Tetrabenazine transdermal delivery device

Abstract

This document provides compositions, delivery devices, and methods relating to the delivery of buphenazine and / or deuterated buphenazine (e.g., continuous or substantially continuous delivery, such as transdermal delivery) for the treatment of a hyperkinetic disorder. Also provided are transdermal delivery devices comprising buphenazine, a deuterated buphenazine, or a combination thereof; pharmaceutical compositions comprising buphenazine and / or a deuterated buphenazine; methods for preparing them; and methods of using them, for example, for the treatment of a hyperkinetic disorder.

Description

Technical Field

[0001] Invention Field

[0002] In various specific examples, the present invention generally relates to the delivery of tetrabenazine and / or a deuterated tetrabenazine, for example, continuous or substantially continuous delivery (such as transdermal delivery). In various specific examples, the present invention also relates to pharmaceutical compositions and delivery devices, such as transdermal delivery devices comprising tetrabenazine and / or a deuterated tetrabenazine, pharmaceutical compositions comprising tetrabenazine and / or a deuterated tetrabenazine, methods of preparing them, and methods of using them. Prior Technology

[0003] Background of the Invention

[0004] Bubenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor. Bubenazine is approved by the U.S. Food and Drug Administration (FDA) as Xenazine® tablets for oral use and is indicated for the treatment of chorea associated with Huntington's disease. The active ingredient in Xenazine® tablets is (3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one (hereinafter referred to as "R,R-bubenazine" or "R,R-bubenazine"). A racemic mixture of (3S,11bS)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one ((3S,11bS)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one) (hereinafter “S,S-butenazine or S,S-TBZ”).

[0005] In 2017, the FDA approved deutetrabenazine as an oral Austedo™ tablet for the treatment of chorea associated with Huntington's disease. The active ingredient in Austedo™ tablets is a selectively deuterated, stable, non-radioactive isotope form of butylbenazine, in which the six hydrogen atoms on the two O-linked methyl groups are replaced with deuterium atoms (i.e., -OCD3 instead of the -OCH3 moiety). The active ingredient in Austedo™ tablets is also a racemic mixture. Summary of the Invention

[0006] Invention Summary In various specific examples, the present invention relates to pharmaceutical compositions, drug delivery devices, methods of preparation, and methods of use, such as those relating to the delivery of buphenazine and / or a deuterated buphenazine to an individual who bypasses first-pass metabolism (e.g., in a continuous or substantially continuous manner). Not wishing to be bound by theory, the delivery of buphenazine and / or a deuterated buphenazine as described herein (such as transdermal delivery as described herein) offers numerous advantages over conventional oral delivery, such as avoiding first-pass metabolism, providing a pharmacokinetic profile with a low peak-to-trough ratio, providing the ability to provide multi-day treatment from a single administration, avoiding food effects on absorption, discontinuation of treatment by removing the patch if necessary, and easier patient compliance, etc. Furthermore, compared to oral administration of the same dose of buphenazine or deuterated buphenazine, delivery herein (such as percutaneous delivery as described herein) may reduce inter-individual variability in plasma levels of buphenazine or deuterated buphenazine and / or one of its metabolites, and / or may reduce the Cmax of buphenazine or deuterated buphenazine and / or one of its metabolites (e.g., by 10%, 40%, 60% or more), without reducing therapeutic efficacy. Moreover, this delivery (such as percutaneous delivery herein) may similarly be administered to individuals genotyped as poor metabolizers (PM), intermediate metabolizers (IM), or extensive metabolizers (EM) based on CYP2D6 expression. Furthermore, unlike Xenazine® and Austedo™ treatments, the R,R-TBZ transdermal delivery system (TDDS) here can be administered to individuals without the need for genotyping prior to administration (even at higher doses). As detailed herein, most metabolizer effects are due to off-target binding, which cannot be expected from administration of the R,R-TBZ TDDSR here. These advantages ultimately lead to a simplified dosing regimen for buphenazine and / or a deuterated buphenazine (e.g., deuterated buphenazine), for example, the need for genotyping analysis can be minimized or eliminated, and / or dose-related side effects are reduced.

[0007] In some specific examples, this disclosure provides a method for treating a hyperkinetic movement disorder in an individual (e.g., a human individual) with a need for it. In some specific examples, the method comprises administering to the individual a pharmaceutical composition comprising an active ingredient containing R,R-buphenazine, wherein the administration bypasses first-pass metabolism and is delivered (e.g., continuously or substantially continuously) to the individual at a dose of about 0.1 mg / day to about 20 mg / day of R,R-buphenazine. In some specific examples, the pharmaceutical composition is administered transdermally, intravenously, subcutaneously, intramuscularly, or via a depot. In some particularly specific examples, the administration bypasses first-pass metabolism and is transdermally delivered to the individual at a dose of about 0.1 mg / day to about 20 mg / day of R,R-buphenazine. In some specific examples, the administration comprises applying the pharmaceutical composition to the individual's skin for transdermal delivery of approximately 0.1 mg / day to approximately 20 mg / day of R,R-butylbenazine. In some specific examples, the sole active ingredient in the pharmaceutical composition is a substantially pure R,R-isomer of butylbenazine. In some specific examples, the administration provides any of the applicable pharmacokinetic (PK) profiles as described herein, for example, a PK profile relating to the plasma concentration profiles described herein for R,R-butylbenazine, R,R,R-dihydrotetrabenazine (HTBZ), and S,R,R-HTBZ. In some specific examples, the administration does not provide any detectable S,S-isomers of butylbenazine or its metabolites (including S,S,S-HTBZ and R,S,S-HTBZ) in the individual's plasma. Suitable pharmaceutical compositions, drug delivery devices, administration methods, and individuals for use in this method include any of those described herein. For example, in some specific instances, the pharmaceutical composition may be any of the adhesive compositions described herein, which may be included in any of the transdermal delivery devices described herein. The pharmaceutical composition may be administered to the individual at any frequency as needed. In some specific instances, individual doses of the pharmaceutical composition may be delivered (e.g., continuously or substantially continuously) to the individual at doses of about 0.1 mg / day to about 20 mg / day of R,R-bufenazine 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 within any range between the cited values. In some specific instances, the administration may be performed without taking into account the individual's food intake status. The dosage and / or plasma exposure ranges described herein are suitable for adult patients as well as pediatric and adolescent patients.However, as those skilled in this art understand, the desired dosage and / or plasma exposure for a particular individual can be adjusted, taking into account the individual's age and weight. In some specific cases, the individual is a pediatric or adolescent patient (e.g., 6 to 18 years old). In some specific cases, the administration can be performed without considering the individual's genotype; for example, the individual may be a broad metabolizer. In some specific cases, the hyperkinetic motor disorder can be Huntington's disease, Wilson's disease, Tourette syndrome, restless leg syndrome, tardive dyskinesia, tic, dyskinetic cerebral palsy / cerebral palsy, other dystonia, and dyskinesia disorder, as well as combinations thereof.

[0008] Some specific examples disclosed herein also relate to a method for treating an ADHD in an individual with a need, comprising administering to the individual a pharmaceutical composition comprising an active ingredient containing R,R-bufenazine, wherein the administration provides a desired PK profile. In some specific examples, the PK profile is characterized in that the administration provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-HTBZ, and S,R,R-HTBZ, wherein the ratio of the maximum plasma concentration of R,R-bufenazine to the maximum plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ is in the range from about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5), or in any range between the cited values ​​(e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some specific examples, the PK profile is characterized by the following: the dosing provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-HTBZ, and S,R,R-HTBZ, wherein the steady-state plasma concentration of R,R-bufenazine is in the ratio of the steady-state plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ to the steady-state plasma concentration of the combination of R,R,R-HTBZ 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 in any range between the cited values ​​(e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some specific examples, the dosing does not provide detectable S,S-bufenazine, R,S,S-HTBZ, or S,S,S-HTBZ in the individual's plasma. In some specific examples, the PK chromatogram is characterized by: a first time period during which the plasma concentration of R,R-bufenazine increases to reach a maximum concentration of about 150 pg / ml to about 3500 pg / ml with respect to that first time period, wherein the first time period is from time 0 (the time of administration of the pharmaceutical composition) to about 24 hours thereafter. In some specific examples, the PK chromatogram is characterized by: a mean final half-life of R,R-bufenazine of about 8.5 hours ± 40% CV. In some specific examples, the PK chromatogram is further characterized by: after the first time period, the plasma concentration of R,R-bufenazine remains substantially constant for a sustained period of time (such as about 24 hours, about 48 hours, about 72 hours, about 96 hours or more). In some specific examples, the PK profile is characterized by the dosing providing a substantially constant steady-state plasma concentration of R,R-bufenazine at or 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.Suitable pharmaceutical compositions, drug delivery devices, administration methods, and individuals for use in this method include any of those described herein. In some specific examples, the dosing bypasses first-pass metabolism and delivers (e.g., continuously or substantially continuously) R,R-bufenazine to the individual, for example, at a substantially constant rate. In some specific examples, the pharmaceutical composition is administered transdermally. In some specific examples, the pharmaceutical composition may be any of the adhesive compositions described herein. In some specific examples, the dosing may be performed without regard to the individual's feeding status. In some specific examples, the individual is a pediatric or adolescent patient (e.g., 6 to 18 years of age). In some specific examples, the dosing may be performed without regard to the individual's genotype, for example, the individual may be a broad metabolizer. In some specific examples, this hyperactive movement disorder can be Huntington's disease, Wilson's disease, Tourette syndrome, restless legs syndrome, tardive dyskinesia, tic disorders, dyskinesia-type cerebral palsy / cerebral palsy, other hypotonia and movement disorders, and combinations thereof.

[0009] Some specific examples disclosed herein pertain to the delivery (such as continuous or substantially continuous delivery) of a deuterated buphenazine (e.g., R,R-deuterated buphenazine), for example, to treat a hyperkinetic disorder. In some specific examples, the method comprises administering to the individual a pharmaceutical composition comprising an active ingredient containing a deuterated R,R-buphenazine (e.g., R,R-deuterated buphenazine), wherein the administration bypasses first-pass metabolism and is delivered (such as continuously or substantially continuously) to the individual at a dose of about 0.1 mg / day to about 20 mg / day of the deuterated R,R-buphenazine. In some specific examples, the pharmaceutical composition is administered transdermally, intravenously, subcutaneously, intramuscularly, or via a reservoir. In some particular specific examples, the administration bypasses first-pass metabolism and is transdermally delivered to the individual at a dose of about 0.1 mg / day to about 20 mg / day of the deuterated R,R-buphenazine. In some specific examples, the administration comprises applying the pharmaceutical composition to the individual's skin for transdermal delivery of approximately 0.1 mg / day to approximately 20 mg / day of deuterated R,R-butylbenazine. In some specific examples, the sole active ingredient in the pharmaceutical composition is a substantially pure R,R-isomer of deuterated butylbenazine (such as a substantially pure R,R-deuterated butylbenazine). In some specific examples, the administration does not provide any detectable S,S-isomers of deuterated butylbenazine and / or its metabolites in the individual's plasma. In some specific examples, the administration may provide any applicable pharmacokinetic (PK) profile as described herein, for example, a PK profile relating to the plasma concentration profiles described herein for deuterated R,R-butylbenazine, deuterated R,R,R-HTBZ, and deuterated S,R,R-HTBZ. Suitable pharmaceutical compositions, drug delivery devices, administration methods, and individuals for use in this method include any of those described herein. In some specific examples, the pharmaceutical composition may be any of the adhesive compositions described herein. The pharmaceutical composition may be administered to the individual at any frequency as needed. In some specific examples, individual administrations of the pharmaceutical composition may be (e.g., continuously or substantially continuously) of about 0.1 mg / day to about 20 mg / day of deuterated R,R-bufenazine to the individual 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 within any range between the cited values. In some specific examples, the administration may be performed without taking into account the individual's eating status. In some specific examples, the individual is a pediatric or adolescent patient (e.g., 6 to 18 years of age). In some specific cases, the drug can be administered without taking into account the individual's genotype; for example, the individual may be a broad metabolizer.In some specific examples, the hyperactive motor disorder can be Huntington's disease, Wilson's disease, Tourette syndrome, restless legs syndrome, tardive dyskinesia, tic disorders, dyskinesia-type cerebral palsy, other hypotonia and motor disorders, and combinations thereof. In any of the specific examples described herein, the deuterated buprofen can be deuterated buprofen (such as R,R-deuterated buprofen).

[0010] Some specific examples disclosed herein also relate to a method for treating an ADHD in an individual with a need, comprising administering to the individual a pharmaceutical composition comprising an active ingredient containing a deuterated R,R-bubenazine, wherein the administration provides a desired PK profile. In some specific examples, the PK profile is characterized in that the administration provides a therapeutically effective plasma concentration of deuterated R,R-bubenazine, deuterated R,R,R-HTBZ, and deuterated S,R,R-HTBZ, wherein the ratio of the maximum plasma concentration of deuterated R,R-bubenazine to the maximum plasma concentration of the combination of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ is in the range of about 1:1 to about 1:7.5. In some specific examples, the PK profile is characterized by the following: the administration provides a therapeutically effective plasma concentration of deuterated R,R-bubenazine, deuterated R,R,R-HTBZ, and deuterated S,R,R-HTBZ, wherein the steady-state plasma concentration of deuterated R,R-bubenazine is in the ratio of the steady-state plasma concentration of the combination of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ in a range from about 1:1 to about 1:7.5. In some specific examples, the administration does not provide detectable deuterated S,S-bubenazine, deuterated R,S,S-HTBZ, or deuterated S,S,S-HTBZ in the individual's plasma. In some specific examples, the PK chromatogram is characterized by: a first time period during which the plasma concentration of deuterated R,R-bufenazine increases to reach a maximum concentration of about 150 pg / ml to about 3500 pg / ml with respect to that first time period, wherein the first time period is from time 0 (the time of administration of the pharmaceutical composition) to about 24 hours thereafter. In some specific examples, the PK chromatogram is characterized by: a mean final half-life of deuterated R,R-bufenazine of about 8.5 hr ± 40% CV. In some specific examples, the PK chromatogram is further characterized by: after the first time period, the plasma concentration of deuterated R,R-bufenazine remains substantially constant for a sustained period of time (such as about 24 hours, about 48 hours, about 72 hours, about 96 hours or more). In some specific examples, the PK profile is characterized by the administration providing a substantially constant steady-state plasma concentration of deuterated R,R-buphenazine at a level 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. Suitable pharmaceutical compositions, drug delivery devices, administration practices, and individuals for use in this method include any of those described herein. In some specific examples, the administration bypasses first-pass metabolism and delivers (e.g., continuously or substantially continuously) deuterated R,R-buphenazine to the individual, for example, at a substantially constant rate. In some specific examples, the pharmaceutical composition is administered transdermally.In some specific examples, the pharmaceutical composition may be any of the adhesive compositions described herein. In some specific examples, the administration may be performed without considering the individual's eating status. In some specific examples, the individual is a pediatric or adolescent patient (e.g., 6 to 18 years of age). In some specific examples, the administration may be performed without considering the individual's genotype; for example, the individual may be a broad metabolizer. In some specific examples, the hyperkinetic disorder may be Huntington's disease, Wilson's disease, Tourette syndrome, restless legs syndrome, tardive dyskinesia, tic disorders, dyskinesia-type cerebral palsy / cerebral palsy, other atonic and motor disorders, and combinations thereof. In any of the specific examples described herein, the deuterated buprofen may be deuterated buprofen (such as R,R-deuterated buprofen).

[0011] Some specific examples of the invention pertain to the transdermal delivery of buphenazine or deuterated buphenazine to an individual in need. The transdermal pharmaceutical composition and transdermal delivery device are also novel aspects of this disclosure.

[0012] In some specific examples, the present invention provides a transdermal delivery device comprising butylbenazine and / or a deuterated butylbenazine (e.g., deuterated butylbenazine). In various other specific examples, the present invention also provides a pharmaceutical composition (e.g., an adhesive composition) comprising butylbenazine and / or a deuterated butylbenazine (e.g., deuterated butylbenazine). In some specific examples, the present invention further provides a method for preparing or using a transdermal delivery device or a pharmaceutical composition comprising butylbenazine and / or a deuterated butylbenazine (e.g., deuterated butylbenazine).

[0013] Typically, the transdermal delivery device comprises a backing layer, a drug layer comprising a drug selected from buphenazine, a deuterated buphenazine, or a combination thereof (e.g., in an amount of about 2% to about 30% by weight 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, such as any of those defined herein. Typically, the transdermal delivery device may have an active surface area ranging from about 5 cm² to about 300 cm² (e.g., about 10 cm² to about 100 cm²).

[0014] The transdermal delivery device described herein is not limited to any particular patch design. For example, the transdermal delivery device may be an adhesive-in-adhesive patch, a drug-in-reservoir patch, a microneedle patch, or another patch design that may contain enhanced chemical or physical modalities. In some specific examples, the transdermal delivery device may be an adhesive-in-adhesive patch, such as a single-layer DIA patch. In some specific examples, the transdermal delivery device may contain more than one drug layer, such as two or more adhesive-in-adhesive drug layers. In some specific examples, the transdermal delivery device may be a reservoir-in-reservoir patch, for example, the drug layer being a reservoir containing buphenazine and / or a deuterated buphenazine.

[0015] The drug layer may contain butylbenazine, deuterated butylbenazine, or a combination thereof. In any of the specific examples described herein, the drug layer may be an adhesive-coated drug layer. In any of the specific examples described herein, the drug layer may contain butylbenazine, for example, a substantially pure R,R-butylbenazine. In some specific examples, butylbenazine (e.g., a substantially pure R,R-butylbenazine) is the sole active ingredient in the drug layer. In any of the specific examples described herein, the drug layer may contain deuterated butylbenazine, for example, a substantially pure R,R-deuterated butylbenazine. In some specific examples, deuterated butylbenazine (e.g., a substantially pure R,R-deuterated butylbenazine) is the sole active ingredient in the drug layer. In some specific examples, the drug layer comprises buphenazine, deuterated buphenazine, or a combination thereof in an amount of about 2% to about 30% (e.g., about 2%, about 2.5%, about 5%, about 8%, about 10%, about 15%, about 18%, about 20%, about 25%, about 30%, or any range between the cited values) by weight. In some particular specific examples, the drug layer comprises buphenazine, deuterated buphenazine, or a combination thereof in an amount of about 2%, about 2.5%, about 5%, about 8%, about 10%, about 15%, or about 20% by weight. In some specific examples, the drug layer may optionally include one or more other components, such as those selected from skin penetration enhancers, moisturizers, plasticizers, antioxidants, anti-irritants, gelling agents, drug release modifiers, solvents, crystallization inhibitors, and additional active ingredients. In some specific examples, the drug layer may have a coating weight with an active surface area of ​​about 0.1 g / cm2 to about 0.90 g / cm2 (e.g., about 0.1 g / cm2 to about 0.5 g / cm2).

[0016] In some specific examples, the drug layer comprises buphenazine, deuterated buphenazine, or a combination thereof dispersed (e.g., uniformly dispersed) in an adhesive (e.g., a pressure-sensitive adhesive). Suitable pressure-sensitive adhesives are described herein. In some specific examples, the pressure-sensitive adhesive may comprise a polyisobutylene (PIB) adhesive, a silicone polymer adhesive (e.g., Bio-7-4202), an acrylate copolymer adhesive (e.g., DuroTak 87-2287), or a combination thereof. In some specific examples, the pressure-sensitive adhesive may be a non-reactive acrylate adhesive, for example, an acrylate adhesive without a functional group containing a reactive hydrogen moiety, or an acrylate adhesive without a functional group selected from epoxy, –OH, –COOH, and combinations thereof.

[0017] The adhesive layer is typically formulated so that the transdermal delivery device can adhere to a user's skin for a desired period of time. For example, in some specific cases, the transdermal delivery device can adhere to a user's skin 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 more.

[0018] Certain specific embodiments of the present invention also relate to an adhesive composition. In some specific embodiments, the adhesive composition comprises a drug selected from buphenazine, deuterated buphenazine (e.g., deuterated buphenazine), and combinations thereof in an adhesive. In some specific embodiments, the drug is uniformly dispersed in the adhesive (e.g., a pressure-sensitive adhesive). In some specific embodiments, the pressure-sensitive adhesive may be a non-reactive acrylate adhesive, for example, an acrylate adhesive without a functional group containing a reactive hydrogen moiety, or an acrylate adhesive without a functional group selected from epoxy, –OH, –COOH, and combinations thereof. In some specific embodiments, the pressure-sensitive adhesive comprises a polyisobutylene (PIB) adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some specific examples, the adhesive composition contains about 2% to about 30% by weight of butylbenazine (e.g., a substantially pure R,R-butylbenazine). In some specific examples, the adhesive composition contains about 2% to about 30% by weight of deuterated butylbenazine (e.g., a substantially pure R,R-deuterated butylbenazine). In some specific examples, the active ingredient is present in about 2% to about 7% by weight. In some specific examples, the adhesive composition does not contain a penetration enhancer, for example, isopropyl myristate. However, in some specific examples, the adhesive composition further contains a penetration enhancer. In some specific examples, the adhesive composition may contain an antioxidant, for example, a gallate antioxidant (such as propyl gallate). In some specific examples, the adhesive composition may 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 graft copolymer based on polyvinyl acetate and polyvinylcaprolactam (PVAc-PVCap-PEG), or a combination thereof. In some preferred examples, the adhesive composition includes a crystallization inhibitor that is a copolymer of butyl methacrylate and methyl methacrylate. In some specific examples, the adhesive composition includes a crystallization inhibitor that is a polyethylene glycol, a graft copolymer based on polyvinyl acetate and polyvinylcaprolactam.In some specific examples, the adhesive composition can adhere continuously to a user's skin for a duration selected from an extended period of about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more. The adhesive composition described herein can be used in a transdermal delivery device. For example, in some specific examples, the transdermal delivery device may include any of the adhesive compositions described herein, a backing layer, and a release liner.

[0019] In some specific examples, the present invention provides a method for transdermal administration of buphenazine, deuterated buphenazine, or a combination thereof to an individual (e.g., a human individual) in need. In some specific examples, the method comprises applying any of these transdermal delivery devices or pharmaceutical compositions (e.g., adhesive compositions) to the individual, for example, to the individual's skin. In some specific examples, the administration provides any of the desired daily doses described herein and / or any of the PK profiles provided herein (if applicable).

[0020] In some specific examples, the present invention also provides a method for inhibiting VMAT-2 in an individual with a need for it. In some specific examples, the method comprises administering any of the transdermal delivery devices or pharmaceutical compositions (e.g., adhesive compositions) to the individual, for example, to the individual's skin. In some specific examples, the administration provides any of the desired daily doses described herein and / or any of the PK profiles provided herein (if applicable).

[0021] In some specific examples, the present invention also provides a method for treating a vesicular monoamine transporter isoform 2 (VMAT2)-mediated disease or ailment in an individual (e.g., a human individual) in need of treatment. In some specific examples, the method comprises administering any of these transdermal delivery devices or pharmaceutical compositions (e.g., adhesive compositions) to the individual, for example, to the individual's skin. In some specific examples, the administration provides any of the desired daily doses described herein and / or any of the PK profiles provided herein (if applicable).

[0022] In some specific examples, the present invention provides a method for treating a hyperkinetic disorder in an individual (e.g., a human individual) who has a need for it. In some specific examples, the method comprises percutaneously administering a therapeutically effective amount of buphenazine and / or deuterated buphenazine to the individual. In some specific examples, the method comprises applying either of these percutaneous delivery devices or pharmaceutical compositions (e.g., adhesive compositions) to the individual, for example, to the individual's skin. In some specific examples, the hyperkinetic disorder is a chronic hyperkinetic disorder. In some specific examples, the hyperkinetic disorder is chorea associated with Huntington's disease, Wilson's disease, Tourette syndrome, restless legs syndrome, tardive dyskinesia, and / or a seizure. In some specific examples, the hyperkinetic disorder is chorea associated with Huntington's disease. In some specific instances, the administration provides either the desired daily dose described herein and / or either the PK profile provided herein (if applicable).

[0023] In some specific examples, this disclosure also provides a method for identifying a pharmaceutical composition for treating a hyperkinetic disorder. In some specific examples, the method includes administering an experimental pharmaceutical composition to an individual, bypassing first-pass metabolism to deliver R,R-bufenazine to the individual continuously or substantially continuously, and identifying a pharmaceutical composition providing either of the PK profiles described herein. In some specific examples, the method is for identifying a pharmaceutical composition suitable for transdermal delivery for treating a hyperkinetic disorder. In some specific examples, the method includes measuring the skin flux characteristics of an experimental adhesive composition in vitro using human cadaver skin, and identifying an adhesive composition providing either of the in vitro flux characteristics described herein. Simple Explanation of the Diagram

[0024] Figure 1 presents a graph showing the in vivo in vitro flux of bubenazine from the whole matrix containing Duro-Tak 87-2287 adhesive at different concentrations (10%, 15%, 5% and 2.5%) of bubenazine through the epidermis of a human (black) cadaver.

[0025] Figure 2 presents a graph showing the in vivo in vitro flux of buphenazine from a monolithic matrix of a mixture of Duro-Tak 87-2287 adhesive and BIO-7-4202 in different ratios (including 5:95, 10:90, 25:75, and 50:50 (Duro-Tak 87-2287 vs. BIO-7-4202)) through the epidermis of a human cadaver. All matrices in this graph contain 10% buphenazine.

[0026] Figure 3 presents a graph showing the in vivo in vitro flux of bubenazine from the patch formulation prepared using DuroTak 87-900A through the human cadaver epidermis.

[0027] Figure 4A presents a graph showing the mean plasma concentration versus time. The combined concentrations of buphenazine (R,R and S,S-isomers are combined) are used in this graph. Figure 4B presents a graph showing the mean plasma concentration of R,R,R-HTBZ versus time. Figure 4C presents a graph showing the mean plasma concentration of S,R,R-HTBZ versus time. Figure 4D presents a graph showing the mean plasma concentration of total buphenazine (including buphenazine, R,R,R-HTBZ, and S,R,R-HTBZ) versus time. Implementation

[0028] Detailed Description of Preferred Embodiments

[0029] Both FDA-approved labels for Xenazine® and Austedo™ include a boxed warning about the potential risks of depression and suicide. For both products, actual dosing requires monitoring and titration. For example, the Xenazine® label states that for patients requiring doses exceeding 50 mg daily, they should be genotyped using the drug-metabolizing enzyme CYP2D6 to determine whether they are an adverse metabolizer (PM) or an extensive metabolizer (EM). For adverse metabolizers, the maximum daily dose can be as low as 50 mg, with a maximum single dose of 25 mg. For extensive or intermediate metabolizers, the maximum daily dose is 100 mg, with a maximum single dose of 37.5 mg. Similarly, the Austedo™ label states that for adverse metabolizers, the maximum daily dose can be as low as 36 mg, with two single doses of 18 mg each.

[0030] Despite current advancements, buphenazine / deuterated buphenazine pharmaceuticals remain complex, involving dose titration to mitigate potential dose-related side effects. Therefore, novel buphenazine formulations and dosage selections are needed.

[0031] In various specific examples, the present invention relates to pharmaceutical compositions, drug delivery devices, methods of preparation, and methods of use, such as those relating to the delivery of buphenazine and / or a deuterated buphenazine to an individual bypassing first-pass metabolism (e.g., in a continuous or substantially continuous manner). For example, some specific examples of the invention relate to the transdermal delivery of buphenazine and / or a deuterated buphenazine. Some specific examples disclosed herein relate to the intravenous, subcutaneous, intramuscular, or receptacle-based delivery of buphenazine and / or a deuterated buphenazine, such as continuous delivery, for example, at a substantially constant rate. Continuous delivery of bubenazine

[0032] Some specific examples disclosed herein are based on unique pharmacokinetic (PK) profiles obtained from a sustained or substantially sustained delivery, transdermal delivery (which bypasses first-pass metabolism) of bubenazine. As detailed herein, compared to three daily doses of TBZ tablets administered in healthy males under fasting conditions from day 1 to day 4 (total dose of 150 mg), transdermal delivery of R,R-bubenazine at a dose of 8 mg / 96 hours provides a higher concentration of R,R-bubenazine, with no interconversion to the SS isomer, and a lesser degree of metabolism to the active HTBZ isomers and a lower dose. This data firstly demonstrates that a sustained or substantially sustained delivery method (such as transdermal delivery) can provide therapeutically effective plasma concentrations of R,R-bubenazine and its dihydro-metabolites (R,R,R-HTBZ and S,R,R-HTBZ), for example, in the treatment of hyperkinetic dyskinesia. Because the R,R-isomers of buphenazine, R,R,R-HTBZ, and S,R,R-HTBZ are believed to have low off-target binding (e.g., for dopamine D1 or D2 receptors), using the R,R-isomer of buphenazine as the main active ingredient will also cause fewer side effects compared to using a racemic mixture of buphenazine (which is the active ingredient of Xenazine®). Furthermore, the PK data show that this continuous delivery method provides a relatively stable plasma concentration of R,R-buphenazine and its active dihydro-metabolite, with a reduced Cmax and a reduced peak-to-trough ratio, compared to a dose-equal oral delivery of buphenazine, and therefore may be advantageous in treating an individual with hyperkinetic motor disorder.

[0033] Although the PK data illustrated herein are generated using a transdermal delivery device, this disclosure is not limited to transdermal delivery. Specifically, for any of the methods described herein, the inventors have particularly considered administering any buphenazine formulation or delivery device to an individual requiring treatment that produces a PK profile as described herein. The PK profile described herein is a novel aspect of this disclosure. In some specific examples, the PK profile can be achieved via the transdermal delivery device administered herein. In some specific examples, the PK profile can be achieved via any continuous or substantially continuous delivery method bypassing first-pass metabolism, such as a transdermal delivery, a continuous intravenous delivery, a subcutaneous delivery, an intramuscular delivery, or via a reservoir. These delivery methods share a common characteristic: each can be adjusted to deliver buphenazine systemically at a desired rate (e.g., at a rate of about 0.1 mg / day to about 20 mg / day of R,R-buphenazine). In some specific examples, during the drug delivery period (e.g., during the patch-on period), the delivery of buphenazine may be at a substantially constant rate and with similar zero-order kinetics to the individual. For example, in some specific examples, the desired delivery rate may be about 12 mg / day of R,R-buphenazine, and the desired drug delivery period is 24 hours, followed by the amount of R,R-buphenazine delivered to the treated individual at approximately 0.5 mg / hour in each hour. For example, "substantially continuous" as used in the context of "substantially continuous delivery" means involving the delivery of a drug (e.g., buphenazine) in a substantially uninterrupted manner over a pre-selected drug delivery period. Furthermore, "substantially continuous" drug delivery may also include the delivery of the drug at a substantially constant, pre-selected rate or range of rates (e.g., amount of drug per unit time or volume of drug formulation for one unit time), substantially uninterrupted over a pre-selected drug delivery period. The duration of drug delivery can vary, for example, from about 8 hours to about 192 hours, such as 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 cited values. Clearly, the performance of continuous or substantially continuous delivery does not require that the active ingredient / drug be continuously delivered to the individual throughout the treatment; unlike a pellet delivery, this performance only requires that the drug be continuously or substantially continuously delivered during the period of drug delivery. For example, when a pharmaceutical composition is administered once daily, it is permissible that there is a time period between two administrations during which no drug is delivered to the individual to be treated.

