Tetrabenazine transdermal delivery device

Abstract

Provided herein are compositions, delivery devices, and methods relating to the delivery, e.g., sustained or substantially sustained delivery, such as transdermal delivery, of tetrabenazine and / or deuterated tetrabenazine for the treatment of hyperkinetic movement disorders. Also provided are transdermal delivery devices comprising tetrabenazine, deuterated tetrabenazine, or combinations thereof, pharmaceutical compositions comprising tetrabenazine and / or deuterated tetrabenazine, methods for preparing them, and methods of using them, e.g., for the treatment of hyperkinetic movement disorders.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 924,325, filed October 22, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] In various embodiments, the present invention generally relates to the delivery, e.g., sustained or substantially sustained delivery, such as transdermal delivery, of tetrabenazine and / or deuterated tetrabenazine. In various embodiments, the present invention also relates to pharmaceutical compositions and delivery devices, e.g., transdermal delivery devices comprising tetrabenazine and / or deuterated tetrabenazine, pharmaceutical compositions comprising tetrabenazine and / or deuterated tetrabenazine, methods for their preparation, and methods for their use. [Background technology]

[0003] Tetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor. Tetrabenazine has been approved by the U.S. Food and Drug Administration (FDA) as Xenazine® tablets for oral use, indicated for the treatment of chorea associated with Huntington's disease. The active ingredient in Xenazine® tablets is a racemic mixture of (3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one (hereinafter referred to as "R,R-tetrabenazine or R,R-TBZ") and (3S,11bS)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one (hereinafter referred to as "S,S-tetrabenazine or S,S-TBZ"). [ka]

[0004] In 2017, the FDA approved deuterated tetrabenazine, deutetrabenazine, as Austedo™ tablets for oral use, which are also indicated for the treatment of chorea associated with Huntington's disease. The active ingredient in Austedo™ tablets is a stable, non-radioactive isotopic form of tetrabenazine that has been selectively deuterium-substituted, in which six hydrogen atoms in two O-linked methyl groups have been replaced with deuterium atoms (i.e., -OCH3 moieties instead of -OCD3 moieties). The active ingredient in Austedo™ tablets is also a racemic mixture. Summary of the Invention

[0005] In various embodiments, the present invention is directed to pharmaceutical compositions, drug delivery devices, methods of preparation, and methods of use of such, e.g., relating to the delivery of tetrabenazine and / or deuterated tetrabenazine to a subject in a continuous or substantially continuous manner, bypassing first-pass metabolism. Without wishing to be bound by theory, delivery of tetrabenazine and / or deuterated tetrabenazine as described herein, such as transdermal delivery as described herein, may offer many advantages over traditional oral delivery, such as avoiding first-pass metabolism, providing a pharmacokinetic profile with a low peak-to-trough ratio, allowing for multi-day treatment from a single application, avoiding the effect of food on absorption, discontinuing treatment by removing the patch if necessary, and facilitating patient compliance. Furthermore, compared to oral administration of an equivalent dose of tetrabenazine or deuterated tetrabenazine, delivery herein, such as transdermal delivery as described herein, may reduce inter-individual variability in plasma levels of tetrabenazine or deuterated tetrabenazine and / or its metabolites, and / or may increase the C of tetrabenazine or deuterated tetrabenazine and / or its metabolites, for example, without reducing therapeutic efficacy. maxThe R,R-TBZ transdermal delivery system (TDDS) herein can reduce tetrabenazine and / or deuterated tetrabenazine (e.g., deutetrabenazine) dosing regimens (e.g., by 10%, 40%, 60%, or more). Furthermore, delivery, such as transdermal delivery, herein can be administered to subjects genotyped as poor metabolizers (PMs), intermediate metabolizers (IMs), or extensive metabolizers (EMs) based on CYP2D6 expression. Furthermore, unlike Xenazine® and Austedo™ treatments, the R,R-TBZ transdermal delivery system (TDDS) herein can be administered to subjects (even at higher doses) without the need for genotyping prior to administration. As detailed herein, most of the metabolic effects are due to off-target binding that would not be expected from administration of the R,R-TBZ TDDS herein. These advantages ultimately simplify the dosing regimen for tetrabenazine and / or deuterated tetrabenazine (e.g., deutetrabenazine), e.g., minimizing or eliminating the need to perform genotyping and / or reducing dose-related side effects.

[0006] In some embodiments, the present disclosure provides a method of treating a hyperkinetic movement disorder in a subject (e.g., a human subject) in need of such treatment. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising an active ingredient comprising R,R-tetrabenazine, wherein the administration bypasses first-pass metabolism and delivers, e.g., continuously or substantially continuously, about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine to the subject. In some embodiments, the pharmaceutical composition is administered transdermally, intravenously, subcutaneously, intramuscularly, or via a depot. In some particular embodiments, the administration bypasses first-pass metabolism and transdermally delivers about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine to the subject. In some embodiments, the administration comprises applying the pharmaceutical composition to the skin of the subject to transdermally deliver about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine to the subject. In some embodiments, the only active ingredient in the pharmaceutical composition is the substantially pure R,R-isomer of tetrabenazine. In some embodiments, administration can provide any of the applicable pharmacokinetic (PK) profiles described herein, e.g., PK profiles related to the plasma concentration profiles described herein for R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ. In some embodiments, administration does not provide detectable amounts of the S,S-isomer of tetrabenazine or its metabolites, e.g., S,S,S-HTBZ and R,S,S-HTBZ, in the subject's plasma. Suitable pharmaceutical compositions, drug delivery devices, dosing regimens, and subjects for this method include any of those described herein. For example, in some embodiments, the pharmaceutical composition can be any of the adhesive compositions described herein, which can be included in any of the transdermal delivery devices described herein. The pharmaceutical composition can be administered to the subject at any frequency and for as long as needed.In some embodiments, each administration of the pharmaceutical composition can deliver, for example, about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine to a subject continuously or substantially continuously for about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range between the recited values. In some embodiments, administration can be performed regardless of the subject's fed state. The dose and / or plasma exposure ranges described herein may be suitable for adult patients as well as pediatric and adolescent patients. However, as will be understood by those skilled in the art, the desired dose and / or plasma exposure for a particular subject may be adjusted taking into account the subject's age and weight. In some embodiments, the subject is a pediatric or adolescent patient (e.g., 6 to 18 years old). In some embodiments, administration can be performed regardless of the subject's genotype, for example, the subject may be an extensive metabolizer. In some embodiments, the hyperkinetic movement disorder can be Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tics, dyskinetic cerebral palsy / cerebral palsy, other dystonia and dyskinesia disorders, and combinations thereof.

[0007] Some embodiments of the present disclosure are also directed to methods of treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising R,R-tetrabenazine, wherein administration provides a desired PK profile. In some embodiments, the PK profile is characterized in that administration provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-HTBZ, and S,R,R-HTBZ, and the ratio of the maximum plasma concentration of R,R-tetrabenazine to the maximum plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ is in the range of about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any ranges therebetween, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some embodiments, the PK profile is characterized in that administration provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-HTBZ, and S,R,R-HTBZ, and the ratio of the steady-state plasma concentration of R,R-tetrabenazine to the combined steady-state plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ is in the range of about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any range between the recited values, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some embodiments, administration does not provide detectable S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ in the plasma of the subject. In some embodiments, the PK profile is characterized by the plasma concentration of R,R-tetrabenazine increasing over a first period of time and reaching a maximum concentration of about 150 pg / ml to about 3500 pg / ml at a first time point within the first period, the first period extending from time 0 (the time of administration of the pharmaceutical composition) to about 24 hours thereafter. In some embodiments, the PK profile is characterized by a mean terminal half-life of R,R-tetrabenazine of about 8.5 hours ± 40%CV.In some embodiments, the PK profile is further characterized in that, after the first period of time, the plasma concentration of R,R-tetrabenazine remains substantially constant for a sustained period, such as about 24 hours, about 48 hours, about 72 hours, about 96 hours, or more. In some embodiments, the PK profile is characterized in that administration provides a substantially constant steady-state plasma concentration of R,R-tetrabenazine of greater than 150 pg / ml (e.g., about 150 pg / ml to about 3500 pg / ml) for a sustained period of at least 6 hours, or at least 12 hours, preferably at least 24 hours. Other novel PK profiles are described herein. Suitable pharmaceutical compositions, drug delivery devices, dosing regimens, and subjects for this method include any of those described herein. In some embodiments, administration bypasses first-pass metabolism and delivers R,R-tetrabenazine to the subject at a substantially constant rate, e.g., continuous or substantially continuous delivery. In some embodiments, the pharmaceutical composition is administered transdermally. In some embodiments, the pharmaceutical composition can be any of the adhesive compositions described herein. In some embodiments, administration can be performed regardless of the subject's feeding status. In some embodiments, the subject is a pediatric or adolescent patient (e.g., 6 to 18 years old). In some embodiments, administration can be performed regardless of the subject's genotype, for example, the subject can be an extensive metabolizer. In some embodiments, the hyperkinetic movement disorder can be Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tics, dyskinetic cerebral palsy / cerebral palsy, other dystonia and dyskinesia disorders, and combinations thereof.

[0008] Some embodiments of the present disclosure are directed to the delivery, e.g., sustained or substantially sustained delivery, of deuterated tetrabenazine (e.g., R,R-deutetrabenazine), e.g., to treat hyperkinetic movement disorders. In some embodiments, the method comprises administering to a subject a pharmaceutical composition comprising an active ingredient comprising deuterated R,R-tetrabenazine (e.g., R,R-deutetrabenazine), wherein the administration bypasses first-pass metabolism and delivers, e.g., sustained or substantially sustained delivery, of about 0.1 mg / day to about 20 mg / day of deuterated R,R-tetrabenazine to the subject. In some embodiments, the pharmaceutical composition is administered transdermally, intravenously, subcutaneously, intramuscularly, or via a depot. In some particular embodiments, the administration bypasses first-pass metabolism and delivers about 0.1 mg / day to about 20 mg / day of deuterated R,R-tetrabenazine transdermally to the subject. In some embodiments, administering comprises applying a pharmaceutical composition to the subject's skin to transdermally deliver about 0.1 mg / day to about 20 mg / day of deuterated R,R-tetrabenazine to the subject. In some embodiments, the only active ingredient in the pharmaceutical composition is a substantially pure R,R-isomer of deuterated tetrabenazine, e.g., substantially pure R,R-deutetrabenazine. In some embodiments, administration does not provide a detectable amount of the S,S-isomer of deuterated tetrabenazine and / or its metabolites in the subject's plasma. In some embodiments, administration can provide any of the applicable pharmacokinetic (PK) profiles described herein, e.g., PK profiles related to the plasma concentration profiles described herein for deuterated R,R-tetrabenazine, deuterated R,R,R-HTBZ, and deuterated S,R,R-HTBZ. Suitable pharmaceutical compositions, drug delivery devices, administration regimens, and subjects for this method include any of those described herein. In some embodiments, the pharmaceutical composition can be any of the adhesive compositions described herein. The pharmaceutical composition can be administered to a subject at any frequency and for as long as necessary.In some embodiments, each administration of the pharmaceutical composition can deliver about 0.1 mg / day to about 20 mg / day of deuterated R,R-tetrabenazine to a subject for about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range between the recited values, e.g., continuously or substantially continuously. In some embodiments, administration can be performed regardless of the subject's feeding status. In some embodiments, the subject is a pediatric or adolescent patient (e.g., 6 to 18 years of age). In some embodiments, administration can be performed regardless of the subject's genotype, e.g., the subject can be an extensive metabolizer. In some embodiments, the hyperkinetic movement disorder can be Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tics, dyskinetic cerebral palsy / cerebral palsy, other dystonia and dyskinesia disorders, and combinations thereof. In any of the embodiments described herein, the deuterated tetrabenazine may be deutetrabenazine, such as R,R-deutetrabenazine.

[0009] Some embodiments of the present disclosure are also directed to methods of treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising deuterated R,R-tetrabenazine, wherein administration provides a desired PK profile. In some embodiments, the PK profile is characterized in that administration provides therapeutically effective plasma concentrations of deuterated R,R-tetrabenazine, deuterated R,R,R-HTBZ, and deuterated S,R,R-HTBZ, and the ratio of the maximum plasma concentration of deuterated R,R-tetrabenazine to the combined maximum plasma concentration of deuterated R,R,R-HTBZ and S,R,R-HTBZ is in the range of from about 1:1 to about 1:7.5. In some embodiments, the PK profile is characterized in that administration provides therapeutically effective plasma concentrations of deuterated R,R-tetrabenazine, deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ, and the ratio of the steady-state plasma concentration of deuterated R,R-tetrabenazine to the combined steady-state plasma concentrations of deuterated R,R,R-HTBZ and S,R,R-HTBZ is in the range of from about 1:1 to about 1:7.5. In some embodiments, administration does not provide detectable deuterated S,S-tetrabenazine, deuterated R,S,S-HTBZ or deuterated S,S,S-HTBZ in the plasma of a subject. In some embodiments, the PK profile is characterized by the plasma concentration of deuterated R,R-tetrabenazine increasing over a first period of time and reaching a maximum concentration of about 150 pg / ml to about 3500 pg / ml at a first time point within the first period, the first period being from time 0 (the time of administration of the pharmaceutical composition) to about 24 hours thereafter. In some embodiments, the PK profile is characterized by a mean terminal half-life of deuterated R,R-tetrabenazine of about 8.5 hours ± 40% CV. In some embodiments, the PK profile is further characterized by the plasma concentration of R,R-tetrabenazine remaining substantially constant after the first period of time for a duration such as about 24 hours, about 48 hours, about 72 hours, about 96 hours, or more.In some embodiments, the PK profile is characterized in that administration provides a substantially constant steady-state plasma concentration of deuterated R,R-tetrabenazine of greater than 150 pg / ml (e.g., about 150 pg / ml to about 3500 pg / ml) for a duration of at least 6 hours, or at least 12 hours, preferably at least 24 hours. Other novel PK profiles are described herein. Suitable pharmaceutical compositions, drug delivery devices, dosing regimens, and subjects for this method include any of those described herein. In some embodiments, administration bypasses first-pass metabolism and delivers deuterated R,R-tetrabenazine to the subject at a substantially constant rate, e.g., continuous or substantially continuous delivery. In some embodiments, the pharmaceutical composition is administered transdermally. In some embodiments, the pharmaceutical composition can be any of the adhesive compositions described herein. In some embodiments, administration can be performed regardless of the subject's fed state. In some embodiments, the subject is a pediatric or adolescent patient (e.g., 6 to 18 years of age). In some embodiments, administration can be performed regardless of the subject's genotype, e.g., the subject can be an extensive metabolizer. In some embodiments, the hyperkinetic movement disorder can be Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tics, dyskinetic cerebral palsy / cerebral palsy, other dystonia and dyskinesia disorders, and combinations thereof. In any of the embodiments described herein, the deuterated tetrabenazine can be duetetrabenazine, such as R,R-deutetrabenazine.

[0010] Some particular embodiments of the present invention are directed to the transdermal delivery of tetrabenazine or deuterated tetrabenazine to a subject in need thereof. Transdermal pharmaceutical compositions and transdermal delivery devices are also novel aspects of the present disclosure.

[0011] In some embodiments, the present invention provides transdermal delivery devices comprising tetrabenazine and / or deuterated tetrabenazine (e.g., deutetrabenazine). In various embodiments, the present invention also provides pharmaceutical compositions (e.g., adhesive compositions) comprising tetrabenazine and / or deuterated tetrabenazine (e.g., deutetrabenazine). In some embodiments, the present invention further provides methods of preparing or using transdermal delivery devices or pharmaceutical compositions comprising tetrabenazine and / or deuterated tetrabenazine (e.g., deutetrabenazine).

[0012] Typically, a transdermal delivery device includes a backing layer, a drug layer containing a drug selected from tetrabenazine, deuterated tetrabenazine, or a combination thereof, for example, in an amount of about 2% to about 30% by weight of the drug layer, and an adhesive layer that defines an active surface area. Transdermal delivery devices are generally designed to have certain flux characteristics, such as any of those defined herein. Typically, a transdermal delivery device has a thickness of about 5 cm. 2 ~about 300cm 2 , for example, about 10 cm 2 ~about 100cm 2 The active surface area can range from 0.01 to 0.1.

[0013] The transdermal delivery device herein is not limited to a particular patch design. For example, the transdermal delivery device herein may be a drug-in-adhesive patch, a drug-in-reservoir patch, a microneedle patch, or another patch design that may contain chemical or physical enhancements. In some embodiments, the transdermal delivery device may be a drug-in-adhesive patch, for example, a single-layer DIA patch. In some embodiments, the transdermal delivery device may include two or more drug layers, for example, two or more drug-in-adhesive layers. In some embodiments, the transdermal delivery device may be a drug-in-reservoir patch, for example, the drug layer is a reservoir containing tetrabenazine and / or deuterated tetrabenazine.

[0014] The drug layer can comprise tetrabenazine, deuterated tetrabenazine, or a combination thereof. In any of the embodiments described herein, the drug layer can be a drug-containing adhesive layer. In any of the embodiments described herein, the drug layer can comprise tetrabenazine, e.g., substantially pure R,R-tetrabenazine. In some embodiments, tetrabenazine (e.g., substantially pure R,R-tetrabenazine) is the only active ingredient in the drug layer. In any of the embodiments described herein, the drug layer can comprise deutetrabenazine, e.g., substantially pure R,R-deutetrabenazine. In some embodiments, deutetrabenazine (e.g., substantially pure R,R-deutetrabenazine) is the only active ingredient in the drug layer. In some embodiments, the drug layer comprises tetrabenazine, deuterated tetrabenazine, or a combination thereof, in an amount of about 2% to about 30% by weight of the drug layer (e.g., about 2%, about 2.5%, about 5%, about 8%, about 10%, about 15%, about 18%, about 20%, about 25%, about 30%, or any range between the recited values). In some specific embodiments, the drug layer comprises tetrabenazine, deuterated tetrabenazine, or a combination thereof in an amount of about 2%, about 2.5%, about 5%, about 8%, about 10%, about 15%, or about 20% by weight of the drug layer. In some embodiments, the drug layer can optionally comprise one or more other ingredients selected from, for example, a skin permeation enhancer, a humectant, a plasticizer, an antioxidant, an anti-irritant, a gel-forming agent, a drug release modifier, a solvent, a crystallization inhibitor, and an additional active ingredient. In some embodiments, the drug layer has a coating weight of about 0.1 g / cm 2 ~Approx. 0.90g / cm 2 (For example, about 0.1 g / cm 2 ~about 0.5g / cm 2 ) active surface area.

[0015] In some embodiments, the drug layer comprises tetrabenazine, deuterated tetrabenazine, or a combination thereof dispersed (e.g., homogeneously dispersed) in an adhesive (e.g., a pressure-sensitive adhesive). Suitable pressure-sensitive adhesives are described herein. In some embodiments, the pressure-sensitive adhesive may comprise a polyisobutylene (PIB) adhesive, a silicone polymer adhesive (e.g., Bio-7-4202), an acrylate copolymer adhesive (e.g., DuroTak 87-2287), or a combination thereof. In some embodiments, the pressure-sensitive adhesive may be a non-reactive acrylate adhesive, for example, an acrylate adhesive that does not have a functional group containing a reactive hydrogen moiety, or an acrylate adhesive that does not have a functional group selected from epoxy, -OH, -COOH, and combinations thereof.

[0016] The adhesive layer is typically formulated to allow the transdermal delivery device to adhere to the user's skin for a desired period of time. For example, in some embodiments, the transdermal delivery device can be persistently adhered to the user's skin for about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more.

[0017] Certain embodiments of the present invention are also directed to adhesive compositions. In some embodiments, the adhesive composition comprises a drug selected from tetrabenazine, deuterated tetrabenazine (e.g., deutetrabenazine), and combinations thereof. In some embodiments, the drug is homogeneously dispersed in the adhesive (e.g., pressure-sensitive adhesive). In some embodiments, the pressure-sensitive adhesive can be a non-reactive acrylate adhesive, such as an acrylate adhesive that does not have a functional group containing a reactive hydrogen moiety, or an acrylate adhesive that does not have a functional group selected from epoxy, -OH, -COOH, and combinations thereof. In some embodiments, the pressure-sensitive adhesive comprises a polyisobutylene (PIB) adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some embodiments, the adhesive composition comprises tetrabenazine (e.g., substantially pure R,R-tetrabenazine) in an amount of about 2% to about 30% by weight of the adhesive composition. In some embodiments, the adhesive composition comprises deutetrabenazine (e.g., substantially pure R,R-deutetrabenazine) in an amount of about 2% to about 30% by weight of the adhesive composition. In some embodiments, the active ingredient is present in an amount of about 2% to about 7% by weight. In some embodiments, the adhesive composition does not include a permeation enhancer, e.g., does not include isopropyl myristate. However, in some embodiments, the adhesive composition further includes a permeation enhancer. In some embodiments, the adhesive composition can include an antioxidant, e.g., a gallic acid antioxidant such as propyl gallate. In some embodiments, the adhesive composition can include a crystallization inhibitor such as polyvinylpyrrolidone polymer, crosslinked polyvinylpyrrolidone polymer, polyvinylpyrrolidone copolymer, cellulose-based polymer, polycarboxylic acid polymer, polymethacrylate, polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof. In some preferred embodiments, the adhesive composition includes a crystallization inhibitor that is a copolymer of butyl methacrylate and methyl methacrylate.In some preferred embodiments, the adhesive composition comprises a crystallization inhibitor that is polyethylene glycol, polyvinyl acetate, and a polyvinyl caprolactam-based graft copolymer. In some embodiments, the adhesive composition can sustainably adhere to a user's skin for an extended period selected from about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days, or more. The adhesive compositions described herein can be used in transdermal delivery devices. For example, in some embodiments, a transdermal delivery device can include any of the adhesive compositions described herein, a backing layer, and a release liner.

[0018] In some embodiments, the present invention provides methods of transdermally administering tetrabenazine, deuterated tetrabenazine, or a combination thereof to a subject (e.g., a human subject) in need thereof. In some embodiments, the method comprises applying either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition) to the subject, e.g., the skin of the subject. In some embodiments, administration provides any of the desired daily doses described herein and / or any of the PK profiles provided herein (if applicable).

[0019] In some embodiments, the present invention also provides methods for inhibiting VMAT-2 in a subject in need thereof. In some embodiments, the method includes applying either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition) to a subject, e.g., the skin of a subject. In some embodiments, application provides any of the desired daily doses described herein and / or any of the PK profiles provided herein (if applicable).

[0020] In some embodiments, the present invention also provides methods of treating a vesicular monoamine transporter isoform 2 (VMAT2)-mediated disease or disorder in a subject (e.g., a human subject) in need thereof. In some embodiments, the method includes applying either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition) to the subject, e.g., the skin of the subject. In some embodiments, application provides any of the desired daily doses described herein and / or any of the PK profiles provided herein (if applicable).

[0021] In some embodiments, the present disclosure provides methods of treating a hyperkinetic movement disorder in a subject (e.g., a human subject) in need thereof. In some embodiments, the method comprises transdermally administering a therapeutically effective amount of tetrabenazine and / or deuterated tetrabenazine to the subject. In some embodiments, the method comprises applying either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition) to the subject, e.g., the subject's skin. In some embodiments, the hyperkinetic movement disorder is chronic hyperkinetic movement disorder. In some embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, and / or tics. In some embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease. In some embodiments, application provides any of the desired daily doses described herein and / or any of the PK profiles provided herein (if applicable).

[0022] In some embodiments, the present disclosure also provides a method for identifying a pharmaceutical composition for treating hyperkinetic movement disorders. In some embodiments, the method includes administering to a subject a test pharmaceutical composition that bypasses first-pass metabolism and delivers R,R-tetrabenazine to the subject in a sustained or substantially sustained manner, and identifying a pharmaceutical composition that provides any of the PK profiles described herein. In some embodiments, the method is for identifying a pharmaceutical composition suitable for transdermal delivery to treat hyperkinetic movement disorders. In some embodiments, the method includes measuring the skin flux properties of test adhesive compositions in vitro using human cadaver skin, and identifying an adhesive composition that provides any of the in vitro flux properties described herein. [Brief explanation of the drawings]

[0023] [Figure 1] A graph is presented showing the in vitro flux of tetrabenazine through human (Black) cadaver epidermis from a monolithic matrix of Duro-Tak 87-2287 adhesive containing tetrabenazine at different concentrations (10%, 15%, 5%, and 2.5%). [Figure 2] A graph is presented showing the in vitro flux of tetrabenazine through human cadaver epidermis from monolithic matrices of various ratios of Duro-Tak 87-2287 adhesive and BIO-7-4202 mixtures, including 5:95, 10:90, 25:75, and 50:50 (Duro-Tak 87-2287 to BIO-7-4202). All matrices in this figure contain 10% tetrabenazine. [Figure 3] 1 presents a graph showing the in vitro flux of tetrabenazine through human cadaver epidermis from patch formulations prepared using DuroTak 87-900A. [Figure 4-1]A presents a graph showing the mean plasma concentration versus time plots for combined tetrabenazine (R,R- and S,S-isomers combined) concentrations. B presents a graph showing the mean plasma concentration versus time plots for R,R,R-HTBZ. [Figure 4-2] C presents a graph showing the mean plasma concentration versus time plot of S,R,R-HTBZ. D presents a graph showing the mean plasma concentration versus time plot of total tetrabenazine (including tetrabenazine, R,R,R-HTBZ, and S,R,R-HTBZ). DETAILED DESCRIPTION OF THE INVENTION

[0024] The FDA-approved labels for Xenazine® and Austedo™ each contain a black box warning for the potential risks of depression and suicidality. Both products require monitoring of actual administration and titration. For example, the Xenazine® label indicates that patients requiring doses greater than 50 mg per day should be genotyped for the drug-metabolizing enzyme CYP2D6 to determine whether they are poor metabolizers (PMs) or extensive metabolizers (EMs). For poor metabolizers, the maximum daily dose is only 50 mg, with a maximum single dose of 25 mg. For extensive or intermediate metabolizers, the maximum daily dose is 100 mg, with a maximum single dose of 37.5 mg. Similarly, the Austedo™ label also states that for poor metabolizers, the maximum daily dose is only 36 mg, with two 18 mg single doses possible.

[0025] Despite recent advances, tetrabenazine / deutetrabenazine dosing remains associated with complications and requires dose titration to reduce potential dose-related side effects. Therefore, novel tetrabenazine formulations and administration options are needed.

[0026] In various embodiments, the present invention is directed to pharmaceutical compositions, drug delivery devices, methods of preparation, and methods of use thereof, e.g., relating to the delivery of tetrabenazine and / or deuterated tetrabenazine to a subject in a sustained or substantially sustained manner, bypassing first-pass metabolism. For example, some embodiments of the present invention are directed to transdermal delivery of tetrabenazine and / or deuterated tetrabenazine. Some embodiments of the present disclosure are directed to intravenous, subcutaneous, intramuscular, or depot-mediated delivery of tetrabenazine and / or deuterated tetrabenazine, e.g., sustained delivery at a substantially constant rate.

[0027] Sustained delivery of tetrabenazine Some embodiments of the present disclosure are based on the unique pharmacokinetic (PK) profile obtained from sustained or substantially sustained transdermal delivery of tetrabenazine, bypassing first-pass metabolism. As detailed herein, transdermal delivery of R,R-tetrabenazine at a dose of 8 mg / 96 h provides much higher concentrations of R,R-tetrabenazine at lower doses and with less metabolism to the active HTBZ isomer, without interconversion to the S-S isomer, compared to three doses of TBZ tablets per day (total dose of 150 mg) administered under fasting conditions on days 1 through 4 in healthy male subjects. This data demonstrates for the first time that sustained or substantially sustained delivery methods, such as transdermal delivery, can provide therapeutically effective plasma concentrations of R,R-tetrabenazine and its dihydro metabolites, R,R,R-HTBZ and S,R,R-HTBZ, for treating, for example, the hyperkinetic movement disorders described herein. As the R,R-isomers of tetrabenazine, R,R,R-HTBZ and S,R,R-HTBZ are believed to have reduced off-target binding, such as to dopamine D1 or D2 receptors, and the use of the R,R-isomer of tetrabenazine as the primary active ingredient results in fewer side effects compared to the use of a racemic mixture of tetrabenazine, the active ingredient in Xenazine®. Furthermore, PK data demonstrate that the sustained delivery method herein provides a C value comparable to that of a dose-equivalent oral delivery of tetrabenazine. maxThese results indicate that the present invention can provide relatively stable plasma concentrations of R,R-tetrabenazine and its active dihydro metabolite with reduced peak-to-trough ratios and therefore may be advantageous in treating subjects with hyperkinetic movement disorders.

[0028] While the PK data exemplified herein are generated using a transdermal delivery device, the present disclosure is not limited to transdermal delivery. Rather, for any of the methods described herein, the inventors specifically contemplate administering to a subject in need of treatment any tetrabenazine formulation or delivery device that generates the PK profile described herein. The PK profile described herein is one novel aspect of the present disclosure. In some embodiments, the PK profile can be achieved by applying a transdermal delivery device described herein. In some embodiments, the PK profile can be achieved by any continuous or substantially continuous delivery means that bypasses first-pass metabolism, such as transdermal delivery, continuous intravenous delivery, subcutaneous delivery, intramuscular delivery, or via a depot. These delivery methods share the common feature that each can be tailored to deliver tetrabenazine systemically at a desired rate, for example, from about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine. In some embodiments, delivery of tetrabenazine may be at a substantially constant rate during the drug delivery period, e.g., during the patch-on period, such that delivery of tetrabenazine to the subject resembles zero-order kinetics. For example, in some embodiments, the desired delivery rate may be about 12 mg / day of R,R-tetrabenazine, and the desired drug delivery period may be 24 hours, such that the amount of R,R-tetrabenazine delivered to the treated subject per hour may be about 0.5 mg / hour. For example, "substantially continuous," as used in the context of "substantially continuous delivery," is meant to refer to delivery of a drug (e.g., tetrabenazine) in a substantially uninterrupted manner over a preselected period of drug delivery. Furthermore, "substantially continuous" drug delivery may also include delivery of a drug at a substantially constant, preselected rate or range of rates (e.g., amount of drug per unit time, or amount of drug formulation per unit time) that is substantially uninterrupted over a preselected period of drug delivery.The drug delivery period herein can be, for example, about 8 hours to about 192 hours, e.g., about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range therebetween. For clarity, the term "sustained or substantially continuous delivery" does not require that the active ingredient / drug be continuously delivered to the subject throughout the treatment. This term, in contrast to bolus delivery, only requires that the drug be continuously or substantially continuously delivered during the drug delivery period. For example, if the pharmaceutical composition is administered once daily, it is acceptable for there to be a period between two administrations during which the drug is not delivered to the treated subject.

