form into the patient via an art-recognized means of introduction.
• disorder is intended to be generally synonymous, and is used interchangeably with, the terms “disease,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms.
• a “dose” means the measured quantity of an active agent to be taken at one time by a patient.
• the quantity is the molar equivalent to the corresponding amount of valbenazine free base.
• a drug is packaged in a pharmaceutically acceptable salt form, for example valbenazine ditosylate, and the dosage for strength refers to the mass of the molar equivalent of the corresponding free base, valbenazine.
• 73 mg of valbenazine tosylate is the molar equivalent of 40 mg of valbenazine free base.
• dose regimen means the dose of an active agent taken at a first time by a patient and the interval (time or symptomatic) at which any subsequent doses of the active agent are taken by the patient such as from about 20 to about 160 mg once daily, e.g., about 20, about 40, about 60, about 80, about 100, about 120, or about 160 mg once daily.
• the additional doses of the active agent can be different from the dose taken at the first time.
• labeling means all labels or other means of written, printed, graphic, electronic, verbal, or demonstrative communication that is upon a pharmaceutical product or a dosage form or accompanying such pharmaceutical product or dosage form.
• “Medication Guide” means an FDA-approved patient labeling for a pharmaceutical product conforming to the specifications set forth in 21 CFR 208 and other applicable regulations which contains information for patients on how to safely use a pharmaceutical product.
• a medication guide is scientifically accurate and is based on, and does not conflict with, the approved professional labeling for the pharmaceutical product under 21 CFR 201.57, but the language need not be identical to the sections of approved labeling to which it corresponds.
• a medication guide is typically available for a pharmaceutical product with special risk management information.
• patient package insert means information for patients on how to safely use a pharmaceutical product that is part of the FDA-approved labeling. It is an extension of the professional labeling for a pharmaceutical product that may be distributed to a patient when the product is dispensed which provides consumer-oriented information about the product in lay language, for example it may describe benefits, risks, how to recognize risks, dosage, or administration.
• “pharmaceutically acceptable” refers to a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
• pharmaceutically acceptable refers to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
• “Pharmacologically active” as in a “pharmacologically active” (or “active”) derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.
• pharmaceutically acceptable salts include acid addition salts which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
• a “product” or “pharmaceutical product” means a dosage form of an active agent plus published material, and optionally packaging.
• published material means a medium providing information, including printed, audio, visual, or electronic medium, for example a flyer, an advertisement, a product insert, printed labeling, an internet web site, an internet web page, an internet pop-up window, a radio or television broadcast, a compact disk, a DVD, an audio recording, or other recording or electronic medium.
• risk means the probability or chance of adverse reaction, injury, or other undesirable outcome arising from a medical treatment.
• An “acceptable risk” means a measure of the risk of harm, injury, or disease arising from a medical treatment that will be tolerated by an individual or group. Whether a risk is “acceptable” will depend upon the advantages that the individual or group perceives to be obtainable in return for taking the risk, whether they accept whatever scientific and other advice is offered about the magnitude of the risk, and numerous other factors, both political and social.
• An “acceptable risk” of an adverse reaction means that an individual or a group in society is willing to take or be subjected to the risk that the adverse reaction might occur since the adverse reaction is one whose probability of occurrence is small, or whose consequences are so slight, or the benefits (perceived or real) of the active agent are so great.
• An “unacceptable risk” of an adverse reaction means that an individual or a group in society is unwilling to take or be subjected to the risk that the adverse reaction might occur upon weighing the probability of occurrence of the adverse reaction, the consequences of the adverse reaction, and the benefits (perceived or real) of the active agent.
• “At risk” means in a state or condition marked by a high level of risk or susceptibility. Risk assessment consists of identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a product.
• safety means the incidence or severity of adverse events associated with administration of an active agent, including adverse effects associated with patient-related factors (e.g., age, gender, ethnicity, race, target illness, abnormalities of renal or hepatic function, co-morbid illnesses, genetic characteristics such as metabolic status, or environment) and active agent-related factors (e.g., dose, plasma level, duration of exposure, or concomitant medication).
• patient-related factors e.g., age, gender, ethnicity, race, target illness, abnormalities of renal or hepatic function, co-morbid illnesses, genetic characteristics such as metabolic status, or environment
• active agent-related factors e.g., dose, plasma level, duration of exposure, or concomitant medication
• t max is a pharmacokinetic parameter denoting the time to maximum blood plasma concentration following delivery of an active pharmaceutical ingredient
• t 1/2 or “plasma half-life” or “elimination half-life” or the like is a pharmacokinetic parameter denoting the apparent plasma terminal phase half-life, i.e., the time, after absorption and distribution of a drug is complete, for the plasma concentration to fall by half.
• 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 cellular cytosol into synaptic vesicles.
• VMAT2 inhibitor refers to the ability of a compound disclosed herein to alter the function of VMAT2.
