RU2800536C2 - Tetrabenazine transdermal delivery device - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to an adhesive composition for transdermal delivery of an active ingredient, containing the following: an active ingredient dispersed in an inert acrylate pressure-sensitive adhesive, the active ingredient being selected from tetrabenazine, deuterated tetrabenazine, or a combination thereof, while the inert acrylate sensitive to pressure adhesive is present in an amount of from 50–97% by weight, and the inert acrylate pressure-sensitive adhesive is a copolymer of 2-ethylhexyl acrylate, methyl acrylate and either one or more acrylamide monomers without functional groups selected from epoxy, -OH, -COOH and their combinations; and an inert acrylate pressure-sensitive adhesive free or substantially free of vinyl acetate, also refers to a transdermal delivery device comprising the following: a backing layer, an adhesive composition, and a release liner, also refers to a method of administering tetrabenazine, deuterated tetrabenazine, or a combination thereof to a person in need, comprising the use of an adhesive composition or transdermal delivery device on the skin of a subject, also refers to a method of inhibiting vesicular monoamine transporter isoform 2 (VMAT2) in a subject in need, also refers to a method of treating a disease or disorder mediated by vesicular monoamine transporter isoform 2 (VMAT2) in a subject in need also relates to a method of treating hyperkinetic movement disorder in a subject in need.

EFFECT: group of inventions provides an adhesive composition suitable for transdermal delivery of tetrabenazine with a therapeutically significant penetration rate of tetrabenazine with improved storage stability.

31 cl, 3 dwg, 4 tbl, 8 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[1] This application claims benefit from U.S. Provisional Application No. 62/662,456, filed April 25, 2018, the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Field of invention

[2] In various embodiments, the present invention per se relates to transdermal delivery devices containing tetrabenazine and/or deuterated tetrabenazine, pharmaceutical compositions containing tetrabenazine and/or deuterated tetrabenazine, methods of making them, and methods of using them.

Prior Art

[3] Tetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor. Tetrabenazine is approved by the US Food and Drug Administration (FDA) as Xenazine® oral tablets for the treatment of chorea associated with Huntington's disease. The active ingredient of the Xenazine® tablet is a racemic mixture of (3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolysine -2-one (hereinafter referred to as “R,R-tetrabenazine”) and (3S,11bS)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2- methylpropyl)-2H-benzo[a]quinolisin-2-one (hereinafter referred to as “S,S-tetrabenazine”).

[4] In 2017, the FDA approved the use of deuterated tetrabenazine (deutetrabenazine), Austedo™ Oral Tablets, which is also indicated for the treatment of chorea associated with Huntington's disease. The active ingredient of the Austedo™ tablet is a selectively deuterium-substituted, stable, non-radioactive isotopic form of tetrabenazine in which six hydrogen atoms in the two O-linked methyl groups are replaced by deuterium atoms (i.e. —OCD ₃ moieties rather than —OCH ₃ moieties). The active ingredient of the Austedo™ tablet is also a racemic mixture.

SUMMARY OF THE INVENTION

[5] The FDA-approved package inserts for each of Xenazine® and Austedo™ contain a black box warning regarding potential risks of depression, suicidal ideation, and behavior. For both drugs, it is necessary to monitor and adjust the actual doses. For example, the prescribing information for Xenazine® states that for patients who require doses above 50 mg per day, genotyping for the CYP2D6 drug-metabolizing enzyme should be performed to determine whether the patient is a weak metabolizer (SM) or an active metabolizer. (AM). For weak metabolizers, the maximum daily dose may be only 50 mg, while the maximum single dose is 25 mg. At the same time, for active metabolizers or intermediate metabolizers, the maximum daily dose is 100 mg with a maximum single dose of 37.5 mg. Similarly, the instructions for use of Austedo™ also state that for poor metabolizers, the maximum daily dose can be only 36 mg with two single doses of 18 mg.

[6] Despite recent advances, administration of tetrabenazine/deutetrabenazine remains challenging and requires dose adjustments to reduce potential dose-dependent side effects. Thus, new formulations of tetrabenazine and options for their administration are needed.

[7] In various embodiments, the present invention provides a transdermal delivery device comprising tetrabenazine and/or deuterated tetrabenazine (eg, deitetrabenazine). In various embodiments, the present invention also provides a pharmaceutical composition (eg, adhesive composition) containing tetrabenazine and/or deuterated tetrabenazine (eg, deutetrabenazine). In various embodiments, the present invention further provides a method for making or using a transdermal delivery device or pharmaceutical composition that contains tetrabenazine and/or deuterated tetrabenazine (eg, deutetrabenazine).

[8] Some embodiments of the present invention relate to devices for transdermal delivery. Typically, a transdermal delivery device comprises a protective layer, a drug layer containing a drug selected from tetrabenazine, deuterated tetrabenazine, or a combination thereof, for example, in an amount of from about 2% to about 30% by weight of the drug layer, and an adhesive layer. , which determines the area of the active surface. The transdermal delivery device is typically configured to have certain flow characteristics, such as any of those defined herein. The active surface area may determine the amount of drug to be administered/delivered. Typically, the active surface area may range from about 5 cm ² to about 300 cm ² , for example, from about 10 cm ² to about 100 cm ² .

[9] The transdermal delivery device is not limited herein to any particular patch designs. For example, the transdermal delivery device described herein may have a drug-in-adhesive, drug-in-reservoir, or other patch design. In some embodiments, the transdermal delivery device may be a drug-in-adhesive patch, such as a single layer LSA patch. In some embodiments, the transdermal delivery device may comprise more than one drug layer, such as two or more drug layers in an adhesive. In some embodiments, the transdermal delivery device may be a drug-in-reservoir patch, for example: the drug layer is a reservoir containing tetrabenazine and/or deuterated tetrabenazine.

[10] The drug layer may contain tetrabenazine, deuterated tetrabenazine, or a combination thereof. In any of the embodiments described herein, the drug layer may contain tetrabenazine, eg, substantially pure R,R-tetrabenazine. In some embodiments, tetrabenazine (eg, substantially pure R,R-tetrabenazine) is the only active ingredient in the drug layer. In any of the embodiments described herein, the drug layer may contain deitetrabenazine, eg, substantially pure R,R-deutetrabenazine. In some embodiments, deitetrabenazine (e.g., substantially pure R,R-deutetrabenazine) is the only active

ingredient in the drug layer. In some embodiments, the drug layer contains tetrabenazine, deuterated tetrabenazine, or a combination thereof in an amount of from 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 in between) by weight of the drug layer. In some specific embodiments, the drug layer contains tetrabenazine, deuterated tetrabenazine, or a combination thereof in an amount of about 2%, about 2.5%, about 5%, about 8%, about 10%, about 15%, or about 20% by weight of the layer. medicinal product. In some embodiments, the drug layer may optionally contain one or more other ingredients, for example, selected from transdermal penetration enhancers, humectants, plasticizers, antioxidants, emollients, gelling agents, drug release modifiers, solvents, crystallization inhibitors, and additional active ingredients. . In some embodiments, the drug layer may have a coating weight of from about 0.1 g/cm ² to about 0.90 g/cm ² (e.g., from about 0.1 g/cm ² to about 0.5 g/cm ² ) active surface area.

[11] In some embodiments, the drug layer comprises tetrabenazine, deuterated tetrabenazine, or a combination thereof, dispersed (eg, homogeneously dispersed) in an adhesive (eg, a pressure-sensitive adhesive). This document describes pressure-sensitive adhesives. In some embodiments, the pressure-sensitive adhesive may comprise a polyisobutylene (PIB) adhesive, a silicone polymer adhesive (eg, Bio-7-4202), an acrylate copolymer adhesive (eg, DuroTak 87-2287), or a combination thereof. In some embodiments, the pressure-sensitive adhesive may be an inert acrylate adhesive, such as an acrylate adhesive lacking functional groups containing reactive hydrogen moieties, or an acrylate adhesive lacking functional groups selected from epoxy, -OH, -COOH, and their combinations.

[12] Typically, the adhesive layer is formulated such that the transdermal delivery device can adhere to the user's skin for a desired period of time. For example, in some embodiments, the transdermal delivery device is configured to continuously adhere to the user's skin for about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days. days, about 6 days

or about 7 days or more.

[13] Some embodiments of the present invention also relate to an adhesive composition. In some embodiments, the implementation of the adhesive composition contains a drug selected from tetrabenazine, deuterated tetrabenazine (eg, deuterabenazine) and combinations thereof, in the adhesive. In some embodiments, the drug is homogeneously dispersed in an adhesive (eg, a pressure-sensitive adhesive). In some embodiments, the pressure-sensitive adhesive may be an inert acrylate adhesive, such as an acrylate adhesive lacking functional groups containing reactive hydrogen moieties, or an acrylate adhesive lacking functional groups selected from epoxy, -OH, -COOH, and their combinations. In some embodiments, the pressure-sensitive adhesive comprises a polyisobutylene (PIB) adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some embodiments, the implementation of the adhesive composition contains tetrabenazine (for example, essentially pure R,R-tetrabenazine) in an amount of from about 2% to about 30% by weight of the adhesive composition. In some embodiments, the adhesive composition contains deitetrabenazine (eg, substantially pure R,R-deutetrabenazine) in an amount of from about 2% to about 30% by weight of the adhesive composition. In some embodiments, the active ingredient is present in an amount of from about 2% to about 7% by weight. In some embodiments, the implementation of the adhesive composition does not contain a penetration enhancer, for example, does not contain isopropyl myristate. However, in some embodiments, the adhesive composition further comprises a penetration enhancer. In some embodiments, the implementation of the adhesive composition may contain an antioxidant, such as a gallate antioxidant, such as propyl gallate. In some embodiments, the adhesive composition may contain a crystallization inhibitor such as polyvinylpyrrolidone polymer, crosslinked polyvinylpyrrolidone polymer, polyvinylpyrrolidone copolymer, cellulose-based polymer, polycarboxylic acid polymer, polymethacrylate, and polyethylene glycol-polyvinyl acetate-polyvinylcaprolactam (PVAc-PVCap-PEG) graft copolymer or a combination of them. In some preferred embodiments, the implementation of the adhesive composition contains a crystallization inhibitor, which is a copolymer of butyl methacrylate and methyl methacrylate. In some embodiments, the implementation of the adhesive composition contains a crystallization inhibitor, which is a graft copolymer

based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam. In some embodiments, the adhesive composition is configured to adhere continuously to the user's skin for an extended period of time selected from about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more. The adhesive composition described herein can be used in a transdermal delivery device. For example, in some embodiments, a transdermal delivery device may comprise any of the adhesive compositions described herein, a backing layer, and a release liner.

[14] In some embodiments, the present invention provides a method for transdermal administration of tetrabenazine, deuterated tetrabenazine, or a combination thereof to a subject (eg, a human subject) in need thereof. In some embodiments, the method includes applying any of the transdermal delivery devices or pharmaceutical compositions (eg, adhesive compositions) to the subject, eg, to the subject's skin.

[15] In some embodiments, the present invention also provides a method for inhibiting VMAT-2 in a subject in need thereof. In some embodiments, the method includes applying any of the transdermal delivery devices or pharmaceutical compositions (eg, adhesive compositions) to the subject, eg, to the subject's skin.

[16] In some embodiments, the present invention also provides a method of treating a disease or disorder mediated by vesicular monoamine transporter isoform 2 (VMAT2) in a subject in need (eg, a human subject). In some embodiments, the method includes applying any of the transdermal delivery devices or pharmaceutical compositions (eg, adhesive compositions) to the subject, eg, to the subject's skin.

[17] In some specific embodiments, the present invention provides a method for treating hyperkinetic movement disorder in a subject (eg, a human subject) in need thereof. In some embodiments, the method comprises transdermally administering to a subject a therapeutically effective amount of tetrabenazine and/or deuterated tetrabenazine. In some embodiments, the method comprises administering to the subject any of the transdermal delivery devices or pharmaceutical compositions.

(eg, adhesive compositions), for example, on the skin of the subject. In some embodiments, the hyperkinetic movement disorder is a chronic hyperkinetic movement disorder. In some embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, and/or tics. In some embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease.

BRIEF DESCRIPTION OF GRAPHICS / FIGURES

[18] FIG. 1 is a graph showing the flux of tetrabenazine from Duro-Tak 87-2287 monolithic adhesive matrices containing tetrabenazine at various concentrations (10%, 15%, 5% and 2.5%) through the epidermis of a human (black) cadaver in vitro.

[19] FIG. 2 is a graph showing tetrabenazine flux from monolithic matrices consisting of a mixture of Duro-Tak 87-2287 and BIO-7-4202 adhesive in various ratios, including ratios of (Duro-Tak 87-2287 and BIO-7-4202) 5 : 95 , 10 : 90, 25 : 75 and 50 : 50, through the epidermis of a human corpse in vitro. All matrices in this figure contain 10% tetrabenazine.

[20] FIG. 3 is a graph showing the flux of tetrabenazine from patch dosage forms prepared using DuroTak 87-900A adhesive through human cadaver epidermis in vitro.