[0029] Typically, R,R-tetrabenazine is delivered to a subject in need thereof at a therapeutically effective dose to treat the hyperkinetic movement disorders described herein. In some embodiments, the methods herein provide for administering to a subject in need of treatment for a hyperkinetic movement disorder described herein about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine, e.g., about 0.1 mg / day, about 0.5 mg / day, about 1 mg / day, about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 10 mg / day, about 12 mg / day, about 14 mg / day, or about 16 mg / day. / day, about 16 mg / day, about 18 mg / day, or about 20 mg / day of R,R-tetrabenazine, or any range between the listed values, e.g., about 0.5 mg / day to about 10 mg / day of R,R-tetrabenazine, about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine, about 0.5 mg / day to about 6 mg / day of R,R-tetrabenazine, about 0.5 mg / day to about 4 mg / day of R,R-tetrabenazine, about R,R-tetrabenazine 1 mg / day to about 10 mg / day, R,R-tetrabenazine about 1 mg / day to about 8 mg / day, R,R-tetrabenazine about 1 mg / day to about 6 mg / day, R,R-tetrabenazine about 1 mg / day to about 4 mg / day, R,R-tetrabenazine about 2 mg / day to about 10 mg / day, R,R-tetrabenazine about 2 mg / day to about 8 mg / day, R,R-tetrabenazine about 2 mg / day to about 6 mg / day The method delivers tetrabenazine, about 2 mg / day to about 4 mg / day of R,R-tetrabenazine, about 4 mg / day to about 10 mg / day of R,R-tetrabenazine, about 4 mg / day to about 8 mg / day of R,R-tetrabenazine, about 4 mg / day to about 6 mg / day of R,R-tetrabenazine, about 6 mg / day to about 10 mg / day of R,R-tetrabenazine, or about 6 mg / day to about 8 mg / day of R,R-tetrabenazine. In some preferred embodiments, the method delivers about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine or about 2 mg / day to about 6 mg / day of R,R-tetrabenazine. As used herein, the term R,R-tetrabenazine should be understood to include R,R-tetrabenazine base, a pharmaceutically acceptable salt thereof, or a combination thereof.Typically, in transdermal compositions such as the adhesive compositions described herein, R,R-tetrabenazine can be present primarily in its free base form. For example, in any of the embodiments described herein, an adhesive composition or drug-containing adhesive composition containing R,R-tetrabenazine can be prepared by mixing R,R-tetrabenazine free base with other ingredients, such as adhesive, antioxidant, crystallization inhibitor, etc., in the described amounts. Delivery of R,R-tetrabenazine to a subject herein should be understood as the amount of R,R-tetrabenazine delivered to the subject, e.g., the amount that has permeated the skin of the subject, where the amount is expressed as an equivalent amount of R,R-tetrabenazine base and can be in any form. Other terms, such as tetrabenazine, deuterated tetrabenazine, deuterated R,R-tetrabenazine, deutetrabenazine, R,R-deutetrabenazine, and the like, and delivery of such to a subject, should be understood in the same way.

[0030] In some embodiments, R,R-tetrabenazine can be included in a pharmaceutical composition or delivery device, such as a sustained delivery device, which can be configured to deliver the doses described herein to a subject at a substantially constant rate. For example, in some embodiments, the daily dose of R,R-tetrabenazine can be about 0.5 mg / day to about 10 mg / day, and the sustained delivery device can be applied to a subject in need thereof once daily, delivering R,R-tetrabenazine to the subject continuously or substantially continuously over a preselected period of time, e.g., 12 hours or 24 hours, and the delivery rate of R,R-tetrabenazine during the preselected period of time can be substantially the same. For the methods described herein, the pharmaceutical composition or delivery device comprising R,R-tetrabenazine is not particularly limited and can be any suitable for delivering R,R-tetrabenazine at a desired dose and at a desired rate.

[0031] Although many of the exemplary embodiments are described as being directed to methods of treating a hyperkinetic movement disorder in a subject in need thereof, the present disclosure is not limited to such methods of treatment. Any of the methods of delivery of R,R-tetrabenazine and / or deuterated R,R-tetrabenazine described herein can be used in methods of inhibiting VMAT-2 in a subject in need thereof, methods of treating a hyperkinetic movement disorder in a subject (e.g., a human subject) in need thereof, and / or methods of treating a vesicular monoamine transporter isoform 2 (VMAT2)-mediated disease or disorder in a subject (e.g., a human subject) in need thereof.

[0032] In some embodiments, the disclosure provides a method of treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising R,R-tetrabenazine, wherein the administration bypasses first pass metabolism and provides a continuous or substantially continuous dose of from about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine, e.g., from about 0.5 mg / day to about 10 mg / day of R,R-tetrabenazine, from about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine, from about 0.5 mg / day to about 6 mg / day of R,R-tetrabenazine, from about 0.5 mg / day to about 4 mg / day of R,R-tetrabenazine, from about 1 mg / day to about 10 mg / day of R,R-tetrabenazine, from about 1 mg / day to about 8 mg / day of R,R-tetrabenazine, R,R-tetrabenazine, about 1 mg / day to about 6 mg / day of R,R-tetrabenazine, about 1 mg / day to about 4 mg / day of R,R-tetrabenazine, about 2 mg / day to about 10 mg / day of R,R-tetrabenazine, about 2 mg / day to about 8 mg / day of R,R-tetrabenazine, about 2 mg / day to about 6 mg / day of R,R-tetrabenazine, about 2 mg / day to about 4 mg / day of R,R-tetrabenazine, about 4 mg / day to about 10 mg / day of R,R-tetrabenazine, about 4 mg / day to about 8 mg / day of R,R-tetrabenazine, about 4 mg / day to about 6 mg / day of R,R-tetrabenazine, about 6 mg / day to about 10 mg / day of R,R-tetrabenazine, or about 6 mg / day to about 8 mg / day of R,R-tetrabenazine is delivered to the subject. In some preferred embodiments, the method delivers about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine, or about 2 mg / day to about 6 mg / day of R,R-tetrabenazine. The duration of drug delivery herein can vary, for example, from about 8 hours to about 72 hours, or more than 72 hours. The pharmaceutical composition can be administered to a subject at any frequency and for as long as needed. For example, in some embodiments, each administration can provide a subject with continuous or substantially continuous delivery of R,R-tetrabenazine for about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range between the recited values.In some embodiments, during the period of sustained or substantially sustained delivery, R,R-tetrabenazine may be delivered to a subject at a substantially constant rate, e.g., the average delivery rate for each hour is substantially the same, e.g., within 80-125% of the average rate for the entire drug delivery period. In some embodiments, during the period of sustained or substantially sustained delivery, R,R-tetrabenazine may be delivered to a subject at, e.g., a different average delivery rate for each hour. For example, in some embodiments, the average delivery rate may be high initially but then decrease over the course of the sustained or substantially sustained delivery. Typically, the exact hourly delivery rate of R,R-tetrabenazine is not critical, and one of skill in the art after considering this disclosure will know how to select and design a dosing regimen to deliver a desired daily dose to a subject, for example, about 0.5 mg / day to about 10 mg / day of R,R-tetrabenazine, about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine, or about 2 mg / day to about 6 mg / day of R,R-tetrabenazine. In some embodiments, delivery of the desired daily dose to a subject also provides a pharmacokinetic profile as described herein.

[0033] In some embodiments, the disclosure provides a method of treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising R,R-tetrabenazine, wherein the administration provides from about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine, for example, from about 0.5 mg / day to about 10 mg / day of R,R-tetrabenazine, from about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine, from about 0.5 mg / day to about 6 mg / day of R,R-tetrabenazine, from about 0.5 mg / day to about 4 mg / day of R,R-tetrabenazine, from about 1 mg / day to about 10 mg / day of R,R-tetrabenazine, from about 1 mg / day to about 8 mg / day of R,R-tetrabenazine, About 1 mg / day to about 6 mg / day of R,R-tetrabenazine, about 1 mg / day to about 4 mg / day of R,R-tetrabenazine, about 2 mg / day to about 10 mg / day of R,R-tetrabenazine, about 2 mg / day to about 8 mg / day of R,R-tetrabenazine, about 2 mg / day to about 6 mg / day of R,R-tetrabenazine, about 2 mg / day to about 4 mg / day of R,R-tetrabenazine, about 4 mg / day to about 10 mg / day of R,R-tetrabenazine, about 4 mg / day to about 8 mg / day of R,R-tetrabenazine, about 4 mg / day to about 6 mg / day of R,R-tetrabenazine, about 6 mg / day to about 10 mg / day of R,R-tetrabenazine, or about 6 mg / day to about 8 mg / day of R,R-tetrabenazine is delivered transdermally to a subject. In some preferred embodiments, the method delivers about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine or about 2 mg / day to about 6 mg / day of R,R-tetrabenazine. In some embodiments, administering comprises applying the pharmaceutical composition to the subject's skin. While the exact location on the skin is not critical, the pharmaceutical composition is typically applied to an intact area of ​​skin, such as the outer arm of the subject. The duration of drug delivery herein can vary, for example, from about 8 hours to about 72 hours, or for more than 72 hours. In some embodiments, the pharmaceutical composition is applied to the subject's skin to provide continuous or substantially continuous delivery of R,R-tetrabenazine to the subject for about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range between the recited values.The frequency of application of the pharmaceutical composition to a subject for the methods herein can vary, for example, once a day, more than once a day, or once a week. In some embodiments, for each application, the pharmaceutical composition can be applied to the subject's skin and adhere continuously or substantially continuously to the subject's skin for about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range between the recited values, thereby providing continuous or substantially continuous delivery of R,R-tetrabenazine to the subject during the patch-on period. In some embodiments, there is no delay between the application of transdermal patches according to the administration frequencies herein. For example, in some embodiments, a transdermal delivery device is applied to a subject once a day, and each application of the transdermal delivery device can typically last (adhered to the subject's skin) for about 24 hours before being replaced with another substantially identical transdermal delivery device. However, in some embodiments, there may be an overlap or delay between the two applications.

[0034] Typically, for transdermal delivery, the pharmaceutical composition comprises an active ingredient dispersed in an adhesive (preferably a pressure-sensitive adhesive), e.g., an adhesive composition in a transdermal delivery device (e.g., as described herein). In some embodiments, the adhesive composition is applied to a subject to deliver about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine (e.g., any of the exemplified ranges described herein) at a substantially constant rate for up to 24 hours, up to 48 hours, up to 96 hours, or up to 1 week after application. Suitable adhesive compositions include any of those described herein, e.g., any of those described in exemplary embodiments 1-18 applicable to tetrabenazine, or any of the specific compositions shown in the Examples section (e.g., Example 4A). In some embodiments, the adhesive composition comprises an active ingredient dispersed in a non-reactive acrylate pressure-sensitive adhesive. The active ingredient can be present in an amount of about 1% to about 20% by weight, e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 10%, about 15%, or about 20% by weight, or any range therebetween, e.g., about 1% to about 15%, about 2% to about 15%, about 2% to about 10%, about 2% to about 7%, about 3% to about 15%, about 3% to about 10%, about 3% to about 7%, about 5% to about 15%, about 5% to about 10%, about 5% to about 7%, about 7% to about 15%, about 7% to about 10%, about 10% to about 20%, about 10% to about 15% by weight, etc. In some embodiments, the adhesive composition comprises a substantially pure R,R-isomer of tetrabenazine as the sole active ingredient. In some embodiments, the substantially pure R,R-isomer of tetrabenazine is in free base form. Suitable adhesives include any of the adhesives described herein, such as any of the pressure-sensitive adhesives described herein. In some embodiments, the adhesive can be a non-reactive acrylate pressure-sensitive adhesive described herein, such as Duro-Tak 87-900A, or as described in exemplary embodiments 2-7.The adhesive is typically present in an amount of about 50% to about 97% by weight, e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 97% by weight, or any range therebetween, e.g., about 50% to about 95%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, about 50% to about 60%, about 60% The active ingredient is present in an amount of about 2% to about 7% by weight, and the non-reactive acrylate pressure-sensitive adhesive is present in an amount of about 50% to about 97% by weight, about 60% to about 95% by weight, about 60% to about 90% by weight, about 60% to about 80% by weight, about 60% to about 70% by weight, about 70% to about 97% by weight, about 70% to about 95% by weight, about 70% to about 90% by weight, about 70% to about 80% by weight, about 80% to about 97% by weight, about 80% to about 95% by weight, or about 80% to about 90% by weight. In some specific embodiments, the active ingredient is present in an amount of about 2% to about 7% by weight, and the non-reactive acrylate pressure-sensitive adhesive is present in an amount of about 50% to about 97% by weight. The adhesive composition can also optionally include other ingredients, such as antioxidants, crystallization inhibitors, plasticizers, and / or permeation enhancers. In some embodiments, the adhesive composition includes an antioxidant, such as a gallic acid antioxidant, e.g., propyl gallate. The antioxidant is typically present in an amount of about 0% to about 1% by weight, e.g., about 0.001%, about 0.01%, about 0.1%, about 0.5%, about 1%, or any range therebetween, e.g., about 0.001% to about 0.5%, or about 0.01% to about 0.5% by weight. In some embodiments, the adhesive composition includes a crystallization inhibitor, e.g., a means for preventing the formation of drug crystals (e.g., crystals of the active ingredient of the adhesive composition, e.g., R,R-tetrabenazine) after storage at ambient temperature for two weeks.In some embodiments, the adhesive composition comprises a polyvinylpyrrolidone polymer (e.g., Kollidon K30 or K90F (manufactured by BASF), Plasdone K20 / 32 or Plasdone K90 (manufactured by Ashland Chemical)), a crosslinked polyvinylpyrrolidone polymer (e.g., Kollidon CL), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone (Ashland)), a cellulosic polymer (e.g., hydroxylpropylmethylcellulose, ethylcellulose, hydroxypropylcellulose), a polycarboxylic acid polymer (e.g., Cabopol (manufactured by Lubrizol)), a polymethacrylate (e.g., Plastoid B, Eudragit E100, Eudragit L100-55), a cellulose-based polymer (e.g., hydroxy ... polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone (Ashland)), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone (Ashland)), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone (manufactured by Evonik), polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam-based graft copolymers (PVAc-PVCap-PEG) (e.g., Soluplus (BASF)), and combinations thereof. In some embodiments, the adhesive composition comprises a crystallization inhibitor selected from polymethacrylate (e.g., Plastoid B (a copolymer of butyl methacrylate and methyl methacrylate), Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG) (e.g., Soluplus (BASF)), and combinations thereof. The crystallization inhibitor can typically be present in an amount of about 0 to about 40% by weight, e.g., about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 30% by weight, about 40% by weight, or any range therebetween, e.g., about 10% to about 40% by weight, about 10% to about 30% by weight, about 10% to about 20% by weight, 15% to about 40% by weight, about 15% to about 30% by weight, about 15% to about 20% by weight, 20% to about 40% by weight, about 20% to about 30% by weight, etc.In some embodiments, the adhesive composition may also include a skin permeation enhancer as described herein, such as isopropyl myristate. In some embodiments, the adhesive composition may also be free of a skin permeation enhancer as described herein, for example, in some embodiments, the adhesive composition may also be free of isopropyl myristate. Suitable drug loadings, active surface areas, thicknesses, adhesive properties, and the like include any of those described herein in any combination.

[0035] In some embodiments, the disclosure provides a method of treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising R,R-tetrabenazine, wherein the administration is via injection or infusion, such as intravenous injection (not including only bolus injections for immediate release), subcutaneous injection, or intramuscular injection, and the administration provides a dose of about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine, for example, about 0.5 mg / day to about 10 mg / day of R,R-tetrabenazine, about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine, about 0.5 mg / day to about 6 mg / day of R,R-tetrabenazine, about 0.5 mg / day to about 4 mg / day of R,R-tetrabenazine, about 1 mg / day to about 10 mg / day of R,R-tetrabenazine, Rabenazine, R,R-tetrabenazine from about 1 mg / day to about 8 mg / day, R,R-tetrabenazine from about 1 mg / day to about 6 mg / day, R,R-tetrabenazine from about 1 mg / day to about 4 mg / day, R,R-tetrabenazine from about 2 mg / day to about 10 mg / day, R,R-tetrabenazine from about 2 mg / day to about 8 mg / day, R,R-tetrabenazine from about 2 mg / day to about 6 mg / day, R,R-tetrabenazine from about 2 mg / day to about 10 mg / day, The method transdermally delivers to a subject about 4 mg / day to about 4 mg / day of R,R-tetrabenazine, about 4 mg / day to about 10 mg / day of R,R-tetrabenazine, about 4 mg / day to about 8 mg / day of R,R-tetrabenazine, about 4 mg / day to about 6 mg / day of R,R-tetrabenazine, about 6 mg / day to about 10 mg / day of R,R-tetrabenazine, or about 6 mg / day to about 8 mg / day of R,R-tetrabenazine. In some preferred embodiments, the method delivers about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine or about 2 mg / day to about 6 mg / day of R,R-tetrabenazine. In some embodiments, administration comprises continuous or substantially continuous intravenous injection or infusion of the pharmaceutical composition to the subject. The duration of drug delivery can vary, for example, from about 8 hours to about 72 hours, or to more than 72 hours.For example, in some embodiments, the pharmaceutical composition is intravenously injected or infused into a subject to provide continuous or substantially continuous delivery of R,R-tetrabenazine to the subject for about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range between the recited values. The rate of such intravenous injection or infusion can be controlled, for example, by a pump, and adjusted to deliver R,R-tetrabenazine to the subject at a substantially constant rate during the drug delivery period, such as the infusion period. In some embodiments, administration involves subcutaneous or intramuscular injection of the pharmaceutical composition into the subject. Typically, for subcutaneous or intramuscular injection, the pharmaceutical composition is formulated to release R,R-tetrabenazine to the subject over a preselected period of time, for example, from about 8 hours to about 72 hours or for systemic absorption over more than 72 hours. For example, in some embodiments, subcutaneous or intramuscular pharmaceutical compositions are formulated into or contained in a drug delivery device, such as an implant, to continuously or substantially continuously release R,R-tetrabenazine into a subject for systemic absorption for about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range between the recited values. Suitable implants include any known in the art for subcutaneous or intramuscular delivery of pharmaceutical agents, such as passive polymeric implants, including biodegradable and non-biodegradable implants, or active implants, such as osmotic pressure gradient and electromechanical drive. Non-limiting examples of formulating implants for subcutaneous delivery include those described in U.S. Pat. No. 8,921,387 (buprenorphine), U.S. Pat. No. 6,835,194 (fentanyl), etc. See also Stewart SA, et al. “Implantable polymeric drug delivery devices, classification, manufacture, materials, and clinical applications,” Polymers, 10:1379 (2018).In some embodiments, the pharmaceutical composition is formulated as a long-acting injectable formulation, such as microspheres, which may be configured to release R,R-tetrabenazine to a subject for systemic absorption over a preselected period of time, for example, from about 8 hours to about 72 hours or more. In some embodiments, the long-acting injectable formulation may be configured to release R,R-tetrabenazine to a subject for systemic absorption at a substantially constant rate over a preselected period of time to deliver a desired daily dose, as described herein.

[0036] The hyperkinetic movement disorders listed in the treatment methods herein include any known to be treatable with tetrabenazine or deutetrabenazine, e.g., any indication approved by a regulatory agency, including the U.S. FDA, or any under clinical investigation. Non-limiting examples include Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tics, dyskinetic cerebral palsy / cerebral palsy, other dystonia and dyskinesia disorders, and combinations thereof. In some embodiments, the hyperkinetic movement disorder can be Huntington's disease, e.g., chorea associated with Huntington's disease. In some embodiments, the hyperkinetic movement disorder can be Wilson's disease. In some embodiments, the hyperkinetic movement disorder can be Tourette's syndrome. In some embodiments, the hyperkinetic movement disorder can be restless legs syndrome. In some embodiments, the hyperkinetic movement disorder can be tardive dyskinesia. In some embodiments, the hyperkinetic movement disorder can be tics.

[0037] In some embodiments, the hyperkinetic movement disorder may be dyskinetic cerebral palsy. Cerebral palsy ("CP") refers to a group of neurological disorders that manifest in infancy or early childhood and permanently affect body movement and muscle coordination. CP is caused by damage or abnormalities in the developing brain, disrupting the brain's ability to control movement and maintain posture and balance. Signs of CP typically appear within the first few months of life, but specific diagnosis may be delayed until the child is two years of age or older. Currently, there are no approved treatments available for dyskinesia in cerebral palsy (DCP). Available treatment options address some of the symptoms of DCP. Teva is currently conducting a Phase III clinical trial using deutetrabenazine. According to Teva, the study population includes pediatric and adolescent patients (ages 6-18) with DCP and primary choroidal movement disorder who have had non-progressive CP symptoms since infancy (ages 2 and under). The inventors believe that the methods and compositions described herein may provide an alternative and / or superior treatment option for dyskinetic cerebral palsy.

[0038] In some embodiments, the hyperkinetic movement disorder is dystonia or a dyskinetic disorder. See, e.g., Thengnatt MA and Jankovic J. neurotherapeutics, 11(1):139-152 (2014) for a review of dystonia treatments.

[0039] The treatment methods herein are not limited to a particular type of subject. For example, the methods herein can be administered to a subject regardless of the subject's feeding status. In other words, the subject's feeding or fasting status is not important to the methods herein. In some embodiments, the subject is a pediatric or adolescent patient (e.g., 6-18 years old). Also, in some embodiments, the methods are not limited to a particular genotype of subject. In some embodiments, the same or substantially the same dose of R,R-tetrabenazine can be administered to subjects characterized as PM, IM, or EM. In some embodiments, the subject is characterized as an EM. In some embodiments, the subject is characterized as a PM. In some embodiments, the subject is characterized as an IM. In some embodiments, the methods do not require dose titration and / or genotyping, as is required when treated with either Xenazine® or Austedo™ tablets. In some embodiments, any of the methods herein can be adapted to treat pediatric and adolescent patients (e.g., 6-18 years old) with any of the diseases or disorders herein. As discussed herein, dose and / or plasma exposure ranges may be suitable for adult patients as well as pediatric and adolescent patients. However, as will be understood by those skilled in the art, the desired dose and / or plasma exposure for pediatric and adolescent patients may be adjusted, typically to a lower dose or exposure, taking into account the age and weight of the subject. Without wishing to be bound by theory, the convenient and controlled delivery of R,R-tetrabenazine herein may, in some embodiments, provide safety and treatment options superior to currently available therapies.

[0040] The administration regimen of the treatment methods herein is not particularly limited, so long as the desired dose of R,R-tetrabenazine is delivered to the subject at the desired rate for the desired period of time, including any of those described herein. For example, in some embodiments, the pharmaceutical composition is administered to the subject once daily. In some embodiments, the pharmaceutical composition is administered to the subject more than once a day, for example, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, or more than once a week. In some embodiments, each administration provides continuous or substantially continuous delivery of R,R-tetrabenazine to the subject for about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range therebetween. In some embodiments, there is no or substantially no lag time between two successive administrations, so that R,R-tetrabenazine can continue to be delivered to the subject according to the dosing regimen herein. In some embodiments, there may be an overlap or lag time between two successive administrations.

[0041] Pharmacokinetics of sustained delivery tetrabenazine. Some embodiments of the present disclosure are also directed to a method of treating a hyperkinetic movement disorder in a subject in need thereof, comprising delivering a therapeutically effective amount of R,R-tetrabenazine to the subject, wherein the delivery provides a particular novel pharmacokinetic profile in the subject's plasma.

[0042] As discussed herein, currently approved tetrabenazine or deuterated tetrabenazine products, such as Xenazine® and Austedo™, require complex dose titration and necessitate genotyping of treated subjects at higher doses. Furthermore, oral administration of such products also results in high peak-to-trough ratios, accompanied by significant interindividual variability in plasma levels of tetrabenazine or deutetrabenazine or their metabolites. Typically, as also shown herein, R,R-tetrabenazine itself, a potent VMAT-2 inhibitor, is not present in significant amounts in the circulation after oral administration. In some embodiments, the inventors herein first demonstrate that, by using continuous or substantially continuous delivery of tetrabenazine, the mean terminal half-life of R,R-tetrabenazine administered via first-pass bypass can be approximately 8.5 hours ± 40% CV. By comparison, R,R-tetrabenazine is typically not systemically available when administered orally.

[0043] In various embodiments, the sustained or substantially sustained delivery of tetrabenazine described herein that achieves the novel pharmacokinetic profile herein may be advantageously used, for example, to deliver tetrabenazine for the treatment of hyperkinetic movement disorders.

[0044] In some embodiments, the present disclosure provides a method of treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising R,R-tetrabenazine, wherein the administration provides a desired pharmacokinetic profile (PK profile). For example, in some embodiments, the desired PK profile is one in which administration provides plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ, and the ratio of the maximum therapeutically effective plasma concentration of R,R-tetrabenazine to the maximum combined plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ is in the range of about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any range between the recited values, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.), i.e., the C of R,R-tetrabenazine max / (R,R,R-HTBZ C max +S,R,R-HTBZ C max ) is characterized in that the ratio is in the range of about 1:1 to about 1:5. As used herein, in some embodiments, the term "maximum plasma concentration" can refer to the maximum plasma concentration obtained after administration of a single dose of a pharmaceutical composition, e.g., after application of a single transdermal patch according to the present invention for delivery for 1, 2, 3, or more days. As used herein, in some embodiments, the term "maximum plasma concentration" can also refer to the maximum plasma concentration obtained after administration of multiple doses of a pharmaceutical composition, preferably the maximum plasma concentration obtained after reaching a steady state. However, the ratios herein should be based on a comparison of the same type of concentration between the respective compounds (e.g., from a single dose, steady state, etc.), and the ratio should be based on the following: (1) single-dose C max and / or (2) multiple dose C max (preferably steady state C maxIt is understood that, when calculated based on the respective ranges recited herein, the desired PK profile can be said to be within the respective ranges recited herein. In some embodiments, the desired PK profile is one in which administration results in a ratio of the steady-state plasma concentration of R,R-tetrabenazine to the combined steady-state plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ in the range of about 1:1 to about 1:5, i.e., a C of R,R-tetrabenazine ss / (R,R,R-HTBZ C ss +S,R,R-HTBZ C ss) is characterized by a ratio ranging from about 1:1 to about 1:5. In the sustained or substantially sustained delivery described herein, a steady state is typically reached, and this state can be maintained for a desired period of time. For example, in some embodiments, a steady state can be reached by applying a single transdermal patch described herein for about 32 to 48 hours or more, and this steady state can be maintained with the same patch or by replacing the transdermal patch with a new patch capable of delivering R,R-tetrabenazine at substantially the same rate at any frequency. In some embodiments, a steady state is not reached by a single application of a transdermal patch described herein, but can be reached continuously by multiple applications of the transdermal patch. As will be understood by those skilled in the art, at steady state, the drug concentration obtained from a transdermal delivery patch can be substantially constant; in other words, the PK curve at steady state can be substantially flat or plateau for a period of time. As used herein, steady state for R,R-TBZ refers to a situation in which the overall intake of R,R-TBZ is in a fairly dynamic equilibrium with its elimination. The steady state for R,R,R-HTBZ refers to a situation where the overall production of R,R,R-HTBZ is in fairly dynamic equilibrium with its elimination. The steady state for S,R,R-HTBZ refers to a situation where the overall production of S,R,R-HTBZ is in fairly dynamic equilibrium with its elimination. For clarity, as used herein, the ratio of steady-state concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and / or S,R,R-HTBZ can be said to be within the recited ranges herein when calculated based on (1) the concentration of each compound at any time when all three compounds, R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ, are at steady state, and / or (2) the average concentration of each compound over a sustained period when all three compounds, R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ, are at steady state. Ratios of steady-state concentrations of other compounds herein should be understood similarly.As used herein, a therapeutically effective plasma concentration of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ does not require that each of the three compounds be at a therapeutically effective plasma concentration by itself. It is sufficient that the combination of the three compounds is therapeutically effective, for example, at their respective steady-state concentrations. In some embodiments, the ratio of maximum or steady-state plasma concentrations of R,R,R-HTBZ to S,R,R-HTBZ can be in the range of about 1:5 to about 1:30 (e.g., about 1:5, about 1:7, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, or any range therebetween, e.g., about 1:10 to about 1:20, about 1:5 to about 1:15, etc.). In some embodiments, the ratio of maximum plasma concentrations of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ can be in the range of about 17 to 40:3 to 10:50 to 80. In some embodiments, the ratio of steady-state plasma concentrations of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ can be in the range of about 17 to 40:3 to 10:50 to 80. In some embodiments, the AUC of S,R,R-HTBZ can be increased by administration. 0-∞ AUC of R,R-tetrabenazine 0-∞ to about 1 to about 15, for example, about 1.5 to about 11, and / or the AUC of RRR-HTBZ 0-∞ AUC of R,R-tetrabenazine 0-∞to about 0.1 to about 0.75, e.g., about 0.15 to about 0.5. In some embodiments, the desired PK profile can also be characterized by administration providing therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ for at least 6 hours, or at least 12 hours, preferably at least 24 hours, e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, or more. In some embodiments, the desired PK profile may also be characterized in that administration provides a substantially constant steady-state plasma concentration of R,R-tetrabenazine of greater than 150 pg / ml (e.g., from about 150 pg / ml to about 3000 pg / ml) for a sustained period of at least 6 hours, or at least 12 hours, preferably at least 24 hours, e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, or more. In some embodiments, administration does not provide detectable amounts of S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ in the plasma of a subject. In some embodiments, the present disclosure also provides a method of identifying a pharmaceutical composition for treating a hyperkinetic movement disorder. In some embodiments, the method comprises administering to a subject a test pharmaceutical composition that bypasses first-pass metabolism and delivers R,R-tetrabenazine to the subject in a sustained or substantially sustained manner, and identifying a pharmaceutical composition that provides any of the PK profiles described in this paragraph in any combination.

