Transdermal delivery of dextromethorphan

Abstract

Provided herein are novel transdermal delivery devices (or patches) containing dextromethorphan, pharmaceutical compositions containing dextromethorphan, methods for preparing the same, and methods for transdermally administering dextromethorphan. Also provided herein are methods for treating various diseases and disorders, such as neurological diseases or disorders (e.g., PBA), using the transdermal delivery devices and / or pharmaceutical compositions described herein.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 001,607, filed March 30, 2020, the entire contents of which are incorporated herein by reference.

[0002] In various embodiments, the present disclosure generally relates to transdermal delivery devices containing dextromethorphan, methods for their preparation, and methods for their use in treating diseases or disorders, such as, for example, the neurological diseases described herein. [Background technology]

[0003] NUEDEXTA® (dextromethorphan hydrobromide and quinidine sulfate) capsules 20 mg / 10 mg are a combination drug containing dextromethorphan hydrobromide (a noncompetitive N-methyl-D-aspartate [NMDA] receptor antagonist and sigma-1 agonist) and quinidine sulfate (a CYP450 2D6 inhibitor). This medication is indicated for the treatment of mood dysregulation (PBA). Dextromethorphan hydrobromide is the pharmacologically active ingredient in NUEDEXTA® that acts on the central nervous system (CNS). Quinidine sulfate is a specific inhibitor of CYP2D6-dependent oxidative metabolism used in NUEDEXTA® to enhance the systemic bioavailability of dextromethorphan.

[0004] The recommended starting dose of NUEDEXTA® (dextromethorphan hydrobromide and quinidine sulfate) Capsules 20 mg / 10 mg is one capsule orally daily for the first 7 days of treatment. After the 8th day of treatment, the daily dose should be increased to one capsule every 12 hours for a total of two capsules per day. Because some patients experience spontaneous improvement of PBA, the need for continued treatment should be periodically reassessed.

[0005] The most common adverse reactions (incidence ≥ 3% and > 2 times that of placebo) in patients taking NUEDEXTA® are, in descending order, diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, urinary tract infection, influenza, increased gamma glutamyltransferase, and flatulence. The following adverse reactions have been reported with the use of the single ingredient dextromethorphan: drowsiness, dizziness, irritability or restlessness, nausea, vomiting, and stomach pain. Summary of the Invention

[0006] In various embodiments, the present disclosure is based, in part, on the unexpected discovery that dextromethorphan can be administered transdermally with a continuous, high flux of dextromethorphan from the transdermal delivery device (patch) herein. The transdermal delivery of dextromethorphan herein achieves therapeutically effective plasma dextromethorphan concentrations for treating the diseases or disorders described herein, such as PBA. Compared to currently available oral delivery via formulations such as NUEDEXTA®, the transdermal delivery of dextromethorphan herein has many advantages and addresses many of the unmet medical needs of such oral formulations. For example, the transdermal delivery device or transdermal formulation (e.g., adhesive composition) herein can be administered to achieve therapeutically effective plasma concentrations regardless of whether a CYP2D6 inhibitor, such as quinidine, is co-administered. Thus, the transdermal delivery device or transdermal formulation herein can be administered to transdermally deliver dextromethorphan to subjects who are sensitive to or intolerant of CYP2D6 inhibitors, such as quinidine. The transdermal delivery devices or formulations herein can be conveniently administered to transdermally deliver dextromethorphan to a subject, regardless of whether or not the subject is first determined to be a poor, intermediate, or extensive metabolizer of dextromethorphan. Administration of dextromethorphan using the transdermal delivery devices or formulations herein may also result in, for example, more accurate dosing, less frequent dosing, fewer quinidine-associated side effects, and / or increased dextromethorphan exposure (e.g., C ) compared to NUEDEXTA®. max ), reducing the potential for side effects associated with steroids, reducing pill burden, and improving patient compliance may provide a superior clinical experience.

[0007] In various embodiments, provided herein are novel transdermal delivery devices (or patches) containing dextromethorphan, pharmaceutical compositions containing dextromethorphan (e.g., transdermal formulations such as adhesive compositions), methods for their preparation, and methods for transdermal administration of dextromethorphan. The transdermal delivery devices, pharmaceutical compositions, and methods herein are useful for treating various diseases and disorders, such as neurological diseases or disorders (e.g., PBA).

[0008] Some embodiments of the present disclosure are directed to transdermal delivery devices containing dextromethorphan. Typically, the transdermal delivery device is a DIA matrix-type patch, such as a single-layer drug-in-adhesive (DIA) patch. In some embodiments, the transdermal delivery device can have additional layers, such as an optional reservoir layer. Other suitable patch designs are also described herein. In some embodiments, the transdermal delivery device comprises, consists essentially of, or consists of a backing layer, a drug-in-adhesive layer, and an optional release liner. The drug-in-adhesive layer typically comprises an adhesive composition described herein. In some embodiments, the drug-in-adhesive layer comprises dextromethorphan, a skin permeation enhancer, a pressure-sensitive adhesive, and optionally a crystallization inhibitor. The drug-in-adhesive layer typically contains dextromethorphan as the only active ingredient. The dextromethorphan and the skin permeation enhancer are typically dispersed (e.g., homogeneously dispersed or dissolved) in the pressure-sensitive adhesive. In some embodiments, the drug-in-adhesive layer is a homogeneous mixture. In some embodiments, the skin permeation enhancer is isopropyl myristate. In some embodiments, the pressure-sensitive adhesive is an acrylate-based pressure-sensitive adhesive, such as Duro-Tak 87-2287. It has also been discovered that the inclusion of a crystallization inhibitor, a vinylpyrrolidone polymer (Plasdone K29 / 32), in a dextromethorphan transdermal patch significantly improves the permeability of dextromethorphan from the patch in vitro and in vivo. Thus, in some embodiments, a crystallization inhibitor is present, preferably a vinylpyrrolidone polymer, e.g., a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, Plasdone K29 / 32, and the like. Transdermal administration devices are typically in the form of a monolithic patch, e.g., about 30 cm 2 ~about 100cm 2The transdermal administration device typically contains an amount of dextromethorphan sufficient to provide a subject in need with a daily dose of about 15 mg to about 50 mg, e.g., about 35 mg, of dextromethorphan. The transdermal delivery device typically has an effective surface area of ​​at least about 200 μg / cm, as measured in vitro using human cadaver skin. 2 / day dextromethorphan flux, e.g., about 200-800ug / cm 2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2 / day. Suitable types and amounts of components of the transdermal delivery device include those described herein in any combination. Methods for preparing the transdermal delivery device or transdermal formulation herein are also provided in the present disclosure.

[0009] In some embodiments, the present disclosure also provides a method for treating a disease or disorder described herein in a subject (typically a human subject) in need of such treatment, comprising transdermally delivering a therapeutically effective amount of dextromethorphan to the subject. Generally, the method comprises applying a transdermal patch described herein to the subject. The transdermal patch is applied to the subject at a dosing frequency of once daily to once weekly to transdermally deliver a daily dose of dextromethorphan of, for example, about 15 mg to about 50 mg to the subject. The disease or disorder is typically a neurological disease or disorder described herein, such as emotion dysregulation, depression (e.g., major depressive disorder or treatment-resistant depression), stroke, traumatic brain injury, seizures, pain, methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof. In some embodiments, the subject is an extensive metabolizer of dextromethorphan. In some embodiments, the subject is a poor metabolizer of dextromethorphan. Suitable dosing regimens, dosages, durations, transdermal delivery devices, etc. include any of those described herein in any combination.

[0010] In some embodiments, the present disclosure provides methods for treating a disease or disorder in a subject (typically a human subject) in need of such treatment, the methods comprising administering dextromethorphan to the subject according to one or more pharmacokinetic (PK) profiles described herein. Generally, the methods comprise transdermally delivering a desired daily dose of dextromethorphan (e.g., about 15 mg to about 50 mg, such as about 35 mg) to the subject to achieve the PK profile described herein. For example, in some embodiments, the methods comprise applying a transdermal patch to the subject at a dosing frequency of once daily to once weekly to deliver a therapeutically effective plasma dextromethorphan concentration to the subject at steady state. The transdermal patch can contain from about 15 mg to about 700 mg of dextromethorphan. Generally, the transdermal patch contains from about 30 mg to about 100 mg of dextromethorphan and is applied once daily. The disease or disorder is typically a neurological disease or disorder described herein, such as emotional dysregulation, depression (e.g., major depressive disorder or treatment-resistant depression), stroke, traumatic brain injury, seizures, pain, methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof. Suitable dosing regimens, dosages, durations, transdermal delivery devices, etc., include any of those described herein in any combination.

[0011] Some embodiments of the present disclosure are directed to methods of administering dextromethorphan to a subject in need thereof. Generally, the method includes applying a transdermal patch described herein to the subject. The transdermal patch can be applied to the subject at a dosing frequency of once daily to once weekly to transdermally deliver a daily dose of dextromethorphan of, for example, about 15 mg to about 50 mg to the subject. The subject typically suffers from a disease or disorder described herein, typically a neurological disease or disorder described herein, such as emotion dysregulation, depression (e.g., major depressive disorder or treatment-resistant depression), stroke, traumatic brain injury, seizures, pain, methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof. In some embodiments, the subject is an extensive metabolizer of dextromethorphan. In some embodiments, the subject is a poor metabolizer of dextromethorphan. Suitable dosing regimens, dosages, durations, transdermal delivery devices, and the like, include any of those described herein, in any combination.

[0012] Compared to methods of administering NUEDEXTA® tablets, the methods herein may be particularly advantageous for certain subjects, such as those who are sensitive or intolerant to quinidine, or CYP2D6 inhibitors in general. In some embodiments, the subject may be sensitive or intolerant to CYP2D6 inhibitors. In some embodiments, the subject may be sensitive or intolerant to quinidine. In some embodiments, the subject has one or more side effects associated with quinidine. In some embodiments, the subject is co-administered with a drug whose metabolism is affected by a CYP2D6 inhibitor. In some embodiments, the subject is co-administered with a drug whose metabolism is affected by quinidine. In some embodiments, the subject is co-administered with a drug that may affect the pharmacological effects of quinidine.