DETAILED DESCRIPTION OF THE INVENTION

[21] In various embodiments, the present invention relates to pharmaceutical compositions or devices for transdermal delivery containing tetrabenazine and/or deuterated tetrabenazine (eg, deitetrabenazine). Pharmaceutical compositions and devices for transdermal delivery provide novel options for transdermal delivery of tetrabenazine and/or deuterated tetrabenazine to a subject in need thereof. It has not been previously shown that tetrabenazine and/or deuterated tetrabenazine can be administered via the transdermal route. As detailed herein, the inventor has demonstrated that the transdermal delivery device and pharmaceutical compositions disclosed herein (e.g., the adhesive compositions described herein) can be administered to a subject in order to achieve a therapeutically relevant flow and therefore can be useful in the treatment of various diseases or disorders such as hyperkinetic

movement disorder.

[22] The transdermal delivery of tetrabenazine and/or deuterated tetrabenazine described herein may have many advantages over conventional oral delivery, such as preventing first-pass metabolism, providing a pharmacokinetic profile with a low peak-to-trough ratio, allowing multi-day therapy with single use, avoiding the effect of food intake on absorption, discontinuing therapy by removing the patch (if necessary), improving patient compliance, etc. In addition, compared to similar oral doses of tetrabenazine or deitetrabenazine, the transdermal delivery described herein , may reduce inter-individual variation in plasma levels of tetrabenazine or deitetrabenazine or its metabolite, and/or may reduce _Cmax (eg, 10%, 40%, 60% or more) for tetrabenazine or deitetrabenazine or its metabolite, for example, without concomitant decrease in therapeutic efficacy. In addition, the transdermal delivery described herein may provide similar plasma levels of tetrabenazine or deitetrabenazine or their metabolites when administered at similar doses to subjects who are genotyping for CYP2D6 expression and found to be poor metabolizers (MW), intermediate metabolizers (IM), or active metabolizers. metabolizers (AM). These advantages may ultimately lead to a simplified regimen for tetrabenazine and/or deuterated tetrabenazine (eg, deutetrabenazine), for example, may minimize or eliminate the need for genotyping and/or may reduce side effects associated with the use of the drug.

Transdermal delivery device containing tetrabenazine

[23] Some embodiments of the present invention relate to a transdermal delivery device containing tetrabenazine or deuterated tetrabenazine (eg, deitetrabenazine). In some embodiments, the transdermal delivery device comprises a protective layer; a drug layer containing a drug selected from tetrabenazine, deuterated tetrabenazine (eg, deutetrabenazine), and combinations thereof; and an adhesive layer defining an active surface area. In some embodiments, the drug is present in an amount of about 2% to about 30% by weight of the drug layer. In some embodiments, the transdermal delivery device comprises a single layer

medicinal product. In some embodiments, the transdermal delivery device comprises more than one drug layer. In some embodiments, the transdermal delivery device comprises a single adhesive layer. In some embodiments, the transdermal delivery device comprises more than one adhesive layer.

[24] Various patch designs can be used in the transdermal delivery device described herein. For example, in some embodiments, the transdermal delivery device may be a drug-in-adhesive (DLA) patch. In some embodiments, the LSA patch is a single layer patch in which the drug layer and the adhesive layer are the same layer, eg, the drug is homogeneously dispersed in the adhesive. In some embodiments, the LSA patch is a multilayer patch. For example, the patch may include two layers of drug in an adhesive, optionally separated by a membrane. In some embodiments, the two LSA layers may have different release characteristics, for example, one of the layers is an immediate release layer and the other is a controlled release layer. In some embodiments, the two layers of LSA may have different release characteristics, for example, one of the layers releases the drug relatively quickly over a relatively short period of time, while the other layer releases the drug over a longer period of time.

[25] The transdermal delivery device described herein can also use a drug-in-reservoir (DCR) patch design. In some embodiments, the drug layer and the adhesive layer may be two separate layers, layered on top of each other or separated, such as by a rate control membrane. For example, in some embodiments, the drug layer is a reservoir layer, such as a drug matrix, overlaid on an adhesive layer.

[26] Other patch designs can also be used in the transdermal delivery device described herein. For example, in some embodiments, the transdermal delivery device may be an active patch, such as an iontophoresis patch. In some embodiments of the invention, a device for

transdermal delivery may be a minimally invasive patch such as a microneedle patch.

[27] Typically, a transdermal delivery device (eg, LSA patch) is provided with an impervious protective film and its adhesive surface is protected by a removable protective coating. Various materials can be used as the protective layer in the transdermal delivery device described herein. As a rule, the protective layer is impermeable. For example, the protective layer may consist of impervious polymeric films such as polyester (PET) or polyethylene (PE) films. In some embodiments, the backsheet may comprise a polyester film such as Scotchpak 9723, Scotchpak 9736, or Scotchpak 1012, a polyurethane film such as Scotchpak 9701, or a polyethylene film such as CoTran 9720.

[28] For the present invention, the removable protective coating can be made in the required size. The removable protective coating may consist of a silicone or fluoropolymer coated polyester film. The release liner protects the transdermal delivery device during storage and is removed prior to use. Removable silicone coated protective covers include those manufactured by Mylan Corporation, Loparex Corporation, and 3M Drug Delivery Systems. Removable fluoropolymer coated protective covers include those manufactured and supplied by 3M Drug Delivery Systems and Loparex. In some embodiments, the release liner comprises ScotchPak 9744 or Scotchpak 1022 from 3M.

[29] The transdermal delivery devices (eg, LSA patches) described herein may have different sizes (patch sizes) depending on their application. Typically, the dimensions of the patch may be from about 5 cm ² to about 300 cm ² (for example, about 5 cm ² , about 10 cm ² , about 20 cm 2 , about 30 cm ² , about 40 cm ^{2 ,} about 50 cm ² , about 60 cm ² , about 80 cm ² , about 100 cm ² , about 120 cm ² , about 150 cm ² , about 200 cm ² or any range in between), for example, from about 10 cm ² to about 100 cm ² .

[30] When applying the transdermal delivery devices (eg, LSA patches) described herein to the skin of a subject, the entire adhesive surface could theoretically come into contact with the skin. Thus, the area of the adhesive surface determines the area of contact with the skin on which the active

the ingredient from the device can penetrate the skin, and which is also referred to herein as the active surface area. In some embodiments, the adhesive surface is the only surface of the transdermal delivery device in contact with the skin upon application, and the active surface area is the same as the adhesive surface area. In some embodiments, the adhesive surface and one or more other surfaces of the transdermal delivery device are in contact with the skin upon application, and the entire skin contact area is the active surface area.

[31] The area of the active surface can determine the dose of drug for delivery. Typically, the active surface area may be from about 5 cm ² to about 300 cm ² (eg, about 5 cm ² , about 10 cm ² , about 20 cm 2 , about 30 cm ² , about 40 cm ^{2 ,} about 50 cm ² , about 60 cm ² , about 80 cm ² , about 100 cm ² , about 120 cm ² , about 150 cm ² , about 200 cm ² or be in any range between the indicated values), for example, from about 10 cm ² to about 100 cm ² .

drug layer

[32] Typically, the drug layer contains tetrabenazine, deuterated tetrabenazine, or a combination thereof. In some embodiments, the drug layer may optionally contain one or more other ingredients, for example, selected from transdermal penetration enhancers, humectants, plasticizers, antioxidants, emollients, gelling agents, drug release modifiers, solvents, crystallization inhibitors, and additional active ingredients. . In some embodiments, the drug layer is selected such that the transdermal delivery device achieves the skin flow characteristics described herein. It should be understood that the pharmaceutical compositions used in the drug layer described herein may also be novel formulations independent of the transdermal delivery device and/or skin flow characteristics described herein. Therefore, some embodiments of the present invention also relate to pharmaceutical compositions.

[33] In some embodiments, the drug in the drug layer may be tetrabenazine. Tetrabenazine in the transdermal delivery device described herein is not

limited to a particular enantiomer and may be in racemic form, be essentially pure R,R-tetrabenazine (e.g., contain less than 10%, less than 5%, less than 1%, or less than 0.1% of the S,S isomer), be essentially pure S,S-tetrabenazine (eg contain less than 10%, less than 5%, less than 1%, or less than 0.1% of the R,R isomer) or a mixture of R,R-tetrabenazine and S,S-tetrabenazine in any ratio. In some embodiments, the tetrabenazine in the transdermal delivery device is in racemic form. In some embodiments, the tetrabenazine in the transdermal delivery device is substantially pure R,R-tetrabenazine. In some embodiments, tetrabenazine is the only drug in the drug layer. In some embodiments, tetrabenazine is the only drug in the transdermal delivery device. In some embodiments, the drug layer and/or transdermal delivery device may also contain other active ingredients.

[34] In some embodiments, the drug in the drug layer may be deuterated tetrabenazine. As used herein, the term "deuterated tetrabenazine" refers to a compound obtained by replacing one or more hydrogen atoms of tetrabenazine with deuterium, resulting in a deuterium content higher than the natural content at each substituted position, i.e., the substituted position is enriched in deuterium. In some embodiments, the deuterated tetrabenazine has at least one position with deuterium enriched to greater than 10% deuterium, greater than 50% deuterium, greater than 90% deuterium, greater than 95% deuterium, or greater than 98% deuterium. A preferred example of a deuterated tetrabenazine is deitetrabenazine, the racemic form of which is the active ingredient in Austedo™ tablets. The deuterated tetrabenazine in the transdermal delivery device described herein is not limited to a particular enantiomer and may be in racemic form, be an essentially pure R,R isomer, e.g., R,R-deutetrabenazine (see below) (e.g., contain less 10%, less than 5%, less than 1%, or less than 0.1% S,S isomer), be essentially pure S,S isomer, e.g. S,S-deutetrabenazine (see below) (e.g., contain less than 10 %, less than 5%, less than 1% or less than 0.1% R,R-isomer) or be a mixture of R,R-isomer and S,S-isomer in any ratio. In some embodiments, the transdermal delivery device contains deitetrabenazine in racemic form. In some embodiments, the transdermal delivery device comprises

deitetrabenazine as essentially pure R,R-deutetrabenazine. In some embodiments, deitetrabenazine is the only drug in the drug layer. In some embodiments, deitetrabenazine is the only drug in the transdermal delivery device. In some embodiments, the drug layer and/or transdermal delivery device may also contain other active ingredients.

,

[35] The drug may be present in the drug layer of the transdermal delivery device in varying amounts. In some embodiments, the drug layer contains tetrabenazine, deuterated tetrabenazine, or a combination thereof in an amount of from 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 in between) by weight of the drug layer. In some specific embodiments, the drug layer contains tetrabenazine, deuterated tetrabenazine, or a combination thereof in an amount of about 2%, about 2.5%, about 5%, about 8%, about 10%, about 15%, or about 20% by weight of the layer. medicinal product. In some embodiments, tetrabenazine, deuterated tetrabenazine, or a combination thereof is only present in the drug layer (eg, drug layer in the adhesive) of the transdermal delivery device.

[36] The weight and thickness of the drug layer may vary depending on various factors such as drug concentration, desired duration of administration, etc. The drug layer is typically designed to be applied (eg, delivering tetrabenazine or deutetrabenazine) over a period of time. selected from about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, and

about 7 days. In some embodiments, the drug layer may have a coating weight of from about 0.01 g/cm ² to about 5 g/cm ² , for example, from about 0.05 g/cm ² to about 5 g/cm ² , from about 0 1 g/cm ² to about 5 g/cm ² , for example, from about 0.05 g/cm ² to about 0.90 g/cm ² , from about 0.1 g/cm ² to about 0.90 g /cm ² (for example, from about 0.1 g/cm ² to about 0.5 g/cm ² ) active surface area. In some embodiments, the drug layer may have a thickness of about 1.5 mm to about 10 mm, such as about 1.5 mm to about 3.5 mm (eg, about 2 mm to about 3.5 mm). In some embodiments, the drug layer may have a thickness of about 0.1 mil to about 100 mil, such as about 1 mil to about 50 mil (e.g., about 1 mil to about 10 mil or about 1.5 mil to about 3.5 mils).

[37] Transdermal penetration enhancers can enhance the penetration of tetrabenazine or deuterated tetrabenazine through the skin and can optionally be included in the drug layer. In some embodiments, the drug layer does not or substantially does not contain a penetration enhancer. However, in some embodiments, various transdermal penetration enhancers may be included. Non-limiting examples of suitable transdermal penetration enhancers include, for example, sulfoxides (eg, dimethyl sulfoxide, DMSO), azones (eg, laurocapram), pyrrolidones (eg, 2-pyrrolidone, 2P), alcohols and alkanols (eg, ethanol or decanol), esters , glycols (eg, propylene glycol (PG)), surfactants (eg, Tween 80), terpenes, and combinations thereof. See, for example, Williams et al., Adv Drug Deliv Rev. 27;56(5):603-18 (2004). In some embodiments, the transdermal penetration enhancer comprises one or more compounds selected from sulfoxides, alcohols, alkanols, esters, glycols, and surfactants. In some embodiments, the percutaneous penetration enhancer comprises one or more compounds selected from dimethyl sulfoxide (DMSO), oleic alcohol, oleyl oleate, oleic acid, levulinic acid, other fatty acids and fatty acid esters, propylene glycol, dipropylene glycol, ethanol, and surfactants. substances, such as Tween 80. Typically, the transdermal penetration enhancer is present in an amount of from about 1% to about 25% by weight of the pharmaceutical composition, for example, about 2%, about 5%, about 10%, about 15%, about 20 %, about 25%, or is in any range between the indicated values by weight of the pharmaceutical composition.