• a VMAT2 inhibitor may block or reduce the activity of VMAT2 by forming a reversible or irreversible covalent bond between the inhibitor and VMAT2 or through formation of a noncovalently bound complex. Such inhibition may be manifest only in particular cell types or may be contingent on a particular biological event.
• VMAT2 inhibitor also refers to altering the function of VMAT2 by decreasing the probability that a complex forms between a VMAT2 and a natural substrate.
• VMAT2 vesicular monoamine transport 2
• VMAT2 inhibitor chosen from valbenazine and (+)- ⁇ -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof
• the method further comprises determining whether the patient is being administered digoxin. monitoring the patient for signs and symptoms of digoxin toxicity and clinical response.
• VMAT2 vesicular monoamine transport 2
• a method of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)- ⁇ -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof comprising: administering to the patient a therapeutically effective amount of the VMAT2 inhibitor, subsequently determining that the patient is to begin treatment with digoxin, and continuing administration of the therapeutically effective amount of the VMAT2 inhibitor to the patient.
• VMAT2 vesicular monoamine transport 2
• the method further comprises monitoring the patient signs and symptoms of digoxin toxicity and clinical response.
• the method further comprises reducing the amount of the digoxin administered to the patient based on the patient's ability to tolerate one or more digoxin exposure-related adverse reactions.
• VMAT2 vesicular monoamine transport 2
• the method further comprises informing the patient or a medical care worker that co-administration of the VMAT2 inhibitor and digoxin may result in increased risk of one or more digoxin exposure-related adverse reactions.
• monitoring for signs and symptoms of digoxin toxicity and clinical response comprises determining whether the patient experiences one or more exposure-related adverse reaction associated with serum digoxin concentration.
• digoxin toxicity is indicated by anorexia, nausea, vomiting, visual changes and cardiac arrhythmias [first-degree, second-degree (Wenckebach), or third-degree heart block (including asystole); atrial tachycardia with block; AV dissociation; accelerated junctional (nodal) rhythm; unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation].
• Toxicity is usually associated with digoxin levels greater than 2 ng/ml although symptoms may also occur at lower levels.
• the method further comprises obtaining a baseline serum digoxin concentration prior to administering to the patient the therapeutically effective amount of the VMAT2 inhibitor.
• the method further comprises comparing the baseline serum digoxin concentration to the serum digoxin concentration after administering to the patient the therapeutically effective amount of the VMAT2 inhibitor.
• the dosage and/or frequency of administration of the digoxin is reduced.
• the dosage of digoxin is decreased.
• the frequency of administration of the digoxin is decreased.
• the amount of digoxin being administered is 10-90% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor.
• the amount of digoxin being administered is 20-80% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor.
• the amount of digoxin being administered is 30-70% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor.
• the amount of digoxin being administered is 40-60% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor.
• the amount of digoxin being administered is 50% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor.
• the amount of digoxin being administered to a patient is reduced to, for example, 75% or less, 50% or less, or 25% or less of the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor.
• the VMAT2 inhibitor is administered to the patient to treat a neurological or psychiatric disease or disorder.
• the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, mania in mood disorder, depression in mood disorder, treatment-refractory obsessive compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, Fragile X syndrome or Fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or chorea-acanthocytosis.
• the VMAT2 inhibitor is administered orally.
• the VMAT2 inhibitor is administered in the form of a tablet or capsule.
• the VMAT2 inhibitor is an isotopic variant that is L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d 3 )-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester or a pharmaceutically acceptable salt thereof.
• the VMAT2 inhibitor is (+)- ⁇ -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof.
• the VMAT2 inhibitor is (+)- ⁇ -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol dihydrotetrabenazine or a pharmaceutically acceptable salt thereof.
• the VMAT2 inhibitor is administered in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 20 mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 40 mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 60 mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 80 mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 120 mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 160 mg of valbenazine free base.
• the VMAT2 inhibitor is administered for a first period of time in a first amount and then the amount is increased to a second amount.
• the first period of time is a week.
• the first amount is equivalent to about 40 mg of valbenazine free base.
• the second amount is equivalent to about 80 mg of valbenazine free base.
• the VMAT2 inhibitor is administered in an amount sufficient to achieve a maximal blood plasma concentration (C max ) of (+)- ⁇ -DHTBZ of between about 15 ng to about 60 ng per mL plasma and a minimal blood plasma concentration (C min ) of (+)- ⁇ -DHTBZ of at least 15 ng per mL plasma over an 8 hour period.
• C max maximal blood plasma concentration
• C min minimal blood plasma concentration
• the VMAT2 inhibitor is administered in an amount sufficient to achieve: (i) a therapeutic concentration range of about 15 ng to about 60 ng of (+)- ⁇ -DHTBZ per mL plasma; and (ii) a threshold concentration of at least 15 ng (+)- ⁇ -DHTBZ per mL plasma over a period of about 8 hours to about 24 hours.
• the C max of 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.
• the C min of R,R,R-DHTBZ is 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 hrs, 12 hrs, 16 hrs, 20 hrs, 24 hrs, 28 hrs, or 32 hrs. In certain embodiments, the C min of R,R,R-DHTBZ is between about 15 ng/mL to about 35 ng/mL.