[0013] The methods herein can be used in combination with other drug therapies. In some embodiments, the methods herein can further include administering to the subject an active agent other than dextromethorphan. For example, in some embodiments, the methods herein include administering to the subject an antidepressant. In some embodiments, the methods herein further include administering to the subject one or more additional active agents selected from amlodipine, capsaicinoids (e.g., capsaicin or its esters), opioid agonists (e.g., μ-opiate analgesics (e.g., tramadol)), adenosinergic agonists, 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, gabapentin, and pharmaceutically acceptable salts thereof. These additional agents can be administered via the same route or different routes, simultaneously or sequentially, in any order. [The present invention 1001] 1. A method of treating a neurological disease or disorder in a subject in need thereof, said method comprising applying to said subject a transdermal patch comprising: a. a backing layer; b. (1) dextromethorphan in an amount of about 6% to about 12% by weight (e.g., about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, or any range therebetween, such as about 8-12% by weight), (2) isopropyl myristate in an amount of about 6% to about 12% by weight (e.g., about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, or any range therebetween, such as about 8-12% by weight), (3) about 65% by weight and (4) a drug-containing adhesive layer comprising a pressure-sensitive adhesive in an amount of about 6% to about 85% by weight (e.g., about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, about 85% by weight, or any range therebetween, e.g., about 65-85% by weight, about 70-85% by weight, about 75-85% by weight, etc.), and optionally (5) a crystallization inhibitor in an amount of about 6% to about 12% by weight (e.g., about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, or any range therebetween, e.g., about 8-12% by weight, etc.). Including, The transdermal patch has a thickness of about 30 cm 2 ~Approx. 100cm 2 , for example, about 30 cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 70cm 2 , about 80cm 2 , about 90cm 2 , about 100cm 2 or any range therebetween, e.g., about 40 to 60 cm 2 , about 60~80cm 2 The method has an effective surface area of [The present invention 1002] The method of the present invention 1001, wherein the pressure-sensitive adhesive is an acrylate-based pressure-sensitive adhesive, preferably an acrylate copolymer adhesive, such as a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as one having non-acidic hydroxyl functionality, such as those described herein, for example, Duro-Tak 87-2287 adhesive and the like. [The present invention 1003] The method of invention 1001 or invention 1002, wherein the drug-containing adhesive layer comprises a crystallization inhibitor in an amount of about 6% by weight to about 12% by weight (e.g., about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, or any range therebetween, such as about 8% to 12% by weight). [The present invention 1004] 1003. The method of claim 1003, wherein said crystallization inhibitor is a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), for example, povidone K30, plasdone K29 / 32, and the like. [The present invention 1005] The drug-containing adhesive layer comprises: 1) about 20 mg to about 100 mg of dextromethorphan, for example, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range therebetween, for example, about 40 to 60 mg, 50 to 60 mg, or about 50 to 70 mg; 2) about 30 mg to about 100 mg of isopropyl myristate, for example, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range therebetween, for example, about 40 to 60 mg, 50 to 60 mg, or about 50 to 70 mg; 4) a crystallization inhibitor in an amount of about 30 mg to about 100 mg, e.g., about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 700 mg, about 800 mg, about 900 mg, or any range between said recited values, e.g., about 300 to 500 mg, 350 to 450 mg, or about 300 to 550 mg; and optionally 5) a crystallization inhibitor in an amount of about 30 mg to about 100 mg, e.g., about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range between said recited values, e.g., about 40 to 60 mg, 50 to 60 mg, or about 50 to 70 mg. [The present invention 1006] The method of claim 1006, wherein said drug-containing adhesive layer contains said crystallization inhibitor in an amount of about 30 mg to about 100 mg. [The present invention 1007] The method of any one of claims 1001 to 1006, wherein said drug-containing adhesive layer contains dextromethorphan as the only active ingredient. [The present invention 1008] The method of any of claims 1001 to 1007, wherein the drug-containing adhesive layer contains about 56 mg of dextromethorphan. [The present invention 1009] The transdermal patch has a length of about 70 cm 2 The method according to any one of claims 1001 to 1008, wherein the effective surface area is [The present invention 1010] The transdermal patch contains about 0.2 mg / cm 2 ~about 5mg / cm 2 , for example, about 0.2 mg / cm 2 , about 0.3mg / cm 2 , about 0.4mg / cm 2 , about 0.5mg / cm 2 , about 0.6mg / cm 2 , about 0.7mg / cm 2 , about 0.8mg / cm 2 , approximately 0.9 mg / cm 2 , about 1mg / cm 2 , about 2mg / cm 2 , about 5mg / cm 2 or any range therebetween, e.g., about 0.2 to 1 mg / cm 2 , about 0.5~1mg / cm 2 The method of any one of claims 1001 to 1009, wherein the total dextromethorphan loading amount is 1001 or more. [The present invention 1011] The method of any of claims 1001 to 1010, wherein said transdermal patch comprises said backing layer, said drug-containing adhesive layer, and optionally a release liner. [The present invention 1012] 1012. The method of any one of claims 1001 to 1011, wherein said transdermal patch is in the form of an integral patch. [The present invention 1013] The transdermal patch has a densitometric value of at least about 200 ug / cm as measured in vitro using human cadaver skin. 2 / day, for example, about 200ug / cm 2 / day, about 300ug / cm 2 / day, about 400ug / cm2 / day, about 500ug / cm 2 / day, about 600ug / cm 2 / day, about 700ug / cm 2 / day, about 800ug / cm 2 / day, about 1000ug / cm 2 / day, or any range therebetween, e.g., about 200-800 ug / cm 2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2 Any of the methods of 1001 to 1012, wherein the method has a dextromethorphan flux of 1001 / day or more. [The present invention 1014] Any of the methods of claims 1001 to 1013, comprising applying the transdermal patch to transdermally deliver a therapeutically effective amount of dextromethorphan to the subject. [The present invention 1015] Any of the methods of inventions 1001 to 1013, comprising applying the transdermal patch to transdermally deliver to the subject a daily dose of about 15 mg to about 50 mg (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any range between the recited values, e.g., about 20 to 50 mg, about 30 to 50 mg, or about 20 to 40 mg). [The present invention 1016] The method of claim 10, wherein said daily dose is about 35 mg of dextromethorphan. [The present invention 1017] 1017. The method of any one of claims 1001 to 1016, wherein said transdermal patch is applied to said subject once a day. [The present invention 1018] 8. The method of any of claims 1001 to 1017, wherein said neurological disease or said neurological disorder is emotional dysregulation, depression such as major depressive disorder or treatment-resistant depression, stroke, traumatic brain injury, seizures, pain, methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof. [The present invention 1019] The method of claim 1018, wherein the neurological disease or disorder is an emotional dysregulation disorder. [The present invention 1020] The method of any of claims 1001 to 1019, wherein said subject does not suffer from a cough and / or does not require antitussive medication. [The present invention 1021] The method of any of claims 1001 to 1020, wherein the subject is characterized as an extensive metabolizer of dextromethorphan. [The present invention 1022] The method of any of claims 1001 to 1021, wherein the subject is characterized as a poor metabolizer of dextromethorphan. [The present invention 1023] The method of any of claims 1001 to 1022, wherein the subject is sensitive or intolerant to a CYP2D6 inhibitor. [The present invention 1024] The method of any of claims 1001 to 1023, wherein the subject has one or more side effects associated with quinidine. [The present invention 1025] The method of any of claims 1001 to 1024, wherein said subject is co-administered a drug whose metabolism is affected by a CYP2D6 inhibitor. [The present invention 1026] Any of the methods of claims 1001 to 1025, further comprising administering an antidepressant to the subject. [The present invention 1027] 1026. The method of claim 1026, wherein said antidepressant is selected from bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, metabolites or prodrugs of any of these compounds, and combinations thereof. [The present invention 1028] The method of any one of claims 1001 to 1027, wherein the subject is not administered quinidine. [The present invention 1029] 1. A method for treating a neurological disease or disorder in a subject in need of such treatment, comprising applying a transdermal patch to the subject at a dosing frequency of once daily to once weekly, wherein the transdermal patch contains about 15 mg to about 700 mg of dextromethorphan (e.g., about 15 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or any range therebetween, e.g., about 15-100 mg, about 30-100 mg, about 30-75 mg, or about 150-500 mg), and wherein the application of the patch provides the subject with a therapeutically effective plasma concentration of dextromethorphan at steady state. [The present invention 1030] The transdermal patch contains about 30 mg to about 100 mg of dextromethorphan, and by applying it, a) AUC on day 7 or in the steady-state phase of about 180 h*ng / mL to about 2000 h*ng / mL, for example, about 200 h*ng / mL to about 600 h*ng / mL or about 300 h*ng / mL to about 500 h*ng / mL 0-24,DXM 、 b) C at day 7 or steady state of about 8 ng / mL to about 100 ng / mL, for example, about 10 ng / mL to about 20 ng / mL, for example, about 15 ng / mL Avg,DXM 、 c) C at day 7 or steady state of about 6 ng / mL to about 65 ng / mL, for example, about 6 ng / mL to about 20 ng / mL min,DXM 、 d) C at day 7 or steady state of about 8 ng / mL to about 90 ng / mL, for example, about 10 ng / mL to about 30 ng / mL max,DXM 、 e) The variability of dextromethorphan at day 7 or steady state stage [(C max -C min ) / C avg ]、 f) a dextromethorphan amplitude ratio [(C max -C min ) / C min ]、 g) an AUC of about 1.5 to about 5, for example, about 1.5 to about 3, for example, about 1.5 to 2.5 0-24,DXM,D1 AUC at steady state phase 0-24,DXM The ratio of h) AUC at steady state of about 12 to about 35 0-24,DOR AUC for 0-24,DXM The ratio of i) C at the steady state stage of about 12 to about 35 max,DOR C against max,DXM The ratio of, and j) C at the steady state stage of about 12 to about 35 Avg,DOR C against Avg,DXM The ratio of The method of claim 1029, wherein the subject is provided with a pharmacokinetic profile characterized by one or more of the following: [The present invention 1031] By applying the patch, a) an AUC of about 200 h*ng / mL to about 600 h*ng / mL on day 7 or at steady state 0-24,DXM b) C at day 7 or steady state of about 10 ng / mL to about 20 ng / mL, for example about 15 ng / mL Avg,DXM c) C at day 7 or steady state of about 6 ng / mL to about 20 ng / mLmin,DXM and / or d) a C at day 7 or steady state of about 10 ng / mL to about 30 ng / mL. max,DXM The method of the present invention 1030, wherein a pharmacokinetic profile characterized by: [The present invention 1032] By applying the patch, e) the fluctuation of dextromethorphan at the 7th day or steady state stage [(C max -C min ) / C avg ], and / or f) a dextromethorphan amplitude ratio [(C max -C min ) / C min ]. The method of claim 1030 or 1031, wherein a pharmacokinetic profile characterized by: [The present invention 1033] By applying the patch, AUC of about 1.5 to about 3 g 0-24,DXM,D1 AUC at steady state phase 0-24,DXM Any of the methods of claims 1029 to 1032, wherein a pharmacokinetic profile characterized by the ratio of [The present invention 1034] By applying the patch, h) AUC at the steady state stage of about 12 to about 35 0-24,DOR AUC for 0-24,DXM i) the ratio of C at the steady state stage between about 12 and about 35 max,DOR C against max,DXM and / or j) a C at the steady state stage of about 12 to about 35 Avg,DOR C against Avg,DXM The method of any of claims 1029 to 1033, wherein a pharmacokinetic profile characterized by the ratio of [This invention 1035] For each application of the transdermal patch other than the first administration, the pre-dose plasma dextromethorphan concentration was determined to be the mean concentration (C Avg,DXM ) does not become less than about 20% of the method of any of the present inventions 1029 to 1034. [The present invention 1036] The method of any of claims 1029 to 1035, wherein the accumulation rate of dextromethorphan is in the range of about 1 to about 5, for example, about 1.2 to about 3, and the subject is an extensive metabolizer or an ultra-extensive metabolizer. [This invention 1037] By applying the patch, k) the half-life of dextromethorphan at steady state is reduced to about 11 to about 29 hours, for example, about 11 to about 24 hours, for example, about 17 hours, in extensive metabolizers or very extensive metabolizers, and / or l) the half-life of dextromethorphan at steady state is reduced to about 0.018 hours in extensive metabolizers or very extensive metabolizers. -1 ~about 0.065h -1 , for example, about 0.020h -1 ~approx. 0.06 hours -1 The apparent first-order terminal elimination rate constant (λ) after the final dose after achieving a steady-state phase z ) Any of the methods of the present inventions 1029 to 1036, wherein [The present invention 1038] Any of the methods of inventions 1029 to 1037, wherein the application transdermally delivers to the subject a daily dose of about 15 mg to about 50 mg (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any range between the aforementioned values, for example, about 20 to 50 mg, about 30 to 50 mg, or about 20 to 40 mg). [This invention 1039] The method of any of claims 1029 to 1038, wherein said applying transdermally delivers a daily dose of about 35 mg of dextromethorphan to said subject. [The present invention 1040] 1039. The method of any one of claims 1029 to 1039, wherein said transdermal patch is applied to said subject once a day. [The present invention 1041] 1040. The method of any of claims 1029 to 1040, wherein said neurological disease or disorder is emotional dysregulation, depression such as major depressive disorder or treatment-resistant depression, stroke, traumatic brain injury, seizures, pain, methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof. [The present invention 1042] 1042. The method of claim 1041, wherein said neurological disease or said neurological disorder is an emotional dysregulation disorder. [This invention 1043] 1043. The method of any of claims 1029 to 1042, wherein the subject does not suffer from a cough and / or does not require antitussive medication. [This invention 1044] The method of any of claims 1029 to 1043, wherein the subject is characterized as an extensive metabolizer of dextromethorphan. [This invention 1045] Any of the methods of claims 1029 to 1044, wherein the subject is characterized as a poor metabolizer of dextromethorphan. [The present invention 1046] The method of any of claims 1029 to 1045, wherein the subject is sensitive or intolerant to a CYP2D6 inhibitor. [This invention 1047] The method of any of claims 1029 to 1046, wherein the subject has one or more side effects associated with quinidine. [This invention 1048] The method of any of claims 1029 to 1047, wherein said subject is co-administered a drug whose metabolism is affected by a CYP2D6 inhibitor. [This invention 1049] Any of the methods of claims 1029 to 1048, further comprising administering an antidepressant to the subject. [The present invention 1050] 1049. The method of claim 1049, wherein said antidepressant is selected from bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, metabolites or prodrugs of any of these compounds, and combinations thereof. [This invention 1051] The method of any one of claims 1029 to 1050, wherein the subject is not administered quinidine. [This invention 1052] The transdermal patch comprises a backing layer and a drug-containing adhesive layer, the drug-containing adhesive layer comprising dextromethorphan as the sole active ingredient, the drug-containing adhesive layer comprising dextromethorphan in an amount of about 6% to about 12% by weight (e.g., about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, or any range therebetween, such as about 8 to 12% by weight). 12% by weight, etc.), isopropyl myristate in an amount of about 65% by weight to about 85% by weight (e.g., about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, about 85% by weight, or any range between said recited values, e.g., about 65-85% by weight, about 70-85% by weight, about 75-85% by weight, etc.), and optionally a crystallization inhibitor in an amount of about 6% by weight to about 12% by weight (e.g., about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, or any range between said recited values, e.g., about 8-12% by weight, etc.). [This invention 1053] The method of claim 1052, wherein the pressure-sensitive adhesive is an acrylate-based pressure-sensitive adhesive, such as an acrylate copolymer adhesive, such as a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as one having non-acidic hydroxyl functional groups, such as those described herein, for example, Duro-Tak 87-2287 adhesive and the like, and the drug-containing adhesive layer contains the crystallization inhibitor, which is preferably a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), for example, povidone K30, plasdone K29 / 32, and the like. [This invention 1054] The transdermal patch has a densitometric value of at least about 200 ug / cm as measured in vitro using human cadaver skin. 2 / day, for example, about 200ug / cm 2 / day, about 300ug / cm 2 / day, about 400ug / cm 2 / day, about 500ug / cm 2 / day, about 600ug / cm 2 / day, about 700ug / cm 2 / day, about 800ug / cm 2 / day, about 1000ug / cm 2 / day, or any range therebetween, e.g., about 200-800 ug / cm2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2 The method of invention 1052 or invention 1053 having a dextromethorphan flux of, for example, 100 mg / day. [This invention 1055] Any of the methods of claims 1001 to 1054, wherein the transdermal delivery device or patch is applied once daily and the residual amount of dextromethorphan in the transdermal patch is less than 50% (e.g., less than 40%) of the initial amount of dextromethorphan in the transdermal patch. [The present invention 1056] Any of the methods of inventions 1001 to 1054, wherein the transdermal patch is applied once daily and the percentage of dextromethorphan delivered to the subject is about 50% to about 80% of the initial amount of dextromethorphan in the patch. [This invention 1057] A transdermal patch comprising: i. a backing layer; ii. a drug-containing adhesive layer comprising: 1) dextromethorphan in an amount of about 2% to about 12% by weight; 2) isopropyl myristate in an amount of about 6% to about 12% by weight; 3) a pressure-sensitive adhesive, preferably an acrylate-based pressure-sensitive adhesive, in an amount of about 65% to about 85% by weight; and optionally 4) a crystallization inhibitor in an amount of about 6% to about 12% by weight. Including, about 30cm 2 ~about 100cm 2 The transdermal patch has an effective surface area of [This invention 1058] The transdermal patch of the present invention 1057, wherein the acrylate-based pressure-sensitive adhesive is an acrylate copolymer adhesive, such as a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as one having non-acidic hydroxyl functionality, such as those described herein, e.g., Duro-Tak 87-2287 adhesive and the like. [This invention 1059] The transdermal patch of invention 1057 or invention 1058, wherein the amount of the acrylate-based pressure-sensitive adhesive is about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, or about 85% by weight, or any range between the recited values, for example, about 70-85%, about 75-85%, etc. [The present invention 1060] The transdermal patch of invention 1057 or invention 1058, wherein said crystallization inhibitor is present, which is a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), for example, povidone K30, plasdone K29 / 32, and the like. [This invention 1061] The transdermal patch of the present invention 1060, wherein the crystallization inhibitor is present in an amount of about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12%, or any range between the recited values, such as about 6-12% or 8-12%. [This invention 1062] The transdermal patch of the present invention 1061, wherein the amount of isopropyl myristate is about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, or about 12% by weight, or any range therebetween, such as about 8-12% by weight. [This invention 1063] The transdermal patch of the present invention 1062, wherein the amount of dextromethorphan is about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, or about 12% by weight, or any range therebetween, such as about 8-12% by weight. [This invention 1064] The transdermal patch of the present invention 1063, wherein the drug-containing adhesive layer contains about 20 mg to about 100 mg of dextromethorphan, for example, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range between the recited values, for example, about 40 to 60 mg, 50 to 60 mg, or about 50 to 70 mg. [This invention 1065] A transdermal patch according to the present invention 1064, wherein the drug-containing adhesive layer comprises about 30 mg to about 100 mg of isopropyl myristate, for example, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range between the aforementioned values, for example, about 40 to 60 mg, 50 to 60 mg, or about 50 to 70 mg of isopropyl myristate. [The present invention 1066] 1065. A transdermal patch according to the present invention, wherein the drug-containing adhesive layer comprises about 150 mg to about 900 mg of the pressure-sensitive adhesive, preferably an acrylate-based pressure-sensitive adhesive, for example, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or any range between the recited values, for example, about 300 to 500 mg, 350 to 450 mg, or about 300 to 550 mg. [This invention 1067] The transdermal patch of the present invention 1066, wherein the drug-containing adhesive layer contains the crystallization inhibitor in an amount of about 30 mg to about 100 mg, for example, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range between the recited values, for example, about 40 to 60 mg, 50 to 60 mg, or about 50 to 70 mg. [The present invention 1068] The transdermal patch of the present invention 1067, wherein the drug-containing adhesive layer contains dextromethorphan as the only active ingredient. [The present invention 1069] 1068. The transdermal patch of the present invention, wherein the drug-containing adhesive layer contains about 56 mg of dextromethorphan. [The present invention 1070] Approximately 70cm 2 The transdermal patch of the present invention has an effective surface area of ​​1068. [This invention 1071] Approximately 0.2mg / cm 2 ~about 5mg / cm 2 , for example, about 0.2 mg / cm 2 , about 0.3mg / cm 2 , about 0.4mg / cm 2 , about 0.5mg / cm 2 , about 0.6mg / cm 2 , about 0.7mg / cm 2 , about 0.8mg / cm 2 , approximately 0.9 mg / cm 2 , about 1mg / cm 2 , about 2mg / cm 2 , about 5mg / cm 2 or any range therebetween, e.g., about 0.2 to 1 mg / cm 2 , about 0.5~1mg / cm 2 The transdermal patch of the present invention having a total dextromethorphan loading of 1068 or more. [This invention 1072] The transdermal patch of the present invention 1068, comprising said backing layer, said drug-containing adhesive layer, and optionally a release liner. [This invention 1073] The transdermal patch of the present invention 1068, which is in the form of an integral patch.