[0045] In some embodiments, the pharmaceutical composition is formulated to provide a dose of about 2 mg / day of R,R-tetrabenazine when administered once for 4 days. In some embodiments, the method includes administering the pharmaceutical composition to provide a pharmacokinetic profile in the subject characterized by: a) Mean T of R,R-tetrabenazine over about 10 hours to about 24 hours, for example, about 20 hours max ; b) Mean T of R,R-tetrabenazine max Slower mean T of R,R,R-HTBZ max and the mean T of S,R,R-HTBZ max ; c) Mean C of R,R-tetrabenazine of approximately 300 pg / ml to approximately 700 pg / ml max ; d) Mean C of R,R,R-HTBZ from about 60 pg / ml to about 200 pg / ml max ; e) Average C of S,R,R-HTBZ from about 1000 pg / ml to about 3000 pg / ml max ; f) Mean AUC of R,R-tetrabenazine from about 20 ng*hr / ml to about 50 ng*hr / ml 0-96 ; g) Mean AUC of R,R,R-HTBZ from approximately 4 ng*hr / ml to approximately 12 ng*hr / ml 0-96 and / or h) Mean AUC of S,R,R-HTBZ from approximately 70 ng*hr / ml to approximately 200 ng*hr / ml 0-96 . In some embodiments, the pharmacokinetic profile in the subject is characterized by any one of a) through h). In some embodiments, the pharmacokinetic profile in the subject is characterized by a) and b). In some embodiments, the pharmacokinetic profile in the subject is characterized by c), d), and e). In some embodiments, the pharmacokinetic profile in the subject is characterized by f), g), and h). In some embodiments, the pharmacokinetic profile in the subject is characterized by 1) a) and / or b); 2) c), d), and / or e); and 3) f), g), and / or h). In some embodiments, the pharmacokinetic profile in the subject is characterized by all of a) through h). In some embodiments, the pharmacokinetic profile in a subject is characterized in that administration provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ, and the ratio of the maximum plasma concentration of R,R-tetrabenazine to the maximum plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ is in the range of from about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any ranges therebetween, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some embodiments, the pharmacokinetic profile in a subject is characterized in that administration provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ, and the ratio of the steady-state plasma concentration of R,R-tetrabenazine to the combined steady-state plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ is in the range of from about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any ranges therebetween, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.).In some embodiments, the ratio of maximum or steady-state plasma concentrations of R,R,R-HTBZ to S,R,R-HTBZ can range from about 1:5 to about 1:30 (e.g., about 1:5, about 1:7, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, or any range between the recited values, e.g., about 1:10 to about 1:20, about 1:5 to about 1:15, etc.). In some embodiments, the ratio of maximum plasma concentrations of R,R-tetrabenazine:R,R-HTBZ:S,R,R-HTBZ can range from about 17-40:3 to 10:50-80. In some embodiments, the ratio of steady-state plasma concentrations of R,R-tetrabenazine:R,R-HTBZ:S,R,R-HTBZ can range from about 17-40:3 to 10:50-80. In some embodiments, the AUC of SRR-HTBZ upon administration. 0-∞ AUC of R,R-tetrabenazine 0-∞ to about 1 to about 15, for example, about 1.5 to about 11, and / or the AUC of RRR-HTBZ 0-∞ AUC of R,R-tetrabenazine 0-∞to about 0.1 to about 0.75, e.g., about 0.15 to about 0.5. In some embodiments, the desired PK profile can also be characterized by administration providing therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ for at least 6 hours, or at least 12 hours, preferably at least 24 hours, e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, or more. In some embodiments, the desired PK profile may also be characterized in that administration provides a substantially constant steady-state plasma concentration of R,R-tetrabenazine of greater than 150 pg / ml (e.g., from about 150 pg / ml to about 3000 pg / ml) for a sustained period of at least 6 hours, or at least 12 hours, preferably at least 24 hours, e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, or more. In some embodiments, administration does not provide detectable S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ in the plasma of a subject. In some embodiments, the present disclosure also provides a method of identifying a pharmaceutical composition for treating a hyperkinetic movement disorder. In some embodiments, the method comprises administering to a subject a test pharmaceutical composition that bypasses first-pass metabolism, and identifying a pharmaceutical composition that, when administered to provide a dose of about 2 mg / day for 4 days, provides any combination of any of the PK profiles described in this paragraph.

[0046] In some embodiments, the pharmaceutical composition is formulated to provide a dose of about 4-6 mg / day of R,R-tetrabenazine for at least 1 day, e.g., 2, 3, 4 days, or 1 week, when administered once. In some embodiments, the method includes administering the pharmaceutical composition to provide a pharmacokinetic profile in the subject characterized by: a) Mean T of R,R-tetrabenazine over about 10 hours to about 24 hours, for example, about 20 hours max ; b) Mean T of R,R-tetrabenazine max Slower mean T of R,R,R-HTBZ max and the mean T of S,R,R-HTBZ max ; c) Mean C of R,R-tetrabenazine from about 600 pg / ml to about 2100 pg / ml max ; d) Mean C of R,R,R-HTBZ from about 120 pg / ml to about 600 pg / ml max ; e) Average C of S,R,R-HTBZ from about 2000 pg / ml to about 9000 pg / ml max ; f) Mean AUC of R,R-tetrabenazine from about 40 ng*hr / ml to about 150 ng*hr / ml 0-96 ; g) Mean AUC of R,R,R-HTBZ from approximately 8 ng*hr / ml to approximately 36 ng*hr / ml 0-96 and / or h) Mean AUC of S,R,R-HTBZ from approximately 140 ng*hr / ml to approximately 600 ng*hr / ml 0-96 . In some embodiments, each administration of the pharmaceutical composition provides a daily dose of about 4-6 mg / day of R,R-tetrabenazine. In some embodiments, each administration of the pharmaceutical composition provides a daily dose of about 4-6 mg / day of R,R-tetrabenazine for two days. In some embodiments, each administration of the pharmaceutical composition provides a daily dose of about 4-6 mg / day of R,R-tetrabenazine for three days. In some embodiments, each administration of the pharmaceutical composition provides a daily dose of about 4-6 mg / day of R,R-tetrabenazine for four days. In some embodiments, each administration of the pharmaceutical composition provides a weekly dose of about 4-6 mg / day of R,R-tetrabenazine. In some embodiments, the pharmaceutical composition is an adhesive composition as described herein, e.g., contained in a transdermal delivery patch as described herein, and the pharmaceutical composition can be administered to adhere to the skin of a subject for the desired period of R,R-tetrabenazine delivery, e.g., 1 day, 2 days, 3 days, 4 days, 1 week, or any range therebetween. Other pharmaceutical compositions for sustained delivery herein can be administered according to usual practices for such compositions to achieve the desired period of R,R-tetrabenazine delivery, e.g., the depot or implant can be formulated to release about 4-6 mg / day of R,R-tetrabenazine for a desired period of time after administration (e.g., injection) to a subject. In some embodiments, the pharmacokinetic profile in a subject is characterized by any one of a) through h). In some embodiments, the pharmacokinetic profile in a subject is characterized by a) and b). In some embodiments, the pharmacokinetic profile in a subject is characterized by c), d), and e). In some embodiments, the pharmacokinetic profile in a subject is characterized by f), g), and h). In some embodiments, the pharmacokinetic profile in a subject is characterized by 1) a) and / or b); 2) c), d), and / or e); and 3) f), g), and / or h). In some embodiments, the pharmacokinetic profile in a subject is characterized by all of a) through h).In some embodiments, the pharmacokinetic profile in a subject is characterized in that administration provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ, and the ratio of the maximum plasma concentration of R,R-tetrabenazine to the maximum plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ is in the range of from about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any ranges therebetween, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some embodiments, the pharmacokinetic profile in a subject is characterized in that administration provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ, and the ratio of the steady-state plasma concentration of R,R-tetrabenazine to the combined steady-state plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ is in the range of from about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any ranges therebetween, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some embodiments, the ratio of maximum or steady-state plasma concentrations of R,R,R-HTBZ to S,R,R-HTBZ can range from about 1:5 to about 1:30 (e.g., about 1:5, about 1:7, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, or any range between the recited values, e.g., about 1:10 to about 1:20, about 1:5 to about 1:15, etc.). In some embodiments, the ratio of maximum plasma concentrations of R,R-tetrabenazine:R,R-HTBZ:S,R,R-HTBZ can range from about 17-40:3 to 10:50-80. In some embodiments, the ratio of steady-state plasma concentrations of R,R-tetrabenazine:R,R-HTBZ:S,R,R-HTBZ can range from about 17-40:3 to 10:50-80. In some embodiments, the AUC of SRR-HTBZ upon administration. 0-∞ AUC of R,R-tetrabenazine 0-∞ to about 1 to about 15, for example, about 1.5 to about 11, and / or the AUC of RRR-HTBZ 0-∞AUC of R,R-tetrabenazine 0-∞ to about 0.1 to about 0.75, e.g., about 0.15 to about 0.5. In some embodiments, the desired PK profile can also be characterized by administration providing therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ for at least 6 hours, or at least 12 hours, preferably at least 24 hours, e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, or more. In some embodiments, the desired PK profile may also be characterized in that administration provides a substantially constant steady-state plasma concentration of R,R-tetrabenazine of greater than 150 pg / ml (e.g., from about 150 pg / ml to about 3000 pg / ml) for a sustained period of at least 6 hours, or at least 12 hours, preferably at least 24 hours, e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, or more. In some embodiments, administration does not provide detectable S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ in the plasma of a subject. In some embodiments, the present disclosure also provides a method of identifying a pharmaceutical composition for treating a hyperkinetic movement disorder. In some embodiments, the method includes administering to a subject a test pharmaceutical composition that bypasses first-pass metabolism, and identifying a pharmaceutical composition that provides any of the PK profiles described in this paragraph, in any combination, when administered to provide a dose of about 4-6 mg / day for at least 1 day, e.g., 2 days, 3 days, 4 days, or 1 week.

[0047] In some embodiments, the pharmaceutical composition is formulated to provide a dose of about 1-10 mg / day of R,R-tetrabenazine for at least 1 day, e.g., 2, 3, 4 days, or 1 week, when administered once. In some embodiments, the method includes administering the pharmaceutical composition to provide a pharmacokinetic profile in the subject characterized by: a) Mean T of R,R-tetrabenazine over about 10 hours to about 24 hours, for example, about 20 hours max ; b) Mean T of R,R-tetrabenazine max Slower mean T of R,R,R-HTBZ max and the mean T of S,R,R-HTBZ max ; c) Mean C of R,R-tetrabenazine from about 150 pg / ml to about 3500 pg / ml max ; d) Mean C of R,R,R-HTBZ from about 30 pg / ml to about 1000 pg / ml max ; e) Mean C of S,R,R-HTBZ from about 500 pg / ml to about 15 ng / ml max ; f) Mean AUC of R,R-tetrabenazine from about 10 ng*hr / ml to about 250 ng*hr / ml 0-96 ; g) Mean AUC of R,R,R-HTBZ from approximately 2 ng*hr / ml to approximately 60 ng*hr / ml 0-96 and / or h) Mean AUC of S,R,R-HTBZ from approximately 35 ng*hr / ml to approximately 1000 ng*hr / ml 0-96 . In some embodiments, each administration of the pharmaceutical composition provides a dose of about 1-10 mg / day of R,R-tetrabenazine over one day. In some embodiments, each administration of the pharmaceutical composition provides a dose of about 1-10 mg / day of R,R-tetrabenazine over two days. In some embodiments, each administration of the pharmaceutical composition provides a dose of about 1-10 mg / day of R,R-tetrabenazine over three days. In some embodiments, each administration of the pharmaceutical composition provides a dose of about 1-10 mg / day of R,R-tetrabenazine over four days. In some embodiments, each administration of the pharmaceutical composition provides a dose of about 1-10 mg / day of R,R-tetrabenazine over one week. In some embodiments, the pharmaceutical composition is an adhesive composition as described herein, e.g., contained in a transdermal delivery patch as described herein, and the pharmaceutical composition can be administered to adhere to the skin of a subject for the desired period of R,R-tetrabenazine delivery, e.g., one day, two days, three days, four days, one week, or any range therebetween. Other pharmaceutical compositions for sustained delivery herein can be administered according to usual practices for such compositions to achieve the desired period of R,R-tetrabenazine delivery, e.g., the depot or implant can be formulated to release about 1 to 10 mg / day of R,R-tetrabenazine for a desired period of time after administration (e.g., injection) to a subject. In some embodiments, the pharmacokinetic profile in a subject is characterized by any one of a) through h). In some embodiments, the pharmacokinetic profile in a subject is characterized by a) and b). In some embodiments, the pharmacokinetic profile in a subject is characterized by c), d), and e). In some embodiments, the pharmacokinetic profile in a subject is characterized by f), g), and h). In some embodiments, the pharmacokinetic profile in a subject is characterized by 1) a) and / or b); 2) c), d), and / or e); and 3) f), g), and / or h). In some embodiments, the pharmacokinetic profile in a subject is characterized by all of a) through h).In some embodiments, the pharmacokinetic profile in a subject is characterized in that administration provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ, and the ratio of the maximum plasma concentration of R,R-tetrabenazine to the maximum plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ is in the range of from about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any ranges therebetween, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some embodiments, the pharmacokinetic profile in a subject is characterized in that administration provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ, and the ratio of the steady-state plasma concentration of R,R-tetrabenazine to the combined steady-state plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ is in the range of from about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any ranges therebetween, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some embodiments, the ratio of maximum or steady-state plasma concentrations of R,R,R-HTBZ to S,R,R-HTBZ can range from about 1:5 to about 1:30 (e.g., about 1:5, about 1:7, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, or any range between the recited values, e.g., about 1:10 to about 1:20, about 1:5 to about 1:15, etc.). In some embodiments, the ratio of maximum plasma concentrations of R,R-tetrabenazine:R,R-HTBZ:S,R,R-HTBZ can range from about 17-40:3 to 10:50-80. In some embodiments, the ratio of steady-state plasma concentrations of R,R-tetrabenazine:R,R-HTBZ:S,R,R-HTBZ can range from about 17-40:3 to 10:50-80. In some embodiments, the AUC of SRR-HTBZ upon administration. 0-∞ AUC of R,R-tetrabenazine 0-∞ to about 1 to about 15, for example, about 1.5 to about 11, and / or the AUC of RRR-HTBZ 0-∞AUC of R,R-tetrabenazine 0-∞ to about 0.1 to about 0.75, e.g., about 0.15 to about 0.5. In some embodiments, the desired PK profile can also be characterized by administration providing therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ for at least 6 hours, or at least 12 hours, preferably at least 24 hours, e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, or more. In some embodiments, the desired PK profile may also be characterized in that administration provides a substantially constant steady-state plasma concentration of R,R-tetrabenazine of greater than 150 pg / ml (e.g., from about 150 pg / ml to about 3000 pg / ml) for a sustained period of at least 6 hours, or at least 12 hours, preferably at least 24 hours, e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, or more. In some embodiments, administration does not provide detectable S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ in the plasma of a subject. In some embodiments, the present disclosure also provides a method of identifying a pharmaceutical composition for treating a hyperkinetic movement disorder. In some embodiments, the method includes administering to a subject a test pharmaceutical composition that bypasses first-pass metabolism, and identifying a pharmaceutical composition that provides any of the PK profiles described in this paragraph, in any combination, when administered to provide a dose of about 1-10 mg / day for at least 1 day, e.g., 2 days, 3 days, 4 days, or 1 week.

[0048] In some embodiments, the disclosure provides a method of treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising R,R-tetrabenazine, wherein the administration provides a PK profile characterized by: (1) the plasma concentration of R,R-tetrabenazine increases over a first period of time, reaching a maximum concentration of about 150 pg / ml to about 3500 pg / ml at a first time point during the first period of time; and, optionally, (2) after the first period of time, the plasma concentration of R,R-tetrabenazine may remain substantially constant for a sustained period of time, e.g., about 24 hours, about 48 hours, about 72 hours, about 96 hours, or longer. In some embodiments, the first period of time refers to the initial rising portion of the PK curve until the plasma concentration begins to plateau and / or decline, while the sustained period of time refers to the substantially flat portion of the PK curve; see, e.g., the figure for this application observed from transdermal delivery. In some embodiments, the duration may continue for as long as treatment is desired. In some embodiments, the first period of time is from time 0 (the time of administration of the pharmaceutical composition) to about 24 hours thereafter, e.g., 0 to 20 hours, or 0 to 18 hours. In some embodiments, the first period of time may also be longer than 0 to 24 hours, such as 0 to 36 hours or 0 to 48 hours. In some embodiments, the first period of time is from time 0 (the time of administration of the pharmaceutical composition) to about 24 hours thereafter, e.g., 0 to 20 hours, or 0 to 18 hours. In some embodiments, the first period of time is from time 0 (the time of administration of the pharmaceutical composition) to about 24 hours thereafter, e.g., 0 to 36 hours, or 0 to 4 ... maxTypically, the plasma concentrations of R,R-tetrabenazine observed during the Sustained Period range from about 40% to about 250% of the maximum concentration observed in the first period, and the plasma concentrations of R,R-tetrabenazine do not change significantly, e.g., by a factor of 2, during any of the 4 hour, 8 hour, and / or 12 hour intervals of the Sustained Period, e.g., the concentration at time t1 is within about 50% to about 200% of the concentration at time t1+12 hours, provided that both times t1 and t1+12 hours are within the Sustained Period. In some embodiments, during the sustained period, the minimum plasma concentration of R,R-tetrabenazine is at least about 40%, e.g., at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, of the maximum concentration during the first period; and / or the maximum plasma concentration of R,R-tetrabenazine is not more than about 250%, e.g., not more than about 200%, not more than about 150%, or not more than about 120%, of the maximum concentration during the first period. In some embodiments, the plasma concentration of R,R-tetrabenazine 24 hours after the first time point is between about 50% and about 200%, e.g., between about 75% and about 150%, of the plasma concentration at the first time point. In some embodiments, the pharmacokinetic profile in a subject is further characterized in that administration provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ for a sustained period of time, and that during that sustained period, the ratio of the plasma concentration of R,R-tetrabenazine to the combined plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ at a given time point is in the range of from about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any ranges between the recited values, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some embodiments, during a sustained period, the plasma concentration ratio of R,R,R-HTBZ to S,R,R-HTBZ at a given time point can range from about 1:5 to about 1:30 (e.g., about 1:5, about 1:7, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, or any range between the recited values, e.g., about 1:10 to about 1:20, about 1:5 to about 1:15, etc.).In some embodiments, during the sustained period, the ratio of plasma concentrations of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ may be in the range of about 17 to 40:3 to 10:50 to 80 at a given time point. In some embodiments, during the sustained period, the ratio of maximum plasma concentrations of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ may be in the range of about 17 to 40:3 to 10:50 to 80. In some embodiments, the AUC of S,R,R-HTBZ may be increased by administration. 0-∞ AUC of R,R-tetrabenazine 0-∞ to about 1 to about 15, for example, about 1.5 to about 11, and / or the AUC of RRR-HTBZ 0-∞ AUC of R,R-tetrabenazine 0-∞ The present disclosure also provides a method for identifying a pharmaceutical composition for treating hyperkinetic movement disorders. In some embodiments, the method comprises administering to a subject a test pharmaceutical composition that bypasses first-pass metabolism, and identifying a pharmaceutical composition that provides any of the PK profiles described in this paragraph, in any combination.

[0049] The route for administering the pharmaceutical composition to achieve the PK profile described herein is not particularly limited, as long as the administration provides the pharmacokinetic profile described above. Typically, the administration bypasses first-pass metabolism. For example, in some embodiments, the pharmaceutical composition is administered transdermally. In some embodiments, the pharmaceutical composition is administered via injection or infusion, such as intravenous injection (excluding only bolus injection for immediate release), subcutaneous injection, or intramuscular injection. In some embodiments, the pharmaceutical formulation is a depot formulation.

[0050] Administration typically provides continuous or substantially continuous delivery of R,R-tetrabenazine to a subject to achieve the PK profile described herein. In some embodiments, administration delivers R,R-tetrabenazine to a subject for a period of, for example, about 8 hours to about 72 hours or greater. For example, in some embodiments, administration provides continuous or substantially continuous delivery of R,R-tetrabenazine to a subject for about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range therebetween. In some embodiments, during the period of continuous or substantially continuous delivery, R,R-tetrabenazine may be delivered to a subject at a substantially constant rate, e.g., the average delivery rate for each hour is substantially the same, e.g., within 80-125% of the overall average rate. In some embodiments, during the period of sustained or substantially sustained delivery, R,R-tetrabenazine may be delivered to a subject, e.g., at different average delivery rates for each hour. For example, in some embodiments, the average delivery rate may be high initially but then decrease over the course of sustained or substantially sustained delivery. Typically, the exact hourly delivery rate of R,R-tetrabenazine is not critical, and one of skill in the art, after reviewing this disclosure, will know how to select and design a dosing regimen to deliver a desired daily dose to a subject that provides the pharmacokinetic profile described herein. For example, in some embodiments, R,R-tetrabenazine may be delivered to a subject at a daily dose of about 0.1 mg / day to about 20 mg / day, e.g., about 0.5 mg / day to about 10 mg / day of R,R-tetrabenazine, about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine, or about 2 mg / day to about 6 mg / day of R,R-tetrabenazine, to provide the pharmacokinetic profile described herein.

[0051] The hyperkinetic movement disorders described in the treatment methods herein include any of those described herein. Non-limiting examples include Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tics, dyskinetic cerebral palsy / cerebral palsy, other dystonia and dyskinesia disorders, and combinations thereof. In some embodiments, the hyperkinetic movement disorder can be Huntington's disease, including chorea associated with Huntington's disease. In some embodiments, the hyperkinetic movement disorder can be Wilson's disease. In some embodiments, the hyperkinetic movement disorder can be Tourette's syndrome. In some embodiments, the hyperkinetic movement disorder can be restless legs syndrome. In some embodiments, the hyperkinetic movement disorder can be tardive dyskinesia. In some embodiments, the hyperkinetic movement disorder can be tics. In some embodiments, the hyperkinetic movement disorder can be dyskinetic cerebral palsy. In some embodiments, the hyperkinetic movement disorder is a dystonia or dyskinetic disorder.

[0052] The treatment methods herein are not limited to a particular type of subject. For example, the methods herein can be administered to subjects regardless of their feeding status. In some embodiments, the subjects are pediatric and adolescent patients (e.g., 6-18 years old). Also, in some embodiments, the methods are not limited to subjects of a particular genotype. In some embodiments, the same or substantially the same dose of R,R-tetrabenazine can be administered to subjects characterized as PM, IM, or EM. In some embodiments, the subject is characterized as an EM. In some embodiments, the subject is characterized as a PM. In some embodiments, the subject is characterized as an IM. In some embodiments, the methods do not require dose titration and / or genotype analysis, as is required when treating with either Xenazine® or Austedo™ tablets.

[0053] The dosing regimen of the treatment methods herein is not particularly limited, so long as the desired dose of R,R-tetrabenazine is delivered to the subject at the desired rate for the desired period of time, including any of those described herein. For example, in some embodiments, the pharmaceutical composition is administered to the subject at a dosing regimen suitable for achieving the PK profile described herein. In some embodiments, the pharmaceutical composition is administered to the subject once daily. In some embodiments, the pharmaceutical composition is administered to the subject more than once a day, for example, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, or more than once a week. In some embodiments, each administration provides a continuous or substantially continuous delivery of R,R-tetrabenazine to the subject for about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range therebetween. As discussed herein, there may be no lag time, no overlap, or some lag time between two consecutive administrations.

[0054] Pharmaceutical compositions suitable for various routes of administration of the methods herein are also described. Typically, for transdermal delivery, the pharmaceutical composition comprises an active ingredient dispersed in an adhesive (preferably a pressure-sensitive adhesive), e.g., an adhesive composition in a transdermal delivery device. In some embodiments, the adhesive composition is applied to a subject to deliver about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine (e.g., any of the exemplified ranges described herein) at a substantially constant rate for up to 24 hours after application, up to 48 hours after application, up to 96 hours after application, or up to 1 week after application. Suitable adhesive compositions include any of those described herein, e.g., any of those described in embodiments 1-18 applicable to tetrabenazine, or any of the specific compositions shown in the Examples section (e.g., Example 4A). In some embodiments, the adhesive composition comprises an active ingredient dispersed in a non-reactive acrylate pressure-sensitive adhesive. The active ingredient can be present in an amount of about 1% to about 20% by weight, e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 10%, about 15%, about 20%, or any range therebetween, e.g., about 1% to about 15%, about 2% to about 15%, about 2% to about 10%, about 2% to about 7%, about 3% to about 15%, about 3% to about 10%, about 3% to about 7%, about 5% to about 15%, about 5% to about 10%, about 5% to about 7%, about 7% to about 15%, about 7% to about 10%, about 10% to about 20%, about 10% to about 15% by weight, etc. In some embodiments, the adhesive composition comprises a substantially pure R,R-isomer of tetrabenazine as the sole active ingredient. In some embodiments, the substantially pure R,R-isomer of tetrabenazine is in free base form. Suitable adhesives include any of the adhesives described herein, such as any of the pressure-sensitive adhesives described herein. In some embodiments, the adhesive can be a non-reactive acrylate pressure-sensitive adhesive described herein, such as Duro-Tak 87-900A, or as described in exemplary embodiments 2-7.The adhesive is typically present in an amount of about 50% to about 97% by weight, e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 97% by weight, or any range therebetween, e.g., about 50% to about 95%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, about 50% to about 60%, about 60% by weight. The active ingredient may be present in an amount of about 2% to about 7% by weight, and the non-reactive acrylate pressure-sensitive adhesive may be present in an amount of about 50% to about 97% by weight, about 60% to about 95% by weight, about 60% to about 90% by weight, about 60% to about 80% by weight, about 60% to about 70% by weight, about 70% to about 97% by weight, about 70% to about 95% by weight, about 70% to about 90% by weight, about 70% to about 80% by weight, about 80% to about 97% by weight, about 80% to about 95% by weight, or about 80% to about 90% by weight. In some specific embodiments, the active ingredient is present in an amount of about 2% to about 7% by weight, and the non-reactive acrylate pressure-sensitive adhesive is present in an amount of about 50% to about 97% by weight. The adhesive composition may also optionally include other ingredients, such as antioxidants, crystallization inhibitors, plasticizers, and / or permeation enhancers. In some embodiments, the adhesive composition includes an antioxidant, such as a gallic acid antioxidant, e.g., propyl gallate. The antioxidant is typically present in an amount of about 0% to about 1% by weight, e.g., about 0.001%, about 0.01%, about 0.1%, about 0.5%, about 1%, or any range therebetween, e.g., about 0.001% to about 0.5%, or about 0.01% to about 0.5% by weight. In some embodiments, the adhesive composition includes a crystallization inhibitor, e.g., a means for preventing the formation of drug crystals (e.g., crystals of the active ingredient of the adhesive composition, e.g., R,R-tetrabenazine) after storage at ambient temperature for two weeks.In some embodiments, the adhesive composition comprises a polyvinylpyrrolidone polymer (e.g., Kollidon K30 or K90F (manufactured by BASF), Plasdone K20 / 32 or Plasdone K90 (manufactured by Ashland Chemical)), a crosslinked polyvinylpyrrolidone polymer (e.g., Kollidon CL), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone (Ashland)), a cellulosic polymer (e.g., hydroxylpropylmethylcellulose, ethylcellulose, hydroxypropylcellulose), a polycarboxylic acid polymer (e.g., Cabopol (manufactured by Lubrizol)), a polymethacrylate (e.g., Plastoid B, Eudragit E100, Eudragit L100-55), a cellulose-based polymer (e.g., hydroxy ... polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone (Ashland)), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone (Ashland)), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone (manufactured by Evonik), polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam-based graft copolymers (PVAc-PVCap-PEG) (e.g., Soluplus (BASF)), and combinations thereof. In some embodiments, the adhesive composition comprises a crystallization inhibitor selected from polymethacrylate (e.g., Plastoid B (a copolymer of butyl methacrylate and methyl methacrylate), Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam-based graft copolymers (PVAc-PVCap-PEG) (e.g., Soluplus (BASF)), and combinations thereof. The crystallization inhibitor is typically present in an amount of about 0 to about 40% by weight, e.g., about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 30% by weight, about 40% by weight, or any range therebetween, e.g., about 10% to about 40% by weight, about 10% to about 30% by weight, about 10% to about 20% by weight, 15% to about 40% by weight, about 15% to about 30% by weight, about 15% to about 20% by weight, 20% to about 40% by weight, about 20% to about 30% by weight, etc.In some embodiments, the adhesive composition may also include a skin permeation enhancer as described herein, such as isopropyl myristate. In some embodiments, the adhesive composition may also be free of a skin permeation enhancer as described herein, for example, in some embodiments, the adhesive composition may also be free of isopropyl myristate. Suitable drug loadings, active surface areas, thicknesses, adhesive properties, etc. include any of those described herein in any combination. Suitable pharmaceutical compositions for other delivery routes include those described herein.

[0055] Method for screening pharmaceutical compositions for treating hypokinetic movement disorder (hypokinetic movement disorder) In some embodiments, the present disclosure also provides methods for identifying pharmaceutical compositions for treating hyperkinetic movement disorders. In some embodiments, the methods include administering to a subject a test pharmaceutical composition that bypasses first-pass metabolism and delivers R,R-tetrabenazine to the subject in a continuous or substantially continuous manner, and identifying a pharmaceutical composition that provides any of the PK profiles described above. In some embodiments, the identifying includes identifying a pharmaceutical composition that provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ, wherein the ratio of the maximum plasma concentration of R,R-tetrabenazine to the combined maximum plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ is in the range of about 1:1 to about 1:5; or the ratio of the steady-state plasma concentration of R,R-tetrabenazine to the combined steady-state plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ is in the range of about 1:1 to about 1:5. The ratio of maximum plasma concentrations of R,R,R-HTBZ to S,R,R-HTBZ ranges from about 1:5 to about 1:30 (e.g., about 1:10 to about 1:20). In some embodiments, identifying includes identifying a pharmaceutical composition that provides any of the PK profiles described herein, if applicable.

