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 Oct. 22, 2019, the contents of which are hereby incorporated by reference in their entirety.

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

Background Art

[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, which are indicated for the treatment of chorea associated with Huntington's disease. The active ingredient of 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, "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, "S,S - tetrabenazine or S,S - TBZ").

Chemical Formula

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

SUMMARY OF THE INVENTION

[0005] In various embodiments, the present invention relates to pharmaceutical compositions, drug delivery devices, methods of preparation, and methods of use thereof, such as those related to delivering tetrabenazine and / or deuterated tetrabenazine to a subject by bypassing first-pass metabolism in a sustained or substantially sustained manner. Without wishing to be bound by theory, delivery of tetrabenazine and / or deuterated tetrabenazine as described herein, such as transdermal delivery as described herein, offers many advantages over conventional oral delivery, such as avoiding first-pass metabolism, providing a pharmacokinetic profile with a low peak-to-trough ratio, enabling multi-day treatment with a single application, avoiding the effect of food on absorption, terminating treatment by removing the patch as needed, and facilitating patient compliance. Further, compared to oral administration of an equidose of tetrabenazine or deutetrabenazine, delivery as described herein, such as transdermal delivery as described herein, can reduce the inter-individual variability in plasma levels of tetrabenazine or deuterated tetrabenazine and / or its metabolites, and / or, for example, without reducing therapeutic efficacy, the C of tetrabenazine or deuterated tetrabenazine and / or its metabolites maxcan be reduced (e.g., 10%, 40%, 60%, or more). Further, delivery such as transdermal delivery herein can be similarly administered to subjects genotyped as poor metabolizers (PM), intermediate metabolizers (IM), or extensive metabolizers (EM) based on CYP2D6 expression. Further, unlike Xenazine® and Austedo™ treatments, the R,R-TBZ transdermal delivery system (TDDS) herein can be administered to a subject without the need to genotype prior to administration (even at higher doses). As detailed herein, most of the metabolic group effects are due to off-target binding that would not be expected from administration of the R,R-TBZ TDDS herein. These advantages ultimately allow for simplification of the dosing regimen of tetrabenazine and / or deuterated tetrabenazine (e.g., dutetrabenazine), e.g., minimizing or eliminating the need to perform genotyping analysis and / or reducing dose-related side effects.

[0006] In some embodiments, the present disclosure provides a method of treating hyperkinetic movement disorder in a subject (e.g., a human subject) in need thereof. 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 from about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine to the subject, e.g., delivers continuously or substantially continuously. In some embodiments, the pharmaceutical composition is administered transdermally, intravenously, subcutaneously, intramuscularly, or via a depot. In some specific embodiments, the administration bypasses first-pass metabolism and delivers R,R-tetrabenazine transdermally to the subject at from about 0.1 mg / day to about 20 mg / day. In some embodiments, the administration comprises applying the pharmaceutical composition to the skin of the subject to deliver R,R-tetrabenazine transdermally to the subject at from about 0.1 mg / day to about 20 mg / day. In some embodiments, the only active ingredient in the pharmaceutical composition is a substantially pure R,R-isomer of tetrabenazine. In some embodiments, the administration can provide any of the applicable pharmacokinetic (PK) profiles described herein, e.g., a PK profile associated with the plasma concentration profiles described herein for R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ. In some embodiments, the administration does not provide a detectable amount of the S,S-isomer of tetrabenazine or its metabolites, e.g., S,S,S-HTBZ and R,S,S-HTBZ, in the plasma of the subject. The pharmaceutical compositions, drug delivery devices, dosing regimens, and subjects suitable 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 as needed at any frequency.In some embodiments, each administration of the pharmaceutical composition can deliver, for example, from about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine to the 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, the administration can be performed regardless of the subject's feeding state. The dosage 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 dosage 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 and adolescent patient (e.g., from 6 years to 18 years). In some embodiments, the administration can be performed regardless of the subject's genotype; for example, the subject can be a rapid metabolizer. In some embodiments, the hyperkinetic movement disorder can be Huntington's disease, Wilson's disease, Tourette 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 also aim to provide a method for 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 R,R-tetrabenazine, wherein the administration provides a desired PK profile. In some embodiments, the PK profile provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-HTBZ, and S,R,R-HTBZ upon administration, and the maximum plasma concentration of R,R-tetrabenazine For The combined maximum plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ ofThe ratio is in the range of about 1:1 to about 1:5 (for example, 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, such as about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some embodiments, the PK profile provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-HTBZ, and S,R,R-HTBZ upon administration, and the steady-state plasma concentration of R,R-tetrabenazine For The combined steady-state plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ ofThe ratio 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 in that the plasma concentration of R,R-tetrabenazine increases during a first period and reaches a maximum concentration of about 150 pg / ml to about 3500 pg / ml at a first time point of the first period, and the first period is from time 0 (the administration time of the pharmaceutical composition) to about 24 hours thereafter. In some embodiments, the PK profile is characterized in that the average terminal phase half-life of R,R-tetrabenazine is about 8.5 hours ± 40% CV. In some embodiments, the PK profile is further characterized in that after the first period, the plasma concentration of R,R-tetrabenazine remains substantially constant 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 R,R-tetrabenazine above 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. Pharmaceutical compositions, drug delivery devices, dosing regimens, and subjects suitable 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, for example, at a substantially constant rate, e.g., continuously or substantially continuously. 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 feeding state of the subject. In some embodiments, the subject is a pediatric and adolescent patient (e.g., 6 to 18 years old).In some embodiments, administration can be carried out regardless of the genotype of the subject. For example, the subject can be a rapid metabolizer. In some embodiments, the hyperkinetic movement disorder can be Huntington's disease, Wilson's disease, Tourette 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-duotetrabenazine) for treating, e.g., 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-duotetrabenazine), the administration bypassing first-pass metabolism and delivering from about 0.1 mg / day to about 20 mg / day of deuterated R,R-tetrabenazine to the subject, e.g., delivering sustainably or substantially sustainably. 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 deuterated R,R-tetrabenazine transdermally to the subject from about 0.1 mg / day to about 20 mg / day. In some embodiments, the administration comprises applying the pharmaceutical composition to the skin of the subject to deliver deuterated R,R-tetrabenazine transdermally to the subject from about 0.1 mg / day to about 20 mg / day. 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-duotetrabenazine. In some embodiments, the administration does not provide a detectable amount of the S,S-isomer and / or metabolites thereof of deuterated tetrabenazine in the plasma of the subject. In some embodiments, the administration can provide any of the applicable pharmacokinetic (PK) profiles described herein, e.g., a PK profile associated with 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, dosing 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 the subject as needed at any frequency.In some embodiments, each administration of the pharmaceutical composition can deliver deuterated R,R-tetrabenazine at about 0.1 mg / day to about 20 mg / day 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, for example, continuously or substantially continuously. In some embodiments, the administration can be performed regardless of the feeding state of the subject. In some embodiments, the subject is a pediatric and adolescent patient (e.g., 6 to 18 years old). In some embodiments, the administration can be performed regardless of the genotype of the subject, for example, the subject can be a rapid metabolizer. In some embodiments, the hyperkinetic movement disorder can be Huntington's disease, Wilson's disease, Tourette 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 a dutetrabenazine such as R,R-dutetrabenazine.

[0009] Some embodiments of the present disclosure are also directed to a method of treating a hyperkinetic movement disorder in a subject in need of treatment for a hyperkinetic movement disorder, the method comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising deuterated R,R-tetrabenazine, wherein the administration provides a desired PK profile. In some embodiments, the PK profile provides therapeutically effective plasma concentrations of deuterated R,R-tetrabenazine, deuterated R,R,R-HTBZ, and deuterated S,R,R-HTBZ upon administration, and the maximum plasma concentration of deuterated R,R-tetrabenazine For The combined maximum plasma concentration of deuterated R,R,R-HTBZ and S,R,R-HTBZ of The ratio is in the range of about 1:1 to about 1:7.5. In some embodiments, the PK profile provides therapeutically effective plasma concentrations of deuterated R,R-tetrabenazine, deuterated R,R,R-HTBZ, and deuterated S,R,R-HTBZ upon administration, and the steady-state plasma concentration of deuterated R,R-tetrabenazineFor Steady-state plasma concentrations of combinations of deuterated R,R,R-HTBZ and S,R,R-HTBZ ofThe ratio is in the range of 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 the subject. In some embodiments, the PK profile is such that the plasma concentration of deuterated R,R-tetrabenazine increases during the first period and reaches a maximum concentration of about 150 pg / ml to about 3500 pg / ml at the first time point of the first period, and the first period is from time 0 (the administration time of the pharmaceutical composition) to about 24 hours thereafter. In some embodiments, the PK profile is characterized in that the average terminal phase half-life of deuterated R,R-tetrabenazine is about 8.5 hours ± 40% CV. In some embodiments, the PK profile is further characterized in that after the first period, the plasma concentration of R,R-tetrabenazine remains substantially constant 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 that exceeds 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. Pharmaceutical compositions, drug delivery devices, dosing regimens, and subjects suitable 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, for example, at a substantially constant rate, for example, continuously or substantially continuously. 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 feeding state of the subject. In some embodiments, the subject is a pediatric and adolescent patient (e.g., 6 to 18 years old). In some embodiments, administration can be performed regardless of the genotype of the subject, for example, the subject can be a rapid metabolizer.In some embodiments, the movement disorder can be Huntington's disease, Wilson's disease, Tourette 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, deutetrabenazine 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 deutetrabenazine 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 a transdermal delivery device comprising tetrabenazine and / or deutetrabenazine (e.g., duetetrabenazine). In various embodiments, the present invention also provides a pharmaceutical composition (e.g., an adhesive composition) comprising tetrabenazine and / or deutetrabenazine (e.g., duetetrabenazine). In some embodiments, the present invention further provides a method of preparing or using a transdermal delivery device or a pharmaceutical composition comprising tetrabenazine and / or deutetrabenazine (e.g., duetetrabenazine).

[0012] Typically, the transdermal delivery device comprises a backing layer, a drug layer comprising a drug selected from tetrabenazine, deutetrabenazine, or a combination thereof, e.g., the drug layer comprising the drug in an amount of about 2 wt% to about 30 wt% of the drug layer, and an adhesive layer defining an active surface area. The transdermal delivery device is generally designed to have certain flux characteristics, e.g., any of those defined herein. Typically, the transdermal delivery device can have an active surface area in the range of about 5 cm 2 to about 300 cm 2 , e.g., about 10 cm 2 to about 100 cm 2 of the active surface area.

[0013] The transdermal delivery devices of the present specification are not limited to a specific patch design. For example, the transdermal delivery devices of the present specification can be a drug-in-adhesive patch, a drug-in-reservoir patch, a microneedle patch, or another patch design that may contain chemical or physical enhancement modalities. In some embodiments, the transdermal delivery device can be a drug-in-adhesive patch, such as a single-layer DIA patch. In some embodiments, the transdermal delivery device can include two or more drug layers, such as two or more drug-containing adhesive layers. In some embodiments, the transdermal delivery device can 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 include 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 include tetrabenazine, for example, 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 include dutetrabenazine, for example, substantially pure R,R-dutetrabenazine. In some embodiments, dutetrabenazine (e.g., substantially pure R,R-dutetrabenazine) is the only active ingredient in the drug layer. In some embodiments, the drug layer includes tetrabenazine, deuterated tetrabenazine, or a combination thereof in an amount of about 2 wt% to about 30 wt% of the drug layer (e.g., about 2 wt%, about 2.5 wt%, about 5 wt%, about 8 wt%, about 10 wt%, about 15 wt%, about 18 wt%, about 20 wt%, about 25 wt%, about 30 wt%, or any range between the recited values). In some particular embodiments, the drug layer includes tetrabenazine, deuterated tetrabenazine, or a combination thereof in an amount of about 2 wt%, about 2.5 wt%, about 5 wt%, about 8 wt%, about 10 wt%, about 15 wt%, or about 20 wt% of the drug layer. In some embodiments, the drug layer can optionally include one or more other components selected from, for example, a skin penetration enhancer, a humectant, a plasticizer, an antioxidant, an anti-irritant, a gelling agent, a drug release regulator, a solvent, a crystallization inhibitor, and additional active ingredients. In some embodiments, the drug layer has a coated weight of about 0.1 g / cm 2 to about 0.90 g / cm 2 (e.g., about 0.1 g / cm 2 to about 0.5 g / cm 2 ) and can have an 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 can 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 is a non-reactive acrylate adhesive, e.g., an acrylate adhesive having no functional groups containing reactive hydrogen moieties, or an acrylate adhesive having no functional groups selected from epoxy, -OH, -COOH, and combinations thereof.

[0016] The adhesive layer is typically formulated such that the transdermal delivery device can adhere to the skin of the user for a desired period of time. For example, in some embodiments, the transdermal delivery device can adhere continuously to the skin of the 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 longer.

[0017] Certain embodiments of the present invention also aim at an adhesive composition. In some embodiments, the adhesive composition contains a drug selected from tetrabenazine, deuterated tetrabenazine (e.g., dutetrabenazine), and combinations thereof in the adhesive. In some embodiments, the drug is homogeneously dispersed in the adhesive (e.g., a pressure-sensitive adhesive). In some embodiments, the pressure-sensitive adhesive can be a non-reactive acrylate adhesive, e.g., an acrylate adhesive having no functional groups containing reactive hydrogen moieties, or an acrylate adhesive having no functional groups selected from epoxy, -OH, -COOH, and combinations thereof. In some embodiments, the pressure-sensitive adhesive includes a polyisobutylene (PIB) adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some embodiments, the adhesive composition contains tetrabenazine (e.g., substantially pure R,R-tetrabenazine) in an amount of about 2 wt% to about 30 wt% of the adhesive composition. In some embodiments, the adhesive composition contains dutetrabenazine (e.g., substantially pure R,R-dutetrabenazine) in an amount of about 2 wt% to about 30 wt% of the adhesive composition. In some embodiments, the active ingredient is present in an amount of about 2 wt% to about 7 wt%. In some embodiments, the adhesive composition does not contain a permeation enhancer, e.g., does not contain isopropyl myristate. However, in some embodiments, the adhesive composition further contains a permeation enhancer. In some embodiments, the adhesive composition can contain an antioxidant, e.g., a gallic acid antioxidant such as propyl gallate. In some embodiments, the adhesive composition contains 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 polyvinylcaprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof. In some preferred embodiments, the adhesive composition contains 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 adhere to the skin of the user continuously over a long 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. The adhesive compositions described herein can be used in transdermal delivery devices. For example, in some embodiments, the 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 a method 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 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, administration provides any of the desired daily amounts described herein and / or any of the PK profiles provided herein (where applicable).

[0019] In some embodiments, the present invention also provides a method of inhibiting VMAT-2 in a subject in need of inhibition of VMAT-2. 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 amounts described herein and / or any of the PK profiles provided herein (where applicable).

[0020] In some embodiments, the invention also 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 of treatment of a VMAT2-mediated disease or disorder. In some embodiments, the method comprises applying either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition) to the subject, such as the subject's skin. In some embodiments, the application provides any of the desired daily amounts described herein and / or any of the PK profiles provided herein (where applicable).

[0021] In some embodiments, the disclosure provides a method for treating a hyperkinetic movement disorder in a subject (e.g., a human subject) in need of treatment of a hyperkinetic movement disorder. In some embodiments, the method comprises transdermally administering to the subject a therapeutically effective amount of tetrabenazine and / or deuterated tetrabenazine. In some embodiments, the method comprises applying either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition) to the subject, such as the subject's skin. In some embodiments, the hyperkinetic movement disorder is a chronic hyperkinetic movement disorder. In some embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease, Wilson's disease, Tourette 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, the application provides any of the desired daily amounts described herein and / or any of the PK profiles provided herein (where 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 comprises administering to a subject a test pharmaceutical composition that bypasses first-pass metabolism and provides sustained or substantially sustained delivery of R,R-tetrabenazine to the subject, 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 for treating hyperkinetic movement disorders. In some embodiments, the method comprises measuring in vitro the skin flux properties of a test adhesive composition using human cadaver skin, and identifying an adhesive composition that provides any of the in vitro flux properties described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023]

Figure 1

Figure 2

Figure 3

Figure 4-1

Figure 4-2

Mode for Carrying Out the Invention

[0024] The FDA-approved labels for Xenazine (registered trademark) and Austedo (trademark) each contain a black box warning regarding the potential risks of depression and suicidal tendencies. For both products, it is necessary to monitor the actual administration and set the dosage. For example, the Xenazine (registered trademark) label indicates that for patients who require a dosage exceeding 50 mg per day, it is necessary to genotype the patient for the drug-metabolizing enzyme CYP2D6 to determine whether the patient is a poor metabolizer (PM) or an extensive metabolizer (EM). In the case of poor metabolizers, the maximum daily dose is only 50 mg, and the maximum single dose is 25 mg. In the case of extensive metabolizers or intermediate metabolizers, the maximum daily dose is 100 mg, and the maximum single dose is 37.5 mg. Similarly, the Austedo (trademark) label also states that in the case of poor metabolizers, the maximum daily dose is only possible at 36 mg with two single doses of 18 mg each.

[0025] Despite recent advancements, the dosing of tetrabenazine / duotetrabenazine still involves complications, and dosing settings are made to reduce potential dose-related side effects. Therefore, new tetrabenazine formulations and dosing options are needed.

[0026] In various embodiments, the present invention relates to pharmaceutical compositions, drug delivery devices, methods of preparation, and methods of use thereof, such as those related to bypassing first-pass metabolism and delivering tetrabenazine and / or deuterated tetrabenazine to a subject in a sustained or substantially sustained manner. For example, some embodiments of the present invention are directed to the 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, such as sustained delivery at a substantially constant rate.

[0027] Sustained delivery of tetrabenazine Some embodiments of the present disclosure are based on the sustained or substantially sustained delivery of tetrabenazine that bypasses first-pass metabolism and the unique pharmacokinetic (PK) profile obtained from transdermal delivery. As detailed herein, transdermal delivery of R,R-tetrabenazine at a dose of 8 mg / 96 hours, compared to three times daily dosing (total dose 150 mg) of TBZ tablets administered under fasting conditions from day 1 to day 4 in healthy male subjects, provides much higher concentrations of R,R-tetrabenazine with less metabolism to the active HTBZ isomers at a lower dose and without interconversion to the SS isomer. This data shows for the first time that sustained or substantially sustained delivery methods, such as transdermal delivery, can provide, for example, the R,R-tetrabenazine and its dihydro metabolites, R,R,R-HTBZ and S,R,R-HTBZ, at therapeutically effective plasma concentrations for treating the hyperkinetic movement disorders described herein. As the R,R-isomers of tetrabenazine, R,R,R-HTBZ and S,R,R-HTBZ are thought to have low off-target binding to, for example, dopamine D1 or D2 receptors, and using the R,R-isomers of tetrabenazine as the main active ingredient results in fewer side effects compared to using the racemic mixture of tetrabenazine, which is the active ingredient of Xenazine (registered trademark). Furthermore, the PK data shows that the sustained delivery method described herein results in a lower C compared to dose-equivalent oral delivery of tetrabenazine. maxwhich provides relatively stable plasma concentrations of R,R-tetrabenazine and its active dihydro metabolite, with decreased trough levels and decreased peak-to-trough ratios, and thus may be advantageous in treating subjects having hyperkinetic movement disorders has been shown.