• the pharmaceutical composition is administered in an amount sufficient to provide a C max of R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a C min of approximately at least 33% of the C max over a 24 hour period. In certain embodiments, the pharmaceutical composition is administered in an amount sufficient to provide a C max of R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a C min of approximately at least 50% of the C max over a 24 hour period.
• the pharmaceutical composition is administered in an amount sufficient to provide a C max of R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a C min of approximately between about at least 33%-50% of the C max over a 24 hour period.
• the pharmaceutical composition is administered in an amount sufficient to provide a C max of R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a C min of approximately at least 33% of the C max over a 12 hour period. In certain embodiments, the pharmaceutical composition is administered in an amount sufficient to provide a C max of R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a C min of approximately at least 50% of the C max over a 12 hour period.
• the pharmaceutical composition is administered in an amount sufficient to provide a C max of R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a C min of approximately between about at least 33%-50% of the C max over a 12 hour period.
• the pharmaceutical composition is administered to a subject in an amount that provides a C max of R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a C min of between about 5 ng/mL to about 30 ng/mL plasma over a 24 hour period. In certain embodiments, the pharmaceutical composition is administered to a subject in an amount that provides a C max of R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a C min of between about 7.5 ng/mL to about 30 ng/mL plasma over a 24 hour period.
• a method for treating neurological or psychiatric diseases or disorders comprises administering to a subject a pharmaceutical composition comprising the VMAT2 inhibitor, as an active pharmaceutical ingredient, in an amount sufficient to provide: (i) a therapeutic concentration range of about 15 ng to about 60 ng of R,R,R-DHTBZ per mL plasma; and (ii) a threshold concentration of at least 15 ng R,R,R-DHTBZ per mL plasma over a period of about 8 hours to about 24 hours.
• the therapeutic concentration range is about 15 ng to about 35 ng, to about 40 ng, to about 45 ng, to about 50 ng, or to about 55 ng R,R,R-DHTBZ per mL plasma.
• the threshold concentration of 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, over a period of about 8 hrs, about 12 hrs, about 16 hrs, about 20 hrs, about 24 hrs, about 28 hrs, or about 32 hrs. In certain embodiments, the threshold concentration of R,R,R-DHTBZ is between about 15 ng/mL to about 35 ng/mL over a period of about 8 hours to about 24 hours.
• Plasma concentrations may be measured by methods known in the art and generally by tandem mass spectroscopy.
• VMAT2 vesicular monoamine transport 2
• valbenazine and (+)- ⁇ -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a patient in need thereof wherein the patient has previously been determined to have been administered digoxin, comprising: administering to the patient a therapeutically effective amount of the VMAT2 inhibitor.
• VMAT2 vesicular monoamine transport 2
• VMAT2 vesicular monoamine transport 2
• valbenazine valbenazine and (+)- ⁇ -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a patient in need thereof, wherein the patient has previously been determined to have been administered digoxin, comprising: administering to the patient a therapeutically effective amount of the VMAT2 inhibitor, subsequently selecting the patient that is able to tolerate one or more digoxin exposure-related adverse reactions, and continuing administering the therapeutically effective amount of digoxin to the patient.
• VMAT2 vesicular monoamine transport 2
• Valbenazine can be prepared according to U.S. Pat. Nos. 8,039,627 and 8,357,697, the disclosure of each of which is incorporated herein by reference in its entirety. Tetrabenazine may be administered by a variety of methods including the formulations disclosed in PCT Publications WO 2010/018408, WO 2011/019956, and WO 2014/047167, the disclosure of each of which is incorporated herein by reference in its entirety. In certain embodiments, the valbenazine for use in the compositions and methods provided herein is in polymorphic Form I as disclosed in U.S. Ser. No. 15/338,214, the disclosure of which is incorporated herein by reference in its entirety.
• VMAT2 vesicular monoamine transport 2
• the patient is monitored for signs and symptoms of digoxin toxicity and clinical response.
• a reduced amount of the digoxin is administered to the patient based on the patient's ability to tolerate one or more digoxin exposure-related adverse reactions following administration of the composition comprising the therapeutically effective amount of the VMAT2 inhibitor.
• compositions for treating a patient in need of a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)- ⁇ -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, comprising the VMAT2 inhibitor, characterized in that the composition comprising a therapeutically effective amount of the VMAT2 inhibitor is administered to the patient subsequently determined to begin treatment with digoxin following administration of the composition comprising the therapeutically effective amount of the VMAT2 inhibitor.
• VMAT2 vesicular monoamine transport 2
• a reduced amount of the VMAT2 inhibitor is administered based on the patient's ability to tolerate one or more exposure-related adverse reactions following administration of the composition comprising a therapeutically effective amount of the VMAT2 inhibitor or the composition comprising a reduced amount of the VMAT2 inhibitor.