[38] Other suitable adjuvants used in the manufacture of transdermal delivery devices, such as humectants, plasticizers, antioxidants, emollients, gelling agents, crystallization inhibitors, drug release modifiers, and the like, may also be included in the drug layer. agent (eg, into a drug layer in an adhesive) or otherwise into the transdermal delivery device described herein. In some embodiments, additional active ingredient(s) may also be included in the drug layer or otherwise in the transdermal delivery device described herein. These excipients are known to those skilled in the art and are presented, for example, in the Handbook of Pharmaceutical Excipients, (7th edition, 2012), the entire content of which is incorporated herein by reference.

adhesive layer

[39] The adhesive layer may be the same as the drug layer or may be a separate layer. In a typical LSA patch, the drug is homogeneously dispersed in the adhesive to form a layer of drug in the adhesive. Other designs, such as the LSR patch, may also contain an adhesive layer separated from the drug layer, for example by a membrane. In some embodiments, more than one adhesive layer may be used in a transdermal delivery device (eg, two or more drug layers in an adhesive).

[40] The adhesive layer typically contains a pressure-sensitive adhesive (PSA). As a rule, NSAs are known in the art. See, for example, Tan et al., Pharm Sci & Tech Today, 2:60-69 (1999). Non-limiting examples of suitable analytical grades include polyisobutylenes (PIB), silicone polymers, acrylate copolymers, and combinations thereof. In some embodiments, the pressure-sensitive adhesive comprises a polyisobutylene adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some embodiments, the pressure-sensitive adhesive comprises an acrylate copolymer adhesive. Non-limiting examples of suitable acrylate copolymers include, for example, acrylic pressure sensitive adhesives such as polyacrylate vinyl acetate copolymer, e.g. Duro-Tak 87-2852 or Duro-Tak 87-2194), which are manufactured by Henkel Adhesives. In some embodiments

the pressure-sensitive adhesive may be an inert acrylate adhesive (e.g., as described herein, such as Duro-Tak 87-900A), for example, an acrylate adhesive having no functional groups containing reactive hydrogen moieties, or an acrylate adhesive having no functional groups selected from epoxy, -OH, -COOH, and combinations thereof. PIBs are elastomeric polymers that are commonly used in analytical analysis, both as primary polymers and as tackifiers. PIBs are homopolymers of isobutylene and have a regular carbon-hydrogen backbone structure with only unsaturated end groups. Non-limiting examples of suitable PIBs include those sold under the trade name Oppanol from BASF. However, in some embodiments, the pressure-sensitive adhesive does not contain a PIB-based adhesive. Silicone polymers are high molecular weight polydimethylsiloxane that contain residual silanol functional groups (SiOH) at the ends of the polymer chains. Non-limiting examples of silicone analytical grades suitable for pharmaceutical use include those available from Dow Corning Corporation, eg under the tradename BIO-PSA, eg BIO-7-4202. In some embodiments, the thickness of the adhesive layer is from about 1.5 mils to about 10 mils (eg, from about 1.5 mils to about 2 mils).

[41] One or more adhesives may be used in the adhesive layer. For example, in some embodiments, 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 varying ratios (e.g., the ratio of acrylate adhesive to silicone adhesive ranges from about 1:10 to about 10:1). As detailed in the Examples section, changing adhesive components can affect the flow characteristics of the transdermal delivery device.

[42] Typically, the adhesive layer is formulated such that the transdermal delivery device can adhere to the user's skin for a desired period of time. For example, in some embodiments, the transdermal delivery device is configured to continuously adhere to the user's skin for about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days. days, about 6 days, or about 7 days or more.

Adhesive composition

[43] In some embodiments, the present invention also provides an adhesive composition comprising a drug selected from tetrabenazine, deuterated tetrabenazine (eg, deitetrabenazine), and combinations thereof, in an adhesive. In some embodiments, the implementation of the drug is homogeneously dispersed in the adhesive. Suitable drug and adhesives include any of those described herein.

[44] In some embodiments, the adhesive composition is configured to continuously adhere to the user's skin for an extended period of time selected from about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more.

[45] In some embodiments, the implementation of the adhesive is a pressure-sensitive adhesive. In some embodiments, the pressure-sensitive adhesive comprises a polyisobutylene (PIB) adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some embodiments, the pressure-sensitive adhesive may be an inert acrylate adhesive (e.g., as described herein, such as Duro-Tak 87-900A), such as an acrylate adhesive having no functional groups containing reactive hydrogen moieties, or an acrylate adhesive , which does not have functional groups selected from epoxy, -OH, -COOH and their combinations. In some embodiments, the pressure-sensitive adhesive does not contain a polyisobutylene (PIB) adhesive and/or a silicone polymer adhesive.

[46] The drug in the adhesive composition is preferably tetrabenazine or deitetrabenazine. In some embodiments, the drug is tetrabenazine. In some embodiments, tetrabenazine is essentially pure R,R-tetrabenazine. In some embodiments, the drug is deitetrabenazine. In some embodiments, deitetrabenazine is essentially pure R,R-deutetrabenazine. In some embodiments, tetrabenazine is the only active ingredient in the adhesive composition. In some embodiments, deitetrabenazine is the only active ingredient in the adhesive composition. In some embodiments, tetrabenazine or deitetrabenazine 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 in between) by weight of the adhesive composition. In some specific embodiments, the adhesive composition comprises tetrabenazine or deitetrabenazine 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 embodiments, the active ingredient is present in an amount of from about 2% to about 7% by weight.

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

[48] In some embodiments, the adhesive composition may optionally contain one or more ingredients selected from humectants, plasticizers, antioxidants, emollients, gelling agents, crystallization inhibitors, drug release modifiers, and additional active ingredients. For example, in some embodiments, the implementation of the adhesive composition may contain an antioxidant, for example, a gallate antioxidant, such as propyl gallate. In some embodiments, the adhesive composition may contain a crystallization inhibitor such as polyvinylpyrrolidone polymer, crosslinked polyvinylpyrrolidone polymer, polyvinylpyrrolidone copolymer, cellulose-based polymer, polycarboxylic acid polymer, polymethacrylate, and polyethylene glycol-polyvinyl acetate-polyvinylcaprolactam (PVAc-PVCap-PEG) graft copolymer or a combination of them. In some preferred embodiments, the implementation of the adhesive composition contains a crystallization inhibitor, which is a copolymer of butyl methacrylate and methyl methacrylate. In some embodiments, the implementation of the adhesive composition contains a crystallization inhibitor, which is a graft copolymer based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam.

[49] The adhesive composition may be included in a transdermal delivery device. Typically, such a transdermal delivery device also includes a backing layer and a release liner that protect the adhesive surface prior to use. In some embodiments, the adhesive composition may be included as a drug layer in

any of the transdermal delivery devices described herein.

Characteristics of the flow through the skin

[50] The transdermal delivery device described herein preferably provides certain desired flow characteristics through the skin. Typically, a transdermal delivery device can deliver a drug (e.g., tetrabenazine or deutetrabenazine) to a subject in need in an amount of from about 0.1 mg/day/cm ² to about 5 mg/day/cm ² (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/cm ² or any range in between), for example, for a period of time selected from about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days and about 7 days. However, in some embodiments, the transdermal delivery device may deliver a drug (eg, tetrabenazine or deutetrabenazine) in an amount greater than about 5 mg/day/cm ² , for example, about 8 mg/day/cm ² , about 10 mg/day/ cm ² , about 15 mg/day/cm ² , about 20 mg/day/cm ² or any range between the indicated values. In some embodiments, the transdermal delivery device can deliver a drug (eg, tetrabenazine or deutetrabenazine) in an amount of less than about 0.1 mg/day/cm ² , for example, about 0.01 mg/day/cm ² , about 0. 02 mg/day/cm ² , about 0.05 mg/day/cm ² , about 0.1 mg/day/cm ² , or any range in between.

[51] In some embodiments, a transdermal delivery device can deliver a drug (e.g., tetrabenazine or deitetrabenazine) to a subject in need in an amount of from about 0.1 mg/day/cm ² to about 1 mg/day/cm ² (e.g. , about 0.1 mg/day/cm ² , about 0.2 mg/day/cm ² , about 0.5 mg/day/cm ² , about 1 mg/day/cm ² or any range in between) over a period of time 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 embodiments, the transdermal delivery device can deliver a drug (eg, tetrabenazine or deutetrabenazine) in an amount of from about 0.1 mg/day/cm ² to about 5 mg/day/cm ² (for example, about 0.1 mg/cm2). day/cm ² , about 0.2 mg/day/cm ² , about 0.5 mg/day/cm ² , about 1 mg/day/cm ² , about 5 mg/day/cm ² , or any range in between values), for example, over a period of more than 7 days. In some embodiments, the transdermal delivery device may also deliver a drug (e.g., tetrabenazine or

deitetrabenazine) in an amount of from about 0.1 mg/day/cm ² to about 5 mg/day/cm ² (for example, about 0.1 mg/day/cm ² , about 0.2 mg/day/cm ² , about 0.5 mg/day/cm ² , about 1 mg/day/cm ² or any range between the indicated values), for example, for a period of time selected from less than 24 hours, for example, less than 18 hours, less than 12 hours, less than 8 hours or less than 4 hours.

[52] In some embodiments, the transdermal delivery device comprises tetrabenazine, wherein the transdermal delivery device provides one or more of the following skin flux characteristics when tested in vitro using human cadaver skin: a) cumulative penetration of tetrabenazine in an amount of about 0 .1 µg/cm ² to about 150 µg/cm ² (eg, about 0.1 µg/cm ² , about 0.5 µg/cm ² , about 1 µg/cm ² , about 5 µg/cm ² , about µg/cm ² , about 15 µg/cm ² , about 20 µg/cm ² , about 50 µg/cm ² , about 75 µg/cm 2 , about 100 µg/cm ² , about 125 µg/cm ^{2 ,} about 150 µg /cm ² or in any range between the indicated values) per active surface area 6 hours after administration; b) cumulative penetration of tetrabenazine in an amount from about 2 µg/cm ² to about 400 µg/cm ² (for example, about 2 µg/cm ² , about 5 µg/cm ² , about 10 µg/cm ² , about 15 µg/cm ² , about 20 µg/cm ² , about 50 µg/cm ² , about 100 µg/cm ² , about 200 µg/cm ² , about 300 µg/cm ² , about 400 µg/cm ^{2 ,} or any range between the indicated values ) in terms of active surface area 12 hours after injection; and c) cumulative penetration of tetrabenazine in an amount from about 5 µg/cm ² to about 1000 µg/cm ² (eg, about 5 µg/cm ² , about 10 µg/cm ² , about 15 µg/cm ² , about 20 µg/cm 2 cm ² , about 25 µg/cm ² , about 50 µg/cm ² , about 100 µg/cm ² , about 200 µg/cm 2, about 300 µg/cm ² , about 400 µg/cm ^{2 ,} about 600 µg/cm ² , about 800 µg/cm ² , about 1000 µg/cm ² or any range between the indicated values) based on active surface area 24 hours after administration. In some embodiments, tetrabenazine is present in an amount of about 2% to about 30% (e.g., about 2% to about 20%, about 2% to about 10%, about 2% to about 5%, about 5% to about 10% , about 10% to about 15%) by weight of the drug layer. In some embodiments, tetrabenazine is present in an amount of about 2%, about 5%, about 8%, about 10%, about 15%, about 20%, or any range in between, by weight of the drug layer. In some embodiments, tetrabenazine is essentially pure R,R-tetrabenazine.

[53] In some embodiments, tetrabenazine is present in an amount of about 2% to about 5% by weight of the drug layer, and wherein the transdermal delivery device provides one or more of the following:

skin ^{flux characteristics} in an in vitro test using human cadaveric skin ^: 0.5 µg/cm ² , about 1 µg/cm ² , about 5 µg/cm ² , about 10 µg/cm ² , about 15 µg/cm 2 , about 20 µg/cm ^{2 ,} about 50 µg/cm ² , about 75 μg/cm ² , about 100 μg/cm ² or any range between the indicated values) based on active surface area 6 hours after administration; b) cumulative penetration of tetrabenazine in an amount of from about 2 µg/cm ² to about 200 µg/cm ² (for example, about 2 µg/cm ² , about 5 µg/cm ² , about 10 µg/cm ² , about

15 µg/cm ² , about 20 µg/cm ² , about 50 µg/cm ² , about 100 µg/cm ² , about 200 µg/cm ² , or any range in between) based on active surface area after 12 hours after the introduction; and c) a cumulative penetration of tetrabenazine in an amount of from about 5 µg/cm ² to about 600 µg/cm ² (eg, about 5 µg/cm ² , about 10 µg/cm ² , about 15 µg/cm ² , about 20 µg/cm cm ² , about 25 µg/cm ² , about

50 µg/cm ² , about 100 µg/cm ² , about 200 µg/cm ² , about 300 µg/cm ² , about 400 µg/cm ² , about 600 µg/cm ² or in any range between the indicated values) in the calculation on the active surface area 24 hours after administration.