[0056] In some embodiments, the method includes measuring the skin flux properties of test adhesive compositions in vitro using human cadaver skin and identifying adhesive compositions that provide any of the in vitro flux properties described herein. In some embodiments, the test adhesive composition comprises about 2% to about 10% by weight (e.g., about 2% to about 7% by weight) of R,R-tetrabenazine and is used in a transdermal delivery device (e.g., an adhesive composition comprising a non-reactive acrylate adhesive described herein).

[0057] Pharmaceutical compositions, such as the adhesive compositions identified herein, are also novel compositions of the present disclosure. In some embodiments, the present disclosure also provides a method of treating a hyperkinetic movement disorder, comprising administering the identified pharmaceutical composition to a subject in need thereof.

[0058] Sustained delivery of deuterated tetrabenazine Some embodiments of the present disclosure are directed to sustained or substantially sustained delivery of deuterated tetrabenazine. In any of the embodiments described herein, deuterated tetrabenazine, such as deutetrabenazine, can replace part or all of tetrabenazine for the respective composition, device, or method. Those skilled in the art will appreciate that the in vitro and / or in vivo parameters of such a substituted composition, device, or method may differ, particularly as these parameters relate to pharmacokinetics, and thus deuteration may alter the metabolic profile of tetrabenazine.

[0059] In some embodiments, the disclosure provides a method of treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising deuterated R,R-tetrabenazine, wherein the administration bypasses first-pass metabolism and provides a continuous or substantially continuous dose of from about 0.1 mg / day to about 20 mg / day of deuterated R,R-tetrabenazine, e.g., from about 0.5 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, from about 0.5 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, from about 0.5 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine, from about 0.5 mg / day to about 4 mg / day of deuterated R,R-tetrabenazine, from about 1 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, from about 1 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, Trabenazine, about 1 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine, about 1 mg / day to about 4 mg / day of deuterated R,R-tetrabenazine, about 2 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, about 2 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, about 2 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine, about 2 mg / day to about 4 mg / day of deuterated R,R-tetrabenazine The method delivers to a subject about 4 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, about 4 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, about 4 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine, about 6 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, or about 6 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine. In some preferred embodiments, the method delivers about 0.5 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine or about 2 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine. The duration of drug delivery herein can vary, for example, from about 8 hours to about 72 hours, or to more than 72 hours.For example, in some embodiments, administration can provide continuous or substantially continuous delivery of deuterated R,R-tetrabenazine to a subject for about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range between the recited values. In some embodiments, during the continuous or substantially continuous delivery period, deuterated R,R-tetrabenazine can be delivered to a subject at a substantially constant rate, e.g., the average delivery rate for each hour is substantially the same, e.g., within 80-125% of the overall average rate. In some embodiments, during the continuous or substantially continuous delivery period, deuterated R,R-tetrabenazine can be delivered to a subject at a different average delivery rate, e.g., for each hour. For example, in some embodiments, the average delivery rate may be high initially but then decrease over the course of the continuous or substantially continuous delivery. Typically, the exact hourly delivery rate of deuterated R,R-tetrabenazine is not critical, and one of skill in the art after considering this disclosure will know how to select and design a dosing regimen to deliver a desired daily dose to a subject, for example, about 0.5 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, about 0.5 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, or about 2 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine. In some embodiments, delivery of the desired daily dose to a subject also provides a pharmacokinetic profile as described herein.

[0060] In some embodiments, the present disclosure provides a method of treating a hyperkinetic movement disorder in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising deuterated R,R-tetrabenazine, wherein the administration provides a pharmacokinetic profile (PK profile). For example, in some embodiments, the desired PK profile is one in which administration provides therapeutically effective plasma concentrations of deuterated R,R-tetrabenazine, deuterated R,R,R-dihydrotetrabenazine (HTBZ), and deuterated S,R,R-HTBZ, and the ratio of the maximum plasma concentration of deuterated R,R-tetrabenazine to the combined maximum plasma concentration of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ is in the range of about 1:1 to about 1:7.5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, about 1:7.5, or any range between the recited values, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.), i.e., the C of deuterated R,R-tetrabenazine is max / (C of deuterated R,R,R-HTBZ) max + C of deuterated S,R,R-HTBZ maxor the ratio of the steady-state plasma concentration of deuterated R,R-tetrabenazine to the combined steady-state plasma concentration of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ is in the range of about 1:1 to about 1:7.5. As used herein, therapeutically effective plasma concentrations of deuterated R,R-tetrabenazine, deuterated R,R,R-dihydrotetrabenazine (HTBZ) and deuterated S,R,R-HTBZ do not require that each of the three compounds be at a therapeutically effective plasma concentration by itself. It is sufficient that the combination of the three compounds is therapeutically effective, for example, at their respective steady-state concentrations. In some embodiments, the ratio of maximum or steady-state plasma concentrations of deuterated R,R,R-HTBZ to deuterated S,R,R-HTBZ can be in the range of about 1:5 to about 1:30 (e.g., about 1:5, about 1:7, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, or any range between the recited values, e.g., about 1:10 to about 1:20, about 1:5 to about 1:15, etc.). In some embodiments, the ratio of maximum plasma concentrations of deuterated R,R-tetrabenazine:deuterated R,R,R-HTBZ:deuterated S,R,R-HTBZ can be in the range of about 14-40:3 to 11:50-85. In some embodiments, administration can increase the AUC of deuterated S,R,R-HTBZ. 0-∞ AUC of deuterated R,R-tetrabenazine 0-∞ to about 1 to about 15, for example, about 1.5 to about 11, and / or the AUC of deuterated RRR-HTBZ 0-∞ AUC of deuterated R,R-tetrabenazine 0-∞to about 0.1 to about 0.75, e.g., about 0.15 to about 0.5. In some embodiments, the desired PK profile can also be characterized in that administration provides therapeutically effective plasma concentrations of deuterated R,R-tetrabenazine, deuterated R,R,R-dihydrotetrabenazine (HTBZ) and deuterated S,R,R-HTBZ for at least 6 hours, or at least 12 hours, preferably at least 24 hours, e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, or more. In some embodiments, the desired PK profile may also be characterized in that administration provides a substantially constant steady-state plasma concentration of deuterated R,R-tetrabenazine of greater than 150 pg / ml (e.g., from about 150 pg / ml to about 3000 pg / ml) for a sustained period of at least 6 hours, or at least 12 hours, preferably at least 24 hours, e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, or more. In some embodiments, administration does not provide detectable amounts of deuterated S,S-tetrabenazine, deuterated S,S,S-HTBZ, or deuterated R,S,S-HTBZ in the plasma of the subject. In some embodiments, the method comprises administering to a subject a test pharmaceutical composition that bypasses first-pass metabolism and delivers deuterated R,R-tetrabenazine to the subject in a sustained or substantially sustained manner, and identifying a pharmaceutical composition that provides any of the PK profiles described in this paragraph in any combination.

[0061] In some embodiments, the disclosure provides a method of treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising deuterated R,R-tetrabenazine, wherein the administration provides a PK profile characterized by: (1) the plasma concentration of deuterated R,R-tetrabenazine increases over a first period of time, reaching a maximum concentration of about 150 pg / ml to about 3500 pg / ml at a first time point during the first period of time; and, optionally, (2) after the first period of time, the plasma concentration of deuterated R,R-tetrabenazine may remain substantially constant for a sustained period of time, e.g., about 24 hours, about 48 hours, about 72 hours, about 96 hours, or more. In some embodiments, the first period of time refers to the initial rising portion of the PK curve until the plasma concentration begins to plateau and / or decline, while the sustained period of time refers to the substantially flat portion of the PK curve; see, e.g., the figure for this application observed from transdermal delivery. In some embodiments, the first period of time is from time 0 (the time of administration of the pharmaceutical composition) to about 24 hours thereafter, e.g., 0 to 20 hours, or 0 to 18 hours. In some embodiments, the first period of time may also be longer than 0 to 24 hours, such as 0 to 36 hours or 0 to 48 hours. In some embodiments, the first period of time is from time 0 (the time of administration of the pharmaceutical composition) to about 24 hours thereafter, e.g., 0 to 20 hours, or 0 to 1 ... maxTypically, the plasma concentration of deuterated R,R-tetrabenazine observed during the Sustained Period ranges from about 40% to about 250% of the maximum concentration observed in the first period, and the plasma concentration of deuterated R,R-tetrabenazine does not change significantly, e.g., by a factor of 2, during any of the 4 hour, 8 hour, and / or 12 hour intervals of the Sustained Period, e.g., the concentration at time t1 is within about 50% to about 200% of the concentration at time t1+12 hours, provided that both times t1 and t1+12 hours are within the Sustained Period. In some embodiments, during the sustained period, the minimum plasma concentration of deuterated R,R-tetrabenazine is at least about 40%, e.g., at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, of the maximum concentration during the first period; and / or the maximum plasma concentration of deuterated R,R-tetrabenazine is not more than about 250%, e.g., not more than about 200%, not more than about 150%, or not more than about 120%, of the maximum concentration during the first period. In some embodiments, the plasma concentration of deuterated R,R-tetrabenazine 24 hours after the first time point is between about 50% and about 200%, e.g., between about 75% and about 150%, of the plasma concentration at the first time point. In some embodiments, the pharmacokinetic profile in a subject is further characterized in that administration provides therapeutically effective plasma concentrations of deuterated R,R-tetrabenazine, deuterated R,R,R-dihydrotetrabenazine (HTBZ), and deuterated S,R,R-HTBZ for a sustained period of time, and that during that sustained period, the ratio of the plasma concentration of deuterated R,R-tetrabenazine to the combined plasma concentration of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ at a given time point is in the range of from about 1:1 to about 1:7.5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, about 1:7.5, or any ranges between the recited values, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.).In some embodiments, the ratio of plasma concentrations of deuterated R,R,R-HTBZ to deuterated S,R,R-HTBZ at a given time point during a sustained period can range from about 1:5 to about 1:30 (e.g., about 1:5, about 1:7, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, or any range between the recited values, e.g., about 1:10 to about 1:20, about 1:5 to about 1:15, etc.). In some embodiments, the ratio of plasma concentrations of deuterated R,R-tetrabenazine:deuterated R,R,R-HTBZ:deuterated S,R,R-HTBZ at a given time point during a sustained period can range from about 14-40:3 to 11:50-85. In some embodiments, during the sustained period, the ratio of maximum plasma concentrations of deuterated R,R-tetrabenazine:deuterated R,R,R-HTBZ:deuterated S,R,R-HTBZ can be in the range of about 14 to 40:3 to 11:50 to 85. In some embodiments, administration can result in an AUC of deuterated S,R,R-HTBZ. 0-∞ AUC of deuterated R,R-tetrabenazine 0-∞ to about 1 to about 15, for example, about 1.5 to about 11, and / or the AUC of deuterated RRR-HTBZ 0-∞ AUC of deuterated R,R-tetrabenazine 0-∞ to about 0.1 to about 0.75, e.g., about 0.15 to about 0.5. In some embodiments, the PK profile is characterized by a mean terminal half-life of deuterated R,R-tetrabenazine of about 8.5 hours ± 40% CV. In some embodiments, administration does not provide detectable deuterated S,S-tetrabenazine, deuterated R,S,S-HTBZ, or deuterated S,S,S-HTBZ in the plasma of the subject. In some embodiments, the disclosure also provides a method for identifying a pharmaceutical composition for treating hyperkinetic movement disorders. In some embodiments, the method comprises administering to a subject a test pharmaceutical composition that bypasses first-pass metabolism, and identifying a pharmaceutical composition that provides any of the PK profiles described in this paragraph, in any combination.

[0062] The route for administering the pharmaceutical composition to achieve the PK profile described herein is not particularly limited, as long as the administration provides the pharmacokinetic profile described above. Typically, the administration bypasses first-pass metabolism. For example, in some embodiments, the pharmaceutical composition is administered transdermally. In some embodiments, the pharmaceutical composition is administered via injection or infusion, such as intravenous injection (excluding bolus injection), subcutaneous injection, or intramuscular injection. In some embodiments, the pharmaceutical formulation is a depot formulation.

[0063] Administration typically provides continuous or substantially continuous delivery of deuterated R,R-tetrabenazine to a subject to achieve the PK profile described herein. In some embodiments, administration delivers deuterated R,R-tetrabenazine to a subject for a period of, for example, about 8 hours to about 72 hours or greater than 72 hours. For example, in some embodiments, administration provides continuous or substantially continuous delivery of deuterated R,R-tetrabenazine to a subject for about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range therebetween. In some embodiments, during the period of continuous or substantially continuous delivery, deuterated R,R-tetrabenazine may be delivered to a subject at a substantially constant rate, e.g., with the average delivery rate for each hour being substantially the same, e.g., within 80-125% of the overall average rate. In some embodiments, during the period of sustained or substantially sustained delivery, deuterated R,R-tetrabenazine may be delivered to a subject, for example, at different average delivery rates for each hour. For example, in some embodiments, the average delivery rate may be high initially and then decrease over the course of the sustained or substantially sustained delivery. Typically, the exact hourly delivery rate of deuterated R,R-tetrabenazine is not critical, and one of skill in the art after reviewing this disclosure will know how to select and design a dosing regimen to deliver a desired daily dose to a subject that provides the pharmacokinetic profile described herein. For example, in some embodiments, deuterated R,R-tetrabenazine may be delivered to a subject at a daily dose of about 0.1 mg / day to about 20 mg / day, e.g., about 0.5 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, about 0.5 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, or about 2 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine to provide the pharmacokinetic profile described herein.

[0064] The hyperkinetic movement disorders described in the treatment methods herein include any of those described herein. Non-limiting examples include Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tics, dyskinetic cerebral palsy / cerebral palsy, other dystonia and dyskinesia disorders, and combinations thereof. In some embodiments, the hyperkinetic movement disorder can be Huntington's disease, including chorea associated with Huntington's disease. In some embodiments, the hyperkinetic movement disorder can be Wilson's disease. In some embodiments, the hyperkinetic movement disorder can be Tourette's syndrome. In some embodiments, the hyperkinetic movement disorder can be restless legs syndrome. In some embodiments, the hyperkinetic movement disorder can be tardive dyskinesia. In some embodiments, the hyperkinetic movement disorder can be tics. In some embodiments, the hyperkinetic movement disorder can be dyskinetic cerebral palsy. In some embodiments, the hyperkinetic movement disorder is a dystonia or dyskinetic disorder.

[0065] The treatment methods herein are not limited to a particular type of subject. For example, the methods herein can be administered to subjects regardless of their feeding status. In some embodiments, the subjects are pediatric and adolescent patients (e.g., 6-18 years old). Also, in some embodiments, the methods are not limited to subjects of a particular genotype. In some embodiments, the same or substantially the same dose of deuterated R,R-tetrabenazine can be administered to subjects characterized as PM, IM, or EM. In some embodiments, the subject is characterized as an EM. In some embodiments, the subject is characterized as a PM. In some embodiments, the subject is characterized as an IM. In some embodiments, the methods do not require dose titration and / or genotyping, as is required when treating with either Xenazine® or Austedo™ tablets.

[0066] The dosing regimen of the treatment methods herein is not particularly limited, so long as the desired dose of deuterated R,R-tetrabenazine is delivered to the subject at the desired rate for the desired period of time, including any of those described herein. For example, in some embodiments, the pharmaceutical composition is administered to the subject at a dosing regimen suitable for achieving the PK profile described herein. In some embodiments, the pharmaceutical composition is administered to the subject once daily. In some embodiments, the pharmaceutical composition is administered to the subject more than once a day, for example, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, or more than once a week. In some embodiments, each administration provides continuous or substantially continuous delivery of deuterated R,R-tetrabenazine to the subject for about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range between the recited values.

[0067] Pharmaceutical compositions suitable for various routes of administration of the methods herein are also described. Typically, for transdermal delivery, the pharmaceutical composition may comprise an adhesive composition in a transdermal delivery device, e.g., comprising an active ingredient dispersed in an adhesive (preferably a pressure-sensitive adhesive). In some embodiments, the adhesive composition is applied to a subject to deliver from about 0.1 mg / day to about 20 mg / day of deuterated R,R-tetrabenazine (e.g., any of the exemplified ranges described herein) at a substantially constant rate for up to 24 hours, up to 48 hours, up to 96 hours, or up to 1 week after application. Suitable adhesive compositions include any of those described herein, e.g., any of those described in embodiments 1-18 applicable to deuterated tetrabenazine, or any of the specific compositions shown in the Examples section in which tetrabenazine is replaced with deuterated tetrabenazine (e.g., Example 4A). The adhesive types, amounts, amounts of active ingredient, and other ingredients and amounts include any of those suitable for tetrabenazine described herein, except that tetrabenazine is replaced with deuterated tetrabenazine. In some embodiments, the adhesive composition may also include a skin permeation enhancer as described herein, such as isopropyl myristate. In some embodiments, the adhesive composition may also be free of a skin permeation enhancer as described herein, for example, in some embodiments, the adhesive composition may also be free of isopropyl myristate. Pharmaceutical compositions suitable for other delivery routes include those described herein. In any applicable embodiment, the deuterated tetrabenazine may be a substantially pure R,R-isomer of deuterated tetrabenazine, e.g., R,R-deutetrabenazine. In some embodiments, the substantially pure R,R-isomer of deuterated tetrabenazine is the only active ingredient in the pharmaceutical composition. In some embodiments, the substantially pure R,R-isomer of deuterated tetrabenazine is in free base form.

[0068] Typically, the methods herein deliver either R,R-tetrabenazine or deuterated R,R-tetrabanazine to a subject in need thereof, although the present disclosure also contemplates delivering a mixture of R,R-tetrabenazine and deuterated R,R-tetrabanazine to a subject in need thereof.

[0069] Transdermal delivery of tetrabenazine or deuterated tetrabenazine As discussed herein, in various embodiments, the methods herein transdermally deliver tetrabenazine or deuterated trabenazine to a subject in need thereof. Pharmaceutical compositions suitable for transdermal delivery include any of those described herein, for example, as described in exemplary embodiments 1-18, or any of the specific compositions shown in the Examples section (e.g., Example 4A). Transdermal pharmaceutical compositions and transdermal delivery devices are also novel aspects of the present disclosure.

[0070] Tetrabenazine transdermal delivery device In various embodiments, the present invention is directed to a pharmaceutical composition or transdermal delivery device comprising tetrabenazine and / or deuterated tetrabenazine (e.g., deutetrabenazine). The pharmaceutical composition and transdermal delivery device provide a novel option for transdermal delivery of tetrabenazine and / or deuterated tetrabenazine to a subject in need thereof. Tetrabenazine and / or deuterated tetrabenazine have not previously been shown to be administrable via the transdermal route. As detailed herein, the inventors have shown that the transdermal delivery devices and pharmaceutical compositions disclosed herein (e.g., the adhesive compositions herein) can be applied to a subject to achieve a therapeutically effective flux and thus may be useful for treating various diseases or disorders, e.g., hyperkinetic movement disorders. See also, e.g., PCT / US2019 / 028900, the contents of which are incorporated herein by reference in their entirety.

[0071] Certain embodiments of the present disclosure are directed to transdermal delivery devices comprising tetrabenazine or deuterated tetrabenazine (e.g., deutetrabenazine). In some embodiments, the transdermal delivery device comprises a backing layer, a drug layer comprising a drug selected from tetrabenazine, deuterated tetrabenazine (e.g., deutetrabenazine), and combinations thereof, and an adhesive layer defining an active surface area. In some embodiments, the drug is in an amount of about 2% to about 30% by weight of the drug layer. In some embodiments, the transdermal delivery device comprises a single drug layer. In some embodiments, the transdermal delivery device comprises multiple drug layers. In some embodiments, the transdermal delivery device comprises a single adhesive layer. In some embodiments, the transdermal delivery device comprises multiple adhesive layers.

[0072] Various patch designs can be used for the transdermal delivery devices herein. For example, in some embodiments, the transdermal delivery device can be a drug-in-adhesive (DIA) patch. In some embodiments, the DIA patch is a single-layer patch, where the drug layer and the adhesive layer are the same layer, e.g., the drug is homogeneously dispersed in the adhesive. In some embodiments, the DIA patch is a multi-layer patch. For example, the patch can include two drug-in-adhesive layers, optionally separated by a membrane. In some embodiments, the two DIA layers can have different release characteristics, e.g., one of the layers is an immediate-release layer and the other is a controlled-release layer. In some embodiments, the two DIA layers can have different release characteristics, e.g., one layer releases the drug relatively quickly over a relatively short period of time, while the other layer releases the drug over a more sustained period of time.

[0073] The transdermal delivery devices herein can also use a drug-containing reservoir (DIR) design. In some embodiments, the drug layer and adhesive layer can be two separate layers, laminated together or separated by, for example, a rate-controlling membrane. For example, in some embodiments, the drug layer is a reservoir layer, such as a drug matrix, laminated with an adhesive layer.

[0074] Other patch designs can also be used for the transdermal delivery device herein. For example, in some embodiments, the transdermal delivery device can be an active patch, such as an iontophoretic patch. In some embodiments, the transdermal delivery device can be a minimally invasive patch, such as a microneedle-based patch. In some embodiments, the transdermal delivery device can also have another patch design that can include chemical or physical modalities of enhancement.

[0075] Typically, a transdermal delivery device (e.g., a DIA patch) is supported by an impermeable backing film, and the adhesive surface is protected by a release liner. Various materials can be used as the backing layer of the transdermal delivery device herein. Typically, the backing layer is impermeable. For example, the backing layer can be composed of an impermeable polymer film such as a polyester (PET) film or a polyethylene (PE) film. In some embodiments, the backing layer can include a polyester such as Scotchpak 9723, Scotchpak 9736, or Scotchpak 1012, a polyurethane film such as Scotchpak 9701, or a polyethylene film such as CoTran 9720.

[0076] The release liner can be manufactured in any desired size for the present invention. The release liner can be made of silicone or fluoropolymer-coated polyester film. The release liner protects the transdermal delivery device during storage and is removed before use. Silicone-coated release liners include those manufactured by Mylan Corporation, Loparex Corporation, and 3M's Drug Delivery Systems. These include those manufactured and supplied by 3M's Drug Delivery Systems and Loparex. In some embodiments, the release liner comprises 3M's ScotchPak 9744 or Scotchpak 1022.

[0077] The transdermal delivery device (e.g., DIA patch) herein can have different sizes (patch size) depending on its application. Typically, the patch size is about 5 cm 2 ~about 300cm 2 (For example, 5 cm 2 , about 10cm 2 , about 20cm 2 , about 30cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 80cm 2 , about 100cm 2 , about 120cm 2 , about 150cm 2 , about 200cm 2 or any range between the specified values), e.g., approximately 1 cm 2 ~about 100cm 2 It could be.

[0078] When the transdermal delivery device (e.g., DIA patch) of the present specification is applied to the skin of a subject, theoretically, the entire adhesive surface may come into contact with the skin. Thus, the area of ​​the adhesive surface defines the skin contact area through which the active ingredient from the device can penetrate the skin, which is also referred to herein as the active surface area. In some embodiments, the adhesive surface is the only surface of the transdermal delivery device that contacts the skin upon application, and the active surface area is the same as the area of ​​the adhesive surface. In some embodiments, the adhesive surface and one or more other surfaces of the transdermal delivery device are in contact with the skin upon application, and the entire skin contact area is the active surface area.

[0079] The active surface area can determine the dose of drug delivered. Typically, the active surface area is about 5 cm 2 ~about 300cm 2 (For example, 5 cm 2 , about 10cm 2 , about 20cm 2 , about 30cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 80cm 2 , about 100cm 2 , about 120cm 2 , about 150cm 2 , about 200cm 2 or any range between the specified values), e.g., approximately 1 cm 2 ~about 100cm 2 It could be.

[0080] Drug layer Typically, the drug layer comprises tetrabenazine, deuterated tetrabenazine, or a combination thereof. In some embodiments, the drug layer can optionally include one or more other ingredients selected from, for example, skin permeation enhancers, humectants, plasticizers, antioxidants, anti-irritants, gel-forming agents, drug release modifiers, solvents, crystallization inhibitors, and additional active ingredients. In some embodiments, the drug layer is tailored to achieve the skin flux characteristics of the transdermal delivery device described herein. It should be noted that the pharmaceutical compositions used in the drug layer herein may also be novel formulations, regardless of the transdermal delivery device and / or skin flux characteristics described herein. Accordingly, some embodiments of the present disclosure are also directed to such pharmaceutical compositions.

[0081] In some embodiments, the drug in the drug layer may be tetrabenazine. The tetrabenazine in the transdermal delivery devices described herein is not limited to a particular enantiomer and may be in racemic form, substantially pure R,R-tetrabenazine (e.g., less than 10%, less than 5%, less than 1%, or less than 0.1% of the S,S-isomer), substantially pure S,S-tetrabenazine (e.g., less than 10%, less than 5%, less than 1%, or less than 0.1% of the R,R-isomer), or a mixture of R,R-tetrabenazine and S,S-tetrabenazine in any ratio. In some embodiments, the tetrabenazine in the transdermal delivery device is in racemic form. In some embodiments, the tetrabenazine in the transdermal delivery device is substantially pure R,R-tetrabenazine. In some embodiments, tetrabenazine is the only drug in the drug layer. In some embodiments, tetrabenazine is the only drug in the transdermal delivery device. In some embodiments, the drug layer and / or the transdermal delivery device may also include other active ingredients.

[0082] In some embodiments, the drug in the drug layer may be deuterated tetrabenazine. As used herein, deuterated tetrabenazine refers to a compound resulting from the replacement of one or more hydrogen atoms of tetrabenazine with deuterium, with each replacement position having a deuterium content greater than the natural abundance, i.e., the replacement position is enriched with deuterium. In some embodiments, the deuterated tetrabenazine has at least one position with deuterium enriched to greater than 10% deuterium, greater than 50% deuterium, greater than 90% deuterium, greater than 95% deuterium, or greater than 98% deuterium. A preferred example of deuterated tetrabenazine is deutetrabenazine, the racemic form of which is the active ingredient in Austedo™ tablets. The deuterated tetrabenazine in the transdermal delivery devices described herein is not limited to a particular enantiomer, and can be in racemic form, a substantially pure R,R-isomer, e.g., R,R-deutetrabenazine (see below) (e.g., less than 10%, less than 5%, less than 1%, or less than 0.1% of the S,S-isomer), a substantially pure S,S-isomer, e.g., S,S-deutetrabenazine (see below) (e.g., less than 10%, less than 5%, less than 1%, or less than 0.1% of the R,R-isomer), or a mixture of the R,R- and S,S-isomers in any ratio. In some embodiments, the transdermal delivery device comprises deutetrabenazine in racemic form. In some embodiments, the transdermal delivery device comprises deutetrabenazine as substantially pure R,R-deutetrabenazine. In some embodiments, deutetrabenazine is the only drug in the drug layer. In some embodiments, deutetrabenazine is the only drug in the transdermal delivery device. In some embodiments, the drug layer and / or the transdermal delivery device may also include other active ingredients. [ka]

[0083] The drug can be present in various amounts in the drug layer of the transdermal delivery device. In some embodiments, the drug layer comprises tetrabenazine, deuterated tetrabenazine, or a combination thereof in an amount of about 2% to about 30% by weight of the drug layer (e.g., about 2%, about 2.5%, about 5%, about 8%, about 10%, about 15%, about 18%, about 20%, about 25%, about 30%, or any range between the recited values). In some specific embodiments, the drug layer comprises tetrabenazine, deuterated tetrabenazine, or a combination thereof in an amount of about 2%, about 2.5%, about 5%, about 8%, about 10%, about 15%, or about 20% by weight of the drug layer. In some embodiments, the tetrabenazine, deuterated tetrabenazine, or a combination thereof is present only in the drug layer (e.g., the drug-containing adhesive layer) of the transdermal delivery device.

[0084] The weight and thickness of the drug layer can vary depending on different factors, such as drug concentration and desired duration of administration. The drug layer is typically designed for application (e.g., delivery of tetrabenazine or deutetrabenazine) for a period selected from about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, and about 7 days. In some embodiments, the drug layer has a weight of about 0.01 g / cm 2 ~about 5g / cm 2 , for example, about 0.05 g / cm 2 ~about 5g / cm 2 , about 0.1g / cm 2 ~about 5g / cm 2 , for example, about 0.05 g / cm 2 ~Approx. 0.90g / cm 2 , about 0.1g / cm 2 ~Approx. 0.90g / cm 2 (For example, about 0.1 g / cm 2 ~about 0.5g / cm 2In some embodiments, the drug layer can have a thickness of about 1.5 mil to about 10 mil, such as about 1.5 mil to about 3.5 mil (e.g., about 2 mil to about 3.5 mil). In some embodiments, the drug layer can have a thickness of about 0.1 mil to about 100 mil, such as about 1 mil to about 50 mil (e.g., about 1 mil to about 10 mil, or about 1.5 mil to about 3.5 mil).

[0085] A skin permeation enhancer can enhance the skin permeability of tetrabenazine or deuterated tetrabenazine through the skin and can optionally be included in the drug layer. In some embodiments, the drug layer is free of or substantially free of permeation enhancers. However, in some embodiments, various skin permeation enhancers can be included. Non-limiting examples of useful skin permeation enhancers include, for example, sulfoxides (e.g., dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), esters, glycols (e.g., propylene glycol (PG)), surfactants (e.g., Tween 80), terpenes, and combinations thereof. See, e.g., Williams et al., Adv Drug Deliv Rev. 27;56(5):603-18 (2004). In some embodiments, the permeation enhancer comprises one or more compounds selected from sulfoxides, alcohols, alkanols, esters, glycols, and surfactants. In some embodiments, the permeation enhancer comprises one or more compounds selected from dimethyl sulfoxide (DMSO), oleic alcohol, oleyl oleate, oleic acid, levulinic acid, other fatty acids and fatty acid esters, propylene glycol, dipropylene glycol, ethanol, and surfactants such as Tween 80. The skin permeation enhancer is typically included in an amount of about 1% to about 25% by weight of the pharmaceutical composition, e.g., about 2%, about 5%, about 10%, about 15%, about 20%, about 25% by weight of the pharmaceutical composition, or any range therebetween.