[0014] In some embodiments, the present disclosure provides: [1] A method for treating a neurological disease or disorder (e.g., any of those described herein) in a subject in need of such treatment, comprising transdermally delivering to the subject a daily dose of about 15 mg to about 50 mg (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any range therebetween, e.g., about 20-50 mg, about 30-50 mg, or about 20-40 mg) of dextromethorphan. [2] The method of [1], wherein the neurological disease or disorder is emotional dysregulation, depression (e.g., major depressive disorder or treatment-resistant depression), stroke, traumatic brain injury, seizures, pain, methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof. [3] The method according to [1], wherein the neurological disease or disorder is an emotional dysregulation disorder. [4] The method according to any one of [1] to [3], wherein the daily dose is about 20 mg to 40 mg of dextromethorphan. [5] The method according to any one of [1] to [3], wherein the daily dose is about 35 mg of dextromethorphan. [6] The method of any one of [1] to [5], comprising applying a transdermal delivery device once daily to a subject to transdermally deliver a daily dose, wherein the transdermal delivery device comprises a drug-containing adhesive layer comprising dextromethorphan in an amount of about 2% by weight to about 12% by weight, preferably about 6% by weight to about 12% by weight (e.g., about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, or any range therebetween, e.g., about 6% to 12% by weight, 8% to 12% by weight, etc.), a pressure-sensitive adhesive, and a skin permeation enhancer. [7] The transdermal delivery device is approximately 30 cm 2 ~about 200cm 2 , for example, about 30 cm 2 ~about 100cm 2 , for example, about 30 cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 70cm 2 , about 80cm 2 , about 90cm 2 , about 100cm 2 , or any range between the stated values, e.g., about 40-60 cm 2 , about 60~80cm 2 The method according to [6], having an effective surface area of [8] The method of [6] or [7], wherein the pressure-sensitive adhesive is an acrylate adhesive, e.g., a polyacrylate vinyl acetate copolymer, e.g., one having non-acidic hydroxyl functionality, such as those described herein, e.g., Duro-Tak 87-2287 adhesive and the like, and is present in an amount of about 65% to about 85% by weight (e.g., about 65%, about 70%, about 75%, about 80%, or about 85% by weight, or any range therebetween, e.g., about 70-85%, about 75-85% by weight, etc.) of the drug-containing adhesive layer. [9] The method of any one of [6] to [8], wherein the skin permeation enhancer is isopropyl myristate and is present in an amount of about 6% to about 12% by weight (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12% by weight, or any range therebetween, such as about 8-12% by weight) of the drug-containing adhesive layer.

[10] The method of any one of [6] to [9], wherein the drug-containing adhesive layer further comprises a crystallization inhibitor, preferably a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like, in an amount of about 6% to about 12% by weight of the drug-containing adhesive layer (e.g., about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, or any range therebetween, such as about 8 to 12% by weight).

[11] The method of any one of [6] to

[10] , wherein the drug-containing adhesive layer contains about 20 mg to about 100 mg of dextromethorphan, e.g., about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range between the recited values, e.g., about 40 to 60 mg, 50 to 60 mg, or about 50 to 70 mg of dextromethorphan.

[12] The method of any one of [6] to

[11] , wherein the drug-containing adhesive layer comprises about 30 mg to about 100 mg of isopropyl myristate, for example, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range between the recited values, for example, about 40 to 60 mg, 50 to 60 mg, or about 50 to 70 mg of isopropyl myristate.

[13] The method of any one of [6] to

[12] , wherein the drug-containing adhesive layer comprises about 150 mg to about 900 mg of pressure-sensitive adhesive, e.g., about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or any range between the recited values, e.g., about 300 to 500 mg, 350 to 450 mg, or about 300 to 550 mg.

[14] The method of any one of

[10] to

[13] , wherein the crystallization inhibitor is present in an amount of about 30 mg to about 100 mg, e.g., about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range therebetween, e.g., about 40-60 mg, 50-60 mg, or about 50-70 mg.

[15] The method according to any one of [6] to

[14] , wherein the daily dose is about 35 mg of dextromethorphan, and the drug-containing adhesive layer contains about 50 mg to about 70 mg of dextromethorphan.

[16] A transdermal delivery device provides approximately 0.2 mg / cm 2 ~about 5mg / cm 2 , for example, about 0.2 mg / cm 2 , about 0.3mg / cm 2 , about 0.4mg / cm 2 , about 0.5mg / cm 2 , about 0.6mg / cm 2 , about 0.7mg / cm 2 , about 0.8mg / cm 2 , approximately 0.9 mg / cm 2 , about 1mg / cm 2 , about 2mg / cm 2 , about 5mg / cm 2or any range between the values ​​listed, e.g., about 0.2 to 1 mg / cm 2 , about 0.5~1mg / cm 2 The method according to any one of [6] to

[15] , wherein the total dextromethorphan loading amount is

[17] The transdermal delivery device has a densitometric value of at least about 200 μg / cm as measured in vitro using human cadaver skin. 2 / day, for example, about 200ug / cm 2 / day, about 300ug / cm 2 / day, about 400ug / cm 2 / day, about 500ug / cm 2 / day, about 600ug / cm 2 / day, about 700ug / cm 2 / day, about 800ug / cm 2 / day, about 1000ug / cm 2 / day, or any range between the stated values, e.g., about 200-800 ug / cm 2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2 The method according to any one of [6] to

[16] , having a dextromethorphan flux of 1000 mg / day or more.

[18] A transdermal patch, i. a backing layer; ii. a drug-containing adhesive layer comprising: 1) dextromethorphan in an amount of about 2% to about 12% by weight; 2) isopropyl myristate in an amount of about 6% to about 12% by weight; 3) a pressure-sensitive adhesive, preferably an acrylate-based pressure-sensitive adhesive, in an amount of about 65% to about 85% by weight; and optionally 4) a crystallization inhibitor in an amount of about 6% to about 12% by weight. Including, about 30cm 2 ~about 200cm 2 , for example, about 30 cm 2 ~Approx. 100cm 2 A transdermal patch having an effective surface area of

[19] The transdermal patch of

[18] , wherein the acrylate-based pressure-sensitive adhesive is an acrylate copolymer adhesive, such as a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as one having non-acidic hydroxyl functionality, such as those described herein, e.g., Duro-Tak 87-2287 adhesive and the like.

[20] The transdermal patch of

[18] or

[19] , wherein the amount of acrylate-based pressure-sensitive adhesive is about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, or about 85% by weight, or any range therebetween, such as about 70-85%, about 75-85%, etc.

[21] The transdermal patch according to any one of

[18] to

[20] , wherein a crystallization inhibitor is present, which is a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), for example, povidone K30, plasdone K29 / 32, and analogs thereof.

[22] The transdermal patch according to any one of

[18] to

[21] , wherein the crystallization inhibitor is present in an amount of about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12%, or any range therebetween, such as about 6-12% or 8-12%.

[23] The transdermal patch according to any one of

[18] to

[22] , wherein the amount of isopropyl myristate is about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, or about 12% by weight, or any range therebetween, such as about 8 to 12% by weight.

[24] The transdermal patch according to any one of

[18] to

[23] , wherein the amount of dextromethorphan is about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, or about 12% by weight, or any range therebetween, such as about 8 to 12% by weight.

[25] The transdermal patch according to any one of

[18] to

[24] , wherein the drug-containing adhesive layer contains about 20 mg to about 100 mg of dextromethorphan, e.g., about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range between the recited values, e.g., about 40 to 60 mg, 50 to 60 mg, or about 50 to 70 mg of dextromethorphan.

[26] The transdermal patch according to any one of

[18] to

[25] , wherein the drug-containing adhesive layer comprises about 30 mg to about 100 mg of isopropyl myristate, for example, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range between the recited values, for example, about 40-60 mg, 50-60 mg, or about 50-70 mg of isopropyl myristate.

[27] The transdermal patch according to any one of

[18] to

[26] , wherein the drug-containing adhesive layer comprises about 150 mg to about 900 mg of pressure-sensitive adhesive, preferably an acrylate-based pressure-sensitive adhesive, for example, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or any range between the recited values, for example, about 300 to 500 mg, 350 to 450 mg, or about 300 to 550 mg.

[28] The transdermal patch according to any one of

[18] to

[27] , wherein the drug-containing adhesive layer comprises the crystallization inhibitor in an amount of about 30 mg to about 100 mg, e.g., about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range therebetween, e.g., about 40-60 mg, 50-60 mg, or about 50-70 mg.

[29] A transdermal patch according to any one of

[18] to

[28] , wherein the drug-containing adhesive layer contains dextromethorphan as the only active ingredient.

[30] The transdermal patch according to any one of

[18] to

[29] , wherein the drug-containing adhesive layer contains approximately 56 mg of dextromethorphan.

[31] Approximately 70cm 2The transdermal patch according to any one of

[18] to

[30] , having an effective surface area of

[32] Approximately 0.2mg / cm 2 ~about 5mg / cm 2 , for example, about 0.2 mg / cm 2 , about 0.3mg / cm 2 , about 0.4mg / cm 2 , about 0.5mg / cm 2 , about 0.6mg / cm 2 , about 0.7mg / cm 2 , about 0.8mg / cm 2 , approximately 0.9 mg / cm 2 , about 1mg / cm 2 , about 2mg / cm 2 , about 5mg / cm 2 or any range between the values ​​listed, e.g., about 0.2 to 1 mg / cm 2 , about 0.5~1mg / cm 2 The transdermal patch according to any one of

[18] to

[31] , having a total dextromethorphan loading amount of

[33] A transdermal patch according to any one of

[18] to

[32] , which comprises a backing layer, a drug-containing adhesive layer, and optionally a release liner.

[34] The transdermal patch according to any one of

[18] to

[33] , which is in the form of an integrated patch.

[35] At least about 200 μg / cm when measured in vitro using human cadaver skin 2 / day, for example, about 200ug / cm 2 / day, about 300ug / cm 2 / day, about 400ug / cm 2 / day, about 500ug / cm 2 / day, about 600ug / cm 2 / day, about 700ug / cm 2 / day, about 800ug / cm 2 / day, about 1000ug / cm 2 / day, or any range between the stated values, e.g., about 200-800 ug / cm 2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2The transdermal patch according to any one of

[18] to

[34] , having a dextromethorphan flux of 100 mg / day or more.

[36] A method for treating a neurological disease or disorder (e.g., any of those described herein) in a subject in need of treatment, comprising applying to the subject a transdermal patch described in any one of

[18] to

[35] .

[37] The method according to

[36] , wherein a therapeutically effective amount of dextromethorphan is transdermally delivered to a subject by application.

[38] The method according to

[36] , wherein by application, a daily dose of about 15 mg to about 50 mg (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any range between the values ​​listed, e.g., about 20 to 50 mg, about 30 to 50 mg, or about 20 to 40 mg) of dextromethorphan is transdermally delivered to a subject.

[39] The method according to

[38] , wherein the daily dose is about 35 mg of dextromethorphan.

[40] The method according to any one of

[36] to

[39] , wherein the transdermal patch is applied to the subject once a day.

[41] The method of any one of

[36] to

[40] , wherein the neurological disease or disorder is emotional dysregulation, depression (e.g., major depressive disorder or treatment-resistant depression), stroke, traumatic brain injury, seizures, pain, methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof.

[42] The method according to

[41] , wherein the neurological disease or disorder is an emotional dysregulation disorder. 43. A method of treating a neurological disease or disorder (e.g., any of those described herein) in a subject in need thereof, comprising applying to the subject a transdermal patch at a dosing frequency of once daily to once weekly, wherein the transdermal patch contains from about 15 mg to about 700 mg of dextromethorphan (e.g., about 15 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or any range therebetween, e.g., about 15-100 mg, about 30-100 mg, about 30-75 mg, or about 150-500 mg), and wherein application of the patch provides the subject with a therapeutically effective plasma concentration of dextromethorphan at steady state.

[44] The method according to

[43] , wherein the transdermal patch contains about 30 mg to about 100 mg of dextromethorphan.

[45] The method according to

[43] or

[44] , wherein the administration frequency is once a day.

[46] By applying the patch, the AUC at day 7 or steady state is increased by about 180 h*ng / mL to about 2000 h*ng / mL, for example, about 200 h*ng / mL to about 600 h*ng / mL or about 300 h*ng / mL to about 500 h*ng / mL. 0-24,DXM The method according to any one of

[43] to

[45] , wherein a pharmacokinetic profile characterized by the following is provided to the subject.

[47] By applying the patch, the C at day 7 or steady state stage is about 8 ng / mL to about 100 ng / mL, for example, about 10 ng / mL to about 20 ng / mL, for example, about 15 ng / mL. Avg,DXM The method according to any one of

[43] to

[46] , wherein a pharmacokinetic profile characterized by the following is provided to the subject.

[48] ​​By applying the patch, the C at day 7 or steady state stage is about 6 ng / mL to about 65 ng / mL, for example, about 6 ng / mL to about 20 ng / mL. min,DXM The method according to any one of

[43] to

[47] , wherein a pharmacokinetic profile characterized by the following is provided to the subject.

[49] By applying the patch, the C value at day 7 or steady state is about 8 ng / mL to about 90 ng / mL, for example, about 10 ng / mL to about 30 ng / mL. max,DXM The method according to any one of

[43] to

[48] , wherein a pharmacokinetic profile characterized by the following is provided to the subject.

[50] By applying the patch, the fluctuation of dextromethorphan [(C max -C min ) / C avg The method according to any one of

[43] to

[49] , wherein a pharmacokinetic profile characterized by:

[51] By applying the patch, the amplitude ratio of dextromethorphan at the 7th day or steady state stage [(C max -C min ) / C min The method according to any one of

[43] to

[50] , wherein a pharmacokinetic profile characterized by:

[52] By applying, the AUC of about 1.5 to about 5, for example, about 1.5 to about 3, for example, about 1.5 to 2.5 0-24,DXM,D1 AUC at steady state phase 0-24,DXM The method according to any one of

[43] to

[51] , wherein a pharmacokinetic profile characterized by the ratio of

[53] By applying the patch, the AUC at steady state is increased from about 12 to about 35. 0-24,DOR AUC for 0-24,DXM The method according to any one of

[43] to

[52] , wherein a pharmacokinetic profile characterized by the ratio of

[54] By applying the adhesive, the C max,DOR C against max,DXM The method according to any one of

[43] to

[53] , wherein a pharmacokinetic profile characterized by the ratio of

[55] By applying the adhesive, the C in the steady state phase is about 12 to about 35. Avg,DORC against Avg,DXM The method according to any one of

[43] to

[54] , wherein a pharmacokinetic profile characterized by the ratio of

[56] By applying the patch, a) the AUC at day 7 or steady state was increased to approximately 200 h*ng / mL to approximately 600 h*ng / mL. 0-24,DXM b) C at day 7 or steady state of about 10 ng / mL to about 20 ng / mL, for example about 15 ng / mL Avg,DXM c) C at day 7 or steady state of about 6 ng / mL to about 20 ng / mL min,DXM and / or d) a C at day 7 or steady state of about 10 ng / mL to about 30 ng / mL. max,DXM The method according to any one of

[43] to

[55] , wherein a pharmacokinetic profile characterized by the following is provided to the subject.

[57] By applying the patch, the fluctuation of dextromethorphan at the 7th day or steady state stage [(C max -C min ) / C avg ], and / or f) a dextromethorphan amplitude ratio [(C max -C min ) / C min The method according to any one of

[43] to

[56] , wherein a pharmacokinetic profile characterized by:

[58] By applying, AUC of about 1.5 to about 3 g 0-24,DXM,D1 AUC at steady state phase 0-24,DXM The method according to any one of

[43] to

[57] , wherein a pharmacokinetic profile characterized by the ratio of

[59] By applying the 0-24,DOR AUC for 0-24,DXM i) the ratio of C at the steady state stage between about 12 and about 35 max,DOR C against max,DXM and / or j) a C at the steady state stage of about 12 to about 35 Avg,DOR C against Avg,DXMThe method according to any one of

[43] to

[58] , wherein a pharmacokinetic profile characterized by the ratio of

[60] By applying the transdermal patch, each application other than the first dose will increase the pre-dose plasma dextromethorphan concentration to the mean concentration observed from the previous dose (C Avg,DXM The method according to any one of

[43] to

[59] , wherein the subject is provided with a pharmacokinetic profile characterized by not being less than about 20% of the normal pharmacokinetic profile (dose).

[61] The method according to any one of

[43] to

[60] , wherein, by application, the accumulation rate of dextromethorphan is in the range of about 1 to about 5, for example, about 1.2 to about 3, and a pharmacokinetic profile is imparted to the subject, characterized in that the subject is an extensive metabolizer or an ultra-extensive metabolizer.