[0028] The PK data exemplified in this specification are generated by using a transdermal delivery device, but 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 profiles described herein. The PK profiles described herein are one novel aspect of the present disclosure. In some embodiments, the PK profile can be achieved by applying the transdermal delivery device of this specification. In some embodiments, the PK profile can be achieved by any sustained or substantially sustained 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 adjusted to deliver tetrabenazine systemically at a desired rate, for example, at a rate of about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine. In some embodiments, the delivery of tetrabenazine can be at a substantially constant rate during the drug delivery period, for example, during the patch-on period, and the delivery of tetrabenazine to the subject is similar to zero-order kinetics. For example, in some embodiments, the desired delivery rate can be about 12 mg / day of R,R-tetrabenazine, the desired drug delivery period is 24 hours, and thus the amount of R,R-tetrabenazine delivered to the subject being treated per hour can be about 0.5 mg / hour. For example, "substantially sustained" as used in connection with "substantially sustained delivery" means referring to the delivery of a drug (e.g., tetrabenazine) in a manner that is substantially uninterrupted over a preselected drug delivery period. Further, "substantially sustained" drug delivery can also include the delivery of a drug that is substantially constant at a preselected rate or range of rates (e.g., the amount of drug per unit time, or the amount of drug formulation per unit time) and is substantially uninterrupted over the period of a preselected drug delivery period.The drug delivery period in this specification can be, for example, from about 8 hours to about 192 hours, and can be varied, for example, at 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 stated values. For the sake of clarity, the expression "sustained or substantially sustained delivery" does not require that the active ingredient / drug be continuously delivered to the subject via the treatment. This expression only requires that the drug be delivered continuously or substantially continuously during the drug delivery period, in contrast to bolus delivery. For example, when a pharmaceutical composition is administered once a day, it is permissible for there to be a period during which no drug is delivered to the subject being treated between two administrations.

[0029] Typically, R,R-tetrabenazine is delivered at a therapeutically effective dose to a subject in need thereof for treating the hyperkinetic movement disorders described herein. In some embodiments, the methods herein deliver from about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine, such as 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, about 16 mg / day, about 18 mg / day, or about 20 mg / day of R,R-tetrabenazine, or any range between the recited values, such as 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, from about 1 mg / day to about 6 mg / day of R,R-tetrabenazine, from about 1 mg / day to about 4 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 10 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 8 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 6 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 4 mg / day of R,R-tetrabenazine, from about 4 mg / day to about 10 mg / day of R,R-tetrabenazine, from about 4 mg / day to about 8 mg / day of R,R-tetrabenazine, from about 4 mg / day to about 6 mg / day of R,R-tetrabenazine, from about 6 mg / day to about 10 mg / day of R,R-tetrabenazine, or from about 6 mg / day to about 8 mg / day of R,R-tetrabenazine to a subject in need of treatment of the hyperkinetic movement disorders herein. In some preferred embodiments, the method delivers from about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine or from 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 the R,R-tetrabenazine base, their pharmaceutically acceptable salts, or combinations thereof.Typically, in the case of transdermal compositions such as the adhesive compositions described herein, R,R-tetrabenazine can exist primarily in its free base form. For example, in any of the embodiments described herein, an adhesive composition or a drug-containing adhesive composition comprising R,R-tetrabenazine can be prepared by mixing the R,R-tetrabenazine free base with other components such as an adhesive, an antioxidant, a crystallization inhibitor, etc. in the stated amounts. The 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 subject's skin, and the amount is expressed as the equivalent of the R,R-tetrabenazine base and can be in any form. Other terms such as tetrabenazine, deuterated tetrabenazine, deuterated R,R-tetrabenazine, dutetrabenazine, R,R-dutetrabenazine, etc., and the delivery of such to a subject should be understood similarly.

[0030] In some embodiments, R,R-tetrabenazine can be included in a pharmaceutical composition or a delivery device, e.g., a sustained release delivery device configured to deliver to a subject at a substantially constant rate in the dosages described herein. For example, in some embodiments, the daily dose of R,R-tetrabenazine can be from about 0.5 mg / day to about 10 mg / day, and the sustained release delivery device can be applied once a day to a subject in need thereof, and R,R-tetrabenazine can be delivered to the subject continuously or substantially continuously over a preselected time, e.g., 12 hours, or 24 hours, and the delivery rate of R,R-tetrabenazine during the preselected 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 of those suitable for delivering R,R-tetrabenazine at a desired dosage at a desired rate.

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

[0032] In some embodiments, the present disclosure is a method of treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising R,R-tetrabenazine, wherein the administration bypasses first-pass metabolism and delivers continuously or substantially continuously from about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine, such as 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, from about 1 mg / day to about 6 mg / day of R,R-tetrabenazine, from about 1 mg / day to about 4 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 10 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 8 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 6 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 4 mg / day of R,R-tetrabenazine, from about 4 mg / day to about 10 mg / day of R,R-tetrabenazine, from about 4 mg / day to about 8 mg / day of R,R-tetrabenazine, from about 4 mg / day to about 6 mg / day of R,R-tetrabenazine, from about 6 mg / day to about 10 mg / day of R,R-tetrabenazine, or from about 6 mg / day to about 8 mg / day of R,R-tetrabenazine, to the subject. In some preferred embodiments, the method delivers from about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine or from 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 up to more than 72 hours. The pharmaceutical composition can be administered to the subject as needed at any frequency. For example, in some embodiments, each administration can provide continuous or substantially continuous delivery of R,R-tetrabenazine to the subject at 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 a period of sustained or substantially sustained delivery, R,R-tetrabenazine can be delivered to a subject at a substantially constant rate, e.g., with an average delivery rate per time being substantially the same, e.g., within 80% to 125% of the overall average rate of the drug delivery period. In some embodiments, during a period of sustained or substantially sustained delivery, R,R-tetrabenazine can be delivered to a subject, e.g., with a different average delivery rate for each time. For example, in some embodiments, the average delivery rate may be high initially but then decrease during the course of sustained or substantially sustained delivery. Typically, the exact delivery rate of R,R-tetrabenazine per hour is not critical, and one of ordinary skill in the art after considering the present disclosure will know how to select and design a dosing regimen to deliver a desired daily amount to the subject, 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. In some embodiments, delivery of the desired daily amount to the subject also provides a pharmacokinetic profile as described herein.

[0033] In some embodiments, the present disclosure is a method of treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, the method comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising R,R-tetrabenazine, wherein administration results in transdermal delivery to the subject of from about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine, such as 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, from about 1 mg / day to about 6 mg / day of R,R-tetrabenazine, from about 1 mg / day to about 4 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 10 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 8 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 6 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 4 mg / day of R,R-tetrabenazine, from about 4 mg / day to about 10 mg / day of R,R-tetrabenazine, from about 4 mg / day to about 8 mg / day of R,R-tetrabenazine, from about 4 mg / day to about 6 mg / day of R,R-tetrabenazine, from about 6 mg / day to about 10 mg / day of R,R-tetrabenazine, or from about 6 mg / day to about 8 mg / day of R,R-tetrabenazine. In some preferred embodiments, the method delivers from about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine or from about 2 mg / day to about 6 mg / day of R,R-tetrabenazine. In some embodiments, administration comprises applying the pharmaceutical composition to the subject's skin. The exact location of the skin is not critical, but typically the pharmaceutical composition is applied to an intact area of the skin, such as the subject's outer arm. The duration of drug delivery herein can vary, for example, from about 8 hours to about 72 hours, or up to more than 72 hours. In some embodiments, the pharmaceutical composition is applied to the subject's skin to provide sustained or substantially sustained delivery to the subject 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.The frequency of application of the pharmaceutical composition to the subject for the methods of this specification 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 is applied to the subject's skin and can 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 enabling continuous or substantially continuous delivery of R,R-tetrabenazine to the subject during the patch-on period. In some embodiments, there is no delay time between applications of the transdermal patch according to the dosing frequency of this specification. For example, in some embodiments, the transdermal delivery device is applied to the subject once a day, and each application of the transdermal delivery device can last (adhere to the subject's skin) for about 24 hours before being replaced with another transdermal delivery device that is typically substantially the same. However, in some embodiments, there can be an overlap or a delay between two applications.

[0034] Typically, in the case of transdermal delivery, the pharmaceutical composition can include an adhesive composition (e.g., in a transdermal delivery device as described herein), which contains 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 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, such as 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 contains an active ingredient dispersed in a non-reactive acrylate pressure-sensitive adhesive. The active ingredient can be present in an amount of about 1 wt% to about 20 wt%, for example, about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 10 wt%, about 15 wt%, or about 20 wt%, or any range between the recited values, e.g., about 1 wt% to about 15 wt%, about 2 wt% to about 15 wt%, about 2 wt% to about 10 wt%, about 2 wt% to about 7 wt%, about 3 wt% to about 15 wt%, about 3 wt% to about 10 wt%, about 3 wt% to about 7 wt%, about 5 wt% to about 15 wt%, about 5 wt% to about 10 wt%, about 5 wt% to about 7 wt%, about 7 wt% to about 15 wt%, about 7 wt% to about 10 wt%, about 10 wt% to about 20 wt%, about 10 wt% to about 15 wt%, etc. In some embodiments, the adhesive composition contains 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 the 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 such as Duro-Tak 87-900A described herein or described in exemplary embodiments 2 - 7.The adhesive is typically present in an amount of about 50 wt% to about 97 wt%, for example, about 50 wt%, about 60 wt%, about 70 wt%, about 80 wt%, about 90 wt%, about 95 wt%, or about 97 wt% or any range between the recited values, such as about 50 wt% to about 95 wt%, about 50 wt% to about 90 wt%, about 50 wt% to about 80 wt%, about 50 wt% to about 70 wt%, about 50 wt% to about 60 wt%, about 60 wt% to about 97 wt%, about 60 wt% to about 95 wt%, about 60 wt% to about 90 wt%, about 60 wt% to about 80 wt%, about 60 wt% to about 70 wt%, about 70 wt% to about 97 wt%, about 70 wt% to about 95 wt%, about 70 wt% to about 90 wt%, about 70 wt% to about 80 wt%, about 80 wt% to about 97 wt%, about 80 wt% to about 95 wt%, about 80 wt% to about 90 wt%, etc. In some specific embodiments, the active ingredient is in an amount of about 2 wt% to about 7 wt%, and the non-reactive acrylate pressure-sensitive adhesive is in an amount of about 50 wt% to about 97 wt%. The adhesive composition can also optionally include other components 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, for example, propyl gallate. The amount of the antioxidant is typically in an amount of about 0 wt% to about 1 wt%, for example, about 0.001 wt%, about 0.01 wt%, about 0.1 wt%, about 0.5 wt%, about 1 wt%, or any range between the recited values, such as about 0.001 wt% to about 0.5 wt%, about 0.01 wt% to about 0.5 wt%, etc. In some embodiments, the adhesive composition includes a crystallization inhibitor, for example, means to prevent the formation of drug crystals (such as crystals of the active ingredient of the adhesive composition like (R,R)-tetrabenazine) after storage at room temperature for two weeks at ambient temperature.In some embodiments, the adhesive composition comprises a crystallization inhibitor selected from 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 (Asland)), cellulose-based polymers (e.g., hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose), polycarboxylic acid polymers (e.g., Cabopol (manufactured by Lubrizol)), polymethacrylates (e.g., Plastoid B, Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, polyvinyl acetate, and polyvinylcaprolactam-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 polymethacrylates (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 polyvinylcaprolactam-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 wt%, such as about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 30 wt%, about 40 wt%, or any range between the recited values, for example, in amounts of about 10 wt% to about 40 wt%, about 10 wt% to about 30 wt%, about 10 wt% to about 20 wt%, 15 wt% to about 40 wt%, about 15 wt% to about 30 wt%, about 15 wt% to about 20 wt%, 20 wt% to about 40 wt%, about 20 wt% to about 30 wt%, etc.In some embodiments, the adhesive composition may also include a skin penetration enhancer as described herein, such as isopropyl myristate. In some embodiments, the adhesive composition may also not include a skin penetration enhancer as described herein. For example, in some embodiments, the adhesive composition may also not include isopropyl myristate. Suitable drug loading, active surface area, thickness, adhesive properties, etc. include any combination of those described herein.

[0035] In some embodiments, the present disclosure is a method of treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, the method 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 (excluding only bolus injection for immediate release), subcutaneous injection, or intramuscular injection, and wherein the administration results in transdermal delivery to the subject of from about 0.1 mg / day to about 20 mg / day of R,R-tetrabenazine, such as 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, from about 1 mg / day to about 6 mg / day of R,R-tetrabenazine, from about 1 mg / day to about 4 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 10 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 8 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 6 mg / day of R,R-tetrabenazine, from about 2 mg / day to about 4 mg / day of R,R-tetrabenazine, from about 4 mg / day to about 10 mg / day of R,R-tetrabenazine, from about 4 mg / day to about 8 mg / day of R,R-tetrabenazine, from about 4 mg / day to about 6 mg / day of R,R-tetrabenazine, from about 6 mg / day to about 10 mg / day of R,R-tetrabenazine, or from about 6 mg / day to about 8 mg / day of R,R-tetrabenazine. In some preferred embodiments, the method delivers from about 0.5 mg / day to about 8 mg / day of R,R-tetrabenazine or from about 2 mg / day to about 6 mg / day of R,R-tetrabenazine. In some embodiments, the 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 up to more than 72 hours.For example, in some embodiments, the pharmaceutical composition is intravenously injected or infused into a subject to deliver R,R-tetrabenazine to the 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. 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 a drug delivery period such as the infusion period. In some embodiments, administration includes subcutaneous or intramuscular injection of the pharmaceutical composition into the subject. Typically, in the case of subcutaneous or intramuscular injection, the pharmaceutical composition is formulated to release R,R-tetrabenazine to the subject for systemic absorption over a preselected period, for example, from about 8 hours to about 72 hours or more than 72 hours. For example, in some embodiments, the subcutaneous or intramuscular pharmaceutical composition is formulated or included in a drug delivery device such as an implant to release R,R-tetrabenazine to the subject continuously or substantially continuously 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 passive polymeric implants, including biodegradable and non-biodegradable implants, or active implants such as osmotic pumps and electromechanical drives, any of those known in the art for subcutaneous or intramuscular delivery of pharmaceutical agents. Non-limiting examples of formulating an implant for subcutaneous delivery include those described in U.S. Patent No. 8,921,387 (buprenorphine), 6,835,194 (fentanyl), etc. See also Stewart S. A., 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 a microsphere, which can be configured to release R,R-tetrabenazine for systemic absorption over a preselected period of time, for example, from about 8 hours to about 72 hours or more than 72 hours. In some embodiments, the long-acting injectable formulation can be configured to release R,R-tetrabenazine 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 of those known to be treatable by tetrabenazine or deutetrabenazine, for example, any of the indications approved by regulatory authorities including the US FDA, or any of those under clinical investigation. Non-limiting examples include Huntington's disease, Wilson's disease, Tourette 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, such as chorea associated with Huntington's disease as an example. In some embodiments, the hyperkinetic movement disorder can be Wilson's disease. In some embodiments, the hyperkinetic movement disorder can be Tourette 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 can be dyskinetic cerebral palsy. Cerebral palsy (“CP”) refers to a group of neurological disorders that appear 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. The symptoms of CP usually appear within the first few months of life, but a specific diagnosis may be delayed until the child is over 2 years old. Currently, there are no approved treatment methods available for dystonia in cerebral palsy (DCP). The 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 (6 - 18 years old) with DCP with major chorea movement disorder who have had non - progressive CP symptoms since infancy (under 2 years old). The inventors believe that the methods and compositions herein can provide alternative and / or superior treatment options for dyskinetic cerebral palsy.

[0038] In some embodiments, the hyperkinetic movement disorder is a dystonia or dyskinesia disorder. See, for example, the review of the treatment of dystonia in Thengnatt M.A. and Jankovic J. neurotherapeutics, 11(1):139 - 152 (2014).

[0039] The treatment methods described in this specification are not limited to specific types of subjects. For example, the methods described in this specification can be administered to a subject regardless of the subject's feeding state. In other words, the feeding state and fasting state of the subject are not important for the methods described in this specification. In some embodiments, the subject is a pediatric and adolescent patient (e.g., 6 to 18 years old). Also, in some embodiments, this method is not limited to subjects of a specific genotype. In some embodiments, the same dose or substantially the same dose of R,R-tetrabenazine can be administered to a subject characterized as PM, IM, or EM. In some embodiments, the subject is characterized as EM. In some embodiments, the subject is characterized as PM. In some embodiments, the subject is characterized as IM. In some embodiments, this method does not require the dose setting and / or genotype analysis required when treated with either Xenazine® or Austedo™ tablets. In some embodiments, any of the methods described in this specification can be adapted to treat pediatric and adolescent patients (e.g., 6 to 18 years old) having any of the diseases or disorders described in this specification. As discussed herein, the dose and / or plasma exposure ranges can 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 can typically be adjusted to lower doses or exposures, taking into account the age and weight of the subject. Without wishing to be bound by theory, in some embodiments, the convenient and controlled delivery of R,R-tetrabenazine herein can provide safety and treatment options superior to currently available treatments.

[0040] The dosing regimen of the treatment method of this specification is not particularly limited as long as the desired dose of R,R-tetrabenazine is delivered to the subject at the desired rate for the desired period, including any of those described in this specification. For example, in some embodiments, the pharmaceutical composition is administered to the subject once a day. 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 sustained or substantially sustained 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. In some embodiments, there is no or substantially no delay time between two consecutive administrations, and thus R,R-tetrabenazine can continue to be delivered to the subject according to the dosing regimen of this specification. In some embodiments, there may be an overlap or delay time between two consecutive administrations.

[0041] Pharmacokinetics of Sustained Delivery of Tetrabenazine Some embodiments of the present disclosure also aim to provide a method for treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, comprising delivering a therapeutically effective amount of R,R-tetrabenazine to the subject, wherein the delivery provides a certain specific novel pharmacokinetic profile in the plasma of the subject.

[0042] As discussed herein, currently approved tetrabenazine or deuterated tetrabenazine products such as Xenazine® and Austedo™ require complex dosing regimens and genotyping of treated subjects at higher doses. Additionally, oral administration of such products also results in high peak-to-trough ratios, with significant inter-individual variability in plasma levels of tetrabenazine or dutetrabenazine or their metabolites. Typically, as also shown herein, the potent VMAT-2 inhibitor R,R-tetrabenazine itself is not present in significant amounts in circulation after oral administration. In some embodiments, the inventors first show that by using sustained or substantially sustained delivery of tetrabenazine herein, the mean terminal-phase half-life of R,R-tetrabenazine administered by the first-pass bypass route can be about 8.5 hours ± 40% CV. In comparison, when using typical oral administration, R,R-tetrabenazine is typically not systemically available.