• VMAT2 vesicular monoamine transport 2
• the patient or a medical care worker is informed that co-administration of the VMAT2 composition and digoxin may result in increased digoxin exposure.
• the patient or a medical care worker is informed that co-administration of the VMAT2 composition and digoxin may result in increased risk of one or more digoxin exposure-related adverse reactions.
• the composition is for treating a neurological or psychiatric disease or disorder.
• the composition is administered orally.
• the composition is administered in the form of a tablet or capsule.
• the composition is administered with or without food.
• the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt and/or isotopic variant thereof. In certain embodiments, the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt thereof. In certain embodiments, the VMAT2 inhibitor is a valbenazine tosylate salt. In certain embodiments, the VMAT2 inhibitor is a ditosylate salt of valbenazine.
• the VMAT2 inhibitor is (+)- ⁇ -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof.
• the VMAT2 inhibitor is (+)- ⁇ -3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol dihydrotetrabenazine or a pharmaceutically acceptable salt thereof.
• the VMAT2 inhibitor is an isotopic variant that is (+)- ⁇ -3-isobutyl-9,10-di(methoxy-d 3 )-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.
• the composition is administered in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base. In certain embodiments, the composition is administered in an amount equivalent to about 20 mg of valbenazine free base. In certain embodiments, the composition is administered in an amount equivalent to about 40 mg of valbenazine free base. In certain embodiments, the composition is administered in an amount equivalent to about 60 mg of valbenazine free base. In certain embodiments, the composition is administered in an amount equivalent to about 80 mg of valbenazine free base. In certain embodiments, the composition is administered in an amount equivalent to about 120 mg of valbenazine free base. In certain embodiments, the composition is administered in an amount equivalent to about 160 mg of valbenazine free base.
• the composition is administered for a first period of time in a first amount and then the amount of the VMAT2 inhibitor is increased to a second amount of the VMAT2 inhibitor.
• the first period of time is a week.
• the first amount is equivalent to about 40 mg of valbenazine free base.
• the second amount is equivalent to about 80 mg of valbenazine free base.
• the composition is administered in an amount sufficient to achieve a maximal blood plasma concentration (C max ) of (+)- ⁇ -DHTBZ of between about 15 ng to about 60 ng per mL plasma and a minimal blood plasma concentration (C min ) of (+)- ⁇ -DHTBZ of at least 15 ng per mL plasma over an 8 hour period.
• C max maximal blood plasma concentration
• C min minimal blood plasma concentration
• the composition is administered in an amount sufficient to achieve a maximal blood plasma concentration (C max ) of (+)- ⁇ -DHTBZ of between about 15 ng to about 60 ng per mL plasma and a minimal blood plasma concentration (C min ) of approximately between about at least 33%-50% of the C max over a 12 hour period.
• C max maximal blood plasma concentration
• C min minimal blood plasma concentration
• the composition is administered in an amount sufficient to achieve: (i) a therapeutic concentration range of about 15 ng to about 60 ng of (+)- ⁇ -DHTBZ per mL plasma; and (ii) a threshold concentration of at least 15 ng (+)- ⁇ -DHTBZ per mL plasma over a period of about 8 hours to about 24 hours.
• the amount of digoxin being administered is 20-80% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor.
• the amount of digoxin being administered is 30-70% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor.
• the amount of digoxin being administered is 40-60% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor.
• compositions for use in treating neurological or psychiatric diseases or disorders comprising the VMAT2 inhibitor as an active pharmaceutical ingredient, in combination with one or more pharmaceutically acceptable carriers or excipients.
• the pharmaceutical compositions provided herein may be provided in unit dosage forms or multiple-dosage forms.
• Unit-dosage forms refer to physically discrete units suitable for administration to human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include ampoules, syringes, and individually packaged tablets and capsules. Unit dosage forms may 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.
• the pharmaceutical compositions provided herein may 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 may be formulated in various dosage forms for oral, parenteral, and topical administration.
• the pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art).
• the pharmaceutical compositions provided herein may be administered at once, or multiple times at intervals of time.
• dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing 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 regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
• 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, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups.
• the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.
• pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.
• Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression.
• Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized 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 husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyeth
• 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 may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.
• Suitable diluents include, but are not limited to, dicalcium 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 quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
• Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Vee gum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof.
• the amount of disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
• the pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
• compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
• Suitable glidants include colloidal silicon dioxide, CAB-0-SIL® (Cabot Co. of Boston, Mass.), and asbestos-free talc.
• Coloring agents include any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof.
• a color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, 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 polyvinylpyrolidone.
• Preservatives include glycerin, methyl and propylparaben, 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 and tartaric acid.
• Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
• compositions provided herein may be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets.
• Enteric coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach.
• Enteric-coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.
• Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.
• Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material.
• Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating.
• Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
• the pharmaceutical compositions provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
• the hard gelatin capsule also known as the dry-filled capsule (DFC)
• DFC dry-filled capsule
• the soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
• the soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid.
• liquid, semisolid, and solid dosage forms may be encapsulated in a capsule.
• suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides.