[54] In some embodiments, tetrabenazine is present in an amount of about 5% to about 10% by weight of the drug layer, and wherein the transdermal delivery device provides one or more of the following skin flux characteristics when tested in vitro using human cadaveric skin : a) cumulative penetration of tetrabenazine in an amount from about 0.5 µg/cm ² to about 150 µg/cm ² (for example, about 1 µg/cm ² , about 5 µg/cm ² , about 10 µg/cm ² , about 15 µg/cm ² , about 20 µg/cm ² , about 50 µg/cm ² , about 75 µg/cm ² , about 100 µg/cm ² , about 150 µg/cm ^{2 ,} or any range between these values) per active surface area 6 hours after injection; b) cumulative penetration of tetrabenazine in an amount from about 4 µg/cm ² to about 400 µg/cm ² (for example, about 4 µg/cm ² , about 6 µg/cm ² , about 10 µg/cm ² , about 15 µg/cm ² , about 20 µg/cm ² , about 50 µg/cm ² , about 100 µg/cm ² , about 200 µg/cm ² , about 400 µg/cm ² or any range between the above values) per active surface area 12 hours after administration; and c) a cumulative penetration of tetrabenazine in an amount of from about 6 µg/cm ² to about 1000 µg/cm ² (eg, about 6 µg/cm ² , about 10 µg/cm ² , about 15 µg/cm ² , about 20 µg/cm 2 cm ² , about 25 µg/cm ² , about 50 µg/cm ² , about 100 µg/cm ² , about 200 µg/cm 2, about 300 µg/cm ² , about 400 µg/cm ^{2 ,} about 600 µg/cm ² , about 1000 µg/cm ² or any range between the indicated values) based on active surface area 24 hours after administration.

[55] In some embodiments, tetrabenazine is present in an amount of about 10% to about 15% by weight of the drug layer, and wherein the transdermal delivery device provides one or more of the following skin flux characteristics when tested in vitro using human cadaveric skin : a) cumulative penetration of tetrabenazine in an amount from about 0.5 µg/cm ² to about 150 µg/cm ² (for example, about 1 µg/cm ² , about 2 µg/cm ² , about 5 µg/cm ² , about 10 µg/cm ² , about 15 µg/cm ² , about 20 µg/cm ² , about 50 µg/cm ² , about 75 µg/cm ² , about 100 µg/cm ² , about 150 µg/cm ² or any range between the indicated values) per active surface area 6 hours after administration; b) cumulative penetration of tetrabenazine in an amount from about 4 µg/cm ² to about 400 µg/cm ² (for example, about 4 µg/cm ² , about 6 µg/cm ² , about 10 µg/cm ² , about 15 µg/cm ² , about 20 µg/cm ² , about 30 µg/cm ² , about 40 µg/cm ² , about 50 µg/cm ² , about 100 µg/cm 2 , about 200 µg/cm ^{2 ,} about 400 µg/cm ² or in any range between the indicated values) in terms of active surface area 12 hours after administration; and c) cumulative penetration of tetrabenazine in an amount of from about 8 µg/cm ² to about 1000 µg/cm ² (eg, about 8 µg/cm ² , about 10 µg/cm ² , about 15 µg/cm ² , about 20 µg/cm cm ² , about 30 µg/cm ² , about 40 µg/cm ² , about 50 µg/cm ² , about 60 µg/cm ^{2, about 100 µg/cm 2} , about 200 µg/cm ^{2 ,} about 300 µg/cm ² , about 400 µg/cm ² , about 600 µg/cm ² , about 1000 µg/cm ² or any range in between) based on active surface area 24 hours after administration.

[56] In some embodiments, the transdermal delivery device comprises a deuterated tetrabenazine (e.g., deutetrabenazine), and wherein the transdermal delivery device provides one or more of the following skin flux characteristics when tested in vitro using human cadaveric skin: a) cumulative penetration deuterated tetrabenazine in an amount from about 0.1 µg/cm ² to about 150 µg/cm ² (for example, about 0.1 µg/cm ² , about 0.5 µg/cm ² , about 1 µg/cm ² , about 5 µg/cm ² , about 10 µg/cm ² , about 15 µg/cm ² , about 20 µg/cm ² , about 50 µg/cm 2 , about 75 µg/cm ² , about 100 µg/cm ^{2 ,} about 125 µg /cm ² about 150 µg/cm ² or in any range between the indicated values) based on the area of the active surface after 6 hours after injection; b) cumulative penetration of deuterated tetrabenazine in an amount of from about 2 µg/cm ² to about 400 µg/cm ² (eg, about 2 µg/cm ² , about 5 µg/cm ² , about 10 µg/cm ² , about 15 µg/cm cm ² , about 20 µg/cm ² , about 50 µg/cm ² , about 100 µg/cm ² , about 200 µg/cm ² , about 300 µg/cm ² , about 400 µg/cm ^{2 ,} or any range in between values) per active surface area 12 hours after injection; And

c) cumulative penetration of deuterated tetrabenazine in an amount of from about 5 µg/cm ² to about 1000 µg/cm ² (eg, about 5 µg/cm ² , about 10 µg/cm ² , about 15 µg/cm ² , about 20 µg/cm cm ² , about 25 µg/cm ² , about 50 µg/cm ² , about 100 µg/cm ² , about 200 µg/cm 2, about 300 µg/cm ² , about 400 µg/cm ^{2 ,} about 600 µg/cm ² , about 800 µg/cm ² , about 1000 µg/cm ² or any range between the indicated values) based on active surface area 24 hours after administration. In some embodiments, the deuterated tetrabenazine is present in an amount of about 2% to about 30% (e.g., about 2% to about 20%, about 2% to about 10%, about 2% to about 5%, about 5% to about 10 %, about 10% to about 15%) by weight of the drug layer. In some embodiments, the deuterated tetrabenazine is present in an amount of about 2%, about 5%, about 8%, about 10%, about 15%, about 20%, or any range in between, by weight of the drug layer. In some embodiments, the deuterated tetrabenazine is essentially pure R,R-deutetrabenazine.

[57] Devices for transdermal delivery with the above flow characteristics can be made by experts in the art in view of the present invention. The manufacture of several transdermal delivery devices is also exemplified in the Examples section. The overall penetration of the drug (tetrabenazine, deuterated tetrabenazine, or a combination thereof) can be controlled, for example, by changing the composition of the drug layer (eg, drug concentration, penetration enhancer, coating weight, types of adhesives, etc.).

Compositions containing inert adhesives

[58] Compositions that use inert adhesives can provide certain advantages. As shown in the Examples section, tetrabenazine formulations with inert adhesives can be more stable than corresponding formulations with functionalized adhesives. For example, when using DuroTak 87-900A inert adhesive as the matrix polymer, which is understood to be a 2-EHA (2-ethylhexyl acrylate) copolymer (about 45 wt% based on the monomer composition), MA (methyl acrylate) (about 35 wt.% based on monomer composition) and t-OA (tert-octylacrylamide) (about 20 wt.% based on monomer composition), the resulting tetrabenazine adhesive composition was stable after storage for 4 weeks at 40 °C, no crystals were observed.

drug or its degradation. In contrast, tetrabenazine adhesive composition prepared using the more common adhesive matrix polymer DuroTak 87-2287 (containing epoxy and hydroxyl functional groups) or Duro-Tak 87-2677 (containing carboxylic acid functional groups), the resulting composition took on a yellowish color after storage for 4 weeks at 40°C indicating instability of the active ingredient due to oxidation and/or other degradation.

[59] In some embodiments, the present invention provides an adhesive composition comprising an active ingredient (alternatively referred to as a "drug") dispersed (e.g., homogeneously dispersed or dissolved) in an inert pressure-sensitive acrylate adhesive, the active ingredient being selected from tetrabenazine, deuterated tetrabenazine, or combinations thereof. Unless otherwise clear from the context, in any of the embodiments described herein, the active ingredient may predominantly exist (e.g., at least 80%, at least 90%, or at least 95% by weight) in the form of its free base, such as tetrabenazine base, deitetrabenazine base, etc. The inert acrylate pressure-sensitive adhesive is typically present in an amount of from 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 any range in between) by weight of the adhesive composition.

[60] Inert acrylate pressure-sensitive adhesives useful in embodiments of the present invention include those sold by Henkel, for example under the tradename DuroTak 87-900A. In US Patent

No. 9,056,060, the contents of which are incorporated herein by reference in its entirety, also describes inert acrylate pressure-sensitive adhesives that can be used in embodiments of the present invention.

[61] In some embodiments, the implementation of the inert acrylate pressure-sensitive adhesive does not have functional groups containing reactive hydrogen fragments. In some embodiments, the implementation of the inert acrylate pressure-sensitive adhesive does not have functional groups selected from epoxy, -OH, -COOH, and combinations thereof. For example, in some embodiments, the inert acrylate pressure-sensitive adhesive is an alkyl acrylate copolymer that does not have functional groups containing reactive hydrogen moieties or does not have

functional groups selected from epoxy, -OH, -COOH and combinations thereof. In some embodiments, the inert acrylate pressure-sensitive adhesive may be a copolymer of monomers containing, essentially consisting of, or consisting of alkyl acrylates. For example, in some embodiments, the inert acrylate pressure-sensitive adhesive may be a copolymer derived from monomers consisting of alkyl acrylates, such as a copolymer derived from a C ₂ -C ₁₈ alkyl acrylate monomer (preferably a C ₄ -C ₁₀ branched or linear alkyl acrylate) and a monomer methyl acrylate, more preferably a copolymer derived from a hexylethyl acrylate monomer (eg 2-ethylhexyl acrylate) and a methyl acrylate monomer. In some embodiments, the alkyl acrylate copolymer is a copolymer of hexyl ethyl acrylate (e.g., 2-ethylhexyl acrylate) and methyl acrylate and optionally other monomer(s) without functional groups containing reactive hydrogen moieties, such as -OH, -COOH groups. In some embodiments, the inert acrylate pressure-sensitive adhesive may be a copolymer derived from monomers including alkyl acrylate and other monomers without functional groups containing reactive hydrogen moieties such as -OH, -COOH groups. For example, in some embodiments, the inert acrylate pressure-sensitive adhesive may be a copolymer derived from a hexylethyl acrylate (e.g., 2-ethylhexyl acrylate) monomer, a methyl acrylate monomer, and one or more non-functional monomers containing reactive hydrogen moieties, such as –OH, - COOH, eg acrylamide monomers (eg tert-octylacrylamide, dimethylacrylamide, isopropyl acrylamide or vinylacetamide). In the context of the present description, NH amide groups or NH ₂ amide groups should not be considered as reactive hydrogen moieties. In some embodiments, the inert acrylate pressure-sensitive adhesive may be a copolymer derived from a C ₂ -C ₁₈ alkyl acrylate monomer (preferably a C ₄ -C ₁₀ branched or linear alkyl acrylate), a methyl acrylate monomer, and one or more acrylamide monomers (e.g., t-octylacrylamide ) without functional groups selected from epoxy, –OH, -COOH and their combinations. The weight percentage of monomers can vary, for example, in some embodiments, the percentage of monomers of an inert acrylate pressure-sensitive adhesive can be as follows: percentage of C ₂ -C ₁₈ alkyl acrylate monomer (preferably C ₄ -C ₁₀

alkyl acrylate, such as 2-ethylhexylacrylate) may be about 45 wt.%, the percentage of methyl acrylate monomer may be about 35 wt. %, and the percentage of monomer from one or more acrylamide monomers (eg, tert-octylacrylamide) may be about 20 wt. %.

[62] The inert acrylate pressure-sensitive adhesive typically does not contain vinyl acetate. The inert acrylate pressure sensitive adhesive typically also does not contain a crosslinker. The inert acrylate pressure sensitive adhesive can typically have a variety of viscosities. In some embodiments, the inert acrylate pressure sensitive adhesive may have a viscosity of about 1500 cps to about 20,000 cps, more preferably about 1500 cps to about 10,000 cps, such as about 1800 cps, about 5000 cps, about 10,000 cps, or ranges between the specified values. In some embodiments, the inert acrylate pressure sensitive adhesive may be selected such that the adhesive composition can continuously adhere to the user's skin for about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days. , about 4 days, about 5 days, about 6 days, or about 7 days or more.