[0034] Typically, the R,R-bubenazine is delivered to an individual in need at a dose effective for treating hyperkinetic dyskinesia as described herein. In some specific examples, the method described herein delivers to an individual requiring treatment of hyperkinetic movement disorder of the present invention approximately 0.1 mg / day to approximately 20 mg / day of R,R-bufenazine, such as approximately 0.1 mg / day, approximately 0.5 mg / day, approximately 1 mg / day, approximately 2 mg / day, approximately 3 mg / day, approximately 4 mg / day, approximately 5 mg / day, approximately 6 mg / day, approximately 7 mg / day, approximately 8 mg / day, approximately 10 mg / day, approximately 12 mg / day, approximately 14 mg / day, approximately 16 mg / day, approximately 18 mg / day, or approximately 20 mg / day of R,R-bufenazine, or any range between the cited values, for example, approximately 0.5 mg / day to approximately 10 mg / day of R,R-bufenazine, approximately 0.5 mg / day to approximately 8 mg / day of R,R-bufenazine, approximately 0.5 mg / day to approximately 6 mg / day of R,R-bufenazine, approximately 0.5 mg / day to approximately 4 mg / day of R,R-bufenazine, or approximately 0.5 mg / day to approximately 4 mg / day of R,R-bufenazine. R,R-bufenazine (approximately 1 mg / day to approximately 10 mg / day), R,R-bufenazine (approximately 1 mg / day to approximately 8 mg / day), R,R-bufenazine (approximately 1 mg / day to approximately 6 mg / day), R,R-bufenazine (approximately 1 mg / day to approximately 4 mg / day), R,R-bufenazine (approximately 2 mg / day to approximately 10 mg / day), R,R-bufenazine (approximately 2 mg / day to approximately 8 mg / day), R,R-bufenazine (approximately 2 mg / day to approximately 6 mg / day), R,R-bufenazine (approximately 2 mg / day to approximately 4 mg / day), R,R-bufenazine (approximately 4 mg / day to approximately 10 mg / day), R,R-bufenazine (approximately 4 mg / day to approximately 6 mg / day), R,R-bufenazine (approximately 6 mg / day to approximately 10 mg / day). mg / day of R,R-bufenazine, or about 6 mg / day to about 8 mg / day of R,R-bufenazine. In some preferred embodiments, the method delivers about 0.5 mg / day to about 8 mg / day of R,R-bufenazine or about 2 mg / day to about 6 mg / day of R,R-bufenazine. As used herein, the term R,R-bufenazine should be understood to include an R,R-bufenazine base, a pharmaceutically acceptable salt thereof, or a combination thereof. Typically, for a transdermal composition (such as the adhesive composition described herein), the R,R-bufenazine may be present primarily in its free base form. For example, in any of the embodiments described herein, the adhesive composition or adhesive package pharmaceutical composition containing the R,R-bufenazine may be prepared from a mixture of the R,R-bufenazine free base with other components (such as adhesives, antioxidants, crystallization inhibitors, etc., in cited amounts).The delivery of R,R-butylbenazine to an individual herein should be understood as the amount of R,R-butylbenazine delivered to the individual (e.g., the amount permeated through the individual's skin), which may be in any form and has an equivalent amount expressed as an R,R-butylbenazine base. Other terms such as butylbenazine, deuterated butylbenazine, deuterated R,R-butylbenazine, deuterated butylbenazine, R,R-deuterated butylbenazine, and delivery of such to an individual should be understood similarly.

[0035] In some specific examples, the R,R-buphenazine may be included in a pharmaceutical composition or a delivery device (e.g., a continuous delivery device) configured to deliver the dose described herein to the individual at a substantially constant rate. For example, in some specific examples, the daily dose of R,R-buphenazine may be from about 0.5 mg / day to about 10 mg / day, and the continuous delivery device may be administered to an individual in need once a day, continuously or substantially continuously delivering R,R-buphenazine to the individual for a pre-selected time period (e.g., 12 hours or 24 hours), and the rate of delivery of the R,R-buphenazine during the pre-selected time period may be substantially the same. Regarding the methods described herein, the pharmaceutical composition or delivery device containing the R,R-buphenazine is not particularly limited and may be any of those suitable for delivering R,R-buphenazine at a desired dose and a desired rate.

[0036] While many exemplary specific examples are described as methods for treating an ADHD in an individual in need, this disclosure is not limited to such treatment methods. Any of the delivery methods of R,R-bubenazine and / or a deuterated R,R-bubenazine described herein may also be used in a method for inhibiting VMAT-2 in an individual in need, a method for treating an ADHD in an individual in need (e.g., a human individual), and / or a method for treating a disease or disorder mediated by vesicular monoamine transporter isoform 2 (VMAT2) in an individual in need (e.g., a human individual).

[0037] In some specific examples, this disclosure provides a method for treating an ADHD in an individual with a need, the method comprising administering to the individual a pharmaceutical composition comprising an active ingredient containing R,R-bufenazine, wherein the administration bypasses first-pass metabolism and is continuously or substantially continuously delivered to the individual at about 0.1 mg / day to about 20 mg / day of R,R-bufenazine, for example, about 0.5 mg / day to about 10 mg / day of R,R-bufenazine, about 0.5 mg / day to about 8 mg / day of R,R-bufenazine, about 0.5 mg / day to about 6 mg / day of R,R-bufenazine, about 0.5 mg / day to about 4 mg / day of R,R-bufenazine, about 1 mg / day to about 10 mg / day of R,R-bufenazine, about 1 mg / day to about 8 mg / day of R,R-bufenazine, about 1 mg / day to about 6 mg / day of R,R-bufenazine, about 1 R,R-bufenazine, approximately 0.5 mg / day to approximately 4 mg / day, or approximately 2 mg / day to approximately 10 mg / day, or approximately 6 mg / day, is delivered via a specific method. In some preferred embodiments, the method delivers approximately 0.5 mg / day to approximately 8 mg / day of R,R-bufenazine or approximately 2 mg / day to approximately 6 mg / day of R,R-bufenazine. The duration of drug delivery may vary, for example, from about 8 hours to about 72 hours or more. The pharmaceutical composition may be administered to the individual at any frequency as needed. For example, in some specific instances, each administration provides a continuous or substantially continuous delivery of R,R-bufenazine to the individual 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 cited values. In some specific instances, during the continuous or substantially continuous delivery period, the R,R-bufenazine may be delivered to the individual at a substantially constant rate, for example, at an average rate (such as within 80-125% of the total average rate) for the duration of the drug delivery period, which is substantially the same for each hour.In some specific instances, during continuous or substantially continuous delivery, the R,R-bufenazine may be delivered to the individual at different rates, for example, to varying average delivery rates for different hours. For example, in some specific instances, the average delivery rate may initially be high but then decrease during continuous or substantially continuous delivery. Typically, the precise delivery rate of R,R-bufenazine for each hour is not critical, and those skilled in the art will, upon reviewing this disclosure, know how to select and design a dosing regimen to deliver a desired daily dose to the individual, such as about 0.5 mg / day to about 10 mg / day of R,R-bufenazine, about 0.5 mg / day to about 8 mg / day of R,R-bufenazine, or about 2 mg / day to about 6 mg / day of R,R-bufenazine. In some specific instances, delivery of the desired daily dose to the individual also provides a pharmacokinetic profile as described herein.

[0038] In some specific examples, this disclosure provides a method for treating an ADHD in an individual with a need, the method comprising administering to the individual a pharmaceutical composition comprising an active ingredient containing R,R-bufenazine, wherein the administration is transdermal to the individual at a dose of about 0.1 mg / day to about 20 mg / day of R,R-bufenazine, for example, about 0.5 mg / day to about 10 mg / day of R,R-bufenazine, about 0.5 mg / day to about 8 mg / day of R,R-bufenazine, about 0.5 mg / day to about 6 mg / day of R,R-bufenazine, about 0.5 mg / day to about 4 mg / day of R,R-bufenazine, about 1 mg / day to about 10 mg / day of R,R-bufenazine, about 1 mg / day to about 8 mg / day of R,R-bufenazine, about 1 mg / day to about 6 mg / day of R,R-bufenazine, about 1 mg / day to about 4 ... R,R-bufenazine at approximately 0.5 mg / day to approximately 8 mg / day, R,R-bufenazine at approximately 2 mg / day to approximately 10 mg / day, R,R-bufenazine at approximately 2 mg / day to approximately 8 mg / day, R,R-bufenazine at approximately 2 mg / day to approximately 6 mg / day, R,R-bufenazine at approximately 2 mg / day to approximately 4 mg / day, R,R-bufenazine at approximately 4 mg / day to approximately 10 mg / day, R,R-bufenazine at approximately 4 mg / day to approximately 8 mg / day, R,R-bufenazine at approximately 4 mg / day to approximately 6 mg / day, R,R-bufenazine at approximately 6 mg / day to approximately 10 mg / day, or R,R-bufenazine at approximately 6 mg / day to approximately 8 mg / day. In some preferred embodiments, the method delivers approximately 0.5 mg / day to approximately 8 mg / day of R,R-bufenazine or approximately 2 mg / day to approximately 6 mg / day of R,R-bufenazine. In some specific examples, the administration involves applying the pharmaceutical composition to the individual's skin. While the pharmaceutical composition is typically applied to an entire area of ​​the skin (e.g., the individual's outer arm), the exact location of the skin is not critical. In the context of a percutaneous patch, the duration of drug delivery can also refer to the patch time, which can vary, for example, from about 8 hours to about 72 hours or more. In some specific examples, the pharmaceutical composition is applied to the individual's skin to continuously or substantially continuously deliver R,R-bufenazine to the individual 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 cited values. The frequency of administration of the pharmaceutical composition to the individual can vary depending on the method used herein, such as once a day, more than once a day, or once a week, etc.In some specific examples, for each application, the pharmaceutical composition may be applied to the individual's skin to adhere to the individual's skin for approximately 8 hours, approximately 12 hours, approximately 24 hours, approximately 36 hours, approximately 48 hours, approximately 72 hours, approximately 96 hours, approximately 120 hours, approximately 144 hours, approximately 168 hours, approximately 192 hours, or any range between the cited values, continuously or substantially continuously delivering R,R-bufenazine to the individual during the patch application period. In some specific examples, there is no lag time between transdermal patch applications according to the frequency of administration described herein. For example, in some specific examples, the transdermal delivery device is applied to the individual once daily, and each application of the transdermal delivery device can continue (adhering to the individual's skin) for approximately 24 hours before it is replaced by another typically substantially identical transdermal delivery device. However, in some specific examples, there may also be overlap or lag between two applications.

[0039] Typically, with respect to transdermal delivery, the pharmaceutical composition may include an adhesive composition, for example, in a transdermal delivery device (e.g., described herein) containing the active ingredient dispersed in an adhesive (preferably a pressure-sensitive adhesive). In some specific examples, the adhesive composition is administered to the individual to deliver about 0.1 mg / day to about 20 mg / day of R,R-bufenazine (e.g., any of the exemplary ranges described herein) at a substantially constant rate for up to 24 hours, up to 48 hours, up to 96 hours, or up to 1 week after administration. Suitable adhesive compositions include any of those described herein, such as any of those applicable to bufenazine described in Exemplary Examples 1-18 or any of the specific compositions shown in the Examples section (e.g., Example 4A). In some specific examples, the adhesive composition comprises the active ingredient dispersed in a non-reactive acrylate pressure-sensitive adhesive. The active ingredient may be present in an amount of about 1% to about 20% by weight, such as about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 10%, about 15%, or about 20% by weight, or in any range between the cited values, for example, about 1% to about 15%, about 2% to about 15%, about 2% to about 10%, about 2% to about 7%, about 3% to about 15%, about 3% to about 10%, about 3% to about 7%, about 5% to about 15%, about 5% to about 10%, about 5% to about 7%, about 7% to about 15%, about 7% to about 10%, about 10% to about 20%, about 10% to about 15%, etc., by weight. In some specific examples, the adhesive composition comprises a substantially pure R,R-isomer of butylbenazine as the sole active ingredient. In some specific examples, the substantially pure R,R-isomer of bubenazine is in the form of a free base. Suitable adhesives include any of those described herein, such as any of the pressure-sensitive adhesives described herein. In some specific examples, the adhesive may be a non-reactive acrylate pressure-sensitive adhesive described herein (such as Duro-Tak 87-900A) or as described in exemplary examples 2-7.The adhesive is typically present in an amount of about 50% to about 97% by weight, such as about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 97% by weight, or in any range between the cited values, for example, about 50% to about 95%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, about 50% to about 60%, about 60% to about 97%, about 60% to about 95%, about 60% to about 90%, about 60% to about 80%, about 60% to about 70%, about 70% to about 97%, about 70% to about 95%, about 70% to about 90%, about 70% to about 80%, about 80% to about 97%, about 80% to about 95%, about 80% to about 90%, etc., by weight. In some specific examples, the active ingredient is present in an amount of about 2% to about 7% by weight, and the non-reactive acrylate pressure-sensitive adhesive is present in an amount of about 50% to about 97% by weight. The adhesive composition may also optionally include other components, such as an antioxidant, a crystallization inhibitor, a plasticizer, and / or a penetration enhancer. In some specific examples, the adhesive composition includes an antioxidant, such as a gallate antioxidant (e.g., propyl gallate). The amount of antioxidant is typically present in an amount of about 0% to about 1% by weight, such as about 0.001%, about 0.01%, about 0.1%, about 0.5%, about 1%, or in any range between the cited values, for example, about 0.001% to about 0.5%, about 0.01% to about 0.5%, etc., by weight. In some specific examples, the adhesive composition includes a crystallization inhibitor, for example, a method to prevent the formation of drug crystals (crystallization of the active ingredient of the adhesive composition, such as R,R-bufenazine) after shelf storage at ambient temperature for 2 weeks.In some specific examples, the adhesive composition includes a crystallization inhibitor selected from the following: a polyvinylpyrrolidone polymer (e.g., Kollidon K30 or K90F (manufactured by BASF), Plasdone K20 / 32 or Plasdone K90 (manufactured by Ashland Chemical)), a crosslinked polyvinylpyrrolidone polymer (e.g., Kollidon CL), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 Copovidone (Asland)), a cellulose-based polymer (e.g., hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose), a polycarboxylic acid polymer (e.g., carbopol (manufactured by Lubrizol)), and a polymethacrylate (e.g., Plastoid B, Eudragit E100, Eudragit L100-55). (manufactured by Evonik)), polyethylene glycol, graft copolymers based on polyvinyl acetate and polyvinylcaprolactam (PVAc-PVCap-PEG) (e.g., Soluplus (BASF), and combinations thereof. In some specific examples, the adhesive composition includes a crystallization inhibitor selected from: polymethacrylate (e.g., Plastoid B (a copolymer of butyl methacrylate and methyl methacrylate), Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, graft copolymers based on polyvinyl acetate and polyvinylcaprolactam (PVAc-PVCap-PEG) (e.g., Soluplus) (BASF), and combinations thereof. The crystallization inhibitor is typically present in an amount of about 0 to about 40% by weight, such as about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, or in any range between the cited values, for example, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, 15% to about 40%, about 15% to about 30%, about 15% to about 20%, 20% to about 40%, about 20% to about 30%, etc., by weight. In some specific examples, the adhesive composition may also contain a skin penetration enhancer as described herein, such as isopropyl myristate. In some specific examples, the adhesive composition may also be without a skin penetration enhancer as described herein; for example, in some specific examples, the adhesive composition may also be without isopropyl myristate. Suitable drug loading, active surface area, thickness, adhesive properties, etc., include any combination of those described herein.

[0040] In some specific examples, this disclosure provides a method for treating an ADHD in an individual with a need, the method comprising administering to the individual a pharmaceutical composition comprising an active ingredient containing R,R-bufenazine, wherein the administration is via injection or infusion, such as intravenous injection (excluding bolus injection for immediate release only), subcutaneous injection, or intramuscular injection, delivering to the individual about 0.1 mg / day to about 20 mg / day of R,R-bufenazine, for example, about 0.5 mg / day to about 10 mg / day of R,R-bufenazine, about 0.5 mg / day to about 8 mg / day of R,R-bufenazine, about 0.5 mg / day to about 6 mg / day of R,R-bufenazine, about 0.5 mg / day to about 4 mg / day of R,R-bufenazine, about 1 mg / day to about 10 mg / day of R,R-bufenazine, about 1 mg / day to about 8 mg / day of R,R-bufenazine, or about 1 mg / day to about 8 mg / day of R,R-bufenazine. R,R-bufenazine at approximately 1 mg / day to approximately 6 mg / day, R,R-bufenazine at approximately 1 mg / day to approximately 4 mg / day, R,R-bufenazine at approximately 2 mg / day to approximately 10 mg / day, R,R-bufenazine at approximately 2 mg / day to approximately 8 mg / day, R,R-bufenazine at approximately 2 mg / day to approximately 6 mg / day, R,R-bufenazine at approximately 2 mg / day to approximately 4 mg / day, R,R-bufenazine at approximately 4 mg / day to approximately 10 mg / day, R,R-bufenazine at approximately 4 mg / day to approximately 8 mg / day, R,R-bufenazine at approximately 4 mg / day to approximately 6 mg / day, R,R-bufenazine at approximately 6 mg / day to approximately 10 mg / day, or R,R-bufenazine at approximately 6 mg / day to approximately 8 mg / day. In some preferred embodiments, the method delivers about 0.5 mg / day to about 8 mg / day of R,R-bufenazine or about 2 mg / day to about 6 mg / day of R,R-bufenazine. In some embodiments, the administration comprises continuous or substantially continuous intravenous injection or infusion of the pharmaceutical composition to the individual. The duration of the drug delivery may vary, for example, from about 8 hours to about 72 hours or more. For example, in some embodiments, the pharmaceutical composition is intravenously injected or infused into the individual to deliver R,R-bufenazine to the individual 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 in any range between the cited values. The rate of this intravenous injection or infusion can be controlled (e.g., by a pump) and regulated to deliver R,R-bufenazine to the individual at a substantially constant rate during the drug delivery period (such as the infusion period).In some specific examples, the administration involves a subcutaneous or intramuscular injection of the pharmaceutical composition to the individual. Typically, with respect to subcutaneous or intramuscular injection, the pharmaceutical composition is formulated to release R,R-buphenazine to the individual for systemic absorption over a pre-selected period, for example, from about 8 hours to about 72 hours or more. For example, in some specific examples, the subcutaneous or intramuscular pharmaceutical composition is formulated or included in a drug delivery device (such as an implant) to continuously or substantially continuously release R,R-buphenazine to the individual for systemic absorption over 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 cited values. Suitable implants include any of those known in the art for subcutaneous or intramuscular delivery of pharmaceutical agents, such as passive polymeric implants (including biodegradable and non-biodegradable implants) or active implants (such as osmotic gradients and electromechanical devices). Non-limiting examples of implants for subcutaneous delivery include those described in U.S. Patent No. 8,921,387 (buprenorphine), No. 6,835,194 (fentanyl), and so on. See also Stewart SA, et al. “Implantable polymeric drug delivery devices, classification, manufacture, materials, and clinical applications,” Polymers, 10: 1379 (2018). In some specific examples, the pharmaceutical composition is formulated as a long-acting injectable formulation (such as a microsphere) that can be configured to release R,R-buphenazine to the individual for systemic absorption over a pre-selected period (e.g., from about 8 hours to about 72 hours or more). In some specific examples, the long-acting injectable formulation can be configured to release R,R-buphenazine to the individual at a substantially constant rate for systemic absorption over the pre-selected period to deliver the desired daily dose as described herein.

[0041] The hyperkinetic motor disorders referred to in the treatments herein include any of those known to be treatable with bubenazine or deuterated bubenazine, for example, any of those approved by any regulatory authority (including the US FDA or those under clinical investigation). Non-restrictive examples include Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tic disorders, dyskinesia-type cerebral palsy, other hypotonia and dyskinesia disorders, and combinations thereof. In some specific examples, the hyperkinetic motor disorder may be Huntington's disease, such as chorea associated with Huntington's disease. In some specific examples, the hyperkinetic motor disorder may be Wilson's disease. In some specific examples, the hyperkinetic motor disorder may be Tourette's disease. In some specific examples, the hyperkinetic motor disorder may be restless legs syndrome. In some specific cases, this hyperactive motor disorder can be tardive dyskinesia. In some specific cases, this hyperactive motor disorder can be tic.

[0042] In some specific cases, this hyperactive motor disorder can be dyskinesia-type 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 abnormality in the developing brain that disrupts the brain’s ability to control movement and maintain posture and balance. Signs of CP usually appear in the first few months of life, although a specific diagnosis may be delayed until 2 years of age or older. Currently, there is no approved treatment for motor disorders in cerebral palsy (DCP). Available treatment options address some of the manifestations of DCP. Teva is currently conducting a phase III clinical trial using deuterated benzonazine. According to Teva, the study population will include pediatric and adolescent patients (6 to 18 years of age) with DCP and a motor disorder primarily characterized by chorea, who have had non-progressive CP symptoms since infancy (≤2 years of age). The inventors believe that the methods and compositions herein provide alternative and / or superior treatment options for dyskinesia-type cerebral palsy.

[0043] In some specific cases, the hyperkinetic disorder is a form of hypotonia or movement disorder. See, for example, a review of the treatment of hypotonia in Thengnatt MA and Jankovic J. neurotherapeutics, 11(1): 139-152 (2014).

[0044] The treatment methods described herein are not limited to any particular type of individual. For example, the methods described herein may administer the medication to the individual regardless of their eating status. In other words, the individual's eating and fasting status is not critical to the methods described herein. In some specific cases, the individual is a pediatric or adolescent patient (e.g., 6 to 18 years old). Also, in some specific cases, the method is not limited to any particular genotyped individual. In some specific cases, the same or substantially the same dose of R,R-bufenazine may be administered to an individual characterized as PM, IM, or EM. In some specific cases, the individual is characterized as EM. In some specific cases, the individual is characterized as PM. In some specific cases, the individual is characterized as IM. In some specific cases, the method does not require dose titration and / or genotyping analysis, which is required when the individual is treated with either Xenazine® or Austedo™ tablets. In some specific instances, any of the methods described herein may be adapted for the treatment of pediatric and adolescent patients (e.g., 6 to 18 years of age) who have any of the diseases or ailments described herein. As discussed herein, the ranges of dosage and / or plasma exposure described herein may be suitable for adult patients as well as pediatric and adolescent patients. However, as those skilled in the art will understand, taking into account the individual's age and weight, the desired dosage and / or plasma exposure for pediatric and adolescent patients may be adjusted, typically to a lower dose or exposure. Not wishing to be bound by theory, in some specific instances, convenient and controlled delivery of R,R-bufenazine herein offers superior safety and therapeutic options compared to currently available treatments.

[0045] The administration of R,R-bufenazine for the treatment herein is not particularly limited, provided that the desired dose of R,R-bufenazine is delivered to the individual at a desired rate for a desired period of time, including any of those described herein. For example, in some specific instances, the pharmaceutical composition is administered to the individual once daily. In some specific instances, the pharmaceutical composition is administered to the individual more than once daily, such as 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 specific instances, each administration provides a continuous or substantially continuous delivery of R,R-bufenazine to the individual for approximately 8 hours, approximately 12 hours, approximately 24 hours, approximately 36 hours, approximately 48 hours, approximately 72 hours, approximately 96 hours, approximately 120 hours, approximately 144 hours, approximately 168 hours, approximately 192 hours, or within any range between the cited values. In some specific instances, there may be no or substantially no lag time between two consecutive administrations, thereby allowing the R,R-bubenazine to be continuously delivered to the individual according to the dosing regimen described herein. In some specific instances, there may also be overlap or lag time between two consecutive administrations. Pharmacokinetics of continuous delivery of bubenazine

[0046] Some specific examples disclosed herein also relate to a method for treating an ADHD in an individual in need, comprising delivering to the individual a therapeutically effective amount of R,R-bubenazine, wherein the delivery provides certain novel pharmacokinetic profiles in the individual's plasma.

[0047] As discussed herein, currently approved buphenazine or deuterated buphenazine products (such as Xenazine® and Austedo™) require complex dose titration and genotyping analysis of individuals treated at higher doses. Furthermore, oral administration of these products also results in a high peak-to-trough ratio, with significant inter-individual differences in plasma levels of buphenazine or deuterated buphenazine or one of their metabolites. Typically, as shown herein, R,R-buphenazine itself (which is a potent VMAT-2 inhibitor) does not present in significant amounts in circulation after oral administration. In some respects, the inventors have first shown that by using continuous or substantially continuous delivery of buphenazine, the mean final half-life of R,R-buphenazine administered via first-pass bypass can be around 8.5 hr ± 40% CV. In contrast, with this typical oral administration, R,R-buphenazine is typically not systemically available.

[0048] In various specific examples, sustained or substantially sustained delivery of buphenazine, as described herein, to achieve the novel pharmacokinetic profile described herein, may be advantageously used to deliver buphenazine, for example, for the treatment of a hyperkinetic disorder.

[0049] In some specific examples, this disclosure provides a method for treating an ADHD in an individual with a need, the method comprising administering to the individual a pharmaceutical composition comprising an active ingredient containing R,R-bubenazine, wherein the administration provides a desired pharmacokinetic (PK) profile. For example, in some specific instances, the desired PK profile is characterized in that the dosing provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ, wherein the ratio of the maximum plasma concentration of R,R-bufenazine to the maximum plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ is in the range of about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any range between the cited values ​​(e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.), that is, the Cmax of R,R-bufenazine / (Cmax of R,R,R-HTBZ + Cmax of S,R,R-HTBZ) is in the range of about 1:1 to about 1:5. As used herein, In some specific instances, the term "maximum plasma concentration" may mean the maximum plasma concentration obtained after a single dose of the pharmaceutical composition, for example, the maximum plasma concentration obtained after one, two, three, or more days of administration of a single transdermal patch herein. As used herein, in some specific instances, the term "maximum plasma concentration" may also mean the maximum plasma concentration obtained after multiple doses of the pharmaceutical composition, preferably, the maximum plasma concentration obtained after steady state has been reached. However, it should be understood that the proportions herein should be based on a comparison of concentrations of the same type (e.g., from a single dose, steady state, etc.) in the individual compounds and that such proportions may be said to fall within the individual ranges cited herein when calculated according to: (1) Cmax of a single dose and / or (2) Cmax of multiple doses (preferably, Cmax of steady state). In some specific examples, the desired PK profile is characterized by the following: the dosage provides a steady-state plasma concentration of R,R-bufenazine in a ratio to the steady-state plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ in the range of about 1:1 to about 1:5, that is, the Css of R,R-bufenazine / (Css of R,R,R-HTBZ + Css of S,R,R-HTBZ) is in the range of about 1:1 to about 1:5. In a sustained or substantially sustained delivery herein, steady state can typically be reached and maintained for a desired period of time.For example, in some specific instances, a steady state can be achieved by administering a single transdermal patch here for approximately 32-48 hours or more, and this steady state can be maintained by the same patch or by administering a new patch of R,R-bufenazine at substantially the same rate at any frequency in place of the transdermal patch. In some specific instances, a steady state is not achieved by administering a single transdermal patch here, but can be achieved by administering transdermal patches sequentially multiple times. As will be appreciated by those skilled in the art, in steady state, the drug concentration obtained from the transdermal delivery patch can be substantially constant; in other words, the PK curve in steady state can be substantially flat or stationary over a period of time. As used herein, steady state of R,R-TBZ means that the total uptake of R,R-TBZ is in dynamic equilibrium with its elimination. Steady state of R,R,R-HTBZ means that the total production of R,R,R-HTBZ is in dynamic equilibrium with its elimination. The steady state of S,R,R-HTBZ means that the total formation and elimination of S,R,R-HTBZ are in a state of dynamic equilibrium. Clearly, as used herein, the ratio of steady-state concentrations of R,R-butylbenazine, R,R,R-dihydrobutylbenazine (HTBZ), and / or S,R,R-HTBZ can be said to be within the scope of this reference when calculated: (1) according to the concentration of the individual compounds at any point in time when all three compounds (R,R-butylbenazine, R,R,R-dihydrobutylbenazine (HTBZ), and S,R,R-HTBZ) are in a steady state, and / or (2) according to the average concentration of the individual compounds over a sustained period of time when all three compounds (R,R-butylbenazine, R,R,R-dihydrobutylbenazine (HTBZ), and S,R,R-HTBZ) are in a steady state. The ratio of steady-state concentrations of other compounds herein should be understood similarly. As used herein, a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ does not require each of the three compounds to individually exhibit a therapeutically effective plasma concentration. It is sufficient that the combination of the three compounds is therapeutically effective, for example, at its individual steady-state concentration. In some specific examples, the ratio of the maximum plasma concentration or steady-state plasma concentration of R,R,R-HTBZ to that of S,R,R-HTBZ may 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 cited values ​​(e.g., from about 1:10 to about 1:20, about 1:5 to about 1:15, etc.)). In some specific cases, the ratio of the maximum plasma concentrations of R,R-bubenazine:R,R,R-HTBZ:S,R,R-HTBZ can range from approximately 17-40:3-10:50-80.In some specific examples, the steady-state plasma concentration ratio of R,R-bufenazine:R,R,R-HTBZ:S,R,R-HTBZ can range from about 17-40:3-10:50-80. In some specific examples, the dosing can provide a pharmacokinetic profile characterized in that: the ratio of the AUC0-∞ of SRR-HTBZ to the AUC0-∞ of R,R-bufenazine is about 1 to about 15 (e.g., about 1.5 to about 11), and / or the ratio of the AUC0-∞ of RRR-HTBZ to the AUC0-∞ of R,R-bufenazine is about 0.1 to about 0.75 (e.g., about 0.15 to about 0.5). In some specific examples, the desired PK profile may also be characterized in that the administration provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (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 specific examples, the desired PK profile may also be characterized by the dosing providing a substantially constant steady-state plasma concentration of R,R-bufenazine at or above 150 pg / ml (e.g., about 150 pg / ml to about 3000 pg / ml) 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 specific examples, the dosing does not provide detectable S,S-bufenazine, R,S,S-HTBZ or S,S,S-HTBZ in the individual's plasma. In some specific examples, this disclosure also provides a method for identifying a pharmaceutical composition for treating a hyperkinetic disorder. In some specific examples, the method includes administering an experimental pharmaceutical composition to an individual, bypassing first-pass metabolism to provide a continuous or substantially continuous delivery of R,R-bufenazine to the individual, and identifying a pharmaceutical composition that provides either of the PK profiles described in this paragraph in any combination.

[0050] In some specific examples, the pharmaceutical composition is formulated to provide a dose of approximately 2 mg / day of R,R-bubenazine for 4 days when administered once. In some specific examples, the method comprises administering the pharmaceutical composition to provide a pharmacokinetic profile in the individual, characterized in that: a) The mean Tmax of R,R-bufenazine over approximately 10 to approximately 24 hours (e.g., approximately 20 hours); b) The average Tmax of R,R,R-HTBZ and the average Tmax of S,R,R-HTBZ are later than the average Tmax of R,R-butylbenazine; c) The mean Cmax of R,R-bufenazine at concentrations of approximately 300 pg / ml to approximately 700 pg / ml; d) The average Cmax of R,R,R-HTBZ from approximately 60 pg / ml to approximately 200 pg / ml; e) The average Cmax of S,R,R-HTBZ from approximately 1000 pg / ml to approximately 3000 pg / ml; f) The mean AUC of R,R-bufenazine at concentrations of approximately 20 ng*h / ml to approximately 50 ng*h / ml is 96; g) A mean AUC 0.96 for R,R,R-HTBZ at a concentration of approximately 4 ng*h / ml to approximately 12 ng*h / ml; and / or h) The average AUC0-96 of S,R,R-HTBZ at approximately 70 ng*h / ml to approximately 200 ng*h / ml. In some specific examples, the pharmacokinetic profile in the individual is characterized by any one of a) to h). In some specific examples, the pharmacokinetic profile in the individual is characterized by a) and b). In some specific examples, the pharmacokinetic profile in the individual is characterized by c), d), and e). In some specific examples, the pharmacokinetic profile in the individual is characterized by f), g), and h). In some specific examples, the pharmacokinetic profile in the individual is characterized by 1) a) and / or b); 2) c), d), and / or e); and 3) f), g), and / or h). In some specific examples, the pharmacokinetic profile in the individual is characterized by all of a) to h). In some specific examples, the pharmacokinetic profile in the individual is further characterized in that the administration provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ, wherein the ratio of the maximum plasma concentration of R,R-bufenazine to the maximum plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ is from about 1:1 to about 1:5. The range (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 cited values ​​(e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some specific examples, the pharmacokinetic profile in the individual is further characterized in that the administration provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ, wherein the steady-state plasma concentration of R,R-bufenazine is in the ratio of the steady-state plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ in the range from about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3). The ratio is approximately 1:4, approximately 1:5, or any range between the cited values ​​(e.g., approximately 1:1 to approximately 1:3, approximately 1:2 to approximately 1:4, etc.). In some specific examples, the ratio of the maximum plasma concentration or steady-state plasma concentration of R,R,R-HTBZ to S,R,R-HTBZ may range from approximately 1:5 to approximately 1:30 (e.g., approximately 1:5, approximately 1:7, approximately 1:9, approximately 1:10, approximately 1:15, approximately 1:20, approximately 1:30, or any range between the cited values ​​(e.g., from approximately 1:10 to approximately 1:20, approximately 1:5 to approximately 1:15, etc.). In some specific examples, the ratio of the maximum plasma concentration of R,R-bubenazine:R,R,R-HTBZ:S,R,R-HTBZ may range from approximately 17-40:3-10:50-80.In some specific examples, the steady-state plasma concentration ratio of R,R-bufenazine:R,R,R-HTBZ:S,R,R-HTBZ can range from about 17-40:3-10:50-80. In some specific examples, the dosing can provide a pharmacokinetic profile characterized in that the ratio of the AUC0-∞ of SRR-HTBZ to the AUC0-∞ of R,R-bufenazine is about 1 to about 15 (e.g., about 1.5 to about 11) and / or the ratio of the AUC0-∞ of RRR-HTBZ to the AUC0-∞ of R,R-bufenazine is about 0.1 to about 0.75 (e.g., about 0.15 to about 0.5). In some specific examples, the desired PK profile may also be characterized in that the administration provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (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 specific examples, the desired PK profile may also be characterized by the dosing providing a substantially constant steady-state plasma concentration of R,R-bufenazine at or above 150 pg / ml (e.g., about 150 pg / ml to about 3000 pg / ml) 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 specific examples, the dosing does not provide detectable S,S-bufenazine, R,S,S-HTBZ or S,S,S-HTBZ in the individual's plasma. In some specific examples, this disclosure also provides a method for identifying a pharmaceutical composition for treating a hyperkinetic disorder. In some specific examples, the method includes administering an experimental pharmaceutical composition to an individual, bypassing first-pass metabolism, and identifying a pharmaceutical composition that, when administered at a dose of approximately 2 mg / day for 4 days, provides any combination of the PK profiles described in this paragraph.