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

[0044] In some embodiments, the disclosure provides a method of treating 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 pharmacokinetic profile (PK profile). For example, in some embodiments, the desired PK profile provides plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ upon administration, and the therapeutically effective maximum plasma concentration of R,R-tetrabenazine For the combined maximum plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ ofThe ratio 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., C of R,R - tetrabenazine max / (C of R,R,R - HTBZ max + C of S,R,R - HTBZ max ) 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 single - dose administration of a pharmaceutical composition, e.g., after application of a single transdermal patch as described herein for delivery over 1 day, 2 days, 3 days, or more. As used herein, in some embodiments, the term "maximum plasma concentration" can also refer to the maximum plasma concentration obtained after multiple - dose administration of a pharmaceutical composition, preferably, the maximum plasma concentration obtained after reaching steady state. However, the ratios herein should be based on the comparison of the same type of concentrations between the respective compounds (e.g., from single - dose, steady state, etc.), and the ratios can be said to be within each of the ranges recited herein when calculated based on (1) single - dose C max and / or (2) multiple - dose C max (preferably steady - state C max ). It should be understood that in some embodiments, the desired PK profile is such that, upon administration, the ratio of the steady - state plasma concentration of R,R - tetrabenazine For to the combined steady - state plasma concentration of R,R,R - HTBZ and S,R,R - HTBZ of is in the range of about 1:1 to about 1:5, i.e., C of R,R - tetrabenazine ss / (C of R,R,R - HTBZ ss + C of S,R,R - HTBZ ss) is characterized by being in the range of about 1:1 to about 1:5. In the sustained or substantially sustained delivery herein, typically a steady state is reached and this state can be maintained for a desired period. For example, in some embodiments, the steady state can be reached by applying a single transdermal patch herein for about 32 to 48 hours or more, and this steady state can be maintained with the same patch or by exchanging the transdermal patch with a new patch that can deliver R,R-tetrabenazine at substantially the same rate, at any frequency. In some embodiments, the steady state cannot be reached by a single application of the transdermal patch herein, but can be continuously reached by multiple applications of the transdermal patch. As understood by those skilled in the art, in the steady state, the drug concentration obtained from the transdermal delivery patch can be substantially constant, in other words, the PK curve in the steady state can be substantially flat or plateau for a certain period. As used herein, the steady state of R,R-TBZ refers to a situation where the overall intake of R,R-TBZ is in a substantial dynamic equilibrium with its removal. The steady state of R,R,R-HTBZ refers to a situation where the overall production of R,R,R-HTBZ is in a substantial dynamic equilibrium with its removal. The steady state of S,R,R-HTBZ refers to a situation where the overall production of S,R,R-HTBZ is in a substantial dynamic equilibrium with its removal. For clarity, as used herein, the ratio of the 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 concentrations of each compound at any point in time when all three compounds, R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ are in the steady state, and / or (2) the average concentrations of each compound during the duration when all three compounds, i.e., R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ) and S,R,R-HTBZ are in the steady state. The ratio of the steady state concentrations of other compounds herein should be understood similarly.As used herein, the therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ do not require that each of the three compounds be at a therapeutically effective plasma concentration by itself. A combination of the three compounds is sufficient, for example, if it is therapeutically effective at their respective steady-state concentrations. In some embodiments, R,R,R-HTBZ. For S,R,R-HTBZ of The ratio of the maximum plasma concentration or steady-state plasma concentration 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 the maximum plasma concentrations of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ can range from about 17 - 40:3 - 10:50 - 80. In some embodiments, the ratio of the steady-state plasma concentrations of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ can range from about 17 - 40:3 - 10:50 - 80. In some embodiments, administration results in a ratio of the AUC of SRR-HTBZ 0-∞ to the AUC of R,R-tetrabenazine 0-∞ of about 1 to about 15, e.g., about 1.5 to about 11, and / or a ratio of the AUC of RRR-HTBZ 0-∞ to the AUC of R,R-tetrabenazine 0-∞A pharmacokinetic profile can be provided that is characterized in that the ratio to is from about 0.1 to about 0.75, such as from about 0.15 to about 0.5. In some embodiments, the desired PK profile also provides, upon administration, 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, such as 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 longer. In some embodiments, the desired PK profile also provides, upon administration, a substantially constant steady-state plasma concentration of R,R-tetrabenazine greater than 150 pg / ml (such as from about 150 pg / ml to about 3000 pg / ml) for at least 6 hours, or at least 12 hours, preferably at least 24 hours, such as 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 longer. In some embodiments, administration does not provide a detectable amount of S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ in the plasma of the subject. In some embodiments, the present disclosure also provides a method of 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 continuously or substantially continuously, and identifying a pharmaceutical composition that provides any combination of the PK profiles described in this paragraph.

[0045] In some embodiments, the pharmaceutical composition is formulated to provide a dose of about 2 mg / day of R,R-tetrabenazine for 4 days when administered once. In some embodiments, the method comprises administering the pharmaceutical composition to provide a pharmacokinetic profile in a subject, characterized by the following. a) an average T of R,R-tetrabenazine of about 10 hours to about 24 hours, such as about 20 hours max ; b) an average T of R,R-tetrabenazine max later than the average T of R,R,R-HTBZ max and the average T of S,R,R-HTBZ max ; c) an average C of R,R-tetrabenazine of about 300 pg / ml to about 700 pg / ml max ; d) an average C of R,R,R-HTBZ of about 60 pg / ml to about 200 pg / ml max ; e) an average C of S,R,R-HTBZ of about 1000 pg / ml to about 3000 pg / ml max ; f) an average AUC of R,R-tetrabenazine of about 20 ng*hour / ml to about 50 ng*hour / ml 0-96 ; g) an average AUC of R,R,R-HTBZ of about 4 ng*hour / ml to about 12 ng*hour / ml 0-96 ; and / or h) an average AUC of S,R,R-HTBZ of about 70 ng*hour / ml to about 200 ng*hour / ml 0-96 。 In some embodiments, the pharmacokinetic profile in a subject is characterized by any one of a) to 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) to h). In some embodiments, the pharmacokinetic profile in a subject provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ upon administration, and the maximum plasma concentration of R,R-tetrabenazine For The combined maximum plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ of The ratio 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, the pharmacokinetic profile in a subject provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ upon administration, and the steady-state plasma concentration of R,R-tetrabenazine For The combined steady-state plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ of The ratio 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, R,R,R-HTBZ For S,R,R-HTBZ ofThe ratio of the maximum plasma concentration or steady-state plasma concentration 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 the maximum plasma concentration 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 the steady-state plasma concentration 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, upon administration, the ratio of the AUC of SRR-HTBZ 0-∞ to the AUC of R,R-tetrabenazine 0-∞ is about 1 to about 15, e.g., about 1.5 to about 11, and / or the ratio of the AUC of RRR-HTBZ 0-∞ to the AUC of R,R-tetrabenazine 0-∞A pharmacokinetic profile can be provided that is characterized in that the ratio to is from about 0.1 to about 0.75, such as from about 0.15 to about 0.5. In some embodiments, the desired PK profile also provides, upon administration, 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, such as 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 also provides, upon administration, a substantially constant steady-state plasma concentration of R,R-tetrabenazine greater than 150 pg / ml (such as from about 150 pg / ml to about 3000 pg / ml) for at least 6 hours, or at least 12 hours, preferably at least 24 hours, such as 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, upon administration, no detectable S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ is provided in the plasma of the subject. In some embodiments, the present disclosure also provides a method of identifying a pharmaceutical composition for treating hyperkinetic movement disorders. In some embodiments, the method includes administering a test pharmaceutical composition that bypasses first-pass metabolism to a subject and identifying a pharmaceutical composition that provides any combination of the PK profiles described in this paragraph when administered to provide a dose of about 2 mg / day for 4 days.

[0046] In some embodiments, when the pharmaceutical composition is administered once, it is formulated to provide a dose of R,R-tetrabenazine of at least 1 day, such as 2 days, 3 days, 4 days, or 1 week, about 4 - 6 mg / day. In some embodiments, the method includes administering a pharmaceutical composition to provide a pharmacokinetic profile in a subject, characterized by the following. a) An average T of R,R-tetrabenazine of about 10 hours to about 24 hours, such as about 20 hours max ; b) An average T of R,R-tetrabenazine that is slower than the average T of max the slower R,R,R-HTBZ and the average T of max S,R,R-HTBZ max ; c) An average C of R,R-tetrabenazine of about 600 pg / ml to about 2100 pg / ml max ; d) An average C of R,R,R-HTBZ of about 120 pg / ml to about 600 pg / ml max ; e) An average C of S,R,R-HTBZ of about 2000 pg / ml to about 9000 pg / ml max ; f) An average AUC of R,R-tetrabenazine of about 40 ng*hour / ml to about 150 ng*hour / ml 0-96 ; g) An average AUC of R,R,R-HTBZ of about 8 ng*hour / ml to about 36 ng*hour / ml 0-96 ; and / or h) An average AUC of S,R,R-HTBZ of about 140 ng*hour / ml to about 600 ng*hour / ml 0-96 . In some embodiments, each administration of the pharmaceutical composition provides a dose of R,R-tetrabenazine of about 4 to 6 mg / day over 1 day. In some embodiments, each administration of the pharmaceutical composition provides a dose of R,R-tetrabenazine of about 4 to 6 mg / day over 2 days. In some embodiments, each administration of the pharmaceutical composition provides a dose of R,R-tetrabenazine of about 4 to 6 mg / day over 3 days. In some embodiments, each administration of the pharmaceutical composition provides a dose of R,R-tetrabenazine of about 4 to 6 mg / day over 4 days. In some embodiments, each administration of the pharmaceutical composition provides a dose of R,R-tetrabenazine of about 4 to 6 mg / day over 1 week. In some embodiments, the pharmaceutical composition is the adhesive composition described herein, for example, is included in the transdermal delivery patch described herein, and the pharmaceutical composition can be administered to adhere to the skin of the subject for a desired period of R,R-tetrabenazine delivery, for example, 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 ordinary practice for such compositions, for example, to achieve the desired period of R,R-tetrabenazine delivery, and the depot or implant can be formulated to release about 4 to 6 mg / day of R,R-tetrabenazine for a desired period after being administered (e.g., injected) to the subject. In some embodiments, the pharmacokinetic profile in the subject is characterized by any one of a) - 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) - h).In some embodiments, the pharmacokinetic profile in a subject is such that administration provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ, with the maximum plasma concentration of R,R-tetrabenazine. For Combined maximum plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ of The ratio 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, the pharmacokinetic profile in a subject is such that administration provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ, with the steady-state plasma concentration of R,R-tetrabenazine For Combined steady-state plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ of The ratio 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, R,R,R-HTBZ For S,R,R-HTBZ of The ratio of the maximum plasma concentration or steady-state plasma concentration 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 the maximum plasma concentrations of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ can be in the range of about 17 - 40:3 - 10:50 - 80. In some embodiments, the ratio of the steady-state plasma concentrations of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ can be in the range of about 17 - 40:3 - 10:50 - 80. In some embodiments, administration provides the AUC of SRR-HTBZ 0-∞ of R,R-tetrabenazine0-∞ The ratio to is from about 1 to about 15, such as from about 1.5 to about 11, and / or the AUC of RRR-HTBZ 0-∞ to the AUC of R,R-tetrabenazine 0-∞ A pharmacokinetic profile can be provided, characterized in that the ratio is from about 0.1 to about 0.75, such as from about 0.15 to about 0.5. In some embodiments, the desired PK profile may also, upon administration, provide 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, such as 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 longer. In some embodiments, the desired PK profile may also, upon administration, provide a substantially constant steady-state plasma concentration of R,R-tetrabenazine above 150 pg / ml (such as from about 150 pg / ml to about 3000 pg / ml) for at least 6 hours, or at least 12 hours, preferably at least 24 hours, such as 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 longer. In some embodiments, upon administration, no detectable S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ is provided in the plasma of the subject. 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 comprises administering a test pharmaceutical composition that bypasses first-pass metabolism to a subject, and identifying a pharmaceutical composition that provides any combination of the PK profiles described in this paragraph when administered to provide a dose of about 4 to 6 mg / day for at least 1 day, such as 2 days, 3 days, 4 days, or 1 week.

[0047] In some embodiments, the pharmaceutical composition, when administered as a single dose, is formulated to provide a dose of R,R-tetrabenazine of at least 1 day, such as 2 days, 3 days, 4 days, or 1 week, about 1 to 10 mg / day. In some embodiments, the method includes administering a pharmaceutical composition to provide a pharmacokinetic profile in a subject, characterized by the following. a) An average T of R,R-tetrabenazine of about 10 hours to about 24 hours, such as about 20 hours max ; b) An average T of R,R-tetrabenazine that is slower than the average T of max R,R,R-HTBZ and the average T of max S,R,R-HTBZ max ; c) An average C of R,R-tetrabenazine of about 150 pg / ml to about 3500 pg / ml max ; d) An average C of R,R,R-HTBZ of about 30 pg / ml to about 1000 pg / ml max ; e) An average C of S,R,R-HTBZ of about 500 pg / ml to about 15 ng / ml max ; f) An average AUC of R,R-tetrabenazine of about 10 ng*hour / ml to about 250 ng*hour / ml 0-96 ; g) An average AUC of R,R,R-HTBZ of about 2 ng*hour / ml to about 60 ng*hour / ml 0-96 ; and / or h) An average AUC of S,R,R-HTBZ of about 35 ng*hour / ml to about 1000 ng*hour / ml 0-96 。 In some embodiments, each administration of the pharmaceutical composition provides a dose of R,R-tetrabenazine of about 1 to 10 mg / day over 1 day. In some embodiments, each administration of the pharmaceutical composition provides a dose of R,R-tetrabenazine of about 1 to 10 mg / day over 2 days. In some embodiments, each administration of the pharmaceutical composition provides a dose of R,R-tetrabenazine of about 1 to 10 mg / day over 3 days. In some embodiments, each administration of the pharmaceutical composition provides a dose of R,R-tetrabenazine of about 1 to 10 mg / day over 4 days. In some embodiments, each administration of the pharmaceutical composition provides a dose of R,R-tetrabenazine of about 1 to 10 mg / day over 1 week. In some embodiments, the pharmaceutical composition is an adhesive composition described herein, for example, is included in a transdermal delivery patch described herein, and the pharmaceutical composition can be administered to adhere to the skin of a subject for a desired period of R,R-tetrabenazine delivery, for example, 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 normal practice for such compositions, for example, to achieve a desired period of R,R-tetrabenazine delivery, and a depot or implant can be formulated to release about 1 to 10 mg / day of R,R-tetrabenazine for a desired period after being administered (e.g., injected) to a subject. In some embodiments, the pharmacokinetic profile in a subject is characterized by any one of a) to 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) to h).In some embodiments, the pharmacokinetic profile in a subject provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ upon administration, with the maximum plasma concentration of R,R-tetrabenazine. For Combined maximum plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ of The ratio 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, the pharmacokinetic profile in a subject provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ upon administration, with the steady-state plasma concentration of R,R-tetrabenazine For Combined steady-state plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ of The ratio 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, R,R,R-HTBZ For S,R,R-HTBZ of The ratio of the maximum plasma concentration or steady-state plasma concentration 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 the maximum plasma concentrations of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ can be in the range of about 17 - 40:3 - 10:50 - 80. In some embodiments, the ratio of the steady-state plasma concentrations of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ can be in the range of about 17 - 40:3 - 10:50 - 80. In some embodiments, upon administration, the AUC of SRR-HTBZ 0-∞ to the AUC of R,R-tetrabenazine0-∞ The ratio to is from about 1 to about 15, such as from about 1.5 to about 11, and / or the AUC of RRR-HTBZ 0-∞ to the AUC of R,R-tetrabenazine 0-∞ is from about 0.1 to about 0.75, such as from about 0.15 to about 0.5. A pharmacokinetic profile can be provided. In some embodiments, the desired PK profile also provides, upon administration, 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, such as 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 also provides, upon administration, a substantially constant steady-state plasma concentration of R,R-tetrabenazine above 150 pg / ml (such as from about 150 pg / ml to about 3000 pg / ml) for at least 6 hours, or at least 12 hours, preferably at least 24 hours, such as 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, upon administration, detectable S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ is not provided in the plasma of the subject. 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 a test pharmaceutical composition that bypasses first-pass metabolism to a subject, and identifying a pharmaceutical composition that provides any combination of the PK profiles described in this paragraph when administered to provide a dose of about 1 to 10 mg / day for at least 1 day, such as 2 days, 3 days, 4 days, or 1 week.

[0048] In some embodiments, the present disclosure provides a method of treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, the method comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising R,R-tetrabenazine, wherein upon administration, (1) the plasma concentration of R,R-tetrabenazine increases during a first period and reaches a maximum concentration of from about 150 pg / ml to about 3500 pg / ml at a first time point of the first period, and optionally (2) after the first period, the plasma concentration of R,R-tetrabenazine may remain substantially constant for a duration, such as about 24 hours, about 48 hours, about 72 hours, about 96 hours, or more. In some embodiments, the first period refers to the first ascending portion of the PK curve until the plasma concentration begins to plateau and / or decline, while the duration refers to the substantially flat portion of the PK curve. For example, refer to the figure for this application observed from transdermal delivery. In some embodiments, the duration may continue as long as treatment is desired. In some embodiments, the first period is from time 0 (the time of administration of the pharmaceutical composition) to about 24 hours thereafter, such as 0 to 20 hours, or 0 to 18 hours. In some embodiments, the first period 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 is from time 0 (the time of administration of the pharmaceutical composition) to the T of R,R-tetrabenazine maxis up to. Typically, the plasma concentration of R,R-tetrabenazine observed during the duration is in the range of about 40% to about 250% of the maximum concentration observed in the first period, and the plasma concentration of R,R-tetrabenazine does not change significantly, for example, by a factor of 2, during any of the intervals of 4 hours, 8 hours, and / or 12 hours of the duration. For example, under the condition that both time t1 and t1 + 12 hours are within the duration, the concentration at time t1 is within about 50% to about 200% of the concentration at time t1 + 12 hours. In some embodiments, during the duration, the minimum plasma concentration of R,R-tetrabenazine is at least about 40%, for example, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% of the maximum concentration of the first period; and / or the maximum plasma concentration of R,R-tetrabenazine is about 250% or less, for example, about 200% or less, about 150% or less, about 120% or less of the maximum concentration of the first period. In some embodiments, the plasma concentration of R,R-tetrabenazine 24 hours after the first time point is about 50% to about 200%, for example, about 75% to about 150% of the plasma concentration at the first time point. In some embodiments, the pharmacokinetic profile in the subject provides therapeutically effective plasma concentrations of R,R-tetrabenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ during the duration by administration, and during the duration, the plasma concentration of R,R-tetrabenazine For The combined plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ of ratio is further characterized in that at a given time point, it is in the range of about 1:1 to about 1:5 (for example, 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, for example, about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some embodiments, during the duration, R,R,R-HTBZ For S,R,R-HTBZ ofThe ratio of plasma concentrations 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.) at a given time point. In some embodiments, during the duration, the ratio of the plasma concentrations of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ can be in the range of about 17 - 40:3 - 10:50 - 80 at a given time point. In some embodiments, during the duration, the ratio of the maximum plasma concentrations of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ can be in the range of about 17 - 40:3 - 10:50 - 80. In some embodiments, administration provides a pharmacokinetic profile characterized in that the ratio of the AUC of SRR-HTBZ 0-∞ to the AUC of R,R-tetrabenazine 0-∞ is about 1 to about 15, e.g., about 1.5 to about 11, and / or the ratio of the AUC of RRR-HTBZ 0-∞ to the AUC of R,R-tetrabenazine 0-∞ is about 0.1 to about 0.75, e.g., about 0.15 to about 0.5. In some embodiments, the PK profile is characterized in that the mean terminal phase half-life of R,R-tetrabenazine is about 8.5 hours ± 40% CV. In some embodiments, administration does not provide a detectable amount of tet S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ in the plasma of the subject. In some embodiments, the present disclosure also provides a method of identifying a pharmaceutical composition for treating hyperkinetic movement disorders. In some embodiments, the method includes administering a test pharmaceutical composition that bypasses first-pass metabolism to a subject and identifying a pharmaceutical composition that provides any combination of the PK profiles described in this paragraph.

[0049] The route for administering the pharmaceutical composition to achieve the PK profile of this specification is not particularly limited as long as the pharmacokinetic profile as described above is provided by the administration. 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 delivers R,R-tetrabenazine typically continuously or substantially continuously to achieve the PK profiles herein. In some embodiments, administration delivers R,R-tetrabenazine to a subject for a period of, for example, from about 8 hours to about 72 hours or more than 72 hours. For example, in some embodiments, administration delivers R,R-tetrabenazine to a subject for a period of 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, to provide for continuous or substantially continuous delivery of R,R-tetrabenazine. In some embodiments, during the period of continuous or substantially continuous delivery, R,R-tetrabenazine can be delivered to the subject at a substantially constant rate, for example, with an average delivery rate per hour being substantially the same, for example, within 80 - 125% of the overall average rate. In some embodiments, during the period of continuous or substantially continuous delivery, R,R-tetrabenazine can be delivered to the subject at, for example, a different average delivery rate for each hour. For example, in some embodiments, the average delivery rate may be high initially but then decreases during the course of continuous or substantially continuous delivery. Typically, the exact delivery rate of R,R-tetrabenazine per hour is not critical, and one of ordinary skill in the art, after considering the present disclosure, will know how to select and design an administration regimen to deliver the desired daily dose to a subject to provide the pharmacokinetic profiles described herein. For example, in some embodiments, R,R-tetrabenazine can be delivered to a subject at a daily dose of from about 0.1 mg / day to about 20 mg / day, for example, R,R-tetrabenazine at about 0.5 mg / day to about 10 mg / day, R,R-tetrabenazine at about 0.5 mg / day to about 8 mg / day, or R,R-tetrabenazine at about 2 mg / day to about 6 mg / day, to provide the pharmacokinetic profiles described herein.