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

[64] Antioxidants are typically included in the adhesive composition described herein. For example, antioxidants may be added to reduce degradation of the active ingredient. Surprisingly, however, some antioxidants have been found to work better to protect tetrabenazine from degradation than others. For example, it has been found that adhesive compositions

containing a gallate antioxidant (eg propyl gallate in the examples) are storage stable. In any of the embodiments described herein, the term “shelf-stable”, “shelf-stable”, or “storage-stable”, etc., may mean that after the test device or composition has been stored at 40 °C for 4 weeks

(1) HPLC analysis indicates that the device or composition tested contains no or substantially no (e.g. less than 1%, less than 0.5%, less than 0.05%, or not detectable by HPLC) one or more ( preferably all) degradation products selected from TBZ01, TBZ02 and TBZ04; and/or (2) no drug crystals are observed (eg, on visual inspection). In some embodiments, in the storage-stable device or composition described herein, after storage at 40 °C for 4 weeks, none of the degradation products of TBZ01, TBZ02, and TBZ04 are detected by HPLC, or their amount is below the limit of quantitation. Examples of HPLC analysis conditions and retention times of TBZ01, TBZ02 and TBZ04 are shown in Example 5. However, in cases where the antioxidant is not used or when the added antioxidant is BHT, degradation products (including TBZ01, TBZ02 and TBZ04) are generated. In some embodiments, the adhesive composition may contain a gallate antioxidant. In some preferred embodiments, the implementation of the adhesive composition may contain propyl gallate. In some preferred embodiments, propyl gallate is the only antioxidant in the adhesive composition. In some embodiments, other antioxidants may be used in combination with propyl gallate. In some embodiments, the implementation of the adhesive composition as an antioxidant may also contain propyl gallate, citric acid, ascorbic acid, vitamin E or tocopherol acetate, or a combination thereof. When present, an antioxidant, such as propyl gallate, is typically present in an amount of from 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.

[65] The active ingredient is typically present in the adhesive composition in an amount of from about 2% to about 30% by weight. Preferably, in some embodiments, the active ingredient may be present in the adhesive composition in an amount of from about 2% to about 15% by weight, such as from about 2% to about 10% or from about 2% to about 7% by weight. Tetrabenazine in the adhesive compositions described herein is not limited to a particular enantiomer and may be in

racemic form, be essentially pure R,R-tetrabenazine (e.g., contain less than 10%, less than 5%, less than 1%, or less than 0.1% S,S isomer), be essentially pure S,S-tetrabenazine ( for example, contain less than 10%, less than 5%, less than 1% or less than 0.1% R,R-isomer) or a mixture of R,R-tetrabenazine and S,S-tetrabenazine in any ratio. Similarly, the deuterated tetrabenazine in the adhesive compositions described herein is not limited to a particular enantiomer and may be in racemic form, be an essentially pure R,R isomer, e.g., R,R-deutetrabenazine (e.g., contain less than 10%, less 5%, less than 1% or less than 0.1% S,S isomer), be essentially pure S,S isomer, e.g. S,S-deutetrabenazine (e.g., contain less than 10%, less than 5%, less than 1 % or less than 0.1% R,R-isomer) or be a mixture of R,R-isomer and S,S-isomer in any ratio. In some embodiments, the only active ingredient in the adhesive composition is tetrabenazine, for example, the substantially pure R,R isomer of tetrabenazine. In some embodiments, the only active ingredient in the adhesive composition is deitetrabenazine, for example, the substantially pure R,R isomer of deitetrabenazine. In some embodiments, the adhesive compositions may also contain other active ingredients, such as those described herein.

[66] Typically, a crystallization inhibitor is also included in the adhesive composition to prevent crystallization of the drug during storage. Such drug crystals may delay the penetration of such adhesive compositions through the skin. Accordingly, in some embodiments, the implementation of the adhesive composition may contain a crystallization inhibitor in an amount effective to prevent the formation of crystals of the drug after storage for two weeks at ambient temperature. In some embodiments, the adhesive composition may contain 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), polyvinylpyrrolidone copolymer (for example, Plasdone S-630 Copovidone (Asland)), cellulose-based polymer (for example, hydroxylpropylmethylcellulose, ethylcellulose, hydroxypropylcellulose), polycarboxylic acid polymer (for example, Cabopol (manufactured by Lubrizol)), polymethacrylate (for example, Plastoid B, Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol based graft copolymer,

polyvinyl acetate and polyvinyl caprolactam (PVAc-PVCap-PEG) (eg, Soluplus (BASF) and combinations thereof. In some embodiments, the crystallization inhibitor is not Kollidon VA64 (BASF).

[67] In some preferred embodiments, the adhesive composition may include a crystallization inhibitor selected from a polymethacrylate (e.g., Plastoid B (a copolymer of butyl methacrylate and methyl methacrylate), Eudragit E100, Eudragit L100-55 (manufactured by Evonik)), polyethylene glycol-based graft copolymer , polyvinyl acetate and polyvinyl caprolactam (PVAc-PVCap-PEG) (e.g., Soluplus (BASF) and combinations thereof. For example, in some specific embodiments, the adhesive composition comprises a copolymer of butyl methacrylate and methyl methacrylate, such as the Plastoid B polymer from Evonic. In some specific embodiments, the adhesive composition comprises a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, such as BASF's Soluplus polymer. by weight, for example, in an amount of about 10%, about 20%, about 30%, about 40% by weight, or any range between these values.

[68] In some specific embodiments, the present invention provides adhesive compositions with the following ingredients:

Ingredient Percentage by mass (based on dry
substances) Typical Preferred More
preferred Active ingredient (e.g. base
tetrabenazine) 2–10% 5–10% 5–7% (for example,
6.8%, 7.1%) Adhesive (ChDA)
(e.g. Duro-Tak 87-900A) 50-97% 60-95% 65-95% (for example,
72.9%, 92.5%) Antioxidants (eg.
propyl gallate) 0–1% 0.001–0.5% 0.01–0.1%
(e.g. 0.05%) Inhibitors
crystallization 0-40% 10–40% 15-30% (for example,
20%, 19.3%) (for example, Plastoid B,
Soluplus)

Numerical values in the table should be understood as if they were preceded by the term "about". Optionally, other ingredients may be included. In some embodiments, the adhesive composition does not contain a penetration enhancer. In some embodiments, the implementation of the adhesive composition does not contain isopropyl myristate. Suitable active ingredients, adhesives (eg, an inert acrylate adhesive), antioxidants, and crystallization inhibitors include those described herein. For example, in some preferred embodiments, the active ingredient is a tetrabenazine base (e.g., a substantially pure R,R isomer), the adhesive is an acrylate polymer such as an inert acrylate adhesive, preferably a hexylethyl acrylate/methyl acrylate copolymer 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 graft copolymer based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam. In some embodiments, the present disclosure also provides a method for preparing an adhesive composition (eg, as described herein). In some embodiments, the method includes mixing an active ingredient (eg, tetrabenazine base), an adhesive, optionally an antioxidant, optionally a crystallization inhibitor in a suitable solvent (eg, ethanol, etc.) to form a wet adhesive composition. Suitable amounts and suitable active ingredients, adhesives, antioxidants, crystallization inhibitors include any of those described and preferred herein, such as those discussed in this paragraph and the previous 10 paragraphs. This document also describes other optional ingredients and their amounts. In some embodiments, the method further comprises casting the wet adhesive composition onto the backing layer. In some embodiments, the method further comprises drying the wet adhesive composition. The products obtained by the methods described herein are also novel compositions.

[69] The adhesive composition (eg, the inert acrylate adhesive adhesive composition described herein) is typically included in a transdermal delivery device, eg, as a drug layer or as a drug layer in an adhesive. For example, in some variants

embodiment, the present disclosure provides a transdermal delivery device that comprises a backing layer, any of the adhesive compositions described herein (e.g., an inert acrylate adhesive adhesive composition described herein as a drug layer or as a drug layer in an adhesive), and removable protective coating. The transdermal delivery device can be cut into various sizes as desired, which are typically from about 10 cm ² to about 100 cm ² . Other patch designs are described herein. Preferably, the transdermal delivery device described herein (and/or the adhesive composition, e.g., with an inert acrylate adhesive, described herein) is storage stable (or alternatively referred to as long-term storage), e.g., after it has been stored at 40 °C, no drug crystals are observed within 4 weeks and/or after storage at 40 °C for 4 weeks, HPLC analysis shows no degradation of the drug. For example, in some embodiments, the transdermal delivery device described herein (and/or the adhesive composition, e.g., with an inert acrylate adhesive, described herein) can be stored 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.

[70] Typically, the transdermal delivery device (and/or adhesive composition) described herein can also be configured to achieve the desired permeability of the active ingredient (eg, tetrabenazine or deutetrabenazine) through the skin. For example, in some embodiments, a transdermal delivery device (e.g., comprising an inert acrylate adhesive adhesive composition described herein) can deliver an active ingredient (e.g., tetrabenazine or deitetrabenazine) to a subject in need in an amount of about 0.01 mg/day. days/cm ² to about 5 mg/day/cm ² (for example, about 0.01 mg/day/cm ² , about 0.02 mg/day/cm ² , about 0.05 mg/day/cm ² , about 0.1 mg / day / cm ² , about 0.2 mg / day / cm ² , about 0.5 mg / day / cm ² , about 1 mg / day / cm ² , about 2 mg / day / cm ² , about 5 mg/day/cm ² or any range between these values), for example, for a period of time selected from about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days and about 7 days. In some embodiments, a transdermal delivery device (e.g., comprising

adhesive composition with an inert acrylate adhesive described herein) can deliver a drug (eg, tetrabenazine or deutetrabenazine) in an amount of more than about 5 mg/day/cm ² , for example, about 8 mg/day/cm ² , about 10 mg /day/cm ² , about 15 mg/day/cm ² , about 20 mg/day/cm ² or in any range between the indicated values. In some embodiments, a transdermal delivery device (eg, comprising an inert acrylate adhesive adhesive composition described herein) can deliver the active ingredient (eg, tetrabenazine or deutetrabenazine) in an amount of less than about 0.1 mg/day/ ^cm2 . for example, about 0.01 mg/day/cm ² , about 0.02 mg/day/cm ² , about 0.05 mg/day/cm ² , about 0.1 mg/day/cm ² , or any range in between values.

[71] For example, in some embodiments, the transdermal delivery device adhesive composition contains about 2% to about 10% by weight (e.g., about 2% to about 7%) tetrabenazine, with the transdermal delivery device (e.g., comprising adhesive composition with an inert acrylate adhesive described herein) provides one or more of the following skin flux characteristics when tested in ^vitro using human cadaveric skin: μg/cm ² (for example, about 1 μg/cm ² , about 5 μg/cm ² , about 10 μg/cm ² , about 15 μg/cm ² , about 20 μg/cm ² , about 50 μg/cm ² or any ranges between the indicated values) per active surface area 8 hours after injection; b) cumulative penetration of tetrabenazine in an amount from about 5 µg/cm ² to about 500 µg/cm ² (for example, about 5 µg/cm ² , about 10 µg/cm ² , about 15 µg/cm ² , about 20 µg/cm ² , about 50 µg/cm ² , about 100 µg/cm ² , about 200 µg/cm ² , about 500 µg/cm ^{2 ,} or any range in between) based on active surface area 24 hours after administration; and c) cumulative penetration of tetrabenazine in an amount of from about 10 µg/cm ² to about 1000 µg/cm ² (eg, about 10 µg/cm ² , about 20 µg/cm ² , about 50 µg/cm ² , about 100 µg/cm 2 cm ² , about 200 µg/cm ² , about 300 µg/cm ² , about 400 µg/cm ² , about 600 µg/cm ² , about 1000 µg/cm ² or any range between the above values) per active area surfaces 48 hours after administration. In some embodiments, the in vitro test is carried out in accordance with the method described in example 6 of this application.

Methods of using tetrabenazine

[72] In various embodiments, in the present invention

further provided is a method of using the transdermal delivery device described herein or pharmaceutical compositions (eg, the adhesive compositions described herein). In some embodiments, transdermal delivery devices or pharmaceutical compositions can be used for any indication that would benefit from VMAT-2 inhibition. In some embodiments, transdermal delivery devices or pharmaceutical compositions can be used to treat or prevent a VMAT-2 mediated disease or disorder. In some embodiments, transdermal delivery devices or pharmaceutical compositions can be used for any indication that would benefit from the use of tetrabenazine or deuterated tetrabenazine. For example, in addition to the indication for the treatment of chorea associated with Huntington's disease, other indications approved or associated with the use of tetrabenazine or deuterated tetrabenazine include hemibalism, tic disorders, tardive dyskinesia, and Tourette's syndrome. And in various embodiments, transdermal delivery devices or pharmaceutical compositions can also be used for any of these indications.

[73] In some embodiments, the present invention provides a method of administering tetrabenazine, deuterated tetrabenazine, or a combination thereof to a subject (eg, human subject) in need thereof. In some embodiments, the method includes applying to the subject any of the transdermal delivery devices or pharmaceutical compositions (eg, the adhesive compositions described herein), for example, to the subject's skin. In some embodiments, the subject (eg, human subject) is characterized as having a hyperkinetic movement disorder (eg, chronic hyperkinetic movement disorder). In some embodiments, the hyperkinetic movement disorder is selected from chorea associated with Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tics, and combinations thereof. In some embodiments, the method includes using a transdermal delivery device containing tetrabenazine (eg, substantially pure R,R-tetrabenazine). In some embodiments, the method includes using a transdermal delivery device containing deitetrabenazine (eg, substantially pure R,R-deutetrabenazine).