[0051] In some specific examples, the pharmaceutical composition is formulated to provide a dose of approximately 4-6 mg / day of R,R-bufenazine when administered once for at least 1 day (e.g., 2 days, 3 days, 4 days, or 1 week). In some specific examples, the method comprises administering the pharmaceutical composition to provide a pharmacokinetic profile in the individual, characterized by: a) The mean Tmax of R,R-bufenazine over approximately 10 to approximately 24 hours (e.g., approximately 20 hours); b) The average Tmax of R,R,R-HTBZ and the average Tmax of S,R,R-HTBZ are later than the average Tmax of R,R-butylbenazine; c) The mean Cmax of R,R-bufenazine at a concentration of approximately 600 pg / ml to approximately 2100 pg / ml; d) The average Cmax of R,R,R-HTBZ from approximately 120 pg / ml to approximately 600 pg / ml; e) The average Cmax of S,R,R-HTBZ from approximately 2000 pg / ml to approximately 9000 pg / ml; f) The average AUC of R,R-bufenazine at concentrations of approximately 40 ng*h / ml to approximately 150 ng*h / ml is 96; g) A mean AUC0-96 for R,R,R-HTBZ at a concentration of approximately 8 ng*h / ml to approximately 36 ng*h / ml; and / or h) The average AUC0-96 of S,R,R-HTBZ from approximately 140 ng*h / ml to approximately 600 ng*h / ml. In some specific examples, each dosage of this pharmaceutical composition provides a dose of approximately 4-6 mg / day of R,R-buphenazine for 1 day. In some specific examples, each dosage of this pharmaceutical composition provides a dose of approximately 4-6 mg / day of R,R-buphenazine for 2 days. In some specific examples, each dosage of this pharmaceutical composition provides a dose of approximately 4-6 mg / day of R,R-buphenazine for 3 days. In some specific examples, each dosage of this pharmaceutical composition provides a dose of approximately 4-6 mg / day of R,R-buphenazine for 4 days. In some specific examples, each dosage of this pharmaceutical composition provides a dose of approximately 4-6 mg / day of R,R-buphenazine for 1 week. In some specific examples, the pharmaceutical composition is an adhesive composition described herein (e.g., included in a transdermal delivery patch described herein), and the pharmaceutical composition may be administered to adhere to the individual's skin for the desired duration of R,R-buphenazine delivery (such as 1 day, 2 days, 3 days, 4 days, 1 week, or any range therein). Other pharmaceutical compositions used for continuous delivery herein may be administered in accordance with the normal practice of this composition to achieve the desired duration of R,R-buphenazine delivery; for example, a reservoir or implant may be formulated to deliver (e.g., by injection) to the individual, releasing approximately 4-6 mg / day of R,R-buphenazine for the desired duration. In some specific examples, the pharmacokinetic profile in the individual is characterized by any of a) to h). In some specific examples, the pharmacokinetic profile in the individual is characterized by both a) and b). In some specific examples, the pharmacokinetic profile in the individual is characterized by c), d), and e). In some specific examples, the pharmacokinetic profile in the individual is characterized by f), g), and h). In some specific examples, the pharmacokinetic profile in the individual is characterized by 1) a) and / or b); 2) c), d), and / or e); and 3) f), g), and / or h). In some specific examples, the pharmacokinetic profile in the individual is characterized by all of a) to h). In some specific examples, the pharmacokinetic profile in the individual is further characterized in that the administration provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ, wherein the ratio of the maximum plasma concentration of R,R-bufenazine to the maximum plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ is in the range of about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any range between the cited values ​​(e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.)).In some specific examples, the pharmacokinetic profile in the individual is further characterized in that the administration provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ, wherein the steady-state plasma concentration of R,R-bufenazine is in the ratio of the steady-state plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ to the steady-state plasma concentration of the combination of R,R,R-HTBZ 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 in any range between the cited values ​​(e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.)). In some specific examples, the ratio of the maximum or steady-state plasma concentration of R,R,R-HTBZ to S,R,R-HTBZ can range from about 1:5 to about 1:30 (e.g., about 1:5, about 1:7, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, or any range between the cited values ​​(e.g., from about 1:10 to about 1:20, about 1:5 to about 1:15, etc.)). In some specific examples, the ratio of the maximum plasma concentration of R,R-bubenazine:R,R,R-HTBZ:S,R,R-HTBZ can range from about 17-40:3-10:50-80. In some specific examples, the ratio of the steady-state plasma concentration of R,R-bubenazine:R,R,R-HTBZ:S,R,R-HTBZ can range from about 17-40:3-10:50-80. In some specific examples, the dosing can provide a pharmacokinetic profile, characterized in that: the ratio of the AUC0-∞ of SRR-HTBZ to that of R,R-bufenazine is about 1 to about 15 (e.g., about 1.5 to about 11) and / or the ratio of the AUC0-∞ of RRR-HTBZ to that of R,R-bufenazine is about 0.1 to about 0.75 (e.g., about 0.15 to about 0.5). In some specific examples, the desired PK profile may also be characterized in that the administration provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTB 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 specific examples, the desired PK profile may also be characterized by the dosing providing a substantially constant steady-state plasma concentration of R,R-bufenazine at or above 150 pg / ml (e.g., about 150 pg / ml to about 3000 pg / ml) 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 specific examples, the dosing does not provide detectable S,S-bufenazine, R,S,S-HTBZ or S,S,S-HTBZ in the individual's plasma. In some specific examples, this disclosure also provides a method for identifying a pharmaceutical composition for treating a hyperkinetic disorder. In some specific examples, the method includes administering an experimental pharmaceutical composition to an individual, bypassing first-pass metabolism, and identifying a pharmaceutical composition that, when administered at a dose of about 4-6 mg / day for at least 1 day (e.g., 2 days, 3 days, 4 days, or 1 week), provides any combination of the PK profiles described in this paragraph.

[0052] In some specific examples, the pharmaceutical composition is formulated to provide a dose of approximately 1-10 mg / day of R,R-bufenazine for at least one day (e.g., two, three, four days, or one week) when administered once. In some specific examples, the method comprises administering the pharmaceutical composition to provide a pharmacokinetic profile in the individual, characterized by: a) The mean Tmax of R,R-bufenazine over approximately 10 to approximately 24 hours (e.g., approximately 20 hours); b) The average Tmax of R,R,R-HTBZ and the average Tmax of S,R,R-HTBZ are later than the average Tmax of R,R-butylbenazine; c) The mean Cmax of R,R-bufenazine from approximately 150 pg / ml to approximately 3500 pg / ml; d) The average Cmax of R,R,R-HTBZ from approximately 30 pg / ml to approximately 1000 pg / ml; e) The average Cmax of S,R,R-HTBZ from approximately 500 pg / ml to approximately 15 ng / ml; f) The mean AUC of R,R-bufenazine at concentrations from approximately 10 ng*h / ml to approximately 250 ng*h / ml is 96; g) A mean AUC 0.96 for R,R,R-HTBZ at a concentration of approximately 2 ng*h / ml to approximately 60 ng*h / ml; and / or h) The average AUC0-96 of S,R,R-HTBZ from approximately 35 ng*h / ml to approximately 1000 ng*h / ml. In some specific examples, each dosage of the pharmaceutical composition provides a dose of approximately 1-10 mg / day of R,R-buphenazine for 1 day. In some specific examples, each dosage of the pharmaceutical composition provides a dose of approximately 1-10 mg / day of R,R-buphenazine for 2 days. In some specific examples, each dosage of the pharmaceutical composition provides a dose of approximately 1-10 mg / day of R,R-buphenazine for 3 days. In some specific examples, each dosage of the pharmaceutical composition provides a dose of approximately 1-10 mg / day of R,R-buphenazine for 4 days. In some specific examples, each dosage of the pharmaceutical composition provides a dose of approximately 1-10 mg / day of R,R-buphenazine for 1 week. In some specific examples, the pharmaceutical composition is an adhesive composition described herein (e.g., included in a transdermal delivery patch described herein), and the pharmaceutical composition may be administered to adhere to the individual's skin for the desired duration of R,R-buphenazine delivery (such as 1 day, 2 days, 3 days, 4 days, 1 week, or any range therein). Other pharmaceutical compositions used for continuous delivery herein may be administered in accordance with the normal practice of this composition to achieve the desired duration of R,R-buphenazine delivery; for example, a reservoir or implant may be formulated to deliver (e.g., by injection) to the individual, releasing approximately 1-10 mg / day of R,R-buphenazine for the desired duration. In some specific examples, the pharmacokinetic profile in the individual is characterized by any of a) to h). In some specific examples, the pharmacokinetic profile in the individual is characterized by both a) and b). In some specific examples, the pharmacokinetic profile in the individual is characterized by c), d), and e). In some specific examples, the pharmacokinetic profile in the individual is characterized by f), g), and h). In some specific examples, the pharmacokinetic profile in the individual is characterized by 1) a) and / or b); 2) c), d), and / or e); and 3) f), g), and / or h). In some specific examples, the pharmacokinetic profile in the individual is characterized by all of a) to h). In some specific examples, the pharmacokinetic profile in the individual is further characterized in that the administration provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ, wherein the ratio of the maximum plasma concentration of R,R-bufenazine to the maximum plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ is in the range of about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any range between the cited values ​​(e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.)).In some specific examples, the pharmacokinetic profile in the individual is further characterized in that the administration provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ, wherein the steady-state plasma concentration of R,R-bufenazine is in the ratio of the steady-state plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ to the steady-state plasma concentration of the combination of R,R,R-HTBZ 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 cited values ​​(e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.)). In some specific examples, the ratio of the maximum or steady-state plasma concentration of R,R,R-HTBZ to S,R,R-HTBZ can range from about 1:5 to about 1:30 (e.g., about 1:5, about 1:7, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, or any range between the cited values ​​(e.g., from about 1:10 to about 1:20, about 1:5 to about 1:15, etc.)). In some specific examples, the ratio of the maximum plasma concentration of R,R-bubenazine:R,R,R-HTBZ:S,R,R-HTBZ can range from about 17-40:3-10:50-80. In some specific examples, the ratio of the steady-state plasma concentration of R,R-bubenazine:R,R,R-HTBZ:S,R,R-HTBZ can range from about 17-40:3-10:50-80. In some specific examples, the dosing can provide a pharmacokinetic profile, characterized in that: the ratio of the AUC0-∞ of SRR-HTBZ to that of R,R-bufenazine is about 1 to about 15 (e.g., about 1.5 to about 11), and / or the ratio of the AUC0-∞ of RRR-HTBZ to that of R,R-bufenazine is about 0.1 to about 0.75 (e.g., about 0.15 to about 0.5). In some specific examples, the desired PK profile may also be characterized in that the administration provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (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 specific examples, the desired PK profile may also be characterized by the dosing providing a substantially constant steady-state plasma concentration of R,R-bufenazine at or above 150 pg / ml (e.g., about 150 pg / ml to about 3000 pg / ml) 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 specific examples, the dosing does not provide detectable S,S-bufenazine, R,S,S-HTBZ or S,S,S-HTBZ in the individual's plasma. In some specific examples, this disclosure also provides a method for identifying a pharmaceutical composition for treating a hyperkinetic disorder. In some specific examples, the method includes administering an experimental pharmaceutical composition to an individual, bypassing first-pass metabolism, and identifying a pharmaceutical composition that, when administered at a dose of about 1-10 mg / day for at least 1 day (e.g., 2 days, 3 days, 4 days, or 1 week), provides any combination of the PK profiles described in this paragraph.

[0053] In some specific examples, this disclosure provides a method for treating an ADHD in an individual with a need, the method comprising administering to the individual a pharmaceutical composition comprising an active ingredient containing R,R-bufenazine, wherein the administration provides a PK profile, characterized in that: (1) during a first time period, the plasma concentration of R,R-bufenazine increases to reach a maximum concentration of about 150 pg / ml to about 3500 pg / ml with respect to the first time period at a first time point, and selectively (2) after the first time period, the plasma concentration of R,R-bufenazine can be maintained substantially constant for a sustained period of time (such as about 24 hours, about 48 hours, about 72 hours, about 96 hours or more). In some specific examples, the first time period means the initial rising portion of the PK profile until the plasma concentration begins to plateau and / or decrease, while the sustained period of time means the substantially flat portion of the PK profile, see, for example, a profile of this administration observed from a transdermal delivery. In some specific examples, this duration can continue as long as treatment is desired. In some specific examples, the first time period is from time 0 (the time of administration of the pharmaceutical composition) to approximately 24 hours thereafter, such as 0-20 hours or 0-18 hours. In some specific examples, the first time period may also be longer than 0-24 hours, such as 0-36 hours or 0-48 hours. In some specific examples, the first time period is from time 0 (the time of administration of the pharmaceutical composition) to the Tmax of R,R-bufenazine. Typically, the plasma concentration of R,R-bufenazine observed during the duration is from about 40% to about 250% of the maximum concentration observed with respect to the first time period, and the plasma concentration of R,R-bufenazine does not change significantly (e.g., by 2-fold) at any of the 4-hour, 8-hour, and / or 12-hour intervals during the duration, for example, the concentration at time t1 is from about 50% to about 200% of the concentration at time t1 + 12 hours, assuming that both t1 and t1 + 12 hours are within the duration. In some specific examples, during the duration of the event, the minimum plasma concentration of R,R-bufenazine is at least about 40% (e.g., at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%) of the maximum concentration during the first time period; and / or the maximum plasma concentration of R,R-bufenazine is not greater than about 250% (e.g., not greater than about 200%, not greater than about 150%, not greater than about 120%) of the maximum concentration during the first time period. In some specific examples, the plasma concentration of R,R-bufenazine 24 hours after the first time point is about 50% to about 200% (e.g., about 75% to about 150%) of the concentration at the first time point.In some specific examples, the pharmacokinetic profile in the individual is further characterized in that: during the duration of administration, the drug delivery provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ, and wherein, during the duration of administration, at a given time point, the ratio of the plasma concentration of R,R-bufenazine to the plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ is in the range of about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any range between the cited values ​​(e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some specific examples, during the duration of administration, at a given time point, the ratio of the plasma concentration of R,R,R-HTBZ to S,R,R-HTBZ is... Examples can be in the range of approximately 1:5 to approximately 1:30 (e.g., approximately 1:5, approximately 1:7, approximately 1:9, approximately 1:10, approximately 1:15, approximately 1:20, approximately 1:30), or any range between the cited values ​​(e.g., from approximately 1:10 to approximately 1:20, approximately 1:5 to approximately 1:15, etc.). In some specific examples, during this duration, at a given point in time, R,R-bubenazine:R,R,R-HTBZ:S,R,R-HT The ratio of plasma concentrations of BZ can range from approximately 17-40:3-10:50-80. In some specific examples, during this duration, the maximum plasma concentration ratio of R,R-bubenazine:R,R,R-HTBZ:S,R,R-HTBZ can range from approximately 17-40:3-10:50-80. In some specific examples, this dosing can provide a pharmacokinetic profile, characterized in that: the AUC0-∞ of SRR-HTBZ... The ratio of the AUC0-∞ of R,R-bufenazine to that of R,R-bufenazine is about 1 to about 15 (e.g., about 1.5 to about 11), and / or the ratio of the AUC0-∞ of RRR-HTBZ to that of R,R-bufenazine is about 0.1 to about 0.75 (e.g., about 0.15 to about 0.5). In some specific examples, the PK chromatogram is characterized by a mean final half-life of about 8.5 hours ± 40% CV for R,R-bufenazine. In some specific examples, the dosing does not provide detectable S,S-bufenazine, R,S,S-HTBZ, or S,S,S-HTBZ. In the individual's plasma. In some specific examples, this disclosure also provides a method for identifying a pharmaceutical composition for treating an ADHD. In some specific examples, the method comprises administering an experimental pharmaceutical composition to an individual, bypassing first-pass metabolism, and identifying a pharmaceutical composition that provides any combination of the PK profiles described in this paragraph.

[0054] The route by which the pharmaceutical composition is administered to achieve the pharmacokinetic profile described above is not particularly limited, provided that the administration provides a pharmacokinetic profile as described above. Typically, the administration bypasses first-pass metabolism. For example, in some specific instances, the pharmaceutical composition is administered transdermally. In some specific instances, the pharmaceutical composition is administered via injection or infusion, such as intravenous injection (excluding bolus injection for immediate release only), subcutaneous injection, or intramuscular injection. In some specific instances, the pharmaceutical composition is a reservoir formulation.

[0055] The dosing typically delivers R,R-buphenazine to the individual continuously or substantially continuously to achieve the PK profile described here. In some specific examples, the dosing delivers R,R-buphenazine to the individual for a period of, for example, from about 8 hours to about 72 hours or more. For example, in some specific examples, the dosing provides a continuous or substantially continuous delivery of R,R-buphenazine to the individual 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 cited values. In some specific examples, during the continuous or substantially continuous delivery period, the R,R-buphenazine may be delivered to the individual at a substantially constant rate, for example, at an average rate for substantially the same delivery in each hour (such as within 80-125% of the total average rate). In some specific instances, during continuous or substantially continuous delivery, the R,R-bufenazine may be delivered to the individual at a different rate, for example, to an average rate of delivery that varies for each hour. For example, in some specific instances, the average rate of delivery may initially be high, but then decrease during continuous or substantially continuous delivery. Typically, the precise delivery rate of R,R-bufenazine for each hour is not critical, and those skilled in the art will, upon reviewing this disclosure, know how to select and design a dosing regimen to deliver a desired daily dose to the individual, providing a pharmacokinetic profile as described herein. For example, in some specific cases, the R,R-bufenazine may be delivered to the individual at a daily dose of about 0.1 mg / day to about 20 mg / day (such as about 0.5 mg / day to about 10 mg / day of R,R-bufenazine, about 0.5 mg / day to about 8 mg / day of R,R-bufenazine, or about 2 mg / day to about 6 mg / day of R,R-bufenazine) to provide a pharmacokinetic profile as described herein.

[0056] The hyperactive motor disorders cited in the treatment methods herein include any of those described herein. Non-restrictive examples include Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tic disorders, dyskinesia-type cerebral palsy, other hypotonia and dyskinesia disorders, and combinations thereof. In some specific examples, the hyperactive motor disorder may be Huntington's disease, such as chorea associated with Huntington's disease. In some specific examples, the hyperactive motor disorder may be Wilson's disease. In some specific examples, the hyperactive motor disorder may be Tourette's disease. In some specific examples, the hyperactive motor disorder may be restless legs syndrome. In some specific examples, the hyperactive motor disorder may be tardive dyskinesia. In some specific examples, the hyperactive motor disorder may be tic disorders. In some specific examples, the hyperactive motor disorder may be dyskinesia-type cerebral palsy. In some specific cases, this hyperkinetic disorder is a condition of insufficient tension or movement disorder.

[0057] The treatment methods described herein are not limited to any particular type of individual. For example, the method described herein may be administered to the individual regardless of their eating status. In some specific cases, the individual is a pediatric or adolescent patient (e.g., 6 to 18 years old). Also, in some specific cases, the method is not limited to any particular genotyped individual. In some specific cases, the same or substantially the same dose of R,R-bufenazine may be administered to an individual characterized as PM, IM, or EM. In some specific cases, the individual is characterized as EM. In some specific cases, the individual is characterized as PM. In some specific cases, the individual is characterized as IM. In some specific cases, the method does not require dose titration and / or genotyping analysis, which is required when the individual is treated with either Xenazine® or Austedo™ tablets.

[0058] The administration regimen used for the treatment herein is not particularly limited, provided that the desired dose of R,R-bufenazine is delivered to the individual at a desired rate for a desired period of time, including any of those described herein. For example, in some specific instances, the pharmaceutical composition is administered to the individual using an administration regimen suitable for achieving the PK profile described herein. In some specific instances, the pharmaceutical composition is administered to the individual once daily. In some specific instances, the pharmaceutical composition is administered to the individual more than once daily, such as 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 specific examples, each dosing provides a continuous or substantially continuous delivery of R,R-bufenazine to the individual for approximately 8 hours, approximately 12 hours, approximately 24 hours, approximately 36 hours, approximately 48 hours, approximately 72 hours, approximately 96 hours, approximately 120 hours, approximately 144 hours, approximately 168 hours, approximately 192 hours, or any range between the cited values. As discussed herein, there may be no lag time, overlap, or some lag time between two consecutive dosings.

[0059] Pharmaceutical compositions suitable for various routes of administration as described herein are also described. Typically, with regard to transdermal delivery, the pharmaceutical composition may include an adhesive composition (e.g., in a transdermal delivery device) containing the active ingredient dispersed in an adhesive (preferably a pressure-sensitive adhesive). In some specific examples, the adhesive composition is administered to the individual to deliver about 0.1 mg / day to about 20 mg / day of R,R-bufenazine (e.g., any of the exemplary ranges described herein) at a substantially constant rate for up to 24 hours, up to 48 hours, up to 96 hours, or up to 1 week after administration. Suitable adhesive compositions include any of those described herein, such as any of those applicable to bufenazine described in Exemplary Examples 1-18 or any of the specific compositions shown in the Examples section (e.g., Example 4A). In some specific examples, the adhesive composition comprises the active ingredient dispersed in a non-reactive acrylate pressure-sensitive adhesive. The active ingredient may be present in an amount of about 1% to about 20% by weight, such as about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 10%, about 15%, about 20%, or in any range between the cited values ​​(e.g., about 1% to about 15%, about 2% to about 15%, about 2% to about 10%, about 2% to about 7%, about 3% to about 15%, about 3% to about 10%, about 3% to about 7%, about 5% to about 15%, about 5% to about 10%, about 5% to about 7%, about 7% to about 15%, about 7% to about 10%, about 10% to about 20%, about 10% to about 15%, etc.). In some specific examples, the adhesive composition comprises a substantially pure R,R-isomer of butylbenazine as the sole active ingredient. In some specific examples, the substantially pure R,R-isomer of bubenazine is in the form of a free base. Suitable adhesives include any of those described herein, such as any of the pressure-sensitive adhesives described herein. In some specific examples, the adhesive may be a non-reactive acrylate pressure-sensitive adhesive described herein (such as Duro-Tak 87-900A) or as described in exemplary examples 2-7.The adhesive is typically present in an amount of about 50% to about 97% by weight, such as about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 97%, or in any range between the cited values ​​(e.g., about 50% to about 95%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, about 50% to about 60%, about 60% to about 97%, about 60% to about 95%, about 60% to about 90%, about 60% to about 80%, about 60% to about 70%, about 70% to about 97%, about 70% to about 95%, about 70% to about 90%, about 70% to about 80%, about 80% to about 97%, about 80% to about 95%, about 80% to about 90%, etc.). In some specific examples, the active ingredient is present in an amount of about 2% to about 7% by weight, and the non-reactive acrylate pressure-sensitive adhesive is present in an amount of about 50% to about 97% by weight. The adhesive composition may also optionally include other components, such as an antioxidant, a crystallization inhibitor, a plasticizer, and / or a penetration enhancer. In some specific examples, the adhesive composition includes an antioxidant, such as a gallate antioxidant (e.g., propyl gallate). The amount of antioxidant is typically included in an amount of about 0% to about 1% by weight, such as about 0.001%, about 0.01%, about 0.1%, about 0.5%, about 1%, or any range between the cited values ​​(e.g., about 0.001% to about 0.5%, about 0.01% to about 0.5%, etc. by weight). In some specific examples, the adhesive composition includes a crystallization inhibitor, for example, a method to prevent the formation of drug crystals (crystallization of the active ingredient of the adhesive composition, such as R,R-bufenazine) after shelf storage at ambient temperature for 2 weeks.In some specific examples, the adhesive composition includes a crystallization inhibitor selected from the following: a polyvinylpyrrolidone polymer (e.g., Kollidon K30 or K90F (manufactured by BASF), Plasdone K20 / 32 or Plasdone K90 (manufactured by Ashland Chemical)), a crosslinked polyvinylpyrrolidone polymer (e.g., Kollidon CL), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 copolyvinylpyrrolidone (Asland)), a cellulose-based polymer (e.g., hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose), a polycarboxylic acid polymer (e.g., carbomer (manufactured by Lubrizol)), a polymethacrylate (e.g., Plastoid B, Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, a graft copolymer based on polyvinyl acetate and polyvinylcaprolactam (PVAc-PVCap- PEG) (e.g., Soluplus (BASF), and combinations thereof. In some specific examples, the adhesive composition includes a crystallization inhibitor selected from: polymethacrylate (e.g., Plastoid B (a copolymer of butyl methacrylate and methyl methacrylate), Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, and graft copolymers based on polyvinyl acetate and polyvinylcaprolactam (PVAc-PVCap-PEG) (e.g., Soluplus). (BASF), and combinations thereof. The crystallization inhibitor is typically present in amounts from about 0 to about 40% by weight, such as about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, or in any range between the cited values ​​(e.g., about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, 15% to about 40%, about 15% to about 30%, about 15% to about 20%, 20% to about 40%, about 20% to about 30%, etc. by weight). In some... In this embodiment, the adhesive composition may also contain a skin penetration enhancer as described herein (such as isopropyl myristate). In some specific embodiments, the adhesive composition may also be without a skin penetration enhancer as described herein; for example, in some specific embodiments, the adhesive composition may also be without isopropyl myristate. Suitable drug loading, active surface area, thickness, adhesive properties, etc., include any combination of those described herein. Suitable pharmaceutical compositions for other delivery routes include those described herein. Methods for screening pharmaceutical components for the treatment of inactive exercise disorders

[0060] In some specific examples, this disclosure also provides a method for identifying a pharmaceutical composition for treating a hyperkinetic disorder. In some specific examples, the method comprises administering an experimental pharmaceutical composition to an individual, the administration bypassing first-pass metabolism to deliver R,R-bufenazine to the individual continuously or substantially continuously, and identifying a pharmaceutical composition that provides either of the PK profiles described above. In some specific examples, the identification includes identifying a pharmaceutical composition of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ that provides a therapeutically effective plasma concentration, wherein the ratio of the maximum plasma concentration of R,R-bufenazine to the maximum plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ is in the range of about 1:1 to about 1:5; or the ratio of the steady-state plasma concentration of R,R-bufenazine to the steady-state plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ is in the range of about 1:1 to about 1:5. In some specific examples, the ratio of the maximum plasma concentration of R,R,R-HTBZ to S,R,R-HTBZ is in the range of about 1:5 to about 1:30 (e.g., about 1:10 to about 1:20). In some specific instances, the identification includes identifying a pharmaceutical composition of any of the PK profiles described herein (if applicable).

[0061] In some specific examples, the method includes measuring the skin flux characteristics of a test adhesive composition in vitro using human cadaver skin, and identifying an adhesive composition that provides either of the in vitro flux characteristics described herein. In some specific examples, the test adhesive composition contains about 2% to about 10% by weight (e.g., about 2% to about 7%) of R,R-bubenazine, and the transdermal delivery device (e.g., comprising the adhesive composition and a non-reactive acrylate adhesive described herein).

[0062] The pharmaceutical composition (such as the adhesive composition identified herein) is also a novel composition disclosed herein. In some specific examples, this disclosure also provides a method for treating a hyperkinetic disorder comprising administering the identified pharmaceutical composition to an individual in need. Continuous delivery of deuterated benzodiazepine

[0063] Some specific examples disclosed herein pertain to the continuous or substantially continuous delivery of a deuterated butylbenazine. In any of the specific examples described herein, a deuterated butylbenazine (such as deuterated butylbenazine) may partially or completely replace butylbenazine in that particular composition, device, or method. Those skilled in the art will understand that the in vitro and / or in vivo parameters of such alternative compositions, devices, or methods may differ, particularly those relating to pharmacokinetics, because deuteration can modify the metabolic profile of butylbenazine.

[0064] In some specific examples, this disclosure provides a method for treating an ADHD in an individual with a need, the method comprising administering to the individual a pharmaceutical composition comprising an active ingredient containing a deuterated R,R-buphenazine, wherein the administration bypasses first-pass metabolism and is continuously or substantially continuously delivered to the individual at about 0.1 mg / day to about 20 mg / day of deuterated R,R-buphenazine, for example, about 0.5 mg / day to about 10 mg / day of deuterated R,R-buphenazine, about 0.5 mg / day to about 8 mg / day of deuterated R,R-buphenazine, about 0.5 mg / day to about 6 mg / day of deuterated R,R-buphenazine, about 0.5 mg / day to about 4 mg / day of deuterated R,R-buphenazine, about 1 mg / day to about 8 mg / day of deuterated R,R-buphenazine, about 1 mg / day to about 8 mg / day of deuterated R,R-buphenazine, about 1 mg / day to about 8 mg / day of deuterated R,R-buphenazine, or about 1 mg / day to about 8 mg / day of deuterated R,R-buphenazine. R-butylbenazine (r.) per day, approximately 1 mg / day to approximately 6 mg / day, approximately 1 mg / day to approximately 4 mg / day, approximately 2 mg / day to approximately 10 mg / day, approximately 2 mg / day to approximately 8 mg / day, approximately 2 mg / day to approximately 6 mg / day, approximately 4 mg / day to approximately 10 mg / day, approximately 4 mg / day to approximately 8 mg / day, approximately 4 mg / day to approximately 10 ... The dosage is approximately 0.5 mg / day to approximately 8 mg / day of deuterated R,R-butylbenazine, or approximately 6 mg / day to approximately 8 mg / day of deuterated R,R-butylbenazine. In some preferred embodiments, the method delivers approximately 0.5 mg / day to approximately 8 mg / day of deuterated R,R-butylbenazine, or approximately 2 mg / day to approximately 6 mg / day of deuterated R,R-butylbenazine. The duration of drug delivery may vary, for example, from approximately 8 hours to approximately 72 hours or more. For example, in some embodiments, the dosing provides a continuous or substantially continuous delivery of deuterated R,R-butylbenazine to the individual for approximately 8 hours, approximately 12 hours, approximately 24 hours, approximately 36 hours, approximately 48 hours, approximately 72 hours, approximately 96 hours, approximately 120 hours, approximately 144 hours, approximately 168 hours, approximately 192 hours, or any range between the cited values. In some specific instances, during continuous or substantially continuous delivery, the deuterated R,R-butylbenazine may be delivered to the individual at a substantially constant rate, for example, at an average rate for delivery that is substantially the same for each hour (such as within 80-125% of the total average rate).In some specific instances, during continuous or substantially continuous administration, the deuterated R,R-butylbenazine may be administered to the individual at a different rate, for example, to an average rate of administration that varies for each hour. For example, in some specific instances, the average rate of administration may initially be high, but then decrease during continuous or substantially continuous administration. Typically, the precise rate of administration of the deuterated R,R-butylbenazine for each hour is not critical, and those skilled in the art will, upon reviewing this disclosure, know how to select and design a dosing regimen to deliver a desired daily dose to the individual, such as about 0.5 mg / day to about 10 mg / day of deuterated R,R-butylbenazine, about 0.5 mg / day to about 8 mg / day of deuterated R,R-butylbenazine, or about 2 mg / day to about 6 mg / day of deuterated R,R-butylbenazine. In some specific cases, administering the desired daily dose to the individual also provides a pharmacokinetic profile as described herein.