[0086] Other suitable excipients, such as humectants, plasticizers, antioxidants, anti-irritants, gel-forming agents, crystallization inhibitors, drug-release modifiers, etc., can also be included in the drug layer (e.g., drug-containing adhesive layer) herein or otherwise in the transdermal delivery device. In some embodiments, additional active ingredient(s) can also be included in the drug layer herein or otherwise in the transdermal delivery device. These excipients are within the purview of those skilled in the art and can be found, for example, in the Handbook of Pharmaceutical Excipients, (7 th ed. 2012), the entire contents of which are incorporated herein by reference.

[0087] adhesive layer The adhesive layer may be the same layer as the drug layer or a separate layer. In a typical DIA patch, the drug is uniformly dispersed in the adhesive to form a drug-containing adhesive layer. Other designs, such as a DIR patch, may also include an adhesive layer separated from the drug layer, for example, by a membrane. In some embodiments, multiple adhesive layers (e.g., two or more drug-containing adhesive layers) can be used in the transdermal delivery device.

[0088] The adhesive layer typically comprises a pressure-sensitive adhesive (PSA). PSAs are generally known in the art. See, for example, Tan et al., Pharm Sci & Tech Today, 2:60-69 (1999). Non-limiting examples of useful PSAs include polyisobutylene (PIB), silicone polymers, acrylate copolymers, and combinations thereof. In some embodiments, the pressure-sensitive adhesive comprises a polyisobutylene adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some embodiments, the pressure-sensitive adhesive comprises an acrylate copolymer adhesive. Non-limiting examples of useful acrylate copolymers include poly(acrylate / vinyl acetate) copolymers, such as acrylic pressure-sensitive adhesives such as Duro-Tak 87-2287, Duro-Tak 87-4098, Duro-Tak 87-4287, or Duro-Tak 87-2516, Duro-Tak 87-2852, or Duro-Tak 87-2194 manufactured by Henkel Adhesives. In some embodiments, the pressure-sensitive adhesive can be a non-reactive acrylate adhesive (such as Duro-Tak 87-900A, as described herein), for example, an acrylate adhesive that does not have a functional group containing a reactive hydrogen moiety or a functional group selected from epoxy, -OH, -COOH, and combinations thereof. PIB is an elastomeric polymer commonly used as both the primary base polymer and tackifier in PSAs. PIB is a homopolymer of isobutylene, characterized by a regular structure of a carbon-hydrogen backbone with only terminal unsaturation. Non-limiting examples of useful PIBs include those sold by BASF under the trade name Oppanol. However, in some embodiments, the pressure-sensitive adhesive does not include a PIB-based adhesive. The silicone polymer is a high molecular weight polydimethylsiloxane containing residual silanol functional groups (SiOH) at the ends of the polymer chain.Non-limiting examples of useful silicone PSAs for use in pharmaceutical applications include those available from Dow Corning Corporation under the trade name BIO-PSA, e.g., BIO-7-4202. In some embodiments, the adhesive layer is about 1.5 mil to about 10 mil (e.g., about 1.5 mil to about 2 mil) thick.

[0089] One or more adhesives can be used in the adhesive layer. For example, in some embodiments, the adhesive layer can include a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios (e.g., acrylate adhesive to silicone adhesive ratios ranging from about 1:10 to about 10:1). As detailed in the Examples section, varying the adhesive components can affect the flux properties of the transdermal delivery device.

[0090] The adhesive layer is typically formulated to allow the transdermal delivery device to adhere to the user's skin for a desired period of time. For example, in some embodiments, the transdermal delivery device can be persistently adhered to the user's skin for about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more.

[0091] adhesive composition In some embodiments, the present invention also provides adhesive compositions comprising a drug selected from tetrabenazine, deuterated tetrabenazine (e.g., deutetrabenazine), and combinations thereof in an adhesive. In some embodiments, the drug is homogeneously dispersed in the adhesive. Suitable drugs and adhesives include any of those described herein.

[0092] In some embodiments, the adhesive composition is capable of sustained adhesion to the skin of a user for an extended period of time selected from about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more.

[0093] In some embodiments, the adhesive is a pressure-sensitive adhesive. In some embodiments, the pressure-sensitive adhesive comprises a polyisobutylene (PIB) adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some embodiments, the pressure-sensitive adhesive can be a non-reactive acrylate adhesive (e.g., Duro-Tak 87-900A, as described herein), for example, an acrylate adhesive that does not have a functional group containing a reactive hydrogen moiety, or an acrylate adhesive that does not have a functional group selected from epoxy, -OH, -COOH, and combinations thereof. In some embodiments, the pressure-sensitive adhesive does not comprise a polyisobutylene (PIB) adhesive and / or a silicone polymer adhesive.

[0094] The drug in the adhesive composition is preferably tetrabenazine or deutetrabenazine. In some embodiments, the drug is tetrabenazine. In some embodiments, the tetrabenazine is substantially pure R,R-tetrabenazine. In some embodiments, the drug is deutetrabenazine. In some embodiments, the deutetrabenazine is substantially pure R,R-deutetrabenazine. In some embodiments, the tetrabenazine is the only active ingredient in the adhesive composition. In some embodiments, the deutetrabenazine is the only active ingredient in the adhesive composition. In some embodiments, the tetrabenazine or deutetrabenazine is present in an amount of about 2% to about 30% by weight of the adhesive composition (e.g., about 2%, about 2.5%, about 5%, about 8%, about 10%, about 15%, about 18%, about 20%, about 25%, about 30%, or any range therebetween). In some specific embodiments, the adhesive composition comprises tetrabenazine or deutetrabenazine in an amount of about 2%, about 2.5%, about 5%, about 8%, about 10%, about 15%, or about 20% by weight of the adhesive composition, hi some embodiments, the active ingredient is present in an amount of about 2% to about 7% by weight.

[0095] In some embodiments, the adhesive composition further comprises a permeation enhancer. Suitable permeation enhancers include any of those described herein. In some embodiments, the adhesive composition does not comprise a permeation enhancer. In some embodiments, the adhesive composition does not comprise isopropyl myristate.

[0096] In some embodiments, the adhesive composition can optionally include one or more components selected from humectants, plasticizers, antioxidants, anti-irritants, gel-forming agents, crystallization inhibitors, drug-release modifiers, and additional active ingredients. For example, in some embodiments, the adhesive composition can include an antioxidant, such as a gallic acid antioxidant such as propyl gallate. In some embodiments, the adhesive composition can include a crystallization inhibitor such as a polyvinylpyrrolidone polymer, a crosslinked polyvinylpyrrolidone polymer, a polyvinylpyrrolidone copolymer, a cellulose-based polymer, a polycarboxylic acid polymer, a polymethacrylate, a polyethylene glycol, a polyvinyl acetate, and a polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof. In some preferred embodiments, the adhesive composition includes a crystallization inhibitor that is a copolymer of butyl methacrylate and methyl methacrylate. In some preferred embodiments, the adhesive composition includes a crystallization inhibitor that is a polyethylene glycol, polyvinyl acetate, and a polyvinyl caprolactam-based graft copolymer.

[0097] The adhesive composition can be included in a transdermal delivery device. Typically, such a transdermal delivery device also includes a backing layer and a release liner that protects the adhesive surface before use. In some embodiments, the adhesive composition can be included as a drug layer in any one of the transdermal delivery devices described herein.

[0098] Skin Flux Characteristics The transdermal delivery devices described herein preferably provide certain desired skin flux characteristics. Typically, the transdermal delivery devices provide a flux of about 0.1 mg / day / cm. 2 ~About 5mg / day / cm 2 (e.g., about 0.1 mg / day / cm 2 , about 0.2mg / day / cm 2 , about 0.5mg / day / cm 2 , about 1mg / day / cm 2 , about 2mg / day / cm 2 , about 5mg / day / cm 2, or any range between the recited values) of a drug (e.g., tetrabenazine or deutetrabenazine) to a subject in need thereof for a period selected from, for example, about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, and about 7 days. However, in some embodiments, the transdermal delivery device can deliver up to about 5 mg / day / cm 2 greater than, for example, about 8 mg / day / cm 2 , about 10mg / day / cm 2 , about 15mg / day / cm 2 , about 20mg / day / cm 2 , or any range between the recited values. In some embodiments, the transdermal delivery device can deliver about 0.1 mg / day / cm 2 Less than, for example, about 0.01 mg / day / cm 2 , approximately 0.02 mg / day / cm 2 , about 0.05mg / day / cm 2 , about 0.1mg / day / cm 2 , or any range of drugs (e.g., tetrabenazine or deutetrabenazine) between the stated values ​​can be delivered.

[0099] In some embodiments, the transdermal delivery device provides about 0.1 mg / day / cm 2 ~About 1mg / day / cm 2 (e.g., about 0.1 mg / day / cm 2 , about 0.2mg / day / cm 2 , about 0.5mg / day / cm 2 , about 1mg / day / cm 2 , or any range between the recited values) to a subject in need thereof for a period selected from, for example, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, and about 7 days. In some embodiments, the transdermal delivery device can deliver about 0.1 mg / day / cm 2 ~About 5mg / day / cm 2 (e.g., about 0.1 mg / day / cm 2 , about 0.2mg / day / cm 2, about 0.5mg / day / cm 2 , about 1mg / day / cm 2 , about 5mg / day / cm 2 , or any range between the recited values) of a drug (e.g., tetrabenazine or deutetrabenazine), for example, for a period of greater than 7 days. In some embodiments, the transdermal delivery device is capable of delivering about 0.1 mg / day / cm 2 ~About 5mg / day / cm 2 (e.g., about 0.1 mg / day / cm 2 , about 0.2mg / day / cm 2 , about 0.5mg / day / cm 2 , about 1mg / day / cm 2 , or any range between the recited values) of a drug (e.g., tetrabenazine or deutetrabenazine), can be delivered, for example, over a period of less than 24 hours, e.g., less than 18 hours, less than 12 hours, less than 8 hours, or less than 4 hours.

[0100] In some embodiments, the transdermal delivery device comprises tetrabenazine, and the transdermal delivery device, when tested in vitro using human cadaver skin, exhibits the following skin flux properties: a) about 0.1 μg / cm based on active surface area after 6 hours of administration; 2 ~Approx. 150μg / cm 2 (For example, about 0.1 μg / cm 2 , about 0.5μg / cm 2 , about 1μg / cm 2 , about 5μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , about 50μg / cm 2 , about 75μg / cm 2 , about 100μg / cm 2 , about 125μg / cm 2 , about 150μg / cm 2 or any range between the stated values) of cumulative tetrabenazine permeated; b) approximately 2 μg / cm2 based on active surface area at 12 hours after administration. 2 ~about 400μg / cm 2 (e.g., about 2 μg / cm2 , about 5μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , about 50μg / cm 2 , about 100μg / cm 2 , about 200μg / cm 2 , about 300μg / cm 2 , about 400μg / cm 2 , or any range between the stated values) of cumulative tetrabenazine permeated; and c) approximately 5 μg / cm2, based on active surface area, 24 hours after administration. 2 ~Approx. 1000μg / cm 2 (e.g., about 5 μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 2μg / cm 2 , 25 μg / cm 2 , about 50μg / cm 2 , about 100μg / cm 2 , about 200μg / cm 2 , about 300μg / cm 2 , about 400μg / cm 2 , 600 μg / cm 2 , 800 μg / cm 2 , 1000 μg / cm 2 , or any range between the recited values). In some embodiments, the tetrabenazine is present in an amount of about 2% to about 30% by weight of the drug layer (e.g., about 2% to about 20% by weight, about 2% to about 10% by weight, about 2% to about 5% by weight, about 5% to about 10% by weight, about 10% to about 15% by weight). In some embodiments, the tetrabenazine is present in about 2%, about 5%, about 8%, about 10%, about 15%, about 20% by weight of the drug layer, or any range between the recited values. In some embodiments, the tetrabenazine is substantially pure R,R-tetrabenazine.

[0101] In some embodiments, tetrabenazine is present in an amount of about 2% to about 5% by weight of the drug layer, and the transdermal delivery device, when tested in vitro using human cadaver skin, exhibits the following skin flux properties: a) about 0.1 μg / cm based on active surface area at 6 hours after administration; 2 ~Approx. 100μg / cm 2 (For example, about 0.1 μg / cm 2 , about 0.5μg / cm 2 , about 1μg / cm 2 , about 5μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , about 50μg / cm 2 , about 75μg / cm 2 , about 100μg / cm 2 or any range between the stated values) of cumulative tetrabenazine permeated; b) approximately 2 μg / cm2 based on active surface area at 12 hours after administration. 2 ~about 200μg / cm 2 (e.g., about 2 μg / cm 2 , about 5μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , about 50μg / cm 2 , about 100μg / cm 2 , about 200μg / cm 2 , or any range between the stated values) of cumulative tetrabenazine permeated; and c) approximately 5 μg / cm2, based on active surface area, 24 hours after administration. 2 ~about 600μg / cm 2 (e.g., about 5 μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , 25 μg / cm 2 , about 50μg / cm 2 , about 100μg / cm 2 , about 200μg / cm 2 , about 300μg / cm 2 , about 400μg / cm 2 , 600 μg / cm2 or any range between the recited values).

[0102] In some embodiments, tetrabenazine is present in an amount of about 5% to about 10% by weight of the drug layer, and the transdermal delivery device, when tested in vitro using human cadaver skin, exhibits the following skin flux properties: a) about 0.5 μg / cm based on active surface area at 6 hours after administration; 2 ~Approx. 150μg / cm 2 (e.g., about 1 μg / cm 2 , about 5μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , about 50μg / cm 2 , about 75μg / cm 2 , about 100μg / cm 2 , about 150μg / cm 2 or any range between the stated values) of cumulative tetrabenazine permeated; b) approximately 4 μg / cm2 based on active surface area at 12 hours after administration. 2 ~about 400μg / cm 2 (e.g., about 4 μg / cm 2 , about 6μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , about 50μg / cm 2 , about 100μg / cm 2 , about 200μg / cm 2 , about 400μg / cm 2 , or any range therebetween); and c) approximately 6 μg / cm2 of cumulative tetrabenazine permeated, based on active surface area, 24 hours after administration. 2 ~Approx. 1000μg / cm 2 (For example, about 6 μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , 25 μg / cm 2 , about 50μg / cm 2, about 100μg / cm 2 , about 200μg / cm 2 , about 300μg / cm 2 , about 400μg / cm 2 , 600 μg / cm 2 , about 1000μg / cm 2 or any range between the recited values).

[0103] In some embodiments, the drug is present in an amount of about 10% to about 15% by weight of the drug layer, and the transdermal delivery device exhibits the following skin flux properties when tested in vitro using human cadaver skin: a) about 0.5 μg / cm based on active surface area after 6 hours of administration; 2 ~Approx. 150μg / cm 2 (e.g., about 1 μg / cm 2 , about 2μg / cm 2 , about 5μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , about 50μg / cm 2 , about 75μg / cm 2 , about 100μg / cm 2 , about 150μg / cm 2 or any range between the stated values) of cumulative tetrabenazine permeated; b) approximately 4 μg / cm2 based on active surface area at 12 hours after administration. 2 ~about 400μg / cm 2 (e.g., about 4 μg / cm 2 , about 6μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , about 30μg / cm 2 , about 40μg / cm 2 , about 50μg / cm 2 , about 100μg / cm 2 , about 200μg / cm 2 , about 400μg / cm 2, or any range therebetween); and c) approximately 8 μg / cm2 of cumulative tetrabenazine permeated, based on active surface area, 24 hours after administration. 2 ~Approx. 1000μg / cm 2 (e.g., about 8 μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , about 30μg / cm 2 , about 40μg / cm 2 , about 50μg / cm 2 , about 60μg / cm 2 , about 100μg / cm 2 , about 200μg / cm 2 , about 300μg / cm 2 , about 400μg / cm 2 , about 600μg / cm 2 , about 1000μg / cm 2 or any range between the recited values).

[0104] In some embodiments, the transdermal delivery device comprises deuterated tetrabenazine (e.g., deutetrabenazine), and the transdermal delivery device, when tested in vitro using human cadaver skin, exhibits the following skin flux characteristics: a) about 0.1 μg / cm based on active surface area at 6 hours after administration; 2 ~Approx. 150μg / cm 2 (For example, about 0.1 μg / cm 2 , about 0.5μg / cm 2 , about 1μg / cm 2 , about 5μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , about 50μg / cm 2 , about 75μg / cm 2 , about 100μg / cm 2 , about 125μg / cm 2 , about 150μg / cm 2or any range therebetween) of cumulative deuterated tetrabenazine permeated; b) approximately 2 μg / cm2 based on active surface area at 12 hours after administration. 2 ~about 400μg / cm 2 (e.g., about 2 μg / cm 2 , about 5μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , about 50μg / cm 2 , about 100μg / cm 2 , about 200μg / cm 2 , about 300μg / cm 2 , about 400μg / cm 2 , or any range therebetween); and c) about 5 μg / cm2, based on active surface area, at 24 hours after administration. 2 ~Approx. 1000μg / cm 2 (e.g., about 5 μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , 25 μg / cm 2 , about 50μg / cm 2 , about 100μg / cm 2 , about 200μg / cm 2 , about 300μg / cm 2 , about 400μg / cm 2 , 600 μg / cm 2 , 800 μg / cm 2 , 1000 μg / cm 2, or any range between the recited values). In some embodiments, the deuterated tetrabenazine is present in an amount of about 2% to about 30% by weight of the drug layer (e.g., about 2% to about 20% by weight, about 2% to about 10% by weight, about 2% to about 5% by weight, about 5% to about 10% by weight, about 10% to about 15% by weight). In some embodiments, the deuterated tetrabenazine is present in about 2%, about 5%, about 8%, about 10%, about 15%, about 20% by weight of the drug layer, or any range between the recited values. In some embodiments, the deuterated tetrabenazine is substantially pure R,R-deuterabenazine.

[0105] Transdermal delivery devices having the above flux characteristics can be prepared by one skilled in the art in light of the present disclosure. The preparation of some transdermal delivery devices is also illustrated in the Examples section. The cumulative drug permeated (tetrabenazine, deuterated tetrabenazine, or a combination thereof) can be adjusted, for example, by varying the composition of the drug layer (e.g., drug concentration, permeation enhancer, coating weight, adhesive type, etc.).

[0106] Compositions containing non-reactive adhesives Compositions using non-reactive adhesives can offer certain advantages. As shown in the Examples section, tetrabenazine formulations containing non-reactive adhesives can be more stable than corresponding formulations containing adhesives with functional groups. For example, when the non-reactive adhesive DuroTak 87-900A, which is understood to be a copolymer of 2-EHA (2-ethylhexyl acrylate) (approximately 45% by weight based on the monomer composition), MA (methyl acrylate) (approximately 35% by weight based on the monomer composition), and t-OA (tert-octylacrylamide) (approximately 20% by weight based on the monomer composition), was used as the matrix polymer, the resulting tetrabenazine adhesive composition was found to be stable after storage at ambient temperature of 40°C for 4 weeks, with no observed drug crystallization or drug degradation. In contrast, when tetrabenazine adhesive compositions were formed using the more common adhesive matrix polymers DuroTak 87-2287 (containing epoxy and hydroxyl functional groups) or Duro-Tak 87-2677 (containing carboxylic acid functional groups), the resulting formulations exhibited a yellowish color after 4 weeks of ambient storage at 40°C, indicating instability of the active ingredient due to oxidation and / or other degradation.

[0107] In some embodiments, the present invention provides adhesive compositions comprising an active ingredient (or alternatively referred to as a "drug") dispersed (e.g., homogeneously dispersed or dissolved) in a non-reactive acrylate pressure-sensitive adhesive, where the active ingredient is selected from tetrabenazine, deuterated tetrabenazine, or a combination thereof. Unless otherwise apparent from the context, in any of the embodiments described herein, the active ingredient may be present predominantly (e.g., at least 80%, at least 90%, or at least 95% by weight) in its free base form, e.g., as tetrabenazine base, deutetrabenazine base, etc. The non-reactive acrylate pressure-sensitive adhesive is typically present in an amount of about 50% to about 97% by weight of the adhesive composition (e.g., about 50%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, or any range between the recited values).

[0108] Non-reactive acrylate pressure-sensitive adhesives useful in embodiments of the present disclosure include, for example, those sold by Henkel under the product name DuroTak 87-900A. U.S. Patent No. 9,056,060, the entire contents of which are incorporated herein by reference, also describes non-reactive acrylate pressure-sensitive adhesives that can be used in embodiments of the present disclosure.

[0109] In some embodiments, the non-reactive acrylate pressure-sensitive adhesive does not have a functional group containing a reactive hydrogen moiety. In some embodiments, the non-reactive acrylate pressure-sensitive adhesive does not have a functional group selected from epoxy, -OH, -COOH, and combinations thereof. For example, in some embodiments, the non-reactive acrylate pressure-sensitive adhesive is a copolymer of alkyl acrylate that does not have a functional group containing a reactive hydrogen moiety and does not have a functional group selected from epoxy, -OH, -COOH, and combinations thereof. In some embodiments, the non-reactive acrylate pressure-sensitive adhesive can be a copolymer of monomers that include, consist essentially of, or consist of alkyl acrylate. For example, in some embodiments, the non-reactive acrylate pressure-sensitive adhesive is a copolymer derived from monomers that consist of alkyl acrylate, such as C2-C 18 Alkyl acrylate (preferably C4-C 10The non-reactive acrylate pressure-sensitive adhesive may be a copolymer derived from a monomer comprising a branched or linear alkyl acrylate and a monomer comprising methyl acrylate, more preferably a copolymer derived from a monomer comprising an ethylhexyl acrylate (e.g., 2-ethylhexyl acrylate) and a monomer comprising methyl acrylate. In some embodiments, the alkyl acrylate copolymer is a copolymer of ethylhexyl acrylate (e.g., 2-ethylhexyl acrylate), methyl acrylate, and, optionally, other monomer(s) that do not have a functional group containing a reactive hydrogen moiety, such as an -OH or -COOH group. In some embodiments, the non-reactive acrylate pressure-sensitive adhesive may be a copolymer derived from a monomer comprising an alkyl acrylate and another monomer that does not have a functional group containing a reactive hydrogen moiety, such as an -OH or -COOH group. For example, in some embodiments, the non-reactive acrylate pressure-sensitive adhesive is a copolymer derived from monomers of ethylhexyl acrylate (e.g., 2-ethylhexyl acrylate), monomers of methyl acrylate, and one or more monomers that do not have functional groups containing reactive hydrogen moieties such as -OH, -COOH groups, for example, acrylamide monomers (e.g., tert-octylacrylamide, dimethylacrylamide, isopropylacrylamide, or vinylacetamide). As used herein, amide NH or amide NH groups should not be considered reactive hydrogen moieties. In ... C2-C 18 Alkyl acrylate (preferably C4-C 10 The non-reactive acrylate pressure-sensitive adhesive may be a copolymer derived from monomers of branched or linear alkyl acrylate, monomers of methyl acrylate, and one or more acrylamide monomers (e.g., tert-octylacrylamide) that do not have functional groups selected from epoxy, -OH, -COOH groups, and combinations thereof. The weight percentage of the monomers can vary; for example, in some embodiments, the percentage of monomers in the non-reactive acrylate pressure-sensitive adhesive may be: C2-C 18 Alkyl acrylate (preferably C4-C 10The monomer percentage of branched or linear alkyl acrylate (e.g., 2-ethylhexyl acrylate) can be about 45% by weight, the monomer percentage of methyl acrylate can be about 35% by weight, and the monomer percentage of one or more acrylamide monomers (e.g., tert-octylacrylamide) can be about 20% by weight.

[0110] Non-reactive acrylate pressure-sensitive adhesives typically do not contain vinyl acetate. Non-reactive acrylate pressure-sensitive adhesives also typically do not contain a crosslinker. Non-reactive acrylate pressure-sensitive adhesives can typically have a variety of viscosities. In some embodiments, the non-reactive acrylate pressure-sensitive adhesive can have a viscosity of about 1,500 cP to about 20,000 cP, more preferably about 1,500 cP to about 10,000 cP, such as about 1,800 cP, about 5,000 cP, about 10,000 cP, or any range between the recited values. In some embodiments, the non-reactive acrylate pressure-sensitive adhesive can be selected so that the adhesive composition can continuously adhere to a user's skin for about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days, or longer.

[0111] In some formulations, the addition of a permeation enhancer may cause significant degradation of the active ingredient (e.g., tetrabenazine) in the patch formulation. Thus, in some embodiments, the adhesive composition may be free of or substantially free of a permeation enhancer. For example, in some embodiments, the adhesive composition herein may be free of a permeation enhancer. In some embodiments, the adhesive composition herein may be free of a permeation enhancer selected from a fatty alcohol, a fatty acid, a fatty acid ester, and combinations thereof. In some embodiments, the adhesive composition herein may be free of isopropyl myristate. However, it should be understood that in some cases, a permeation enhancer may be added to the adhesive composition, for example, in an amount that does not cause significant degradation of the active ingredient.

[0112] An antioxidant is typically included in the adhesive compositions herein. For example, antioxidants can be added to reduce the degree of degradation of the active ingredient. However, it has been surprisingly found that some antioxidants work better than others at protecting tetrabenazine from degradation. For example, adhesive compositions containing a gallic acid antioxidant (e.g., propyl gallate in the examples) have been found to be shelf-stable. In any of the embodiments herein, shelf-stable, shelf-stable, or shelf-stable after storage at room temperature, may mean that for a tested device or composition after 4 weeks of storage at room temperature at 40°C, (1) HPLC analysis shows that the tested device or composition is free or substantially free (e.g., less than 1%, less than 0.5%, less than 0.05%, or not detected by HPLC) of one or more (preferably all) degradants selected from TBZ01, TBZ02, and TBZ04; or (2) no drug crystals are observed (e.g., not visually observable). In some embodiments, the degradants TBZ01, TBZ02, and TBZ04 are not detected by HPLC or below the limit of quantitation in shelf-stable devices or compositions herein after 4 weeks of ambient storage at 40°C. Exemplary conditions for HPLC analysis and retention times for TBZ01, TBZ02, and TBZ04 are shown in Example 5. However, when no antioxidant was used or when the added antioxidant was BHT, degradants (including TBZ01, TBZ02, and TBZ04) were formed. In some embodiments, the adhesive composition can include a gallic acid antioxidant. In some preferred embodiments, the adhesive composition can include propyl gallate. In some preferred embodiments, propyl gallate is the only antioxidant in the adhesive composition. In some embodiments, other antioxidants can be used in combination with propyl gallate. In some embodiments, the adhesive composition can also include propyl gallate, citric acid, ascorbic acid, vitamin E, or tocopherol acetate, or a combination thereof, as an antioxidant.When present, an antioxidant such as propyl gallate is typically present in an amount of about 0.001% to about 0.5% by weight (e.g., about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%) of the adhesive composition.

[0113] The active ingredient is typically present in the adhesive composition in an amount of about 2% to about 30% by weight. Preferably, in some embodiments, the active ingredient is present in the adhesive composition in an amount of about 2% to about 15% by weight, such as about 2% to about 10% by weight, or about 2% to about 7% by weight. The tetrabenazine in the adhesive composition herein is not limited to a particular enantiomer, and may be racemic, substantially pure R,R-tetrabenazine (e.g., less than 10%, 5%, 1%, or 0.1% of the S,S-isomer), substantially pure S,S-tetrabenazine (e.g., less than 10%, 5%, 1%, or 0.1% of the R,R-isomer), or a mixture of R,R-tetrabenazine and S,S-tetrabenazine in any ratio. The deuterated tetrabenazine in the transdermal delivery devices described herein is not limited to a particular enantiomer, and can be in racemic form, a substantially pure R,R-isomer, e.g., R,R-deutetrabenazine (e.g., less than 10%, less than 5%, less than 1%, or less than 0.1% of the S,S-isomer), a substantially pure S,S-isomer, e.g., S,S-deutetrabenazine (e.g., less than 10%, less than 5%, less than 1%, or less than 0.1% of the R,R-isomer), or a mixture of the R,R- and S,S-isomers in any ratio. In some embodiments, the only active ingredient in the adhesive composition is tetrabenazine, e.g., a substantially pure R,R-isomer of tetrabenazine. In some embodiments, the only active ingredient in the adhesive composition is deutetrabenazine, e.g., a substantially pure R,R-isomer of deutetrabenazine. In some embodiments, the adhesive composition can also include other active ingredients, e.g., as described herein.

[0114] Typically, a crystallization inhibitor is also included in the adhesive composition to prevent the formation of drug crystals during storage. Such drug crystals may slow the skin permeation of such adhesive compositions. Therefore, in some embodiments, the adhesive composition can include a crystallization inhibitor in an amount effective to prevent the formation of drug crystals after storage at ambient temperature for 2 weeks. In some embodiments, the adhesive composition comprises a polyvinylpyrrolidone polymer (e.g., Kollidon K30 or K90F (manufactured by BASF), Plasdone K20 / 32 or Plasdone K90 (manufactured by Ashland Chemical)), crosslinked polyvinylpyrrolidone polymer (e.g., Kollidon CL), polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone (Ashland)), cellulosic polymer (e.g., hydroxylpropylmethylcellulose, ethylcellulose, hydroxypropylcellulose), polycarboxylic acid polymer (e.g., Cabopol (manufactured by Lubrizol)), polymethacrylate (e.g., Plastoid B, Eudragit E100, Eudragit L100-55), or a combination of these polymers. (manufactured by Evonik), polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam-based graft copolymers (PVAc-PVCap-PEG) (e.g., Soluplus (BASF)), and combinations thereof. In some embodiments, the crystallization inhibitor is not Kollidon VA64 (BASF).