• the capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
• compositions provided herein may be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.
• An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil.
• Emulsions may include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative.
• Suspensions may include a pharmaceutically acceptable suspending agent and preservative.
• Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde (the term “lower” means an alkyl having between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol.
• Elixirs are clear, sweetened, and hydroalcoholic solutions.
• Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative.
• a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
• liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or polyalkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
• a dialkylated mono- or polyalkylene glycol including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
• formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
• antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
• antioxidants such as but
• compositions provided herein for oral administration may be also provided in the forms of liposomes, micelles, microspheres, or nanosystems.
• compositions provided herein may be provided as noneffervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
• Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents.
• Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide. Coloring and flavoring agents can be used in all of the above dosage forms.
• the pharmaceutical compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
• compositions provided herein may be co-formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action, such as antacids, proton pump inhibitors, and Hz-receptor antagonists.
• compositions provided herein may be administered parenterally by injection, infusion, or implantation, for local or systemic administration.
• Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.
• compositions provided herein may be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
• dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science.
• compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, 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.
• aqueous vehicles water-miscible vehicles
• non-aqueous vehicles non-aqueous vehicles
• antimicrobial agents or preservatives against the growth of microorganisms stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emuls
• Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide.
• Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl phydroxybenzates, thimerosal, benzalkonium chloride, benzethonium chloride, methyl- and propylparabens, and sorbic acid.
• Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose.
• Suitable buffering agents include, but are not limited to, phosphate and citrate.
• Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite.
• Suitable local anesthetics include, but are not limited to, procaine hydrochloride.
• Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
• Suitable emulsifying agents include those 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.
• compositions provided herein may be formulated for single or multiple dosage administration.
• the single dosage formulations are packaged in an ampule, a vial, or a syringe.
• the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
• the pharmaceutical compositions are provided as ready-to-use sterile solutions.
• the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use.
• the pharmaceutical compositions are provided as ready-to-use sterile suspensions.
• the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use.
• the pharmaceutical compositions are provided as ready-to-use sterile emulsions.
• the pharmaceutical compositions may be formulated as a suspension, solid, semisolid, or thixotropic liquid, for administration as an implanted depot.
• the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
• Suitable inner matrixes include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
• Suitable outer polymeric membranes include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
• compositions provided herein may be administered topically to the skin, orifices, or mucosa.
• topical administration include (intra)dermal, conjuctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, uretheral, respiratory, and rectal administration.
• compositions provided herein may be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, dermal patches.
• the topical formulation of the pharmaceutical compositions provided herein may also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.
• 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 the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, 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.
• compositions may also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection, such as POWDERJECTTM (Chiron Corp., Emeryville, Calif.), and BIOJECTTM (Bioject Medical Technologies Inc., Tualatin, Oreg.).
• electroporation iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection
• BIOJECTTM Bioject Medical Technologies Inc., Tualatin, Oreg.
• Suitable ointment vehicles include oleaginous or hydrocarbon bases, including such as lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption bases, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable bases, such as hydrophilic ointment; water-soluble ointment bases, including polyethylene glycols of varying molecular weight; 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. These vehicles are emollient but generally require addition of antioxidants and preservatives.
• Suitable cream base can 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 is also called the “internal” phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
• the aqueous phase usually, although 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.
• Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, Carbopol®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin.
• dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
• compositions provided herein may be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas.
• These dosage forms can be manufactured using conventional processes.
• Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices.
• Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include vehicles, such as stiffening agents, which produce a melting point in the proximity of 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 appropriate mixtures of mono-, di- and triglycerides of fatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; glycerinated gelatin. Combinations of the various vehicles may be used. Rectal and vaginal suppositories may be prepared by the compressed method or molding. The typical weight of a rectal and vaginal suppository is about 2 to 3 g.
• compositions provided herein may be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.
• the pharmaceutical compositions provided herein may be administered intranasally or by inhalation to the respiratory tract.
• the pharmaceutical compositions may be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or 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.
• atomizer such as an atomizer using electrohydrodynamics to produce a fine mist, or 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.
• a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.
• Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer may be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein, a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
• compositions provided herein may be micronized to a size suitable for delivery by inhalation, such as 50 micrometers or less, or 10 micrometers or less.
• Particles of such sizes may be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
• Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as /-leucine, mannitol, or magnesium stearate.
• the lactose may be anhydrous or in the form of the monohydrate.
• Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
• the pharmaceutical compositions provided herein for inhaled/intranasal administration may further comprise a suitable flavor, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.
• compositions provided herein for topical administration may be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.
• modified release dosage forms may be formulated as a modified release dosage form.
• modified release refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route.
• Modified release dosage forms include delayed-, extended-, prolonged-, sustained-, pulsatile- or pulsed-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
• compositions in modified release dosage forms can be prepared using a variety of 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 the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s).
• compositions provided herein in a modified release dosage form may be fabricated using a matrix controlled release device known to those skilled in the art.