[0065] In some specific examples, this disclosure provides a method for treating an ADHD in an individual with a need, the method comprising administering to the individual a pharmaceutical composition comprising an active ingredient containing a deuterated R,R-bubenazine, wherein the administration provides a desired pharmacokinetic (PK) profile. For example, in some specific instances, the desired PK profile is characterized in that the dosing provides a therapeutically effective plasma concentration of deuterated R,R-butylbenazine, deuterated R,R,R-dihydrobutylbenazine (HTBZ), and deuterated S,R,R-HTBZ, wherein the ratio of the maximum plasma concentration of deuterated R,R-butylbenazine to the maximum plasma concentration of the combination of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ is in the range of about 1:1 to about 1:7.5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, about 1:7.5 or any range between the cited values ​​(e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.), that is, the Cmax of deuterated R,R-butylbenazine. / (Cmax of deuterated R,R,R-HTBZ + Cmax of deuterated S,R,R-HTBZ) is in the range of about 1:1 to about 7.5; or the ratio of the steady-state plasma concentration of deuterated R,R-butylbenazine to the maximum plasma concentration of the combination of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ is in the range of about 1:1 to about 1:7.5. As used herein, a therapeutically effective plasma concentration of deuterated R,R-butylbenazine, deuterated R,R,R-dihydrobutylbenazine (HTBZ), and deuterated S,R,R-HTBZ does not require each of the three compounds to individually exhibit a therapeutically effective plasma concentration. It is sufficient that the combination of the three compounds is therapeutically effective, for example, at its individual steady-state concentration. In some specific examples, deuterated R,R The ratio of the maximum or steady-state plasma concentration of R-HTBZ to that of deuterated S,R,R-HTBZ can range from about 1:5 to about 1:30 (e.g., about 1:5, about 1:7, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, or any range between the cited values ​​(e.g., from about 1:10 to about 1:20, about 1:5 to about 1:15, etc.)). In some specific examples, the ratio of the maximum or steady-state plasma concentration of deuterated R,R-butylbenazine: deuterated R,R,R-HTBZ: deuterated S,R,R-HTBZ can range from about 14-40:3-11:50-85.In some specific examples, the dosing can provide a pharmacokinetic profile, characterized in that: the ratio of the AUC0-∞ of deuterated SRR-HTBZ to the AUC0-∞ of deuterated R,R-bufenazine is about 1 to about 15 (e.g., about 1.5 to about 11), and / or the ratio of the AUC0-∞ of deuterated RRR-HTBZ to the AUC0-∞ of deuterated R,R-bufenazine is about 0.1 to about 0.75 (e.g., about 0.15 to about 0.5). In some specific examples, the desired PK profile may also be characterized in that the administration provides a therapeutically effective plasma concentration of deuterated R,R-bufenazine, deuterated R,R,R-dihydrobufenazine (HTBZ), and deuterated 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 specific examples, the desired PK profile may also be characterized by the dosing providing a substantially constant steady-state plasma concentration of deuterated R,R-bufenazine at 150 pg / ml or higher (e.g., about 150 pg / ml to about 3000 pg / ml) 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 specific examples, the dosing does not provide detectable deuterated S,S-bufenazine, deuterated R,S,S-HTBZ, or deuterated S,S,S-HTBZ in the individual's plasma. In some specific examples, the method includes administering an experimental pharmaceutical composition to an individual, bypassing first-pass metabolism to deliver deuterated R,R-bufenazine to the individual continuously or substantially continuously, and identifying a pharmaceutical composition that provides either of the PK profiles described in this paragraph in any combination.

[0066] In some specific examples, this disclosure provides a method for treating an ADHD in an individual with a need, the method comprising administering to the individual a pharmaceutical composition comprising an active ingredient containing a deuterated R,R-butylbenazine, wherein the administration provides a p-p-chromosome, characterized in that: (1) during a first time period, the plasma concentration of deuterated R,R-butylbenazine increases to reach a maximum concentration of about 150 pg / ml to about 3500 pg / ml with respect to the first time period at a first time point, and selectively (2) after the first time period, the plasma concentration of deuterated R,R-butylbenazine can be maintained substantially constant for a sustained time period, such as about 24 hours, about 48 hours, about 72 hours, about 96 hours or more. In some specific examples, the first time period refers to the initial rising portion of the PK curve until the plasma concentration begins to plateau and / or decrease, while the duration refers to the substantially flat portion of the PK curve, see, for example, a graph of this administration observed from a transdermal delivery. In some specific examples, the first time period is from time 0 (the time of administration of the pharmaceutical composition) to approximately 24 hours thereafter, such as 0–20 hours or 0–18 hours. In some specific examples, the first time period may also be longer than 0–24 hours, such as 0–36 hours or 0–48 hours. In some specific examples, the first time period is from time 0 (the time of administration of the pharmaceutical composition) to the Tmax of deuterated R,R-bufenazine. Typically, the plasma concentration of deuterated R,R-bubenazine observed during the duration is in the range of about 40% to about 250% of the maximum concentration observed during the first time period, and the plasma concentration of deuterated R,R-bubenazine does not change significantly (e.g., by 2-fold) at any of the 4-hour, 8-hour, and / or 12-hour intervals during the duration, for example, the concentration at time t1 is about 50% to about 200% of the concentration at time t1 + 12 hours, assuming that both t1 and t1 + 12 hours are within the duration. In some specific examples, during the duration of the event, the minimum plasma concentration of deuterated R,R-butylbenazine is at least about 40% (e.g., at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%) of the maximum concentration during the first time period; and / or the maximum plasma concentration of deuterated R,R-butylbenazine is not greater than about 250% (e.g., not greater than about 200%, not greater than about 150%, not greater than about 120%) of the maximum concentration during the first time period. In some specific examples, the plasma concentration of deuterated R,R-butylbenazine 24 hours after the first time point is about 50% to about 200% (e.g., about 75% to about 150%) of that at the first time point.In some specific examples, the pharmacokinetic profile in the individual is further characterized in that: during the duration of administration, the drug delivery provides a therapeutically effective plasma concentration of deuterated R,R-bufenazine, deuterated R,R,R-dihydrobufenazine (HTBZ), and deuterated S,R,R-HTBZ, and wherein, during the duration of administration, at a given time point, the plasma concentration of deuterated R,R-bufenazine is higher than that of deuterated R,R,R-HTBZ and deuterated S,R,R-HTBZ. The ratio of the combined plasma concentrations is in the range from about 1:1 to about 1:7.5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, about 1:7.5), or any range between the cited values ​​(e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.). In some specific examples, during this duration, at a given time point, the plasma concentrations of deuterated R,R,R-HTBZ are higher than those of deuterated S,R,R-HTBZ. The pulp concentration ratio 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 cited values ​​(e.g., from about 1:10 to about 1:20, about 1:5 to about 1:15, etc.). In some specific examples, during this duration, at a given time point, deuterated R,R-butylbenazine: deuterated R,R,R-HTBZ: deuterated S,R,R- The plasma concentration ratio of HTBZ can range from approximately 14-40:3-11:50-85. In some specific examples, during this duration, the maximum plasma concentration ratio of deuterated R,R-bubenazine: deuterated R,R,R-HTBZ: deuterated S,R,R-HTBZ can range from approximately 14-40:3-11:50-85. In some specific examples, this dosing can provide a pharmacokinetic profile, characterized by: the AUC0-∞ of deuterated SRR-HTBZ. The ratio of the AUC0-∞ of deuterated R,R-bubenazine is about 1 to about 15 (e.g., about 1.5 to about 11), and / or the ratio of the AUC0-∞ of deuterated RRR-HTBZ to the AUC0-∞ of deuterated R,R-bubenazine is about 0.1 to about 0.75 (e.g., about 0.15 to about 0.5). In some specific examples, the PK chromatogram is characterized by a mean final half-life of about 8.5 hours ± 40% CV for deuterated R,R-bubenazine. In some specific examples, the dosing does not provide detectable deuterated S,S-bubenazine, deuterated R,S,S-HTBZ, or deuterated S,S,S-HTBZ in the individual's plasma. In some specific examples, this disclosure also provides a method for identifying a pharmaceutical composition for treating a hyperkinetic disorder.In some specific examples, the method includes administering an experimental pharmaceutical composition to an individual, bypassing first-pass metabolism, and identifying a pharmaceutical composition that provides either of the PK profiles described in this paragraph in any combination.

[0067] The route of administration of the pharmaceutical composition to achieve the pharmacokinetic profile described above is not particularly limited, provided that the administration provides a pharmacokinetic profile as described above. Typically, the administration bypasses first-pass metabolism. For example, in some specific cases, the pharmaceutical composition is administered transdermally. In some specific cases, the pharmaceutical composition is administered via injection or infusion (such as intravenous injection (excluding bolus injection), subcutaneous injection, or intramuscular injection). In some specific cases, the pharmaceutical composition is a reservoir formulation.

[0068] The dosing typically delivers deuterated R,R-bubenazine to the individual continuously or substantially continuously to achieve the PK profile described here. In some specific examples, the dosing delivers deuterated R,R-bubenazine to the individual for a period of, for example, from about 8 hours to about 72 hours or more. For example, in some specific examples, the dosing provides a continuous or substantially continuous delivery of deuterated R,R-bubenazine to the individual 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 cited values. In some specific instances, during continuous or substantially continuous delivery, the deuterated R,R-butylbenazine may be delivered to the individual at a substantially constant rate, for example, at an average rate that is substantially the same for each hour (e.g., within 80-125% of the total average rate). In some specific instances, during continuous or substantially continuous delivery, the deuterated R,R-butylbenazine may be delivered to the individual at a different rate, for example, at an average rate that is different for each hour. For example, in some specific instances, the average rate of delivery may initially be high but then decrease during continuous or substantially continuous delivery. Typically, the precise hourly delivery rate of the deuterated R,R-butylbenazine is not critical, and those skilled in the art will, upon reviewing this disclosure, know how to select and design a dosing regimen to deliver a desired daily dose to the individual providing a pharmacokinetic profile as described herein. For example, in some specific instances, the deuterated R,R-bubenazine may be delivered to the individual at a daily dose of about 0.1 mg / day to about 20 mg / day (such as about 0.5 mg / day to about 10 mg / day of deuterated R,R-bubenazine, about 0.5 mg / day to about 8 mg / day of deuterated R,R-bubenazine, or about 2 mg / day to about 6 mg / day of deuterated R,R-bubenazine) to provide a pharmacokinetic profile as described herein.

[0069] The hyperactive motor disorders cited in the treatments herein include any of those described herein. Non-restrictive examples include Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tic disorders, dyskinesia-type cerebral palsy, other hypotonia and dyskinesia disorders, and combinations thereof. In some specific examples, the hyperactive motor disorder may be Huntington's disease, such as chorea associated with Huntington's disease. In some specific examples, the hyperactive motor disorder may be Wilson's disease. In some specific examples, the hyperactive motor disorder may be Tourette's disease. In some specific examples, the hyperactive motor disorder may be restless legs syndrome. In some specific examples, the hyperactive motor disorder may be tardive dyskinesia. In some specific examples, the hyperactive motor disorder may be tic disorders. In some specific examples, the hyperactive motor disorder may be dyskinesia-type cerebral palsy. In some specific cases, this hyperkinetic disorder is a condition of insufficient tension or movement disorder.

[0070] The treatment methods described herein are not limited to any particular type of individual. For example, the methods described herein may be used to administer the medication to the individual regardless of their eating status. In some specific cases, the individual is a pediatric or adolescent patient (e.g., 6 to 18 years old). Also, in some specific cases, the methods are not limited to individuals with any particular genotype. In some specific cases, the same or substantially the same dose of deuterated R,R-bubenazine may be administered to an individual characterized as PM, IM, or EM. In some specific cases, the individual is characterized as EM. In some specific cases, the individual is characterized as PM. In some specific cases, the individual is characterized as IM. In some specific cases, the method does not require dose titration and / or genotyping analysis, which is required when the treatment is administered with either Xenazine® or Austedo™ tablets.

[0071] The administration regimen used for the treatment herein is not particularly limited, provided that the desired dose of deuterated R,R-buphenazine is delivered to the individual at a desired rate for a desired period of time, including any of those described herein. For example, in some specific instances, the pharmaceutical composition is administered to the individual in an administration regimen suitable for achieving the PK profile described herein. In some specific instances, the pharmaceutical composition is administered to the individual once daily. In some specific instances, the pharmaceutical composition is administered to the individual more than once daily, such as once every two days, three days, four days, five days, six days, once a week, or more than once a week. In some specific instances, each dosing provides a continuous or substantially continuous delivery of deuterated R,R-bubenazine to the individual for approximately 8 hours, approximately 12 hours, approximately 24 hours, approximately 36 hours, approximately 48 hours, approximately 72 hours, approximately 96 hours, approximately 120 hours, approximately 144 hours, approximately 168 hours, approximately 192 hours, or any range between the cited values.

[0072] Pharmaceutical compositions suitable for various routes of administration as described herein are also described. Typically, with regard to transdermal delivery, the pharmaceutical composition may include an adhesive composition (e.g., in a transdermal delivery device) containing the active ingredient dispersed in an adhesive (preferably a pressure-sensitive adhesive). In some specific examples, the adhesive composition is administered to the individual to deliver approximately 0.1 mg / day to approximately 20 mg / day of deuterated R,R-bufenazine (e.g., any of the exemplary ranges described herein) at a substantially constant rate for up to 24 hours, up to 48 hours, up to 96 hours, or up to 1 week after administration. Suitable adhesive compositions include any of those described herein, such as any of those applicable to deuterated butylbenazine described in Exemplary Examples 1-18 or any of the specific compositions shown in the Examples section (e.g., Example 4A) (with butylbenazine replaced by deuterated butylbenazine). The type, quantity, amount of active ingredient, other components, and quantity of the adhesive include any of those suitable for butylbenazine described herein, except that the butylbenazine is replaced by deuterated butylbenazine. In some examples, the adhesive composition may also contain a skin penetration enhancer as described herein (such as isopropyl myristate). In some examples, the adhesive composition may also be without a skin penetration enhancer as described herein; for example, in some examples, the adhesive composition may also be without isopropyl myristate. Suitable pharmaceutical compositions for other delivery routes include those described herein. In any applicable specific example, the deuterated butylbenazine may be a substantially pure R,R-isomer of deuterated butylbenazine (e.g., R,R-deuterated butylbenazine). In some specific examples, the substantially pure R,R-isomer of deuterated butylbenazine is the sole active ingredient in the pharmaceutical composition. In some specific examples, the substantially pure R,R-isomer of deuterated butylbenazine is in the form of a free base.

[0073] While typically the method described herein delivers R,R-butenarazine or a deuterated R,R-butenarazine to an individual in need, this disclosure also anticipates delivering to an individual in need a mixture of R,R-butenarazine and a deuterated R,R-butenarazine. Transdermal delivery of bubenazine or deuterated bubenazine

[0074] As discussed herein, in various specific examples, the methods herein deliver buphenazine or deuterated buphenazine percutaneously to an individual in need. Suitable pharmaceutical compositions for percutaneous delivery include any of those described herein, such as any of the specific compositions described in exemplary examples 1-18 or shown in the Examples section (e.g., Example 4A). This percutaneous pharmaceutical composition and percutaneous delivery device are also novel aspects of this disclosure. Transdermal delivery device for bubenazine

[0075] In various specific examples, the present invention relates to pharmaceutical compositions or transdermal delivery devices comprising buphenazine and / or a deuterated buphenazine (e.g., deuterated buphenazine). These pharmaceutical compositions and transdermal delivery devices provide novel options for the transdermal delivery of buphenazine and / or a deuterated buphenazine to an individual in need. Buphenazine and / or deuterated buphenazine have not previously been shown as a drug administered via the transdermal route. As detailed herein, the inventors have shown that the transdermal delivery devices and pharmaceutical compositions disclosed herein (e.g., the adhesive composition herein) can be applied to an individual to achieve a therapeutically effective flux and are therefore useful for treating a variety of diseases or disorders (such as hyperkinetic dyskiniasis). See also, for example, PCT / US2019 / 028900, the contents of which are incorporated herein by reference in their entirety.

[0076] Certain specific examples disclosed herein pertain to a transdermal delivery device comprising buphenazine or a deuterated buphenazine (e.g., deuterated buphenazine). In some specific examples, the transdermal delivery device comprises a back layer; a drug layer comprising a drug selected from buphenazine, a deuterated buphenazine (e.g., deuterated buphenazine), and combinations thereof; and an adhesive layer defining an active surface area. In some specific examples, the drug is present in an amount of about 2% to about 30% by weight of the drug layer. In some specific examples, the transdermal delivery device comprises a single drug layer. In some specific examples, the transdermal delivery device comprises more than one drug layer. In some specific examples, the transdermal delivery device comprises a single adhesive layer. In some specific examples, the transdermal delivery device comprises more than one adhesive layer.

[0077] Various patch designs can be used in the transdermal delivery device described herein. For example, in some specific examples, the transdermal delivery device can be an adhesive-coated drug (DIA) patch. In some specific examples, the DIA patch is a single-layer patch in which the drug layer and the adhesive layer are the same layer, for example, the drug is uniformly dispersed in the adhesive. In some specific examples, the DIA patch is a multi-layer patch. For example, two adhesive-coated drug layers can be included in the patch, selectively separated by a membrane. In some specific examples, the two DIA layers can have different release characteristics, for example, one of the layers is a direct-release layer and the other is a controlled-release layer. In some specific examples, the two DIA layers can have different release characteristics, for example, one of the layers releases the drug relatively rapidly over a relatively short period of time, while the other layer releases the drug over a longer period of time.

[0078] A drug reservoir (DIR) design can also be used in the transdermal delivery device described herein. In some specific examples, the drug layer and the adhesive layer can be two separate layers that are laminated to each other or separated (e.g., by a rate-control membrane). For example, in some specific examples, the drug layer is a reservoir layer, such as a drug matrix laminated with the adhesive layer.

[0079] Other patch designs can also be used in the transdermal delivery device described herein. For example, in some specific examples, the transdermal delivery device can be an active patch, such as an iontophoresis patch. In some specific examples, the transdermal delivery device can be a minimally invasive patch, such as a microneedle-based patch. In some specific examples, the transdermal delivery device can also have another patch design that may contain enhanced chemical or physical modalities.

[0080] Typically, the 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 a transdermal delivery device used herein. Typically, the backing layer is impermeable. For example, the backing layer may consist of an impermeable polymer film (such as polyester (PET) or polyethylene (PE) film). In some specific examples, the backing layer may comprise 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).

[0081] The release liner can be manufactured in the desired size for use in this invention. The release liner can consist of a polyester film coated with silicone or fluoropolymer. During storage, the release liner protects the transdermal delivery device and is removed before its use. Silicone-coated release liners include those manufactured by Mylan Corporation, Loparex Corporation, and 3M's drug delivery systems. Fluoropolymer-coated release liners include those manufactured and supplied by 3M's drug delivery systems and Loparex. In some specific examples, the release liner comprises 3M's ScotchPak 9744 or Scotchpak 1022.

[0082] The transdermal delivery devices (e.g., DIA patches) described herein may have different sizes (patch sizes) depending on their application. Typically, such patch sizes can be from about 5 cm² to about 300 cm² (e.g., about 5 cm², about 10 cm², about 20 cm², about 30 cm², about 40 cm², about 50 cm², about 60 cm², about 80 cm², about 100 cm², about 120 cm², about 150 cm², about 200 cm², or any range between these specific values), for example, from about 10 cm² to about 100 cm².

[0083] When a transdermal delivery device (e.g., a DIA patch) is applied to an individual's skin, theoretically all of the adhesive surface becomes in contact with the skin. Therefore, the area of ​​the adhesive surface is defined as the skin contact area from which the active ingredient of the device can penetrate the skin, which is also referred to herein as an active surface area. In some specific examples, the adhesive surface is the only surface of the transdermal delivery device in contact with the skin after application, and the active surface area is the same as the area of ​​the adhesive surface. In some specific examples, after application, the adhesive surface and one or more other surfaces of the transdermal delivery device are in contact with the skin, and the entire skin contact area is the active surface area.

[0084] The active surface area determines the dosage of the drug to be delivered. Typically, the active surface area can be from about 5 cm² to about 300 cm² (e.g., about 5 cm², about 10 cm², about 20 cm², about 30 cm², about 40 cm², about 50 cm², about 60 cm², about 80 cm², about 100 cm², about 120 cm², about 150 cm², about 200 cm², or any range between these specific values), for example, from about 10 cm² to about 100 cm². The drug layer

[0085] Typically, the drug layer comprises buphenazine, deuterated buphenazine, or a combination thereof. In some specific examples, the drug layer may selectively include one or more other components, such as those selected from skin penetration enhancers, moisturizers, plasticizers, antioxidants, anti-irritants, gelling agents, drug release modifiers, solvents, crystallization inhibitors, and additional active ingredients. In some specific examples, the drug layer is modulated to achieve the skin flux characteristics described herein via the transdermal delivery device. It should be noted that the pharmaceutical composition of the drug layer used herein may also be a novel formulation, independent of the transdermal delivery device and / or the skin flux characteristics herein. Therefore, some specific examples disclosed herein also pertain to such pharmaceutical compositions.

[0086] In some specific examples, the drug in the drug layer may be buphenazine. The buphenazine in the transdermal delivery device described herein is not limited to a specific mirror-image isomer and may be in a racemic form, a substantially pure R,R-buphenazine (e.g., having less than 10%, less than 5%, less than 1%, or less than 0.1% of the S,S-isomer), a substantially pure S,S-buphenazine (e.g., having 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-buphenazine and S,S-buphenazine in any ratio. In some specific examples, the buphenazine in the transdermal delivery device is in a racemic form. In some specific examples, the buphenazine in the transdermal delivery device is a substantially pure R,R-buphenazine. In some specific examples, buphenazine is the only drug in the drug layer. In some specific examples, buphenazine is the only drug in the transdermal delivery device. In some specific examples, the drug layer and / or the transdermal delivery device may also include other active ingredients.

[0087] In some specific examples, the drug in the pharmaceutical layer can be a deuterated butylbenazine. As used herein, a deuterated butylbenazine means a compound in which one or more hydrogen atoms of butylbenazine are substituted with deuterium, thereby each substituted position having a deuterium content exceeding the natural abundance (i.e., the substituted position is enriched with deuterium). In some specific examples, the deuterated butylbenazine has at least one position enriched with 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 a deuterated butylbenazine is deuterated butylbenazine, the racemic form of which is the active ingredient in Austedo™ tablets. The deuterated butylbenazine in the transdermal delivery device described herein is not limited to a specific mirror-image isomer and may be in a racemic form, a substantially pure R,R-isomer, such as R,R-deuterated butylbenazine (see below) (e.g., having less than 10%, less than 5%, less than 1%, or less than 0.1% of S,S-isomer), a substantially pure S,S-isomer, such as S,S-deuterated butylbenazine (see below) (e.g., having less than 10%, less than 5%, less than 1%, or less than 0.1% of R,R-isomer), or a mixture of R,R-isomers and S,S-isomers in any ratio. In some specific examples, the transdermal delivery device comprises deuterated butylbenazine in a racemic form. In some specific examples, the transdermal delivery device comprises deuterated butylbenazine as in a substantially pure R,R-deuterated butylbenazine. In some specific examples, deuterated butylbenazine is the sole drug in the drug layer. In some specific examples, deuterated butylbenazine is the sole drug in the transdermal delivery device. In some specific examples, the drug layer and / or the transdermal delivery device may also include other active ingredients.

[0088] The drug may be present in the drug layer of the transdermal delivery device in various amounts. In some specific examples, the drug layer contains butylbenazine, deuterated butylbenazine, or a combination thereof in an amount of the drug layer of about 2% to about 30% (e.g., about 2%, about 2.5%, about 5%, about 8%, about 10%, about 15%, about 18%, about 20%, about 25%, about 30%, or any range between the cited values) by weight. In some particular specific examples, the drug layer contains butylbenazine, deuterated butylbenazine, or a combination thereof in an amount of the drug layer of about 2%, about 2.5%, about 5%, about 8%, about 10%, about 15%, or about 20% by weight. In some specific examples, butylbenazine, deuterated butylbenazine, or a combination thereof is present only in the drug layer of the transdermal delivery device (e.g., in an adhesive package drug layer).

[0089] The weight and thickness of the drug layer can vary depending on various factors, such as drug concentration and the desired duration of administration. The drug layer is typically designed for administration (e.g., delivery of buphenazine or deuterated buphenazine) over a period selected from approximately 8 hours, approximately 12 hours, approximately 18 hours, approximately 24 hours, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, and approximately 7 days. In some specific examples, the drug layer may have a coating weight with an active surface area of ​​approximately 0.01 g / cm² to approximately 5 g / cm², for example, approximately 0.05 g / cm² to approximately 5 g / cm², approximately 0.1 g / cm² to approximately 5 g / cm², such as approximately 0.05 g / cm² to approximately 0.90 g / cm², approximately 0.1 g / cm² to approximately 0.90 g / cm² (e.g., approximately 0.1 g / cm² to approximately 0.5 g / cm²). In some specific examples, the drug layer may have a thickness of about 1.5 mils to about 10 mils, such as about 1.5 mils to about 3.5 mils (e.g., about 2 mils to about 3.5 mils). In some specific examples, the drug layer may have a thickness of about 0.1 mils to about 100 mils, such as about 1 mil to about 50 mils (e.g., about 1 mil to about 10 mils, or about 1.5 mils to about 3.5 mils).

[0090] Skin penetration enhancers can enhance the skin permeability of buphenazine or deuterated buphenazine through the skin and may be selectively included in the drug layer. In some specific examples, the drug layer has no or substantially no penetration enhancer. However, in some specific examples, a variety of different skin penetration enhancers may be included. Non-limiting useful skin penetration enhancers include, for example, sulfoxides (e.g., dimethylsulfoxide (DMSO)), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidon, 2P), alcohols and alkanols (e.g., ethanol or decanol), esters, glycols (e.g., propylene glycol (PG)), surfactants (e.g., polysorbate 80 (Tween 80)), terpenes, and combinations thereof. See, for example, Williams et al., Adv Drug Deliv Rev. 27;56(5):603-18 (2004). In some specific examples, the penetration enhancer comprises one or more compounds selected from sulfoxides, alcohols, alkanols, esters, glycols, and surfactants. In some specific examples, the penetration enhancer comprises one or more compounds selected from dimethyl sulfoxide (DMSO), oleic acid alcohol, oleic acid ester, oleic acid, levulinic acid, other fatty acids and fatty acid esters, propylene glycol, dipropylene glycol, ethanol, and surfactants (such as polysorbate 80). The skin penetration enhancer is typically included in an amount of about 1% to about 25% by weight of the pharmaceutical composition (e.g., about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, or any range between these specific values ​​by weight of the pharmaceutical composition).

[0091] Other suitable excipients useful in the preparation of transdermal delivery devices (such as humectants, plasticizers, antioxidants, anti-irritants, gelling agents, crystallization inhibitors, drug release modifiers, etc.) may also be included in the drug layer (e.g., an adhesive-coated drug layer) or in the transdermal delivery device herein. In some specific examples, additional active ingredients(s) may also be included in the drug layer or in the transdermal delivery device herein. These excipients are within the knowledge of those skilled in the art and can be found, for example, in the Handbook of Pharmaceutical Excipients, (7th ed. 2012), the entire contents of which are hereby incorporated herein by reference. The adhesive layer

[0092] The adhesive layer can be the same as or a separate layer from the drug layer. In a typical DIA patch, the drug is uniformly dispersed in an adhesive to form an adhesive-encapsulated drug layer. Other designs (such as a DIR patch) may also include an adhesive layer separate from the drug layer (e.g., via a membrane). In some specific examples, more than one adhesive layer (e.g., two or more adhesive-encapsulated drug layers) may be used in the transdermal delivery device.

[0093] The adhesive layer typically comprises a pressure-sensitive adhesive (PSA). PSAs are generally known in the art. See, for example, Tan et al., Pharm Sci & Tech Today, 2:60-69 (1999). Non-limiting useful PSAs include polyisobutylene (PIB), silicone polymers, acrylate copolymers, and combinations thereof. In some specific examples, the pressure-sensitive adhesive comprises a polyisobutylene adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some specific examples, the pressure-sensitive adhesive comprises an acrylate copolymer adhesive. Non-limiting useful acrylate copolymers include, for example, acrylic pressure-sensitive adhesives, such as a polyacrylate-vinyl acetate copolymer, for example, 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 prepared by Henkel adhesive. In some specific examples, the pressure-sensitive adhesive may be a non-reactive acrylate adhesive (e.g., as described herein, such as Duro-Tak 87-900A), for example, an acrylate adhesive without a functional group containing a reactive hydrogen moiety, or an acrylate adhesive without a functional group selected from epoxy, –OH, -COOH and combinations thereof. PIB is a resilient polymer commonly used in PSAs, both as a primary base polymer and as an adhesive. PIB is a homopolymer of isobutylene and is characterized by a regular structure having a hydrocarbon backbone with only terminal unsaturation. Non-limiting useful PIBs include those sold by BASF under the trademark Oppanol. However, in some specific examples, the pressure-sensitive adhesive does not contain a PIB-based adhesive. These silicone polymers are high molecular weight polydimethylsiloxanes containing residual silanol functionalization (SiOH) at the ends of the polymer chains. Non-limiting useful silicone PSAs for use in pharmaceutical applications include those available from Dow Corning Corporation, for example, under the trademark BIO-PSA (e.g., BIO-7-4202). In some specific examples, the adhesive layer is about 1.5 mils to about 10 mils thick (e.g., about 1.5 mils to about 2 mils).

[0094] One or more adhesives may be used in the adhesive layer. For example, in some specific examples, the adhesive layer may comprise a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various proportions (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 these adhesive components can affect the throughput characteristics of the transdermal delivery device.

[0095] The adhesive layer is typically formulated so that the transdermal delivery device can adhere to a user's skin for a desired period of time. For example, in some specific cases, the transdermal delivery device can adhere to a user's skin 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 more. The adhesive composition

[0096] In some specific examples, the present invention also provides an adhesive composition comprising a drug selected from buphenazine, deuterated buphenazine (e.g., deuterated buphenazine), and combinations thereof in an adhesive. In some specific examples, the drug is uniformly dispersed in the adhesive. Suitable drugs and adhesives include any of those described herein.

[0097] In some specific examples, the adhesive composition can adhere to a user's skin for a duration selected from an extended period of about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more.

[0098] In some specific examples, the adhesive is a pressure-sensitive adhesive. In some specific examples, the pressure-sensitive adhesive comprises a polyisobutylene (PIB) adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some specific examples, the pressure-sensitive adhesive may be a non-reactive acrylate adhesive (e.g., as described herein, such as Duro-Tak 87-900A), for example, an acrylate adhesive without a functional group containing a reactive hydrogen moiety, or an acrylate adhesive without a functional group selected from epoxy, –OH, –COOH, and combinations thereof. In some specific examples, the pressure-sensitive adhesive does not include a polyisobutylene (PIB) adhesive and / or a silicone polymer adhesive.