[74] In some embodiments, the present invention also

provided is a method for inhibiting VMAT-2 in a subject in need thereof. In some embodiments, the method includes applying to the subject any of the transdermal delivery devices or pharmaceutical compositions (eg, the adhesive compositions described herein), for example, to the subject's skin.

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

[76] In some specific embodiments, the present invention provides a method for treating hyperkinetic movement disorder in a subject in need (eg, a human subject). In some embodiments, the method includes applying to the subject any of the transdermal delivery devices or pharmaceutical compositions (eg, the adhesive compositions described herein), for example, to the subject's skin. In some embodiments, the hyperkinetic movement disorder is a chronic hyperkinetic movement disorder. In some embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease, Wilson's disease,

Tourette's syndrome, restless legs syndrome, tardive dyskinesia and/or tic. In some embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease. In certain specific embodiments, the present invention provides a method of treating chorea associated with Huntington's disease in a subject in need thereof, the method comprising administering to the subject any of the transdermal delivery devices or pharmaceutical compositions (e.g., the adhesive compositions described herein). document), for example, on the subject's skin. In some specific embodiments, the present invention provides a method of treating tardive dyskinesia in a subject in need thereof, the method comprising administering to the subject any of the transdermal delivery devices or pharmaceutical compositions (e.g., the adhesive compositions described herein), for example, on the subject's skin. In some specific embodiments, the present invention provides a method of treating Tourette's syndrome in a subject in need thereof, the method comprising administering to the subject any of the transdermal delivery devices or pharmaceutical compositions (e.g., the adhesive compositions described herein), for example, on the subject's skin. In some specific embodiments, the present invention provides a method of treating a tic in a subject in need thereof, the method comprising administering to the subject any of the transdermal delivery devices or pharmaceutical compositions (e.g., the adhesive compositions described herein), e.g., subject's skin. In some specific embodiments, the present invention provides a method of treating hemibalism in a subject in need thereof, the method comprising administering to the subject any of the transdermal delivery devices or pharmaceutical compositions (e.g., the adhesive compositions described herein), e.g., subject's skin.

[77] Tetrabenazine and/or deuterated tetrabenazine (eg, deitetrabenazine) can be used in the methods described herein. Typically, the method involves the use of the transdermal delivery device described herein, which contains tetrabenazine or deitetrabenazine as the sole active ingredient. In some embodiments, the method includes using the transdermal delivery device described herein that contains substantially pure R,R-tetrabenazine, e.g., contains substantially pure R,R-tetrabenazine as

the only active ingredient. In some embodiments, the method includes using the transdermal delivery device described herein that contains substantially pure R,R-deutetrabenazine, for example, contains substantially pure R,R-deutetrabenazine as the sole active ingredient.

[78] In one embodiment described herein, the method may include administering to the subject a drug (eg, tetrabenazine or deutetrabenazine) in an amount of from about 0.1 mg/day/cm ² to about 5 mg/day/cm ² ( for example, 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/ cm ² , about 5 mg/day/cm ² or any range in between), for example, for a period of time selected from about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days and about 7 days. However, in some embodiments, the method may include administering to the subject a drug (eg, tetrabenazine or deutetrabenazine) in an amount greater than about 5 mg/day/cm ² , for example, about 8 mg/day/cm ² , about 10 mg/day/cm 2 ² , about 15 mg/day/cm ² , about 20 mg/day/cm ² , or any range between the indicated values. In some embodiments, the method may also include administering a drug (eg, tetrabenazine or deutetrabenazine) to the subject in an amount of less than about 0.1 mg/day/cm ² , for example. 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 in between. .

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

[80] Various advantages are associated with the methods described herein. For example, in some embodiments, the method may reduce inter-individual variation in plasma levels of tetrabenazine or deitetrabenazine or their metabolite when compared to similar oral doses of tetrabenazine or deitetrabenazine. In some embodiments, the implementation of the method may reduce (for example, 10%, 40%, 60% or more)

Cmax of tetrabenazine or deitetrabenazine or their metabolite in plasma compared with similar doses of tetrabenazine or deitetrabenazine for oral administration, for example, without a simultaneous decrease in therapeutic efficacy. In some embodiments, the method can provide similar plasma levels of tetrabenazine or deitetrabenazine or their metabolites when administered at similar doses to subjects who are genotyping for CYP2D6 expression as weak metabolizers (SM), intermediate metabolizers (IM), or active metabolizers (AM). In some embodiments, subjects characterized as SM, PM, or AM may be administered the same or substantially the same dose of tetrabenazine or deitetrabenazine. In some embodiments, the methods described herein allow transdermal administration of a drug (eg, tetrabenazine or deutetrabenazine) to a subject, regardless of whether the subject is characterized as SM, PM, or AM based on a determination of CYP2D6 expression.

Combination Therapy

[81] The transdermal delivery devices or pharmaceutical compositions disclosed herein (eg, the adhesive compositions described herein) can also be combined or used in combination with other agents used to treat VMAT2-mediated disorders. Such other agents may be administered in the manner and in the amount normally used thereto, simultaneously or sequentially with the transdermal delivery devices or pharmaceutical compositions disclosed herein (eg, the adhesive compositions described herein). In some embodiments, such other agents are included in the transdermal delivery devices or pharmaceutical compositions disclosed herein (eg, the adhesive compositions described herein). However, in some embodiments, such other agents are administered as a separate composition or otherwise independent of the transdermal delivery devices or pharmaceutical compositions disclosed herein (eg, the adhesive compositions described herein).

[82] In some embodiments, the transdermal delivery devices or pharmaceutical compositions disclosed herein (e.g., the adhesive compositions described herein) can be used in combination with one or more antipsychotics, including, but not limited to, chlorpromazine, levomepromazine, promazine, acepromazine,

triflupromazine, cyamemazine, chlorproetazine, dixirazine, fluphenazine, perphenazine, prochlorperazine, thiopropazate, trifluoperazine, acetophenazine, thioproperazine, butaperazine, perazine, periciazine, thioridazine, mesoridazine, pipothiazine, haloperidol, trifluperidol, melperone, moperone , pipamperone, bromperidol, benperidol, droperidol, fluanisone, oxypertine, molindone, sertindole, ziprasidone, flupentixol, clopenthixol, chlorprothixene, thiothixene, zuclopenthixol, fluspirilene, pimozide, penfluridol, loxapine, clozapine, olanzapine, quetiapine, tetrabenazine, sulpiride, sulfopride, tiapride, remoxipride, ami sulpride, veralipride, levosulpiride, lithium, protipendil, risperidone, clothiapine, mosapramine, zotepine, pripiprazole and paliperidone.

[83] In some embodiments, the transdermal delivery devices or pharmaceutical compositions disclosed herein (e.g., the adhesive compositions described herein) can be used in combination with one or more benzodiazepines ("mild tranquilizers"), including, without limitation alprazolam, adinazolam, bromazepam, camazepam, clobazam, clonazepam, clothiazepam, cloxazolam, diazepam, ethylloflazepat, estizolam, fludiazepam, flunitrazepam, halazepam, ketazolam, lorazepam, medazepam, dazolam, nitrazepam, nordazepam, oxazepam am, potassium clorazepate, pinazepam, prazepam, tofisopam , triazolam, temazepam and chlordiazepoxide.

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

[85] In some embodiments, transdermal delivery devices or pharmaceutical compositions disclosed herein (eg, adhesive compositions described herein) can be used in combination with other classes of compounds, including, without limitation, antiretroviral agents; CYP3A inhibitors; CYP3A inducers; protease inhibitors; adrenergic receptor agonists; anticholinergics; mast cell stabilizers; xanthines; leukotriene antagonists; glucocorticoid drugs; means for local or general anesthesia; non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen; antibacterial agents such as amoxicillin; cholesterol ester transfer protein (CETP) inhibitors such as anacetrapib; antifungals such as isoconazole; drugs for the treatment of sepsis, such as drotrecogin-α; steroid drugs such as hydrocortisone; agents for local or general anesthesia, such as ketamine;

norepinephrine reuptake inhibitors (SNRIs) such as atomoxetine; dopamine reuptake inhibitors (IDRIs) such as methylphenidate; serotonin-norepinephrine reuptake inhibitors (SNRIs) such as milnacipran; sedatives such as diazepham; a norepinephrine-dopamine reuptake inhibitor (SNRI) such as bupropion; serotonin-norepinephrine-dopamine reuptake inhibitors (SNRIs) such as venlafaxine; monoamine oxidase inhibitors such as selegiline; hypothalamic phospholipids; endothelin converting enzyme (EPF) 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 modulators of PDGF activity; platelet activating factor (PAF) antagonists; antiplatelet agents such as GPIIb/IIIa blockers (eg abdximab, eptifibatide and tirofiban), P2Y (AC) antagonists (eg clopidogrel, ticlopidine and CS-747) and aspirin; anticoagulants such as warfarin; low molecular weight heparins such as enoxaparin; factor VIIa inhibitors and factor Xa inhibitors; renin inhibitors; inhibitors of neutral endopeptidase (NEP); vasopepsidase inhibitors (dual NEP-ACE inhibitors) such as omapatrilat and hemopatrilat; HMG-CoA reductase inhibitors such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as itavastatin, nivastatin or nizbastatin) and ZD-4522 (also known as rosuvastatin, atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants such as questran; niacin; anti-atherosclerotic agents such as ACAT inhibitors; MTP inhibitors; calcium channel blockers such as amlodipine besylate; potassium channel activators; agents that affect alpha-muscarinic receptors; agents affecting beta-muscarinic receptors such as carvedilol and metoprolol; antiarrhythmic agents; diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid, tricrinafen, chlorthalidone, furosemide, muzolimin, bumetanide, triamterene, amiloride, and spironolactone; thrombolytic agents such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated streptokinase plasminogen activator complex (CAASP); antidiabetic agents such as biguanides (eg metformin), glucosidase inhibitors (eg acarbose), insulins, meglitinides (eg repaglinide), sulfonylureas (eg glimepiride, glyburide and glipizide),

thiozolidinediones (eg, troglitazone, rosiglitazone, and pioglitazone) and PPAR-gamma agonists; mineralocorticoid receptor antagonists such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors such as PDE III inhibitors (eg cilostazol) and PDE V inhibitors (eg sildenafil, tadalafil, vardenafil); protein tyrosine kinase inhibitors; anti-inflammatory; antiproliferatives such as methotrexate, FK506 (tacrolimus, prograf), mycophenolate mofetil; chemotherapeutic agents; immunosuppressants; antitumor agents and cytotoxic agents (eg, alkylating agents such as nitrogen mustard, alkylsulfonates, nitrosoureas, ethyleneimines, and triazenes); antimetabolites such as folic acid antagonists, purine analogs and pyridine analogs; antibiotics such as anthracyclines, bleomycins, mitomycin, dactinomycin and plicamycin; enzymes such as L-asparaginase; farnesyl protein transferase inhibitors; hormonal agents such as glucocorticoids (eg, cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists and octreotide acetate; microtubule disrupting agents such as ecteinascidins; microtubule stabilizing agents such as paclitaxel, docetaxel and epothilones A-F; vegetable products such as vinca alkaloids, epipodophyllotoxins and taxanes; and topoisomerase inhibitors; prenyl protein transferase inhibitors; and cyclosporine; steroids such as prednisone and dexamethasone; cytotoxic drugs such as azathioprine and cyclophosphamide; TNF-alpha inhibitors such as tenidap; antibodies to TNF or soluble TNF receptor such as etanercept, rapamycin and leflunimide; and cyclooxygenase-2 (COX-2) inhibitors such as celecoxib and rofecoxib; and miscellaneous agents such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes such as cisplatin, satraplatin and carboplatin.

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

Definitions

[87] As used herein, the term "about" modifying an amount relating to the invention refers to a change in the numerical amount,

which may occur, for example, as a result of routine testing and processing; due to an unintentional error in such testing and processing; due to differences in manufacturing, source or purity of the ingredients/materials used in the invention; and the like. As used herein, the term "about" referring to a specific value also includes the specific value, for example, about 10% includes 10%. Whether or not the listed amounts are modified by the term "about", the claims include their equivalents. In one embodiment, the term "about" means a value within 20% of the specified numerical value.

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

[89] As used herein, the term "cumulative drug penetration" refers to the total amount of drug penetrating per square centimeter during a given time period. Unless otherwise clear from the context, "cumulative drug penetration" for a given time (e.g., 24 hours after administration), refers to the total amount of drug that has penetrated per square centimeter since time 0 (i.e., from the time of administration) up to this point in time. Unless otherwise clear from the context, "cumulative drug penetration" refers to the arithmetic mean value measured and/or calculated in accordance with the methods described herein. The term used in this document

"mean", if not specified, also refers to the arithmetic mean, unless this is contrary to common practice in this area.

[90] As used herein, the term "flux" refers to the amount of drug permeated through the skin per unit area per unit time. Unless otherwise apparent from the context, the term "flux" refers to the arithmetic mean value measured and/or calculated in accordance with the methods described herein. A typical unit of flow is milligrams per square centimeter per hour.