[62] By applying the patch, k) the half-life of dextromethorphan at steady state is reduced to about 11 to about 29 hours, e.g., about 11 to about 24 hours, e.g., about 17 hours, in extensive or very extensive metabolizers, and / or l) the half-life of dextromethorphan at steady state is reduced to about 0.018 hours in extensive or very extensive metabolizers. -1 ~about 0.065h -1 , for example, about 0.020h -1 ~approx. 0.06 hours -1 The apparent first-order terminal elimination rate constant (λ) after the final dose after achieving a steady-state phase z The method according to any one of

[43] to

[61] , wherein a pharmacokinetic profile characterized by:

[63] The method according to any one of

[43] to

[62] , wherein the application of the patch transdermally delivers to a subject a daily dose of about 15 mg to about 50 mg (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any range between the values ​​listed, e.g., about 20 to 50 mg, about 30 to 50 mg, or about 20 to 40 mg).

[64] The method according to any one of

[43] to

[62] , wherein the patch delivers a daily dose of about 35 mg of dextromethorphan transdermally to the subject.

[65] The method of any one of

[43] to

[64] , wherein the neurological disease or disorder is emotional dysregulation, depression (e.g., major depressive disorder or treatment-resistant depression), stroke, traumatic brain injury, seizures, pain, methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof.

[66] The method according to any one of

[43] to

[65] , wherein the neurological disease or disorder is emotional dysregulation.

[67] The method according to any one of

[43] to

[66] , wherein the transdermal patch is any one of those described herein, such as the transdermal patch described in any one of

[18] to

[35] .

[68] A transdermal patch comprises a backing layer and a drug-containing adhesive layer, the drug-containing adhesive layer comprising dextromethorphan as the sole active ingredient, the drug-containing adhesive layer comprising dextromethorphan in an amount of about 6% to about 12% by weight (e.g., about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, or any range between the recited values, e.g., about 8-12% by weight). % by weight, etc.), a pressure-sensitive adhesive in an amount of about 65% to about 85% by weight (e.g., about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, about 85% by weight, etc.), and optionally a crystallization inhibitor in an amount of about 6% to about 12% by weight (e.g., about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, or any range between the recited values, e.g., about 8% to 12% by weight).

[69] The method of

[68] , wherein the pressure-sensitive adhesive is an acrylate-based pressure-sensitive adhesive, such as an acrylate copolymer adhesive, such as a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as one having non-acidic hydroxyl functional groups, such as those described herein, e.g., Duro-Tak 87-2287 adhesive and the like, and the drug-containing adhesive layer comprises a crystallization inhibitor, which is preferably a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like.

[70] The transdermal patch has a densitometric value of at least about 200 μg / cm2 as measured in vitro using human cadaver skin. 2 / day, for example, about 200ug / cm 2 / day, about 300ug / cm 2 / day, about 400ug / cm 2 / day, about 500ug / cm 2 / day, about 600ug / cm 2 / day, about 700ug / cm 2 / day, about 800ug / cm 2 / day, about 1000ug / cm 2 / day, or any range between the stated values, e.g., about 200-800 ug / cm 2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2 The method according to

[68] or

[69] , having a dextromethorphan flux of 100 mg / day or more.

[71] A transdermal patch containing approximately 56 mg of dextromethorphan is administered over a 70 cm 2 The method according to any one of

[68] to

[70] , having an effective surface area of

[72] The method according to any one of [1] to

[17] and

[36] to

[71] , wherein the subject is not suffering from a cough and / or does not require antitussive medication.

[73] The method according to any one of [1] to

[17] and

[36] to

[72] , wherein the subject is characterized as an extensive metabolizer of dextromethorphan.

[74] The method according to any one of [1] to

[17] and

[36] to

[72] , wherein the subject is characterized as a poor metabolizer of dextromethorphan.

[75] The method according to any one of [1] to

[17] and

[36] to

[74] , wherein the subject is sensitive or intolerant to a CYP2D6 inhibitor.

[76] The method according to any one of [1] to

[17] and

[36] to

[75] , wherein the subject has one or more side effects associated with quinidine.

[77] The method according to any one of [1] to

[17] and

[36] to

[76] , wherein the subject is co-administered a drug whose metabolism is affected by a CYP2D6 inhibitor.

[78] The method according to any one of [1] to

[17] and

[36] to

[77] , further comprising administering an antidepressant to the subject.

[79] The method according to any one of [1] to

[17] and

[36] to

[78] , wherein the antidepressant is selected from bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, metabolites or prodrugs of any of these compounds, and combinations thereof.

[80] The method according to any one of [1] to

[17] and

[36] to

[79] , wherein the subject is not administered quinidine.

[81] The method according to any one of [1] to

[17] and

[36] to

[80] , wherein the subject is a human subject.

[82] The method according to any one of [1] to

[17] and

[36] to

[81] , wherein the transdermal delivery device or transdermal patch is applied once a day, and the residual amount of dextromethorphan in the transdermal delivery device or transdermal patch is less than 50% (e.g., less than 40%) of the initial amount of dextromethorphan in the transdermal delivery device or transdermal patch.

[83] The method according to any one of [1] to

[17] and

[36] to

[82] , wherein the transdermal delivery device or transdermal patch is applied once daily and the proportion of dextromethorphan delivered to the subject is about 50% to about 80% of the initial amount of dextromethorphan in the transdermal delivery device or transdermal patch. [Brief explanation of the drawings]

[0015] [Figure 1] Graphs are presented showing in vitro flux test results of transdermal delivery devices with different adhesive formulations A and B, with the flux of dextromethorphan (DXM) from patches with formulation A (acrylate adhesive) having faster flux than patches with formulation B (silicone adhesive) shown at the top. [Figure 2] Graphs are presented showing in vitro flux test results for patches with formulations C1-C3, including different ratios of silicone adhesive to acrylic adhesive: 54:46 (middle), 18:82 (bottom), and 9:91 (top). [Figure 3A] Graphs are presented showing the effect of a skin permeation enhancer (isopropyl myristate, IPM) on in vitro flux (10% IPM (top), 7.7% IPM (middle), and 0% IPM (bottom)). [Figure 3B] 1 presents a graph showing the mean permeation dextromethorphan versus time profile for patches with formulation E1. [Figure 4] A shows dextromethorphan plasma concentrations over 96 hours in a human clinical trial comparing the effects of a 24-hour administration of a DXM transdermal patch (Test A) with twice-daily oral administration of NUEDEXTA (DXM 20 mg / quinidine 10 mg) (Reference B). B shows the plasma concentrations of the metabolite dextrorphan (DOR) over 96 hours in the same study. In A and B, both test and reference administrations were administered under fasting conditions in subjects. Plasma concentrations refer to mean plasma concentrations, N=16. [Figure 5] 1 shows a multi-layer patch design, where the top layer is a skin contact adhesive layer, the middle layer is a reservoir layer, and the bottom layer is a backing or adhesive layer, which may be the same as or different from the top layer. [Figure 6A]Figure 1 shows mean dextromethorphan plasma concentrations over 11 days in a human clinical trial comparing the effects of a DXM transdermal patch (Treatment A) administered every 24 hours for 7 days with the effects of NUEDEXTA® (DXM 20 mg / quinidine 10 mg) (Treatment B) administered orally twice daily for 7 days; N=20 for this study. [Figure 6B] 1 shows the mean dextromethorphan plasma concentration versus time profile on Day 1 after Treatment A or Treatment B of the same study. [Figure 6C] 1 shows the mean dextromethorphan plasma concentration versus time profile on day 7 after Treatment A or Treatment B of the same study. [Figure 6D] 1 shows the mean dextrorphan plasma concentrations over 11 days in a human clinical trial following Treatment A or Treatment B of the same study. [Figure 6E] 1 shows the mean dextrorphan plasma concentration versus time profile on Day 1 after Treatment A or Treatment B of the same study. [Figure 6F] 1 shows the mean dextrorphan plasma concentration versus time profile on day 7 after Treatment A or Treatment B of the same study. DETAILED DESCRIPTION OF THE INVENTION

[0016] Detailed Description Dextromethorphan (DXM) is used orally to treat neurological disorders such as dysregulation of affect (PBA), emotional lability, agitation in Alzheimer's disease, major depressive disorder, treatment-resistant disorders, pain management, other CNS disorders, and the like. However, to be effective, DXM must be delivered with a substance that competitively inhibits the hepatic enzyme cytochrome P450 2D6 (CYP2D6). Specifically, this means that DXM is coadministered with quinidine. Otherwise, small amounts of DXM will be subject to hepatic action on ingested food.

[0017] The present disclosure generally relates to the transdermal delivery of dextromethorphan using the transdermal delivery devices, formulations (e.g., adhesive compositions), and methods herein, which offer many advantages over currently available oral formulations (e.g., NUEDEXTA®) and address many unmet medical needs associated with such oral formulations. For example, the transdermal delivery devices or formulations herein can be administered to achieve therapeutically effective plasma concentrations regardless of whether a CYP2D6 inhibitor, such as quinidine, is co-administered. Thus, the transdermal administration devices or formulations herein can be administered to transdermally deliver dextromethorphan to subjects who are sensitive to or intolerant of CYP2D6 inhibitors, such as quinidine (e.g., subjects who have one or more side effects associated with quinidine or who are co-administering a drug whose metabolism is affected by a CYP2D6 inhibitor, such as quinidine). Furthermore, the transdermal delivery device or formulation herein can be conveniently administered to transdermally deliver dextromethorphan to a subject, regardless of whether the subject is first determined to be a poor, intermediate, or extensive metabolizer of dextromethorphan. For brevity, as used herein, unless otherwise clear from the context, poor metabolizer (PM), intermediate metabolizer (IM), or extensive metabolizer (EM) refers to a subject's ability to metabolize dextromethorphan. Classifying subjects as PM, IM, or EM (also referred to as extreme metabolizers or ultrarapid metabolizers or UMs) is known in the art. See, for example, Treducu ALD et al., Frontiers in Pharmacology, Vol. 9, Article 305 (April 2018), which assigns subjects as UMs if they contain "three or more copies of the gene that function normally" based on genotype.

[0018] Administration of dextromethorphan using the transdermal delivery devices or transdermal formulations herein may also result in, for example, more accurate dosing, less frequent dosing, fewer quinidine-associated side effects and / or increased dextromethorphan exposure (e.g., C ) compared to NUEDEXTA®.max ), reducing the potential for side effects associated with dextromethorphan, reducing pill burden, and improving patient compliance, may provide a superior clinical experience. Given this disclosure, one skilled in the art will be able to select an appropriate patch to more precisely deliver a therapeutically effective amount of dextromethorphan to a treated subject. Furthermore, the steady-state PK profiles described herein demonstrate that transdermal delivery of dextromethorphan can achieve a much lower yet effective plasma exposure of dextromethorphan compared to twice-daily oral dosing of NUEDEXTA® tablets. Thus, the methods herein are intended to provide a therapeutically effective treatment for at least high dextromethorphan exposure (e.g., C max It is expected that this will result in a reduced incidence of side effects associated with steroids (e.g., AUC). The transdermal delivery devices herein can be configured as a 1-day patch, 2-day patch, 3-day patch, 4-day patch, 5-day patch, 6-day patch, or 7-day patch, and are suitable for dosing frequencies ranging from once daily to once weekly, e.g., once over 24 hours, once over 36 hours, once over 48 hours, etc., or once weekly, twice weekly, three times weekly, four times weekly, five times weekly, or six times weekly. Use of the transdermal delivery devices herein can improve patient compliance by avoiding at least a twice-daily dosing regimen of NUEDEXTA®.

[0019] Prior to the applicant's research, it was unknown whether dextromethorphan could be delivered transdermally to achieve therapeutically effective plasma concentrations for treating neurological diseases or disorders such as PBA. The unpredictability of transdermal administration is well known. For example, testosterone can be delivered transdermally without enhancers at rates three orders of magnitude higher than beta-estradiol. This difference was unexpected because these compounds are similar structurally and based on LogP calculations. See U.S. Provisional Application No. 62 / 568,028, filed October 4, 2017, the contents of which are incorporated by reference in their entirety. U.S. Pat. No. 6,335,030 B1 describes several examples of dextromethorphan patches intended to achieve antitussive effects. However, prior to applicant's work described in U.S. Provisional Application No. 62 / 680,182 and International Application No. PCT / US2018 / 054178 (published as WO2019 / 070864), the contents of each of which are incorporated by reference in their entirety, no pharmacokinetic data were known regarding transdermal administration of dextromethorphan.

[0020] PCT / US2018 / 054178 demonstrated that transdermal delivery of dextromethorphan without quinidine can produce significant dextromethorphan blood concentrations in humans. PCT / US2018 / 054178 also included a study in which healthy subjects were given a 45cm dose containing approximately 35mg of dextromethorphan. 2 An exemplary patch of size 15 mg (designed to transdermally deliver 15 mg per day and containing about 80% by weight adhesive (Duro-Tak 87-2287), about 10% by weight dextromethorphan base, and about 10% by weight permeation enhancer isopropyl myristate in the adhesive layer (drug-containing adhesive layer)) applied for about 24 hours resulted in a mean C of about 6 ng / mL, which approaches, among other things, that observed following oral administration of NUEDEXTA® tablets (20 mg dextromethorphan and 10 mg quinidine) twice daily to human subjects. max and a mean AUC of approximately 92 h·ng / mL. 0-24hA human pharmacokinetic study has been described in which it was found that

[0021] In a further development, as detailed herein, the inclusion of a crystallization inhibitor, vinylpyrrolidone polymer (Plasdone K29 / 32), in a dextromethorphan transdermal patch is shown to significantly enhance the permeability of dextromethorphan from the patch in vitro and in vivo. 2 The patch, worn for 24 hours, can deliver a daily dose of about 32.4 mg to about 41.1 mg of dextromethorphan to a human subject, resulting in a dextromethorphan flux of about 0.46 mg / cm. 2 / day~about 0.59mg / cm 2 This is a significantly greater flux compared to a similar patch without the vinylpyrrolidone polymer (which was replaced by the adhesive matrix Duro-Tak 87-2287), with an estimated flux of approximately 0.33 mg / cm. 2 Additional in vivo data also showed that patches with vinylpyrrolidone polymers reduced the per unit patch area (cm 2 For example, as shown in Example 4, when the patch has a vinylpyrrolidone polymer, the C on day 1 normalized by patch area is max or AUC 0-24 is approximately 20% higher than that observed with patches without the vinylpyrrolidone polymer. This improvement in flux is due to the 2 A high dextromethorphan loading per patch is not required. In fact, the dextromethorphan loading of both patches is approximately 0.8 mg / cm. 2 And there is no difference.

[0022] It has also been found that the amount of dextromethorphan required for the transdermal patch herein to achieve a desired daily dose does not exceed twice the desired daily dose. For example, this example demonstrates that a transdermal patch containing less than 70 mg of dextromethorphan (approximately 56 mg of dextromethorphan) was able to deliver a desired daily dose of approximately 35 mg. Thus, transdermal bioavailability (i.e., delivered dextromethorphan divided by the initial dextromethorphan in the patch) is generally greater than 50%, and can be as high as 80% or greater. This high bioavailability is made possible, in part, by the unexpected discovery that the transdermal patch herein can achieve a continuously high flux of dextromethorphan. In light of these results, the use of the patch herein may have further advantages, including, for example, delivering a similar amount of dextromethorphan from a smaller patch size and reducing the amount of residual dextromethorphan in the applied patch.

[0023] In various embodiments, the present disclosure provides transdermal delivery devices and transdermal formulations comprising dextromethorphan, methods for preparing the same, methods for transdermal delivery of dextromethorphan using the transdermal delivery devices or transdermal formulations herein, and methods for treating a disease or disorder using the transdermal delivery devices or transdermal formulations herein.

[0024] Transdermal delivery devices containing dextromethorphan Certain embodiments of the present disclosure are directed to novel transdermal delivery devices containing dextromethorphan.