[0099] The drug in the adhesive composition is preferably butylbenazine or deuterated butylbenazine. In some specific examples, the drug is butylbenazine. In some specific examples, the butylbenazine is a substantially pure R,R-butylbenazine. In some specific examples, the drug is deuterated butylbenazine. In some specific examples, the deuterated butylbenazine is a substantially pure R,R-deuterated butylbenazine. In some specific examples, butylbenazine is the sole active ingredient in the adhesive composition. In some specific examples, deuterated butylbenazine is the sole active ingredient in the adhesive composition. In some specific examples, the butylbenazine or deuterated butylbenazine is present in an amount of about 2% to about 30% (e.g., about 2%, about 2.5%, about 5%, about 8%, about 10%, about 15%, about 18%, about 20%, about 25%, about 30%, or any range between the cited values) of the adhesive composition by weight. In some particular specific examples, the adhesive composition comprises butylbenazine or deuterated butylbenazine in an amount of about 2%, about 2.5%, about 5%, about 8%, about 10%, about 15%, or about 20% by weight of the adhesive composition. In some specific examples, the active ingredient is present in an amount of about 2% to about 7% by weight.

[0100] In some specific examples, the adhesive composition further comprises a penetration enhancer. Suitable penetration enhancers include any of those described herein. In some specific examples, the adhesive composition does not contain a penetration enhancer. In some specific examples, the adhesive composition does not contain isopropyl myristate.

[0101] In some specific examples, the adhesive composition may selectively include one or more components selected from humectants, plasticizers, antioxidants, anti-irritants, gel-forming agents, crystallization inhibitors, drug release modifiers, and additional active ingredients. For example, in some specific examples, the adhesive composition may contain an antioxidant, such as a gallate antioxidant (e.g., propyl gallate). In some specific examples, the adhesive composition may contain 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 graft copolymer based on polyvinyl acetate and polyvinylcaprolactam (PVAc-PVCap-PEG), or a combination thereof. In some preferred examples, the adhesive composition contains a crystallization inhibitor that is a copolymer of butyl methacrylate and methyl methacrylate. In some specific examples, the adhesive composition includes a crystallization inhibitor, which is a graft copolymer based on polyethylene glycol, polyvinyl acetate, and polyvinylcaprolactam.

[0102] The adhesive composition may be included in a transdermal delivery device. Typically, this transdermal delivery device also includes a backing layer and a release liner to protect the adhesive surface before use. In some specific examples, the adhesive composition may be included when the drug layer is in any of the transdermal delivery devices described herein. Skin flux characteristics

[0103] The transdermal delivery device described herein preferably provides certain desired skin flux characteristics. Typically, the transdermal delivery device can deliver the drug (e.g., bubenazine or deuterated bubenazine) to an individual in need at a dose of about 0.1 mg / day / cm² to about 5 mg / day / cm² (e.g., about 0.1 mg / day / cm², about 0.2 mg / day / cm², about 0.5 mg / day / cm², about 1 mg / day / cm², about 2 mg / day / cm², about 5 mg / day / cm², or any range between these specific values), for example, during a time 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. However, in some specific examples, the transdermal delivery device may deliver more than about 5 mg / day / cm² (e.g., about 8 mg / day / cm², about 10 mg / day / cm², about 15 mg / day / cm², about 20 mg / day / cm², or any range between the cited values) of the drug (e.g., bubenazine or deuterated bubenazine). In some specific examples, the transdermal delivery device may deliver less than about 0.1 mg / day / cm² (such as about 0.01 mg / day / cm², about 0.02 mg / day / cm², about 0.05 mg / day / cm², about 0.1 mg / day / cm², or any range between the cited values) of the drug (e.g., bubenazine or deuterated bubenazine).

[0104] In some specific examples, the transdermal delivery device can deliver the drug (e.g., bubenazine or deuterated bubenazine) to an individual in need at a dose of about 0.1 mg / day / cm² to about 1 mg / day / cm² (e.g., about 0.1 mg / day / cm², about 0.2 mg / day / cm², about 0.5 mg / day / cm², about 1 mg / day / cm², or any range between these specific values), for example, during a time period selected from about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, and about 7 days. In some specific examples, the transdermal delivery device can deliver the drug (e.g., bubenazine or deuterated bubenazine) at a dose of about 0.1 mg / day / cm² to about 5 mg / day / cm² (e.g., about 0.1 mg / day / cm², about 0.2 mg / day / cm², about 0.5 mg / day / cm², about 1 mg / day / cm², about 5 mg / day / cm², or any range between these specific values), for example, over a period of time (a period of more than 7 days). In some specific examples, the transdermal delivery device may also deliver the drug (e.g., bubenazine or deuterated bubenazine) at doses of about 0.1 mg / day / cm² to about 5 mg / day / cm² (e.g., about 0.1 mg / day / cm², about 0.2 mg / day / cm², about 0.5 mg / day / cm², about 1 mg / day / cm², or any range between these specific values), for example, over a period of less than 24 hours (e.g., less than 18 hours, less than 12 hours, less than 8 hours, or less than 4 hours).

[0105] In some specific examples, when human cadaver skin is used for in vitro testing, the transdermal delivery device contains buphenazine, and the transdermal delivery device provides one or more of the following skin flux characteristics: a) a cumulative buphenazine permeation of about 0.1 μg / cm² to about 150 μg / cm² (e.g., about 0.1 μg / cm², about 0.5 μg / cm², about 1 μg / cm², about 5 μg / cm², about 10 μg / cm², about 15 μg / cm², about 20 μg / cm², about 50 μg / cm², about 75 μg / cm², about 100 μg / cm², about 125 μg / cm², about 150 μg / cm², or any range between the cited values) based on the active surface area 6 hours after administration; b) a cumulative buphenazine permeation of about 2 μg / cm² based on the active surface area 12 hours after administration. The cumulative concentration of buprofen at a permeation of approximately 400 μg / cm² (e.g., approximately 2 μg / cm², approximately 5 μg / cm², approximately 10 μg / cm², approximately 15 μg / cm², approximately 20 μg / cm², approximately 50 μg / cm², approximately 100 μg / cm², approximately 200 μg / cm², approximately 300 μg / cm², approximately 400 μg / cm², or any range between the cited values); and c) at a concentration of approximately 5 μg / cm² to approximately 1000 μg / cm² (e.g., approximately 5 μg / cm², approximately 10 μg / cm², approximately 15 μg / cm², approximately 20 μg / cm², approximately 25 μg / cm², approximately 50 μg / cm², approximately 100 μg / cm², approximately 200 μg / cm², or any range between the cited values) 24 hours after administration, based on the active surface area. The cumulative amount of buphenazine permeates at concentrations of approximately 300 μg / cm², 400 μg / cm², 600 μg / cm², 800 μg / cm², 1000 μg / cm², or any range between the cited values. In some specific examples, the buphenazine is present in an amount of the drug layer of approximately 2% to approximately 30% (e.g., approximately 2% to approximately 20%, approximately 2% to approximately 10%, approximately 2% to approximately 5%, approximately 5% to approximately 10%, approximately 10% to approximately 15%) by weight. In some specific examples, the buphenazine is present in an amount of the drug layer of approximately 2%, approximately 5%, approximately 8%, approximately 10%, approximately 15%, approximately 20%, or any range between the cited values ​​by weight. In some specific examples, the buphenazine is a substantially pure R,R-buphenazine.

[0106] In some specific examples, the buphenazine is present in an amount of about 2% to about 5% by weight of the drug layer, and when tested in vitro using human cadaver skin, the transdermal delivery device provides one or more of the following skin flux characteristics: a) a cumulative buphenazine permeation of about 0.1 μg / cm² to about 100 μg / cm² (e.g., about 0.1 μg / cm², about 0.5 μg / cm², about 1 μg / cm², about 5 μg / cm², about 10 μg / cm², about 15 μg / cm², about 20 μg / cm², about 50 μg / cm², about 75 μg / cm², about 100 μg / cm², or any range between the cited values) based on the active surface area 6 hours after administration; b) a permeation of about 2 μg / cm² to about 200 μg / cm² based on the active surface area 12 hours after administration. (e.g., about 2 μg / cm², about 5 μg / cm², about 10 μg / cm², about 15 μg / cm², about 20 μg / cm², about 50 μg / cm², about 100 μg / cm², about 200 μg / cm², or any range between the cited values) cumulative buprofenazine permeation; and c) based on the active surface area 24 hours after administration, from about 5 μg / cm² to about 600 μg / cm² (e.g., about 5 μg / cm², about 10 μg / cm², about 15 μg / cm², about 20 μg / cm², about 25 μg / cm², about 50 μg / cm², about 100 μg / cm², about 200 μg / cm², about 300 μg / cm², about 400 μg / cm², about 600 μg / cm², etc.) Cumulative buphenazine permeation (μg / cm2, or any range between the cited values).

[0107] In some specific examples, the buphenazine is present in an amount of about 5% to about 10% by weight of the drug layer, and when tested in vitro using human cadaver skin, the transdermal delivery device provides one or more of the following skin flux characteristics: a) a cumulative buphenazine permeation of about 0.5 μg / cm² to about 150 μg / cm² (e.g., about 1 μg / cm², about 5 μg / cm², about 10 μg / cm², about 15 μg / cm², about 20 μg / cm², about 50 μg / cm², about 75 μg / cm², about 100 μg / cm², about 150 μg / cm², or any range between the cited values) based on the active surface area 6 hours after administration; b) a permeation of about 4 μg / cm² to about 400 μg / cm² (e.g., about 4 μg / cm²) based on the active surface area 12 hours after administration. The cumulative osmotic concentration of buprofen (approximately 6 μg / cm², approximately 10 μg / cm², approximately 15 μg / cm², approximately 20 μg / cm², approximately 50 μg / cm², approximately 100 μg / cm², approximately 200 μg / cm², approximately 400 μg / cm², or any range between the cited values); and c) based on the active surface area 24 hours after administration, approximately 6 μg / cm² to approximately 1000 μg / cm² (e.g., approximately 6 μg / cm², approximately 10 μg / cm², approximately 15 μg / cm², approximately 20 μg / cm², approximately 25 μg / cm², approximately 50 μg / cm², approximately 100 μg / cm², approximately 200 μg / cm², approximately 300 μg / cm², approximately 400 μg / cm², approximately 6 ... Cumulative buphenazine permeation (approximately 1000 μg / cm2, or any range between the cited values) in μg / cm2, approximately 1000 μg / cm2, or any range between the cited values.

[0108] In some specific examples, the buphenazine is present in an amount of about 10% to about 15% by weight of the drug layer, and when tested in vitro using human cadaver skin, the transdermal delivery device provides one or more of the following skin flux characteristics: a) a cumulative buphenazine permeation of about 0.5 μg / cm² to about 150 μg / cm² (e.g., about 1 μg / cm², about 2 μg / cm², about 5 μg / cm², about 10 μg / cm², about 15 μg / cm², about 20 μg / cm², about 50 μg / cm², about 75 μg / cm², about 100 μg / cm², about 150 μg / cm², or any range between the cited values) based on the active surface area 6 hours after administration; b) a permeation of about 4 μg / cm² to about 400 μg / cm² based on the active surface area 12 hours after administration. (e.g., about 4 μg / cm², about 6 μg / cm², about 10 μg / cm², about 15 μg / cm², about 20 μg / cm², about 30 μg / cm², about 40 μg / cm², about 50 μg / cm², about 100 μg / cm², about 200 μg / cm², about 400 μg / cm², or any range between the cited values) cumulative buprofenazine permeation; and c) based on the active surface area, approximately 8 μg / cm² to approximately 1000 μg / cm² (e.g., about 8 μg / cm², about 10 μg / cm², about 15 μg / cm², about 20 μg / cm², about 30 μg / cm², about 40 μg / cm², about 50 μg / cm², about 60 μg / cm²) 24 hours after administration. Cumulative buphenazine permeation at approximately 100 μg / cm², approximately 200 μg / cm², approximately 300 μg / cm², approximately 400 μg / cm², approximately 600 μg / cm², approximately 1000 μg / cm², or any range between the cited values.

[0109] In some specific examples, the transdermal delivery device comprises a deuterated bubenazine (e.g., deuterated bubenazine), and when tested in vitro using human cadaver skin, the transdermal delivery device provides one or more of the following skin flux characteristics: a) at 6 hours post-administration, based on the active surface area, a flux of approximately 0.1 μg / cm² to approximately 150 μg / cm² (e.g., approximately 0.1 μg / cm², approximately 0.5 μg / cm², approximately 1 μg / cm², approximately 5 μg / cm², approximately 10 μg / cm², approximately 15 μg / cm², approximately 20 μg / cm², approximately 50 μg / cm², approximately 75 μg / cm², approximately 100 μg / cm², approximately 125 μg / cm², approximately 150 μg / cm²). a) Cumulative deuterated buprofenazine permeation at approximately 2 μg / cm² to approximately 400 μg / cm² (e.g., approximately 2 μg / cm², approximately 5 μg / cm², approximately 10 μg / cm², approximately 15 μg / cm², approximately 20 μg / cm², approximately 50 μg / cm², approximately 100 μg / cm², approximately 200 μg / cm², approximately 300 μg / cm², approximately 400 μg / cm², or any range between the cited values) based on the active surface area at 12 hours after administration; and c) Cumulative deuterated buprofenazine permeation at approximately 5 μg / cm² to approximately 1000 μg / cm² (e.g., approximately 5 μg / cm², approximately 10 μg / cm², approximately 15 μg / cm², approximately 20 μg / cm², approximately 50 μg / cm², approximately 100 μg / cm², approximately 200 μg / cm², approximately 300 μg / cm², approximately 400 μg / cm², or any range between the cited values) based on the active surface area at 24 hours after administration. The cumulative deuterated buphenazine permeates at concentrations of approximately 20 μg / cm², 25 μg / cm², 50 μg / cm², 100 μg / cm², 200 μg / cm², 300 μg / cm², 400 μg / cm², 600 μg / cm², 800 μg / cm², 1000 μg / cm², or within any range between the cited values. In some specific examples, the deuterated buphenazine is present in an amount of the drug layer of approximately 2% to approximately 30% (e.g., approximately 2% to approximately 20%, approximately 2% to approximately 10%, approximately 2% to approximately 5%, approximately 5% to approximately 10%, approximately 10% to approximately 15%) by weight. In some specific examples, the deuterated butylbenazine is present in an amount of the drug layer by weight of about 2%, about 5%, about 8%, about 10%, about 15%, about 20%, or in any range between the cited values. In some specific examples, the deuterated butylbenazine is substantially pure R,R-deuterated butylbenazine.

[0110] Transdermal delivery devices with the above-mentioned flux characteristics can be prepared by those skilled in the art in light of this disclosure. The preparation of some transdermal delivery devices is also illustrated in the Examples section. The cumulative drug penetration (bubenazine, deuterated bubenazine, or a combination thereof) can be adjusted, for example, by changing the composition of the drug layer (e.g., drug concentration, penetration enhancer, coating weight, type of adhesive, etc.). [Contains non--] [Composition of reactive adhesives]

[0111] Compositions using non-reactive adhesives offer certain advantages. As illustrated in the Examples section, bubenazine formulations with non-reactive adhesives can be more stable than corresponding formulations with functionalized adhesives. For example, when a non-reactive adhesive, DuroTak 87-900 A, is used as a matrix polymer, known to be a copolymer of 2-EHA (2-ethylhexyl acrylate) (about 45 wt% based on monomer composition), MA (methyl acrylate) (about 35 wt% based on monomer composition), and t-OA (tert octyl acrylamide) (about 20 wt% based on monomer composition), the resulting bubenazine adhesive composition was found to be stable after shelf storage at 40°C for 4 weeks, with no drug crystallization observed and no drug degradation. Conversely, formulations using a more common adhesive matrix polymer (DuroTak 87-2287 (containing epoxy and hydroxyl functional groups) or Duro-Tak 87-2677 (containing carboxylic acid functional groups)) showed a yellow color after 4 weeks of shelf storage at 40°C, indicating instability of the active ingredient due to oxidation and / or other degradation.

[0112] In some specific examples, the present invention provides an adhesive composition comprising an active ingredient (or alternatively referred to as a "pharmaceutical") dispersed (e.g., uniformly dispersed or dissolved) in a non-reactive acrylate pressure-sensitive adhesive, wherein the active ingredient is selected from butylbenazine, deuterated butylbenazine, or a combination thereof. Unless otherwise apparent from the context, in any of the specific examples described herein, the active ingredient may be present primarily in its free base form (e.g., at least 80%, at least 90%, or at least 95% by weight), such as butylbenazine base, deuterated butylbenazine base, etc. The non-reactive acrylate pressure-sensitive adhesive is typically present in an amount of about 50% to about 97% (e.g., about 50%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, or in any range between the cited values) of the adhesive composition by weight.

[0113] Non-reactive acrylic pressure-sensitive adhesives useful for specific examples of this disclosure include those sold by Henkel, for example, under the product name DuroTak 87-900A. U.S. Patent No. 9,056,060 (the contents of which are incorporated herein by reference in their entirety) also describes non-reactive acrylic pressure-sensitive adhesives that can be used in specific examples of this disclosure.

[0114] In some specific examples, the non-reactive acrylate pressure-sensitive adhesive does not have a functional group containing a reactive hydrogen moiety. In some specific examples, the non-reactive acrylate pressure-sensitive adhesive does not have a functional group selected from epoxy groups, –OH, -COOH, and combinations thereof. For example, in some specific examples, the non-reactive acrylate pressure-sensitive adhesive is a copolymer of alkyl acrylate without a functional group containing a reactive hydrogen moiety or without a functional group selected from epoxy groups, –OH, -COOH, and combinations thereof. In some specific examples, the non-reactive acrylate pressure-sensitive adhesive may be a copolymer of monomers comprising alkyl acrylates, substantially composed of alkyl acrylates, or composed of alkyl acrylates. For example, in some specific examples, the non-reactive acrylate pressure-sensitive adhesive may be a copolymer of monomers derived from alkyl acrylates, such as a copolymer of a monomer derived from a C2-C18 alkyl acrylate (preferably C4-C10 branched or straight-chain alkyl acrylate) and a monomer of methyl acrylate, more preferably, a copolymer of a monomer derived from hexylethyl acrylate (e.g., 2-ethylhexyl acrylate) and a monomer of methyl acrylate. In some specific examples, the alkyl acrylate copolymer is a copolymer of hexylethyl acrylate (e.g., 2-ethylhexyl acrylate) and methyl acrylate, and selectively other monomers(s) that do not have functional groups containing reactive hydrogen moieties (such as –OH, -COOH groups). In some specific examples, the non-reactive acrylate pressure-sensitive adhesive may be a copolymer derived from monomers including alkyl acrylates, and other monomers that do not have functional groups containing reactive hydrogen moieties (such as –OH, -COOH groups). For example, in some specific examples, the non-reactive acrylate pressure-sensitive adhesive may be a copolymer derived from a monomer of hexyl ethyl acrylate (e.g., 2-ethylhexyl acrylate), a monomer of methyl acrylate, and one or more monomers that do not have functional groups containing reactive hydrogen moieties (such as –OH, -COOH groups) (such as acrylamide monomers (e.g., tri-octyl acrylamide, dimethyl acrylamide, isopropyl acrylamide, or vinyl acetamide)). As used herein, the acetamide NH or acetamide NH2 group should not be considered as a reactive hydrogen moieties. In some specific examples, the non-reactive acrylate pressure-sensitive adhesive may be a monomer derived from a C2-C18 alkyl acrylate (preferably C4-C10 branched or straight-chain alkyl acrylate), a monomer of methyl acrylate, and a copolymer of one or more acrylamide monomers (e.g., tert-octyl acrylamide) that do not have functional groups selected from epoxy, –OH, –COOH groups and combinations thereof.The weight percentage of the monomers can vary. For example, in some specific examples, the percentage of the monomers in the non-reactive acrylate pressure-sensitive adhesive can be as follows: the percentage of C2-C18 alkyl acrylate monomers (preferably C4-C10 branched or straight-chain alkyl acrylates, such as 2-ethylhexyl acrylate) can be about 45 wt%, the percentage of methyl acrylate monomers can be about 35 wt%, and the percentage of one or more acrylamide monomers (e.g., tert-octylacrylamide) can be about 20 wt%.

[0115] This non-reactive acrylic pressure-sensitive adhesive typically does not include vinyl acetate. It also typically does not include a crosslinking agent. This non-reactive acrylic pressure-sensitive adhesive can typically have a variety of different viscosities. In some specific examples, the non-reactive acrylic 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 within the range of the cited values). In some specific examples, the non-reactive acrylic pressure-sensitive adhesive can be selected such that the adhesive composition can sustainably adhere to a user's skin for about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more.

[0116] In some formulations, the addition of a penetration enhancer can cause significant degradation of the active ingredient (e.g., butylbenazine) in the patch formulation. Therefore, in some specific examples, the adhesive composition may contain no or substantially no penetration enhancer. For example, in some specific examples, the adhesive composition may not contain a penetration enhancer. In some specific examples, the adhesive composition may not contain a penetration enhancer selected from fatty alcohols, fatty acids, fatty esters, and combinations thereof. In some specific examples, the adhesive composition may not contain isopropyl myristate. However, it should be understood that in some examples, a penetration enhancer may be added to such adhesive compositions, for example, in an amount that does not cause significant degradation of the active ingredient.

[0117] Antioxidants are typically included in the adhesive compositions described herein. For example, antioxidants may be added to reduce the degree of degradation of the active ingredient. However, it has been unexpectedly found that some antioxidants are better at protecting buphenazine from degradation than others. For example, adhesive compositions containing a gallate antioxidant (e.g., propyl gallate in the examples) have been found to be shelf stable. In any of the specific examples herein, shelf stability, storage stability, or shelf-storage stability and the like may mean that after a tested device or composition has been stored on a shelf at 40°C for 4 weeks, (1) HPLC analysis shows that the tested device or composition has no or substantially no (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; and / or (2) no drug crystals are observed (e.g., visually). In some specific examples, all such degradation products TBZ01, TBZ02, and TBZ04 are not detected by HPLC or are below the quantitative limits for a shelf-stable device or composition thereof after being stored on a shelf at 40°C for 4 weeks. Exemplary conditions for HPLC analysis and residence times of TBZ01, TBZ02, and TBZ04 have been shown in Example 5. However, when no antioxidant is used or the added antioxidant is BHT, degradation products (including TBZ01, TBZ02, and TBZ04) are formed. In some specific examples, the adhesive composition may contain a gallate antioxidant. In some preferred examples, the adhesive composition may contain propyl gallate. In some preferred examples, propyl gallate is the sole antioxidant in the adhesive composition. In some specific examples, other antioxidants may be used in combination with propyl gallate. In some specific examples, the adhesive composition may also include propyl gallate, citric acid, ascorbic acid, vitamin E, or tocopheryl acetate, or a combination thereof, as an antioxidant. When present, the antioxidant (such as propyl gallate) is typically present in an amount of about 0.001% to about 0.5% (e.g., about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%) by weight of the adhesive composition.

[0118] The active ingredient is typically present in the adhesive composition in an amount of about 2% to about 30% by weight. Preferably, in some specific examples, the active ingredient may be present in the adhesive composition in an amount of about 2% to about 15% by weight (such as about 2% to about 10%, or about 2% to about 7% by weight). The butylbenazine in the adhesive composition herein is not limited to a specific mirror-image isomer and may be in a racemic form, a substantially pure R,R-butylbenazine (e.g., having less than 10%, less than 5%, less than 1%, or less than 0.1% of the S,S-isomer), a substantially pure S,S-butylbenazine (e.g., having 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-butylbenazine and S,S-butylbenazine in any proportion. Similarly, the deuterated butylbenazine in the adhesive composition described herein is not limited to a specific mirror-image isomer and may be in a racemic form, a substantially pure R,R-isomer (e.g., R,R-deuterated butylbenazine (e.g., having less than 10%, less than 5%, less than 1%, or less than 0.1% of S,S-isomer)), and a substantially pure S,S-isomer (e.g., S,S-deuterated butylbenazine (e.g., having less than 10%, less than 5%, less than 1%, or less than 0.1% of R,R-isomer)). The adhesive composition may contain, for example, an R,R-isomer or a mixture of R,R-isomers and S,S-isomers in any proportion. In some specific examples, the sole active ingredient in the adhesive composition is butylbenazine, such as a substantially pure R,R-isomer of butylbenazine. In some specific examples, the sole active ingredient in the adhesive composition is deuterated butylbenazine, such as a substantially pure R,R-isomer of deuterated butylbenazine. In some specific examples, the adhesive composition may also include other active ingredients, such as those described herein.

[0119] Typically, a crystallization inhibitor is also included in the adhesive composition to prevent the formation of drug crystals after storage. Such drug crystals can delay skin penetration of the adhesive composition. Therefore, in some specific examples, the adhesive composition may include a crystallization inhibitor in an amount effective in preventing drug crystal formation after shelf storage at ambient temperature for two weeks. In some specific examples, the adhesive composition may include a crystallization inhibitor selected from the following: a polyvinylpyrrolidone polymer (e.g., Kollidon K30 or K90F (manufactured by BASF), Plasdone K20 / 32 or Plasdone K90 (manufactured by Ashland Chemical)), a crosslinked polyvinylpyrrolidone polymer (e.g., Kollidon CL), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 copolyvinylpyrrolidone (Asland)), a cellulose-based polymer (e.g., hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose), a polycarboxylic acid polymer (e.g., carbomer (manufactured by Lubrizol)), and a polymethacrylate (e.g., Plastoid B, Eudragit E100, Eudragit L100-55). (manufactured by Evonik), polyethylene glycol, graft copolymers based on polyvinyl acetate and polyvinylcaprolactam (PVAc-PVCap-PEG) (e.g., Soluplus (BASF) and combinations thereof. In some specific examples, the crystallization inhibitor is not Kollidon VA64 (BASF).

[0120] 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, a graft copolymer (PVAc-PVCap-PEG) based on polyvinyl acetate and polyvinylcaprolactam (e.g., Soluplus (BASF)), and combinations thereof. For example, in some particular embodiments, the adhesive composition includes a copolymer of butyl methacrylate and methyl methacrylate, such as a polymer according to the trademark name Plastoid B (manufactured by Evonic). In some particular embodiments, the adhesive composition includes polyethylene glycol, a graft copolymer based on polyvinyl acetate and polyvinylcaprolactam, such as a polymer according to the trademark name Soluplus. The polymer (manufactured by BASF). When present in the adhesive composition, the crystallization inhibitor is typically present in an amount of about 5% to about 40% by weight (such as about 10%, about 20%, about 30%, about 40% by weight or any range between the cited values).

[0121] In some specific examples, the present invention provides adhesive compositions having the following components: Element Percentage by weight (dry) Typical better Better Active ingredients (For example, buphenazine) 2-10% 5-10% 5-7% (e.g., 6.8%, 7.1%) PSA adhesive (For example, Duro-Tak 87-900A) 50-97% 60-95% 65-95% (e.g., 72.9%, 92.5%) antioxidants (For example, propyl gallate) 0-1% 0.001-0.5% 0.01-0.1% (e.g., 0.05%) Crystallization inhibitors (For example, Plastoid B, Soluplus) 0-40% 10-40% 15-30% (e.g., 20%, 19.3%) The values ​​in the table should be understood as including the term "about". Other components may be selectively included. In some specific examples, the adhesive composition does not contain a penetration enhancer. In some specific examples, the adhesive composition does not contain isopropyl myristate. Suitable active ingredients, adhesives (e.g., non-reactive acrylate adhesives), antioxidants, and crystallization inhibitors include those described herein. For example, in some preferred embodiments, the active ingredient is tetrabenazine base (e.g., a substantially pure R,R-isomer), the adhesive is an acrylate polymer (such as a non-reactive acrylate adhesive, preferably a copolymer of hexyl ethyl acrylate and methyl acrylate (such as Duro-Tak 87-900A)), the antioxidant is preferably propyl gallate, and the crystallization inhibitor is preferably a copolymer of butyl methacrylate and methyl methacrylate or a polyethylene glycol graft copolymer based on polyvinyl acetate and polyvinyl caprolactam. In some specific examples, this disclosure also provides a method for preparing an adhesive composition (e.g., as described herein). In some specific examples, the method comprises mixing an active ingredient (e.g., butylbenazine), an adhesive, selectively an antioxidant, and selectively a crystallization inhibitor in a suitable solvent (e.g., ethanol, etc.) to form a wet adhesive composition. Suitable amounts and suitable active ingredients, adhesives, antioxidants, and crystallization inhibitors include any of those described herein and preferred ones, for example, those discussed in this paragraph and the preceding 10 paragraphs. Other alternative components and amounts are also described herein. In some specific examples, the method further comprises casting the wet adhesive composition onto a backing layer. In some specific examples, the method further comprises drying the wet adhesive composition. The product produced by the method herein is also a novel composition.

[0122] The adhesive composition (e.g., the adhesive composition having a non-reactive acrylate adhesive as described herein) is typically included in a transdermal delivery device, for example, as a drug layer or an adhesive-encapsulated drug layer. For example, in some specific examples, this disclosure provides a transdermal delivery device comprising a backing layer, any of the adhesive compositions described herein (e.g., the adhesive composition having a non-reactive acrylate adhesive as described herein as a drug layer or an adhesive-encapsulated drug layer), and a release liner. The transdermal delivery device can be cut to various sizes as desired, typically from about 10 cm² to about 100 cm². Other patch designs are described herein. Preferably, the transdermal delivery device (and / or the adhesive composition, for example, having a non-reactive acrylate adhesive as described herein) is storage stable (or alternatively meant to be shelf stable), for example, not exhibiting drug crystallization as observed after shelf storage at 40°C for 4 weeks, and / or not exhibiting drug degradation as observed by HPLC after shelf storage at 40°C for 4 weeks. For example, in some specific examples, the transdermal delivery device (and / or the adhesive composition, for example, having a non-reactive acrylate adhesive as described herein) may be storage stable for 4 weeks or more, 8 weeks or more, 12 weeks or more, 16 weeks or more, 6 months or more, 12 months or more, etc.

[0123] Typically, the transdermal delivery device (and / or the adhesive composition herein) can also be configured to achieve a desired skin penetration of the active ingredient (e.g., bubenazine or deuterated bubenazine). For example, in some specific examples, the transdermal delivery device (e.g., an adhesive composition comprising the non-reactive acrylate adhesive described herein) can deliver approximately 0.01 mg / day / cm² to approximately 5 mg / day / cm² to an individual in need (e.g., approximately 0.01 mg / day / cm², approximately 0.02 mg / day / cm², approximately 0.05 mg / day / cm², approximately 0.1 mg / day / cm², approximately 0.2 mg / day / cm², approximately 0.5 mg / day / cm², approximately 1 mg / day / cm², approximately 2 mg / day / cm², approximately 5 mg / day / cm²). The active ingredient (e.g., bubenazine or deuterated bubenazine) is delivered, for example, within a time 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 specific examples, the transdermal delivery device (e.g., comprising the adhesive composition having a non-reactive acrylate adhesive as described herein) can deliver more than about 5 mg / day / cm² (e.g., about 8 mg / day / cm², about 10 mg / day / cm², about 15 mg / day / cm², about 20 mg / day / cm², or within any range of the cited values). In some specific examples, the transdermal delivery device (e.g., comprising the adhesive composition having a non-reactive acrylate adhesive as described herein) can deliver less than about 0.1 mg / day / cm² (such as about 0.01 mg / day / cm², about 0.02 mg / day / cm², about 0.05 mg / day / cm², about 0.1 mg / day / cm², or any range between the cited values) of the active ingredient (e.g., bubenazine or deuterated bubenazine).