[0115] In some preferred embodiments, the adhesive composition may comprise a crystallization inhibitor selected from polymethacrylate (e.g., Plastoid B (a copolymer of butyl methacrylate and methyl methacrylate), Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam-based graft copolymers (PVAc-PVCap-PEG) (e.g., Soluplus (BASF)), and combinations thereof. For example, in some particular embodiments, the adhesive composition may comprise a crystallization inhibitor selected from a copolymer of butyl methacrylate and methyl methacrylate, such as Plastoid B (a copolymer of butyl methacrylate and methyl methacrylate), manufactured by Evonik under the trade name Plastoid E100, Eudragit L100-55 (manufactured by Evonik)). In some particular embodiments, the adhesive composition comprises a polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam-based graft copolymer, such as the polymer manufactured by BASF under the trade name Soluplus. When present in the adhesive composition, the crystallization inhibitor is typically present in an amount of about 5% to about 40% by weight, e.g., about 10%, about 20%, about 30%, about 40% by weight, or any range between the recited values.

[0116] In some particular embodiments, the present invention provides an adhesive composition having the following components: [Table 1] The numerical values ​​in the tables should be understood as preceded by the word "about." Other ingredients may optionally be included. In some embodiments, the adhesive composition does not include a permeation enhancer. In some embodiments, the adhesive composition does not include isopropyl myristate. Suitable active ingredients, adhesives (e.g., non-reactive acrylate adhesives), antioxidants, and crystallization inhibitors include those described herein. For example, in some preferred embodiments, the active ingredient is tetrabenazine base (e.g., a substantially pure R,R-isomer), the adhesive is an acrylate polymer such as a non-reactive acrylate adhesive, preferably a copolymer of ethylhexyl acrylate and methyl acrylate, e.g., Duro-Tak 87-900A, the antioxidant is preferably propyl gallate, and the crystallization inhibitor is preferably a copolymer of butyl methacrylate and methyl methacrylate, or a graft copolymer based on polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam. In some embodiments, the present disclosure also provides a method of preparing an adhesive composition (e.g., as described herein). In some embodiments, the method includes mixing an active ingredient (e.g., tetrabenazine base), an adhesive, optionally an antioxidant, and optionally a crystallization inhibitor in a suitable solvent (e.g., ethanol, etc.) to form a wet adhesive composition. Suitable amounts and suitable active ingredients, adhesives, antioxidants, and crystallization inhibitors include any of those described and preferred herein, e.g., those discussed in this paragraph and the preceding 10 paragraphs. Other optional ingredients and their amounts are also described herein. In some embodiments, the method further includes casting the wet adhesive composition onto a backing layer. In some embodiments, the method further includes drying the wet adhesive composition. Products produced by the methods herein are also novel compositions.

[0117] The adhesive composition (e.g., an adhesive composition comprising a non-reactive acrylate adhesive described herein) is typically included in a transdermal delivery device, e.g., as a drug layer or drug-containing adhesive layer. For example, in some embodiments, the present disclosure provides a transdermal delivery device comprising a backing layer, any of the adhesive compositions described herein (e.g., an adhesive composition comprising a non-reactive acrylate adhesive described herein as a drug layer or drug-containing adhesive layer), and a release liner. The transdermal delivery device can be cut to different sizes as needed, which are typically about 10 cm. 2 ~about 100cm 2 Other patch designs are described herein. Preferably, the transdermal delivery devices herein (and / or adhesive compositions, e.g., comprising a non-reactive acrylate adhesive described herein) are shelf-stable (or alternatively referred to as shelf-stable), e.g., no drug crystals are observed after 4 weeks of ambient storage at 40°C, and / or no drug degradation is observed by HPLC after 4 weeks of ambient storage at 40°C. For example, in some embodiments, the transdermal delivery devices herein (and / or adhesive compositions, e.g., comprising a non-reactive acrylate adhesive described herein) can be shelf-stable for 4 weeks or more, 8 weeks or more, 12 weeks or more, 16 weeks or more, 6 months or more, 12 months or more, etc.

[0118] Typically, the transdermal delivery devices (and / or adhesive compositions) herein can also be configured to achieve a desired skin permeability of the active ingredient (e.g., tetrabenazine or deutetrabenazine). For example, in some embodiments, a transdermal delivery device (e.g., comprising an adhesive composition including a non-reactive acrylate adhesive described herein) can achieve a permeability of about 0.01 mg / day / cm. 2 ~About 5mg / day / cm 2 (e.g., about 0.01 mg / day / cm 2 , approximately 0.02 mg / day / cm 2 , about 0.05mg / day / cm 2 , about 0.1mg / day / cm 2 , about 0.2mg / day / cm 2, about 0.5mg / day / cm 2 , about 1mg / day / cm 2 , about 2mg / day / cm 2 , about 5mg / day / cm 2 , or any range between the recited values) of an active ingredient (e.g., tetrabenazine or deutetrabenazine) to a subject in need thereof for a period selected from, for example, about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, and about 7 days. In some embodiments, the transdermal delivery device (e.g., comprising an adhesive composition comprising a non-reactive acrylate adhesive described herein) can deliver about 5 mg / day / cm 2 greater than, for example, about 8 mg / day / cm 2 , about 10mg / day / cm 2 , about 15mg / day / cm 2 , about 20mg / day / cm 2 , or any range between the recited values. In some embodiments, a transdermal delivery device (e.g., comprising an adhesive composition comprising a non-reactive acrylate adhesive described herein) can deliver about 0.1 mg / day / cm 2 Less than, for example, about 0.01 mg / day / cm 2 , approximately 0.02 mg / day / cm 2 , about 0.05mg / day / cm 2 , about 0.1mg / day / cm 2 , or any range of the active ingredient (e.g., tetrabenazine or deutetrabenazine) between the recited values ​​can be delivered.

[0119] For example, in some embodiments, the adhesive composition of a transdermal delivery device comprises about 2% to about 10% by weight (e.g., about 2% to about 7% by weight) of tetrabenazine, and the transdermal delivery device (e.g., comprising an adhesive composition comprising a non-reactive acrylate adhesive described herein) exhibits the following skin flux properties when tested in vitro using human cadaver skin: a) about 0.5 μg / cm based on active surface area at 8 hours after administration; 2 ~Approx. 50μg / cm 2(e.g., about 1 μg / cm 2 , about 5μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , about 50μg / cm 2 or any range between the stated values) of cumulative tetrabenazine permeated; b) approximately 5 μg / cm2 based on active surface area at 24 hours after administration. 2 ~Approx. 500μg / cm 2 (e.g., about 5 μg / cm 2 , about 10μg / cm 2 , about 15μg / cm 2 , about 20μg / cm 2 , about 50μg / cm 2 , about 100μg / cm 2 , about 200μg / cm 2 , about 500μg / cm 2 , or any range between the stated values) of cumulative tetrabenazine permeated; and c) approximately 10 μg / cm2, based on active surface area, 48 hours after administration. 2 ~Approx. 1000μg / cm 2 (e.g., about 10 μg / cm 2 , about 20μg / cm 2 , about 50μg / cm 2 , about 100μg / cm 2 , about 200μg / cm 2 , about 300μg / cm 2 , about 400μg / cm 2 , about 600μg / cm 2 , about 1000μg / cm 2 (or any range between the recited values), the cumulative tetrabenazine permeated. In some embodiments, the in vitro testing is performed according to the method described in Example 6 of the present application.

[0120] How to administer tetrabenazine In various embodiments, the present invention further provides methods of using the transdermal delivery devices or pharmaceutical compositions described herein (e.g., the adhesive compositions herein). In some embodiments, the transdermal delivery devices or pharmaceutical compositions can be used for any indication in which inhibition of VMAT-2 is beneficial. In some embodiments, the transdermal delivery devices or pharmaceutical compositions can be used to treat or prevent diseases or disorders mediated by VMAT-2. In some embodiments, the transdermal delivery devices or pharmaceutical compositions can be used for any indication in which administration of tetrabenazine or deuterated tetrabenazine is beneficial. For example, in addition to the indication of chorea associated with Huntington's disease, other indications approved for use with tetrabenazine or deuterated tetrabenazine include hemiballismus, tics, tardive dyskinesia, and Tourette's syndrome. In various embodiments, the transdermal delivery devices or pharmaceutical compositions can also be used for any of these indications.

[0121] In some embodiments, the present invention provides methods of administering tetrabenazine, deuterated tetrabenazine, or a combination thereof to a subject (e.g., a human subject) in need thereof. In some embodiments, the method comprises applying either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition herein) to the subject, e.g., the skin of the subject. In some embodiments, the subject (e.g., a human subject) is characterized by having a hyperkinetic movement disorder (e.g., chronic hyperkinetic movement disorder). In some embodiments, the hyperkinetic movement disorder is selected from chorea associated with Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tics, and combinations thereof. In some embodiments, the method comprises applying a transdermal delivery device comprising tetrabenazine (e.g., substantially pure R,R-tetrabenazine). In some embodiments, the method comprises applying a transdermal delivery device comprising deutetrabenazine (e.g., substantially pure R,R-deutetrabenazine).

[0122] In some embodiments, the present invention also provides a method for inhibiting VMAT-2 in a subject in need thereof. In some embodiments, the method includes applying either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition herein) to a subject, e.g., the skin of a subject.

[0123] In some embodiments, the present invention also provides methods for treating a vesicular monoamine transporter isoform 2 (VMAT2)-mediated disease or disorder in a subject (e.g., a human subject) in need of such treatment. In some embodiments, the method includes applying either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition herein) to the subject, e.g., the subject's skin. VMAT2-mediated diseases or disorders include, but are not limited to, hyperkinetic movement disorders (e.g., chronic hyperkinetic movement disorder), Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia, Tourette's syndrome, depression, cancer, rheumatoid arthritis, psychosis, multiple sclerosis, asthma, and / or any disorder that can be alleviated, alleviated, or prevented by administering a VMAT2 inhibitor. In some embodiments, the VMAT2-mediated disease or disorder is tardive dyskinesia. In some embodiments, the VMAT2-mediated disease or disorder is Huntington's disease. In some embodiments, the VMAT2-mediated disease or disorder is hemiballismus. In some embodiments, the VMAT2-mediated disease or disorder is Tourette's syndrome.

[0124] In some embodiments, the present disclosure provides methods of treating hyperkinetic movement disorder in a subject (e.g., a human subject) in need of such treatment. In some embodiments, the method comprises applying either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition herein) to the subject, e.g., the subject's skin. In some embodiments, the hyperkinetic movement disorder is chronic hyperkinetic movement disorder. In some embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, and / or tics. In some embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease. In some particular embodiments, the present disclosure provides methods of treating chorea associated with Huntington's disease in a subject in need of such treatment, the method comprising applying either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition herein) to the subject, e.g., the subject's skin. In some specific embodiments, the present invention provides a method of treating tardive dyskinesia in a subject in need of such treatment, comprising applying either a transdermal delivery device or a pharmaceutical composition (e.g., the adhesive composition herein) to the subject, e.g., the subject's skin. In some specific embodiments, the present invention provides a method of treating Tourette's syndrome in a subject in need of such treatment, comprising applying either a transdermal delivery device or a pharmaceutical composition (e.g., the adhesive composition herein) to the subject, e.g., the subject's skin. In some specific embodiments, the present invention provides a method of treating tics in a subject in need of such treatment, comprising applying either a transdermal delivery device or a pharmaceutical composition (e.g., the adhesive composition herein) to the subject, e.g., the subject's skin. In some specific embodiments, the present invention provides a method of treating hemiballismus in a subject in need of such treatment, comprising applying either a transdermal delivery device or a pharmaceutical composition (e.g., the adhesive composition herein) to the subject, e.g., the subject's skin.

[0125] Tetrabenazine and / or deuterated tetrabenazine (e.g., deutetrabenazine) can be used in the methods herein. Typically, the methods involve applying a transdermal delivery device herein comprising either tetrabenazine or deutetrabenazine as the only active ingredient. In some embodiments, the methods involve applying a transdermal delivery device herein comprising substantially pure R,R-tetrabenazine, e.g., comprising substantially pure R,R-tetrabenazine as the only active ingredient. In some embodiments, the methods involve applying a transdermal delivery device herein comprising substantially pure R,R-deutetrabenazine, e.g., comprising substantially pure R,R-deutetrabenazine as the only active ingredient.

[0126] In any of the embodiments described herein, the method comprises administering a dose of about 0.1 mg / day / cm 2 ~About 5mg / day / cm 2 (e.g., about 0.1 mg / day / cm 2 , about 0.2mg / day / cm 2 , about 0.5mg / day / cm 2 , about 1mg / day / cm 2 , about 2mg / day / cm 2 , about 5mg / day / cm 2 , or any range between the recited values) of a drug (e.g., tetrabenazine or deutetrabenazine) to a subject for a period selected from, for example, about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, and about 7 days. However, in some embodiments, the method may include administering about 5 mg / day / cm 2 greater than, for example, about 8 mg / day / cm 2 , about 10mg / day / cm 2 , about 15mg / day / cm 2 , about 20mg / day / cm 2 or any range between the recited values. In some embodiments, the method comprises administering to the subject a drug (e.g., tetrabenazine or deutetrabenazine) at a dose of about 0.1 mg / day / cm 2Less than, for example, about 0.01 mg / day / cm 2 , approximately 0.02 mg / day / cm 2 , about 0.05mg / day / cm 2 , about 0.1mg / day / cm 2 or any range between the stated values ​​(e.g., tetrabenazine or deutetrabenazine) to the subject.

[0127] In some embodiments, the present invention provides a method for treating a vesicular monoamine transporter isoform 2 (VMAT2)-mediated disease or disorder in a subject (e.g., a human subject) in need thereof, comprising transdermally administering to the subject a therapeutically effective amount of tetrabenazine or deutetrabenazine. Suitable VMAT2-mediated diseases or disorders are described herein.

[0128] The methods described herein are associated with various advantages. For example, in some embodiments, the methods can reduce inter-individual variability in plasma levels of tetrabenazine or deutetrabenazine or metabolites thereof compared to oral administration of an equivalent dose of tetrabenazine or deutetrabenazine. In some embodiments, the methods can reduce inter-individual variability in plasma levels of tetrabenazine or deutetrabenazine or metabolites thereof compared to oral administration of an equivalent dose of tetrabenazine or deutetrabenazine, for example, without reducing therapeutic efficacy. maxcan be reduced (e.g., by 10%, 40%, 60%, or more). In some embodiments, the method can provide similar plasma levels of tetrabenazine or deutetrabenazine or their metabolites when administered at equal doses to subjects genotyped as poor metabolizers (PMs), intermediate metabolizers (IMs), or extensive metabolizers (EMs) based on CYP2D6 expression. In some embodiments, the same or substantially the same dose of tetrabenazine or deutetrabenazine can be administered to subjects characterized as PMs, IMs, or EMs. In some embodiments, the methods herein can transdermally administer a drug (e.g., tetrabenazine or deutetrabenazine) to a subject regardless of whether the subject is characterized as a PM, IM, or EM based on CYP2D6 expression.

[0129] Exemplary Transdermal Delivery of Tetrabenazine or Deuterated Tetrabenazine In some embodiments, tetrabenazine or deuterated tetrabenazine can be administered to a subject in need thereof to achieve a therapeutic effect at a desired dose and / or with a suitable PK profile as described herein. Any of the transdermal delivery devices disclosed herein may be useful. In some embodiments, the present disclosure provides the following specific embodiments, SE1-SE8.

[0130] SE1: A method of treating hyperkinetic movement disorder in a subject in need thereof, comprising applying to the subject a transdermal delivery device described herein, preferably a transdermal delivery device comprising a drug-containing adhesive layer, wherein the drug-containing adhesive layer comprises: (1) an active ingredient comprising R,R-tetrabenazine; (2) a pressure-sensitive adhesive described herein, e.g., a non-reactive acrylate pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant, wherein the transdermal delivery device is applied to administer to the subject about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine, e.g., about 0.5 mg / day to about 10 mg / day of R,R-tetrabenazine, about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine, about 0.5 mg / day to about 6 mg / day of R,R-tetrabenazine, about 0.5 mg / day to about 4 mg / day of R,R-tetrabenazine, R,R-tetrabenazine from about 1 mg / day to about 10 mg / day, R,R-tetrabenazine from about 1 mg / day to about 8 mg / day, R,R-tetrabenazine from about 1 mg / day to about 6 mg / day, R,R-tetrabenazine from about 1 mg / day to about 4 mg / day, R,R-tetrabenazine from about 2 mg / day to about 10 mg / day, R,R-tetrabenazine from about 2 mg / day to about 8 mg / day, R,R-tetrabenazine from about 2 mg / day to about 6 mg / day In some embodiments according to SE1, a transdermal delivery device is applied to transdermally deliver to a subject about 0.5 mg / day to about 10 mg / day of R,R-tetrabenazine, about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine, about 2 mg / day to about 4 mg / day of R,R-tetrabenazine, about 4 mg / day to about 10 mg / day of R,R-tetrabenazine, about 4 mg / day to about 8 mg / day of R,R-tetrabenazine, about 4 mg / day to about 6 mg / day of R,R-tetrabenazine, about 6 mg / day to about 10 mg / day of R,R-tetrabenazine, or about 6 mg / day to about 8 mg / day of R,R-tetrabenazine. In some embodiments according to SE1, the drug-drug-adhesive layer can include an optional permeation enhancer and / or plasticizer.

[0131] SE2: A method of treating hyperkinetic movement disorder in a subject in need thereof, comprising applying to the subject a transdermal delivery device described herein, preferably a transdermal delivery device comprising a drug-containing adhesive layer, wherein the drug-containing adhesive layer comprises: (1) an active ingredient comprising R,R-tetrabenazine; (2) a pressure-sensitive adhesive described herein, e.g., a non-reactive acrylate pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant, wherein the transdermal delivery device provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ, and the maximum plasma concentration of R,R-tetrabenazine is less than or equal to 100% of the R,R,R-HTBZ. the ratio of R,R-tetrabenazine to the combined maximum plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ is in the range of about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any range between the recited values, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.), or the ratio of R,R-tetrabenazine steady-state plasma concentration to the combined steady-state plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ is in the range of about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any range between the recited values, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some embodiments according to SE2, the ratio of maximum or steady-state plasma concentrations of R,R,R-HTBZ to S,R,R-HTBZ ranges from about 1:5 to about 1:30 (e.g., about 1:5, about 1:7, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, or any range therebetween, e.g., about 1:10 to about 1:20, about 1:5 to about 1:15, etc.). In some embodiments according to SE2, the ratio of maximum or steady-state plasma concentrations of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ ranges from about 17-40:3 to 10:50-80. In some embodiments according to SE2, depending on the application, the AUC of SRR-HTBZ 0-∞ AUC of R,R-tetrabenazine 0-∞ to about 1 to about 15, for example, about 1.5 to about 11, and / or the AUC of RRR-HTBZ0-∞ AUC of R,R-tetrabenazine 0-∞ to about 0.1 to about 0.75, e.g., about 0.15 to about 0.5. In some embodiments according to SE2, administration does not provide detectable amounts of S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ in the subject's plasma. In some embodiments according to SE2, the PK profile is characterized by a mean terminal half-life of R,R-tetrabenazine of about 8.5 hours ± 40% CV. In some embodiments according to SE2, the drug-in-adhesive layer can include an optional permeation enhancer and / or plasticizer. In some embodiments according to SE2, a transdermal delivery device is applied to transdermally deliver to the subject any of the daily doses described in SE1. In some embodiments according to SE2, a transdermal delivery device is applied to achieve any of the PK profiles described herein, in any combination.

[0132] SE3: A method of treating hyperkinetic movement disorder in a subject in need thereof, comprising applying to the subject a transdermal delivery device described herein, preferably a transdermal delivery device comprising a drug-in-adhesive layer, wherein the drug-in-adhesive layer comprises (1) an active ingredient comprising R,R-tetrabenazine, (2) a pressure-sensitive adhesive described herein, e.g., a non-reactive acrylate pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant, wherein applying the transdermal delivery device to the subject achieves a therapeutically effective plasma concentration of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ for at least 6 hours, or at least 12 hours, preferably at least 24 hours, e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours or more. In some embodiments according to SE3, the drug-in-adhesive layer can include an optional permeation enhancer and / or plasticizer. In some embodiments according to SE3, a transdermal delivery device is applied to transdermally deliver to a subject any of the daily doses described in SE1. In some embodiments according to SE3, a transdermal delivery device is applied to achieve any of the PK profiles in a subject described in SE2.

[0133] SE4: A method of treating hyperkinetic movement disorder in a subject in need thereof, comprising applying to the subject a transdermal delivery device as described herein, preferably a transdermal delivery device comprising a drug-in-adhesive layer, wherein the drug-in-adhesive layer comprises (1) an active ingredient comprising R,R-tetrabenazine, and (2) a pressure-sensitive adhesive herein, e.g., a non-reactive acrylate pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant, wherein applying the transdermal delivery device to the subject achieves a substantially constant steady-state plasma concentration of R,R-tetrabenazine of greater than 150 pg / ml for a sustained period of at least 6 hours, or at least 12 hours, preferably at least 24 hours, e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, or more. In some embodiments according to SE4, the transdermal delivery device is applied to a subject to achieve a substantially constant steady-state plasma concentration of R,R-tetrabenazine of greater than 150 pg / ml to about 3000 pg / ml over a sustained period, wherein the plasma concentration of R,R-tetrabenazine does not change significantly, e.g., by more than two-fold, during any of the 4-hour, 8-hour, and / or 12-hour intervals of the sustained period. In some embodiments according to SE4, the ratio of the minimum plasma concentration of R,R-tetrabenazine to the maximum plasma concentration of R,R-tetrabenazine over the sustained period is about 0.4 or greater, e.g., about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, or any range between the recited values. In some embodiments according to SE4, the drug-containing adhesive layer can include an optional permeation enhancer and / or plasticizer. In some embodiments according to SE4, the transdermal delivery device is applied to transdermally deliver to a subject any of the daily doses set forth in SE1. In some embodiments according to SE4, a transdermal delivery device is applied to achieve any of the PK profiles in subjects described in SE2.

[0134] SE5: A method of treating hyperkinetic movement disorder in a subject in need thereof, comprising applying to the subject a transdermal delivery device described herein, preferably a transdermal delivery device comprising a drug-containing adhesive layer, the drug-containing adhesive layer comprising: (1) an active ingredient comprising deuterated R,R-tetrabenazine; (2) a pressure-sensitive adhesive herein, e.g., a non-reactive acrylate pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant. and applying a transdermal delivery device to administer from about 0.1 mg / day to about 20 mg / day of deuterated R,R-tetrabenazine, for example, from about 0.5 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, from about 0.5 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, from about 0.5 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine, from about 0.5 mg / day to about 4 mg / day of deuterated R,R-tetrabenazine, from about 1 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine. Deuterated R,R-tetrabenazine, about 1 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, about 1 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine, about 1 mg / day to about 4 mg / day of deuterated R,R-tetrabenazine, about 2 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, about 2 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, about 2 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine, A method for transdermally delivering to a subject 2 mg / day to about 4 mg / day of deuterated R,R-tetrabenazine, about 4 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, about 4 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, about 4 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine, about 6 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, or about 6 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine. In some embodiments according to SE5, a transdermal delivery device is applied to transdermally deliver to a subject about 0.5 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, about 0.5 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, or about 2 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine. In some embodiments according to SE5, the drug-containing adhesive layer may include an optional permeation enhancer and / or plasticizer.

[0135] SE6. A method of treating hyperkinetic movement disorder in a subject in need thereof, comprising applying to the subject a transdermal delivery device described herein, preferably a transdermal delivery device comprising a drug-containing adhesive layer, wherein the drug-containing adhesive layer comprises: (1) an active ingredient comprising deuterated R,R-tetrabenazine; (2) a pressure-sensitive adhesive described herein, e.g., a non-reactive acrylate pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant, wherein the transdermal delivery device is capable of administering to the subject a therapeutically effective amount of deuterated R,R-tetrabenazine, a dihydrotetrabenazine metabolite of deuterated R,R-tetrabenazine, deuterated R,R,R-HTBZ, and deuterated S,R,R-HTBZ. a method for providing therapeutically effective plasma concentrations, wherein the ratio of the maximum plasma concentration of deuterated R,R-tetrabenazine to the maximum combined plasma concentration of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ is in the range of about 1:1 to about 1:7.5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, about 1:7.5, or any range therebetween, e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.), or the ratio of the steady-state plasma concentration of deuterated R,R-tetrabenazine to the maximum combined plasma concentration of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ is in the range of about 1:1 to about 1:7.5. In some embodiments according to SE6, the ratio of maximum plasma concentrations of deuterated R,R,R-HTBZ to deuterated S,R,R-HTBZ can be in the range of about 1:5 to about 1:30 (e.g., about 1:5, about 1:7, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, or any range between the recited values, e.g., about 1:10 to about 1:20, about 1:5 to about 1:15, etc.). In some embodiments according to SE6, the ratio of maximum plasma concentrations of deuterated R,R-tetrabenazine:deuterated R,R,R-HTBZ:deuterated S,R,R-HTBZ can be in the range of about 14-40:3 to 11:50-85. In some embodiments according to SE6, administration can reduce the AUC of deuterated S,R,R-HTBZ. 0-∞ AUC of deuterated R,R-tetrabenazine 0-∞to about 1 to about 15, for example, about 1.5 to about 11, and / or the AUC of deuterated RRR-HTBZ 0-∞ AUC of deuterated R,R-tetrabenazine 0-∞ to about 0.1 to about 0.75, e.g., about 0.15 to about 0.5. In some embodiments according to SE6, administration does not provide detectable amounts of deuterated S,S-tetrabenazine, deuterated R,S,S-HTBZ, or deuterated S,S,S-HTBZ in the subject's plasma. In some embodiments according to SE6, the PK profile is characterized by a mean terminal half-life of deuterated R,R-tetrabenazine of about 8.5 hours ± 40% CV. In some embodiments according to SE6, the drug-in-adhesive layer can include an optional permeation enhancer and / or plasticizer. In some embodiments according to SE6, a transdermal delivery device is applied to transdermally deliver to the subject any of the daily doses described in SE5. In some embodiments according to SE6, a transdermal delivery device is applied to achieve any of the PK profiles described herein.

[0136] SE7: A method of treating hyperkinetic movement disorder in a subject in need thereof, comprising applying to the subject a transdermal delivery device described herein, preferably a transdermal delivery device comprising a drug-containing adhesive layer, wherein the drug-containing adhesive layer comprises: (1) an active ingredient comprising deuterated R,R-tetrabenazine; (2) a pressure-sensitive adhesive herein, e.g., a non-reactive acrylate pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant; wherein applying the transdermal delivery device to the subject results in at least 6 or at least 12 hours, preferably at least 24 hours, e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, or more. In some embodiments according to SE7, the drug-containing adhesive layer can include an optional permeation enhancer and / or plasticizer. In some embodiments according to SE7, a transdermal delivery device is applied to transdermally deliver to the subject any of the daily doses described in SE5. In some embodiments according to SE7, a transdermal delivery device is applied to achieve any of the PK profiles described in SE6.

[0137] SE8: A method of treating hyperkinetic movement disorder in a subject in need thereof, comprising applying to the subject a transdermal delivery device as described herein, preferably a transdermal delivery device comprising a drug-in-adhesive layer, wherein the drug-in-adhesive layer comprises (1) an active ingredient comprising deuterated R,R-tetrabenazine, and (2) a pressure-sensitive adhesive as described herein, e.g., a non-reactive acrylate pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant, wherein applying the transdermal delivery device to the subject achieves a substantially constant steady-state plasma concentration of deuterated R,R-tetrabenazine of 150 pg / ml for a sustained period of at least 6 hours, or at least 12 hours, preferably at least 24 hours, e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, or more. In some embodiments according to SE8, the transdermal delivery device is applied to a subject to achieve a substantially constant steady-state plasma concentration of deuterated R,R-tetrabenazine of greater than 150 pg / ml to greater than about 3000 pg / ml over a sustained period, wherein the plasma concentration of deuterated R,R-tetrabenazine does not change significantly, e.g., by more than two-fold, during any of the 4-hour, 8-hour, and / or 12-hour intervals of the sustained period. In some embodiments according to SE8, the ratio of the minimum plasma concentration of deuterated R,R-tetrabenazine to the maximum plasma concentration of deuterated R,R-tetrabenazine over the sustained period is about 0.4 or greater, e.g., about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, or any range between the recited values. In some embodiments according to SE8, the drug-containing adhesive layer can include an optional permeation enhancer and / or plasticizer. In some embodiments according to SE8, the transdermal delivery device is applied to transdermally deliver to a subject any of the daily doses described in SE5. In some embodiments according to SE8, a transdermal delivery device is applied to achieve any of the PK profiles in subjects described in SE6.