[0025] Various patch designs can be used for the transdermal delivery devices herein. The transdermal delivery devices herein typically include a backing layer, an adhesive layer (e.g., a drug-containing adhesive layer) that serves as the skin-contacting layer during use, and an optional reservoir layer. The adhesive layer typically contains dextromethorphan dispersed (e.g., uniformly dispersed, including dissolved) in an adhesive, preferably a pressure-sensitive adhesive. Multiple adhesive layers can be used in the transdermal delivery devices herein. The adhesive layer is generally formulated to allow the transdermal delivery device to adhere to the user's skin for a desired period of time. For example, in some embodiments, the transdermal delivery device can be continuously adhered to the user's skin for about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more.

[0026] In some embodiments, the transdermal delivery device can be a drug-in-adhesive (DIA) patch. In some embodiments, the DIA patch is a single-layer patch, e.g., the single layer contains dextromethorphan uniformly dispersed in the adhesive. In some embodiments, the DIA patch is a multi-layer patch. For example, the patch can contain two drug-in-adhesive layers, optionally separated by a membrane, e.g., a rate-controlling membrane, or a reservoir layer. In some embodiments, one of the drug-in-adhesive layers can be a reservoir layer, e.g., having a higher dextromethorphan concentration than the other layer. In some embodiments, the two drug-in-adhesive layers can sandwich the reservoir layer.

[0027] The transdermal delivery devices herein may also employ a drug-containing reservoir (DIR) design. In some embodiments, the reservoir layer and adhesive layer may be laminated together or separated, for example, by a rate-controlling membrane. For example, in some embodiments, a reservoir layer, such as a drug matrix, may be laminated with the adhesive layer. Those skilled in the art will appreciate that such adhesive layers may also contain a certain amount of drug, for example, through equilibrium.

[0028] Other patch designs can also be used for the transdermal delivery devices herein. For example, in some embodiments, the transdermal delivery device can be an active patch, such as an iontophoretic patch. In some embodiments, the transdermal delivery device can be a minimally invasive patch, such as a patch using microneedles.

[0029] The transdermal delivery device can contain dextromethorphan as the sole drug or in combination with another drug. Unless clearly contradicted, in any of the embodiments described herein, dextromethorphan can be the sole drug in the transdermal delivery device. Dextromethorphan can exist in various forms, e.g., as the free base or a pharmaceutically acceptable salt. As used herein, weight percentages, concentrations, fluxes, etc., referring to dextromethorphan should be understood as the measured and / or calculated total amount of dextromethorphan, and the values ​​are expressed in terms of the equivalent value relative to the dextromethorphan base. Furthermore, unless otherwise clear from the context, all weight percentages should refer to weight percentages based on the final formulation (e.g., the final adhesive layer or final reservoir layer, etc.) or the final transdermal delivery device, as appropriate. In any of the embodiments described herein, dextromethorphan can exist in its free base form, except that it may be protonated through equilibrium with other component(s). For example, in any of the embodiments described herein, the transdermal delivery device or pharmaceutical composition described herein can be prepared by directly or indirectly mixing the described amount of dextromethorphan base with other ingredients.

[0030] In any of the embodiments described herein, dextromethorphan in the transdermal delivery device can be partially or completely replaced with deuterated dextromethorphan, such as a d3 analog (O-CD3, or N-CD3) or a d6 analog (N-CD3, O-CD3). See, e.g., claims 1 and 17 of U.S. Pat. No. 7,973,049, the contents of which are incorporated by reference in their entirety. In such embodiments, it will be apparent that the method of using a deuterated dextromethorphan patch provides deuterated dextromethorphan to the user. As used herein, deuterated dextromethorphan refers to a compound resulting from the replacement of one or more hydrogen atoms of dextromethorphan with deuterium, such that each replacement position has a deuterium content greater than the natural abundance, i.e., the replacement position is enriched with deuterium. In some embodiments, the deuterated dextromethorphan has at least one position enriched with deuterium to at least 10% deuterium, at least 50% deuterium, at least 90% deuterium, at least 95% deuterium, or at least 98% deuterium. In any of the embodiments described herein, the dextromethorphan in the transdermal delivery device can also be partially or completely replaced with a dextromethorphan analog, such as a fluorinated dextromethorphan or a skin-permeable prodrug of dextromethorphan.

[0031] The adhesive layer typically comprises a pressure-sensitive adhesive (PSA). Useful features of a pressure-sensitive adhesive include adequate tack, good adhesive strength, and cohesive strength. Further useful attributes include biocompatibility (e.g., non-irritating, non-sensitizing, non-toxic), formulation compatibility, delivery system compatibility, etc. Useful pressure-sensitive adhesives include, for example, polyacrylates, polyacrylic esters, silicones, polyisobutylene, etc.

[0032] PSAs are generally known in the art. See, for example, Tan et al., Pharm Sci & Tech Today, 2:60-69 (1999). Non-limiting examples of useful PSAs include polyisobutylene (PIB), silicone polymers, acrylate copolymers, and combinations thereof. In some embodiments, the pressure-sensitive adhesive comprises a polyisobutylene adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some embodiments, the pressure-sensitive adhesive comprises an acrylate copolymer adhesive. Non-limiting examples of useful acrylate copolymers include polyacrylate vinyl acetate copolymers, such as acrylic pressure-sensitive adhesives such as Duro-Tak 87-2287, Duro-Tak 87-4098, Duro-Tak 87-4287, or Duro-Tak 87-2516, Duro-Tak 87-2852, or Duro-Tak 87-2194 manufactured by Henkel Adhesives. PIB is an elastomeric polymer commonly used in PSAs as both the main base polymer and tackifier. PIB is a homopolymer of isobutylene, characterized by a regular structure of a carbon-hydrogen backbone with only terminal unsaturation. Non-limiting examples of useful PIBs include those sold by BASF under the trade name Oppanol. Silicone polymers are high-molecular-weight polydimethylsiloxanes containing residual silanol functionality (SiOH) at the ends of the polymer chain. Non-limiting examples of useful silicone PSAs for use in pharmaceutical applications include those available from Dow Corning Corporation under the trade name BIO-PSA, e.g., BIO-7-4202. In some embodiments, the adhesive layer is from about 0.1 mil to about 10 mil, e.g., from about 1.5 mil to about 10 mil (e.g., from about 1.5 mil to about 2 mil) thick.

[0033] In some embodiments, suitable adhesives include, for example, the following silicone adhesives manufactured by Dow Corning: BIO-PSA 7-410X, BIO-PSA 7-420X, BIO-PSA 7-430X, BIO-PSA 7-440X, BIO-PSA 7-450X, BIO-PSA 7-460X, and BIO-PSA hot melt adhesive. In some embodiments, suitable adhesives include, for example, the following polyacrylate / polyacrylic ester adhesives manufactured by Henkel Adhesives: Duro-Tak 87-900A, 87-9301, 87-4098, 87-2510, 87-2287, 87-2677, 87-4287, 87-2516, 87-2074, 87-235A, 87-2353, 87-2852, 87-2051, 87-2052, 87-2054, 87-2194, 87-2196, 87-6908, 387-2510, 387-2287, 387-2516, 387-2353, 387-2051, 387-2051, and 387-2054; GELVA Examples include GMS 3083, 3253, 788, and 9073. These may contain, for example, hydroxyl, carboxyl, hydroxyl, and carboxyl functional groups, or no functional groups (as previously described). They may or may not contain, for example, vinyl acetate monomers. In some embodiments, the pressure-sensitive adhesive may be a copolymer formed from acrylate monomers and vinyl acetate, including those containing non-acidic hydroxyl functional groups, such as DuroTak® 2287 (e.g., 87-2287, 387-2287, etc.) adhesives and the like. A representative composition of DuroTak® 2287 may include a random copolymer formed from the following monomers: 2-ethylhexyl acrylate (e.g., about 68.2%), vinyl acetate (e.g., about 26.5%), hydroxyethyl acrylate (e.g., about 5.2%), and glycidyl methacrylate (e.g., about 0.15%).In some embodiments, the acrylate copolymer adhesive may be formed from monomers including about 5.2 wt% 2-hydroxyethyl acrylate, about 20-40 wt% vinyl acetate, and about 55-75 wt% 2-ethylhexyl acrylate. See also U.S. Published Application No. US20060257462A1 and U.S. Patent No. 5,693,335, the contents of each of which are incorporated herein by reference in their entirety.

[0034] Typically, transdermal delivery devices (e.g., DIA patches) are supported by a backing layer, such as an impermeable backing film, and the adhesive surface is protected by a release liner before use. Various materials can be used as the backing layer of the transdermal delivery device herein. Typically, the backing layer is impermeable. For example, the backing layer can be composed of an impermeable polymer film, such as a polyester (PET) film or a polyethylene (PE) film. In some embodiments, the backing layer can comprise a polyester, such as Scotchpak 9736 or Scotchpak 1012, a polyurethane film, such as Scotchpak 9701, or a polyethylene film, such as CoTran 9720. In some embodiments, the backing is part of an overlay and can be a nonwoven fabric, a polyurethane film, or other flexible material that provides flexibility and better wear.

[0035] The release liner can be manufactured in any desired size for the present invention. The release liner can be composed of a silicone- or fluoropolymer-coated polyester film. The release liner protects the transdermal delivery device during storage and is removed before use. Silicone-coated release liners include those manufactured by Mylan Corporation, Loparex Corporation, and 3M's Drug Delivery Systems. Fluoropolymer-coated release liners include those manufactured and supplied by 3M's Drug Delivery Systems and Loparex. In some embodiments, the release liner comprises 3M's ScotchPak 9744 or Scotchpak 1022.

[0036] The transdermal delivery devices herein may also optionally include other suitable excipients such as humectants, plasticizers, antioxidants, anti-irritants, gel-forming agents, crystallization inhibitors, drug-release modifiers, etc. These excipients are within the purview of those skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients, (7 th ed. 2012), the entire contents of which are incorporated herein by reference. In some embodiments, additional active ingredient(s) may also be included in the transdermal delivery devices herein.

[0037] The transdermal delivery device (e.g., DIA patch) herein can have different sizes (patch size) depending on its application. Typically, the patch size is about 5 cm 2 ~about 300cm 2 (For example, about 5 cm 2 , about 10cm 2 , about 20cm 2 , about 30cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 80cm 2 , about 100cm 2 , about 120cm2 , about 150cm 2 , about 200cm 2 or any range between the specified values), e.g., about 10 cm 2 ~about 100cm 2 It could be.

[0038] When a transdermal delivery device (e.g., a DIA patch) herein is applied to the skin of a subject, theoretically, all of the adhesive surface may come into contact with the skin. Thus, the area of ​​the adhesive surface defines the skin contact area through which the active ingredient from the device can penetrate the skin, which is also referred to herein as the effective surface area. In some embodiments, the adhesive surface is the only surface of the transdermal delivery device that contacts the skin upon application, and the effective surface area is the same as the area of ​​the adhesive surface. In some embodiments, the adhesive surface and one or more other surfaces of the transdermal delivery device are in contact with the skin upon application, and the entire skin contact area is the effective surface area. In a typical DIA patch, the patch size is the same as the effective surface area. Unless otherwise clear from the context, the unit " / cm 2 " should be understood as the effective surface area as defined herein per square centimeter.

[0039] The effective surface area can determine the dose of drug to be delivered. Typically, the effective surface area is about 5 cm 2 ~about 300cm 2 (For example, about 5 cm 2 , about 10cm 2 , about 20cm 2 , about 30cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 80cm 2 , about 100cm 2 , about 120cm 2 , about 150cm 2 , about 200cm 2 or any range between the specified values), e.g., about 10 cm 2 ~about 100cm 2 It could be.

[0040] In some embodiments, the transdermal delivery devices herein can be configured to provide dextromethorphan to a user (e.g., a human subject) at a dose of at least about 2 mg / day (e.g., about 2 mg / day to about 50 mg / day) for one or more days, e.g., 2, 3, 4, 5, 6, or 7 days. For example, in some embodiments, the transdermal delivery devices can be configured to transdermally deliver dextromethorphan to a user at a dose of about 5 mg / day to about 50 mg / day (e.g., about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, or any ranges therebetween) for one or more days (e.g., 1.5 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or any ranges therebetween).

[0041] The total dextromethorphan loading of the transdermal delivery device can be adjusted based on the total desired dose. Typically, the total dextromethorphan loading is (e.g., at least 2 mg / cm 2 , at least 3 mg / cm 2 , at least 4 mg / cm 2 , at least 5 mg / cm 2 , at least 6 mg / cm 2 etc.) 0.2mg / cm 2 For example, in some embodiments, the transdermal delivery device may be greater than about 0.2 mg / cm 2 ~about 8mg / cm 2 , for example, about 0.2 mg / cm 2 ~about 2mg / cm 2 (For example, about 0.2 mg / cm 2 , about 0.3mg / cm 2 , about 0.4mg / cm 2 , about 0.5mg / cm 2 , about 0.6mg / cm 2 , about 0.7mg / cm 2 , about 0.8mg / cm 2 , approximately 0.9 mg / cm 2 , about 1mg / cm 2 , about 1.2mg / cm 2 , about 1.5mg / cm 2 , about 1.8mg / cm 2 , about 2mg / cm2 or any range between the values ​​listed, e.g., about 0.2 to 1 mg / cm 2 , about 0.5~1mg / cm 2 , about 0.5~1.5mg / cm 2 etc.), approximately 0.5 mg / cm 2 ~about 8mg / cm 2 or approximately 2 mg / cm 2 ~about 6mg / cm 2 (For example, about 2 mg / cm 2 , about 3mg / cm 2 , about 4mg / cm 2 , about 5mg / cm 2 , about 6mg / cm 2 , or any range between the recited values). As used herein, the total dextromethorphan loading of a patch can be calculated by dividing the total amount of dextromethorphan in the patch by the effective surface area of ​​the patch.

[0042] Exemplary Transdermal Delivery Devices and Transdermal Formulations In some embodiments, the present disclosure may also provide the following non-limiting exemplary transdermal delivery devices, or what may alternatively be referred to herein as transdermal patches or simply patches, and transdermal formulations such as adhesive compositions.

[0043] In some embodiments, the present disclosure provides an adhesive composition comprising (1) dextromethorphan, (2) a pressure-sensitive adhesive, (3) a skin permeation enhancer (e.g., isopropyl myristate), and optionally (4) a crystallization inhibitor (e.g., a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), e.g., Povidone K30, Plasdone K29 / 32, and the like). In some embodiments, the amount of dextromethorphan is from about 2% to about 12% by weight of the adhesive composition, preferably from about 6% to about 12% by weight (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any range therebetween, such as about 8-12% by weight), and the amount of skin permeation enhancer (e.g., isopropyl myristate) is from about 6% to about 12% by weight of the adhesive composition (e.g., about 8% to about 12% by weight). , about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, or any range therebetween, such as about 8-12 wt%, and the amount of pressure-sensitive adhesive is about 65 wt% to about 85 wt% of the adhesive composition (e.g., about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, or any range therebetween, such as about 65-85 wt%, about 70-85 wt%, about 75-85 wt%, etc.). The dextromethorphan and dermal permeation enhancer are typically dispersed (e.g., homogeneously dispersed or dissolved) in the pressure-sensitive adhesive. In some embodiments, the dextromethorphan and dermal permeation enhancer are homogeneously mixed with the pressure-sensitive adhesive. In some embodiments, the adhesive composition is a homogeneous mixture. In some embodiments, the adhesive composition comprises the crystallization inhibitor in an amount of about 6% to about 12% by weight (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any range therebetween, such as about 8-12% by weight). In some embodiments, the adhesive composition comprises dextromethorphan as the only active ingredient. In some embodiments, the skin permeation enhancer is isopropyl myristate. The pressure-sensitive adhesive may be any of those described herein.Typically, the pressure-sensitive adhesive is an acrylate copolymer adhesive, such as a polyacrylate vinyl acetate copolymer, e.g., one having non-acidic hydroxyl functionality, such as those described herein, e.g., Duro-Tak 87-2287 adhesive and its analogs manufactured by Henkel Adhesives. In some embodiments, the pressure-sensitive adhesive comprises an acrylate copolymer adhesive and an additional adhesive. For example, in some embodiments, the pressure-sensitive adhesive can be a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios (e.g., a weight ratio of acrylate adhesive to silicone adhesive ranging from about 1:20 to about 20:1, e.g., from about 10:1 to about 1:10, e.g., about 10:1, about 4:1, about 1:1, about 1:4, etc., or any range therebetween). The crystallization inhibitor, if present, can be a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like. In some embodiments, the crystallization inhibitor is a vinylpyrrolidone polymer having a nominal K value of about 25-35, e.g., about 29-32. The K values ​​assigned to various grades of PVP polymer are a function of average molecular weight, degree of polymerization, and intrinsic viscosity. K values ​​are derived from viscosity measurements and calculated according to the Fikentscher equation. Those skilled in the art will appreciate that any nominal K value allows for a certain variation from the nominal value, typically 90-108%. For example, for povidone K30, i.e., with a nominal K value of 30, the United States Pharmacopoeia and the European Pharmacopoeia typically allow for a variation of 90%-108% from the specified value. Thus, povidone having a K value ranging from 27.0 to 32.4 is within the specification range for povidone K30 polymer. Unless otherwise clear from the context, K values ​​referred to herein should be understood as nominal K values. In any of the embodiments described herein, unless otherwise specified or contradicted by context, a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), can have a nominal K value of about 25 to 35, such as about 29 to 32.As used herein, vinylpyrrolidone polymers should be generally understood to encompass both homopolymers and copolymers. The adhesive compositions are typically used as adhesive layers (e.g., drug-containing adhesive layers) in the transdermal delivery devices described herein.