[91] The flow rate referred to in this patent application may mean that it is measured by in vivo or in vitro methods. One way to measure flow is to place the transdermal delivery device or formulation on a known

on the skin of a human volunteer and measuring the amount of drug that can penetrate the skin for a certain limited time. In some embodiments, when it is specifically indicated that the measurement was performed by an in vitro method using human cadaveric skin, the flow rate is measured in accordance with the method described in Example 3 or 6. Although the in vitro method uses a human epidermal membrane prepared from a cadaver, rather than measuring drug flux through the skin of human volunteers, it is generally recognized by those skilled in the art that the results of a properly designed and performed in vitro test can be used with reasonable confidence to evaluate or predict the results of an in vivo test.

[92] The terms "skin flow characteristics" and "flow characteristics" are used interchangeably herein.

[93] As used herein, the terms "treat", "treatment",

"administering treatment" and the like refers to the elimination, reduction or amelioration of a disease or condition and/or associated symptoms. While not excluded, treatment of a disease or condition does not require complete elimination of the disease, condition, or associated symptoms.

[94] As used herein, the term "therapeutically effective amount" refers to an amount of a drug (eg, tetrabenazine) that is sufficient to result in the reduction of one or more symptoms of a disorder or condition (eg, Huntington's disease) or to prevent the onset or further development of the disorder or condition, or cause regression or cure of the disorder or condition.

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

[96] As used herein, the term "use or administration of a transdermal delivery device" described herein should be understood in accordance with the manner in which such a transdermal delivery device is routinely used or administered, for example, on human skin.

[97] The term "chronic hyperkinetic movement disorders" refers to disorders characterized by unintentional, repetitive, erratic movements, which are variously called: "compulsive",

"rhythmic" or "stereotypical". In humans, chronic hyperkinetic movement disorders may be psychogenic (eg, tics), idiopathic (eg, Tourette's syndrome and Parkinson's disease), genetic (eg, chorea characteristic of Huntington's disease), infectious (eg, Sydenham's chorea), or, as in drug-induced tardive dyskinesia Unless otherwise noted, "chronic hyperkinetic movement disorders" refers to and includes all psychogenic, idiopathic, genetic, and drug-induced movement disorders.

[98] The term "stereotypical" refers to repetitive behavior that is repeated with little variation or, less commonly, as a complex series of movements.

[99] The term "VMAT2" refers to vesicular monoamine transporter 2, an integral membrane protein that acts as a transporter of monoamines, especially neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine, from the cellular cytosol to synaptic vesicles.

[100] The term "VMAT2-mediated disorder" refers to a disorder characterized by abnormal VMAT2 activity. The VMAT2-mediated disorder may be wholly or partly mediated by VMAT2 modulation. In particular, a VMAT2-mediated disorder is a disorder in which inhibition of VMAT2 results in some effect on the underlying disease, for example, administration of a VMAT2 inhibitor results in some improvement in at least some of the treated patients.

Exemplary Embodiments 1-32

[101] Some illustrative embodiments (embodiments 1-32) of the present disclosure are shown below.

Embodiment 1. A transdermal delivery device comprising:

protective layer,

a drug layer containing tetrabenazine in an amount of from about 2% to about 30% by weight of the drug layer, and

an adhesive layer that determines the area of the active surface,

wherein the transdermal delivery device provides one or more of the following skin flux characteristics when tested in vitro using human cadaver skin:

(a) cumulative penetration of tetrabenazine from about 0.1 µg/cm ² to about

150 μg/cm ² in terms of active surface area 6 hours after administration;

(b) a cumulative penetration of tetrabenazine from about 2 µg/cm ² to about 400 µg/cm ² based on active surface area 12 hours after administration; And

(c) cumulative penetration of tetrabenazine from about 5 µg/cm ² to about 1000 µg/cm ² based on active surface area 24 hours after administration.

Embodiment 2. The transdermal delivery device of Embodiment 1, wherein tetrabenazine is present in an amount of about 2% to about 5% by weight of the drug layer, wherein the transdermal delivery device provides one or more of the following skin flow characteristics when in vitro test using human cadaveric skin:

(i) a cumulative penetration of tetrabenazine from about 0.1 µg/cm ² to about 100 µg/cm ² based on active surface area 6 hours after administration;

(ii) a cumulative penetration of tetrabenazine from about 2 μg/cm ² to about 200 μg/cm ² based on active surface area 12 hours after administration;

(iii) a cumulative penetration of tetrabenazine from about 5 µg/cm ² to about 600 µg/cm ² based on active surface area 24 hours after administration.

Embodiment 3. The transdermal delivery device of Embodiment 1, wherein tetrabenazine is present in an amount of about 10% to about 15% by weight of the drug layer, wherein the transdermal delivery device provides one or more of the following skin flow characteristics when in vitro test using human cadaveric skin:

(i) a cumulative penetration of tetrabenazine from about 0.5 µg/cm ² to about 150 µg/cm ² based on active surface area 6 hours after administration;

(ii) a cumulative penetration of tetrabenazine from about 4 µg/cm ² to about 400 µg/cm ² based on active surface area 12 hours after administration; And

(iii) a cumulative penetration of tetrabenazine from about 6 μg/cm ² to about 1000 μg/cm ² based on active surface area 24 hours after administration.

Embodiment 4. The transdermal delivery device of Embodiment 1 wherein tetrabenazine is present in an amount of about 8% by weight of the drug layer.

Embodiment 5. The transdermal delivery device of any one of Embodiments 1-4, wherein the active surface area is from about 5 cm ² to about 300 cm ² .

Embodiment 6. The transdermal delivery device of any one of Embodiments 1-5, wherein the active surface area is from about 10 cm ² to about 100 cm ² .

Embodiment 7. The transdermal delivery device of any of Embodiments 1-6, which is a drug-in-reservoir patch, wherein the drug layer is a reservoir containing tetrabenazine.

Embodiment 8. The transdermal delivery device of any one of Embodiments 1-6, which is a drug-in-adhesive patch, wherein the drug layer contains tetrabenazine dispersed in a pressure-sensitive adhesive.

Embodiment 9. The transdermal delivery device of Embodiment 8 comprising a single drug layer.

Embodiment 10. The transdermal delivery device of Embodiment 8 or 9, wherein the pressure sensitive adhesive comprises a polyisobutylene (PIB) adhesive, a silicone polymer adhesive (e.g., Bio-7-4202), an acrylate copolymer adhesive (e.g., Duro -Tak 87-2287) or a combination.

Embodiment 11. The transdermal delivery device according to any one of embodiments 1-10, wherein the drug layer further comprises a permeation enhancer, an additional active ingredient, a humectant, a plasticizer, a gelling agent, an antioxidant, an emollient, a drug release modifier , a solvent, a crystallization inhibitor, or a combination thereof.

Embodiment 12. The transdermal delivery device of any one of embodiments 1-11, wherein the drug layer has a coating weight of about 0.1 g/cm ² to about 0.5 g/cm ² active surface area.

Embodiment 13. The transdermal delivery device of any one of Embodiments 1-12, configured to adhere continuously to the user's skin for about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days , about 4 days, about 5 days, about 6 days, or about 7 days or more.

Embodiment 14. The transdermal delivery device of any one of Embodiments 1-13 wherein tetrabenazine is an essentially pure R,R isomer.

Embodiment 15. A method of administering tetrabenazine to a human subject in need, comprising applying the transdermal delivery device of any one of Embodiments 1-14 to the skin of the human subject.

Embodiment 16. The method of Embodiment 15 wherein the human subject is characterized as having a hyperkinetic movement disorder (eg, chronic hyperkinetic movement disorder).

Embodiment 17. The method of Embodiment 16 wherein the hyperkinetic movement disorder is chorea associated with a disease or disorder selected from Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tics, and combinations thereof.

Embodiment 18 A method of inhibiting vesicular monoamine transporter isoform 2 (VMAT2) in a subject, said method comprising applying the transdermal delivery device of any one of Embodiments 1-14 to the subject's skin.

Embodiment 19 A method of treating a disease or disorder mediated by vesicular monoamine transporter isoform 2 (VMAT2) in a subject in need thereof, said method comprising applying the transdermal delivery device of any one of Embodiments 1-14 to the subject's skin.

Embodiment 20. A method of treating hyperkinetic movement disorder in a subject in need thereof, comprising applying the transdermal delivery device of any one of Embodiments 1-14 to the subject's skin.

Embodiment 21. The method of Embodiment 20 wherein the hyperkinetic movement disorder is a chronic hyperkinetic movement disorder.

Embodiment 22. The method of Embodiment 20 or 21 wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia and/or a tic.

Embodiment 23 An adhesive composition comprising tetrabenazine homogeneously dispersed in a pressure-sensitive adhesive, wherein the adhesive composition is configured to adhere continuously to the user's skin for an extended period of time selected from about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more.

Embodiment 24. The adhesive composition of Embodiment 23, wherein the pressure-sensitive adhesive comprises a polyisobutylene (PIB) adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof.

Embodiment 25. The adhesive composition of Embodiment 23 or 24 further comprising a penetration enhancer.

Embodiment 26 An adhesive composition according to any one of Embodiments 23-25 wherein tetrabenazine is an essentially pure R,R isomer.

Embodiment 27. The adhesive composition of any one of Embodiments 23-26 wherein tetrabenazine is present in an amount of from about 2% to about 30% by weight of the adhesive composition.

Embodiment 28. A transdermal delivery device comprising:

protective layer,

an adhesive composition according to any one of embodiments 23-27; and removable protective coating.

Embodiment 29 A method of treating hyperkinetic movement disorder in a subject in need thereof, said method comprising applying the adhesive composition of any of Embodiments 23-27 or the transdermal delivery device of Embodiment 28 to the subject's skin.

Embodiment 30. The method of Embodiment 29 wherein the hyperkinetic movement disorder is a chronic hyperkinetic movement disorder.

Embodiment 31. The method of Embodiment 29 or 30 wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease, tardive dyskinesia, Tourette's syndrome and/or tics.

Embodiment 32. A method of treating hyperkinetic movement disorder in a subject in need thereof, said method comprising transdermally administering to the subject a therapeutically effective amount of tetrabenazine or deuterated tetrabenazine.

EXAMPLES

Example 1 Preparation of a transdermal patch containing tetrabenazine

[102] This example shows one procedure for preparing a patch containing a drug such as tetrabenazine in an adhesive. Tetrabenazine base is commonly available for sale as a high purity compound (eg, 99%), for example, from Octagon Chemical Ltd, Hangzhou, China, via the Internet on the Alibaba website.

[103] In this example, tetrabenazine base was thoroughly mixed with Durotak 87-2287 adhesive (manufactured by Henkel Adhesives) until the mixture became homogeneous. After that, the adhesive mixture was applied to the removable protective coating using a "draw knife" and subjected to enhanced drying for 1.5 minutes using a conventional hair dryer, followed by layering on the protective film.

[104] Adhesive mixtures may contain tetrabenazine in various concentrations. Four concentrations were used in this example: 1) a 2.5% formulation prepared by mixing 2.5% tetrabenazine with 97.5% Durotak 87-2287; 2) 5% formulation prepared by mixing 5% tetrabenazine with 95% Durotak 87-2287; 3) 10% formulation prepared by mixing 10% tetrabenazine with 90% Durotak 87-2287; and 4) a 15% formulation prepared by mixing 15% tetrabenazine with 85% Durotak 87-2287. All percentages of tetrabenazine and Durotak refer to weight percent based on the final weight of the respective formulations.

Example 2 Transdermal patch containing tetrabenazine and two adhesives

[105] Following the same procedure as in example 1, transdermal patches were also made containing tetrabenazine and a mixture of two different adhesives in various ratios, while the concentration of tetrabenazine was maintained at

level of 10% by weight.

[106] The two adhesives used in this example were a silicone polymer (BIO-7-4202 from Dow Corning Co.) and an acrylate copolymer (Durotak 87-2287). In this example, four different ratios were used: 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 Flow Test

[107] Transdermal flux of tetrabenazine from the patch was tested using human cadaver epidermis by the Franz diffusion cell method. Cadaver epidermis was obtained from the Health Science tissue bank in Phoenix, Arizona, USA.

[108] The transdermal flux of tetrabenazine through the epidermis of a human cadaver was analyzed using the HPLC method described below.

[109] Mobile phase: 55/45 acetonitrile/water - 0.05% Triethylamine adjusted to pH-6.5

HPLC column: Kinetex C18, 150 x 4.6 mm, 5 µm from Pheneomenex Wavelength: 230 nm, flow: 1.2 ml/min

[110] The patches of Examples 1 and 2 were tested and the transdermal flow results are shown in FIG. 1 and 2, respectively.

[111] As shown in FIG. 1, the highest transdermal flux was observed for the patches described in Example 1, which are an adhesive matrix with a 10% concentration of tetrabenazine.

[112] As shown in FIG. 2, changing the ratio of silicone polymer to acrylate copolymer does not significantly change the flow characteristics. However, compared to the results shown in FIG. 1, the flux observed for the patches made according to Example 2 is markedly lower than the flux from the 10% tetrabenazine patch made in Example 1.