[0138] Any of the transdermal delivery device designs described herein can be used in the described methods. Typically, for any of the embodiments according to SE1-SE8, the transdermal delivery device can be a DIA patch comprising a drug-containing adhesive layer, a backing layer, and a release liner that protects the adhesive surface prior to use. The drug-containing adhesive layer typically comprises an active ingredient dispersed, preferably homogeneously dispersed, in the adhesive. In some embodiments, the transdermal delivery device is applied to a subject to deliver about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine (e.g., any of the exemplified ranges described herein) at a substantially constant rate for up to 24 hours, up to 48 hours, up to 96 hours, or up to 1 week after application. Suitable compositions for the drug-containing adhesive layer include any of the adhesive compositions described herein, such as any of those described in embodiments 1-18 applicable to tetrabenazine or deuterated tetrabenazine, or any of the specific compositions shown in the Examples section (e.g., Example 4A). In some embodiments, the drug-containing adhesive layer comprises an active ingredient dispersed in a non-reactive acrylate pressure-sensitive adhesive. The active ingredient can be present in an amount of about 1% to about 20% by weight, e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 10%, about 15%, about 20%, or any range therebetween, e.g., about 1% to about 15%, about 2% to about 15%, about 2% to about 10%, about 2% to about 7%, about 3% to about 15%, about 3% to about 10%, about 3% to about 7%, about 5% to about 15%, about 5% to about 10%, about 5% to about 7%, about 7% to about 15%, about 7% to about 10%, about 10% to about 20%, about 10% to about 15% by weight, etc. In some embodiments, the drug-containing adhesive layer comprises a substantially pure R,R-isomer of tetrabenazine as the sole active ingredient, hi some embodiments, the drug-containing adhesive layer comprises a substantially pure deuterated R,R-isomer of tetrabenazine as the sole active ingredient.Typically, the R,R-isomer of tetrabenazine or the deuterated R,R-isomer of tetrabenazine is present in the form of the free base. Suitable adhesives include any of the adhesives described herein, such as any of the pressure-sensitive adhesives described herein. In some embodiments, the adhesive can be a non-reactive acrylate pressure-sensitive adhesive described herein, such as Duro-Tak 87-900A, or as described in exemplary embodiments 2-7. The adhesive typically comprises an amount of about 50% to about 97% by weight, e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 97% by weight, or any range therebetween, e.g., about 50% to about 95%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, about 50% to about 60%, about 60% by weight. The active ingredient may be present in an amount of about 2% to about 7% by weight, and the non-reactive acrylate pressure-sensitive adhesive may be present in an amount of about 50% to about 97% by weight, about 60% to about 95% by weight, about 60% to about 90% by weight, about 60% to about 80% by weight, about 60% to about 70% by weight, about 70% to about 97% by weight, about 70% to about 95% by weight, about 70% to about 90% by weight, about 70% to about 80% by weight, about 80% to about 97% by weight, about 80% to about 95% by weight, or about 80% to about 90% by weight. In some specific embodiments, the active ingredient is present in an amount of about 2% to about 7% by weight, and the non-reactive acrylate pressure-sensitive adhesive is present in an amount of about 50% to about 97% by weight. The adhesive composition may also optionally include other ingredients, such as antioxidants, crystallization inhibitors, plasticizers, and / or permeation enhancers. In some embodiments, the drug-containing adhesive layer includes an antioxidant, such as a gallic acid antioxidant, e.g., propyl gallate. The amount of antioxidant is typically about 0% to about 1% by weight, e.g., about 0.001%, about 0.01%, about 0.1%, about 0.5%, about 1%, or any range therebetween, e.g., about 0.001% to about 0.5%, about 0.01% to about 0.5%, etc. In some embodiments, the drug-containing adhesive layer includes a crystallization inhibitor, e.g., a means for preventing the formation of drug crystals (e.g., crystals of the active ingredient of the drug-containing adhesive layer, such as R,R-tetrabenazine) after storage at ambient temperature for two weeks.In some embodiments, the adhesive composition comprises a polyvinylpyrrolidone polymer (e.g., Kollidon K30 or K90F (manufactured by BASF), Plasdone K20 / 32 or Plasdone K90 (manufactured by Ashland Chemical)), a crosslinked polyvinylpyrrolidone polymer (e.g., Kollidon CL), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone (Ashland)), a cellulosic polymer (e.g., hydroxylpropylmethylcellulose, ethylcellulose, hydroxypropylcellulose), a polycarboxylic acid polymer (e.g., Cabopol (manufactured by Lubrizol)), a polymethacrylate (e.g., Plastoid B, Eudragit E100, Eudragit L100-55), a cellulose-based polymer (e.g., hydroxy ... polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone (Ashland)), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone (Ashland)), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone In some embodiments, the drug-containing adhesive layer comprises a crystallization inhibitor selected from polymethacrylate (e.g., Plastoide B (a copolymer of butyl methacrylate and methyl methacrylate), Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam-based graft copolymers (PVAc-PVCap-PEG) (e.g., Soluplus (BASF)), and combinations thereof. The crystallization inhibitor is typically present in an amount of about 0 to about 40% by weight, e.g., about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 30% by weight, about 40% by weight, or any range therebetween, e.g., about 10% to about 40% by weight, about 10% to about 30% by weight, about 10% to about 20% by weight, 15% to about 40% by weight, about 15% to about 30% by weight, about 15% to about 20% by weight, 20% to about 40% by weight, about 20% to about 30% by weight, etc.In some embodiments, the drug-containing adhesive layer may also include a skin permeation enhancer, such as isopropyl myristate, as described herein. In some embodiments, the drug-containing adhesive layer may also not include a skin permeation enhancer, such as isopropyl myristate, as described herein. For example, in some embodiments, the drug-containing adhesive layer may also not include isopropyl myristate. The weight and thickness of the drug-containing adhesive layer may vary depending on various factors, such as the drug concentration and the desired dose and duration of administration. The drug-containing adhesive layer is typically designed for application (e.g., delivery of R,R-tetrabenazine or deuterated R,R-tetrabenazine) for a period selected from about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, and about 7 days. In some embodiments, the drug-containing adhesive layer has a coating weight of about 0.1 g / cm. 2 ~about 5g / cm 2 , for example, about 0.1 g / cm 2 ~Approx. 0.90g / cm 2 (For example, about 0.1 g / cm 2 ~about 0.5g / cm 2 In some embodiments, the active surface area is 5 cm 2 ~about 100cm 2 (Other suitable ranges are described herein.) In some embodiments, the drug-in-adhesive layer can have a thickness of about 1.5 mil to about 10 mil, such as about 1.5 mil to about 3.5 mil (e.g., about 2 mil to about 3.5 mil). In some embodiments, the transdermal delivery device can also be configured to have any of the in vitro flux properties described herein.

[0139] The hyperkinetic movement disorders listed in the methods according to any one of SE1 to SE8 include any of those described herein. Non-limiting examples of hyperkinetic movement disorders include Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tics, dyskinetic cerebral palsy / cerebral palsy, other dystonia and dyskinesia disorders, and combinations thereof. In some embodiments, the hyperkinetic movement disorder can be Huntington's disease, including chorea associated with Huntington's disease. In some embodiments, the hyperkinetic movement disorder can be Wilson's disease. In some embodiments, the hyperkinetic movement disorder can be Tourette's syndrome. In some embodiments, the hyperkinetic movement disorder can be restless legs syndrome. In some embodiments, the hyperkinetic movement disorder can be tardive dyskinesia. In some embodiments, the hyperkinetic movement disorder can be tics. In some embodiments, the hyperkinetic movement disorder can be dyskinetic cerebral palsy. In some embodiments, the hyperkinetic movement disorder is a dystonia or dyskinetic disorder.

[0140] The treatment method with any one of SE1 to SE8 is not limited to a particular type of subject. For example, the method herein can be administered to a subject regardless of the subject's feeding status. In some embodiments, the subject is a pediatric or adolescent patient (e.g., 6 to 18 years old). Also, in some embodiments, the method is not limited to a particular genotype of the subject. In some embodiments, the same or substantially the same dose of R,R-tetrabenazine or deuterated R,R-tetrabenazine can be administered to subjects characterized as PM, IM, or EM. In some embodiments, the subject is characterized as an EM. In some embodiments, the subject is characterized as a PM. In some embodiments, the subject is characterized as an IM. In some embodiments, the method does not require titration and / or genotype analysis, which is required when treating with either Xenazine® or Austedo™ tablets.

[0141] The dosing regimen for the treatment method using any one of SE1 to SE8 is not particularly limited, so long as the desired dose of R,R-tetrabenazine or deuterated R,R-tetrabenazine is delivered to the subject at a desired rate for a desired period of time, including any of those described herein. For example, in some embodiments, a transdermal delivery device is applied to the subject at a dosing regimen suitable for achieving the PK profile described herein. In some embodiments, the transdermal delivery device is applied to the subject once daily. In some embodiments, the transdermal delivery device is applied to the subject more than once a day, for example, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, or more than once a week. In some embodiments, for each application, the transdermal delivery device can be applied to the subject's skin to provide continuous or substantially continuous delivery of R,R-tetrabenazine to the subject for about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, or any range between the recited values, thereby providing continuous or substantially continuous delivery of R,R-tetrabenazine to the subject during the patch-on period. In some embodiments, there is no delay between two consecutive applications of the transdermal patch according to the administration frequency described herein. For example, in some embodiments, the transdermal delivery device is applied to the subject once daily, and each application of the transdermal delivery device can typically last (be adhered to the subject's skin) for about 24 hours before being replaced with another substantially identical transdermal delivery device. However, in some embodiments, there can be an overlap or delay between two consecutive applications.

[0142] (combination therapy) The methods herein can use tetrabenazine and / or deuterated tetrabenazine as the sole active ingredient(s). In other words, the methods herein can be used as monotherapy. However, in some embodiments, the methods herein can also be used in combination with one or more additional treatments. Examples of transdermal delivery methods, devices, and pharmaceutical compositions for combination therapy are provided below.

[0143] In some embodiments, the transdermal delivery device or pharmaceutical composition disclosed herein (e.g., the adhesive composition herein) may also be combined with or used in combination with other drugs useful for treating VMAT2-mediated disorders. Such other drugs can be administered simultaneously or sequentially with the transdermal delivery device or pharmaceutical composition disclosed herein (e.g., the adhesive composition herein) by a route and in an amount commonly used therefor. In some embodiments, such other drugs are included in the transdermal delivery device or pharmaceutical composition disclosed herein (e.g., the adhesive composition herein). However, in some embodiments, such other drugs are administered as a separate composition or otherwise independently from the transdermal delivery device or pharmaceutical composition disclosed herein (e.g., the adhesive composition herein).

[0144] In some embodiments, the transdermal delivery device or pharmaceutical composition disclosed herein (e.g., the adhesive composition herein) may be any of chlorpromazine, levomepromazine, promazine, acepromazine, triflupromazine, cyamemazine, chlorproethazine, dixyrazine, fluphenazine, perphenazine, prochlorperazine, thiopropazate, trifluoperazine, acetophenazine, thioproperazine, butaperazine, perazine, pericyazine, thioridazine, mesoridazine, pipotiazine, haloperidol, trifluperidol, melperone, moperone, pipamperone, bromperidol, benperidol, droperidol, fluanisone, oxypertine, It may be used in combination with one or more antipsychotic agents, including, but not limited to, molindone, sertindole, ziprasidone, flupenthixol, clopenthixol, chlorprothixol, chlorprothixene, thiothixene, zuclopenthixol, fluspirilene, pimozide, penfluridol, loxapine, clozapine, olanzapine, quetiapine, tetrabenazine, sulpiride, sultopride, tiapride, remoxipride, amisulpride, veralipride, levosulpiride, lithium, prothipendyl, risperidone, clotiapine, mosapramine, zotepine, pripiprazole, and paliperidone.

[0145] In some embodiments, the transdermal delivery devices or pharmaceutical compositions disclosed herein (e.g., the adhesive compositions herein) can be used in combination with one or more benzodiazepines ("anti-anxiety medications"), including, but not limited to, alprazolam, adinazolam, bromazepam, camazepam, clobazam, clonazepam, clotiazepam, cloxazolam, diazepam, ethyl loflazepate, estizolam, fludiazepam, flunitrazepam, halazepam, ketazolam, lorazepam, medazepam, dazolam, nitrazepam, nordazepam, oxazepam, potassium clorazepate, pinazepam, prazepam, tofisopam, triazolam, temazepam, and chlordiazepoxide.

[0146] In some embodiments, the transdermal delivery devices or pharmaceutical compositions disclosed herein (eg, the adhesive compositions herein) can be used in combination with olanzapine or pimozide.

[0147] In some embodiments, the transdermal delivery device or pharmaceutical composition disclosed herein (e.g., the adhesive composition herein) may be administered with or without any of the following agents: antiretroviral agents; CYP3A inhibitors; CYP3A inducers; protease inhibitors; adrenergic agonists; anticholinergics; mast cell stabilizers; xanthines; leukotriene antagonists; glucocorticoid treatments; local or general anesthetics; nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen; antibacterial agents, such as amoxicillin; cholesteryl ester transfer protein (CETP) inhibitors, such as anacetrapib; antifungals, such as isoconazole; sepsis treatments, such as drotrecogin-α; steroids, such as hydrocortisone; local or general anesthetics, such as ketamine; norepinephrine reuptake inhibitors (NRIs), such as atomoxetine; dopamine reuptake inhibitors (DARIs), such as methylphenidate; serotonin-norepinephrine reuptake inhibitors (SNRIs), such as milnacipran; sedatives, such as diazepam; norepinephrine-dopamine reuptake inhibitors (NDRIs), such as bupromethazine piones; serotonin-norepinephrine-dopamine-reuptake inhibitors (SNDRIs), e.g., venlafaxine; monoamine oxidase inhibitors, e.g., selegiline; hypothalamic phospholipids; endothelin-converting enzyme (ECE) inhibitors, e.g., phosphoramidon; opioids, e.g., tramadol; thromboxane receptor antagonists, e.g., ifetroban; potassium channel openers; thrombin inhibitors, e.g., hirudin; hypothalamic phospholipids; growth factor inhibitors, e.g., PDGF activity modulators; platelet-activating factor (PAF) antagonists; antiplatelet agents, such as GPIIb / IIIa blockers (e.g., abdoximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine, and CS-747), and aspirin; anticoagulants, such as warfarin; low molecular weight heparins, such as enoxaparin; factor VIIa inhibitors and factor Xa inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors; vasopeptidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat;HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (rosuvastatin, or atavastatin or visastatin); squalene synthase inhibitors; fibrates; bile acid sequestrants, such as Questran; niacin; antiatherosclerotic agents, such as ACAT inhibitors; MTP inhibitors calcium channel blockers, e.g., amlodipine besylate; potassium channel activators; alpha-muscarinic agents; beta-muscarinic agents, e.g., carvedilol and metoprolol; antiarrhythmic agents; diuretics, e.g., chlorothlazide, hydrochiorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide azide), polythiazides, benzothlazides, ethacrynic acid, triclinafen, chlorthalidone, furosenild, musolimine, bumetanide, triamterene, amiloride, and spironolactone; thrombolytic agents, such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); antidiabetic agents, such as biguanides (e.g., , metformin), glucosidase inhibitors (e.g., acarbose), insulin, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, e.g., spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors, e.g., PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, vardenafil); protein tyrosine kinase inhibitors; anti-inflammatory agents;Antiproliferative agents, such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil; chemotherapeutic agents; immunosuppressants; anticancer and cytotoxic agents (e.g., alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes); antimetabolites, such as antifolates, purine analogs, and pyridine analogs; antibiotics, such as anthracyclines, bleomycin, mitogens, and the like. enzymes such as L-asparaginase; farnesyl-protein transferase inhibitors; hormonal agents such as glucocorticoids (e.g., cortisone), estrogens / antiestrogens, androgens / antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; microtubule disruptors such as ecteinascidins; microtubule stabilizers such as They may be used in combination with other classes of compounds, including, but not limited to, paclitaxel, docetaxel, and epothilones A-F; plant-derived products such as vinca alkaloids, epipodophyllotoxins, and taxanes; and topoisomerase inhibitors; prenyl-protein transferase inhibitors; and cyclosporines; steroids such as prednisone and dexamethasone; cytotoxic drugs such as azathioprine and cyclophosphamide; TNF-α inhibitors such as tenidap; anti-TNF antibodies or soluble TNF receptors such as etanercept, rapamycin, and leflunomide; and cyclooxygenase-2 (COX-2) inhibitors such as celecoxib and rofecoxib; and various drugs such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes such as cisplatin, satraplatin, and carboplatin.

[0148] In some embodiments, the transdermal delivery devices or pharmaceutical compositions disclosed herein (e.g., the adhesive compositions herein) can be used in combination with dextromethorphan and / or cannabinoids, such as cannabidiol.

[0149] definition As used herein, the term "about" modifying a quantity in connection with the present invention refers to variations in the quantity that may occur, for example, through routine testing and handling; through inadvertent errors in such testing and handling; through differences in the manufacture, source, or purity of the components / materials used in the present invention; etc. As used herein, "about" a particular value is inclusive of the specific value, for example, about 10% includes 10%. Whether modified by the term "about," the claims include equivalents of the stated quantity. In one embodiment, the term "about" means within 20% of the reported numerical value.

[0150] As used herein, the "coating weight" of a drug layer refers to the weight of the drug layer (e.g., drug-containing adhesive layer or drug-containing reservoir layer) per unit area of ​​the active surface area of ​​the transdermal drug delivery system.

[0151] As used herein, the term "cumulative drug permeated" refers to the total amount of drug permeated per square centimeter during a given period of time. Unless otherwise clear from the context, "cumulative drug permeated" at a given time (e.g., 24 hours after administration) refers to the total amount of drug permeated per square centimeter from time 0 (i.e., time of administration) to the given time. Unless otherwise clear from the context, "cumulative drug permeated" refers to the arithmetic mean value measured and / or calculated according to the methods described herein. As used herein, the term "mean value" also refers to the arithmetic mean value, unless otherwise specified and consistent with common practice in the art.

[0152] As used herein, the term "flux" refers to the amount of drug permeating the skin per unit area per unit time. Unless otherwise clear from the context, "flux" refers to the arithmetic mean value measured and / or calculated according to the methods described herein. Typical units of flux are milligrams per square centimeter per hour.

[0153] The flux rates referred to in this patent application can refer to those measured by either in vivo or in vitro methods. One method for measuring flux is to place a transdermal delivery device or formulation on a known skin area of ​​a human volunteer and measure the amount of drug that can permeate across the skin within a certain time constraint. In some embodiments, when specifically referred to as measured by an in vitro method using human cadaver skin, the flux rate is measured according to the method described in Examples 3 or 6. While in vitro methods use human epidermal membranes obtained from cadavers, rather than using human volunteers to measure drug flux through the skin, it is generally accepted by those skilled in the art that the results of properly designed and executed in vitro tests can be used to extrapolate or predict the results of in vivo tests with reasonable reliability.

[0154] The terms "skin flux profile" and "flux profile" are used interchangeably herein.

[0155] As used herein, the terms "treat," "treating," "treatment," and the like refer to eliminating, reducing, or ameliorating a disease or condition and / or its associated symptoms. Although not excluded, treating a disease or condition does not require that the associated disease, condition, or symptoms be completely eliminated.

[0156] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent (e.g., tetrabenazine) sufficient to result in amelioration of one or more symptoms of a disorder or condition (e.g., Huntington's disease), or to prevent the onset or progression of the disorder or condition, or to cause regression or cure of the disorder or condition.

[0157] The term "subject" (alternatively referred to herein as "patient"), as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0158] As used herein, application or administration of a transdermal delivery device herein should be understood according to how such a transdermal delivery device is normally applied or administered to the skin of, for example, a human subject.

[0159] The term "chronic hyperkinetic movement disorder" refers to a disorder characterized by non-purposeful, repetitive, disorganized motor behaviors, variously referred to as "compulsive," "rhythmic," or "hyperkinetic." In humans, chronic hyperkinetic movement disorders can be psychogenic (e.g., tics), idiopathic (e.g., as in Tourette's syndrome and Parkinson's disease), genetic (e.g., as in chorea characteristic of Huntington's disease), infectious (e.g., as in Sydenham's chorea), or drug-induced, as in tardive dyskinesia. Unless otherwise specified, "chronic hyperkinetic movement disorder" refers to and includes all psychogenic, idiopathic, genetic, and drug-induced movement disorders.

[0160] The term "stereokinesis" refers to repetitive movements with slight variations that are seen repeatedly or less commonly as a complex series of movements.

[0161] The term "VMAT2" refers to vesicular monoamine transporter 2, an integral membrane protein that acts to transport monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from the cell cytosol into synaptic vesicles.

[0162] The term " VMAT2-mediated disorder " refers to the disorder characterized by abnormal VMAT2 activity.VMAT2-mediated disorder can be mediated completely or partially by regulating VMAT2.In particular, VMAT2-mediated disorder is the disorder in which the inhibition of VMAT2 has some effect on the underlying disorder, for example, the administration of VMAT2 inhibitor causes some improvement in at least some of the patients who are treated.

[0163] Exemplary Embodiments 1 to 30 The following describes certain exemplary embodiments (embodiments 1 to 30) of the present disclosure.

[0164] Embodiment 1. A composition comprising an active ingredient dispersed in a non-reactive acrylate pressure sensitive adhesive, the active ingredient is selected from tetrabenazine, deuterated tetrabenazine, or a combination thereof; The adhesive composition, wherein the non-reactive acrylate pressure sensitive adhesive is in an amount of about 50% to about 97% by weight.

[0165] Embodiment 2. The adhesive composition of embodiment 1, wherein the non-reactive acrylate pressure sensitive adhesive does not have functional groups that include reactive hydrogen moieties.

[0166] Embodiment 3. The adhesive composition of embodiment 1, wherein the non-reactive acrylate pressure sensitive adhesive does not have a functional group selected from epoxy, —OH, —COOH, and combinations thereof.

[0167] Embodiment 4. The adhesive composition of any one of embodiments 1-3, wherein the non-reactive acrylate pressure sensitive adhesive is a copolymer of alkyl acrylate.

[0168] Embodiment 5. The non-reactive acrylate pressure-sensitive adhesive is C2-C 18 Alkyl acrylate (preferably C4-C 10 4. The adhesive composition of any one of embodiments 1-3, wherein the copolymer is a copolymer of a branched or linear alkyl acrylate, methyl acrylate, and, optionally, one or more acrylamide monomers (e.g., tert octylacrylamide) that do not have a functional group selected from epoxy, —OH, —COOH, and combinations thereof.

[0169] Embodiment 6. The adhesive composition of any one of embodiments 1 to 3, wherein the non-reactive acrylate pressure-sensitive adhesive is a copolymer of hexyl ethyl acrylate (e.g., 2-ethylhexyl acrylate), methyl acrylate, and, optionally, one or more acrylamide monomers (e.g., tert-octylacrylamide) that do not have a functional group selected from epoxy, —OH, —COOH, and combinations thereof.

[0170] Embodiment 7. The adhesive composition of any one of Embodiments 1-6, wherein the non-reactive acrylate pressure sensitive adhesive is free or substantially free of vinyl acetate.

[0171] Embodiment 8. The adhesive composition of any one of embodiments 1 to 7, which does not contain a permeation enhancer.

[0172] Embodiment 9. The adhesive composition of any one of embodiments 1-7, wherein the adhesive composition does not include isopropyl myristate.

[0173] Embodiment 10. The adhesive composition of any one of embodiments 1-7, which does not include a permeation enhancer selected from fatty alcohols, fatty acids, fatty acid esters, and combinations thereof.

[0174] Embodiment 11. The adhesive composition of any one of embodiments 1 to 10, wherein the active ingredient is present in an amount of about 2% to about 7% by weight.

[0175] Embodiment 12. The adhesive composition of any one of embodiments 1 to 11, further comprising a gallic acid antioxidant.

[0176] Embodiment 13. The adhesive composition of any one of embodiments 1 to 11, further comprising propyl gallate, for example, in an amount of about 0.001% to about 0.5% by weight.

[0177] Embodiment 14. The adhesive composition of any one of embodiments 1-13, wherein the adhesive composition further comprises a crystallization inhibitor in an amount effective to prevent the formation of drug crystals after two weeks of ambient storage.

[0178] Embodiment 15. Polyvinylpyrrolidone polymers (e.g., Kollidon K30 or K90F (manufactured by BASF), Plasdone K20 / 32 or Plasdone K90 (manufactured by Ashland Chemical)), crosslinked polyvinylpyrrolidone polymers (e.g., Kollidon CL), polyvinylpyrrolidone copolymers (e.g., Plasdone S-630 Copovidone (Ashland)), cellulosic polymers (e.g., hydroxylpropylmethylcellulose, ethylcellulose, hydroxypropylcellulose), polycarboxylic acid polymers (e.g., Cabopol (manufactured by Lubrizol)), polymethacrylates (e.g., Plastoid B, Eudragit E100, Eudragit L100-55 14. The adhesive composition of any one of the preceding embodiments, further comprising a crystallization inhibitor selected from polyvinyl acetate, polyethylene glycol, polyvinyl acetate- and polyvinyl caprolactam-based graft copolymers (PVAc-PVCap-PEG) (e.g., manufactured by Evonik), polyethylene glycol, polyvinyl acetate- and polyvinyl caprolactam-based graft copolymers (PVAc-PVCap-PEG) (e.g., Soluplus (BASF)), and combinations thereof.

[0179] Embodiment 16. The adhesive composition of any one of embodiments 1 to 13, further comprising a crystallization inhibitor selected from polymethacrylate (e.g., Plastoid B (a copolymer of butyl methacrylate and methyl methacrylate), Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam-based graft copolymers (PVAc-PVCap-PEG) (e.g., Soluplus (BASF)), and combinations thereof.

[0180] Embodiment 17. The adhesive composition of any one of embodiments 1 to 16, wherein the only active ingredient is the substantially pure R,R-isomer of tetrabenazine.

[0181] Embodiment 18. The adhesive composition of any one of embodiments 1 to 17, which is capable of sustained adhesion to the skin of a user for about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days, or more.

[0182] Embodiment 19. A backing layer; The adhesive composition according to any one of embodiments 1 to 18; and a release liner.

[0183] Embodiment 20. The transdermal delivery device of embodiment 19, which is shelf stable.

[0184] Embodiment 21. About 0.01 mg / day / cm 2 ~About 5mg / day / cm 2 21. The transdermal delivery device of embodiment 19 or 20, wherein the transdermal delivery device provides the active ingredient to the intended user at a rate of about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more.

[0185] Embodiment 22. A method of administering tetrabenazine, deuterated tetrabenazine, or a combination thereof to a subject in need thereof, comprising applying to the skin of the subject an adhesive composition described in any one of embodiments 1-18 or a transdermal delivery device described in any one of embodiments 19-21.

[0186] Embodiment 23. The method of embodiment 22, wherein the subject (e.g., a human subject) has a hyperkinetic movement disorder (e.g., chronic hyperkinetic movement disorder).

[0187] Embodiment 24. The method of embodiment 23, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tics, and combinations thereof.

[0188] Embodiment 25. A method of inhibiting vesicular monoamine transporter isoform 2 (VMAT2) in a subject in need thereof, comprising applying to the skin of the subject an adhesive composition described in any one of embodiments 1-18 or a transdermal delivery device described in any one of embodiments 19-21.

[0189] Embodiment 26. A method of treating a vesicular monoamine transporter isoform 2 (VMAT2)-mediated disease or disorder in a subject in need thereof, comprising applying an adhesive composition according to any one of embodiments 1-18 or a transdermal delivery device according to any one of embodiments 19-21 to the skin of the subject.

[0190] Embodiment 27. A method of treating a hyperkinetic movement disorder in a subject in need thereof, comprising applying to the skin of the subject an adhesive composition described in any one of embodiments 1-18 or a transdermal delivery device described in any one of embodiments 19-21.

[0191] Embodiment 28. The method of embodiment 27, wherein the hyperkinetic movement disorder is chronic hyperkinetic movement disorder.

[0192] Embodiment 29. The method of embodiment 27 or 28, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, and / or tics.

[0193] Embodiment 30. A method of treating a hyperkinetic movement disorder in a subject in need thereof, comprising transdermally administering to the subject a therapeutically effective amount of tetrabenazine or deuterated tetrabenazine. [Example]

[0194] Example 1. Preparation of tetrabenazine transdermal patch This example shows one procedure for preparing a tetrabenazine adhesive patch. Tetrabenazine base is generally commercially available in high purity (e.g., 99%) from Octagon Chemical Ltd, Hangzhou, China, via the Internet, for example, on the Alibaba website.

[0195] In this example, tetrabenazine base was thoroughly mixed into the adhesive Durotak 87-2287 (manufactured by Henkel Adhesives) until the mixture was homogeneous. The adhesive mixture was then dispensed onto a release liner using a "drawdown knife" and forced dry using a typical hair dryer for 1.5 minutes before laminating to a backing film.

[0196] The adhesive mixture can contain different concentrations of tetrabenazine. In this example, four concentrations were used: 1) a 2.5% formulation prepared by mixing 2.5% tetrabenazine with 97.5% Durotak 87-2287; 2) a 5% formulation prepared by mixing 5% tetrabenazine with 95% Durotak 87-2287; 3) a 10% formulation prepared by mixing 10% tetrabenazine with 90% Durotak 87-2287; and 4) a 15% formulation prepared by mixing 15% tetrabenazine with 85% Durotak 87-2287. All percentages of tetrabenazine and Durotak refer to weight percentages based on the final weight of the respective formulation.

[0197] Example 2. Tetrabenazine transdermal patch containing two adhesives Following the same procedure as in Example 1, tetrabenazine transdermal patches were also prepared by mixing two different adhesives in different ratios, keeping the concentration of tetrabenazine at 10% by weight.

[0198] The two adhesives used in this example were a silicone polymer (BIO-7-4202 from Dow Corning Co.) and an acrylate copolymer (Durotak 87-2287). Four different ratios were used in this example: 1) 5 / 95 (Durotak 87-2287 / BIO-7-4202); 2) 10 / 90 (Durotak 87-2287 / BIO-7-4202); 3) 25 / 75 (Durotak 87-2287 / BIO-7-4202); and 4) 50 / 50 (Durotak 87-2287 / BIO-7-4202).

[0199] Example 3. Transdermal flux test The transdermal flux of tetrabenazine from the patch was tested using Franz diffusion cell methodology using human cadaver epidermis obtained from the Health Science Tissue Bank in Phoenix, AZ.

[0200] The transdermal flux of tetrabenazine through human cadaver epidermis was analyzed using the following HPLC method.

[0201] Mobile phase: 55 / 45 acetonitrile / water - pH 6.5 adjusted with 0.05% triethylamine HPLC column: Pheneomenex Kinetex C18, 150 x 4.6 mm, 5 μm Wavelength: 230nm, flow rate: 1.2mL / min

[0202] The patches of Examples 1 and 2 were tested and the transdermal flux results are shown in Figures 1 and 2, respectively.

[0203] As shown in Figure 1, the highest transdermal flux observed for the patch of Example 1 is the adhesive matrix with a 10% tetrabenazine concentration.

[0204] As shown in Figure 2, varying the ratio of silicone polymer to acrylate copolymer does not significantly change the flux properties. However, when compared to the results shown in Figure 1, the flux observed for the patches prepared according to Example 2 is significantly lower than the flux from the 10% tetrabenazine concentration patches prepared in Example 1.