[0051] The hyperkinetic movement disorders described in the treatment methods of this specification include any of those described in this specification. Non-limiting examples include Huntington's disease, Wilson's disease, Tourette 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, such as 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 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 dyskinesia disorder.

[0052] The treatment methods of this specification are not limited to a specific type of subject. For example, the methods of this specification can be administered to a subject regardless of the subject's feeding status. In some embodiments, the subject is a pediatric and adolescent patient (e.g., 6 to 18 years old). Also, in some embodiments, this method is not limited to subjects of a specific genotype. In some embodiments, the same dose or substantially the same dose of R,R-tetrabenazine can be administered to a subject characterized as PM, IM, or EM. In some embodiments, the subject is characterized as EM. In some embodiments, the subject is characterized as PM. In some embodiments, the subject is characterized as IM. In some embodiments, this method does not require the dose setting and / or genotype analysis required when treated with either Xenazine® and Austedo™ tablets.

[0053] The dosing regimen of the treatment methods described herein is not particularly limited as long as the desired dose of R,R-tetrabenazine is delivered to the subject at the desired rate for the desired period, including any of those described herein. For example, in some embodiments, the pharmaceutical composition is administered to the subject in 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, e.g., 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 sustained or substantially sustained 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. As discussed herein, there may be no delay time, no overlap, or some delay time between two consecutive administrations.

[0054] Pharmaceutical compositions suitable for various routes of administration of the methods of this specification are also described. Typically, for transdermal delivery, the pharmaceutical composition can include an active ingredient dispersed in an adhesive (preferably a pressure-sensitive adhesive), for example, an adhesive composition in a transdermal delivery device. 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 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, for example, 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 includes an active ingredient dispersed in a non-reactive acrylate pressure-sensitive adhesive. The active ingredient can be present in an amount of from about 1 wt% to about 20 wt%, by way of example about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 10 wt%, about 15 wt%, about 20 wt%, or any range between the recited values, for example, from about 1 wt% to about 15 wt%, from about 2 wt% to about 15 wt%, from about 2 wt% to about 10 wt%, from about 2 wt% to about 7 wt%, from about 3 wt% to about 15 wt%, from about 3 wt% to about 10 wt%, from about 3 wt% to about 7 wt%, from about 5 wt% to about 15 wt%, from about 5 wt% to about 10 wt%, from about 5 wt% to about 7 wt%, from about 7 wt% to about 15 wt%, from about 7 wt% to about 10 wt%, from about 10 wt% to about 20 wt%, from about 10 wt% to about 15 wt%, etc. In some embodiments, the adhesive composition includes 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 the 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 described in Exemplary Embodiments 2-7.The adhesive is typically present in an amount of about 50% to about 97% by weight, for example, about 50% by weight, about 60% by weight, about 70% by weight, about 80% by weight, about 90% by weight, about 95% by weight, or about 97% by weight, or any range between the recited values, such as about 50% to about 95% by weight, about 50% to about 90% by weight, about 50% to about 80% by weight, about 50% to about 70% by weight, about 50% to about 60% by weight, about 60% 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, about 80% to about 90% by weight, etc. In some specific embodiments, the active ingredient is in an amount of about 2% to about 7% by weight, and the non-reactive acrylate pressure-sensitive adhesive is in an amount of about 50% to about 97% by weight. The adhesive composition can also optionally contain other components such as antioxidants, crystallization inhibitors, plasticizers, and / or permeation enhancers. In some embodiments, the adhesive composition contains an antioxidant, such as a gallic acid antioxidant, for example, propyl gallate. The amount of the antioxidant is typically in an amount of about 0% to about 1% by weight, for example, about 0.001% by weight, about 0.01% by weight, about 0.1% by weight, about 0.5% by weight, about 1% by weight, or any range between the recited values, such as about 0.001% to about 0.5% by weight, about 0.01% to about 0.5% by weight, etc. In some embodiments, the adhesive composition contains a crystallization inhibitor, for example, means to prevent the formation of drug crystals (crystals of the active ingredient of the adhesive composition such as (R,R)-tetrabenazine) after storage at room temperature for 2 weeks at ambient temperature.In some embodiments, the adhesive composition comprises a crystallization inhibitor selected from 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 (Asland)), cellulose-based polymers (e.g., hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose), polycarboxylic acid polymers (e.g., Cabopol (manufactured by Lubrizol)), polymethacrylates (e.g., Plastoid B, Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, polyvinyl acetate, and polyvinylcaprolactam-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 polymethacrylates (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 polyvinylcaprolactam-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 wt%, e.g., about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 30 wt%, about 40 wt%, or any range between the recited values, e.g., about 10 wt% to about 40 wt%, about 10 wt% to about 30 wt%, about 10 wt% to about 20 wt%, 15 wt% to about 40 wt%, about 15 wt% to about 30 wt%, about 15 wt% to about 20 wt%, 20 wt% to about 40 wt%, about 20 wt% to about 30 wt%, etc.In some embodiments, the adhesive composition may also include a skin penetration enhancer as described herein, such as isopropyl myristate. In some embodiments, the adhesive composition may also not include a skin penetration enhancer as described herein; for example, in some embodiments, the adhesive composition may also not include isopropyl myristate. Suitable drug loading, active surface area, thickness, adhesive properties, etc. include any combination of those described herein. Pharmaceutical compositions suitable for other delivery routes include those described herein.

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

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

[0057] Pharmaceutical compositions such as the adhesive compositions specified 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, the method including administering an identified pharmaceutical composition to a subject in need thereof.

[0058] Sustained Delivery of Deutetrabenazine Some embodiments of the present disclosure are directed to the sustained or substantially sustained delivery of deutetrabenazine. Those skilled in the art will understand that in any of the embodiments described herein, deutetrabenazine, such as dutetrabenazine, can replace some or all of the tetrabenazine for each respective composition, device, or method. It will be understood that the in vitro and / or in vivo parameters of such replaced compositions, devices, or methods may be different, particularly as these parameters are related to pharmacokinetics and thus the metabolic profile of tetrabenazine may be modified by deuteration.

[0059] In some embodiments, the present disclosure is a method of treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, 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 delivers continuously or substantially continuously from about 0.1 mg / day to about 20 mg / day of deuterated R,R-tetrabenazine, such as 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, from about 1 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine, from about 1 mg / day to about 4 mg / day of deuterated R,R-tetrabenazine, from about 2 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, from about 2 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, from about 2 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine, from about 2 mg / day to about 4 mg / day of deuterated R,R-tetrabenazine, from about 4 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, from about 4 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, from about 4 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine, from about 6 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, or from about 6 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, to the subject. In some preferred embodiments, the method delivers from about 0.5 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine or from 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 up to more than 72 hours.For example, in some embodiments, administration can provide for sustained or substantially sustained delivery of deuterated 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, deuterated R,R-tetrabenazine can be delivered to the subject at a substantially constant rate, for example, with an average delivery rate per hour being substantially the same, for example, within 80-125% of the overall average rate. In some embodiments, during the period of sustained or substantially sustained delivery, deuterated R,R-tetrabenazine can be delivered to the subject at, for example, different average delivery rates for each time. For example, in some embodiments, the average delivery rate may be high initially but then decreases during the process of sustained or substantially sustained delivery. Typically, the exact delivery rate of deuterated R,R-tetrabenazine per hour is not critical, and those skilled in the art after considering the present disclosure will know how to select and design a dosing regimen to deliver a desired daily amount to the 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 amount to the subject also provides a pharmacokinetic profile as described herein.

[0060] In some embodiments, the present disclosure provides a method of treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, the method comprising administering to the subject a pharmaceutical composition comprising an active ingredient comprising deuterated R,R-tetrabenazine, wherein administration provides a pharmacokinetic profile (PK profile). For example, in some embodiments, the desired PK profile provides therapeutically effective plasma concentrations of deuterated R,R-tetrabenazine, deuterated R,R,R-dihydrotetrabenazine (HTBZ), and deuterated S,R,R-HTBZ upon administration, and the maximum plasma concentration of deuterated R,R-tetrabenazineFor Combined maximum plasma concentration of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ of The ratio 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., C of deuterated R,R-tetrabenazine max / (C of deuterated R,R,R-HTBZ max + C of deuterated S,R,R-HTBZ max ) is in the range of about 1:1 to about 1:7.5, or the steady-state plasma concentration of deuterated R,R-tetrabenazine For Combined steady-state plasma concentration of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ of The ratio is in the range of about 1:1 to about 1:7.5. As used herein, the 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. A combination of the three compounds is sufficient, for example, if it is therapeutically effective at their respective steady-state concentrations. In some embodiments, deuterated R,R,R-HTBZ For Deuterated S,R,R-HTBZ of The ratio of the maximum plasma concentration or steady-state plasma concentration 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 the 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 - 11:50 - 85. In some embodiments, by administration, the AUC of deuterated SRR-HTBZ 0-∞ of the AUC of deuterated R,R-tetrabenazine 0-∞The ratio to is from about 1 to about 15, such as from about 1.5 to about 11, and / or the AUC of deuterated RRR-HTBZ 0-∞ of deuterated R,R-tetrabenazine 0-∞ The ratio to is from about 0.1 to about 0.75, such as from about 0.15 to about 0.5, and a pharmacokinetic profile can be provided. In some embodiments, the desired PK profile also provides, upon administration, 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, such as 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 also provides, upon administration, a substantially constant steady-state plasma concentration of deuterated R,R-tetrabenazine greater than 150 pg / ml (such as from about 150 pg / ml to about 3000 pg / ml) for at least 6 hours, or at least 12 hours, preferably at least 24 hours, such as 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 a detectable amount 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 the subject a test pharmaceutical composition that bypasses first-pass metabolism and delivers deuterated R,R-tetrabenazine to the subject continuously or substantially continuously, and identifying a pharmaceutical composition that provides any combination of the PK profiles described in this paragraph.

[0061] In some embodiments, the present disclosure provides a method of treating 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 administration results in a PK profile characterized by: (1) the plasma concentration of deuterated R,R-tetrabenazine increasing during a first period and reaching a maximum concentration of from about 150 pg / ml to about 3500 pg / ml at a first time point of the first period; and optionally (2) after the first period, the plasma concentration of deuterated R,R-tetrabenazine remaining substantially constant for a duration, such as about 24 hours, about 48 hours, about 72 hours, about 96 hours, or more. In some embodiments, the first period refers to the initial ascending portion of the PK curve until the plasma concentration begins to plateau and / or decline, while the duration refers to the substantially flat portion of the PK curve. See, for example, the figure for this application observed from transdermal delivery. In some embodiments, the first period is from time 0 (the time of administration of the pharmaceutical composition) to about 24 hours thereafter, such as 0 to 20 hours, or 0 to 18 hours. In some embodiments, the first period 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 is from time 0 (the time of administration of the pharmaceutical composition) to the T of deuterated R,R-tetrabenazine maxUp to. Typically, the plasma concentration of deuterated R,R-tetrabenazine observed during the duration is in the range of 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, for example, by a factor of 2, during any of the intervals of 4 hours, 8 hours, and / or 12 hours of the duration. For example, under the condition that both time t1 and t1 + 12 hours are within the duration, the concentration at time t1 is within about 50% to about 200% of the concentration at time t1 + 12 hours. In some embodiments, during the duration, the minimum plasma concentration of deuterated R,R-tetrabenazine is at least about 40%, for example, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% of the maximum concentration of the first period; and / or the maximum plasma concentration of deuterated R,R-tetrabenazine is about 250% or less, for example, about 200% or less, about 150% or less, about 120% or less of the maximum concentration of the first period. In some embodiments, the plasma concentration of deuterated R,R-tetrabenazine 24 hours after the first time point is about 50% to about 200%, for example, about 75% to about 150% of the plasma concentration at the first time point. In some embodiments, the pharmacokinetic profile in the subject provides therapeutically effective plasma concentrations of deuterated R,R-tetrabenazine, deuterated R,R,R-dihydrotetrabenazine (HTBZ) and deuterated S,R,R-HTBZ during the duration by administration, and during the duration, the plasma concentration of deuterated R,R-tetrabenazine For The combined plasma concentration of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ of The ratio is further characterized in that at a given time point, it is in the range of about 1:1 to about 1:7.5 (for example, 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, for example, about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some embodiments, during the duration, deuterated R,R,R-HTBZ For Deuterated S,R,R-HTBZ ofThe ratio of plasma concentrations 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.) at a given time point. In some embodiments, during the duration, the ratio of the 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 - 11:50 - 85 at a given time point. In some embodiments, during the duration, the ratio of the 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 - 11:50 - 85. In some embodiments, administration provides a pharmacokinetic profile characterized in that the ratio of the AUC of deuterated SRR - HTBZ 0-∞ to the AUC of deuterated R,R - tetrabenazine 0-∞ is about 1 to about 15, e.g., about 1.5 to about 11, and / or the ratio of the AUC of deuterated RRR - HTBZ 0-∞ to the AUC of deuterated R,R - tetrabenazine 0-∞ is about 0.1 to about 0.75, e.g., about 0.15 to about 0.5. In some embodiments, the PK profile is characterized in that the mean terminal - phase half - life of deuterated R,R - tetrabenazine is 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 present disclosure also provides a method of identifying a pharmaceutical composition for treating hyperkinetic movement disorders. In some embodiments, the method includes administering a test pharmaceutical composition that bypasses first - pass metabolism to a subject and identifying a pharmaceutical composition that provides any combination of the PK profiles described in this paragraph.

[0062] The route for administering the pharmaceutical composition to achieve the PK profile of the present specification is not particularly limited as long as the pharmacokinetic profile as described above is provided by the administration. Typically, the administration bypasses the 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 delivers deuterated R,R-tetrabenazine to a subject typically continuously or substantially continuously to achieve the PK profiles 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 delivers 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 to provide continuous or substantially continuous delivery of deuterated R,R-tetrabenazine. In some embodiments, during the period of continuous or substantially continuous delivery, deuterated R,R-tetrabenazine can be delivered to the subject at a substantially constant rate, e.g., the average delivery rate per time is substantially the same, e.g., within 80-125% of the overall average rate. In some embodiments, during the period of continuous or substantially continuous delivery, deuterated R,R-tetrabenazine can be delivered to the subject at, for example, a different average delivery rate for each time. For example, in some embodiments, the average delivery rate may be high initially but then decreases during the course of continuous or substantially continuous delivery. Typically, the exact delivery rate of deuterated R,R-tetrabenazine per hour is not critical, and one of ordinary skill in the art, after considering the present disclosure, will know how to select and design a dosing regimen to deliver the desired daily amount of the drug to the subject to provide the pharmacokinetic profiles described herein. For example, in some embodiments, deuterated R,R-tetrabenazine is delivered to the subject at a daily amount of about 0.1 mg / day to about 20 mg / day, e.g., deuterated R,R-tetrabenazine at about 0.5 mg / day to about 10 mg / day, deuterated R,R-tetrabenazine at about 0.5 mg / day to about 8 mg / day, or deuterated R,R-tetrabenazine at about 2 mg / day to about 6 mg / day to provide the pharmacokinetic profiles described herein.

[0064] The hyperkinetic movement disorders described in the treatment methods of this specification include any of those described in this specification. Non-limiting examples include Huntington's disease, Wilson's disease, Tourette 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, such as 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 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 a tic. In some embodiments, the hyperkinetic movement disorder can be dyskinetic cerebral palsy. In some embodiments, the hyperkinetic movement disorder is a dystonia or dyskinesia disorder.

[0065] The treatment methods of this specification are not limited to a particular type of subject. For example, the methods of this specification can be administered to a subject regardless of the subject's feeding status. In some embodiments, the subject is a pediatric and adolescent patient (e.g., 6 to 18 years old). Also, in some embodiments, this method is not limited to subjects of a particular genotype. In some embodiments, the same dose or substantially the same dose of deuterated R,R-tetrabenazine can be administered to a subject characterized as PM, IM, or EM. In some embodiments, the subject is characterized as EM. In some embodiments, the subject is characterized as PM. In some embodiments, the subject is characterized as IM. In some embodiments, this method does not require the dose setting and / or genotype analysis required when treated with either Xenazine® and Austedo™ tablets.

[0066] The dosing regimen of the treatment methods of this specification is not particularly limited as long as the desired dose of deuterated R,R-tetrabenazine is delivered to the subject at the desired rate for the desired period, including any of those described in this specification. For example, in some embodiments, the pharmaceutical composition is administered to the subject in a dosing regimen suitable to achieve the PK profile of this specification. In some embodiments, the pharmaceutical composition is administered to the subject once a day. 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 sustained or substantially sustained 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 described herein are also described. Typically, for transdermal delivery, the pharmaceutical composition can include an active ingredient dispersed in an adhesive (preferably a pressure-sensitive adhesive), for example, 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 deuterated 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, for example, any of those described in embodiments 1-18 applicable to deuterated tetrabenazine, or any of the specific compositions shown in the Examples section where tetrabenazine is replaced with deuterated tetrabenazine (e.g., Example 4A). The type of adhesive, the amount, the amount of the active ingredient, other ingredients and amounts include any of those suitable for tetrabenazine as described herein, except that tetrabenazine is replaced with deuterated tetrabenazine. In some embodiments, the adhesive composition may also include a skin penetration enhancer such as isopropyl myristate as described herein. In some embodiments, the adhesive composition may also not include a skin penetration enhancer as described herein. For example, in some embodiments, the adhesive composition may also not include isopropyl myristate. Pharmaceutical compositions suitable for other delivery routes include those described herein. In any of the applicable embodiments, deuterated tetrabenazine can be a substantially pure R,R-isomer of deuterated tetrabenazine, for example, R,R-dutetrabenazine. 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 the free base form.

[0068] Typically, the methods herein deliver either R,R-tetrabanazine or deuterated R,R-tetrabanazine to a subject in need thereof, although the disclosure also contemplates delivering a mixture of R,R-tetrabanazine 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 tetrabanazine or deuterated tetrabanazine to a subject in need thereof. Pharmaceutical compositions suitable for transdermal delivery include, for example, any of those described herein, or any of the specific compositions shown in the Examples section (e.g., Example 4A), as described in exemplary embodiments 1-18. Transdermal pharmaceutical compositions and transdermal delivery devices are also novel aspects of the disclosure.

[0070] Transdermal Delivery Device for Tetrabenazine In various embodiments, the present invention is directed to a pharmaceutical composition or a transdermal delivery device comprising tetrabenazine and / or deuterated tetrabenazine (e.g., dutetrabenazine). The pharmaceutical composition and the transdermal delivery device provide novel options for transdermally delivering tetrabenazine and / or deuterated tetrabenazine to a subject in need thereof. Tetrabenazine and / or deuterated tetrabenazine has not previously been shown to be administrable via the transdermal route. As detailed herein, the inventors have applied the transdermal delivery devices and pharmaceutical compositions (e.g., the adhesive compositions herein) disclosed herein to a subject and achieved a therapeutically effective flux, and thus have shown that it can be useful for the treatment of various diseases or disorders, such as hyperkinetic movement disorders, by way of example. See, e.g., PCT / US2019 / 028900, the contents of which are hereby incorporated by reference in their entirety.