[0044] In some embodiments, the present disclosure provides a transdermal patch comprising a) a backing layer (e.g., as described herein) and b) an adhesive composition or adhesive layer disclosed herein. The adhesive surface is typically protected with a release liner prior to use. Suitable release liners are described herein. In some embodiments, the transdermal patch comprises, consists essentially of, or consists of a) a backing layer, b) an adhesive composition or adhesive layer disclosed herein, and c) optionally a release liner.

[0045] The transdermal patches herein typically comprise a drug-containing adhesive layer that comprises, consists essentially of, or consists of (1) dextromethorphan, (2) a pressure-sensitive adhesive, (3) a skin permeation enhancer (e.g., isopropyl myristate), and optionally (4) a crystallization inhibitor (e.g., a vinylpyrrolidone polymer, e.g., a vinylpyrrolidone homopolymer (or povidone), e.g., Povidone K30, Plasdone K29 / 32, and the like), wherein the amount of dextromethorphan is from about 2% to about 12% by weight, preferably from about 6% to about 12% by weight (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 12%, about 14%, about 16%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about The amount of the skin permeation enhancer (e.g., isopropyl myristate) is about 6% to about 12% by weight (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any range between the recited values, e.g., about 8% to 12% by weight), and the amount of the pressure-sensitive adhesive is about 65% to about 85% by weight (e.g., about 65%, about 70%, about 75%, about 80%, about 85% by weight, or any range between the recited values, e.g., about 65% to 85% by weight, e.g., about 70% to 85% by weight). The dextromethorphan and the skin permeation enhancer are typically dispersed (e.g., homogeneously dispersed or dissolved) in the pressure-sensitive adhesive. In some embodiments, the dextromethorphan and the skin permeation enhancer are homogeneously mixed with the pressure-sensitive adhesive. In some embodiments, the drug-containing adhesive layer is a homogeneous mixture. In some embodiments, the drug-containing adhesive layer comprises a crystallization inhibitor in an amount of about 6% to about 12% by weight (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any range therebetween, such as about 8-12% by weight). In some embodiments, the drug-containing adhesive layer comprises dextromethorphan as the only active ingredient. In some embodiments, the skin permeation enhancer is isopropyl myristate. The pressure-sensitive adhesive may be any of those described herein.Typically, the pressure-sensitive adhesive is an acrylate copolymer adhesive, such as a polyacrylate vinyl acetate copolymer, e.g., one having non-acidic hydroxyl functionality, such as those described herein, e.g., Duro-Tak 87-2287 adhesive and its analogs manufactured by Henkel Adhesives. In some embodiments, the pressure-sensitive adhesive comprises an acrylate copolymer adhesive and an additional adhesive. For example, in some embodiments, the pressure-sensitive adhesive can be a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios (e.g., a weight ratio of acrylate adhesive to silicone adhesive ranging from about 1:20 to about 20:1, e.g., from about 10:1 to about 1:10, e.g., about 10:1, about 4:1, about 1:1, about 1:4, etc., or any range therebetween). The crystallization inhibitor, when present, can be a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like. In some embodiments, the crystallization inhibitor is a vinylpyrrolidone homopolymer polymer having a nominal K value of about 25-35, e.g., about 29-32. In some embodiments, the drug-containing adhesive layer comprises, consists essentially of, or consists of (1) dextromethorphan, (2) a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as one with non-acidic hydroxyl functionality, such as those described herein, e.g., Duro-Tak 87-2287 adhesive and its analogs, (3) isopropyl myristate, and (4) a vinylpyrrolidone polymer, e.g., vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and its analogs, where the range / amount of each component can be any of those described herein as suitable in any combination. Transdermal patches are typically about 30 cm. 2 ~Approx. 100cm 2 , for example, about 30 cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2, about 70cm 2 , about 80cm 2 , about 90cm 2 , about 100cm 2 , or any range between the stated values, e.g., about 40-60 cm 2 , about 60~80cm 2 In some embodiments, the transdermal patch has an effective surface area of ​​about 70 cm 2 In some embodiments, the transdermal patch has an effective surface area of ​​about 100 cm 2 Larger than, for example, up to 300 cm 2 It may also have an effective surface area of ​​up to 1000 nm.

[0046] The transdermal patches herein can also be constructed to contain a desired amount of dextromethorphan. In some embodiments, the transdermal patch contains: (1) about 20 mg to about 100 mg of dextromethorphan, e.g., about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range between the recited values, e.g., about 40-60 mg, 50-60 mg, or about 50-70 mg; (2) about 30 mg to about 100 mg of isopropyl myristate, e.g., about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range between the recited values, e.g., about 40-60 mg, 50-60 mg, or about 50-70 mg; and (3) about 150 mg to about 90 mg of dextromethorphan. and optionally (4) a drug-containing adhesive layer comprising, consisting essentially of, or consisting of a pressure-sensitive adhesive in an amount of about 30 mg to about 100 mg, e.g., about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or any range between the recited values, e.g., about 300-500 mg, 350-450 mg, or about 300-550 mg, and a crystallization inhibitor in an amount of about 30 mg to about 100 mg, e.g., about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range between the recited values, e.g., about 40-60 mg, 50-60 mg, or about 50-70 mg. Dextromethorphan and isopropyl myristate are typically dispersed (e.g., uniformly dispersed or dissolved) in the pressure-sensitive adhesive. In some embodiments, dextromethorphan and isopropyl myristate are uniformly mixed with the pressure-sensitive adhesive. In some embodiments, the drug-containing adhesive layer is a uniform mixture. In some embodiments, the pressure-sensitive adhesive is an acrylate-based adhesive, for example, an acrylate copolymer.In some embodiments, the pressure-sensitive adhesive is a polyacrylate vinyl acetate copolymer, such as one with non-acidic hydroxyl functionality, such as those described herein, e.g., Duro-Tak 87-2287 adhesive and its analogs. In some embodiments, the pressure-sensitive adhesive comprises an acrylate copolymer adhesive and an additional adhesive. For example, in some embodiments, the pressure-sensitive adhesive can be a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios (e.g., a weight ratio of acrylate adhesive to silicone adhesive ranging from about 1:20 to about 20:1, e.g., from about 10:1 to about 1:10, e.g., about 10:1, about 4:1, about 1:1, about 1:4, etc., or any range therebetween). In some embodiments, the drug-containing adhesive layer comprises a crystallization inhibitor. In some embodiments, the crystallization inhibitor is a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like. In some embodiments, the crystallization inhibitor is a vinylpyrrolidone homopolymer polymer having a nominal K value of about 25-35, such as about 29-32. Typically, the drug-containing adhesive layer comprises dextromethorphan in an amount of about 6% to about 12% by weight (e.g., about 10% by weight, as described herein), isopropyl myristate in an amount of about 6% to about 12% by weight (e.g., about 10% by weight, as described herein), pressure-sensitive adhesive in an amount of about 65% to about 85% by weight (e.g., about 70% or about 80% by weight, as described herein), and the crystallization inhibitor, if present, in an amount of about 6% to about 12% by weight (e.g., about 10% by weight, as described herein). In some embodiments, the drug-containing adhesive layer contains dextromethorphan as the only active ingredient. In some embodiments, the drug-containing adhesive layer contains about 56 mg of dextromethorphan. In some embodiments, the transdermal patch contains about 56 mg of dextromethorphan. The transdermal patch is typically about 30 cm. 2 ~Approx. 100cm 2 , for example, about 30 cm2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 70cm 2 , about 80cm 2 , about 90cm 2 , about 100cm 2 , or any range between the stated values, e.g., about 40-60 cm 2 , about 60~80cm 2 In some embodiments, the transdermal patch has an effective surface area of ​​about 70 cm 2 In some embodiments, the transdermal patch has an effective surface area of ​​about 100 cm 2 Larger than, for example, up to 300 cm 2 In any of the embodiments described herein, the transdermal patch may be in the form of a monolithic patch.

[0047] The transdermal patches herein typically contain about 0.2 mg / cm 2 ~about 5mg / cm 2 , for example, about 0.2 mg / cm 2 , about 0.3mg / cm 2 , about 0.4mg / cm 2 , about 0.5mg / cm 2 , about 0.6mg / cm 2 , about 0.7mg / cm 2 , about 0.8mg / cm 2 , approximately 0.9 mg / cm 2 , about 1mg / cm 2 , about 2mg / cm 2 , about 5mg / cm 2 or any range between the values ​​listed, e.g., about 0.2 to 1 mg / cm 2 , 0.2-2 mg / cm 2 , about 0.5~1mg / cm 2 Typically, for use in a once-daily dosing regimen, the transdermal patches herein have a total dextromethorphan loading of, for example, about 0.2 mg to about 1 mg / cm. 2On the other hand, for longer dosing intervals, such as a once-weekly dosing regimen, or a once-daily to once-weekly dosing regimen, the transdermal patches herein may have a lower total dextromethorphan loading, for example, in the range of about 1 mg to about 5 mg / cm. 2 It is possible to have a relatively high total dextromethorphan loading in the range of

[0048] Typically, the amount of dextromethorphan contained in the transdermal patch herein is sufficient to deliver a therapeutically effective amount of dextromethorphan to a subject in need thereof. In some embodiments, the amount of dextromethorphan contained in the transdermal patch herein is sufficient to transdermally deliver a daily dose of about 15 mg to about 50 mg of dextromethorphan (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any range therebetween, such as about 20-50 mg, about 30-50 mg, or about 20-40 mg) to a subject in need thereof. Preferably, a single patch is used herein to deliver the daily dose. For example, in the case of a once-daily dosing regimen, preferably, a single patch is applied once daily to deliver the daily dose. However, in some cases, two or more patches can be applied once daily at substantially the same time to meet the desired daily dose. In some embodiments, the transdermal patch may be suitable for use as a 1-day patch, 2-day patch, 3-day patch, 4-day patch, 5-day patch, 6-day patch, or 7-day patch, and the patch contains a sufficient amount of dextromethorphan so that, when the patch is attached to a subject for the intended period of time (e.g., 1 day for a 1-day patch, 2 days for a 2-day patch, etc.), it delivers a daily dose of about 15 mg to about 50 mg of dextromethorphan (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any range between the recited values, e.g., about 20-50 mg, about 30-50 mg, or about 20-40 mg, etc.) to a subject in need thereof.

[0049] In some preferred embodiments, the transdermal patches herein (e.g., daily patches) can contain a sufficient amount of dextromethorphan to deliver about 15 mg to about 50 mg of dextromethorphan (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any range between the recited values, e.g., about 20-50 mg, about 30-50 mg, or about 20-40 mg) to a subject in need thereof when the patch is worn on the subject for 24 hours. The amount of dextromethorphan required for the transdermal patches herein to achieve the desired daily dose typically does not exceed twice the desired daily dose. For example, in some embodiments, the desired daily dose is about 35 mg, and the transdermal patch can contain less than 70 mg of dextromethorphan, such as less than 60 mg of dextromethorphan. Thus, transdermal bioavailability (i.e., dextromethorphan delivered divided by the initial dextromethorphan in the patch) is generally greater than 50%, and can be as high as 80% or greater. This high bioavailability is made possible, in part, by the unexpected discovery that the transdermal patches herein can provide a continuously high flux of dextromethorphan. In some embodiments, the patches are designed to be worn for longer periods, such as two days and up to one week. And, in such embodiments, the residual dextromethorphan at the end of application is also typically less than the desired daily dose.

[0050] The transdermal patches herein typically have a dextromethorphan flux suitable for delivering a therapeutically effective amount to a subject in need thereof. For example, in some embodiments, the transdermal patch has a dextromethorphan flux of at least about 200 μg / cm, as measured in vitro using human cadaver skin. 2 / day, for example, about 200ug / cm 2 / day, about 300ug / cm 2 / day, about 400ug / cm 2 / day, about 500ug / cm 2 / day, about 600ug / cm 2 / day, about 700ug / cm 2 / day, about 800ug / cm 2 / day, about 1000ug / cm 2 / day, or any range between the stated values, e.g., about 200-800 ug / cm 2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2 The transdermal patches herein have a dextromethorphan flux of 0.01g / day or more. As described herein, it has been found that a crystallization inhibitor, a vinylpyrrolidone polymer (Plasdone K29 / 32), can significantly enhance the flux of dextromethorphan from the transdermal patches herein both in vitro and in vivo. In any of the embodiments described herein, unless directly contradicted by context, the transdermal patches herein preferably include a crystallization inhibitor described herein, e.g., a vinylpyrrolidone polymer, e.g., a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, Plasdone K29 / 32, and the like, in the drug-containing adhesive layer. The crystallization inhibitor is typically included in an amount of about 6% to about 12% by weight of the drug-containing adhesive layer (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any range therebetween, e.g., about 8-12% by weight). In some embodiments, the crystallization inhibitor can be present in an amount greater than about 12%, for example, up to 50%, as long as the adhesive layer still maintains sufficient adhesion to be suitable for wear by a subject for a desired period of time, such as 24 hours.

[0051] In some embodiments, the present disclosure also provides a method for selecting a transdermal patch for a method herein (e.g., a method for treating PBA), the method comprising measuring in vitro dextromethorphan flux from a transdermal patch disclosed herein (e.g., those shown in

[18] to

[35] in the Summary of the Invention) using, for example, human cadaver skin, and selecting a transdermal patch that exhibits a dextromethorphan flux of at least about 200 μg / cm when measured in vitro using human cadaver skin. 2 / day, for example, about 200ug / cm 2 / day, about 300ug / cm 2 / day, about 400ug / cm 2 / day, about 500ug / cm 2 / day, about 600ug / cm 2 / day, about 700ug / cm 2 / day, about 800ug / cm 2 / day, about 1000ug / cm 2 / day, or any range between the stated values, e.g., about 200-800 ug / cm 2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2 and selecting a transdermal patch with a dextromethorphan flux of 100 mg / day or more.