[0124] For example, in some specific instances, the adhesive composition of the transdermal delivery device contains about 2% to about 10% by weight (e.g., about 2% to about 7%) of buphenazine, which, when tested in vitro using human cadaver skin, provides one or more of the following skin flux characteristics: a) a cumulative buphenazine penetration of about 0.5 μg / cm² to about 50 μg / cm² (e.g., about 1 μg / cm², about 5 μg / cm², about 10 μg / cm², about 15 μg / cm², about 20 μg / cm², about 50 μg / cm², or any range between the cited values) based on the active surface area at 8 hours after administration; b) a buphenazine penetration of about 5 μg / cm² to about 500 μg / cm² (e.g., about 5 μg / cm², about 10 μg / cm², about 15 μg / cm², about 20 μg / cm², about 50 μg / cm², or any range between the cited values) based on the active surface area at 24 hours after administration. Cumulative buprofen at concentrations of approximately 10 μg / cm², 15 μg / cm², 20 μg / cm², 50 μg / cm², 100 μg / cm², 200 μg / cm², 500 μg / cm², or any range between the cited values; and c) at concentrations of approximately 10 μg / cm² to approximately 1000 μg / cm² (e.g., approximately 10 μg / cm², 20 μg / cm², 50 μg / cm², 100 μg / cm², 200 μg / cm², 300 μg / cm², 400 μg / cm², 600 μg / cm², 1000 μg / cm², or 1000 μg / cm²) based on the active surface area 48 hours after administration. The cumulative permeation of buphenazine (or any range between the cited values). In some specific examples, the in vitro test is performed according to the method described in Example 6 of this application. Method of administering bufenozide

[0125] In various specific examples, the present invention further provides a method of using the transdermal delivery device or pharmaceutical composition described herein (e.g., the adhesive composition herein). In some specific examples, such transdermal delivery devices or pharmaceutical compositions may be used for any indication that inhibition of VMAT-2 is beneficial. In some specific examples, such transdermal delivery devices or pharmaceutical compositions may be used for the treatment or prevention of a VMAT-2-mediated disease or disorder. In some specific examples, such transdermal delivery devices or pharmaceutical compositions may be used for any indication that administration of buphenazine or deuterated buphenazine is beneficial. For example, in addition to indications for chorea associated with Huntington's disease, other indications approved for use or associated with buphenazine or deuterated buphenazine include hemiballismus, tic disorders, tardive dyskinesia, and Tourette syndrome. And in various specific examples, such transdermal delivery devices or pharmaceutical compositions may also be used for any of these indications.

[0126] In some specific examples, the present invention provides a method of administering buphenazine, deuterated buphenazine, or a combination thereof to an individual (e.g., a human individual) who requires it. In some specific examples, the method comprises administering either the transdermal delivery device or the pharmaceutical composition (e.g., the adhesive composition herein) to the individual, for example, to the individual's skin. In some specific examples, the individual (e.g., the human individual) is characterized as having a hyperkinetic disorder (e.g., a chronic hyperkinetic disorder). In some specific examples, the hyperkinetic disorder is selected from chorea associated with Huntington's disease, Wilson's disease, Tourette syndrome, restless legs syndrome, tardive dyskinesia, tic disorders, and combinations thereof. In some specific examples, the method comprises administering a transdermal delivery device comprising buphenazine (e.g., a substantially pure R,R-buphenazine). In some specific examples, the method includes the administration of a transdermal delivery device containing deuterated butylbenazine (e.g., a substantially pure R,R-deuterated butylbenazine).

[0127] In some specific examples, the present invention also provides a method for inhibiting VMAT-2 in an individual with a need for it. In some specific examples, the method comprises administering either such transdermal delivery device or pharmaceutical composition (e.g., the adhesive composition herein) to the individual, for example, to the individual's skin.

[0128] In some specific examples, the present invention also provides a method for treating a vesicle monoamine transporter isoform 2 (VMAT2)-mediated disease or disorder in an individual (e.g., a human individual) in need. In some specific examples, the method comprises administering either such transdermal delivery device or pharmaceutical composition (e.g., the adhesive composition herein) to the individual, for example, to the individual's skin. VMAT2-mediated diseases or disorders include, but are not limited to, hyperkinetic disorders (e.g., chronic hyperkinetic disorder), Huntington's disease, unilateral ballet, senile chorea, tic disorders, tardive dyskinesia, dystonia, Tourette syndrome, depression, cancer, rheumatoid arthritis, psychosis, multiple sclerosis, asthma, and / or any disorder that can be reduced, alleviated, or prevented by administering a VMAT2 inhibitor. In some specific cases, the VMAT2-mediated disease or disorder is tardive dyskinesia. In some specific cases, the VMAT2-mediated disease or disorder is Huntington's disease. In some specific cases, the VMAT2-mediated disease or disorder is unilateral ballet syndrome. In some specific cases, the VMAT2-mediated disease or disorder is Tourette syndrome.

[0129] In some specific examples, the present invention provides a method for treating a hyperkinetic disorder in an individual (e.g., a human individual) who has such a need. In some specific examples, the method comprises administering either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition herein) to the individual, for example, to the individual's skin. In some specific examples, the hyperkinetic disorder is a chronic hyperkinetic disorder. In some specific examples, the hyperkinetic disorder is chorea associated with Huntington's disease, Wilson's disease, Tourette syndrome, restless legs syndrome, tardive dyskinesia, and / or a seizure. In some specific examples, the hyperkinetic disorder is chorea associated with Huntington's disease. In some particular examples, the present invention provides a method for treating chorea associated with Huntington's disease in an individual in need, the method comprising administering any of the transdermal delivery devices or pharmaceutical compositions (e.g., adhesive compositions herein) to the individual, for example, to the individual's skin. In some particular examples, the present invention provides a method for treating tardive dyskinesia in an individual in need, the method comprising administering any of the transdermal delivery devices or pharmaceutical compositions (e.g., adhesive compositions herein) to the individual, for example, to the individual's skin. In some particular examples, the present invention provides a method for treating Tourette syndrome in an individual in need, the method comprising administering any of the transdermal delivery devices or pharmaceutical compositions (e.g., adhesive compositions herein) to the individual, for example, to the individual's skin. In some particular examples, the present invention provides a method for treating a seizure in an individual with a need, the method comprising administering either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition herein) to the individual, for example, to the individual's skin. In some particular examples, the present invention provides a method for treating unilateral ballet syndrome in an individual with a need, the method comprising administering either a transdermal delivery device or a pharmaceutical composition (e.g., an adhesive composition herein) to the individual, for example, to the individual's skin.

[0130] Bufenazine and / or a deuterated bufenazine (e.g., deuterated bufenazine) may be used in the methods herein. Typically, the method comprises administering a transdermal delivery device thereof comprising bufenazine or deuterated bufenazine as the sole active ingredient. In some specific examples, the method comprises administering a transdermal delivery device thereof containing substantially pure R,R-bufenazine (e.g., having substantially pure R,R-bufenazine as the sole active ingredient). In some specific examples, the method comprises administering a transdermal delivery device thereof containing substantially pure R,R-deuterated bufenazine (e.g., having substantially pure R,R-deuterated bufenazine as the sole active ingredient).

[0131] In any of the specific examples described herein, the method may include administering the drug (e.g., bubenazine or deuterated bubenazine) to the individual at a dose of about 0.1 mg / day / cm² to about 5 mg / day / cm² (e.g., about 0.1 mg / day / cm², about 0.2 mg / day / cm², about 0.5 mg / day / cm², about 1 mg / day / cm², about 2 mg / day / cm², about 5 mg / day / cm², or any range between these specific values), for example, during a time 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. However, in some specific examples, the method may include administering the drug (e.g., bubenazine or deuterated bubenazine) to the individual at a dose greater than about 5 mg / day / cm² (e.g., about 8 mg / day / cm², about 10 mg / day / cm², about 15 mg / day / cm², about 20 mg / day / cm², or any range between the cited values). In some specific examples, the method may also include administering the drug (e.g., bubenazine or deuterated bubenazine) to the individual at a dose less than about 0.1 mg / day / cm² (e.g., about 0.01 mg / day / cm², about 0.02 mg / day / cm², about 0.05 mg / day / cm², about 0.1 mg / day / cm², or any range between the cited values).

[0132] In some specific examples, the present invention provides a method for treating a vesicle monoamine transporter isoform 2 (VMAT2)-mediated disease or disorder in an individual (e.g., a human individual) in need, comprising transdermal administration of a therapeutically effective amount of bubenazine or deuterated bubenazine to the individual. Suitable VMAT2-mediated diseases or disorders are described herein.

[0133] Various advantages relate to the method described herein. For example, in some specific instances, the method reduces inter-individual variability in plasma levels of buphenazine or deuterated buphenazine or a metabolite thereof compared to an equivalent oral dose of buphenazine or deuterated buphenazine. In some specific instances, the method reduces the Cmax of buphenazine or deuterated buphenazine or a metabolite thereof (e.g., by 10%, 40%, 60%, or more) compared to an equivalent oral dose of buphenazine or deuterated buphenazine, for example, without reducing therapeutic efficacy. In some specific instances, the method provides similar plasma levels of buphenazine or deuterated buphenazine or a metabolite thereof when equivalent doses are administered to individuals genotyped as poor metabolizers (PM), intermediate metabolizers (IM), or extensive metabolizers (EM) based on CYP2D6 expression. In some specific instances, the same or substantially the same dose of buphenazine or deuterated buphenazine may be administered to individuals characterized as PM, IM, or EM. In some specific instances, the method described herein may administer the drug (e.g., buphenazine or deuterated buphenazine) percutaneously to the individual without considering whether the individual is characterized as PM, IM, or EM based on CYP2D6 expression. Exemplary transdermal delivery of bubenazine or deuterated bubenazine

[0134] In some specific examples, the bubenazine or deuterated bubenazine can be administered to an individual in need to achieve a therapeutic effect at a desired dose and / or have a suitable PK profile as described herein. Any of the transdermal delivery devices disclosed herein can be useful. In some specific examples, this disclosure provides the following specific examples SE1 to SE8.

[0135] SE1: A method of treating an ADHD in an individual with a need, comprising administering to the individual a transdermal delivery device (preferably, a transdermal delivery device comprising an adhesive-coated drug layer) as described herein, wherein the adhesive-coated drug layer comprises (1) an active ingredient containing R,R-butylbenazine, (2) a pressure-sensitive adhesive herein (e.g., a non-reactive acrylate pressure-sensitive adhesive); (3) an optional crystallization inhibitor; and (4) an optional antioxidant, wherein the transdermal delivery device is administered to transdermally deliver to the individual about 0.1 mg / day to about 20 mg / day of R,R-butylbenazine, for example, about 0.5 mg / day to about 10 mg / day of R,R-butylbenazine, about 0.5 mg / day to about 8 mg / day of R,R-butylbenazine, about 0.5 mg / day to about 6 mg / day of R,R-butylbenazine, about 0.5 mg / day to about 4 mg / day of R,R-butylbenazine, etc. R,R-bufenazine (approximately 1 mg / day to approximately 10 mg / day), R,R-bufenazine (approximately 1 mg / day to approximately 8 mg / day), R,R-bufenazine (approximately 1 mg / day to approximately 6 mg / day), R,R-bufenazine (approximately 1 mg / day to approximately 4 mg / day), R,R-bufenazine (approximately 2 mg / day to approximately 10 mg / day), R,R-bufenazine (approximately 2 mg / day to approximately 8 mg / day), R,R-bufenazine (approximately 2 mg / day to approximately 6 mg / day), R,R-bufenazine (approximately 2 mg / day to approximately 4 mg / day), R,R-bufenazine (approximately 4 mg / day to approximately 10 mg / day), R,R-bufenazine (approximately 4 mg / day to approximately 6 mg / day), R,R-bufenazine (approximately 6 mg / day to approximately 10 mg / day). mg / day of R,R-bufenazine, or about 6 mg / day to about 8 mg / day of R,R-bufenazine. In some specific examples according to SE1, the transdermal delivery device is administered to transdermally deliver to the individual about 0.5 mg / day to about 10 mg / day of R,R-bufenazine, about 0.5 mg / day to about 8 mg / day of R,R-bufenazine, or about 2 mg / day to about 6 mg / day of R,R-bufenazine. In some specific examples according to SE1, the adhesive package drug layer may include an optional penetration enhancer and / or a plasticizer.

[0136] SE2: A method for treating a hyperkinetic disorder in an individual with a need, the method comprising administering to the individual a percutaneous delivery device described herein (preferably, a percutaneous delivery device comprising an adhesive-coated drug layer), wherein the adhesive-coated drug layer comprises (1) an active ingredient containing R,R-butylbenazine, (2) a pressure-sensitive adhesive herein (e.g., a non-reactive acrylate pressure-sensitive adhesive); (3) an optional crystallization inhibitor; and (4) an optional antioxidant; wherein the percutaneous delivery device provides a therapeutically effective plasma concentration of R,R-butylbenazine, R,R,R-dihydrobutylbenazine (HTBZ), and S,R,R-HTBZ, wherein the maximum plasma concentration of R,R-butylbenazine is greater than that of R,R,R- The ratio of the maximum plasma concentrations of HTBZ and the combination of S,R,R-HTBZ is in the range of about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any range between the cited values ​​(e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.)) or the ratio of the steady-state plasma concentration of R,R-bubenazine to the steady-state plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ is in the range of about 1:1 to about 1:5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, or any range between the cited values ​​(e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.)). In some specific examples according to SE2, 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 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 cited values ​​(e.g., from about 1:10 to about 1:20, about 1:5 to about 1:15, etc.). In some specific examples according to SE2, the ratio of the maximum plasma concentration or steady-state plasma concentration of R,R-bufenazine:R,R,R-HTBZ:S,R,R-HTBZ is about 17-40:3-10:50-80. In some specific examples according to SE2, this administration can provide a pharmacokinetic profile characterized by: the AUC0-∞ of SRR-HTBZ being greater than that of R,R-bufenazine. The ratio is about 1 to about 15 (e.g., about 1.5 to about 11), and / or the ratio of the AUC0-∞ of RRR-HTBZ to the AUC0-∞ of R,R-bufenazine is about 0.1 to about 0.75 (e.g., about 0.15 to about 0.5). In some specific examples according to SE2, the dosing did not provide detectable S,S-bufenazine, R,S,S-HTBZ or S,S,S-HTBZ in the individual's plasma.In some specific examples according to SE2, the PK profile is characterized by a mean final half-life of approximately 8.5 hr ± 40% CV for R,R-bubenazine. In some specific examples according to SE2, the adhesive coating drug layer may include an optional penetration enhancer and / or a plasticizer. In some specific examples according to SE2, the transdermal delivery device is administered for transdermal delivery to the individual at any of the daily doses described in SE1. In some specific examples according to SE2, the transdermal delivery device is administered to achieve any of the PK profiles described herein in any combination.

[0137] SE3: A method for treating a hyperkinetic disorder in an individual with a need, comprising administering to the individual a transdermal delivery device described herein (preferably, a transdermal delivery device comprising an adhesive-coated drug layer), wherein the adhesive-coated drug layer comprises (1) an active ingredient containing R,R-buphenazine, (2) a pressure-sensitive adhesive herein (e.g., a non-reactive acrylate pressure-sensitive adhesive); (3) an optional crystallization inhibitor; and (4) an optional An antioxidant, wherein the transdermal delivery device is administered to the individual to achieve a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ for at least 6 hours or at least 12 hours, preferably, at least 24 hours (e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours, or more). In some specific embodiments according to SE3, the adhesive package drug layer may include an optional penetration enhancer and / or a plasticizer. In some specific embodiments according to SE3, the transdermal delivery device is administered to deliver transdermally to the individual any of the daily doses described in SE1. In some specific embodiments according to SE3, the transdermal delivery device is administered to achieve any of the PK profiles in the individual described in SE2.

[0138] SE4: A method of treating an ADHD in an individual in need, comprising administering to the individual a transdermal delivery device described herein (preferably, a transdermal delivery device comprising an adhesive-coated drug layer), wherein the adhesive-coated drug layer comprises (1) an active ingredient containing R,R-buphenazine, (2) a pressure-sensitive adhesive herein (e.g., a non-reactive acrylate pressure-sensitive adhesive); (3) an optional crystallization inhibitor; and (4) an optional antioxidant, wherein the transdermal delivery device is administered to the individual to achieve a substantially constant steady-state plasma concentration of R,R-buphenazine at 150 pg / ml or higher for a duration of at least 6 hours or at least 12 hours, preferably at least 24 hours (e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours or more). In some specific examples according to SE4, the transdermal delivery device is administered to the individual to achieve a substantially constant steady-state plasma concentration of R,R-bufenazine from more than 150 pg / ml to about 3000 pg / ml for the duration of the duration, wherein the plasma concentration of R,R-bufenazine does not vary significantly (e.g., by more than 2-fold) during any of the 4-hour, 8-hour, and / or 12-hour intervals of the duration. In some specific examples according to SE4, during the duration, the ratio of the lowest plasma concentration of R,R-bufenazine to the highest plasma concentration of R,R-bufenazine is not less than about 0.4 (such as about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1), or in any range between the cited values. In some specific examples according to SE4, the adhesive package drug layer may include an optional penetration enhancer and / or a plasticizer. In some specific examples according to SE4, the transdermal delivery device is applied to deliver transdermally to the individual any of the daily doses described in SE1. In some specific examples according to SE4, the transdermal delivery device is applied to achieve any of the PK profiles in the individual described in SE2.

[0139] SE5: A method of treating a hyperkinetic disorder in an individual with a need, comprising administering to the individual a transdermal delivery device (preferably, a transdermal delivery device comprising an adhesive-coated drug layer) as described herein, wherein the adhesive-coated drug layer comprises (1) an active ingredient containing a deuterated R,R-butylbenazine, (2) a pressure-sensitive adhesive herein (e.g., a non-reactive acrylate pressure-sensitive adhesive); (3) an optional crystallization inhibitor; and (4) an optional antioxidant, wherein the transdermal delivery device is administered to transdermally deliver to the individual about 0.1 mg / day to about 20 mg / day of deuterated R,R-butylbenazine, for example, about 0.5 mg / day to about 10 mg / day of deuterated R,R-butylbenazine, about 0.5 mg / day to about 8 mg / day of deuterated R,R-butylbenazine, about 0.5 mg / day to about 6 mg / day of deuterated R,R-butylbenazine, or about 0.5 mg / day to about 6 mg / day of deuterated R,R-butylbenazine. R-butylbenazine (r. 0.5 mg / day to about 4 mg / day), R-butylbenazine (r. 1 mg / day to about 10 mg / day), R-butylbenazine (r. 1 mg / day to about 8 mg / day), R-butylbenazine (r. 1 mg / day to about 6 mg / day), R-butylbenazine (r. 1 mg / day to about 4 mg / day), R-butylbenazine (r. 2 mg / day to about 10 mg / day), R-butylbenazine (r. 2 mg / day to about 8 mg / day), R-butylbenazine (r. 2 mg / day to about 6 mg / day), R-butylbenazine (r. 2 mg / day to about 4 mg / day), R-butylbenazine (r. 4 mg / day to about 10 mg / day). The dosage is approximately 4 mg / day to approximately 8 mg / day of deuterated R,R-butylbenazine, approximately 4 mg / day to approximately 6 mg / day of deuterated R,R-butylbenazine, approximately 6 mg / day to approximately 10 mg / day of deuterated R,R-butylbenazine, or approximately 6 mg / day to approximately 8 mg / day of deuterated R,R-butylbenazine. In some specific embodiments according to SE5, the transdermal delivery device is applied to transdermally deliver approximately 0.5 mg / day to approximately 10 mg / day of deuterated R,R-butylbenazine, approximately 0.5 mg / day to approximately 8 mg / day of deuterated R,R-butylbenazine, or approximately 2 mg / day to approximately 6 mg / day of deuterated R,R-butylbenazine to the individual. In some specific embodiments according to SE5, the adhesive coating drug layer may include an optional penetration enhancer and / or a plasticizer.

[0140] SE6. A method of treating a hyperkinetic disorder in an individual with a need, the method comprising administering to the individual a percutaneous delivery device described herein (preferably, a percutaneous delivery device comprising an adhesive-coated drug layer), wherein the adhesive-coated drug layer comprises (1) an active ingredient containing a deuterated R,R-butylbenazine, (2) a pressure-sensitive adhesive herein (e.g., a non-reactive acrylate pressure-sensitive adhesive); (3) an optional crystallization inhibitor; and (4) an optional antioxidant, wherein the percutaneous delivery device provides a therapeutically effective plasma concentration of deuterated R,R-butylbenazine, and the dihydrobutylbenazine metabolites of the deuterated R,R-butylbenazine (deuterated R,R,R-HTBZ and deuterated S,R,R-H). (TBZ), wherein the ratio of the maximum plasma concentration of the deuterated R,R-butylbenazine to the maximum plasma concentration of the combination of the deuterated R,R,R-HTBZ and the deuterated S,R,R-HTBZ is in the range of about 1:1 to about 1:7.5 (e.g., about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, about 1:7.5 or any range between the cited values ​​(e.g., about 1:1 to about 1:3, about 1:2 to about 1:4, etc.)), or the ratio of the steady-state plasma concentration of the deuterated R,R-butylbenazine to the maximum plasma concentration of the combination of the deuterated R,R,R-HTBZ and the deuterated S,R,R-HTBZ is in the range of about 1:1 to about 1:7.5. In some specific examples according to SE6, the ratio of the maximum plasma concentration of deuterated R,R,R-HTBZ to deuterated S,R,R-HTBZ can range from about 1:5 to about 1:30 (e.g., about 1:5, about 1:7, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, or any range between the cited values ​​(e.g., from about 1:10 to about 1:20, about 1:5 to about 1:15, etc.)). In some specific examples according to SE6, the ratio of the maximum plasma concentration or steady-state plasma concentration of deuterated R,R-butylbenazine: deuterated R,R,R-HTBZ: deuterated S,R,R-HTBZ can range from about 14-40:3-11:50-85. In some specific examples according to SE6, the dosing provides a pharmacokinetic profile characterized in that the ratio of the AUC0-∞ of deuterated SRR-HTBZ to the AUC0-∞ of deuterated R,R-bufenazine is about 1 to about 15 (e.g., about 1.5 to about 11), and / or the ratio of the AUC0-∞ of deuterated RRR-HTBZ to the AUC0-∞ of deuterated R,R-bufenazine is about 0.1 to about 0.75 (e.g., about 0.15 to about 0.5). In some specific examples according to SE6, the dosing does not provide detectable deuterated S,S-bufenazine, deuterated R,S,S-HTBZ, or deuterated S,S,S-HTBZ in the individual's plasma.In some specific examples according to SE6, the PK profile is characterized by a mean final half-life of deuterated R,R-bubenazine of approximately 8.5 hr ± 40% CV. In some specific examples according to SE6, the adhesive coating drug layer may include an optional penetration enhancer and / or a plasticizer. In some specific examples according to SE6, the transdermal delivery device is administered for transdermal delivery to the individual at any of the daily doses described in SE5. In some specific examples according to SE6, the transdermal delivery device is administered to achieve any of the PK profiles described herein.

[0141] SE7: A method of treating a hyperkinetic disorder in an individual with a need, comprising administering to the individual a transdermal delivery device described herein (preferably, a transdermal delivery device comprising an adhesive-coated drug layer), wherein the adhesive-coated drug layer comprises (1) an active ingredient containing deuterated R,R-butylbenazine, (2) a pressure-sensitive adhesive herein (e.g., a non-reactive acrylate pressure-sensitive adhesive); (3) an optional crystallization inhibitor; and (4) an optional antioxidant, wherein the transdermal delivery device ...5) an optional crystallization inhibitor; and (6) an optional crystallization inhibitor; wherein the transdermal delivery device comprises (1) an active ingredient containing deuterated R,R-butylbenazine, (2) a pressure-sensitive adhesive herein (e.g., a non-reactive acrylate pressure-sensitive adhesive); (7) an optional crystallization inhibitor; and (8) an optional crystallization inhibitor; wherein the transdermal delivery device comprises (1) an active ingredient containing deuterated R The transdermal delivery device is administered to the individual to achieve a therapeutically effective plasma concentration of deuterated R,R-bufenazine, and its dihydrobufenazine metabolites (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 (e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours or more). In some specific embodiments according to SE7, the adhesive package drug layer may include an optional penetration enhancer and / or a plasticizer. In some specific embodiments according to SE7, the transdermal delivery device is administered to deliver transdermally to the individual any of the daily doses described in SE5. In some specific embodiments according to SE7, the transdermal delivery device is administered to achieve any of the PK profiles described in SE6.

[0142] SE8: A method of treating a hyperkinetic disorder in an individual with a need, comprising administering to the individual a percutaneous delivery device described herein (preferably, a percutaneous delivery device comprising an adhesive-coated drug layer), wherein the adhesive-coated drug layer comprises (1) an active ingredient containing a deuterated R,R-butylbenazine, (2) a pressure-sensitive adhesive herein (e.g., a non-reactive acrylate pressure-sensitive adhesive); (3) an optional crystallization inhibitor; and (4) an optional antioxidant, wherein the percutaneous delivery device is administered to the individual to achieve a substantially constant steady-state plasma concentration of the deuterated R,R-butylbenazine at 150 mg / L. The concentration of R,R-butylbenazine is above pg / ml for a duration of at least 6 hours or at least 12 hours, preferably at least 24 hours (e.g., at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 168 hours, at least 192 hours or more). In some specific examples according to SE8, the transdermal delivery device is administered to the individual to achieve a substantially constant steady-state plasma concentration of R,R-butylbenazine deuterated at a concentration of at least 150 pg / ml to about 3000 pg / ml for the duration, wherein the plasma concentration of R,R-butylbenazine deuterated does not change significantly (e.g., by more than 2-fold) during 4-hour, 8-hour and / or 12-hour intervals of the duration. In some specific examples according to SE8, during this duration, the ratio of the lowest plasma concentration of deuterated R,R-butylbenazine to the highest plasma concentration of deuterated R,R-butylbenazine is not less than 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 cited values). In some specific examples according to SE8, the adhesive package drug layer may include an optional penetration enhancer and / or a plasticizer. In some specific examples according to SE8, the transdermal delivery device is applied to transdermally deliver the drug to the individual at any of the daily doses described in SE5. In some specific examples according to SE8, the transdermal delivery device is applied to achieve any of the PK profiles of the individual described in SE6.

[0143] Any of the transdermal delivery device designs described herein can be used in the methods described herein. Typically, with respect to any of the specific examples according to SE1 to SE8, the transdermal delivery device may be a DIA patch comprising the adhesive-coated drug layer, a backing layer, and a release liner protecting the adhesive before use. The adhesive-coated drug layer typically comprises the active ingredient dispersed (preferably, uniformly dispersed) in the adhesive. In some specific examples, the transdermal delivery device is administered to the individual to deliver approximately 0.1 mg / day to approximately 20 mg / day of R,R-bufenazine (e.g., any of the exemplary ranges described herein) at a substantially constant rate for up to 24 hours, up to 48 hours, up to 96 hours, or up to 1 week after administration. Suitable compositions for the adhesive-coated drug layer include any of the adhesive compositions described herein, such as those applicable to buphenazine or deuterated buphenazine, or any of the specific compositions shown in the Examples section (e.g., Example 4A) as described in Specific Examples 1-18. In some specific examples, the adhesive-coated drug layer comprises the active ingredient dispersed in a non-reactive acrylate pressure-sensitive adhesive. The active ingredient may be present in an amount of about 1% to about 20% by weight (such as about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 10%, about 15%, about 20%, or in any range between the cited values ​​(e.g., about 1% to about 15%, about 2% to about 15%, about 2% to about 10%, about 2% to about 7%, about 3% to about 15%, about 3% to about 10%, about 3% to about 7%, about 5% to about 15%, about 5% to about 10%, about 5% to about 7%, about 7% to about 15%, about 7% to about 10%, about 10% to about 20%, about 10% to about 15%, etc.)). In some specific examples, the adhesive coating drug layer contains a substantially pure R,R-isomer of butylbenazine as the sole active ingredient. In some specific examples, the adhesive coating drug layer contains a substantially pure deuterated R,R-isomer of butylbenazine as the sole active ingredient. Typically, the R,R-isomer of butylbenazine or the deuterated R,R-isomer of butylbenazine exists in its free base form. Suitable adhesives include any of those described herein, such as any of the pressure-sensitive adhesives described herein. In some specific examples, the adhesive may be a non-reactive acrylate pressure-sensitive adhesive described herein (such as Duro-Tak 87-900A) or as described in exemplary examples 2-7.The adhesive is typically present in an amount of about 50% to about 97% by weight (such as about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 97%, or in any range between the cited values ​​(e.g., about 50% to about 95%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, about 50% to about 60%, about 60% to about 97%, about 60% to about 95%, about 60% to about 90%, about 60% to about 80%, about 60% to about 70%, about 70% to about 97%, about 70% to about 95%, about 70% to about 90%, about 70% to about 80%, about 80% to about 97%, about 80% to about 95%, about 80% to about 90%, etc.). In some particular specific examples, The active ingredient is present in an amount of about 2% to about 7% by weight, and the non-reactive acrylate pressure-sensitive adhesive is present in an amount of about 50% to about 97% by weight. The adhesive composition may also optionally include other components, such as an antioxidant, a crystallization inhibitor, a plasticizer, and / or a penetration enhancer. In some specific examples, the adhesive coating layer includes an antioxidant, such as a gallate antioxidant (e.g., propyl gallate). The amount of antioxidant is typically from about 0% to about 1% by weight. The amount included is in quantities such as about 0.001%, about 0.01%, about 0.1%, about 0.5%, about 1%, or any range between the cited values ​​(e.g., about 0.001% to about 0.5%, about 0.01% to about 0.5%, etc., by weight). In some specific examples, the adhesive package drug layer includes a crystallization inhibitor, for example, a method to prevent the formation of drug crystals (crystallization of the active ingredient (such as R,R-bufenazine) of the adhesive composition) after shelf storage at ambient temperature for 2 weeks.In some specific examples, the adhesive composition includes a crystallization inhibitor selected from the following: a polyvinylpyrrolidone polymer (e.g., Kollidon K30 or K90F (manufactured by BASF), Plasdone K20 / 32 or Plasdone K90 (manufactured by Ashland Chemical)), a crosslinked polyvinylpyrrolidone polymer (e.g., Kollidon CL), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 copolyvinylpyrrolidone (Asland)), a cellulose-based polymer (e.g., hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose), a polycarboxylic acid polymer (e.g., carbomer (manufactured by Lubrizol)), a polymethacrylate (e.g., Plastoid B, Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, a graft copolymer based on polyvinyl acetate and polyvinylcaprolactam (PVAc-PVCap- PEG) (e.g., Soluplus (BASF), and combinations thereof. In some specific examples, the adhesive coating drug layer includes a crystallization inhibitor selected from: polymethacrylate (e.g., Plastoid B (a copolymer of butyl methacrylate and methyl methacrylate), Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol, and graft copolymers based on polyvinyl acetate and polyvinyl caprolactam (PVAc-PVCap-PEG) (e.g., Soluplus). (BASF), and combinations thereof. The crystallization inhibitor is typically present in a concentration of about 0% to about 40% by weight (such as about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, or in any range between the cited values ​​(e.g., about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, 15% to about 40%, about 15% to about 30%, about 15% to about 20%, 20% to about 40%, about 20% to about 30%, etc.) by weight. The amount of the drug layer (as described herein) is present. In some specific examples, the adhesive pack drug layer may also contain a skin penetration enhancer as described herein, such as isopropyl myristate. In some specific examples, the adhesive pack drug layer may also not contain a skin penetration enhancer as described herein; for example, in some specific examples, the adhesive pack drug layer may also not contain isopropyl myristate. The weight and thickness of the adhesive pack drug layer may vary depending on various factors (such as drug concentration, desired dosage, and duration of administration).The adhesive-coated drug layer is typically designed for application (e.g., delivery of R,R-butylbenazine or deuterated R,R-butylbenazine) over a time 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 specific examples, the adhesive-coated drug layer may have a coating weight with an active surface area of ​​about 0.1 g / cm² to about 5 g / cm², such as about 0.1 g / cm² to about 0.90 g / cm² (e.g., about 0.1 g / cm² to about 0.5 g / cm²). In some specific examples, the active surface area may be from about 5 cm² to about 100 cm² (other suitable ranges are described herein). In some specific examples, the adhesive-coated drug layer may have a thickness of about 1.5 mils to about 10 mils, such as about 1.5 mils to about 3.5 mils (e.g., about 2 mils to about 3.5 mils). In some specific examples, the transdermal delivery device may also be configured to have any of the in vitro throughput characteristics described herein.

[0144] The hyperactive motor disorder cited in the methods according to any of SE1 to SE8 includes any of those described herein. Non-restrictive examples include Huntington's disease, Wilson's disease, Tourette's disease, restless legs syndrome, tardive dyskinesia, tic disorders, dyskinesia-type cerebral palsy, other hypotonia and dyskinesia disorders, and combinations thereof. In some specific examples, the hyperactive motor disorder may be Huntington's disease, such as chorea associated with Huntington's disease. In some specific examples, the hyperactive motor disorder may be Wilson's disease. In some specific examples, the hyperactive motor disorder may be Tourette's disease. In some specific examples, the hyperactive motor disorder may be restless legs syndrome. In some specific examples, the hyperactive motor disorder may be tardive dyskinesia. In some specific examples, the hyperactive motor disorder may be tic disorders. In some specific cases, this hyperactive motor disorder can be a motor disorder-type cerebral palsy. In some specific cases, this hyperactive motor disorder is a hypotonia or motor disorder.