[0071] Certain embodiments of the present disclosure are directed to transdermal delivery devices that include tetrabenazine or deuterated tetrabenazine (e.g., dutetrabenazine). In some embodiments, the transdermal delivery device includes a backing layer, a drug layer that includes a drug selected from tetrabenazine, deuterated tetrabenazine (e.g., dutetrabenazine), and combinations thereof, and an adhesive layer that defines an active surface area. In some embodiments, the drug is present in an amount of about 2 wt% to about 30 wt% of the drug layer. In some embodiments, the transdermal delivery device includes a single drug layer. In some embodiments, the transdermal delivery device includes a plurality of drug layers. In some embodiments, the transdermal delivery device includes a single adhesive layer. In some embodiments, the transdermal delivery device includes a plurality of adhesive layers.

[0072] A variety of patch designs can be used for the transdermal delivery devices described 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, two drug-in-adhesive layers can be included in the patch, 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 of the layers releases the drug relatively quickly over a relatively short period of time and the other layer releases the drug over a more sustained period.

[0073] The transdermal delivery device of this specification can also use a drug-containing reservoir (DIR) design. In some embodiments, the drug layer and the adhesive layer can be two separate layers that are laminated or separated from each other, for example, by a rate-controlling membrane. For example, in some embodiments, the drug layer is a reservoir layer such as a drug matrix with an adhesive layer laminated thereon.

[0074] Other patch designs can also be used for the transdermal delivery device of this specification. For example, in some embodiments, the transdermal delivery device can be an active patch such as an iontophoresis 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 enhancements in chemical or physical modes.

[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 of this specification. 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 the desired size of the present invention. The release liner can be composed of a silicone or fluoropolymer-coated polyester film. The release liner protects the transdermal delivery device during storage and is removed before use. Examples of silicone-coated release liners include those manufactured by Mylan Corporation, Loparex Corporation, and 3M’s Drug Delivery Systems. Examples include those manufactured and supplied by 3M’s Drug Delivery Systems and Loparex. In some embodiments, the release liner includes 3M's ScotchPak 9744 or Scotchpak 1022.

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

[0078] When applying the transdermal delivery device (e.g., DIA patch) of this specification to the skin of a subject, theoretically, it is possible that all of the adhesive surface comes into contact with the skin. Thus, the area of the adhesive surface defines the skin contact area through which the active ingredient can permeate the skin from the device, which is also referred to as the active surface area herein. In some embodiments, the adhesive surface is the only surface of the transdermal delivery device that contacts the skin during 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 contact the skin during application, and the entire skin contact area is the active surface area.

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

[0080] Drug layer Typically, the drug layer contains tetrabenazine, deuterated tetrabenazine, or a combination thereof. In some embodiments, the drug layer can optionally contain one or more other components selected from, for example, a transdermal penetration enhancer, a humectant, a plasticizer, an antioxidant, an anti-irritant, a gelling agent, a drug release regulator, a solvent, a crystallization inhibitor, and additional active ingredients. In some embodiments, the drug layer is adjusted such that the transdermal delivery device achieves the skin flux characteristics described herein. It should be noted that the pharmaceutical composition used for the drug layer herein can also be a novel formulation, regardless of the transdermal delivery device and / or the skin flux characteristics herein. Thus, some embodiments of the present disclosure also aim at such pharmaceutical compositions.

[0081] In some embodiments, the drug in the drug layer can be tetrabenazine. Tetrabenazine in the transdermal delivery device described herein is not limited to a specific enantiomer and can be in racemic form, 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. In some embodiments, tetrabenazine in the transdermal delivery device is in racemic form. In some embodiments, 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 can also contain other active ingredients.

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

Chem.

[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 wt% to about 30 wt% of the drug layer (e.g., about 2 wt%, about 2.5 wt%, about 5 wt%, about 8 wt%, about 10 wt%, about 15 wt%, about 18 wt%, about 20 wt%, about 25 wt%, about 30 wt%, or any range between the recited values). In some particular embodiments, the drug layer comprises tetrabenazine, deuterated tetrabenazine, or a combination thereof, in an amount of about 2 wt%, about 2.5 wt%, about 5 wt%, about 8 wt%, about 10 wt%, about 15 wt%, or about 20 wt% of the drug layer. In some embodiments, 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 the desired duration of administration. The drug layer is typically designed for application (e.g., delivery of tetrabenazine or dutetrabenazine) 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 is from about 0.01 g / cm 2 to about 5 g / cm 2 , e.g., from about 0.05 g / cm 2 to about 5 g / cm 2 , from about 0.1 g / cm 2 to about 5 g / cm 2 , by way of example from about 0.05 g / cm 2 to about 0.90 g / cm 2 , from about 0.1 g / cm 2 to about 0.90 g / cm 2 (e.g., from about 0.1 g / cm 2 to about 0.5 g / cm 2) It can have a coating weight of the active surface area such as etc. In some embodiments, the drug layer can have a thickness of about 1.5 mil to about 10 mil, for example, about 1.5 mil to about 3.5 mil (for example, 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, for example, about 1 mil to about 50 mil (for example, about 1 mil to about 10 mil, or about 1.5 mil to about 3.5 mil).

[0085] The skin penetration enhancer can enhance the skin permeability of tetrabenazine or deuterated tetrabenazine through the skin and can be optionally included in the drug layer. In some embodiments, the drug layer does not contain or substantially does not contain a penetration enhancer. However, in some embodiments, various skin penetration enhancers can be included. Non-limiting and useful skin penetration 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, for example, Williams et al., Adv Drug Deliv Rev. 27;56(5):603-18(2004). In some embodiments, the penetration enhancer comprises one or more compounds selected from sulfoxides, alcohols, alkanols, esters, glycols, and surfactants. In some embodiments, the penetration enhancer comprises one or more compounds selected from dimethyl sulfoxide (DMSO), alcohol oleate, oleyl oleate, oleic acid, levulinic acid, other fatty acids and fatty acid esters, propylene glycol, dipropylene glycol, ethanol, and surfactants such as Tween80. The skin penetration enhancer is typically included in an amount of about 1 wt% to about 25 wt% of the pharmaceutical composition, for example, about 2 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt% of the pharmaceutical composition, or any range between the recited values.

[0086] Other suitable excipients, such as wetting agents, plasticizers, antioxidants, anti-irritants, gelling agents, crystallization inhibitors, drug release regulators, etc., can also be included in the drug layer (e.g., drug-containing adhesive layer) of the present specification or otherwise in the transdermal delivery device. In some embodiments, additional active ingredient(s) can also be included in the drug layer of the present specification or otherwise in the transdermal delivery device. These excipients are within the knowledge of those skilled in the art and can be found, for example, in the Handbook of Pharmaceutical Excipients, (7 th ed. 2012), the entire content of which is 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 DIR patches, can also include an adhesive layer separated from the drug layer by a membrane, for example. 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 includes 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). Useful PSAs, which are non-limiting, include polyisobutylene (PIB), silicone polymers, acrylate copolymers, and combinations thereof. In some embodiments, the pressure-sensitive adhesive includes a polyisobutylene adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some embodiments, the pressure-sensitive adhesive includes an acrylate copolymer adhesive. Useful acrylate copolymers, which are non-limiting, include, for example, poly(acrylate / vinyl acetate) copolymers, such as acrylic pressure-sensitive adhesives like 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 (e.g., Duro-Tak 87-900A as described herein), for example, an acrylate adhesive having no functional groups containing reactive hydrogen moieties, or an acrylate adhesive having no functional groups selected from epoxy, -OH, -COOH, and combinations thereof. PIB is an elastomeric polymer commonly used as both a primary base polymer and a tackifier in PSAs. PIB is a homopolymer of isobutylene and is characterized by a regular structure of a hydrocarbon backbone that is unsaturated only at the ends. Useful PIBs, which are non-limiting, include those sold under the trade name Oppanol by BASF. However, in some embodiments, the pressure-sensitive adhesive does not include a PIB-based adhesive. A silicone polymer is a high molecular weight polydimethylsiloxane that includes residual silanol functional groups (SiOH) at the ends of the polymer chains.Non-limiting useful silicone PSAs for use in pharmaceutical applications include, for example, those available from Dow Corning Corporation under the trade name BIO-PSA, such as BIO-7-4202. In some embodiments, the adhesive layer is from about 1.5 mil to about 10 mil (e.g., from about 1.5 mil to about 2 mil) in thickness.

[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., an acrylate adhesive to silicone adhesive ratio in the range of about 1:10 to about 10:1). As detailed in the Examples section, changing the adhesive components can affect the flux characteristics of the transdermal delivery device.

[0090] The adhesive layer is typically formulated such that the transdermal delivery device can adhere to the user's skin for a desired period of time. For example, in some embodiments, the transdermal delivery device can adhere continuously 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 longer.

[0091] Adhesive composition In some embodiments, the invention also provides an adhesive composition comprising a drug selected from tetrabenazine, deuterated tetrabenazine (e.g., dutetrabenazine), and combinations thereof in the 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 can adhere persistently to the skin of the user over a long 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 includes 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 having no functional groups containing reactive hydrogen moieties, or an acrylate adhesive having no functional groups selected from epoxy, -OH, -COOH, and combinations thereof. In some embodiments, the pressure-sensitive adhesive does not include a polyisobutylene (PIB) adhesive and / or a silicone polymer adhesive.

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

[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 a humectant, a plasticizer, an antioxidant, an anti-irritant, a gelling agent, a crystallization inhibitor, a drug release regulator, and additional active ingredients. For example, in some embodiments, the adhesive composition can include an antioxidant, such as a gallic acid antioxidant like 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 polyvinylcaprolactam-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, a polyvinyl acetate, and a polyvinylcaprolactam-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 device has a skin flux of about 0.1 mg / day / cm 2 to about 5 mg / day / cm 2 (e.g., about 0.1 mg / day / cm 2 , about 0.2 mg / day / cm 2 , about 0.5 mg / day / cm 2 , about 1 mg / day / cm 2 , about 2 mg / day / cm 2 , about 5 mg / day / cm 2or a drug (e.g., tetrabenazine or deutetrabenazine) within any range between the recited values) to a subject in need thereof over 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 is about 5 mg / day / cm 2 sup, e.g., about 8 mg / day / cm 2 , about 10 mg / day / cm 2 , about 15 mg / day / cm 2 , about 20 mg / day / cm 2 or a drug within any range between the recited values (e.g., tetrabenazine or deutetrabenazine). In some embodiments, the transdermal delivery device is less than about 0.1 mg / day / cm 2 , e.g., about 0.01 mg / day / cm 2 , about 0.02 mg / day / cm 2 , about 0.05 mg / day / cm 2 , about 0.1 mg / day / cm 2 or a drug within any range between the recited values (e.g., tetrabenazine or deutetrabenazine).

[0099] In some embodiments, the transdermal delivery device is about 0.1 mg / day / cm 2 to about 1 mg / day / cm 2 (e.g., about 0.1 mg / day / cm 2 , about 0.2 mg / day / cm 2 , about 0.5 mg / day / cm 2 , about 1 mg / day / cm 2 or a drug within any range between the recited values) to a subject in need thereof over 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 is about 0.1 mg / day / cm 2 to about 5 mg / day / cm 2 (e.g., about 0.1 mg / day / cm 2 , about 0.2 mg / day / cm 2, about 0.5 mg / day / cm 2 , about 1 mg / day / cm 2 , about 5 mg / day / cm 2 , or a drug (e.g., tetrabenazine or deutetrabenazine) within any range between the recited values) can be delivered, for example, over a period exceeding 7 days. In some embodiments, the transdermal delivery device is about 0.1 mg / day / cm 2 ~about 5 mg / day / cm 2 (e.g., about 0.1 mg / day / cm 2 , about 0.2 mg / day / cm 2 , about 0.5 mg / day / cm 2 , about 1 mg / day / cm 2 , or a drug (e.g., tetrabenazine or deutetrabenazine) within any range between the recited values) can be delivered, for example, over a period of less than 24 hours, such as 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 contains tetrabenazine, and when the transdermal delivery device is tested in vitro using human cadaver skin, it has the following skin flux characteristics, namely, a) after 6 hours of administration, based on the active surface area, about 0.1 μg / cm 2 ~about 150 μg / cm 2 (e.g., about 0.1 μg / cm 2 , about 0.5 μg / cm 2 , about 1 μg / cm 2 , about 5 μg / cm 2 , about 10 μg / cm 2 , about 15 μg / cm 2 , about 20 μg / cm 2 , about 50 μg / cm 2 , about 75 μg / cm 2 , about 100 μg / cm 2 , about 125 μg / cm 2 , about 150 μg / cm 2 , or the cumulative tetrabenazine permeated within any range between the recited values); b) after 12 hours of administration, based on the active surface area, about 2 μg / cm 2 ~about 400 μg / cm 2 (e.g., about 2 μg / cm2 , about 5 μg / cm 2 , about 10 μg / cm 2 , about 15 μg / cm 2 , about 20 μg / cm 2 , about 50 μg / cm 2 , about 100 μg / cm 2 , about 200 μg / cm 2 , about 300 μg / cm 2 , about 400 μg / cm 2 , or any range between the stated values) of permeated cumulative tetrabenazine; and c) 24 hours after administration, based on the active surface area, about 5 μg / cm 2 ~about 1000 μg / cm 2 (e.g., about 5 μg / cm 2 , about 10 μg / cm 2 , about 15 μg / cm 2 , about 2 μg / cm 2 , 25 μg / cm 2 , about 50 μg / cm 2 , about 100 μg / cm 2 , about 200 μg / cm 2 , about 300 μg / cm 2 , about 400 μg / cm 2 , 600 μg / cm 2 , 800 μg / cm 2 , 1000 μg / cm 2 , or any range between the stated values) of permeated cumulative tetrabenazine, provides one or more of these. In some embodiments, tetrabenazine is present in an amount of about 2 wt% to about 30 wt% (e.g., about 2 wt% to about 20 wt%, about 2 wt% to about 10 wt%, about 2 wt% to about 5 wt%, about 5 wt% to about 10 wt%, about 10 wt% to about 15 wt%) of the drug layer. In some embodiments, tetrabenazine is present in an amount of about 2 wt%, about 5 wt%, about 8 wt%, about 10 wt%, about 15 wt%, about 20 wt%, or any range between the stated values of the drug layer. In some embodiments, tetrabenazine is substantially pure R,R-tetrabenazine.

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

[0102] In some embodiments, tetrabenazine is present in an amount of about 5 wt% to about 10 wt% of the drug layer, and when the transdermal delivery device is tested in vitro using human cadaver skin, it has the following skin flux characteristics, namely, a) after 6 hours of administration, based on the active surface area, about 0.5 μg / cm 2 to about 150 μg / cm 2 (e.g., about 1 μg / cm 2 , about 5 μg / cm 2 , about 10 μg / cm 2 , about 15 μg / cm 2 , about 20 μg / cm 2 , about 50 μg / cm 2 , about 75 μg / cm 2 , about 100 μg / cm 2 , about 150 μg / cm 2 or any range between the stated values) of the permeated cumulative tetrabenazine; b) after 12 hours of administration, based on the active surface area, about 4 μg / cm 2 to about 400 μg / cm 2 (e.g., about 4 μg / cm 2 , about 6 μg / cm 2 , about 10 μg / cm 2 , about 15 μg / cm 2 , about 20 μg / cm 2 , about 50 μg / cm 2 , about 100 μg / cm 2 , about 200 μg / cm 2 , about 400 μg / cm 2 or any range between the stated values) of the permeated cumulative tetrabenazine; and c) after 24 hours of administration, based on the active surface area, about 6 μg / cm 2 to about 1000 μg / cm 2 (e.g., about 6 μg / cm 2 , about 10 μg / cm 2 , about 15 μg / cm 2 , about 20 μg / cm 2 , 25 μg / cm 2 , about 50 μg / cm 2, about 100 μg / cm 2 , about 200 μg / cm 2 , about 300 μg / cm 2 , about 400 μg / cm 2 , 600 μg / cm 2 , about 1000 μg / cm 2 , or one or more of the cumulative tetrabenazine that has passed through any range between the stated values).

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

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

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

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

[0107] In some embodiments, the present invention provides an adhesive composition comprising an active ingredient (alternatively referred to as a "drug") dispersed (e.g., homogeneously dispersed or dissolved) in a non-reactive acrylate pressure-sensitive adhesive, wherein 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 is present primarily (e.g., at least 80 wt%, at least 90 wt%, or at least 95 wt%) in its free base form, such as tetrabenazine base, deutetrabenazine base, etc. The non-reactive acrylate pressure-sensitive adhesive is typically present in an amount of about 50 wt% to about 97 wt% (e.g., about 50 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, about 97 wt%, or any range between the recited values) of the adhesive composition.

[0108] Examples of non-reactive acrylate pressure-sensitive adhesives useful in embodiments of the present disclosure include those sold under the product name DuroTak 87-900A by Henkel. 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 acrylates that does not have a functional group containing a reactive hydrogen moiety and also 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 comprising, consisting essentially of, or consisting of alkyl acrylates. For example, in some embodiments, the non-reactive acrylate pressure-sensitive adhesive is a copolymer derived from monomers consisting of alkyl acrylates, such as C2-C 18 alkyl acrylates (preferably C4-C 10Copolymers derived from monomers of branched or linear alkyl acrylates) and monomers of methyl acrylate, more preferably, copolymers derived from monomers of ethylhexyl acrylate (e.g., 2-ethylhexyl acrylate) and monomers of methyl acrylate, can be. In some embodiments, the copolymer of alkyl acrylate is a copolymer of ethylhexyl acrylate (e.g., 2-ethylhexyl acrylate), methyl acrylate, and optionally, other monomer(s) having no functional group containing reactive hydrogen moieties such as -OH, -COOH groups. In some embodiments, the non-reactive acrylate pressure-sensitive adhesive can be a copolymer derived from monomers containing alkyl acrylate and other monomers having no functional group containing reactive hydrogen moieties such as -OH, -COOH groups. 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 having no functional group containing reactive hydrogen moieties such as -OH, -COOH groups, such as acrylamide monomers (e.g., tert-octylacrylamide, dimethylacrylamide, isopropylacrylamide, or vinylacetamide). As used herein, amide NH or amide NH2 groups should not be considered as reactive hydrogen moieties. In some embodiments, the non-reactive acrylate pressure-sensitive adhesive is C2-C 18 alkyl acrylate (preferably C4-C 10 branched or linear alkyl acrylate), monomers of methyl acrylate, and one or more acrylamide monomers (e.g., tert-octylacrylamide) having no functional group selected from epoxy, -OH, -COOH groups, and combinations thereof. The weight percentages of the monomers can vary and can be changed. For example, in some embodiments, the percentages of the monomers of the non-reactive acrylate pressure-sensitive adhesive can be as follows: C2-C 18 alkyl acrylate (preferably, C4-C 10The percentage of monomers of branched or linear alkyl acrylates, such as 2-ethylhexyl acrylate, can be about 45 wt%, the percentage of monomers of methyl acrylate can be about 35 wt%, and the percentage of monomers of one or more acrylamide monomers (such as tert-octylacrylamide) can be about 20 wt%.

[0110] Non-reactive acrylate pressure-sensitive adhesives typically do not contain vinyl acetate. Non-reactive acrylate pressure-sensitive adhesives typically do not contain cross-linking agents either. Non-reactive acrylate pressure-sensitive adhesives can typically have various 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 such that the adhesive composition can continuously adhere 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 longer.