[0052] In some specific embodiments, the transdermal patch comprises, consists essentially of, or consists of: a) a backing layer (e.g., as described herein); b) a drug-containing adhesive layer; and c) an optional release liner, wherein the drug-containing adhesive layer comprises: (1) dextromethorphan in an amount of about 6% to about 12% by weight (e.g., as described herein, e.g., about 10% by weight); and (2) a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, e.g., one with non-acidic hydroxyl functionality, e.g., as described herein, e.g., Duro-Tak®, in an amount of about 65% to about 85% by weight (e.g., as described herein, e.g., about 70% by weight). 87-2287 adhesive and the like, (3) isopropyl myristate in an amount of about 6% to about 12% by weight (e.g., as described herein, e.g., about 10% by weight), and (4) a vinylpyrrolidone polymer, e.g., vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like, in an amount of about 6% to about 12% by weight (e.g., as described herein, e.g., about 10% by weight). In some embodiments, the transdermal patch has a densitometric value of at least about 400 μg / cm as measured in vitro using human cadaver skin. 2 / day (e.g., about 500ug / cm 2 / day~about 800ug / cm 2 / day) dextromethorphan flux.

[0053] In some specific embodiments, the present disclosure provides a one-piece transdermal patch comprising, consisting essentially of, or consisting of: a) a backing layer (e.g., as described herein); b) a drug-containing adhesive layer; and c) an optional release liner, wherein the drug-containing adhesive layer contains: (1) about 20 mg to about 100 mg (e.g., an amount described herein, e.g., about 56 mg) of dextromethorphan; and (2) about 150 mg to about 900 mg (e.g., an amount described herein, e.g., about 392 mg) of a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, e.g., one having non-acidic hydroxyl functionality, e.g., one described herein, e.g., Duro-Tak 87-2287 adhesive and the like; (3) about 30 mg to about 100 mg (e.g., an amount described herein, e.g., about 56 mg) of isopropyl myristate; and (4) about 30 mg to about 100 mg (e.g., an amount described herein, e.g., about 56 mg) of a vinylpyrrolidone polymer, e.g., a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like. In some embodiments, the weight percentages of the components in the drug-containing adhesive layer can be: (1) dextromethorphan in an amount of about 6% to about 12% by weight (e.g., as described herein, e.g., about 10% by weight); (2) a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as one with non-acidic hydroxyl functionality, such as those described herein, e.g., Duro-Tak 87-2287 adhesive and the like, in an amount of about 65% to about 85% by weight (e.g., as described herein, e.g., about 70% by weight); (3) isopropyl myristate in an amount of about 6% to about 12% by weight (e.g., as described herein, e.g., about 10% by weight); and (4) a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like, in an amount of about 6% to about 12% by weight (e.g., as described herein, e.g., about 10% by weight). In some embodiments, the transdermal patch is about 30 cm 2~about 100cm 2 (e.g., those described herein, e.g., about 70 cm 2 In some embodiments, the transdermal patch has an effective surface area of ​​at least about 400 ug / cm as measured in vitro using human cadaver skin. 2 / day (e.g., about 500ug / cm 2 / day~about 800ug / cm 2 / day) dextromethorphan flux.

[0054] In some embodiments, the disclosure also provides transdermal patches comprising, consisting essentially of, or consisting of a backing layer, a drug-containing adhesive layer, and optionally a release liner, wherein the drug-containing adhesive layer comprises a formulation selected from Formulations A, B, C1, C2, C3, D0, D1, D2, and E1, as shown in the Examples section. In some specific embodiments, the drug-containing adhesive layer comprises, consists essentially of, or consists of Formulation E1, which contains, by dry weight percent, about 10% dextromethorphan base, about 10% isopropyl myristate, about 70% polyacrylate adhesive (DuroTak 387-2287), and about 10% crystallization inhibitor Plasdone K-29 / 32. In some specific embodiments, the drug-containing adhesive layer comprises, consists essentially of, or consists of Formulation E1 produced by the process described in Example 1. In some embodiments, the transdermal patch contains about 56 mg of dextromethorphan base and is about 70 cm 2 In any of the embodiments described herein, unless otherwise contradicted by context, the transdermal patches herein can have a drug-containing adhesive layer that comprises, consists essentially of, or consists of Formulation E1, which contains, by dry weight percent, about 10% dextromethorphan base, about 10% isopropyl myristate, about 70% polyacrylate adhesive (DuroTak 387-2287), and about 10% crystallization inhibitor Plasdone K-29 / 32, or Formulation E1 produced by the process described in Example 1.

[0055] The transdermal patches and formulations of the present invention are preferably shelf-stable when stored at room temperature (25±2°C) and 60%±5% relative humidity (RH) for approximately 1 month, 3 months, 6 months, or longer. Shelf-stable results indicate that the transdermal patch or formulation is equivalent to the original transdermal patch or formulation, i.e., would be accepted by one of ordinary skill in the art as being equivalent to the original patch or formulation at the start of storage. Shelf-stable results are typically characterized by one or more of the following: (1) substantially the same amounts of drug-related impurities, with no significant increase in either individual or total impurities; (2) substantially the same amount of dextromethorphan; (3) substantially the same physical properties, such as peel adhesion, shear retention, tack, and peel strength; and (4) substantially the same drug release rate and / or dextromethorphan permeation rate. "Substantially the same" should be understood to mean 80-125% or within the measurement tolerances. For example, a transdermal patch or formulation containing 56 mg of dextromethorphan and having an effective surface area of ​​approximately 70 cm2 may be used. 2 The patch prepared from formulation E1 was found to be storage stable after being stored at room temperature (25±2°C) and a relative humidity of 60% RH±5% RH for more than 6 months.

[0056] In some embodiments, the present disclosure also provides a method for preparing a transdermal delivery device or adhesive composition. In some embodiments, the method includes: a) mixing dextromethorphan, an adhesive (e.g., a pressure-sensitive adhesive described herein, such as Duro-Tak 87-2287), a permeation enhancer (e.g., isopropyl myristate), and an optional crystallization inhibitor (e.g., one described herein, e.g., a vinylpyrrolidone polymer, e.g., a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like) in a suitable solvent (e.g., an organic solvent, e.g., an ester solvent or an alcohol solvent, typically a volatile material, e.g., ethyl acetate or isopropanol, or a combination thereof) to form a homogeneous mixture; b) casting the homogeneous mixture onto a release liner; and c) drying the casting to remove the solvent, thereby forming an adhesive composition on the release liner. In some embodiments, the method further includes laminating the adhesive composition to a backing layer. The suitable amount of dextromethorphan and suitable adhesive, optional crystallization inhibitor, permeation enhancer, and their respective amounts can include any of those described herein in any combination. The adhesive composition with or without a release liner and transdermal delivery device prepared by the methods herein are also novel aspects of the present disclosure. Some exemplary procedures are described in the Examples section of this specification.

[0057] TDD with optional reservoir layer In some embodiments, the transdermal delivery devices herein can optionally include a reservoir layer, e.g., for high daily doses and / or extended periods of application (e.g., one day or more), the reservoir layer can provide a more sustained flux of dextromethorphan to the user.

[0058] In some embodiments, the transdermal delivery device includes an adhesive layer containing an adhesive and, optionally, a reservoir layer containing dextromethorphan. In some embodiments, the adhesive layer optionally contains dextromethorphan dispersed in the adhesive. In some embodiments, the adhesive layer does not contain dextromethorphan except through equilibrium with the reservoir layer. In some embodiments, the adhesive layer contains dextromethorphan dispersed in the adhesive. In some embodiments, the reservoir layer contains dextromethorphan in the adhesive. In some embodiments, the reservoir layer and the adhesive layer are the same layer. In some embodiments, the reservoir layer is sandwiched between the adhesive layer and the backing layer. In some embodiments, the reservoir layer may be sandwiched between two adhesive layers, which may be the same or different. For example, in some embodiments, the two adhesive layers can have the same concentration of the same ingredient, and in some embodiments, can have the same thickness. However, in some embodiments, the two adhesive layers can have different ingredients, different concentrations of the same ingredient, different thicknesses, etc. An exemplary configuration can be seen in Figure 5, where the adhesive layer is the top layer, the backing layer or adhesive layer, which may be the same as or different from the top layer, is the bottom layer, and the reservoir layer is the middle layer.

[0059] In some embodiments, the reservoir layer is separated from the adhesive layer by a membrane, e.g., a rate-controlling membrane such as a microporous membrane. The reservoir layer preferably contains an adhesive. However, other reservoir layer designs are suitable if they are compatible with the adhesive layer and backing layer. For example, in some embodiments, the reservoir layer can be a scrim / nonwoven saturated with dextromethorphan, or dextromethorphan dispersed in another suitable carrier / substrate.

[0060] Dextromethorphan can be included in various concentrations in the adhesive layer and the reservoir layer. Typically, the concentration of dextromethorphan in the reservoir layer is higher than the concentration of dextromethorphan in the adhesive layer. For example, in some embodiments, the adhesive layer can include dextromethorphan in an amount of about 2% to about 12% by weight of the adhesive layer (e.g., about 2%, about 4%, about 6%, about 8%, about 10%, about 12%, or any range therebetween), while the reservoir layer can include dextromethorphan in an amount of about 20% or more by weight of the reservoir layer, e.g., about 30% or more, about 40% or more, about 50% or more by weight, e.g., about 20% to about 60% by weight, about 30% to about 50% by weight, etc. In some embodiments, the adhesive layer can contain dextromethorphan in an amount of about 6% to about 12% by weight of the adhesive layer (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any range therebetween). In some embodiments, the adhesive layer contains dextromethorphan at or near a saturated concentration in the adhesive, e.g., about 10% by weight in an acrylate adhesive. In some embodiments, the reservoir layer contains dextromethorphan at greater than a saturated concentration in the adhesive. In other words, the reservoir layer can be supersaturated with dextromethorphan and thus contain solid dextromethorphan, which can function as a drug depot.

[0061] Suitable adhesives for the adhesive layer and reservoir layer, where applicable, include any of those described herein, preferably pressure-sensitive adhesives. The adhesives included in the adhesive layer and reservoir layer can be the same or different. In some embodiments, the adhesive included in the adhesive layer and reservoir layer is the same, e.g., an acrylate adhesive. Other suitable adhesives include polyisobutylene adhesives, silicone polymer adhesives, acrylate copolymer adhesives (e.g., polyacrylate vinyl acetate copolymers, e.g., those with non-acidic hydroxyl functionality, e.g., those described herein, e.g., Duro-Tak 87-2287 adhesive and its analogs), or combinations thereof. For example, in any of the embodiments described herein, unless directly contrary to the context, the pressure-sensitive adhesive can be a polyacrylate vinyl acetate copolymer containing non-acidic hydroxyl functionality, e.g., DuroTak® 2287 adhesive described herein. In some embodiments, the adhesive can be a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios (e.g., a weight ratio of acrylate adhesive to silicone adhesive ranging from about 1:20 to about 20:1). In some embodiments, the weight ratio of acrylate adhesive to silicone adhesive ranges from about 10:1 to about 1:10 (e.g., about 10:1, about 4:1, about 1:1, about 1:4, or any range therebetween). In any of the embodiments described herein, the adhesive layer can be configured to continuously adhere to the user's skin for at least one day (e.g., at least two days, at least three days, at least four days, at least five days, at least six days, or at least seven days).

[0062] An adhesive (e.g., a pressure-sensitive adhesive) is typically the major component of the adhesive layer and reservoir layer (if applicable). For example, in some embodiments, the adhesive layer comprises a pressure-sensitive adhesive in an amount of about 50% to about 90% by weight of the adhesive layer. In some embodiments, the pressure-sensitive adhesive is present in an amount of about 60% to about 85% by weight of the adhesive layer (e.g., about 60%, about 70%, about 75%, about 80%, about 85%, or any range between the recited values). In some embodiments, the reservoir layer can comprise a pressure-sensitive adhesive in an amount of about 20% to about 80% by weight of the reservoir layer. For example, in some embodiments, the pressure-sensitive adhesive is present in an amount of about 20% to about 65% by weight of the reservoir layer (e.g., about 20%, about 30%, about 35%, about 40%, about 50%, about 60%, about 65%, or any range between the recited values).

[0063] Suitable sizes for transdermal delivery devices are described herein. In some embodiments, the transdermal delivery device is about 5 cm 2 ~about 200cm 2 In some embodiments, the transdermal delivery device has an effective surface area of ​​about 10 cm 2 ~Approx. 150cm 2 In some embodiments, the transdermal delivery device has an effective surface area of ​​about 30 cm 2 ~about 100cm 2 (For example, about 30 cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 70cm 2 , about 80cm 2 , about 90cm 2 , about 100cm 2 , or any range between the values ​​stated).

[0064] The adhesive layer and reservoir layer can be of various thicknesses. For example, in some embodiments, the adhesive layer is about 0.1 mil to about 10 mils thick (e.g., about 0.5 mil to about 10 mils, about 1 mil to 10 mils). In some embodiments, the reservoir layer can also be about 0.1 mil to about 10 mils thick (e.g., about 0.5 mil to about 10 mils, about 1 mil to 10 mils).

[0065] The adhesive layer and reservoir layer can also contain a skin permeation enhancer. For example, in some embodiments, the adhesive layer contains a compound selected from the group consisting of isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, and hydroxypropyl methylcellulose with a carbon chain length of C. 12 ~C 18 In some embodiments, the adhesive layer comprises a skin permeation enhancer selected from isopropyl myristate. Similarly, in some embodiments, the reservoir layer comprises a soluble polymer selected from isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate ... 12 ~C 18 and other fatty acids and fatty acid esters thereof, and combinations thereof. In some embodiments, the reservoir layer comprises isopropyl myristate.

[0066] Varying amounts of skin permeation enhancers can be used in the adhesive layer and reservoir layer. Typically, the skin permeation enhancer can be present in an amount of about 2% to about 15% by weight of the adhesive or reservoir layer. For example, in some embodiments, the skin permeation enhancer is present in an amount of about 6% to about 12% by weight of the adhesive layer (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any range between the recited values). In some embodiments, the skin permeation enhancer is present in an amount of about 6% to about 12% by weight of the reservoir layer (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any range between the recited values). However, in some embodiments, the adhesive and / or reservoir layer can also contain a skin permeation enhancer such as isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, or a hydroxybenzoate having a carbon chain length of C. 12 ~C 18 The composition may be substantially free of skin permeation enhancers selected from other fatty acids and fatty acid esters, and combinations thereof.

[0067] In some embodiments, the adhesive layer and / or reservoir layer may include an agent selected from a vinylpyrrolidone polymer (e.g., vinylpyrrolidone-vinyl acetate copolymer), Kollidon (e.g., Kollidon 30 LP, Kollidon 90, or Kollidon VA64), silicon dioxide, titanium dioxide, and combinations thereof. In some embodiments, the agent can be present in an amount of about 2% to about 20% by weight of the adhesive or reservoir layer (e.g., about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, about 10%, about 15%, about 20%, or any range therebetween). Without wishing to be bound by theory, it is believed that such agents can improve the cohesive strength of the adhesive or reservoir layer. Additionally, such agents can have other functions, such as inhibiting crystallization. In some embodiments, the adhesive layer includes an agent effective to improve the cohesive strength of the adhesive layer. In some embodiments, the reservoir layer includes an agent effective to improve the cohesion of the reservoir layer.

[0068] It should be noted that the identities and amounts of the components of the adhesive layer and reservoir layer, such as adhesive, skin permeation enhancer, and drug, are independently selected and may be the same or different. Generally, the amounts can be varied while the identities remain the same. In some embodiments, the adhesive layer may be a drug-containing adhesive layer as described herein (e.g., as shown in

[18] to

[35] in the Summary of the Invention). The thicknesses of the adhesive layer and reservoir layer may also be the same or different.

[0069] As detailed in the Examples section, varying the adhesive components can affect the flux characteristics of transdermal delivery devices containing dextromethorphan. Accordingly, in some embodiments, the present disclosure also provides transdermal delivery devices that include an adhesive layer, the adhesive layer including two or more adhesives. Typically, the adhesive layer includes dextromethorphan dispersed (e.g., uniformly dispersed) in the two or more adhesives. Dextromethorphan is typically present in an amount of about 6% to about 12% by weight of the adhesive layer (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any range therebetween).