[0145] Treatment methods based on any of SE1 to SE8 are not limited to any particular type of individual. For example, the method described herein may be administered to the individual regardless of their eating status. In some specific instances, the individual is a pediatric or adolescent patient (e.g., 6 to 18 years old). Also, in some specific instances, the method is not limited to any particular genotyped individual. In some specific instances, the same dose or substantially the same dose of R,R-bufenazine or a deuterated R,R-bufenazine may be administered to an individual characterized as PM, IM, or EM. In some specific instances, the individual is characterized as EM. In some specific instances, the individual is characterized as PM. In some specific instances, the individual is characterized as IM. In some specific instances, the method does not require dose titration and / or genotyping analysis, which is required when the individual is treated with either Xenazine® or Austedo™ tablets.

[0146] The administration regimens for therapeutic purposes according to any of SE1 to SE8 are not particularly limited, provided that the desired dose of R,R-bufenazine or deuterated R,R-bufenazine is delivered to the individual at a desired rate for a desired period of time, including any of those described herein. For example, in some specific examples, the transdermal delivery device is administered to the individual in an administration regimen suitable for achieving the PK profile described herein. In some specific examples, the transdermal delivery device is administered to the individual once daily. In some specific examples, the transdermal delivery device is administered to the individual more than once daily, such as 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 specific examples, with respect to each application, the transdermal delivery device may be applied to the individual's skin to adhere to the individual's skin for approximately 8 hours, approximately 12 hours, approximately 24 hours, approximately 36 hours, approximately 48 hours, approximately 72 hours, approximately 96 hours, approximately 120 hours, approximately 144 hours, approximately 168 hours, approximately 192 hours, or any range between the cited values, continuously or substantially continuously delivering R,R-bufenazine to the individual during the patch application period. In some specific examples, depending on the dosing frequency herein, there is no lag time between two consecutive applications of the transdermal patch. For example, in some specific examples, the transdermal delivery device is applied to the individual once a day, and each application of the transdermal delivery device may continue (adhering to the individual's skin) for approximately 24 hours before it is replaced by another typically substantially identical transdermal delivery device. However, in some specific examples, there may also be overlap or lag between two consecutive applications. Combination therapy

[0147] The methods described herein may use bubenazine and / or deuterated bubenazine as the sole active ingredients(s). In other words, the methods described herein may be used as a single treatment. However, in some specific instances, the methods described herein may also be used in combination with one or more additional treatments. Such transdermal delivery methods, devices, and pharmaceutical compositions for combination therapy are illustrated below as examples.

[0148] In some specific examples, the transdermal delivery devices or pharmaceutical compositions disclosed herein (e.g., the adhesive composition herein) may also be used in combination with or in combination with other agents useful in treating VMAT2-mediated diseases. These other agents may be administered simultaneously or sequentially with the transdermal delivery devices or pharmaceutical compositions disclosed herein (e.g., the adhesive composition herein) via a route and in an amount therefore commonly used. In some specific examples, these other agents are included in the transdermal delivery devices or pharmaceutical compositions disclosed herein (e.g., the adhesive composition herein). However, in some specific examples, these other agents are administered as a separate composition or otherwise independently of the transdermal delivery devices or pharmaceutical compositions disclosed herein (e.g., the adhesive composition herein).

[0149] In some specific examples, the transdermal delivery devices or pharmaceutical compositions disclosed herein (e.g., the adhesive compositions herein) may be used in combination with one or more antipsychotics, including, but not limited to, chlorpromazine, levomepromazine, promazine, acepromazine, triflupromazine, cyamemazine, chlorproethazine, and dixyrazine. e) Fluphenazine, perphenazine, prochlorperazine, thiopropazate, trifluoperazine, acetophenazine, thioproperazine, butaperazine, perazine, periciazine, thioridazine, mesoridazine Pipotiazine, haloperidol, trifluperidol, melperone, moperone, pipamperone, bromperidol, benperidol, droperidol, fluanisone, oxypertine, molindone, sertindole, ziprasidone, flupentixol, clopenthixol, chlorprothixeneThiothixene, zuclopenthixol, fluspirilene, pimozide, penfluridol, loxapine, clozapine, olanzapine, quetiapine, bubenazine, sulpiride, sultopride, tiapride, remoxipride, amisulpride, veralipride, levosulpiride, lithium, prothipendyl, risperidone, clotiapine, mosapramine, zotepine, pripiprazole, and paliperidone.

[0150] In some specific examples, the transdermal delivery devices or pharmaceutical compositions disclosed herein (e.g., the adhesive composition herein) may be used in combination with one or more benzodiazepines (“less tranquilizers”), including, but not limited to, alprazolam, adinazolam, bromazepam, carbamazepam, clobazam, clonazepam, clotiazepam, cloxazolam, diazepam, and ethyl chlorofluorocarbonate. The following drugs are listed: loflazepate, estizolam, fludiazepam, flunitrazepam, halazepam, ketazolam, lorazepam, medazepam, dazolam, nitrazepam, nordazepam, oxazepam, potassium clorazepate, pinazepam, prazepam, tofisopam, triazolam, temazepam, and chlordiazepoxide.

[0151] In some specific instances, the transdermal delivery devices or pharmaceutical compositions disclosed herein (e.g., the adhesive composition herein) may be used in combination with olanzapine or pimozide.

[0152] In some specific examples, the transdermal delivery devices or pharmaceutical compositions disclosed herein (e.g., the adhesive composition herein) may be used in combination with other kinds of compounds, including, but not limited to, anti-retroviral agents; CYP3A inhibitors; CYP3A inducers; protease inhibitors; adrenergic agonists; anticholinergics; mast cell stabilizers; xanthines; leukotriene antagonists; glucocorticoid treatments; local or general anesthetics; non-steroidal anti-inflammatory agents (NSAIDs), such as naproxen; antibacterial agents (such as amoxicillin); cholesterol ester transfer protein, CETP inhibitors, such as anacetrapib; antifungal agents, such as isoconazole; sepsis treatments, such as drotrecogin-α; steroids, such as hydrocortisone; local or general anesthetics, such as ketamine; norepinephrine reuptake inhibitors (NRIs), such as atomoxetine; dopamine reuptake inhibitors (DARIs), such as methylphenidate; serotonin-norepinephrine reuptake inhibitors (SNRIs), such as milnacipran; sedatives, such as diazepam; norepinephrine-dopamine reuptake inhibitors... NDRIs, such as bupropion;Serotonin-norepinephrine-dopamine-reuptake inhibitors (SDRIs), such as venlafaxine; monoamine oxidase inhibitors, such as selegiline; hypothalamic phospholipids; endothelin-converting enzyme (ECE) inhibitors, such as phosphoramidon; opioids, such as tramadol; thromboxane receptor antagonists, such as ifetroban; potassium channel openers; thrombin inhibitors, such as hirudin; hypothalamic phospholipids; growth factor inhibitors, such as regulators of PDGF activity; platelet-activating factor (PDGF). Activating factor (PAF) antagonists; antiplatelet agents, such as GPIIb / IIIa blockers (e.g., abdximab, eptifibatide, and tirofiban), P2Y (AC) antagonists (e.g., clopidogrel, ticlopidine, and CS-747), and aspirin; anticoagulants, such as warfarin; low molecular weight heparins, such as enoxaparin; factor VIIa and factor Xa inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemoptrilat;HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (aka itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, atorvastatin, or vesastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP inhibitors; and calcium channel blockers, such as amlodipine besylate. 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, trichloroomethiazide, polythiazide, benzothiazide, ethacrynic acid. The following are listed: acid, trinicafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride, and spironolactone;Thrombolytic agents, such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); anti-diabetic agents, such as biguanides (e.g., metformin) and glucosidase inhibitors. Inhibitors (e.g., acarbose), insulin, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; αP2 inhibitors; phosphodiesterase inhibitors, such as PDEs. III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, vardenafil); protein tyrosine kinase inhibitors; anti-inflammatory drugs.Antiproliferatives, such as methotrexate, FK506 (tacrolimus, Prograf), and mycophenolate mofetil); chemotherapeutic agents; immunosuppressants; anticancer agents and cytotoxic agents (e.g., alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes); antimetabolites, such as folate antagonists, purine analogues, and pyrridine analogues. Analogous substances; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L-asparaginase; farnesyl-protein transferase inhibitors; hormone agents, such as glucocorticoids (e.g., cortisone, estrogen / antiestrogens, androgens / antiandrogens, progestins, and luteinizing hormone-releasing hormone anatagonists, and octreotide acetate); microtubule-disruptors. Agents, such as ecteina scidins; microtubule-stablizing agents, such as pacitaxel, docetaxel, and epothilones AF;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 agents, such as azathiprine and cyclophosphamide; TNF-α inhibitors (such as tenidap); anti-TNF antibodies or soluble TNF receptors, such as etanercept, rapamycin, and leflunimide; and cyclooxygenase-2 (COP2). COX-2 inhibitors, such as celecoxib and rofecoxib; and various reagents such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, and platinum coordination complexes (such as cisplatin, satraplatin, and carboplatin).

[0153] In some specific examples, the transdermal delivery devices or pharmaceutical compositions disclosed herein (e.g., the adhesive composition herein) may be used in combination with dextromethorphan and / or a cannabinoid (such as cannabidiol). definition

[0154] As used herein, the term "about" modifying a quantity relating to this invention means that it may occur, for example, through routine testing and operation; through unintentional errors in such testing and operation; through differences in the manufacture, origin, or purity of the ingredients / materials used in this invention; and similar variations in quantity. As used herein, "about" also includes a specific value, for example, about 10% includes 10%. Whether or not modified by the term "about," the claims include equivalents of the cited quantity. In one specific example, the term "about" means within 20% of the reported value.

[0155] As used herein, the “coating weight” of a drug layer means the weight of the drug layer (e.g., an adhesive pack drug layer or a reservoir pack drug layer) per unit area of ​​the active surface area of ​​a transdermal drug delivery system.

[0156] As used herein, the term "cumulative drug permeation" means the total amount of drug permeated per square centimeter during a given time period. Unless otherwise apparent from the context, "cumulative drug permeation" at a specific time (e.g., 24 hours after administration) means the total amount of drug permeated per square centimeter from time 0 (i.e., the time of administration) to the given time. Unless otherwise apparent from the context, "cumulative drug permeation" means the arithmetic mean measured and / or calculated according to the methods described herein. Unless contrary to common practice in the art, the term "mean" as used herein also means the arithmetic mean when not specified.

[0157] As used herein, the term "flux" means the amount of drug that penetrates the skin per unit area per unit time. Unless otherwise apparent from the context, "flux" means the arithmetic mean measured and / or calculated according to the methods described herein. A typical unit of flux is milligrams per square centimeter per hour.

[0158] The flux rate, as referenced in this patent application, can refer to a method measured in vivo or in vitro. One way to measure flux is to place a transdermal delivery device or formulation on a known area of ​​skin of a human volunteer and measure how much drug can penetrate through the skin within a certain time limit. In some specific examples, when specifically referenced to an in vitro method using human cadaver skin, the flux rate is measured according to the method described in Examples 3 or 6. Although an in vitro method uses a human epidermal membrane obtained from a cadaver, rather than using human volunteers, to measure the drug flux through the skin, it is generally accepted by those skilled in the art because a properly designed and performed in vitro test can be used to estimate or predict the results of an in vivo test with reasonable reliability.

[0159] The terms “skin flux characteristics” and “flux characteristics” are used interchangeably here.

[0160] As used herein, the terms “treat,” “treating,” “treatment,” and similar terms mean the elimination, reduction, or improvement of a disease or condition, and / or related symptoms. While it is not excluded that the complete elimination of the disease, condition, or symptoms associated with it is necessary to treat a disease or condition.

[0161] As used herein, the term "therapeutic effective amount" means an amount of a therapeutic agent (e.g., bubenazine) sufficient to cause improvement of one or more symptoms of a disease or condition (e.g., Huntington's disease), or to prevent the onset or progression of a disease or condition, or to induce recovery or cure of a disease or condition.

[0162] The term “individual” as used here (or alternatively, “patient”) refers to an animal, preferably a mammal, and most preferably a human being who is the subject of treatment, observation or experimentation.

[0163] The transdermal delivery device used here, for the administration or delivery of drugs, should be understood as being in accordance with how the transdermal delivery device is properly administered or delivered, for example, to the skin of a human individual.

[0164] The term "chronic hyperkinetic disorder" refers to a disorder characterized by purposeless, repetitive, and disordered motor behaviors, which are variously referred to as "compulsive," "rhythmic," or "stereotypical." In humans, chronic hyperkinetic disorders can be psychogenic (e.g., tic disorders), spontaneous (e.g., Tourette syndrome and Parkinson's disease), hereditary (e.g., the chorea aspect of Huntington's disease), infectious (e.g., Sydenham's Chorea), or, as in tardive dyskinesia, drug-induced. Unless otherwise stated, "chronic hyperkinetic disorder" means and includes all psychogenic, spontaneous, hereditary, and drug-induced motor disorders.

[0165] The term "stereotyped" refers to a repetitive behavior that occurs repeatedly with slight variations, or less frequently, like a complex series of movements.

[0166] The term “VMAT2” refers to vesicle monoamine transporter 2, an intact membrane protein that functions to transport monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from the cytoplasm into synaptic vesicles.

[0167] The term "VMAT2-mediated disorder" refers to a disorder characterized by abnormal VMAT2 activity. A VMAT2-mediated disorder can be completely or partially mediated by the regulation of VMAT2. In particular, a VMAT2-mediated disorder is one in which the inhibition of VMAT2 leads to some effect on the underlying disorder; for example, administration of a VMAT2 inhibitor leads to some improvement in at least some patients to be treated. Exemplary Specific Examples 1-30

[0168] The following show some exemplary examples of this disclosure (Examples 1-30). Specific Example 1. An adhesive composition comprising: An active ingredient is dispersed in a non-reactive acrylate pressure-sensitive adhesive. The active ingredient is selected from buphenazine, deuterated buphenazine, or a combination thereof. The non-reactive acrylate pressure-sensitive adhesive is present in an amount of approximately 50% to approximately 97% by weight. Specific Example 2. The adhesive composition of Specific Example 1, wherein the non-reactive acrylate pressure-sensitive adhesive does not have a functional group containing a reactive hydrogen moiety. Specific Example 3. The adhesive composition of Specific Example 1, wherein the non-reactive acrylate pressure-sensitive adhesive does not have a functional group selected from epoxy, –OH, –COOH, and combinations thereof. Specific Example 4. An adhesive composition of any of Specific Examples 1-3, wherein the non-reactive acrylate pressure-sensitive adhesive is a copolymer of alkyl acrylates. Specific Example 5. An adhesive composition of any of Specific Examples 1-3, wherein the non-reactive acrylate pressure-sensitive adhesive is a copolymer of C2-C18 alkyl acrylates (preferably C4-C10 branched or linear alkyl acrylates) and methyl acrylate, and selectively one or more acrylamide monomers (e.g., tertiary octyl acrylamide) that do not have functional groups selected from epoxy, –OH, –COOH and combinations thereof. Specific Example 6. An adhesive composition of any of Specific Examples 1-3, wherein the non-reactive acrylate pressure-sensitive adhesive is a copolymer of hexyl ethyl acrylate (e.g., 2-ethylhexyl acrylate) and methyl acrylate, and selectively one or more acrylamide monomers (e.g., tertiary octyl acrylamide) that do not have functional groups selected from epoxy, –OH, –COOH and combinations thereof. Specific Example 7. An adhesive composition of any of Specific Examples 1-6, wherein the non-reactive acrylate pressure-sensitive adhesive is free of or substantially free of vinyl acetate. Specific Example 8. The adhesive composition of any of Specific Examples 1-7 does not contain a penetration enhancer. Specific Example 9. The adhesive composition of any of Specific Examples 1-7, which does not contain isopropyl myristate. Specific Example 10. The adhesive composition of any of Specific Examples 1-7 does not contain a penetration enhancer selected from fatty alcohols, fatty acids, fatty esters, and combinations thereof. Specific Example 11. An adhesive composition of any of Specific Examples 1-10, wherein the active ingredient is present in an amount of about 2% to about 7% by weight. Specific Example 12. An adhesive composition of any of Specific Examples 1-11, further comprising a gallic acid ester antioxidant. Specific Example 13. An adhesive composition of any of Specific Examples 1-11, further comprising propyl gallate, for example, in an amount of about 0.001% to about 0.5% by weight. Specific Example 14. An adhesive composition of any of Specific Examples 1-13, further comprising a crystallization inhibitor in an amount effective in preventing drug crystallization after shelf storage at ambient temperature for 2 weeks. Specific Example 15. The adhesive composition of any of Specific Examples 1-13 further comprises a crystallization inhibitor selected from: a polyvinylpyrrolidone polymer (e.g., Kollidon K30 or K90F (manufactured by BASF), Plasdone K20 / 32 or Plasdone K90 (manufactured by Ashland Chemical)), a crosslinked polyvinylpyrrolidone polymer (e.g., Kollidon CL), a polyvinylpyrrolidone copolymer (e.g., Plasdone S-630 copolyvinylpyrrolidone (Asland)), a cellulose-based polymer (e.g., hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose), a polycarboxylic acid polymer (e.g., carbomer (manufactured by Lubrizol)), and a polymethacrylate (e.g., Plastoid B, Eudragit E100, Eudragit L100-55). (manufactured by Evonik), polyethylene glycol, graft copolymers based on polyvinyl acetate and polyvinylcaprolactam (PVAc-PVCap-PEG) (e.g., Soluplus (BASF), and combinations thereof). Specific Example 16. An adhesive composition of any of Specific Examples 1-13 further comprises a crystallization inhibitor selected from the following: a polymethacrylate (e.g., Plastoid B (a copolymer of butyl methacrylate and methyl methacrylate), Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), a polyethylene glycol, a graft copolymer (PVAc-PVCap-PEG) based on polyvinyl acetate and polyvinylcaprolactam (e.g., Soluplus (BASF), and combinations thereof). Specific Example 17. An adhesive composition of any of Specific Examples 1-16, wherein the sole active ingredient is a substantially pure R,R-isomer of bubenazine. Specific Example 18. The adhesive composition of any of Specific Examples 1-17, which is able to adhere to a user’s skin for approximately 8 hours, approximately 12 hours, approximately 18 hours, approximately 24 hours, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, or approximately 7 days or more. Specific Example 19. A transdermal delivery device comprising: One back layer, The adhesive composition of any of the specific examples 1-18; and Release the padding. Specific example 20. The transdermal conveying device of specific example 19 is stable on the rack. Specific Example 21. A transdermal delivery device of Specific Example 19 or 20, which provides an individual user with the active ingredient at a rate of about 0.01 mg / day / cm2 to about 5 mg / day / cm2, for example, for a period of about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more. Specific Example 22. A method of administering bubenazine, deuterated bubenazine, or a combination thereof to an individual who requires it, comprising applying an adhesive composition of any of Specific Examples 1-18 or a transdermal delivery device of any of Specific Examples 19-21 to the skin of the individual. Specific Example 23. The method of Specific Example 22, wherein the individual is characterized as having a hyperactive motor disorder (e.g., a chronic hyperactive motor disorder). Specific Example 24. The method of Specific Example 23, wherein the hyperkinetic disorder is chorea associated with Huntington's disease, Wilson's disease, Tourette syndrome, restless legs syndrome, tardive dyskinesia, tic, and combinations thereof. Specific Example 25. A method for inhibiting a vesicular monoamine transporter isoform 2 (VMAT2) in an individual with a need, the method comprising applying an adhesive composition of any of Specific Examples 1-18 or a transdermal delivery device of any of Specific Examples 19-21 to the skin of the individual. Specific Example 26. A method for treating a disease or ailment mediated by a vesicle monoamine transporter isoform 2 (VMAT2) in an individual in need, the method comprising applying an adhesive composition of any of Specific Examples 1-18 or a percutaneous delivery device of any of Specific Examples 19-21 to the skin of the individual. Specific Example 27. A method for treating a hyperkinetic disorder in an individual with a need, comprising applying an adhesive composition of any of Specific Examples 1-18 or a transdermal delivery device of any of Specific Examples 19-21 to the individual's skin. Specific example 28. The method of specific example 27, wherein the hyperkinetic disorder is a chronic hyperkinetic disorder. Specific example 29. The method of specific example 27 or 28, wherein the hyperkinetic disorder is chorea associated with Huntington's disease, Wilson's disease, Tourette syndrome, restless legs syndrome, tardive dyskinesia, and / or a seizure. Specific Example 30. A method for treating a hyperkinetic disorder in an individual with a need, the method comprising percutaneously administering a therapeutically effective amount of buphenazine or deuterated buphenazine to the individual. Example Example 1. Preparation of bubenazine perdermal patch

[0169] This embodiment illustrates a procedure for preparing a buphenazine adhesive-coated drug patch. Buphenazine is generally available in high purity (e.g., 99%) and commercially, for example, via the Internet from Hangzhou Octagon Chemical Ltd., China, on the Alibaba website.

[0170] In this embodiment, butylbenazine is thoroughly mixed into the adhesive Durotak 87-2287 (manufactured by Henkel Adhesives) until the mixture is homogeneous. The adhesive mixture is then dispensed onto a release liner using a draw-down knife and forced to dry using a typical blower for 1.5 minutes before being deposited onto a backing film.

[0171] These adhesive mixtures may contain butylbenazine in different concentrations. In this example, four concentrations were used: 1) a 2.5% formulation, prepared from a mixture of 2.5% butylbenazine and 97.5% Durotak 87-2287; 2) a 5% formulation, prepared from a mixture of 5% butylbenazine and 95% Durotak 87-2287; 3) a 10% formulation, prepared from a mixture of 10% butylbenazine and 90% Durotak 87-2287; and 4) a 15% formulation, prepared from a mixture of 15% butylbenazine and 85% Durotak 87-2287. All percentages for butylbenazine and Durotak refer to weight percentages based on the final weight of the individual formulations. Example 2. A bubenazine transdermal patch with two adhesives

[0172] Following the same operating procedure as in Example 1, a percutaneous patch of bubenazine with a mixture of two different adhesives in different proportions was also prepared, having a concentration of bubenazine maintained at 10% by weight.

[0173] The two adhesives used in this embodiment are a silicone polymer (BIO-7-4202 from Dow Corning Co.) and an acrylate copolymer (Durotak 87-2287). Four different ratios were used in this embodiment: 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). Example 3. Transdermal flux test

[0174] The transdermal flux of buphenazine from the patch was tested using human cadaveric epidermis via the Franz Diffusion Cell method. The cadaveric epidermis was obtained from the Health Science Tissue Bank in Phoenix, AZ.

[0175] The percutaneous flux of bubenazine through the skin of human cadavers was analyzed using the following HPLC method.

[0176] Mobile phase: 55 / 45 acetonitrile / water - pH adjusted to 6.5 with 0.05% triethylamine. HPLC column: Kinetex C18 from Pheneomenex, 150 x 4.6 mm, 5 μm Wavelength: 230 nm, Flow rate: 1.2 mL / min

[0177] The patches in Examples 1 and 2 were tested and the transdermal flux results are presented in Figures 1 and 2, respectively.

[0178] As shown in Figure 1, the highest transdermal flux observed with respect to the patch in Example 1 was with an adhesive matrix having a concentration of 10% bubenazine.

[0179] As shown in Figure 2, changing the ratio of silicone polymer to acrylate copolymer did not significantly alter the flux characteristics. However, when compared to the results shown in Figure 1, the flux observed for the patch prepared according to Example 2 was significantly lower than that for the patch prepared in Example 1 with a 10% butylbenazine concentration.

[0180] Therefore, adding a silicone adhesive to an acrylate adhesive (e.g., Durotak 87-2877) may slow down the flux of bubenazine. Example 4A. Preparation of butylbenazine in non-functional adhesives

[0181] Batch composition Element Function Wet weight solid% dry weight dry% Bubenazine (+) (TBZ) Active ingredients 4.25 4.25 7.1% Ethyl acetate solvent 10.00 ethanol solvent 5.00 DuroTak 87-900A adhesive 100.0 43.70% 43.70 72.9% propyl gallate antioxidants 0.030 0.030 0.050% Plastoid B Crystallization inhibitor / cosolvent 12.00 12.000 20.0% total 119.25 59.98 100.0%

[0182] Plastoid B is a copolymer of butyl methacrylate and methyl methacrylate, manufactured by Evonik. Operating procedures for preparation

[0183] The following procedures were followed for preparing the patch in Example 4A. Propyl gallate was dissolved in ethanol by manual mixing in a 50-mL beaker. Separately, ethyl acetate was added to a 250-mL beaker and mixed at low speed with a mechanical stirrer. TBZ was added, followed by Plastolide B powder, and mixed simultaneously. When Plastolide B dissolved, weighed DuroTak 87-900A was added and mixed simultaneously. Mixing was carried out at medium speed for 30 minutes, or until homogeneous. The solution was cast onto a 3M Scotchpak 9723 backing film using a 10-mil applicator. The casting was air-dried for 10 minutes and then oven-dried at 85°C for 10 minutes. The dried adhesive was covered with a separate Loparex release liner. The covered coating was die-cut into 60 cm² patches using a steel ruler die.

[0184] The patch has good skin adhesion and shear strength, and adheres firmly to the skin for more than 48 hours.

[0185] The patch was die-cut to be attached to the Franz pool for skin penetration studies. The results were reported in Example 6.

[0186] No crystallization was 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. Examples 4B and 4C. Preparation of bubenazine in non-functional adhesives

[0187] Two similar formulations were prepared following the same operating procedure shown in Example 4A. These are provided in the table below (dried compositions): formula Function Ex 4B Ex 4C TBZ(+) active 7.0% 7.1% DT 87-900A adhesive 92.5% 72.9% propyl gallate antioxidants 0.05% 0.05% Soluplus Crystallization inhibitor / cosolvent 20.0%

[0188] The patches prepared in Examples 4B and 4C were also tested in skin penetration studies. Example 5. Stability Study of Butenaazine Patch Formulation

[0189] Various patch formulations of bubenazine were prepared and tested for chemical and / or physical stability. The inventors found that patch formulations prepared with DuroTak 87-2287 or DuroTak 87-2677 adhesives (which contain functional groups) exhibited a pale yellow color after shelf storage at 40°C for 4 weeks, indicating instability of the active ingredient due to oxidation and / or other degradation. DuroTak 87-2287 has a -OH hydroxyl functional group and an epoxy group, while DuroTak 87-2677 has a -COOH acidic functional group. Conversely, referring to Example 4A, patch formulations prepared using DuroTak 87-900A (which does not contain any functional groups) were found to be stable at 40°C for 4 weeks.

[0190] The inventors also discovered that patch formulations prepared without propyl gallate as an antioxidant lead to degradation of the active ingredient. Without the use of an antioxidant, impurities (pharmaceutical-related) (such as TBZ 01, TBZ 02, and TBZ 04) are 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 (tocopheryl acetate), etc.

[0191] Butenaazine and related compounds were analyzed using isocratic reverse-phase HPLC with a UV detector. Column: Gemini C18, 4.6 x 150 mm, 5 µm particle size, or equivalent. Column temperature: 45℃ Injection volume: 10 µL Detection wavelength: 210 nm The ratio of moving phase A to moving phase B is 44:56. Mobile phase A: 10 mM K2HPO4 mixed with H2O Mobile phase B: Acetonitrile Flow rate: 1.2 mL / min Runtime: 12 min Retention time: Approximately 5.5 minutes for buphenazine. The residence time for impurity 1 (TBZ01) was approximately 1.95 minutes; for impurity 2 (TBZ02) it was approximately 3.10 minutes; and for impurity 4 (TBZ04) it was approximately 5.29 minutes.

[0192] The inventors further discovered that, without the use of Soluplus or Plastoid B as a crystallization inhibitor / cosolvent (see, for example, Example 4B), crystals appeared on the patches after two weeks of shelf storage at ambient temperature. The formation of crystals delayed skin penetration of these patch formulations.

[0193] Therefore, a preferred composition should contain a crystallization inhibitor, thereby allowing the active ingredient to remain in an amorphous form within the adhesive matrix for storage at room temperature for at least 12 months. The crystallization inhibitor preferably includes: • 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 (copolyvinylpyrrolidone): Plasdone S-630 copolyvinylpyrrolidone (Asland) • Cellulose-based polymers: Hydroxypropyl methylcellulose (HPMC / Methocel), ethyl cellulose (Ethocel by Dow Chemica), for example, hydroxypropyl cellulose (HPC, for example by Klucel by Ashland) • Polycarboxylic acid polymer: Carbopol (manufactured by Lubrizol) • Polymethyl methacrylate: Plastoid B, Eudragit E100, Eudragit L100-55 (manufactured by Evonik) • Soluplus (BASF): A graft copolymer of polyethylene glycol, polyvinyl acetate, and polyvinylcaprolactam (PVAc-PVCap-PEG) Example 6. Skin penetration study

[0194] The patch formulations prepared in Examples 4A-4C were used in a skin penetration study using the following procedures: • Franz Pool Assembly – Logan Instruments (6-pool unit) Each pool has a volume of 12 mL and a 1.5 cm diameter orifice. • The receptor medium is phosphate-buffered saline (PBS) at pH 7.4. • The pool temperature was maintained at 37°C • Sampling method: Take 1.5 mL for HPLC analysis, empty the cell, and replace with fresh medium. • Sampling time points: 2, 4, 8, 12, 24, and 48 hours • The cadaver's skin was used and obtained from the New York Fighters Skin Bank. • Analytical methods for media: HPLC.

[0195] The results of the study are presented in the tables and figures below. The values ​​presented are the cumulative amount of TBZ per centimeter (i.e., μg / cm²). See also Figure 3. average 2h 4h 8h 24h 48h Ex 4B 0.00 1.95 4.07 25.61 64.56 Ex 4C 0.00 0.05 1.36 17.38 48.59 Ex 4A 0.00 0.47 5.38 32.27 73.99 Example 7. In vivo pharmacokinetic studies

[0196] The aim of this study was to evaluate the comparative bioavailability of a test TBZ patch (when administered over a single 96-hour period, 8 mg / 96 hr (see formulation in Example 4A)) compared to a reference product (bubenazine tablets) administered three times daily (12.5 mg (Lupin) from day 1 to day 4 in healthy adult males under fasting conditions) and a reference product (bubenazine tablets).

[0197] This is an open-label, randomized, two-treatment, two-period, two-sequential crossover study comparing a trial and a reference product under fasting conditions. The study was conducted in 16 healthy, non-smoking, nicotinic adult males. During one period of the study, one (1) TBZ patch (8 mg / 96 hr) was administered to the individual's left lateral upper arm and held in place for 96 hours following an overnight fast of at least 10 hours. During the other period of the study, from day 1 to day 4, 1 × 12.5 mg of buphenazine tablets (Lupin) were administered every 8 hours for a total daily dose of 37.5 mg and a total daily dose of 150 mg for 12 doses over 4 days. For treatment B (reference), the individuals fasted overnight for at least 10 hours only before the 0-hour dose (day 1). Subsequent doses were administered after a fast of at least 2 hours. The order of administration followed a two-sequential randomization. During each study period, individuals were restricted to the clinical facility from at least 10 hours before administration (0-hour) until at least 120 hours after administration on day 1 (0-hour). The interval between administrations (0-hour) was 14 days.

[0198] During each study, blood samples were collected before administration and at intervals of 120 hours after administration of the study drug (0-hour). The samples were analyzed by a bioanalytical laboratory for individuals who were administered at least one of the study products (treatment A or B).

[0199] Plasma concentrations of TBZ (RR and SS isomers) and its active metabolites (RRR, SSS, SRR, and RSS) were measured using a fully validated analytical procedure. Statistical analysis using an analysis of variance methodology was performed to assess the bioavailability of the test formulation relative to a reference product based on the plasma concentrations of these six analytes.

[0200] The research data was collected in the original documents.

[0201] This study was designed based on the known pharmacokinetics of bubenazine tablets and its metabolites, recommendations from the FDA draft guidance on bubenazine tablets, and generally acceptable criteria for conducting bioequivalence and adhesion studies under fasting conditions.