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

[0112] Antioxidants are typically included in the adhesive compositions of the present specification. For example, antioxidants can be added to reduce the degree of decomposition of the active ingredient. However, unexpectedly, it has been found that some antioxidants act better than other antioxidants when protecting tetrabenazine from decomposition. For example, it has been found that adhesive compositions containing gallic acid antioxidants (e.g., propyl gallate in the examples) can be stored at room temperature. In any of the embodiments of the present specification, being storable at room temperature, storage stability, or stability after storage at room temperature, etc., for the tested device or composition after storage at room temperature at 40°C for 4 weeks, (1) HPLC analysis shows that the tested device or composition does not contain or substantially does not contain (e.g., less than 1%, less than 0.5%, less than 0.05%, or not detected by HPLC) one or more (preferably all) degradation products selected from TBZ01, TBZ02, and TBZ04, (2) no drug crystals are observed (e.g., not observed visually), which may mean. In some embodiments, all of the degradation products TBZ01, TBZ02, and TBZ04 are not detected by HPLC or below the limit of quantification in the room temperature storable devices or compositions of the present specification after storage at room temperature at 40°C for 4 weeks. Exemplary conditions for HPLC analysis and retention times of TBZ01, TBZ02, and TBZ04 are shown in Example 5. However, when no antioxidant is used, or when the added antioxidant is BHT, degradation products (including TBZ01, TBZ02, TBZ04) are 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, as antioxidants, propyl gallate, citric acid, ascorbic acid, vitamin E or tocopheryl acetate, or combinations thereof.Antioxidants such as propyl gallate, when present, are typically present in an amount of about 0.001 wt% to about 0.5 wt% (e.g., about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%) of the adhesive composition.

[0113] The active ingredient is typically present in the adhesive composition in an amount of about 2 wt% to about 30 wt%. Preferably, in some embodiments, the active ingredient can be present in the adhesive composition in an amount of about 2 wt% to about 15 wt%, such as about 2 wt% to about 10 wt%, or about 2 wt% to about 7 wt%. Tetrabenazine in the adhesive compositions herein is not limited to a particular enantiomer and can 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. Deuterated tetrabenazine in the transdermal delivery devices described herein is not limited to a particular enantiomer and can be in racemic form, substantially pure R,R-isomer, e.g., R,R-dutetrabenazine (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-isomer, e.g., S,S-dutetrabenazine (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-isomer and S,S-isomer in any ratio. In some embodiments, the only active ingredient in the adhesive composition is tetrabenazine, such as substantially pure R,R-isomer of tetrabenazine. In some embodiments, the only active ingredient in the adhesive composition is dutetrabenazine, such as substantially pure R,R-isomer of dutetrabenazine. In some embodiments, the adhesive composition can also contain other active ingredients, for example, as described herein.

[0114] Typically, crystallization inhibitors are also included in the adhesive composition to prevent the formation of drug crystals during storage. Such drug crystals can delay the skin penetration of such adhesive compositions. Thus, 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 two weeks. In some embodiments, the adhesive composition is a polyvinylpyrrolidone polymer (e.g., Kollidon K30 or K90F (manufactured by BASF), Plasdone K20 / 32 or Plasdone K90 (manufactured by Ashland Chemical)), a cross-linked polyvinylpyrrolidone polymer (e.g., Kollidon CL), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone (Asland)), a cellulose-based polymer (e.g., hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose), a polycarboxylic acid polymer (e.g., Cabopol (manufactured by Lubrizol)), a polymethacrylate (e.g., Plastoid B, Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, polyvinyl acetate, and a polyvinylcaprolactam-based graft copolymer (PVAc-PVCap-PEG) (e.g., Soluplus (BASF), and combinations thereof, may include a crystallization inhibitor selected from. In some embodiments, the crystallization inhibitor is not Kollidon VA64 (BASF).

[0115] In some preferred embodiments, the adhesive composition may include a crystallization inhibitor selected from polymethacrylates (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 specific embodiments, the adhesive composition includes a copolymer of butyl methacrylate and methyl methacrylate, such as the polymer manufactured by Evonic under the trade name Plastoid B. In some specific embodiments, the adhesive composition includes polyethylene glycol, polyvinyl acetate, and a 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 in an amount of about 5 wt% to about 40 wt%, for example, about 10 wt%, about 20 wt%, about 30 wt%, about 40 wt%, or any range between the recited values.

[0116] In some specific embodiments, the present invention provides an adhesive composition having the following components.

Table 1

[0117] The adhesive composition (e.g., an adhesive composition comprising a non-reactive acrylate adhesive as described herein) is typically included in a transdermal delivery device, for example, as a drug layer or a drug-containing adhesive layer. For example, in some embodiments, the present disclosure provides a transdermal delivery device comprising a backing layer, any one of the adhesive compositions described herein (e.g., an adhesive composition comprising a non-reactive acrylate adhesive as described herein as a drug layer or a drug-containing adhesive layer), and a release liner. The transdermal delivery device can be cut to different sizes as needed, which is typically about 10 cm 2 to about 100 cm 2 . Other patch designs are described herein. Preferably, the transdermal delivery device herein (and / or, e.g., an adhesive composition comprising a non-reactive acrylate adhesive as described herein) has storage stability (or alternatively, is called room temperature storable), for example, after storage at room temperature at 40°C for 4 weeks, no drug crystals are observed, and / or after storage at room temperature at 40°C for 4 weeks, no drug degradation is observed by HPLC. For example, in some embodiments, the transdermal delivery device herein (and / or, e.g., an adhesive composition comprising a non-reactive acrylate adhesive as described herein) can have storage stability 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 device herein (and / or the adhesive composition) can also be configured to achieve the desired skin permeability of the active ingredient (e.g., tetrabenazine or deutetrabenazine). For example, in some embodiments, the transdermal delivery device (e.g., comprising an adhesive composition comprising a non-reactive acrylate adhesive as described herein) is about 0.01 mg / day / cm 2 to about 5 mg / day / cm 2 (e.g., about 0.01 mg / day / cm 2 , about 0.02 mg / day / cm 2 , about 0.05 mg / day / cm 2 , about 0.1 mg / day / cm 2 , about 0.2 mg / day / cm 2, about 0.5 mg / day / cm 2 , about 1 mg / day / cm 2 , about 2 mg / day / cm 2 , about 5 mg / day / cm 2 , or an active ingredient (e.g., tetrabenazine or deutetetrabenazine) within any range between the recited values, can be delivered to a subject in need thereof over 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, a transdermal delivery device (e.g., comprising an adhesive composition comprising a non-reactive acrylate adhesive described herein) delivers more than about 5 mg / day / cm 2 , e.g., about 8 mg / day / cm 2 , about 10 mg / day / cm 2 , about 15 mg / day / cm 2 , about 20 mg / day / cm 2 , or a drug within any range between the recited values (e.g., tetrabenazine or deutetetrabenazine). In some embodiments, a transdermal delivery device (e.g., comprising an adhesive composition comprising a non-reactive acrylate adhesive described herein) delivers less than about 0.1 mg / day / cm 2 , e.g., about 0.01 mg / day / cm 2 , about 0.02 mg / day / cm 2 , about 0.05 mg / day / cm 2 , about 0.1 mg / day / cm 2 , or an active ingredient (e.g., tetrabenazine or deutetetrabenazine) within any range between the recited values can be delivered.

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

[0120] Method of administering tetrabenazine In various embodiments, the present invention further provides a method of using a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition of the present specification) described herein. In some embodiments, the transdermal delivery device or the pharmaceutical composition can be used for any indication in which inhibition of VMAT-2 is beneficial. In some embodiments, the transdermal delivery device or the pharmaceutical composition can be used to treat or prevent a disease or disorder mediated by VMAT-2. In some embodiments, the transdermal delivery device or the pharmaceutical composition 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 for which the use of tetrabenazine or deuterated tetrabenazine has been approved include hemiballismus, tic disorder, tardive dyskinesia, and Tourette syndrome. Also, in various embodiments, the transdermal delivery device or the pharmaceutical composition can be used for any of these indications.

[0121] In some embodiments, the present invention provides a method 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 of the present specification) to the subject, e.g., to 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 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 dutetrabenazine (e.g., substantially pure R,R-dutetrabenazine).

[0122] In some embodiments, the invention also provides a method of inhibiting vesicular monoamine transporter isoform 2 (VMAT2) in a subject in need of VMAT2 inhibition. In some embodiments, the method comprises applying either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition of the present specification) to the subject, e.g., the skin of the subject.

[0123] In some embodiments, the invention also provides a method of treating a vesicular monoamine transporter isoform 2 (VMAT2)-mediated disease or disorder in a subject (e.g., a human subject) in need of treatment of a VMAT2-mediated disease or disorder. In some embodiments, the method comprises applying either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition of the present specification) to the subject, e.g., the skin of the subject. 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 syndrome, depression, cancer, rheumatoid arthritis, psychosis, multiple sclerosis, asthma, and / or any disorder that can be alleviated, mitigated, or prevented by administration of 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 syndrome.

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

[0125] Tetrabenazine and / or deuterated tetrabenazine (e.g., dutetrabenazine) can be used in the methods herein. Typically, the method includes applying a transdermal delivery device herein that contains either tetrabenazine or dutetrabenazine as the sole active ingredient. In some embodiments, the method includes applying a transdermal delivery device herein that contains, for example, substantially pure R,R-tetrabenazine as the sole active ingredient. In some embodiments, the method includes applying a transdermal delivery device herein that contains substantially pure R,R-dutetrabenazine, for example, as the sole active ingredient.

[0126] In any of the embodiments described herein, the method includes administering to a subject a drug (e.g., tetrabenazine or dutetrabenazine) at about 0.1 mg / day / cm 2 to about 5 mg / day / cm 2 (e.g., about 0.1 mg / day / cm 2 , about 0.2 mg / day / cm 2 , about 0.5 mg / day / cm 2 , about 1 mg / day / cm 2 , about 2 mg / day / cm 2 , about 5 mg / day / cm 2 , or any range between the recited values) 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 includes administering to the subject a drug (e.g., tetrabenazine or dutetrabenazine) at more than about 5 mg / day / cm 2 , e.g., about 8 mg / day / cm 2 , about 10 mg / day / cm 2 , about 15 mg / day / cm 2 , about 20 mg / day / cm 2 , or any range between the recited values. In some embodiments, the method includes administering to a subject a drug (e.g., tetrabenazine or dutetrabenazine) at about 0.1 mg / day / cm 2Less than, for example, about 0.01 mg / day / cm 2 , about 0.02 mg / day / cm 2 , about 0.05 mg / day / cm 2 , about 0.1 mg / day / cm 2 or a drug in any range between the recited values (e.g., tetrabenazine or deutetetrabenazine) may be administered to the subject.

[0127] In some embodiments, the present invention provides a method of treating a vesicular monoamine transporter isoform 2 (VMAT2)-mediated disease or disorder in a subject (e.g., a human subject) in need of treatment of a VMAT2-mediated disease or disorder, the method comprising transdermally administering to the subject a therapeutically effective amount of tetrabenazine or deutetetrabenazine. 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 method can reduce inter-individual variability in plasma levels of tetrabenazine or deutetetrabenazine or their metabolites as compared to oral administration of an equivalent dose of tetrabenazine or deutetetrabenazine. In some embodiments, the method, as compared to oral administration of an equivalent dose of tetrabenazine or deutetetrabenazine, for example, without reducing therapeutic efficacy, the C of tetrabenazine or deutetetrabenazine or their metabolites maxIt can be reduced (e.g., by 10%, 40%, 60%, or more). In some embodiments, this method can provide similar plasma levels of tetrabenazine or deutetrabenazine or their metabolites when equal doses are administered to subjects genotyped as poor metabolizers (PMs), intermediate metabolizers (IMs), or extensive metabolizers (EMs) based on CYP2D6 expression. In some embodiments, the same dose 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 can be useful. In some embodiments, the present disclosure provides the following specific embodiments, SE1 - SE8.

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

[0131] SE2: A method for treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, 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 of this specification, such as a non-reactive acrylate pressure-sensitive adhesive; (3) any crystallization inhibitor; and (4) any antioxidant, and 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 For The combined maximum plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ of The ratio 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 steady-state plasma concentration of R,R-tetrabenazine For The combined steady-state plasma concentration of R,R,R-HTBZ and S,R,R-HTBZ of The ratio 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, R,R,R-HTBZ For S,R,R-HTBZ of The ratio of the maximum plasma concentration or steady-state plasma concentration is 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 SE2, the ratio of the maximum plasma concentration or steady-state plasma concentration of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ is in the range of about 17 - 40:3 - 10:50 - 80. In some embodiments according to SE2, upon application, the AUC of SRR-HTBZ 0-∞ of R,R-tetrabenazine0-∞ The ratio to is from about 1 to about 15, for example, from about 1.5 to about 11, and / or the AUC of RRR-HTBZ 0-∞ to the AUC of R,R-tetrabenazine 0-∞ The ratio to is from about 0.1 to about 0.75, for example, from about 0.15 to about 0.5, and a pharmacokinetic profile can be provided. In some embodiments according to SE2, administration does not provide a detectable amount of S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ in the plasma of the subject. In some embodiments according to SE2, the PK profile is characterized in that the average terminal phase half-life of R,R-tetrabenazine is about 8.5 hours ± 40% CV. In some embodiments according to SE2, the drug-containing adhesive layer can contain any permeation enhancer and / or plasticizer. In some embodiments according to SE2, a transdermal delivery device is applied to transdermally deliver any of the daily doses described in SE1 to a subject. In some embodiments according to SE2, a transdermal delivery device is applied to achieve any combination of the PK profiles described herein.

[0132] SE3: A method for treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, comprising applying to the subject a transdermal delivery device as described herein, preferably a transdermal delivery device comprising a drug-containing adhesive layer, the drug-containing adhesive layer comprising: (1) an active ingredient comprising R,R-tetrabenazine; (2) a pressure-sensitive adhesive as described herein, for example, a non-reactive acrylate pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant, and 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 6 hours, or at least 12 hours, preferably at least 24 hours, for example, 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-containing adhesive layer can comprise an optional permeation enhancer and / or plasticizer. In some embodiments according to SE3, the transdermal delivery device is applied to achieve transdermal delivery to the subject of any of the daily doses described in SE1. In some embodiments according to SE3, the transdermal delivery device is applied to achieve any of the PK profiles in the subject described in SE2.

[0133] SE4: A method for treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, comprising applying to the subject a transdermal delivery device as described herein, preferably a transdermal delivery device comprising a drug-containing adhesive layer, the drug-containing adhesive layer comprising: (1) an active ingredient comprising R,R-tetrabenazine; (2) a pressure-sensitive adhesive as described herein, such as a non-reactive acrylate pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant, and applying the transdermal delivery device to the subject to achieve a substantially constant steady-state plasma concentration of R,R-tetrabenazine greater than 150 pg / ml for a duration of at least 6 hours, or at least 12 hours, preferably at least 24 hours, such as 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 the subject to achieve a substantially constant steady-state plasma concentration of R,R-tetrabenazine greater than 150 pg / ml to about 3000 pg / ml over the duration, and the plasma concentration of R,R-tetrabenazine does not vary significantly, such as by more than 2-fold, during any of the intervals of 4 hours, 8 hours, and / or 12 hours of the duration. In some embodiments according to SE4, during the duration, the ratio of the minimum plasma concentration of R,R-tetrabenazine to the maximum plasma concentration of R,R-tetrabenazine is at least about 0.4, such as 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 comprise an optional permeation enhancer and / or plasticizer. In some embodiments according to SE4, the transdermal delivery device is applied to achieve transdermal delivery to the subject of any of the daily doses described in SE1. In some embodiments according to SE4, the transdermal delivery device is applied to achieve any of the PK profiles in the subject described in SE2.

[0134] SE5: A method for treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, comprising applying to the subject a transdermal delivery device as 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 as described herein, such as a non-reactive acrylate pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant, and applying the transdermal delivery device to transdermally deliver to the subject from about 0.1 mg / day to about 20 mg / day of deuterated R,R-tetrabenazine, such as 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, from about 1 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine, from about 1 mg / day to about 4 mg / day of deuterated R,R-tetrabenazine, from about 2 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, from about 2 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, from about 2 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine, from about 2 mg / day to about 4 mg / day of deuterated R,R-tetrabenazine, from about 4 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, from about 4 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine, from about 4 mg / day to about 6 mg / day of deuterated R,R-tetrabenazine, from about 6 mg / day to about 10 mg / day of deuterated R,R-tetrabenazine, or from about 6 mg / day to about 8 mg / day of deuterated R,R-tetrabenazine. In some embodiments according to SE5, the transdermal delivery device is applied to transdermally deliver to the subject 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, or from 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 can comprise an optional permeation enhancer and / or plasticizer.

[0135] SE6. A method for treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, comprising applying to the subject a transdermal delivery device as 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 as described herein, such as a non-reactive acrylate pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant, and the transdermal delivery device provides a therapeutically effective plasma concentration of deuterated R,R-tetrabenazine, the dihydrotetrabenazine metabolite of deuterated R,R-tetrabenazine, deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ, and the maximum plasma concentration of deuterated R,R-tetrabenazine For The combined maximum plasma concentration of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ of The ratio 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.), or the steady-state plasma concentration of deuterated R,R-tetrabenazine For The combined maximum plasma concentration of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ of The ratio is in the range of about 1:1 to about 1:7.5. In some embodiments according to SE6, deuterated R,R,R-HTBZ For Deuterated S,R,R-HTBZ of The ratio of the maximum plasma concentrations may 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 the maximum plasma concentrations of deuterated R,R-tetrabenazine:deuterated R,R,R-HTBZ:deuterated S,R,R-HTBZ may be in the range of about 14 to 40:3 to 11:50 to 85. In some embodiments according to SE6, by administration, the AUC of deuterated SRR-HTBZ0-∞ The AUC of deuterated R,R-tetrabenazine 0-∞ has a ratio to that of about 1 to about 15, such as about 1.5 to about 11, and / or the AUC of deuterated RRR-HTBZ 0-∞ The AUC of deuterated R,R-tetrabenazine 0-∞ has a ratio to that of about 0.1 to about 0.75, such as about 0.15 to about 0.5, thereby providing a pharmacokinetic profile. In some embodiments according to SE6, upon administration, a detectable amount of deuterated S,S-tetrabenazine, deuterated R,S,S-HTBZ, or deuterated S,S,S-HTBZ is not provided in the plasma of the subject. In some embodiments according to SE6, the PK profile is characterized in that the mean terminal phase half-life of deuterated R,R-tetrabenazine is about 8.5 hours ± 40% CV. In some embodiments according to SE6, the drug-containing adhesive layer can include any permeation enhancer and / or plasticizer. In some embodiments according to SE6, a transdermal delivery device is applied to transdermally deliver any of the daily doses described in SE5 to a subject. 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 for treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, comprising applying to the subject a transdermal delivery device as 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 as described herein, such as a non-reactive acrylate pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant, and applying the transdermal delivery device to the subject to achieve a therapeutically effective plasma concentration of deuterated R,R-tetrabenazine, the dihydrotetrabenazine metabolite of deuterated R,R-tetrabenazine, deuterated R,R,R-HTBZ, and deuterated S,R,R-HTBZ for at least 6 hours, or at least 12 hours, preferably at least 24 hours, such as 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 comprise an optional permeation enhancer and / or plasticizer. In some embodiments according to SE7, the transdermal delivery device is applied to achieve transdermal delivery to the subject of any of the daily doses described in SE5. In some embodiments according to SE7, the 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 of treatment for hyperkinetic movement disorder, 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 of the present specification, such as a non-reactive acrylate pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant, and applying the transdermal delivery device to the subject to achieve a substantially constant steady-state plasma concentration of deuterated R,R-tetrabenazine of 150 pg / ml for a duration of at least 6 hours, or at least 12 hours, preferably at least 24 hours, such as 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 the subject to achieve a substantially constant steady-state plasma concentration of deuterated R,R-tetrabenazine that exceeds 150 pg / ml and is greater than about 3000 pg / ml over the duration, and the plasma concentration of deuterated R,R-tetrabenazine does not vary significantly, such as by more than 2-fold, during any of the intervals of 4 hours, 8 hours, and / or 12 hours of the duration. In some embodiments according to SE8, during the duration, the ratio of the minimum plasma concentration of deuterated R,R-tetrabenazine to the maximum plasma concentration of deuterated R,R-tetrabenazine is at least about 0.4, such as 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 comprise an optional permeation enhancer and / or plasticizer. In some embodiments according to SE8, the transdermal delivery device is applied to achieve transdermal delivery to the subject of any of the daily doses described in SE5. In some embodiments according to SE8, the transdermal delivery device is applied to achieve any of the PK profiles in the subject described in SE6.