• the pharmaceutical compositions provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water swellable, erodible, or soluble polymers, including synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
• an erodible matrix device which is water swellable, erodible, or soluble polymers, including synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
• Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, 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), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose a
• the pharmaceutical compositions are formulated with a non-erodible matrix device.
• the active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered.
• Materials suitable for use as a non-erodible matrix device included, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinylacetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene
• the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients in the compositions.
• compositions provided herein in a modified release dosage form may be fabricated using an osmotic controlled release device, including one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
• an osmotic controlled release device including one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
• such devices have at least two components: (a) the core which contains the active ingredient(s); and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core.
• the semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
• the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device.
• osmotic agents waterswellable hydrophilic polymers, which are 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, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO
• the core may also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
• Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking.
• Suitable polymers useful in forming the coating 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 dimethylaminoacetate, CAethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxlated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copoly
• Semipermeable membrane may also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water, as disclosed in U.S. Pat. No. 5,798,119.
• Such hydrophobic but water-permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
• the delivery port(s) on the semipermeable membrane may be formed postcoating by mechanical or laser drilling. Delivery port(s) may also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports may be formed during coating process.
• the total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
• compositions in an osmotic controlled-release dosage form may further comprise additional conventional excipients as described herein to promote performance or processing of the formulation.
• the osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art.
• the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), hydroxylethyl cellulose, and other pharmaceutically acceptable excipients.
• excipients as described herein may be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates.
• the resulting particles may themselves constitute the multiparticulate device or may be coated by various filmforming materials, such as enteric polymers, water-swellable, and water-soluble polymers.
• the multiparticulates can be further processed as a capsule or a tablet.
• compositions provided herein may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems.
• the dosage level is about from 25 to 100 mg/kg per day. In certain embodiments, the dosage level is about 0.01 to about 40 mg/kg per day. In certain embodiments, the dosage level is about 0.1 to about 80 mg/kg per day. In certain embodiments, the dosage level is about 0.1 to about 50 mg/kg per day. In certain embodiments, the dosage level is about 0.1 to about 40 mg/kg per day. In certain embodiments, the dosage level is about 0.5 to about 80 mg/kg per day. In certain embodiments, the dosage level is about 0.5 to about 40 mg/kg per day. In certain embodiments, the dosage level is about 0.5 to about 25 mg/kg per day. In certain embodiments, the dosage level is about 1 to about 80 mg/kg per day.
• the dosage level is about 1 to about 75 mg/kg per day. In certain embodiments, the dosage level is about 1 to about 50 mg/kg per day. In certain embodiments, the dosage level is about 1 to about 40 mg/kg per day. In certain embodiments, the dosage level is about 1 to about 25 mg/kg per day.
• the dosage level is about from 5.0 to 150 mg per day, and in certain embodiments from 10 to 100 mg 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.
• the pharmaceutical compositions can be provided in the form of tablets containing 1.0 to 1,000 mg of the active ingredient, particularly about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 75, about 80, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, and about 1,000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
• the pharmaceutical compositions can be provided in the form of tablets containing about 100 mg of the active ingredient.
• the pharmaceutical compositions can be provided in the form of tablets containing about 80 mg of the active ingredient.
• the pharmaceutical compositions can be provided in the form of tablets containing about 75 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions can be provided in the form of tablets containing about 50 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions can be provided in the form of tablets containing about 40 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions can be provided in the form of tablets containing about 25 mg of the active ingredient.
• the compositions may be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
• the compounds provided herein may 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 tic disorders and other conditions commonly treated with antipsychotic medication.
• the compounds provided herein may also be combined or used in combination with a typical antipsychotic drug.
• the typical antipsychotic drug is fluphenazine, haloperidol, loxapine, molindone, perphenazine, pimozide, sulpiride, thioridazine, or trifluoperazine.
• the antipsychotic drug is an atypical antipsychotic drug.
• the atypical antipsychotic drug is aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone.
• the atypical antipsychotic drug is clozapine.
• Such other agents, or drugs may be administered, by a route and in an amount commonly used thereof, simultaneously or sequentially with the compounds provided herein.
• a pharmaceutical composition containing such other drugs in addition to the compounds provided herein may be utilized, but is not required.
• the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to the compounds provided herein.
• the weight ratio of the compounds provided herein to the second active ingredient may be varied, and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when the compounds provided herein are used in combination with the second drug, or a pharmaceutical composition containing such other drug, the weight ratio of the particulates to the second drug may range from about 1,000:1 to about 1:1,000, or about 200:1 to about 1:200.
• Combinations of the particulates provided herein and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
• Subjects were required to fast overnight from midnight until 4 hours postdose on Days 1 and 14. Additionally, clinical laboratory assessments were performed under fasted conditions. On each dosing day, study drug was administered with 240 mL of water. Subjects were given standard meals upon completion of study assessments/dosing at regular meal times during their stay in the study center. Subjects were discharged from the study center on Day 17 (final study day or upon early termination) after all safety evaluations and study assessments were completed.