[0202] To minimize any possibility of a carry-over effect, a clearance period of at least 10 days was chosen for this study. [treat] [A]

[0203] The active pharmaceutical ingredient is the RR stereoisomer of bubenazine. All patches (see formulation shown in Example 4A) were applied to the left lateral upper arm, below the shoulder, and at least 2 inches above the elbow. The patches were applied to the individual's left lateral upper arm and remained in place for 96 hours after an overnight fast of at least 10 hours. [treat] [B]

[0204] The active pharmaceutical ingredient is the racemic form of two stereoisomers (RR and SS) of bubenazine. Dosage is administered every 8 hours from day 1 to day 4. Individuals must fast overnight for at least 10 hours prior to the 0-hour dosing. Subsequent doses are administered after a fast of at least 2 hours. The total daily dose of the reference product over three 8-hour dosing intervals is equivalent to 37.5 mg, or a total dose of 150 mg for 12 doses over 4 days.

[0205] The lower total dose of TBZ administered via the test patch (8 mg) compared to the reference tablet (150 mg) is based on the premise that, since the TBZ is metabolized to HTBZ by bypassing first-pass metabolism and local administration, the absorption of the bioactive RR isomer of the TBZ containing the active pharmaceutical ingredient will be more extensive from the patch. The active pharmaceutical ingredient in the bubenazine tablet is the racemic form (RR, SS), while the active pharmaceutical ingredient in the test TBZ patch is the RR isomer.

[0206] Adverse events were collected and listed. No formal statistical analysis was performed.

[0207] Regarding treatment A (trial), 26 blood samples were collected from individuals at individual times during the study: pre-administration within 60 minutes before patch application (0 hours), and post-administration at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 16.0, 24.0, 32.0, 40.0, 48.0, 56.0, 64.0, 72.0, 80.0, 88.0, 96.0 (within 5 minutes before patch removal), 97.0, 98.0, 100.0, 104.0, 108.0, 114.0, and 120.0 hours. All times are relative to minutes of administration (time of patch application). Regarding treatment B (reference), 51 blood samples were collected from individuals at individual periods during this study: pre-administered within 60 minutes prior to administration (day 1, 0-hour), and at the following doses: 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 administration. All times are in minutes of administration (Day 1, 0-hour). †If necessary, samples are collected immediately before each administration, with a tolerance of -5 minutes, to accommodate the administration activity.

[0208] Plasma concentrations of TBZ (RR and SS isomers) and its HTBZ metabolites (RRR, SSS, SRR, and RSS) were measured by a fully validated analytical procedure in individuals who were administered at least one of the study products (treatment A or B). The total TBZ concentration was expressed in moles as the sum of mole concentrations of TBZ + RRR + SSS + SRR + RSS.

[0209] The following pharmacokinetic parameters were evaluated for each of the six analytes (two TBZ isomers [RR and SS] and four HTBZ metabolites [RRR, SSS, SRR, and RSS]), the TBZ combination (RR+SS), and total TBZ: AUC0-t, AUC0-96, AUC0-∞, Cmax, Tmax, Kel, and T½. Furthermore, the metabolic rate (AUC0-t(met) / AUC0-t(TBZ)) and the apparent clearance (CL / F) of each of the four HTBZ metabolites (RRR, SSS, SRR, and RSS) were evaluated.

[0210] For each of the six analytes, the TBZ combination (RR+SS), and the total TBZ, a variance analysis was performed using the General Linear Model (GLM) procedure in SAS® (version 9.4) at ln-transformed Cmax, AUC0-96, and AUC0-∞. The statistical model included the order, the individual within the order, the treatment, and the primary utility during the period.

[0211] The confidence interval (90%) of AUC0-96, AUC0-∞, and Cmax on the geometric mean ratio (obtained from logarithmically transformed data) was used to compare the test formulation with the reference product to establish two one-sided hypotheses for the test at a significance level of α = 0.05. Similar analyses were performed for additional PK parameters: the metabolic rate of the four metabolites and the CL / F for TBZ. Descriptive statistics were reported for all PK parameters by treatment.

[0212] [Summary of Results] [:] Mean plasma concentration versus time (linear) plots are presented below, as in Figure 4A for TBZ (combination of RR and SS isomers), Figure 4B for RRR HTBZ, Figure 4C for SRR HTBZ, and Figure 4D for total TBZ. The arithmetic mean of these pharmacokinetic parameters (unconverted) is provided in Table 1A for treatment A and Table 1B for treatment B. All available data are presented.

[0213] The geometric mean, the ratio of geometric means, and their associated 90% confidence intervals and intra-individual CV (ISCV %) values ​​are provided according to ANOVA (ln-transformation) in Table 2A regarding TBZ (RR and SS isomer combinations), in Table 2B regarding RRR HTBZ, in Table 2C regarding SRR HTBZ, and in Table 2D regarding total TBZ. Table 1A shows the mean pharmacokinetic parameters of the analyte for treatment A (a single-dose patch of 8 mg / 96 hr). [Analytical material] [AUC, 0-t , , [, (h·pg / mL)] [AUC, 0-∞ , , [, (h·pg / mL)] [AUC, 0-96 , , [, (h·pg / mL)] [C, max , , [, (pg / mL)] [T, max , , , (h), * , ] [K, el , , , (h, -1 , )] [T, 1 / 2 , , , (h)] [CL / F] [ 局部 , ] [ , (L / h)] [AUC, 0-∞(met) , / , , AUC, 0-∞(TBZ) , ] [AUC, 0-t(met) , / , , AUC, 0-t(TBZ) , ] TBZ (RR+SS) 35060.5095 (n=16) 37527.1500 (n=14) 33594.8216 (n=16) 570.1400 (n=16) 20.0083 (n=16) 0.1039 (n=14) 8.4713 (n=14) 255.8089 (n=14) AND AND RR TBZ 35060.5095 (n=16) 37527.1500 (n=14) 33594.8216 (n=16) 570.1400 (n=16) 20.0083 (n=16) 0.1039 (n=14) 8.4713 (n=14) 255.8089 (n=14) NA NA SS TBZ† NO NO NO NO NO NO NO NO NA NA RRR HTBZ 8373.0650 (n=13) 13575.7690 (n= 1) 7798.4167 (n=13) 126.1685 (n=13) 32.0000 (n=13) 0.0689 (n= 1) 10.0542 (n= 1) NA 0.2256 (n= 1) 0.2221 (n=13) SSS HTBZ† NO NO NO NO NO NO NO NA NO NO SRR HTBZ 168212.4133 (n= 8) 132862.9692 (n= 1) 145012.7993 (n= 8) 2424.4751 (n= 8) 48.0000 (n= 8) 0.0548 (n= 1) 12.6436 (n= 1) NA 6.1003 (n= 1) 3.7720 (n= 8) RSS HTBZ† NE NE NE NE NE NE NE NA NE NE Total TBZ‡ 400.4585 (n=16) 480.6111 (n=14) 356.3363 (n=16) 5.8772 (n=16) 28.0000 (n=16) 0.1199 (n=14) 8.0249 (n=14) NA NA NA *Median † All concentrations for all individuals are BLQ (i.e., < LLOQ 498.154 pg / mL for SS TBZ, 628.530 pg / mL for SSS HTBZ, and 499.875 pg / mL for RSS HTBZ) The units for AUC are h·nmol / L and the units for Cmax are nmol / L. NA: Not applicable NE: Not estimated Table 1B shows the mean pharmacokinetic parameters of the analyte for treatment B (1 x 12.5 mg tablets every 8 hours for 4 days). [Analytical material] [AUC, 0-t , , [, (h·pg / mL)] [AUC, 0-∞ , , [, (h·pg / mL)] [AUC, 0-96 , , [, (h·pg / mL)] [C, max , , [, (pg / mL)] [T, max , , , (h), * , ] [K, el , , , (h, -1 , )] [T, 1 / 2 , , , (h)] [CL / F] [ 口服 , ] [ (L / hr)] [AUC, 0-∞(met) , / , AUC 0-∞(TBZ) , ] [AUC, 0-t(met) , / , AUC 0-t(TBZ) , ] TBZ (RR+SS)§ 1164.6280 (n=15) AND 1265.8975 (n=15) 294.2203 (n=15) 16,5000 (n=15) AND AND AND WAS WAS RR TBZ† 999.4895 (n=15) AND 1100.7590 (n=15) 137.8475 (n=15) 16,5000 (n=15) AND AND AND WAS WAS SS TBZ‡ 906.5096 (n= 1) AND 1189.0961 (n= 1) 810.8560 (n= 1) 9,0000 (n= 1) AND AND AND WAS WAS RRR HTBZ 62781.1003 (n=16) 64341.3948 (n=16) 57848.9411 (n=16) 1109.4245 (n=16) 25.0000 (n=16) 0.1068 (n=16) 7.4903 (n=16) AND NO 136.1972 (n=15) SSS HTBZ 1278309.0449 (n=16) 1318201.2129 (n=16) 1161623.5993 (n=16) 24946.1819 (n=16) 25.0000 (n=16) 0.0976 (n=16) 8.3115 (n=16) AND NO 2797.1341 (n=15) SRR HTBZ 922405.6631 (n=16) 1443897.0709 (n=10) 831246.5949 (n=16) 16560.4164 (n=16) 25.5000 (n=16) 0.1339 (n=10) 6.9547 (n=10) AND NO 1916.0880 (n=15) RSS HTBZ 351674.6037 (n=16) 375318.8572 (n=15) 336442.9774 (n=16) 7166.2672 (n=16) 26.0000 (n=16) 0.1288 (n=15) 5.8498 (n=15) NA NE 728.9960 (n=15) Total TBZ¶ 8204.8147 (n=16) 8465.2813 (n=16) 7477.0546 (n=16) 144.9376 (n=16) 25.0000 (n=16) 0.1209 (n=16) 7.1470 (n=16) NA NA NA *Median † The majority concentrations for all individuals are BLQ. An individual (#3012) does not have at least 4 LLOQ concentrations >48.050 pg / mL. ‡ 12 out of 16 individuals had all BLQ concentrations. 3 out of 16 individuals had 1 to 3 concentrations, and one individual (#3013) had 5 LLOQ concentrations >498.154 pg / mL. § The majority concentration for all individuals is BLQ. When combined, an individual (#3012) does not have at least 4 concentrations > LLOQ for RR or SS TBZ. The units for AUC are h·nmol / L and u for Cmax are nmol / L. NA: Not applicable NE: Not estimated Table 2A Summary of Primary Endpoints Based on Plasma TBZ (RR and SS Isomer Combination) Concentration [parameter] [Trt.] [LS, , ] [geometry] [ , ] [Average] [right] [Compare] [ , (#) [individual] [)] [LSGM] [Compare] [Rate] [ , (%) [90%] [trust] [ , ] [Interval] [(%) [ISCV (%)] [P-] [value] [ , ] [period] [P-] [value] [ , ] [order] [90% CI, , ] [exist] [80-125%] [Inside] AUC0-96 (h·pg / mL) A 32375.579 A vs B (n = 15) 3806.18 2257.16-6418.27 95.7 0.4628 0.9175 none B 850.605 Cmax (pg / mL) A 555.313 A vs B (n = 15) 341.20 209.67-555.23 87.1 0.4548 0.8874 none B 162.754 Table 2B Summary of primary endpoints based on plasma RRR HTBZ concentration [parameter] [Trt.] [LS, , ] [geometry] [Average] [right] [Compare] [ , (#) [individual] [)] [LSGM] [Compare] [Rate] [ , (%) [90%] [trust] [ , ] [Interval] [(%) [ISCV (%)] [P-] [value] [ , ] [period] [P-] [value] [ , ] [order] [90% CI, , ] [exist] [80-125%] [Inside] AUC0-96 (h·pg / mL) A 7164.062 A vs B (n = 13) 13.09 10.29 - 16.66 35.1 0.8685 0.7138 None B 54726.280 Cmax (pg / mL) A 120.830 A vs B (n = 13) 11.17 9.30 - 13.41 26.4 0.7710 0.8794 None B 1081.891 [[ID=6S]] AUC0 - t(RRR) / AUC0 - t(TBZ) A 0.198 A vs B (n = 13) 0.22 0.13 - 0.37 82.5 0.8890 0.8039 None Note: There seems to be a mistake in the original text where "[[ID=6S]]" should probably be "". This has been left as is in the translation. B 89.628 Table 2C Summary of primary endpoints based on plasma SRR HTBZ concentration [parameter] [Trt.] [LS, , ] [geometry] [ , ] [Average] [right] [Compare] [ , (#) [individual] [)] [LSGM] [Compare] [Rate] [ , (%) [90%] [trust] [ , ] [Interval] [(%) [ISCV (%)] [P-] [value] [ , ] [period] [P-] [value] [ , ] [order] [90% CI, , ] [exist] [80-125%] [Inside] AUC0-96 (h·pg / mL) A 89903.262 A vs. B (n = 8) 12.36 6.22-24.54 80.4 0.2669 0.7158 none B 727441.779 Cmax (pg / mL) A 1663.555 A vs. B (n = 8) 9.66 5.75-16.24 57.5 0.7489 0.6576 none B 17218.960 AUC0-t(SRR) / AUC0-t(TBZ) A 2.395 A vs. B (n = 8) 0.22 0.08-0.58 135.7 0.8553 0.8952 none B 1111.324 Table 2D Summary of primary endpoints based on total plasma TBZ concentration [parameter] [Trt.] [LS, , ] [Several] [what] [ , ] [Average] [right] [Compare] [ , (#) [individual] [)] [LSGM] [Compare] [Rate] [ , (%) [90%] [trust] [ , ] [Interval] [(%) [ISCV (%)] [P-] [value] [ , ] [period] [P-] [value] [ , ] [order] [90% CI, , ] [exist] [80-125%] [Inside] AUC0-96 (h·nmol / L) A 203.527 A vs B (n = 16) 3.41 2.39-4.87 62.2 0.7135 0.6315 none B 5969.194 AUC0-∞ (h·nmol / L) A 259.219 A vs B (n = 14) 3.93 2.77-5.58 55.7 0.9446 0.6494 none B 6597.700 Cmax (nmol / L) A 3.534 A vs B (n = 16) 2.79 2.00-3.89 57.5 0.2807 0.6284 none B 126.826

[0214] Following application of the patch in treatment A, at a median Tmax of 20 hours, the concentration of the RR isomer of TBZ increased to a mean peak exposure (Cmax) of 570 pg / mL and then slowly decreased until the patch was removed at 96 hours, after which the concentration decreased with a mean final half-life of 8.5 hours. All concentrations of the SS isomer of TBZ were BLQ. Two of the four HTBZ metabolites were detected (the RRR and SRR non-mirror isomers), with the SRR isomer showing approximately 20-fold higher peak (Cmax) and total (AUC0-t) plasma exposure.

[0215] In treatment B, after 96 hours of three daily doses of the tablet, the majority concentrations for RR and SS were BLQ for all individuals. For those with RR concentrations above 48.050 pg / mL, the mean Cmax was 138 pg / mL and the median Tmax was 16.5 hours 0.5 hours after the first dose or the third dose on day 1. All four HTBZ active metabolites were detected, with the SSS isomer being the most prevalent, followed by SRR, RSS, and RRR, based on the highest mean AUC and Cmax values. Due to the lack of AUC0-∞(TBZ) data for RR, SS, and RR+SS analytes, no metabolic AUC ratio (AUC0-∞(met) / AUC0-∞(TBZ)) was calculated, but estimates were made using AUC0-t(met) / AUC0-t(TBZ) data instead.

[0216] Comparing treatments A (patch) and B (tablet), the degree of TBZ metabolism to HTBZ is smaller for treatment A, as indicated by the ratio of the least square geometric mean (LSGM) AUC0-t(met) / AUC0-t(TBZ) that is approximately 500-fold smaller with respect to RRR and SRR. Similarly, the RRR and SRR AUC0-96 and Cmax values ​​(uncorrected for dose differences) for treatment A are 8- to 10-fold lower than those for treatment B, as demonstrated by the LSGM A / B ratio of approximately 10-13% for these RRR and SRR parameters. The LSGM for RR+SS AUC0-96 and Cmax for treatment A is approximately 38-fold and 3.4-fold higher, respectively, than those for treatment B. The LSGM A / B ratios for total TBZ AUC0-96, AUC0-96, and Cmax are low at 3-4%.

[0217] [in conclusion] [:] Compared to three-times daily administration of TBZ tablets (total dose of 150 mg) under fasting conditions in healthy male individuals, the TBZ patch administered at 8 mg / 96 hr over a single 96-hour period provides a higher concentration of RR-bufenazine, with no interconversion to the SS isomer, and less metabolism to the active HTBZ isomers at a lower dose.

[0218] Due to the irritant response, no patch (treatment A [trial]) was removed during the study period. No serious adverse events were reported during the study period, and no individuals discontinued the study due to adverse events.

[0219] It is understood that the detailed description portion, rather than the summary and abstract portion, is intended to be used to interpret the scope of the patent application. The summary and abstract portion may present one or more, but not all, exemplary embodiments of the invention as contemplated by the inventors(s), and therefore is not intended to limit the scope of the invention and the appended patent application in any way.

[0220] The present invention has been described above by way of functional building blocks that illustrate the implementation of specific functions and their relationships. For ease of description, the boundaries of these functional building blocks have been arbitrarily defined herein. Alternative boundaries may be defined, provided that the specific functions and their relationships are properly performed.

[0221] Regarding aspects of the invention described as a class, all individual types are individually considered separate aspects of the invention. If an aspect of the invention is described as "comprising" a feature, specific examples are also contemplated as "consisting of" or "substantially consisting of" a feature.

[0222] The foregoing description of specific examples will fully reveal the general nature of the invention. Others can readily modify and / or adapt these specific examples to various applications by means of knowledge applied within the art, without excessive experimentation or deviation from the general concept of the invention. Therefore, based on the teachings and instructions presented herein, such adaptations and modifications are intended to be within the meaning and scope of equivalents of the disclosed examples. It is understood that the wording or terminology herein is for descriptive purposes and not for limitation, thereby the terminology or terminology in this specification shall be interpreted by those skilled in the art based on the teachings and instructions.

[0223] The breadth and scope of this invention should not be limited by any of the exemplary examples described above, but should be defined solely by the following claims and their equivalents.

[0224] All the various aspects, specific examples, and choices described herein can be combined in any and all variations.

[0225] All...

Claims

1. The use of R,R-tetrabenazine in the preparation of a pharmaceutical preparation for treating an ADHD in an individual in need, the method comprising administering to the individual the pharmaceutical preparation comprising an active ingredient containing the R,R-tetrabenazine, wherein the pharmaceutical preparation comprises an adhesive composition comprising the active ingredient dispersed in an adhesive, wherein the administration comprises applying the pharmaceutical preparation to the skin of the individual for transdermal delivery of 0.5 mg / day to 20 mg / day of R,R-tetrabenazine to the individual.

2. As claimed in claim 1, wherein the drug is continuously delivered to the individual at a dose of 0.5 mg / day to 10 mg / day of R,R-bubenazine.

3. As claimed in claim 1, wherein the drug is continuously delivered to the individual at a dose of 2 mg / day to 6 mg / day of R,R-bubenazine.

4. As claimed in any of claims 1 to 3, wherein during continuous delivery, the R,R-bubenazine is delivered at a rate characterized in that the average rate for each hour during the drug delivery period is 80-125% of the total average rate for the drug delivery period.

5. The use as claimed in any of claims 1 to 3, wherein the adhesive composition comprises the active ingredient dispersed in a non-reactive acrylate pressure-sensitive adhesive, wherein the active ingredient is present in an amount of 1% to 20% by weight, and the non-reactive acrylate pressure-sensitive adhesive is present in an amount of 50% to 97% by weight.

6. The use as claimed in any of claims 1 to 3, wherein the adhesive composition further comprises a gallic acid ester antioxidant.

7. The use of any one of claims 1 to 3, wherein the adhesive composition further comprises a crystallization inhibitor in an amount effective in preventing the formation of drug crystals after shelf storage at ambient temperature for 2 weeks.

8. The use of any one of claims 1 to 3, wherein the adhesive composition further comprises a crystallization inhibitor selected from: a polyvinylpyrrolidone polymer, a crosslinked polyvinylpyrrolidone polymer, a polyvinylpyrrolidone copolymer, a cellulose-based polymer, a polycarboxylic acid polymer, a polymethacrylate, a polyethylene glycol, a graft copolymer based on polyvinyl acetate and polyvinylcaprolactam, and combinations thereof.

9. The use of any of claims 1 to 3, wherein the sole active ingredient in the pharmaceutical preparation is a pure R,R-isomer of bubenazine.

10. As claimed in any of claims 1 to 3, wherein the hyperkinetic disorder is selected from Huntington's disease, Wilson's disease, Tourette syndrome, restless legs syndrome, tardive dyskinesia, tic disorders, dyskinesia-type cerebral palsy, other hypotonia and dyskinesia disorders, and combinations thereof.

11. The use of any of the claims 1 to 3, wherein the drug administration is performed without taking into account the individual’s feeding status.

12. As requested in any of items 1 to 3, wherein the individual is a broad metabolizer.

13. The use as claimed in any of claims 1 to 3, wherein the drug delivery provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ, wherein the ratio of the maximum plasma concentration of R,R-bufenazine (Cmax of R,R-bufenazine) to the maximum plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ (Cmax of R,R,R-HTBZ + Cmax of S,R,R-HTBZ) is in the range of 1:1 to 1:

5.

14. As requested in claim 13, wherein the ratio of the maximum plasma concentrations of R,R-bubenazine:R,R,R-HTBZ:S,R,R-HTBZ is 17-40:3-10:50-80.

15. The use of any of claims 1 to 3, wherein the dosing provides R,R,R-dihydrobutenazone (HTBZ), S,R,R-HTBZ and R,R-butenazone to the individual, wherein the amount of R,R,R-HTBZ provided is less than the amount of R,R-butenazone, and wherein the ratio of the AUC0-∞ of R,R-HTBZ to the AUC0-∞ of R,R-butenazone is 0.1 to 0.

75.

16. Use of R,R-bufenazine in the preparation of a pharmaceutical agent for treating an ADHD in an individual in need, the method comprising transdermal administration of the pharmaceutical agent comprising an active ingredient containing the R,R-bufenazine, wherein the administration provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ, wherein the maximum plasma concentration of R,R-bufenazine is in the ratio of the maximum plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ (Cmax of R,R-bufenazine / (Cmax of R,R,R-HTBZ + S,R,R-HTBZ)). The ratio of the steady-state plasma concentration (Cmax) of R,R-butenazone to the steady-state plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ (Css of R,R-butenazone / (Css of R,R,R-HTBZ + Css of S,R,R-HTBZ)) is in the range of 1:1 to 1:5, or the ratio of the maximum plasma concentration (Cmax) or steady-state plasma concentration (Css) of R,R-butenazone:R,R,R-HTBZ:S,R,R-HTBZ is approximately 17-40:3-10:50-80.

17. The use of R,R-bubenazine in the preparation of a pharmaceutical agent for treating an ADHD in an individual in need, wherein the pharmaceutical agent is in the form of a transdermal delivery device, and the method comprises administering the transdermal delivery device to the individual, wherein the transdermal delivery device comprises a drug-in-adhesive layer, wherein the drug-in-adhesive layer comprises (1) an active ingredient comprising R,R-bubenazine, (2) a pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant, wherein: (A). The percutaneous delivery device provides a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ, wherein the ratio of the maximum plasma concentration of R,R-bufenazine to the maximum plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ (Cmax of R,R-bufenazine / (Cmax of R,R,R-HTBZ + Cmax 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-bufenazine to the steady-state plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ (Css of R,R-bufenazine / (Cmax of R,R,R-HTBZ)). (a) The Css of S,R,R-HTBZ is in the range of 1:1 to 1:5, wherein 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, wherein the ratio of the AUC0-∞ of SRR-HTBZ to the AUC0-∞ of R,R-bufenazine is 1 to 15, and / or the ratio of the AUC0-∞ of RRR-HTBZ to the AUC0-∞ of R,R-bufenazine is 0.1 to 0.75, and wherein the administration does not provide detectable S,S-bufenazine, R,S,S-HTBZ, or S,S,S-HTBZ; (b) The transdermal delivery device is administered to transdermally deliver 0.1 mg / day to 20 mg / day of R,R-bufenazine to the individual; (c) The percutaneous delivery device is administered to the individual to achieve a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ for at least 6 hours; or (D). The percutaneous delivery device is administered to the individual to achieve a substantially constant steady-state plasma concentration of R,R-bufenazine at 150 pg / ml or higher for at least 6 hours.

18. The use of a deuterated R,R-tetrabenazine in the preparation of a pharmaceutical preparation for treating an ADHD in an individual in need, wherein the pharmaceutical preparation is in the form of a transdermal delivery device, and the method comprises administering the transdermal delivery device to the individual, wherein the transdermal delivery device comprises an adhesive-coated drug layer, wherein the adhesive-coated drug layer comprises (1) an active ingredient comprising a deuterated R,R-tetrabenazine, (2) a pressure-sensitive adhesive; (3) an optional crystallization inhibitor; and (4) an optional antioxidant, wherein: (A). The percutaneous delivery device provides a therapeutically effective plasma concentration of deuterated R,R-butylbenazine, a dihydrobutylbenazine metabolite of the deuterated R,R-butylbenazine, deuterated R,R,R-HTBZ, and deuterated S,R,R-HTBZ, wherein the ratio of the maximum plasma concentration of the deuterated R,R-butylbenazine to the maximum plasma concentration of the combination of the deuterated R,R,R-HTBZ and the deuterated S,R,R-HTBZ is in the range of 1:1 to 1:7.5, or the ratio of the maximum plasma concentration of the deuterated R,R-butylbenazine to the maximum plasma concentration of the combination of the deuterated R,R-butylbenazine is in the range of 1:1 to 1:7.

5. The ratio of the steady-state plasma concentration to the steady-state plasma concentration of the deuterated R,R,R-HTBZ and the deuterated S,R,R-HTBZ is in the range of 1:1 to 1:7.5, wherein the ratio of the maximum plasma concentration or steady-state plasma concentration of the deuterated R,R,R-HTBZ to the deuterated S,R,R-HTBZ is in the range of 1:5 to 1:30, and wherein the dosing does not provide detectable deuterated S,S-bubenazine, deuterated R,S,S-HTBZ or deuterated S,S,S-HTBZ; (B) The percutaneous delivery device is administered to deliver 0.1 mg / day to 20 mg / day of deuterated R,R-bufenazine to the individual percutaneously; (C) The percutaneous delivery device is administered to the individual to achieve a therapeutically effective plasma concentration of deuterated R,R-bufenazine, its dihydrobufenazine metabolite, deuterated R,R,R-HTBZ, and deuterated S,R,R-HTBZ for at least 6 hours; or (D) The percutaneous delivery device is administered to the individual to achieve a substantially constant steady-state plasma concentration of deuterated R,R-bufenazine of at least 150 pg / ml for at least 6 hours.

19. The use of any one of claims 16 to 18, wherein the hyperkinetic disorder is selected from Huntington's disease, Wilson's disease, Tourette syndrome, restless legs syndrome, tardive dyskinesia, tic disorders, dyskinesia-type cerebral palsy, other hypotonia and dyskinesia disorders, and combinations thereof.

20. The use of any of the claims 16 to 18, wherein (i) the administration is performed without taking into account the individual’s feeding status; (ii) the individual is a broad metabolizer; and / or the individual is a pediatric or adolescent patient.

21. A method for identifying a pharmaceutical composition for treating an ADHD, the method comprising administering a test pharmaceutical composition to an individual, the administration bypassing first-pass metabolism to provide continuous delivery of R,R-bubenazine to the individual, and (A). Identify a pharmaceutical composition providing a therapeutically effective plasma concentration of R,R-bufenazine, R,R,R-dihydrobufenazine (HTBZ), and S,R,R-HTBZ, wherein the ratio of the maximum plasma concentration of R,R-bufenazine to the maximum plasma concentration of the combination of R,R,R-HTBZ and 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-bufenazine to the steady-state plasma concentration of the combination of R,R,R-HTBZ and S,R,R-HTBZ is in the range of 1:1 to 1:5, wherein 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 wherein the identified pharmaceutical composition does not provide detectable S,S-bufenazine, R,S,S-HTBZ, or S,S,S-HTBZ; (B). A pharmaceutical composition is identified that provides a pharmacokinetic profile in an individual when administered at a dose of 2 mg / day for 4 days, the pharmacokinetic profile being characterized by: a) a mean Tmax of R,R-bufenazine over 10 to 24 hours; b) mean Tmax of R,R,R-HTBZ and S,R,R-HTBZ over a later period than the mean Tmax of R,R-bufenazine; c) a mean Cmax of R,R-bufenazine at 300 pg / ml to 700 pg / ml; d) a mean Cmax of R,R,R-HTBZ at 60 pg / ml to 200 pg / ml; e) a mean Cmax of S,R,R-HTBZ at 1000 pg / ml to 3000 pg / ml; f) a mean Cmax of S,R,R-HTBZ at 20 ng*h / ml to 50 ng*h / ml. The mean AUC0-96 for R,R-bubenazine at ng*h / ml; the mean AUC0-96 for R,R,R-HTBZ at 4 ng*h / ml to 12 ng*h / ml; and / or the mean AUC0-96 for S,R,R-HTBZ at 70 ng*h / ml to 200 ng*h / ml; (C).A pharmaceutical composition is identified that provides a pharmacokinetic profile in an individual when administered at a dose of 4-6 mg / day for at least 1 day, the pharmacokinetic profile being characterized by: a) a mean Tmax of R,R-bufenazine over 10 to 24 hours; b) a mean Tmax of R,R,R-HTBZ and S,R,R-HTBZ that are administered later than the mean Tmax of R,R-bufenazine; c) a mean Cmax of R,R-bufenazine at 600 pg / ml to 2100 pg / ml; d) a mean Cmax of R,R,R-HTBZ at 120 pg / ml to 600 pg / ml; e) a mean Cmax of S,R,R-HTBZ at 2000 pg / ml to 9000 pg / ml; f) a mean Cmax of S,R,R-HTBZ at 40 ng*h / ml to 150 ng*h / ml. (a) Mean AUC0-96 of R,R-bufenazine at ng*h / ml; (b) Mean AUC0-96 of R,R,R-HTBZ at 8 ng*h / ml to 36 ng*h / ml; and / or (c) Mean AUC0-96 of S,R,R-HTBZ at 140 ng*h / ml to 600 ng*h / ml; (D) Identification of a pharmaceutical composition that provides a pharmacokinetic profile in an individual when administered at a dose of 1-10 mg / day for at least 1 day, the pharmacokinetic profile being characterized by: a) Mean Tmax of R,R-bufenazine at 10-24 hours; b) Mean Tmax of R,R,R-HTBZ and S,R,R-HTBZ at a later Tmax than that of R,R-bufenazine; c) Mean AUC0-96 of S,R,R-HTBZ at 150 pg / ml to 3500 pg / ml. The mean Cmax of R,R-bufenazine at pg / ml; d) the mean Cmax of R,R,R-HTBZ at 30 pg / ml to 1000 pg / ml; e) the mean Cmax of S,R,R-HTBZ at 500 pg / ml to 15 ng / ml; f) the mean AUC0-96 of R,R-bufenazine at 10 ng*h / ml to 250 ng*h / ml; g) the mean AUC0-96 of R,R,R-HTBZ at 2 ng*h / ml to 60 ng*h / ml; and / or h) the mean AUC0-96 of S,R,R-HTBZ at 35 ng*h / ml to 1000 ng*h / ml; (E).Identify a pharmaceutical composition providing a pharmacokinetic profile in the individual, the pharmacokinetic profile being characterized by: (1) a maximum plasma concentration of R,R-bufenazine, ranging from 150 pg / ml to 3500 pg / ml, being reached at a first time point during a first time period, wherein the first time period is from the time of initial administration to 24 hours thereafter; and optionally (2) the plasma concentration of R,R-bufenazine remaining substantially constant after the first time point for a duration of 24 hours, 48 ​​hours, 72 hours, 96 hours or more, and optionally wherein the mean final half-life of R,R-bufenazine is 8.5 hours ± 40% CV.

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