[0138] Any of the transdermal delivery device designs described in this specification 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 that includes a drug - containing adhesive layer, a backing layer, and a release liner that protects the adhesive surface before use. The drug - containing adhesive layer typically contains an active ingredient dispersed, preferably homogeneously dispersed, in the adhesive. In some embodiments, the transdermal delivery device is applied to a subject to deliver from 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 compositions for the drug - containing adhesive layer include any of the adhesive compositions described herein, for example, 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 contains an active ingredient dispersed in a non - reactive acrylate pressure - sensitive adhesive. The active ingredient is present in an amount of about 1 wt% to about 20 wt%, for example, about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 10 wt%, about 15 wt%, about 20 wt%, or any range between the recited values, for example, about 1 wt% to about 15 wt%, about 2 wt% to about 15 wt%, about 2 wt% to about 10 wt%, about 2 wt% to about 7 wt%, about 3 wt% to about 15 wt%, about 3 wt% to about 10 wt%, about 3 wt% to about 7 wt%, about 5 wt% to about 15 wt%, about 5 wt% to about 10 wt%, about 5 wt% to about 7 wt%, about 7 wt% to about 15 wt%, about 7 wt% to about 10 wt%, about 10 wt% to about 20 wt%, about 10 wt% to about 15 wt%, etc. In some embodiments, the drug - containing adhesive layer contains a substantially pure R,R - isomer of tetrabenazine as the sole active ingredient. In some embodiments, the drug - containing adhesive layer contains 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 exists 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 an unreactive acrylate pressure-sensitive adhesive described herein, such as Duro-Tak 87-900A, or described in exemplary embodiments 2-7. The adhesive typically exists in an amount of about 50 wt% to about 97 wt%, for example, about 50 wt%, about 60 wt%, about 70 wt%, about 80 wt%, about 90 wt%, about 95 wt%, or about 97 wt%, or any range between the recited values, such as about 50 wt% to about 95 wt%, about 50 wt% to about 90 wt%, about 50 wt% to about 80 wt%, about 50 wt% to about 70 wt%, about 50 wt% to about 60 wt%, about 60 wt% to about 97 wt%, about 60 wt% to about 95 wt%, about 60 wt% to about 90 wt%, about 60 wt% to about 80 wt%, about 60 wt% to about 70 wt%, about 70 wt% to about 97 wt%, about 70 wt% to about 95 wt%, about 70 wt% to about 90 wt%, about 70 wt% to about 80 wt%, about 80 wt% to about 97 wt%, about 80 wt% to about 95 wt%, about 80 wt% to about 90 wt%, etc. In some specific embodiments, the active ingredient is in an amount of about 2 wt% to about 7 wt%, and the unreactive acrylate pressure-sensitive adhesive is in an amount of about 50 wt% to about 97 wt%. The adhesive composition can also optionally contain other components such as antioxidants, crystallization inhibitors, plasticizers, and / or permeation enhancers. In some embodiments, the drug-containing adhesive layer contains an antioxidant, such as a gallic acid antioxidant, for example, propyl gallate. The amount of the antioxidant typically ranges from about 0 wt% to about 1 wt%, for example, about 0.001 wt%, about 0.01 wt%, about 0.1 wt%, about 0.5 wt%, about 1 wt%, or any range between the recited values, such as about 0.001 wt% to about 0.5 wt%, about 0.01 wt% to about 0.5 wt%, etc. In some embodiments, the drug-containing adhesive layer contains a crystallization inhibitor, for example, means for preventing the formation of drug crystals (crystals of the active ingredient of the drug-containing adhesive layer such as R,R-tetrabenazine) after storage at room temperature for 2 weeks at ambient temperature.In some embodiments, the adhesive composition includes a crystallization inhibitor selected from polyvinylpyrrolidone polymers (e.g., Kollidon K30 or K90F (manufactured by BASF), Plasdone K20 / 32 or Plasdone K90 (manufactured by Ashland Chemical)), cross-linked polyvinylpyrrolidone polymers (e.g., Kollidon CL), polyvinylpyrrolidone copolymers (e.g., Plasdone S-630 Copovidone (Asland)), cellulose-based polymers (e.g., hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose), polycarboxylic acid polymers (e.g., Cabopol (manufactured by Lubrizol)), polymethacrylates (e.g., Plastoid B, Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, polyvinyl acetate, and polyvinylcaprolactam-based graft copolymers (PVAc-PVCap-PEG) (e.g., Soluplus (BASF), and combinations thereof. In some embodiments, the drug-containing adhesive layer includes a crystallization inhibitor selected from polymethacrylates (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 polyvinylcaprolactam-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 wt%, such as about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 30 wt%, about 40 wt%, or any range between the recited values, e.g., in amounts of about 10 wt% to about 40 wt%, about 10 wt% to about 30 wt%, about 10 wt% to about 20 wt%, 15 wt% to about 40 wt%, about 15 wt% to about 30 wt%, about 15 wt% to about 20 wt%, 20 wt% to about 40 wt%, about 20 wt% to about 30 wt%, etc.).In some embodiments, the drug-containing adhesive layer may also contain a skin penetration enhancer as described herein, such as isopropyl myristate. In some embodiments, the drug-containing adhesive layer may also not contain a skin penetration enhancer as described herein; for example, in some embodiments, the drug-containing adhesive layer may also not contain isopropyl myristate. The weight and thickness of the drug-containing adhesive layer can vary depending on different factors such as drug concentration, desired dosage, 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 / cm². 2 ~ about 5 g / cm² 2 , for example, about 0.1 g / cm² 2 ~ about 0.90 g / cm² 2 (e.g., about 0.1 g / cm² 2 ~ about 0.5 g / cm² 2 ) and can have an active surface area. In some embodiments, the active surface area can be 5 cm² 2 ~ about 100 cm² 2 (other suitable ranges are described herein). In some embodiments, the drug-containing 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 characteristics described herein.

[0139] The movement disorders enumerated in the method by any one of SE1 to SE8 include any of those described herein. By way of non-limiting example, movement disorders include Huntington's disease, Wilson's disease, Tourette syndrome, restless legs syndrome, tardive dyskinesia, tics, dyskinetic cerebral palsy / cerebral palsy, other dystonia and dyskinesia disorders, and combinations thereof. In some embodiments, the movement disorder can be Huntington's disease, such as chorea associated with Huntington's disease. In some embodiments, the movement disorder can be Wilson's disease. In some embodiments, the movement disorder can be Tourette syndrome. In some embodiments, the movement disorder can be restless legs syndrome. In some embodiments, the movement disorder can be tardive dyskinesia. In some embodiments, the movement disorder can be tics. In some embodiments, the movement disorder can be dyskinetic cerebral palsy. In some embodiments, the movement disorder is a dystonia or dyskinesia disorder.

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

[0141] The dosing regimen of the treatment method by any one of SE1 to SE8 is not particularly limited as long as the desired dose of R,R-tetrabenazine or deuterated R,R-tetrabenazine is delivered to the subject at the desired rate for the desired period, including any of those described herein. For example, in some embodiments, the transdermal delivery device is applied to the subject in a dosing regimen suitable for achieving the PK profile herein. In some embodiments, the transdermal delivery device is applied to the subject once a day. In some embodiments, the transdermal delivery device is applied to the subject more than once a day, e.g., once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, or more than once a week. In some embodiments, for each application, the transdermal delivery device is applied to the subject's skin to deliver 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, continuously or substantially continuously, such that R,R-tetrabenazine can be delivered to the subject continuously or substantially continuously during the patch-on period. In some embodiments, there is no delay time between two consecutive applications of the transdermal patch according to the dosing frequency herein. For example, in some embodiments, the transdermal delivery device is applied to the subject once a day, and each application of the transdermal delivery device can typically continue (adhere to the subject's skin) for about 24 hours before being replaced with another transdermal delivery device that is substantially the same. However, in some embodiments, there may be 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 shown below.

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

[0144] In some embodiments, the transdermal delivery device or pharmaceutical composition disclosed herein (e.g., the adhesive composition herein) can be used in combination with one or more antipsychotics including, but not limited to, chlorpromazine, levomepromazine, promazine, acepromazine, triflupromazine, ciamemazine, chlorproethazine, dixyrazine, fluphenazine, perphenazine, prochlorperazine, thiopropazate, trifluoperazine, acetophenazine, thiopropazine, butaperazine, perazine, pericyazine, thioridazine, mesoridazine, pipothiazine, haloperidol, trifluperidol, melperone, moloperone, pipamperone, bromperidol, benperidol, droperidol, fluanison, oxypertine, molindone, sertindole, ziprasidone, flupentixol, clopenthixol, chlorprothixol, chlorprothixen, thiothixene, zuclopenthixol, fluspirilene, pimozide, penfluridol, loxapine, clozapine, olanzapine, quetiapine, tetrabenazine, sulpiride, sultopride, tiapride, remoxipride, amisulpride, veralipride, levosulpride, lithium, prothipendyl, risperidone, clotiapine, mosapramine, zotepine, aripiprazole, and paliperidone.

[0145] In some embodiments, the transdermal delivery device or pharmaceutical composition disclosed herein (e.g., the adhesive composition herein) can be used in combination with one or more benzodiazepines ( "antianxiety agents") including, but not limited to, alprazolam, adinazolam, bromazepam, camazepam, clobazam, clonazepam, clotiapazam, cloxazolam, diazepam, ethyl loflazepate, estazolam, fludiazepam, flunitrazepam, halazepam, ketazolam, lorazepam, medazepam, dazepam, nitrazepam, nordazepam, oxazepam, potassium clorazepate, pinazepam, plazepam, tofisopam, triazolam, temazepam, and chlordiazepoxide.

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

[0147] In some embodiments, the transdermal delivery devices or pharmaceutical compositions disclosed herein (e.g., the adhesive compositions herein) include an antiviral agent; a CYP3A inhibitor; a CYP3A inducer; a protease inhibitor; an adrenergic agonist; an anticholinergic agent; a mast cell stabilizer; a xanthine; a leukotriene antagonist; a glucocorticoid treatment; a local or general anesthetic; a non-steroidal anti-inflammatory agent (NSAID), e.g., naproxen; an antibacterial agent, e.g., amoxicillin; a cholesteryl ester transfer protein (CETP) inhibitor, e.g., anacetrapib; an antifungal agent, e.g., isoconazole; a sepsis treatment, e.g., drotrecogin-α; a steroid, e.g., hydrocortisone; a local or general anesthetic, e.g., ketamine; a norepinephrine reuptake inhibitor (NRI), e.g., atomoxetine; a dopamine reuptake inhibitor (DARI), e.g., methylphenidate; a serotonin-norepinephrine reuptake inhibitor (SNRI), e.g., milnacipran; a sedative, e.g., diazepam; a norepinephrine-dopamine reuptake inhibitor (NDRI), e.g., bupropion; a serotonin-norepinephrine-dopamine-reuptake inhibitor (SNDRI), e.g., venlafaxine; a monoamine oxidase inhibitor, e.g., selegiline; a hypothalamic phospholipid; an endothelin converting enzyme (ECE) inhibitor, e.g., phosphoramidon; an opioid, e.g., tramadol; a thromboxane receptor antagonist, e.g., ifetroban; a potassium channel opener; a thrombin inhibitor, e.g., hirudin; a hypothalamic phospholipid; a growth factor inhibitor, e.g., a PDGF activity modulator; a platelet activating factor (PAF) antagonist; an antiplatelet agent, e.g., a GPIIb / IIIa blocker (e.g., abciximab, eptifibatide, and tirofiban), a P2Y(AC) antagonist (e.g., clopidogrel, ticlopidine, and CS-747), and aspirin; an anticoagulant, e.g., warfarin; a low molecular weight heparin, e.g., enoxaparin; a factor VIIa inhibitor and a factor Xa inhibitor; a renin inhibitor; a neutral endopeptidase (NEP) inhibitor; a vasopeptidase inhibitor (dual NEP-ACE inhibitor), e.g., 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 (also known as rosuvastatin, atavasatatin, or bisvastatin); squalene synthase inhibitors; fibrates; bile acid sequestrants, such as cholestyramine; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP inhibitors; calcium channel blockers, such as amlodipine besylate; potassium channel activators; alpha-muscarinic agents; beta-muscarinic agents, such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid, tricrinaphene, chlortalidone, furosenedil, musolimine, bumetanide, triamterene, amiloride, and spironolactone; thrombolytics, such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); anti-diabetic agents, such as biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulin, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glipyride, and glypidide), thiazolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors, such as 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; immunosuppressive agents; anticancer agents and cytotoxic agents (e.g., alkylating agents, such as nitrogen mustard, alkyl sulfonates, nitrosoureas, ethyleneimine, and triazenes); antimetabolites, such as folic acid antagonists, purine analogs, and pyridine analogs; antibiotics, such as anthracyclines, bleomycin, mitomycin, dactinomycin, and plicamycin; enzymes, such as L-asparaginase; farnesyl-protein transferase inhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone), estrogen / antiestrogen, androgen / antiandrogen, progestin, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; microtubule-disrupting agents, such as ecteinascidin; microtubule-stabilizing agents, such as paclitaxel, docetaxel, and epothilones A-F; plant-derived products, such as vinca alkaloids, epipodophyllotoxins, and taxanes; and topoisomerase inhibitors; prenyl-protein transferase inhibitors; and cyclosporine; 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 other agents, such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin, can be used in combination with other classes of compounds, including but not limited to these.;

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

[0149] Definition As used herein, the term "about" when modifying a quantity associated with the present invention refers to variations in quantity that can occur, for example, through standard tests and handling; through inadvertent error in such tests and processes; 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 includes that particular value, for example, about 10% includes 10%. Whether or not modified by the term "about", the claims include equivalents of the recited amounts. 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., a drug-containing adhesive layer or a 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 that has permeated per square centimeter over a given period of time. Unless otherwise clear from the context, the "cumulative drug permeated" at a given time (e.g., 24 hours after administration) refers to the total amount of drug that has permeated per square centimeter from time 0 (i.e., the time of administration) to the given time. Unless otherwise clear from the context, "cumulative drug permeated" refers to an additive average value measured and / or calculated according to the methods described herein. As used herein, the term "average value" refers to an additive average value, unless otherwise specified, and not inconsistent with the general 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 an additive average value measured and / or calculated according to the methods described herein. A typical unit of flux is milligrams per square centimeter per hour.

[0153] The flux rate referred to in this patent application can mean that measured by either an in vivo method or an in vitro method. One way to measure 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 through the skin within a certain time constraint. In some embodiments, when specifically referred to as being measured by an in vitro method using human cadaver skin, the flux rate is measured according to the method described in Example 3 or 6. The in vitro method uses a human epidermal membrane obtained from a cadaver, but instead of using human volunteers to measure the drug flux through the skin, it is generally accepted by those skilled in the art that the results of appropriately designed and conducted in vitro tests can be used to estimate or predict the results of in vivo tests with reasonable reliability.

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

[0155] As used herein, terms such as "treating," "treatment," and "treat" refer to removing, reducing, or ameliorating a disease or condition and / or the symptoms associated therewith. Treating a disease or condition, although not excluded, 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 effect amelioration of one or more symptoms of a disorder or condition (e.g., Huntington's disease), or to prevent the appearance or progression of a disorder or condition, or to cause regression or cure of a disorder or condition.

[0157] As used herein, the term "subject" (or "patient" as referred to herein) refers to an animal, preferably a mammal, most preferably a human, that is the object of treatment, observation, or experiment.

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

[0159] The term "chronic hyperkinetic movement disorder" refers to a disorder characterized by involuntary, repetitive, and disorderly motor behavior, variously termed "compulsive," "rhythmic," or "stereotypic." In humans, chronic hyperkinetic movement disorders can be psychogenic (e.g., tics), idiopathic (e.g., as in Tourette syndrome and Parkinson's disease), genetic (e.g., as in the chorea characteristic of Huntington's disease), infectious (e.g., as in Sydenham 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 "stereotypic" refers to a complex series of movements that are repeated with slight variations or less common repetitive actions.

[0161] The term "VMAT2" refers to a membrane integral protein that functions 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 a disorder characterized by abnormal VMAT2 activity. VMAT2-mediated disorders can be mediated wholly or in part by modulating VMAT2. In particular, a VMAT2-mediated disorder is a disorder in which inhibition of VMAT2 has some effect on the underlying disorder, e.g., a disorder in which administration of a VMAT2 inhibitor results in some improvement in at least a portion of the patients being treated.

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

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

[0165] Embodiment 2. The adhesive composition according to Embodiment 1, wherein the non - reactive acrylate pressure - sensitive adhesive does not have a functional group containing a reactive hydrogen moiety.

[0166] Embodiment 3. The adhesive composition according to 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 according to any one of Embodiments 1 - 3, wherein the non - reactive acrylate pressure - sensitive adhesive is a copolymer of alkyl acrylates.

[0168] Embodiment 5. The non - reactive acrylate pressure - sensitive adhesive is a copolymer of a C2 - C 18 alkyl acrylate (preferably a C4 - C 10 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, and the adhesive composition according to any one of Embodiments 1 - 3.

[0169] Embodiment 6. The pressure-sensitive adhesive of non-reactive acrylate is a copolymer of hexyl ethyl acrylate (for example, 2-ethylhexyl acrylate), methyl acrylate, and optionally one or more acrylamide monomers having no functional groups selected from epoxy, -OH, -COOH, and combinations thereof (for example, tert-octyl acrylamide). The adhesive composition according to any one of Embodiments 1 to 3.

[0170] Embodiment 7. The pressure-sensitive adhesive of non-reactive acrylate does not contain vinyl acetate or substantially does not contain vinyl acetate. The adhesive composition according to any one of Embodiments 1 to 6.

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

[0172] Embodiment 9. The adhesive composition according to any one of Embodiments 1 to 7, which does not contain isopropyl myristate.

[0173] Embodiment 10. The adhesive composition according to any one of Embodiments 1 to 7, which does not contain a penetration enhancer selected from fatty alcohols, fatty acids, fatty acid esters, and combinations thereof.

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

[0175] Embodiment 12. The adhesive composition according to any one of Embodiments 1 to 11, which further contains a gallic acid antioxidant.

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

[0177] Embodiment 14. The adhesive composition further comprises a crystallization inhibitor in an amount effective to prevent the formation of drug crystals after storage at ambient temperature for two weeks at room temperature, and is the adhesive composition according to any one of Embodiments 1 to 13.

[0178] Embodiment 15. The adhesive composition further comprises a crystallization inhibitor selected from polyvinylpyrrolidone polymers (for example, Kollidon K30 or K90F (manufactured by BASF), Plasdone K20 / 32 or Plasdone K90 (manufactured by Ashland Chemical)), crosslinked polyvinylpyrrolidone polymers (for example, Kollidon CL), polyvinylpyrrolidone copolymers (for example, Plasdone S-630 Copovidone (Asland)), cellulose-based polymers (for example, hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose), polycarboxylic acid polymers (for example, Cabopol (manufactured by Lubrizol)), polymethacrylates (for example, Plastoid B, Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, polyvinyl acetate, and polyvinylcaprolactam-based graft copolymers (PVAc-PVCap-PEG) (for example, Soluplus (BASF)), and combinations thereof, and is the adhesive composition according to any one of Embodiments 1 to 13.

[0179] Embodiment 16. The adhesive composition further comprises a crystallization inhibitor selected from polymethacrylates (for example, Plastoid B (a copolymer of butyl methacrylate and methyl methacrylate), Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, polyvinyl acetate, and polyvinylcaprolactam-based graft copolymers (PVAc-PVCap-PEG) (for example, Soluplus (BASF)), and combinations thereof, and is the adhesive composition according to any one of Embodiments 1 to 13.