• NBI-98854 40 mg capsules were administered orally.
• the dose of NBI-98854 was based on the ditosylate salt (dose expressed as free base).
• Subjects received a single dose of NBI-98854 80 mg (as two 40 mg capsules) twice during the study on Days 10 through 16 at approximately 0800 hours.
• Plasma samples to determine plasma concentrations of NBI-98854 and its metabolites, NBI-98782 and NBI-136110 were collected on Days 10 to 13 at approximately 30 minutes before NBI-98854 dosing; on Day 14 at approximately 30 minutes before NBI-98854 dosing, and at 30 minutes, and 1, 2, 4, 8, and 12 hours after NBI-98854 dosing; on Days 15 and 16 at approximately 30 minutes before NBI-98854 dosing; and on Day 17 (or upon early termination) at approximately 24 hours after the Day 16 NBI-98854 dose before discharge.
• the following plasma PK parameters were assessed for NBI-98854, NBI-98782, and NBI-136110: AUC 0-24 , C max , and t max .
• PK data were also analyzed excluding the data from these 3 subjects. This analysis is referred to as the PK analysis subset in this report. The results of this PK analysis subset are presented in this section and provide a more conservative estimation of drug interaction between digoxin and NBI-98854.
• Mean digoxin t 1/2 was similar with and without NBI-98854 administration (35 and 36 hours, respectively).
• the PK data for t max , T lag , t 1/2 , MRT, and Vz/F were rounded to 2 significant figures and all other parameters (AUC 0-24 , AUC 0-tlast , AUC 0- ⁇ , C max , and CL/F) were rounded to 3 significant figures. The last significant figure was rounded up if the digit to the right of it was ⁇ 5, and was rounded down if the digit to the right of it was ⁇ 4.
• the PK data for t max , T [ag , and t 1/2 were rounded to 2 significant figures and all other parameters (AUC 0-4 , AUC 0-24 , AUC 0-tlast , AUC 0- ⁇ and C max ) were rounded to 3 significant figures. The last significant figure was rounded up if the digit to the right of it was >5, and was rounded down if the digit to the right of it was ⁇ 4.
• the digoxin geometric mean ratios and associated 90% CIs for AUC 0- ⁇ , AUC 0-tlast , and C max after treatment with digoxin in combination with NBI-98854 or digoxin alone are summarized below.
• Geometric mean ratios for AUC 0- ⁇ , AUC 0-tlast , and C max after treatment with digoxin in combination with NBI-98854 or digoxin alone were 136.4%, 138.5%, and 191.7%, respectively.
• Ratio a (%) (Digoxin + NBI-98854 90% Confidence Parameter vs. Digoxin Interval b AUC 0- ⁇ (ng ⁇ hr/mL) 136.4 126.0, 147.6 AUC 0-tlast (ng ⁇ hr/mL) 138.5 127.0, 151.1 C max (ng/mL) 191.7 166.4, 220.8 a Ratio of geometric least-squares means was based on a mixed model using log- transformed (base 10) data. b The 90% confidence interval for geometric mean ratio was based on least-squares means using log-transformed (base 10) data. Note: Data exclude Subjects 1011008. 1011016, and 1011018.
• PK data for NBI-98854, NBI-98782, and NBI-136110 were summarized for the safety analysis set (excluding the 3 subjects).
• PK parameters for NBI-98854, NBI-98782, and NBI-136110 are summarized below.
• NBI-98854 was readily absorbed after oral administration of NBI-98854.
• the present study was designed to evaluate the PK of digoxin when administered alone and concomitantly with NBI-98854 and the safety and tolerability of NBI-98854 when administered alone and concomitantly with digoxin.
• NBI-98854 was found to be a weak inhibitor of the efflux transporter Pgp. Based on a comparison of the potency of Pgp inhibition (IC 50 of 23.8 pM) and the systemic plasma concentrations of NBI-98854 (observed steady state of C max of NBI-98854 after an 80 mg dose of 916 ng/mL or 2.19 pM in the present study [molecular weight of NBI-98854 is 418.578 g/mol]), a systemic interaction with the transporter was unlikely. However, the concentrations of NBI-98854 in the gastrointestinal tract could be much higher. Therefore, the possibility existed that NBI-98854 could alter digoxin PK by inhibiting the gut Pgp.
• AEs adverse events
• ECGs electrocardiograms
• AEs Three subjects experienced AEs leading to discontinuation from the study. These AEs included anxiety, insomnia, and nausea. The most common AE reported for study discontinuation was anxiety, reported in all 3 subjects. One event of anxiety was considered severe.
• NBI-98854 80 mg was well tolerated in healthy subjects when administered alone or concomitantly with digoxin. No deaths or serious adverse events (SAEs) were reported in this study. AEs leading to discontinuation from the study were reported in 3 subjects (one due to insomnia and anxiety, one due to anxiety and nausea, and one due to anxiety). The most common AEs were somnolence (9 subjects, 39.1%) and anxiety (4 subjects; 17.4%) after beginning NBI-98854 administration, and were considered by the investigator to be possibly or definitely related to study drug. Diarrhea was the most common AE after concomitant administration of digoxin and NBI-98854 (4 subjects; 20.0%) and was considered by the investigator to be not related to study drug.