[113] Thus, adding a silicone adhesive to an acrylate adhesive (eg, Durotak 87-2877) can reduce the flow rate of tetrabenazine.

Example 4A. Preparation of tetrabenazine in adhesives without functional groups

[114] Part composition

Ingredient Function grams,
based on wet
substances solids, % grams,
based on dry
substances dry matter, % Tetrabenazine
(+) (TBZ) Active Ingredient 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 Antioxidant 0.030 0.030 0.050% Plastoid B Crystallization Inhibitor/Solubil
isator 12.00 12,000 20.0% Total 119.25 59.98 100.0%

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

Manufacturing procedure

[116] For the manufacture of the patch in example 4A used the following procedure. In a 50 ml beaker, propyl gallate was dissolved in ethanol using manual stirring. Separately, ethyl acetate was added to a 250 ml beaker, stirred with a mechanical stirrer at low speed. TBZ was added with stirring, followed by Plastoid B powder. After Plastoid B had dissolved, a weighed portion of Duro Tak 87-900A was added with stirring. Mix at moderate speed for 30 minutes or until smooth. The solution was cast and applied with a 10 mil thick applicator onto a protective film, Scotchpak 9723 film manufactured by 3M. The casting was dried in air for 10 min, and also dried in an oven at 85°C for 10 min. The dried adhesive was covered with a removable protective coating - Loparex release coating. The coated layer was cut into 60 cm2 patches using a steel ruler punch.

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

[118] The patch was cut to secure to the Franz cells for skin penetration studies. The test results are presented in example 6.

[119] No crystals were observed on the patch for 4 weeks at 40°C, indicating good physical stability of the transdermal patch formulation. Within 4 weeks at a temperature of 40 ° C, the patch does not

degradation was observed, indicating good chemical stability of the transdermal patch formulation.

Examples 4B and 4C. Preparation of tetrabenazine in non-functional adhesives

groups

[120] Two similar formulations were prepared according to the same

procedure as in example 4A. They are listed in the following table (composition based on dry matter):

Compound Function Etc. 4B Etc. 4C TBZ(+) Active Ingredient 7.0% 7.1% DT 87-900A adhesive 92.5% 72.9% propyl gallate Antioxidant 0.05% 0.05% Soluplus Inhibitor
crystallization/solubilizer 20.0%

[121] The patches prepared in Examples 4B and 4C were also tested for skin penetration.

Example 5 Stability Studies of Tetrabenazine Patch Formulations

[122] Various tetrabenazine patches were made and tested for chemical and/or physical stability. The inventors have found that formulations of patches made with DuroTak 87-2287 or Duro-Tak 87-2677 functional adhesives, after storage at 40°C for 4 weeks, turn yellowish, indicating instability of the active ingredient from - for oxidation and/or other type of decomposition. DuroTak 87-2287 has -OH and epoxy hydroxyl functionality and DuroTak 87-2677 has an -COOH acid functionality. In contrast, patch formulations made using DuroTak 87-900A, which does not have any functional groups, were stable for 4 weeks at 40°C (see Example 4A).

[123] The inventors have also found that patch formulations made without the use of propyl gallate as antioxidants degrade the active ingredients. If no antioxidant was used, impurities (drug-related) such as TBZ 01, TBZ 02 and TBZ 04 were generated and detected by HPLC. Antioxidants that can prevent oxidation and/or other degradation of TBZ include propyl gallate, citric acid, ascorbic acid, vitamin E (tocopherol acetate), etc.

[124] Tetrabenazine and related compounds were analyzed using

isocratic reverse phase HPLC with UV detector.

Column: Gemini C18, 4.6 x 150 mm, 5 µm particle size or equivalent.

Column temperature: 45 °C Injection volume: 10 µl Detector wavelength: 210 nm

Mobile phase: ratio mobile phase A / mobile phase B = 44 : 56 Mobile phase A: 10 mM K ₂ HPO ₄ in H ₂ O

Mobile phase B: acetonitrile Flow rate: 1.2 ml/min

Run time: 12 min

Retention time: about 5.5 min for tetrabenazine

The retention time for impurity 1 (TBZ01) is about 1.95 min; for impurity 2 (TBZ02) - about 3.10 min; and for impurity 4 (TBZ04) about 5.29 min.

[125] The inventors also found that without the use of Soluplus or Plastoid B as a crystallization inhibitor/solubilizer (see, for example, Example 4B), after storage for 2 weeks at ambient temperature, crystals appeared on the patch. The formation of crystals slows down the penetration of the patch formulations through the skin.

[126] Thus, in order for the active ingredient to remain in the adhesive matrix in amorphous form for at least 12 months of storage at room temperature, the preferred composition would contain crystallization inhibitors. Preferred crystallization inhibitors include:

• PVP (polyvinylpyrrolidone) polymers: Kollidon K30 or K90F (from BASF), Plasdone K20/32 or Plasdone K90 (from Ashland Chemical).

• Cross-linked PVP polymers: Kollidon CL.

• PVP copolymers (copovidones): Plasdone S-630 Copovidone (Asland).

• Cellulose-based polymers: hydroxypropyl methyl cellulose (HPMC/Methocel), ethyl cellulose (Ethocel from Dow Chemical), eg hydroxypropyl cellulose (HPC, eg Klucel from Ashland).

• Polycarboxylic acid polymers: Carbopol (manufactured by Lubrizol).

• Polymethacrylates: Plastoid B, Eudragit E100, Eudragit L100-55 (manufactured by

Evonik).

• Soluplus (BASF): graft copolymer based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam (PVAc-PVCap-PEG).

Example 6 Skin Permeation Studies

[127] Patch formulations prepared as described in Examples 4A-4C were used to study skin permeability using the following protocol:

[128] RESULTS of the study are presented in the table and graph below. The values shown are the total amount of TBZ infiltrated per cm ² (ie, µg/cm ² ). See also FIG. 3.

AVERAGE
MEANING 2 h 4 h 8 h 24 hours 48 h Etc. 4B 0.00 1.95 4.07 25.61 64.56 Etc. 4C 0.00 0.05 1.36 17.38 48.59 Etc. 4A 0.00 0.47 5.38 32.27 73.99

[129] It should be understood that the "Detailed Description" section and not the sections

"Summary" and "Abstract" are intended to be used in interpreting the claims. The Summary and Abstract sections may set forth one or more, but not all, exemplary embodiments of the present invention as intended by the inventor(s), and thus are not intended to be limiting in any way. of the present invention and the appended claims.

[130] The present invention has been described above with functional building blocks illustrating the implementation of certain functions and their relationships. The boundaries of these functional building blocks have been arbitrarily defined herein for convenience of description. Alternative boundaries may be defined provided that the specified functions and their relationships are properly performed.

[131] With respect to aspects of the invention described as a genus, all distinct species are individually considered separate aspects of the invention. If aspects of the invention are described as "comprising" a feature, it is contemplated that embodiments of the invention also "consist of" or "consist essentially of" that feature.

[132] The foregoing description of specific embodiments of the invention will so fully disclose the general nature of the invention that others may, using knowledge in the art, easily modify and/or adapt for various applications such specific embodiments of the invention, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments of the invention based on the instructions and guidelines provided herein. It should be understood that the phraseology or terminology described herein is for the purpose of description and not limitation, as a result of which the terminology or phraseology of the present description must be interpreted by a person skilled in the art in light of the instructions and guidelines.

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

[134] All of the various aspects, embodiments of the invention, and options described herein may be combined in any and all embodiments.

[135] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application were specifically and separately indicated for inclusion by reference. To the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

Claims (38)

1. An adhesive composition for transdermal delivery of an active ingredient, comprising: active ingredient dispersed in an inert acrylate pressure-sensitive adhesive, wherein the active ingredient is selected from tetrabenazine, deuterated tetrabenazine, or a combination thereof, while the inert acrylate pressure-sensitive adhesive is present in an amount of 50 to 97% by weight, wherein the inert acrylate pressure-sensitive adhesive is a copolymer of 2-ethylhexyl acrylate, methyl acrylate, and one or more unfunctionalized acrylamide monomers selected from epoxy, -OH, -COOH, and combinations thereof; and an inert acrylate pressure sensitive adhesive free or substantially free of vinyl acetate. 2. The adhesive composition of claim 1 wherein the acrylamide monomer is t-octylacrylamide. 3. An adhesive composition according to claim 1 or 2 that does not contain a penetration enhancer, does not contain isopropyl myristate, or does not contain a penetration enhancer selected from fatty alcohols, fatty acids, fatty acid esters, and combinations thereof. 4. Adhesive composition according to any one of claims 1 to 3, characterized in that the active ingredient is present in an amount of 2 to 7% by weight. 5. Adhesive composition according to any one of claims 1 to 4, additionally containing a gallate antioxidant. 6. The adhesive composition of claim 5 wherein the gallate antioxidant is propyl gallate. 7. Adhesive composition according to claim 6, wherein propyl gallate is from 0.001 to 0.5% by weight. 8. Adhesive composition according to any one of claims 1 to 7, further comprising a crystallization inhibitor selected from polyvinylpyrrolidone polymer, polyvinylpyrrolidone crosslinked polymer, polyvinylpyrrolidone copolymer, cellulose-based polymer, polycarboxylic acid polymer, polymethacrylate, polyethylene glycol-based graft copolymer, polyvinyl acetate and polyvinyl caprolactam (PVAc-PVCap-PEG) and combinations thereof. 9. The adhesive composition of claim 8, wherein the polyvinylpyrrolidone polymer is Kollidon K30 or K90F from BASF, Plasdone K20/32 or Plasdone K90 from Ashland Chemical. 10. The adhesive composition according to claim 8 or 9, wherein the crosslinked polyvinylpyrrolidone polymer is Kollidon CL. 11. Adhesive composition according to any one of claims 8-10, wherein the polyvinylpyrrolidone copolymer is Plasdone S-630 Copovidone from Asland. 12. Adhesive composition according to any one of claims 8 to 11, wherein the cellulose-based polymer is hydroxylpropylmethylcellulose, ethylcellulose or hydroxypropylcellulose. 13. Adhesive composition according to any one of claims 8 to 12, wherein the polycarboxylic acid polymer is Cabopol manufactured by Lubrizol. 14. An adhesive composition according to any one of claims 8-13, wherein the polymethacrylate is Plastoid B, Eudragit E100, Eudragit L100-55 manufactured by Evonik. 15. An adhesive composition according to any one of claims 8-14, wherein the PVAc-PVCap-PEG is Soluplus from BASF. 16. Adhesive composition according to claim 8, containing a crystallization inhibitor selected from polymethacrylate, PVAc-PVCap-PEG and combinations thereof. 17. Adhesive composition according to claim 16, wherein the polymethacrylate is Plastoid B, Eudragit E100 or Eudragit L100-55 manufactured by Evonik. 18. The adhesive composition according to claim 16 or 17, wherein the PVAc-PVCap-PEG is Soluplus from BASF. 19. Adhesive composition according to any one of claims 1-18, additionally containing a crystallization inhibitor, which is a copolymer of butyl methacrylate and methyl methacrylate. 20. Adhesive composition according to any one of claims 1-19, additionally containing a crystallization inhibitor, which is a graft copolymer based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam. 21. Adhesive composition according to any one of claims 1 to 20, characterized in that the only active ingredient is essentially pure R,R isomer of tetrabenazine. 22. Device for transdermal delivery, containing: protective layer an adhesive composition according to any one of claims 1 to 21; And removable protective coating. 23. A method of administering tetrabenazine, deuterated tetrabenazine, or a combination thereof to a subject in need thereof, comprising applying the adhesive composition of any one of claims 1 to 21 or the transdermal delivery device of claim 22 to the subject's skin. 24. The method of claim 23 wherein the subject is characterized as having a hyperkinetic movement disorder. 25. The method of claim 24 wherein the hyperkinetic movement disorder is a chronic hyperkinetic movement disorder. 26. The method of claim 24 or 25, wherein the hyperkinetic movement disorder is selected from chorea associated with Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia, tic, and combinations thereof. 27. A method of inhibiting vesicular monoamine transporter isoform 2 (VMAT2) in a subject in need thereof, said method comprising applying the adhesive composition of any one of claims 1 to 21 or the transdermal delivery device of claim 22 to the subject's skin. 28. A method of treating a disease or disorder mediated by vesicular monoamine transporter isoform 2 (VMAT2) in a subject in need thereof, said method comprising applying an adhesive composition according to any one of claims 1 to 21 or a transdermal delivery device according to claim 22 to the skin subject. 29. A method of treating hyperkinetic movement disorder in a subject in need, comprising applying an adhesive composition according to any one of claims 1 to 21 or a transdermal delivery device according to claim 22 to the subject's skin. 30. The method of claim 29 wherein the hyperkinetic movement disorder is a chronic hyperkinetic movement disorder. 31. The method according to claim 29 or 30, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease, Wilson's disease, Tourette's syndrome, restless legs syndrome, tardive dyskinesia and/or tic.