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

[0181] Embodiment 18. The adhesive composition according to any one of Embodiments 1 to 17, which can adhere to the skin of a user continuously 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.

[0182] Embodiment 19. A backing layer, the adhesive composition according to any one of Embodiments 1 to 18; and a release liner, and a transdermal delivery device comprising the same.

[0183] Embodiment 20. The transdermal delivery device according to Embodiment 19, which can be stored at room temperature.

[0184] Embodiment 21. At a rate of about 0.01 mg / day / cm 2 to about 5 mg / day / cm 2 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, the transdermal delivery device according to Embodiment 19 or 20, which provides an active ingredient to a target user.

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

[0186] Embodiment 23. The method according to 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 according to embodiment 23, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease, Wilson's disease, Tourette syndrome, restless legs syndrome, tardive dyskinesia, tic, and combinations thereof.

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

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

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

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

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

[0193] Embodiment 30. A method for treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, the method comprising transdermal administration of a therapeutically effective amount of tetrabenazine or deuterated tetrabenazine to the subject.

Example

[0194] Example 1. Preparation of a tetrabenazine transdermal patch This example shows one procedure for preparing a tetrabenazine adhesive patch. Tetrabenazine base is generally commercially available at 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 completely mixed into an 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 dried for 1.5 minutes using a typical hair dryer and then laminated to a backing film.

[0196] The adhesive mixture can contain different concentrations of tetrabenazine. In this example, four concentrations were used, namely: 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; 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 each formulation.

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

[0198] The two adhesives used in this example were a silicone polymer (BIO-7-4202 manufactured by Dow Corning Co.) and an acrylate copolymer (Durotak 87-2287). In this example, four different ratios were used, namely, 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 human cadaver skin by the Franz diffusion cell method. The cadaver skin was obtained from the Health Science Tissue Bank in Phoenix, AZ.

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

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

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

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

[0204] As shown in FIG. 2, even when changing the ratio of the silicone polymer to the acrylate copolymer, the flux characteristics do not change significantly. However, compared with the results shown in FIG. 1, the flux observed for the patch prepared according to Example 2 is significantly lower than the flux from the patch with a 10% tetrabenazine concentration prepared in Example 1.

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

[0206] Example 4A: Preparation of Tetrabenazine in an Adhesive without Functional Groups Batch Composition [Table 2]

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

[0208] Preparation Procedure For the preparation of the patch in Example 4A, the following procedure was followed. In a 50-mL beaker, propyl gallate was manually mixed and dissolved in ethanol. Separately, ethyl acetate was added to a 250-mL beaker and mixed at low speed with a mechanical stirrer. TBZ was added, and then Plastoid B powder was added while mixing. Once Plastoid B was dissolved, the weighed DuroTak 87-900A was added while mixing. Mix at a medium speed for 30 minutes or until homogeneous. Cast the solution onto a Scotchpak 9723 film, a 3M backing film, using a 10-mil coating applicator. Allow the casting to air dry for 10 minutes and then oven dry at 85 °C for 10 minutes. Cover the dried adhesive with a split Loparex release liner. Using a steel punching die, die-cut the coated coating into 60 cm2 patches.

[0209] The patch has good skin adhesiveness and shear strength and adheres well to the skin for over 48 hours.

[0210] The patch was die-cut and fixed to a Franz cell for the skin permeation test. The test results are reported in Example 6.

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

[0212] Example 4B and 4C. Preparation of tetrabenazine in an adhesive without functional groups Two similar formulations were prepared following the same procedure as shown in Example 4A. These are shown in the following table (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 containing functional groups showed a yellowish color after storage at room temperature at 40 °C for 4 weeks, indicating instability of the active ingredient due to oxidation and / or other degradation. DuroTak 87-2287 has hydroxyl functional groups of -OH and epoxy, and DuroTak 87-2677 has acidic functional groups of -COOH. In contrast, the patch formulations prepared using DuroTak 87-900A without functional groups were found to be stable at 40 °C for 4 weeks. 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. In the absence of an antioxidant, impurities (drug-related) such as TBZ 01, TBZ 02, and TBZ 04 were formed and detected by HPLC. Antioxidants that can prevent the oxidation and / or other degradation of TBZ include propyl gallate, citric acid, ascorbic acid, vitamin E (tocopherol acetate), and the like.

[0216] Tetrabenazine and related compounds were analyzed using isocratic reverse-phase HPLC equipped with a UV detector. Column: Gemini C18, 4.6 × 150 mm, 5 μm particle size, or equivalent. Column temperature: 45 °C Injection volume: 10 μL Detection wavelength: 210 nm Mobile phase: Ratio of mobile phase A / mobile phase B = 44:56 Mobile phase A: 10 mM K2HPO4 in H2O Mobile phase B: Acetonitrile Flow rate: 1.2 mL / min Execution time: 12 minutes Retention time: Approximately 5.5 minutes in the case of tetrabenazine The retention time of impurity 1 (TBZ01) is approximately 1.95 minutes; impurity 2 (TBZ02) is approximately 3.10 minutes; impurity 4 (TBZ04) is approximately 5.29 minutes.

[0217] The inventors further found that crystals appeared on the patch after storing at ambient temperature for 2 weeks without using Soluplus or Plastoid B as the crystallization inhibitor / solubilizer, for example, referring to Example 4B. The formation of crystals delays the skin permeation of the patch formulation.

[0218] Therefore, the preferred composition should contain a crystallization inhibitor such that the active ingredient remains in the adhesive matrix in an 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) · Cellulose-based polymers: Hydroxypropylmethylcellulose (HPMC / Methocel), ethylcellulose (Ethocel by Dow Chemica), for example, hydroxypropylcellulose (HPC, Klucel by Ashland, etc.) · Polycarboxylic acid polymer: Carbopol (manufactured by Lubrizol) · Polymethacrylate: Plastoid B, Eudragit E100, Eudragit L100-55 (manufactured by Evonik) · Soluplus (BASF): It contains polyethylene glycol, polyvinyl acetate, and a polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG).

[0219] Example 6. Skin Permeation Study The patch formulations prepared in Examples 4A - 4C were used in a skin permeation study 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 - buffered saline (PBS) pH 7.4. · The cell temperature was maintained at 37°C. · Sampling method: 1.5 mL was taken for HPLC assay, the cell was emptied, and replaced with fresh medium. · Sampling time points: 2, 4, 8, 12, 24, and 48 hours · Cadaver skin was used and obtained from the New York Fire Fighters Skin Bank. · Assay method for the medium: HPLC.

[0220] The results of the study are presented in the following tables and plots. The values presented are the cumulative amount of TBZ permeated per cm² (i.e., μg / cm²). See also Figure 3.

Table 4

[0221] Example 7. In Vivo Pharmacokinetics Study The objective of this study was to evaluate the comparative bioavailability of an 8 mg / 96 - hour test TBZ patch (refer to the formulation of Example 4A) when applied for a single 96 - hour application period, relative to the reference product, tetrabenazine tablets (Lupin) at a dose of 12.5 mg three times a day (total dose 150 mg) administered to healthy adult male subjects under fasting conditions from day 1 to day 4.

[0222] This was an open-label, randomized, two-treatment, two-period, two-sequence crossover trial comparing a test product with a reference product under fasting conditions. This study was conducted on 16 healthy, non-smoking, non-nicotine-using adult male subjects. During one period of the study, one (1) TBZ patch, 8 mg / 96 hours was applied to the outer side of the left upper arm of the subject and kept in place for 96 hours following at least 10 hours of overnight fasting. During the other study period, 1 × 12.5 mg tetrabenazine tablets (Lupin) were administered every 8 hours from day 1 to day 4, with a total daily dose of 37.5 mg over 4 days and a total dose of 150 mg over 12 administrations. For treatment B (reference), the subjects performed at least 10 hours of overnight fasting only before the 0-hour administration (day 1). Subsequent doses were administered after at least 2 hours of fasting. The order of administration followed a randomized schedule of two sequences. The subjects were confined to the clinical facility from at least 10 hours before the administration (0 hour) in each study period until at least 120 hours after the day of administration, day 0. The dosing interval (0 hour) was 14 days.

[0223] Blood samples were collected at intervals greater than 120 hours before and after (0 hour) the investigational drug administration in each study period. Samples were analyzed by a bioanalytical laboratory for subjects who received at least one of the study products (treatment 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 formulation compared to the reference product based on the plasma concentrations of these six analytes.

[0225] Study data were collected in source documents.

[0226] This study was designed based on the known pharmacokinetics of tetrabenazine tablets and their metabolites, the recommendations of the FDA draft guidance regarding tetrabenazine tablets, and the generally accepted criteria for conducting bioavailability / bioequivalence tests under fasting conditions.

[0227] To minimize the potential for carry-over effects, a washout period of at least 10 days was selected for this study.

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

[0229] Treatment B The active pharmaceutical ingredient is the racemic form of the two stereoisomers (RR and SS) of tetrabenazine. It was administered every 8 hours from Day 1 to Day 4. The subject fasted overnight for at least 10 hours only before the 0-hour dose. Subsequent doses were administered after at least 2 hours of fasting. The total daily dose of the reference product was equal to 37.5 mg at 3 eight-hour dosing intervals, for a total dose of 150 mg over 12 doses over 4 days.

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

[0231] Adverse events were collected and tabulated. Formal statistical analysis was not performed.

[0232] In Treatment A (test), during each period of the study: before the start of administration within 60 minutes before patch application (0 hours) and 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 before patch removal), 97.0, 98.0, 100.0, 104.0, 108.0, 114.0, and 120.0 hours after administration, 26 blood samples were collected from each subject. All times are based on the dosing interval (the time of patch application). In Treatment B (reference), during each period of the study: before the start of administration within 60 minutes before dosing (Day 1, 0 hours) and 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 † , 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 † , 92.0, 96.0, 100.0, 104.0, 112.0, and 120.0 hours after dosing, 51 blood samples were collected from each subject. All times are based on the dosing interval (Day 1, 0 hours). † Samples collected with an allowable deviation of -5 minutes immediately before each dose, as required to account for dosing activity.

[0233] For subjects administered at least one of the investigational products (Treatment A or B), 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. The total TBZ concentration 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 were evaluated for each of the six analytes (two TBZ isomers [RR and SS] and four HTBZ metabolites [RRR, SSS, SRR, and RSS]), the combination of TBZ (RR + SS), and total TBZ. Additionally, the metabolic ratio (AUC 0-t(met) / AUC 0-t(TBZ) ) for each of the four HTBZ metabolites (RRR, SSS, SRR, RSS) and the apparent clearance of TBZ (CL / F) were evaluated.

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

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

[0237] Summary of results: Mean plasma concentration vs. time plots (linear) are shown below, for TBZ as in Figure 4A (combination of RR and SS isomers) for the RRR HTBZ as in Figure 4B, for the SRR HTBZ as in Figure 4C, and for total TBZ as in Figure 4D. The arithmetic means of the pharmacokinetic parameters (untransformed) are provided in Table 1A for Treatment A and in 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 (combination of RR and SS isomers), in Table 2B for RRR HTBZ, in Table 2C for SRR HTBZ, and in 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 was at the median of T max 20 hours with an average peak exposure (C max) It increased to 570 pg / mL and then slowly decreased until the patch was removed at 96 hours, after which the concentration declined and the mean terminal-phase half-life was 8.5 hours. All concentrations of the SS isomer of TBZ were below the limit of quantification (BLQ). Two of the four HTBZ metabolites were detected (RRR and SRR diastereomers), and the peak of the SRR isomer (C max ) and the total (AUC 0-t ) plasma exposure were approximately 20-fold higher.

[0240] After administration of tablets three times a day for 96 hours in Treatment B, most concentrations of RR and SS in all subjects were below the limit of quantification (BLQ). For RR concentrations above the lower limit of quantification (LLOQ) of 48.050 pg / mL, the mean C max was 138 pg / mL, and the median of T max was 16.5 hours after the first dose on day 1 or 0.5 hours after the third dose. All four active HTBZ metabolites were detected, and the SSS isomer was predominant based on the highest mean AUC and C max values and was ranked in the order of SRR, RSS, and RRR. Since there was no AUC 0-∞(TBZ) (TBZ) data for RR, SS, and RR + SS analytes, the metabolic AUC ratio (AUC 0-∞(met) / AUC 0-∞(TBZ) ) was not calculated. Instead, it was estimated using AUC 0-t(met) / AUC 0-t(TBZ) ) data.

[0241] When comparing Treatment A (patch) and B (tablet), the extent of TBZ metabolism to HTBZ was less for Treatment A, as indicated by a least-squares geometric mean (LSGM) AUC 0-t(met) / AUC 0-t(TBZ) ) of approximately 1 / 500 for RRR and SRR. Similarly, the AUC 0-96 and C max values (uncorrected for dose differences) of Treatment A for RRR and SRR were 1 / 8 - 1 / 10 of the values of Treatment B, as indicated by an LSGM A / B ratio of approximately 10 - 13% for the RRR and SRR parameters. The AUC 0-96 and C maxThe LSGMs are approximately 38 - fold and 3.4 - fold higher, respectively, than the LSGM of treatment B. Total TBZ AUC 0-96 , AUC 0-∞ and C max have a low LSGM A / B ratio of 3 - 4%.

[0242] Conclusion: The 8 mg / 96 - hour TBZ patch applied for a single 96 - hour application provided a higher concentration of RR - tetrabenazine with less metabolism to the active HTBZ isomer at a lower dose, without interconversion to the SS isomer, compared to three - times - daily administration (total dose 150 mg) of TBZ tablets administered under fasting conditions from day 1 to day 4 in healthy male subjects.

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

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

[0245] The present invention has been described above with the aid of functional components that explain the implementation of its specific functions and their relationships. The boundaries of these functional elements are arbitrarily defined in this specification for convenience of explanation. Alternative boundaries can also be defined as long as the specific functions and their relationships are properly implemented.

[0246] With respect to the aspects of the invention described as genera, all individual species are separate aspects of the invention that are considered individually. When an aspect of the invention is described as "comprising" an element, embodiments "consisting of" or "consisting essentially of" that element are also contemplated.

[0247] Since the above specific description of the specific embodiments shows the general nature of the invention without omission, others can, by applying knowledge within the skill of those skilled in the art, without performing unnecessary experiments and without departing from the general concept of the invention, easily modify such specific embodiments and / or adapt them to various uses. Accordingly, such adaptations and modifications are intended to be included within the meaning and scope of equivalents of the disclosed embodiments based on the teachings and advice presented herein. The phrases or terms herein are for purposes of explanation and not of limitation, and the phrases or terms herein should be understood by those skilled in the art in view of the teachings and advice of this specification.

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

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

[0250] All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference as if each individual publication, patent, and patent application had been specifically and individually indicated to be incorporated by reference. If 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. Use of R,R-tetrabenazine in the manufacture of a medicament for a method of treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, said method comprising administering to said subject a medicament comprising an active ingredient comprising R,R-tetrabenazine, said administration bypassing first-pass metabolism and delivering 0.1 mg / day to 20 mg / day of R,R-tetrabenazine continuously to said subject.

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

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

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

6. The use according to claim 5, wherein said gallic acid antioxidant is propyl gallate.

7. The use according to any one of claims 3 to 6, wherein said adhesive composition further comprises a crystallization inhibitor in an amount effective to prevent the formation of drug crystals after storage at ambient temperature for 2 weeks.

8. The use according to any one of claims 3 to 7, wherein said adhesive composition further comprises a crystallization inhibitor selected from polyvinylpyrrolidone polymers, cross-linked polyvinylpyrrolidone polymers, polyvinylpyrrolidone copolymers, cellulose-based polymers, polycarboxylic acid polymers, polymethacrylates, polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam-based 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 said medicament is the pure R,R-isomer of tetrabenazine.

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 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 the 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 a hypermetabolic subject.

13. Use of R,R-tetrabenazine in the manufacture of a medicament for a method of treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, said method comprising administering to said subject a medicament comprising an active ingredient comprising R,R-tetrabenazine, said administration providing 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., C ｍａｘ of R,R-tetrabenazine: (C ｍａｘ of R,R,R-HTBZ + C ｍａｘ of S,R,R-HTBZ) 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., C ｓｓ of R,R-tetrabenazine: (C ｓｓ of R,R,R-HTBZ + C ｓｓ of S,R,R-HTBZ) is in the range of 1:1 to 1:5, the ratio of the maximum plasma concentration or steady-state plasma concentration of R,R,R-HTBZ to S,R,R-HTBZ is in the range of 1:5 to 1:30, and the ratio of the maximum plasma concentration (C ｍａｘ ) or steady-state plasma concentration (C ｓｓ ) of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ is 17-40:3-10:50-80, and the ratio of the AUC ０－∞ of S,R,R-HTBZ to the AUC ０－∞ of R,R-tetrabenazine is 1-15, and / or the ratio of the AUC ０－∞ of R,R,R-HTBZ to the AUC ０－∞ of R,R-tetrabenazine is 0.1-0.75, and said administration does not provide detectable S,S-tetrabenazine, R,S,S-HTBZ, or S,S,S-HTBZ.

14. The use of R,R-tetrabenazine in the manufacture of a medicament for a method of treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, wherein the medicament is in the form of a transdermal delivery device, and the method comprises applying the transdermal delivery device comprising a drug-containing adhesive layer to the subject, the 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 ｍａｘ of R,R-tetrabenazine: (the C ｍａｘ of R,R,R-HTBZ + the C ｍａｘ of S,R,R-HTBZ) 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 of R,R-tetrabenazine: (the C ｓｓ of R,R,R-HTBZ + the C ｓｓ of S,R,R-HTBZ) is in the range of 1:1 to 1:5, the ratio of the maximum plasma concentration or steady-state plasma concentration of R,R,R-HTBZ to S,R,R-HTBZ is in the range of 1:5 to 1:30, the ratio of the maximum plasma concentration or steady-state plasma concentration of R,R-tetrabenazine:R,R,R-HTBZ:S,R,R-HTBZ is 17 - 40:3 - 10:50 - 80, the ratio of the AUC ０－∞ of S,R,R-HTBZ to the AUC ０－∞ of R,R-tetrabenazine is 1 - 15, and / or the ratio of the AUC ０－∞ of R,R,R-HTBZ to the AUC ０－∞ of R,R-tetrabenazine is 0.1 - 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 6 hours; or (D) applying the transdermal delivery device to the subject to achieve a constant steady-state plasma concentration of R,R-tetrabenazine greater than 150 pg / ml for a duration of at least 6 hours.

15. The use of deuterated R,R-tetrabenazine in the manufacture of a medicament for a method of treating hyperkinetic movement disorder in a subject in need of treatment for hyperkinetic movement disorder, wherein the medicament is in the form of a transdermal delivery device, and the method comprises applying the transdermal delivery device comprising a drug-containing adhesive layer to the subject, the 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, the dihydrotetrabenazine metabolite 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 1:1 to 1:7.5, or 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 1:1 to 1:7.5, and 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, the dihydrotetrabenazine metabolite of deuterated R,R-tetrabenazine, deuterated R,R,R-HTBZ, and deuterated S,R,R-HTBZ for at least 6 hours; or (D) Applying the transdermal delivery device to the subject to achieve a constant steady-state plasma concentration of deuterated R,R-tetrabenazine greater than 150 pg / ml for a duration of at least 6 hours, such use.

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 syndrome, restless legs syndrome, tardive dyskinesia, tic, dyskinetic cerebral palsy / cerebral palsy, other dystonia and dyskinesia disorders, and combinations thereof.

17. The use according to any one of claims 13 to 16, wherein (i) the administration is carried out regardless of the feeding state of the subject; (ii) the subject is a hyper-metabolizer; and / or (iii) the subject is a pediatric or adolescent patient.

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