• TBZ Upon oral administration, TBZ is reduced to form four discrete isomeric secondary alcohol metabolites, collectively referred to as dihydrotetrabenazine (DHTBZ), which contains three asymmetric carbon centers (C-2, C-3, and C-11 ⁇ ), which could hypothetically result in eight stereoisomers.
• DHTBZ dihydrotetrabenazine
• the affinity of each compound was measured by inhibition of [ 3 H]-DHTBZ binding to rat forebrain membranes.
• the affinities relative to R,R,R-DHTBZ were also calculated and are presented. Data are reported as both the negative logarithm of the Ki (pKi) for statistical calculation with the normally distributed binding parameter used to determine the mean and SEM.
• the Ki value was determined from the mean pKi as 10(-pKi).
• valbenazine The primary metabolic clearance pathways of valbenazine (VBZ, NBI-98854) are hydrolysis (to form R,R,R-DHTBZ) and mono-oxidation (to form the metabolite NBI-136110).
• R,R,R-DHTBZ and NBI-136110 the two most abundant circulating metabolites of VBZ, are formed gradually and their plasma concentrations decline with half-lives similar to VBZ.
• the affinity of each compound was measured by inhibition of [ 3 H]-DHTBZ binding to either human platelets or rat striatal membranes.
• the primary metabolite R,R,R-DHTBZ was the most potent inhibitor of VMAT2 in rat striatum and human platelet homogenates.
• Rat Striatum Human Platelets Affinity Affinity pK i Relative pK i Relative K i , mean to R,R,R- K i , mean to R,R,R- Compound nm (SEM) DHTBZ nm (SEM) DHTBZ Valbenazine 110 6.95 39 150 6.82 45 (0.02) (0.02) R,R,R- 1.98 8.70 1.0 3.1 8.52 1.0 DHTBZ (0.09) (0.03) NBI-136610 160 6.80 57 220 6.65 67 (0.02) (0.04)
• VBZ and NBI-136110 had similar effects on VMAT2 inhibition, but with Ki values that were approximately 40-65 times the Ki values (lower affinity) of R,R,R-DHTBZ.
• Results expressed as percent of control specific binding: (tested compound specific binding/control specific binding) ⁇ 100. All compounds were tested at 1 or 10 ⁇ M final concentration and results are an excerpt of a larger 80 target panel performed as an initial screen at Cerep (n 2 for each compound at each target). Bolded results (>50%) indicate activity at target receptor.
• radioligand binding assays were performed for dopamine, serotonin and adrenergic receptor subtypes as well as the transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET) for the common metabolite of TBZ and VBZ (R,R,R-DHTBZ) and the other relevant metabolites unique to TBZ and VBZ.
• DAT dopamine
• SERT serotonin
• NET norepinephrine
• R,R,R-DHTBZ common metabolite of TBZ and VBZ
• This detailed analysis revealed the high specificity of R,R,R-DHTBZ for the VMAT2 transporter and the non-specific activities of the other TBZ metabolites, including relatively high affinity for dopamine and serotonin receptor subtypes.
• the R,R,R-DHTBZ metabolite showed the greatest non-selectivity with respect to the monoamine receptors. None of the TBZ or VBZ metabolites had any affinity for the monoamine transporters DAT, SERT or NET.
• the functional activity for the human VMAT1 transporter of these compounds was tested in cells expressing VMAT1. While the non-selective irreversible high-affinity uptake inhibitor of VMAT1, reserpine, substantially inhibited uptake through VMAT1, there was no significant inhibitory activity of TBZ, VBZ, or its metabolites R,R,R-DHTBZ or NBI-136110 at concentrations up to 10 ⁇ M. For both VMAT1 and VMAT2, uptake was measured in the untransfected host cells and was found to be similar to transfected cells in the presence of excess reserpine.
• results from the broad panel screen indicate that VBZ and its major metabolites (R,R,R-DHTBZ and NBI-136110) have little to no affinity for more than 80 binding sites, including receptors, monoamine transporters, and ion channels. This profile suggests a low potential for off-target pharmacological effects.
• uptake studies using TBZ, VBZ and its metabolites, R,R,R-DHTBZ and NBI-136110 confirmed the selectivity of these compounds for VMAT2 as they had no significant effect on the uptake of monoamines through VMAT1 compared to reserpine, a known VMAT1/VMAT2 inhibitor.
• VBZ The selectivity and specificity of VBZ was distinctively demonstrated using two in vivo surrogate measures of pharmacological effects.
• Ptosis known to occur via adrenergic activation and prolactin release from the pituitary, modulated through the D2 dopamine receptor, demonstrated the difference between treatment with TBZ and VBZ.
• TBZ, VBZ and R,R,R-DHTBZ induced ptosis in an equivalent manner.

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