[0205] Therefore, it may be possible to slow the flux rate of tetrabenazine by adding a silicone adhesive to an acrylate adhesive (eg, Durotak 87-2877).

[0206] Example 4A: Preparation of Tetrabenazine in a Non-Functionalized Adhesive Batch Composition [Table 2]

[0207] Plastoid B is a copolymer of butyl methacrylate and methyl methacrylate manufactured by Evonik.

[0208] Preparation procedure The following procedure was followed for preparing the patches in Example 4A: In a 50-mL beaker, dissolve propyl gallate in ethanol by manual mixing. In a separate 250-mL beaker, add ethyl acetate and mix at low speed with a mechanical stirrer. Add TBZ, then add Plastoid B powder while mixing. Once Plastoid B is dissolved, add a weighed amount of DuroTak 87-900A while mixing. Mix at medium speed for 30 minutes or until uniform. Cast the solution onto a 3M backing film, Scotchpak 9723 film, using a 10-mil coating applicator. Allow the casting to air dry for 10 minutes and oven dry at 85°C for 10 minutes. Cover the dried adhesive with a segmented Loparex release liner. Die-cut the coated coating into 60 cm2 patches using a steel die.

[0209] The patch has good skin adhesion and shear strength and remains tightly attached to the skin for more than 48 hours.

[0210] The patches were die cut and mounted in Franz cells for skin permeation testing, the results of which are reported in Example 6.

[0211] No crystals were observed on the patch for 4 weeks at 40°C, indicating good physical stability of the transdermal patch formulation. No degradation was observed on the patch for 4 weeks at 40°C, indicating good chemical stability of the transdermal patch formulation.

[0212] Examples 4B and 4C. Preparation of tetrabenazine in a non-functional adhesive Following the same procedure as set forth in Example 4A, two similar formulations were prepared, which are shown in the table below (dry composition). [Table 3]

[0213] The patches prepared in Examples 4B and 4C were also tested for skin permeation studies.

[0214] Example 5. Stability study of tetrabenazine patch formulations Various patch formulations of tetrabenazine were prepared and tested for chemical and / or physical stability. The inventors found that patch formulations prepared with DuroTak 87-2287 or Duro-Tak 87-2677 adhesives, which contain functional groups, exhibited a yellowish color after 4 weeks of ambient storage at 40°C, indicating instability of the active ingredient due to oxidation and / or other degradation. DuroTak 87-2287 contains -OH and epoxy hydroxyl functional groups, while DuroTak 87-2677 contains -COOH acid functional groups. In contrast, patch formulations prepared using DuroTak 87-900A, which does not contain functional groups, were found to be stable for 4 weeks at 40°C. See Example 4A.

[0215] The inventors also found that patch formulations prepared without propyl gallate as an antioxidant resulted in degradation of the active ingredient. Without the use of an antioxidant, drug-related impurities such as TBZ 01, TBZ 02, and TBZ 04 were formed and detected by HPLC. Antioxidants that can prevent oxidation and / or other degradation of TBZ include propyl gallate, citric acid, ascorbic acid, and vitamin E (tocopheryl acetate).

[0216] Tetrabenazine and related compounds were analyzed using isocratic reversed-phase HPLC with UV detection. Column: Gemini C18, 4.6 x 150 mm, 5 μm particle size, or equivalent. Column temperature: 45℃ Injection volume: 10μL Detection wavelength: 210 nm Mobile phase: Mobile phase A / Mobile phase B ratio = 44:56 Mobile phase A: 10mM K2HPO4 in H2O Mobile phase B: acetonitrile Flow rate: 1.2mL / min Run Time: 12 minutes Retention time: Approximately 5.5 minutes for tetrabenazine The retention time of impurity 1 (TBZ01) is about 1.95 min; impurity 2 (TBZ02) is about 3.10 min; impurity 4 (TBZ04) is about 5.29 min.

[0217] The inventors further found that without the use of Soluplus or Plastoid B as a crystallization inhibitor / solubilizer, see e.g., Example 4B, crystals appear on the patch after two weeks of ambient storage. The formation of crystals retards skin penetration of the patch formulation.

[0218] Therefore, preferred compositions should contain a crystallization inhibitor so that the active ingredient remains in the adhesive matrix in amorphous form during storage at room temperature for at least 12 months. Preferred crystallization inhibitors are: PVP (polyvinylpyrrolidone) polymers: Kollidon K30 or K90F (manufactured by BASF), Plasdone K20 / 32 or Plasdone K90 (manufactured by Ashland Chemical). Cross-linked PVP polymer: Kollidon CL PVP copolymer (copovidone): Plasdone S-630 Copovidone (Asland) Cellulosic polymers: hydroxylpropyl methylcellulose (HPMC / Methocel), ethylcellulose (Ethocel by Dow Chemica), e.g., hydroxylpropyl cellulose (HPC, Klucel by Ashland, etc.) Polycarboxylic acid polymer: Carbopol (manufactured by Lubrizol) Polymethacrylates: Plastoid B, Eudragit E100, Eudragit L100-55 (manufactured by Evonik) Soluplus (BASF): Contains polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG).

[0219] Example 6. Skin Permeation Studies The patch formulations prepared in Examples 4A-4C were used in skin permeation studies using the following protocol: Franz Cell Assembly - Logan Instruments (6-cell unit) Each cell has a volume of 12 mL and an orifice with a diameter of 1.5 cm. The receptor medium was phosphate buffer solution (PBS) pH 7.4. The cell temperature was maintained at 37°C. Sampling method: 1.5 mL was taken for the HPLC assay, the cell was emptied, and replaced with fresh medium. Sampling times: 2, 4, 8, 12, 24, and 48 hours Cadaver skin was used and obtained from the New York Fire Fighters Skin Bank. · Media assay method: HPLC.

[0220] The results of the study are presented in the table and plot below. The values ​​presented are the cumulative amount of TBZ permeated per cm (i.e., μg / cm). See also Figure 3. [Table 4]

[0221] Example 7. In vivo pharmacokinetic studies The objective of this study was to evaluate the comparative bioavailability of the 8 mg / 96 hour test TBZ patch (see formulation in Example 4A) when applied for a single 96 hour application period versus the reference product, a 12.5 mg three times daily dose of tetrabenazine tablets (Lupin) (total dose 150 mg) administered under fasting conditions on days 1 through 4 to healthy adult male subjects under fasting conditions.

[0222] This was an open-label, randomized, two-treatment, two-period, two-sequence crossover study under fasting conditions comparing the test product with a reference product. The study was conducted on 16 healthy, tobacco- and nicotine-free, adult male subjects. During one study period, one TBZ patch, 8 mg / 96 h, was applied to the lateral left upper arm of the subject and held in place for 96 hours following at least a 10-hour overnight fast. During the other study period, one 12.5 mg tetrabenazine tablet (Lupin) was administered every 8 hours on days 1 through 4, for a total daily dose of 37.5 mg over 4 days, or 12 doses totaling 150 mg. For treatment B (reference), subjects fasted overnight for at least 10 hours only before the 0-hour dose (day 1). Subsequent doses were administered after at least a 2-hour fast. The order of administration followed a two-sequence randomization schedule. Subjects were confined to the clinical facility for at least 10 hours prior to dosing (hour 0) in each study period, from hour 0 to at least 120 hours after dosing on Day 1. The dosing interval (hour 0) was 14 days.

[0223] Blood samples were collected before and over 120-hour intervals after study drug administration (time 0) in each study period. Samples were analyzed by the bioanalytical laboratory for subjects who received at least one of the study products (treatments A or B).

[0224] Plasma concentrations of TBZ (RR and SS isomers) and its active metabolites (RRR, SSS, SRR, and RSS) were measured by a fully validated analytical procedure. Statistical analysis using analysis of variance was performed to evaluate the bioavailability of the test formulations compared to that of the reference product based on the plasma concentrations of these six analytes.

[0225] Research data were collected in source documents.

[0226] The study was designed based on the known pharmacokinetics of tetrabenazine tablets and its metabolites, the recommendations of the FDA draft guidance for tetrabenazine tablets, and generally accepted standards for conducting bioavailability / bioequivalence studies under fasting conditions.

[0227] A washout period of at least 10 days was chosen for this study to minimize the possibility of carryover effects.

[0228] Treatment A The active pharmaceutical ingredient is the RR stereoisomer of tetrabenazine. All patches (see formulation shown in Example 4A) were applied to the lateral left upper arm at least 2 inches below the shoulder and above the elbow. Patches were applied to the subject's lateral left upper arm and kept in place for 96 hours following an overnight fast of at least 10 hours.

[0229] Treatment B The active pharmaceutical ingredient is the racemic form of the two stereoisomers (RR and SS) of tetrabenazine. Doses were administered every 8 hours on days 1 through 4. Subjects fasted overnight for at least 10 hours only prior to the 0-hour dose. Subsequent doses were administered after at least 2 hours of fasting. The total daily dose of the reference product was equivalent to 37.5 mg given over three 8-hour dosing intervals, for a total dose of 150 mg given over 12 doses over 4 days.

[0230] The lower total dose of TBZ administered via the test patch (8 mg) compared with the reference tablet (150 mg) was based on the premise that absorption of the biologically active RR isomer of TBZ from the active pharmaceutical ingredient would be more extensive from the patch as a result of reduced metabolism of TBZ to HTBZ due to bypass of first-pass metabolism with topical administration. The active pharmaceutical ingredient in tetrabenazine tablets is in racemic form (RR, SS), whereas the active pharmaceutical ingredient in the test TBZ patch is the RR isomer.

[0231] Adverse events were collected and tabulated. No formal statistical analysis was performed.

[0232] For Treatment A (Test), 26 blood samples were collected from each subject during each period of the study: prior to the start of dosing within 60 minutes of patch application (0 hours), and at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 16.0, 24.0, 32.0, 40.0, 48.0, 56.0, 64.0, 72.0, 80.0, 88.0, 96.0 (within 5 minutes of patch removal), 97.0, 98.0, 100.0, 104.0, 108.0, 114.0, and 120.0 hours after dosing. All times are relative to the dose (time of patch application). For Treatment B (reference), during each period of the study: 0.17, 0.33, 0.5, 0.75, 1.0, 1.33, 1.67, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0, 20.0, 21.0, 22.0, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0 † , 8.33, 8.67, 9.0, 9.5, 10.0, 12.0, 16.0 † , 16.5, 17.0, 18.0, 20.0, 24.0 † , 25.0, 26.0, 28.0, 32.0 † , 34.0, 36.0, 40.0 † , 44.0, 48.0 † , 52.0, 56.0 † , 60.0, 64.0 † , 68.0, 72.0 † , 76.0, 80.0 † , 84.0, 88.0 † 51 blood samples were collected from each subject at 92.0, 96.0, 100.0, 104.0, 112.0, and 120.0 hours. All times are relative to the dosing time (Day 1, 0 hours). † If necessary, collect samples immediately prior to each dose with an allowable deviation of -5 min to accommodate dosing activity.

[0233] Plasma concentrations of TBZ (RR and SS isomers) and its HTBZ metabolites (RRR, SSS, SRR, and RSS) were measured by a fully validated analytical procedure in subjects receiving at least one of the study products (Treatment A or B). The concentration of total TBZ was expressed in molar units as the sum of the molar concentrations of TBZ + RRR + SSS + SRR + RSS.

[0234] The following PK parameters: AUC 0-t , AUC 0-96 , AUC 0-∞ , C max , T max , K. el , T 1 / 2 was evaluated for each of six analytes (two TBZ isomers [RR and SS] and four HTBZ metabolites [RRR, SSS, SRR, and RSS]), the TBZ combination (RR+SS), and total TBZ. Additionally, metabolic ratios (AUC 0-t(met) / AUC 0-t(TBZ) ) and the apparent clearance (CL / F) of TBZ were evaluated.

[0235] Analysis of variance was performed using the General Linear Model (GLM) procedure in SAS® (Version 9.4) for each of the six analytes, the TBZ combination (RR+SS), and total TBZ, with ln-transformed C max , AUC 0-96 and AUC 0-∞ The statistical model included main effects of sequence, within-subject sequence, treatment, and period.

[0236] AUC for comparing test formulations with reference products 0-96 , AUC 0-∞ and C max Confidence intervals (90%) for the geometric mean ratios (obtained from log-transformed data) were constructed to test two one-sided hypotheses at the α=0.05 level of significance. Similar analyses were performed for additional PK parameters: metabolic ratios of the four metabolites and CL / F of TBZ. Descriptive statistics are reported for all PK parameters by treatment.

[0237] Summary of Results: Mean plasma concentration versus time plots (linear) are shown below in Figure 4A for TBZ (combined RR and SS isomers), in Figure 4B for RRR HTBZ, in Figure 4C for SRR HTBZ, and in Figure 4D for total TBZ. Arithmetic means of pharmacokinetic parameters (untransformed) are provided in Table 1A for Treatment A and Table 1B for Treatment B.

[0238] The geometric means, ratios of geometric means, and their associated 90% confidence intervals and within-subject CV (ISCV%) values ​​based on ANOVA (ln-transformed) are shown in Table 2A for TBZ (combined RR and SS isomers), Table 2B for RRR HTBZ, Table 2C for SRR HTBZ, and Table 2D for total TBZ. [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10]

[0239] After applying the patch to Treatment A, the TBZ concentration of the RR isomer increased to T max The mean peak exposure (C maxThe concentration of TBZ increased to 570 pg / mL at 96 hours and then slowly decreased until the patch was removed, after which the concentration declined with a mean terminal half-life of 8.5 hours. All concentrations of the SS isomers of TBZ were BLQ. Two of the four HTBZ metabolites were detected (the RRR and SRR diastereomers), with the peak of the SRR isomer (C max ) and total (AUC 0-t ) plasma exposure was approximately 20-fold higher.

[0240] After 96 hours of three-times-daily tablet administration in Treatment B, most RR and SS concentrations in all subjects were at the BLQ. For RR concentrations above the LLOQ of 48.050 pg / mL, the mean C max was 138 pg / mL, and T max The median AUC and C were 16.5 hours after the first dose or 0.5 hours after the third dose on day 1. All four active HTBZ metabolites were detected, with the SSS isomer having the highest mean AUC and C max The AUCs for RR, SS, and RR+SS analytes were ranked in order of predominance based on the values ​​of the analytes and were ranked in order of SRR, RSS, and RRR. 0-∞(TBZ) (TBZ) data are not available, so the metabolic AUC ratio (AUC 0-∞(met) / AUC 0-∞(TBZ) ) was not calculated, but instead AUC 0-t(met) / AUC 0-t(TBZ) ) data was used to estimate the

[0241] Comparing treatments A (patch) and B (tablet), the extent of TBZ metabolism to HTBZ was approximately 500-fold lower for RRR and SRR with a least squares geometric mean (LSGM) AUC 0-t(met) / AUC 0-t(TBZ) ) for Treatment A. Similarly, the RRR and SRR AUC for Treatment A 0-96 and C max The values ​​(unadjusted for dose differences) are 8-10 times lower than those for Treatment B, as indicated by LSGM A / B ratios of approximately 10-13% for the RRR and SRR parameters. 0-96 and C maxThe LSGM of Treatment B was approximately 38-fold and 3.4-fold higher than that of Treatment B, respectively. 0-96 , AUC 0-∞ and C max The LSGM A / B ratio is low at 3-4%.

[0242] Conclusions: The 8 mg / 96-hour TBZ patch applied in a single 96-hour application provides higher concentrations of RR-tetrabenazine at lower doses and with a lesser extent of metabolism to the active HTBZ isomer without interconversion to the SS-isomer compared with three doses of TBZ tablets administered under fasting conditions on days 1 through 4 (total dose of 150 mg) in healthy male subjects.

[0243] The patch (Treatment A [Test]) was not removed during the study due to irritation. There were no serious adverse events reported during the study, and no subjects discontinued due to adverse events.

[0244] It should be recognized that the "Detailed Description of the Invention" section, and not the "Summary of the Invention" and "Abstract" sections, are intended to be used for interpreting the claims. The "Summary of the Invention" and "Abstract" sections may describe one or more (but not all) exemplary embodiments of the invention contemplated by the inventor(s), and therefore are not intended to limit the scope of the invention and the appended claims in any way.

[0245] The present invention has been described above with the aid of functional components that illustrate the performance of certain functions thereof and the relationships between them. The boundaries of these functional components have been arbitrarily defined herein for the convenience of the description. Alternative boundaries may be defined so long as the specified functions and the relationships between them are appropriately performed.

[0246] For aspects of the invention described as genus, all individual species are separate aspects of the invention considered individually. When aspects of the invention are described as "comprising" an element, embodiments "consisting of" or "consisting essentially of" that element are also contemplated.

[0247] The above specific descriptions of specific embodiments fully illustrate the general nature of the present invention, so that others, applying knowledge within the skill of those skilled in the art, can easily modify and / or adapt such specific embodiments for various uses without undue experimentation and without departing from the general concept of the present invention. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. The words and terms used herein are for the purpose of description and not limitation, and the words and terms used herein would be understood by one of ordinary skill in the art in light of the teaching and guidance provided herein.

[0248] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0249] Any of the various aspects, embodiments, and options described herein can be combined in any and all variations.

[0250] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, and patent application was specifically and individually indicated to be incorporated by reference. In the event that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition of the term in this document shall control.

Claims

1. 1. Use of R,R-tetrabenazine in the manufacture of a medicament for a method of treating a hyperkinetic movement disorder in a subject in need thereof, said method comprising administering to said subject said medicament comprising an active ingredient which comprises R,R-tetrabenazine, said administration bypassing first pass metabolism and providing sustained delivery of 0.1 mg / day to 20 mg / day of R,R-tetrabenazine to said subject.

2. 2. The use of claim 1, wherein said administering comprises applying said agent to the skin of said subject to transdermally deliver 0.1 mg / day to 20 mg / day of R,R-tetrabenazine to said subject.

3. 3. The use according to claim 1 or 2, wherein the medicament comprises an adhesive composition comprising the active ingredient dispersed in a pressure sensitive adhesive.

4. 4. The use according to claim 3, wherein the adhesive composition comprises the active ingredient dispersed in a non-reactive acrylate pressure sensitive adhesive, the active ingredient being in an amount of 1% to 20% by weight and the non-reactive acrylate pressure sensitive adhesive being in an amount of 50% to 97% by weight.

5. 5. The use according to claim 3 or 4, wherein the adhesive composition further comprises a gallic acid antioxidant.

6. The use described in claim 5, wherein the gallic acid antioxidant is propyl gallate.

7. The use according to any one of claims 3 to 6, wherein the adhesive composition further comprises a crystallization inhibitor in an amount effective to prevent the formation of drug crystals after two weeks of ambient storage.

8. 8. The use according to any one of claims 3 to 7, wherein the adhesive composition further comprises a crystallization inhibitor selected from polyvinylpyrrolidone polymers, crosslinked polyvinylpyrrolidone polymers, polyvinylpyrrolidone copolymers, cellulose-based polymers, polycarboxylic acid polymers, polymethacrylates, polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers (PVAc-PVCap-PEG), and combinations thereof.

9. The use according to any one of claims 1 to 8, wherein the only active ingredient in the medicament is the pure R,R-isomer of tetrabenazine.

10. 10. The use according to any one of claims 1 to 9, wherein the hyperkinetic movement disorder is selected from Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tics, dyskinetic cerebral palsy / cerebral palsy, other dystonia and dyskinesia disorders, and combinations thereof.

11. The use according to any one of claims 1 to 10, wherein said administration is carried out regardless of the feeding state of the subject.

12. The use according to any one of claims 1 to 11, wherein the subject is an extensive metabolizer.

13. 1. Use of R,R-tetrabenazine in the manufacture of a medicament for a method of treating a hyperkinetic movement disorder in a subject in need thereof, the method comprising administering to the subject the medicament comprising an active ingredient comprising R,R-tetrabenazine, wherein said administration provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ, and wherein the ratio of the maximum plasma concentration of R,R-tetrabenazine to the combined maximum plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ, i.e. the C of R,R-tetrabenazine, ｍａｘ / (R,R,R-HTBZ C ｍａｘ +S, R, R-HTBZ C ｍａｘ) is in the range of 1:1 to 1:5, or the ratio of the steady-state plasma concentration of R,R-tetrabenazine to the combined steady-state plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ, i.e., the C ｓｓ / (R,R,R-HTBZ C ｓｓ +S, R, R-HTBZ C ｓｓ ) ranged from 1:1 to 1:5, the ratio of maximum or steady-state plasma concentrations of R,R,R-HTBZ to S,R,R-HTBZ ranged from 1:5 to 1:30, and the maximum plasma concentrations (C ｍａｘ ) or steady-state plasma concentration (C ｓｓ ) was 17-40:3-10:50-80, and the AUC of SRR-HTBZ was ０－∞ AUC of R,R-tetrabenazine ０－∞ and / or the AUC of RRR-HTBZ is 1 to 15. ０－∞ AUC of R,R-tetrabenazine ０－∞ is 0.1 to 0.75, and said administration provides no detectable S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ.

14. 1. Use of R,R-tetrabenazine in the manufacture of a medicament for a method of treating a hyperkinetic movement disorder in a subject in need thereof, said medicament being in the form of a transdermal delivery device, said method comprising applying to said subject said transdermal delivery device comprising a drug-containing adhesive layer, said drug-containing adhesive layer comprising: (1) an active ingredient comprising R,R-tetrabenazine; (2) a non-reactive acrylate pressure sensitive adhesive; (3) a crystallization inhibitor; and (4) an antioxidant. (A) the transdermal delivery device provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ, and the ratio of the maximum plasma concentration of R,R-tetrabenazine to the combined maximum plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ, i.e., the C of R,R-tetrabenazine ｍａｘ / (R,R,R-HTBZ C ｍａｘ +S, R, R-HTBZ C ｍａｘ ) is in the range of 1:1 to 1:5, or the ratio of the steady-state plasma concentration of R,R-tetrabenazine to the combined steady-state plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ, i.e., the C ｓｓ / (R,R,R-HTBZ C ｓｓ +S, R, R-HTBZ C ｓｓ ) ranged from 1:1 to 1:5, the ratio of maximum or steady-state plasma concentrations of R,R,R-HTBZ to S,R,R-HTBZ ranged from 1:5 to 1:30, the ratio of maximum or steady-state plasma concentrations of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ was 17-40:3 to 10:50-80, and the AUC of SRR-HTBZ was 10:1 to 10:

20. ０－∞ AUC of R,R-tetrabenazine ０－∞ and / or the AUC of RRR-HTBZ is 1 to 15. ０－∞ AUC of R,R-tetrabenazine ０－∞ is between 0.1 and 0.75, and administration does not provide detectable S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ; (B) applying the transdermal delivery device to transdermally deliver 0.1 mg / day to 20 mg / day of R,R-tetrabenazine to the subject; (C) applying the transdermal delivery device to the subject to achieve a therapeutically effective plasma concentration of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ for at least six hours; or (D) applying the transdermal delivery device to the subject to achieve a constant steady-state plasma concentration of R,R-tetrabenazine of greater than 150 pg / ml for a sustained period of at least 6 hours.

15. 1. Use of deuterated R,R-tetrabenazine in the manufacture of a medicament for a method of treating a hyperkinetic movement disorder in a subject in need thereof, said medicament being in the form of a transdermal delivery device, said method comprising applying to said subject said transdermal delivery device comprising a drug-containing drug-containing adhesive layer, said drug-containing adhesive layer comprising: (1) an active ingredient comprising deuterated R,R-tetrabenazine; (2) a non-reactive acrylate pressure sensitive adhesive; (3) a crystallization inhibitor; and (4) an antioxidant. (A) the transdermal delivery device provides therapeutically effective plasma concentrations of deuterated R,R-tetrabenazine, a dihydrotetrabenazine metabolite of deuterated R,R-tetrabenazine, deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ, wherein the ratio of the maximum plasma concentration of deuterated R,R-tetrabenazine to the combined maximum plasma concentration of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ is in the range of 1:1 to 1:7.5, or the ratio of the steady state plasma concentration of tetrabenazine to the combined steady state plasma concentrations of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ is in the range of 1:1 to 1:7.5, the ratio of the maximum plasma concentration or steady state plasma concentration of deuterated R,R,R-HTBZ to deuterated S,R,R-HTBZ is in the range of 1:5 to 1:30, and administration does not provide detectable deuterated S,S-tetrabenazine, deuterated R,S,S-HTBZ, or deuterated S,S,S-HTBZ; (B) applying the transdermal delivery device to transdermally deliver 0.1 mg / day to 20 mg / day of deuterated R,R-tetrabenazine to the subject; (C) applying the transdermal delivery device to the subject to achieve therapeutically effective plasma concentrations of deuterated R,R-tetrabenazine, its dihydrotetrabenazine metabolites, deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ, for at least six hours; or (D) applying the transdermal delivery device to the subject to achieve a constant steady-state plasma concentration of deuterated R,R-tetrabenazine of greater than 150 pg / ml for a sustained period of at least 6 hours.

16. 16. The use according to any one of claims 13 to 15, wherein the hyperkinetic movement disorder is selected from Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tics, dyskinetic cerebral palsy / cerebral palsy, other dystonia and dyskinesia disorders, and combinations thereof.

17. 17. The use of any one of claims 13 to 16, wherein: (i) the administration is performed regardless of the feeding state of the subject; (ii) the subject is an extensive metabolizer; and / or (iii) the subject is a child or adolescent patient.

18. 1. A method for identifying a pharmaceutical composition for treating a hyperkinetic movement disorder, comprising administering to a subject a test pharmaceutical composition that bypasses first-pass metabolism and delivers R,R-tetrabenazine to the subject in a sustained manner; (A) identifying a pharmaceutical composition that provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ, wherein the ratio of the maximum plasma concentration of R,R-tetrabenazine to the combined maximum plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ is in the range of 1:1 to 1:5, or the steady state plasma concentration of R,R-tetrabenazine to R, the ratio of combined steady state plasma concentrations of R,R-HTBZ and S,R,R-HTBZ is in the range of 1:1 to 1:5, the ratio of maximum or steady state plasma concentrations of R,R,R-HTBZ to S,R,R-HTBZ is in the range of 1:5 to 1:30, and administration of the identified pharmaceutical composition provides no detectable S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ; (B) identifying a pharmaceutical composition that, when administered to provide a dose of 2 mg / day for 4 days, provides a pharmacokinetic profile in said subject characterized by: a) Mean T of R,R-tetrabenazine from 10 hours to 24 hours ｍａｘ ; b) Mean T of R,R-tetrabenazine ｍａｘ The mean T of slower R, R, R-HTBZ ｍａｘ and the average T of S, R, and R-HTBZ ｍａｘ ; c) Mean C of R,R-tetrabenazine between 300 pg / ml and 700 pg / ml ｍａｘ ; d) Mean C of R,R,R-HTBZ between 60 pg / ml and 200 pg / ml ｍａｘ ; e) Mean C of S,R,R-HTBZ between 1000 pg / ml and 3000 pg / ml ｍａｘ ; f) Mean AUC of R,R-tetrabenazine from 20 ng*hr / ml to 50 ng*hr / ml ０－９６ ; g) Mean AUC of R,R,R-HTBZ from 4 ng*hr / ml to 12 ng*hr / ml ０－９６ and / or h) Mean AUC of S,R,R-HTBZ from 70 ng*hr / ml to 200 ng*hr / ml ０－９６ ; (C) identifying a pharmaceutical composition that when administered to provide a dose of 4-6 mg / day for at least 1 day, 2 days, 3 days, 4 days, or 1 week, provides a pharmacokinetic profile in said subject characterized by: a) Mean T of R,R-tetrabenazine from 10 hours to 24 hours ｍａｘ ; b) Mean T of R,R-tetrabenazine ｍａｘ The mean T of slower R, R, R-HTBZ ｍａｘ and the average T of S, R, and R-HTBZ ｍａｘ ; c) Mean C of R,R-tetrabenazine between 600 pg / ml and 2100 pg / ml ｍａｘ ; d) Mean C of R,R,R-HTBZ between 120 pg / ml and 600 pg / ml ｍａｘ ; e) Mean C of S,R,R-HTBZ between 2000 pg / ml and 9000 pg / ml ｍａｘ ; f) Mean AUC of R,R-tetrabenazine from 40 ng*hr / ml to 150 ng*hr / ml ０－９６ ; g) Mean AUC of R,R,R-HTBZ from 8 ng*hr / ml to 36 ng*hr / ml ０－９６ and / or h) Mean AUC of S,R,R-HTBZ from 140 ng*hr / ml to 600 ng*hr / ml ０－９６ ; (D) identifying a pharmaceutical composition that, when administered to provide a dose of 1-10 mg / day for at least one day, provides a pharmacokinetic profile in said subject characterized by: a) Mean T of R,R-tetrabenazine from 10 hours to 24 hours ｍａｘ ; b) Mean T of R,R-tetrabenazine ｍａｘ The mean T of slower R, R, R-HTBZ ｍａｘ and the average T of S, R, and R-HTBZ ｍａｘ ; c) Mean C of R,R-tetrabenazine from 150 pg / ml to 3500 pg / ml ｍａｘ ; d) Mean C of R,R,R-HTBZ between 30 pg / ml and 1000 pg / ml ｍａｘ ; e) Mean C of S,R,R-HTBZ from 500 pg / ml to 15 ng / ml ｍａｘ ; f) Mean AUC of R,R-tetrabenazine from 10 ng*hr / ml to 250 ng*hr / ml ０－９６ ; g) Mean AUC of R,R,R-HTBZ from 2 ng*hr / ml to 60 ng*hr / ml ０－９６ and / or h) Mean AUC of S,R,R-HTBZ from 35 ng*hr / ml to 1000 ng*hr / ml ０－９６ ; or (E) identifying a pharmaceutical composition that provides a pharmacokinetic profile in the subject characterized in that (1) a maximum plasma concentration of R,R-tetrabenazine of 150 pg / ml to 3500 pg / ml is reached during a first time period at a first time point during said first time period, said first time period being from the time of initial administration up to 24 hours thereafter; and (2) after said first time point, the plasma concentration of R,R-tetrabenazine remains constant for a sustained period of 24 hours, 48 ​​hours, 72 hours, 96 hours or more, and the mean terminal half-life of R,R-tetrabenazine is 8.5 hours ± 40%CV.

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