[0070] In some embodiments, the adhesive layer can comprise a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios (e.g., a weight ratio of acrylate adhesive to silicone adhesive ranging from about 1:20 to about 20:1). In some embodiments, the weight ratio of acrylate adhesive to silicone adhesive ranges from about 10:1 to about 1:10 (e.g., about 10:1, about 4:1, about 1:1, about 1:4, or any range therebetween). In some embodiments, unless otherwise clear from the context, a mixture of an acrylate copolymer adhesive and a silicone adhesive can be used in any of the drug-containing adhesive layers described herein. Other ingredients, such as skin permeation enhancers, that can optionally be included in the adhesive layer, and suitable amounts thereof, include those described herein.

[0071] Any of the transdermal delivery devices herein can include / use an adhesive layer having two or more adhesives. For example, in some embodiments, a transdermal delivery device including a reservoir layer described herein can have an adhesive layer including a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios as described herein. In some embodiments, a transdermal delivery device, with or without a reservoir layer as described herein, includes an adhesive layer including a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios as described herein.

[0072] A skin permeation enhancer (transdermal enhancer) can increase the permeability of dextromethorphan through the skin and can optionally be included in the transdermal delivery device herein. Various skin permeation enhancers can be included. Non-limiting examples of useful skin permeation enhancers include sulfoxides (e.g., dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), esters, glycols (e.g., propylene glycol (PG)), surfactants (e.g., Tween 80), terpenes, and combinations thereof. See, for example, Williams et al., Adv Drug Deliv Rev. 27;56(5):603-18 (2004). In some embodiments, the permeation enhancer comprises one or more compounds selected from sulfoxides, alcohols, alkanols, esters, glycols, and surfactants. In some embodiments, the permeation enhancer comprises one or more compounds selected from dimethyl sulfoxide (DMSO), oleic alcohol, oleyl oleate, oleic acid, levulinic acid, other fatty acids and fatty acid esters, propylene glycol, dipropylene glycol, ethanol, and surfactants such as Tween 80. In some embodiments, the transdermal device can comprise one or more compounds selected from DMSO, N-methyl-2-pyrrolidone, azone, myristic acid, sesquiterpene oils, 4-decyloxazolidin-2-one, urea, and the like. In some embodiments, the skin permeation enhancer comprises one or more compounds selected from isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, hydroxybenzoates having a carbon chain length of C 12 ~C 18 and other fatty acids and fatty acid esters thereof, and combinations thereof. In any of the embodiments described herein, unless the context specifically states otherwise, the skin permeation enhancer may be isopropyl myristate.

[0073] The skin permeation enhancer is typically present in an amount of about 1% to about 25% by weight of the adhesive layer, e.g., about 2%, about 5%, about 10%, about 15%, about 20%, about 25% by weight of the adhesive layer, or any range between the specified values. In some embodiments, the transdermal device may be substantially free of a transdermal enhancer. In some embodiments, the transdermal device is substantially free of a transdermal enhancer when the amount of any potential such enhancer is about 20% or less of the minimum amount shown to enhance transdermal flux by about 50% or more.

[0074] In some embodiments, the skin permeation enhancer and its amount are selected to provide certain improved flux characteristics. For example, in some embodiments, the present disclosure provides a transdermal delivery device with an adhesive layer containing dextromethorphan dispersed in an adhesive, the adhesive layer containing the skin permeation enhancer in an amount that provides an average cumulative permeation of dextromethorphan at 24 hours after application that is at least about 25% (e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any range between the recited values) higher than the average cumulative permeation of dextromethorphan of an otherwise equivalent transdermal delivery device without the skin permeation enhancer, when tested in vitro using human cadaver skin. The dextromethorphan is typically present in an amount of about 6% to about 12% by weight of the adhesive layer (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any range between the recited values). The pressure-sensitive adhesive is typically present in an amount of about 60% to about 85% by weight of the adhesive layer (e.g., about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or any range between the recited values, e.g., about 65-85%, about 60-80%, etc.). The term "an otherwise equivalent transdermal delivery device without a skin permeation enhancer" should be understood as a control transdermal delivery device in which the skin permeation enhancer content in the adhesive layer is replaced with an adhesive, with all other aspects remaining the same. For example, if a transdermal delivery device includes an adhesive layer containing 10% by weight of a skin permeation enhancer and 10% by weight of dextromethorphan dispersed in 80% by weight of an acrylate adhesive, and an otherwise equivalent device includes a separate adhesive layer containing 10% by weight of dextromethorphan dispersed in 90% by weight of the same acrylate adhesive, with all other aspects of the two devices being the same.

[0075] The skin permeation enhancer and its amount can also be adjusted to achieve increased flux at different times after application. For example, in some embodiments, the permeation enhancer is in an amount that provides one or more of the following: 1) an average flux of dextromethorphan from 8 to 24 hours after application that is at least about 25% (e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any range between the recited values) higher than the average flux of dextromethorphan from an otherwise equivalent transdermal delivery device without the skin permeation enhancer; 2) an average flux of dextromethorphan that is at least about 2 times (e.g., about 3 times, about 4 times, about 5 times, about 8 times, or and 3) an average flux of dextromethorphan from 0 to 4 hours after application that is at least about 5 times (e.g., about 5 times, about 8 times, about 10 times, about 20 times, or any range between the recited values) the average flux of dextromethorphan of an otherwise equivalent transdermal delivery device without a skin permeation enhancer, when tested in vitro using human cadaver skin. As detailed in the Examples, in one example, a significant increase in flux was observed at or before 4 hours after application when the amount of the permeation enhancer isopropyl myristate was increased to about 10 wt %.

[0076] In some embodiments, the present disclosure also provides a method for selecting a skin permeation enhancer and an amount thereof for a transdermal patch herein, the method comprising measuring in vitro dextromethorphan flux from a test transdermal patch having a test skin permeation enhancer, e.g., using human cadaver skin, and selecting a skin permeation enhancer in an amount that provides one or more of the following: 1) an average flux of dextromethorphan from 8 to 24 hours after application that is at least about 25% (e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any range between the recited values) greater than the average flux of dextromethorphan from an otherwise equivalent transdermal delivery device without the skin permeation enhancer; 2) an average flux of dextromethorphan that is at least about 2 times (e.g., about 3 times, about 4 times, about 5 times, about 8 times, or and 3) an average flux of dextromethorphan from 0 to 4 hours after application that is at least about 5 times (e.g., about 5 times, about 8 times, about 10 times, about 20 times, or any range between the recited values) the average flux of dextromethorphan of an otherwise equivalent transdermal delivery device that does not contain a skin permeation enhancer, when tested in vitro using human cadaver skin.

[0077] Any of the transdermal delivery devices herein can include / use an adhesive layer that includes a skin permeation enhancer. For example, in some embodiments, a transdermal delivery device that includes a reservoir layer described herein can have an adhesive layer that includes an adhesive layer that includes a skin permeation enhancer. Other ingredients that can optionally be included in the adhesive layer and suitable amounts include those described herein.

[0078] In some specific embodiments, the transdermal delivery device can include an adhesive layer and a reservoir layer, and the adhesive layer and reservoir layer can have, for example, the ingredients and amounts shown in the table below.

[0079] TIFF0007798361000001.tif115165

[0080] All amounts in the table refer to the weight percent of each layer (based on the final formulation) with the total amount of each layer being 100%. In some embodiments, the transdermal delivery device is about 60 cm 2 For example, about 70 cm 2 For example, in some embodiments, the transdermal delivery device is configured to provide a user with about 15 mg / day to about 40 mg / day of dextromethorphan, e.g., about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, or any range between the recited values. In some embodiments, the transdermal delivery device contains about 50 mg to about 700 mg of dextromethorphan (e.g., about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or any range between the recited values). In some embodiments, the reservoir layer may be sandwiched between two adhesive layers, which may be the same or different. Typically, such transdermal delivery devices also include a backing layer and a release liner to protect the adhesive surface prior to use. Typically, these patches can be used at a dosing frequency of less than once a day, for example, once a day, or once every two or more days, for example, once a week, or two, three, four, five, or six times a week, for example, twice a week.

[0081] In some specific embodiments, the transdermal delivery device can include an adhesive layer, which can have, for example, the ingredients and amounts shown in the table below.

[0082] TIFF0007798361000002.tif73165

[0083] All amounts in the table refer to the weight percent of the final adhesive layer, with the total being 100%. In some embodiments, the transdermal delivery device is about 10 cm2 More than, for example, about 30 cm 2 , approximately 45cm 2 , about 60cm 2 , about 75cm 2 , about 90cm 2 For example, in some embodiments, the transdermal delivery device is configured to provide a user with about 15 mg / day to about 40 mg / day of dextromethorphan, e.g., about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, or any range between the recited values. In some embodiments, the transdermal delivery device contains about 5 mg to about 100 mg of dextromethorphan (e.g., about 15 mg, about 30 mg, about 45 mg, about 60 mg, about 90 mg, or any range between the recited values). Typically, such transdermal delivery devices also include a backing layer and a release liner that protects the adhesive surface prior to use. Typically, these patches can be used at a dosing frequency of one or more times per day, e.g., once per day or once every 12 hours.

[0084] In vitro flux properties In some embodiments, the transdermal delivery devices herein are configured to provide a certain in vitro dextromethorphan flux profile, for example, when tested using human cadaver skin. For example, in some embodiments, any of the transdermal delivery devices herein, when tested in vitro using human cadaver skin, can provide: 1) a dextromethorphan flux profile of at least about 200 ug / cm 24 hours after application; 2 (ug refers to micrograms) (e.g., about 200ug / cm 2 ~About 2000ug / cm 2 ) mean cumulative dextromethorphan permeation, and / or 2) at least about 5 μg / cm from 8 to 24 hours after application. 2 *h (e.g., about 5ug / cm 2 *h~about 20ug / cm 2 *h, about 10ug / cm 2 *h~approx.18ug / cm 2In some embodiments, the present disclosure also provides a method for selecting a transdermal patch for a method herein (e.g., a method for treating PBA), the method comprising measuring the dextromethorphan flux from a transdermal patch disclosed herein (e.g., those shown in

[18] to

[35] in the Summary of the Invention) in vitro using, for example, human cadaver skin, and selecting a transdermal patch that, when tested in vitro using human cadaver skin, 1) provides a dextromethorphan flux of at least about 200 μg / cm 24 hours after application. 2 (ug refers to micrograms) (e.g., about 200ug / cm 2 ~About 2000ug / cm 2 ) mean cumulative dextromethorphan permeation, and / or 2) at least about 5 μg / cm from 8 to 24 hours after application. 2 *h (e.g., about 5ug / cm 2 *h~about 20ug / cm 2 *h, about 10ug / cm 2 *h~about 18ug / cm 2 and selecting a transdermal patch having a dextromethorphan flux characterized by an average dextromethorphan flux of 0.1% to 0.2%.

[0085] In some embodiments, the transdermal delivery device provides at least about 200 ug / cm per day to a subject in need thereof. 2 (For example, about 200ug / cm 2 ~About 2000ug / cm 2) can be transdermally delivered to a subject in need thereof. In some embodiments, the transdermal delivery device is configured to have flux characteristics such that application of the transdermal delivery device to a subject in need thereof transdermally delivers from about 2 mg / day to about 50 mg / day of dextromethorphan. In some embodiments, the transdermal delivery device can transdermally deliver from about 5 mg / day to about 50 mg / day (e.g., about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, or any range between the recited values) to a subject for one or more days (e.g., 1.5 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or any range between the recited values). The size of the transdermal delivery device is typically about 5 cm 2 ~about 200cm 2 , for example, about 10 cm 2 ~Approx. 100cm 2 is.

[0086] Transdermal delivery devices having the above flux characteristics can be prepared by those skilled in the art in light of the present disclosure. The Examples section also illustrates the preparation of several transdermal delivery devices. The cumulative permeation of drug (dextromethorphan, deuterated dextromethorphan, or a combination thereof) can be adjusted, for example, by changing the composition of the adhesive layer (e.g., drug concentration, permeation enhancer, drug loading, adhesive type, etc.).

[0087] It should be noted that pharmaceutical compositions formulated for the adhesive layer and / or reservoir layer described herein are also novel aspects of the present disclosure.

[0088] The transdermal delivery devices herein can also be characterized by a certain in vivo release profile that provides, for example, a desired pharmacokinetic (PK) profile, e.g., any of those described herein. In some embodiments, the transdermal delivery device can be configured to provide, in a subject in need thereof, a PK profile, e.g., any of the PK profiles described herein (e.g., in paragraphs

[46] -

[62] of the Summary of the Invention). In some embodiments, the transdermal delivery device is configured to provide, for example, a PK profile effective for treating a disease or disorder (e.g., as described herein, e.g., PBA) in a subject.

[0089] The various aspects of the transdermal delivery devices and transdermal formulations of the present disclosure can be combined in all possible combinations.

[0090] Dextromethorphan administration and treatment methods In various embodiments, the present disclosure also provides methods of using a transdermal delivery device or pharmaceutical composition described herein, e.g., to administer dextromethorphan to a subject in need thereof, e.g., a subject suffering from any of the diseases or disorders described herein.

[0091] Some embodiments are directed to methods of administering dextromethorphan to a subject (e.g., a human subject) in need thereof. In some embodiments, the subject is sensitive to or intolerant of a CYP2D6 inhibitor, such as quinidine, e.g., has one or more side effects associated with quinidine, and / or is co-administered with (or requires) a drug whose metabolism is affected by a CYP2D6 inhibitor, such as quinidine. In some embodiments, the subject is sensitive to or intolerant of quinidine, e.g., has QTc prolongation. In some embodiments, the method includes applying either a transdermal delivery device (e.g., those shown in paragraphs

[18] -

[35] in the Summary of the Invention) or a pharmaceutical composition to the subject, e.g., to the subject's skin. In some embodiments, the subject is not administered dextromethorphan via another source, e.g., via oral administration. However, in some embodiments, the subject may be supplemented with another source of dextromethorphan, e.g., by co-administering an oral formulation of dextromethorphan to the subject. In some embodiments, the subject does not suffer from a cough and / or does not require cough suppressants. In some embodiments, the subject is characterized as an extensive metabolizer. In some embodiments, the subject is characterized as a poor metabolizer. In some embodiments, the subject is not concomitantly administered a CYP2D6 inhibitor. In some embodiments, the subject is not concomitantly administered quinidine. In some embodiments, the subject is concomitantly administered a CYP2D6 inhibitor, such as quinidine or bupropion.

[0092] Various dosing regimens are suitable for the methods herein. For example, in some embodiments, the methods involve administering a transdermal delivery device (e.g., as described herein, e.g., as shown in

[18] -

[35] in the Summary of the Invention) to a subject once daily (e.g., replaced every 24 hours) for a desired period of time. In some embodiments, the transdermal delivery device contains about 5 mg to about 100 mg of dextromethorphan. In some embodiments, the methods can also involve administering a transdermal delivery device (e.g., as described herein) to a subject once every two or more days (e.g., once every two days, once every three days, once every four days, once every five days, once every six days, once per week, etc.) for a desired period of time. In some embodiments, the methods can also involve administering a transdermal delivery device (e.g., as described herein) to a subject at least once daily, e.g., once every two or more days (e.g., once per week), or once, twice, three, four, five, or six times per week for a desired period of time. In some embodiments, the method may also include administering a transdermal delivery device (e.g., those described herein in paragraphs

[18] to

[35] of the Summary of the Invention) to a subject once a week. In some embodiments, the transdermal delivery device contains about 50 mg to about 700 mg of dextromethorphan. In the methods herein, the transdermal delivery device is typically applied to the subject once a day or more than once a day; however, in some embodiments, the method may also apply the transdermal delivery device to the subject less than once a day, such as twice a day or three times a day. For the avoidance of doubt, when it is stated that a transdermal delivery device is applied to a subject once a day, it should be understood that each application of the transdermal delivery device lasts for about 24 hours, or that the transdermal delivery device is replaced every 24 hours during the treatment period. Similarly, when it is said that a transdermal delivery device is applied to a subject once per week, it should be understood that each application of the transdermal delivery device lasts for about one week, or that the transdermal delivery device is replaced every other week during the treatment period. Other expressions should be understood similarly.

[0093] The methods of administering dextromethorphan herein typically provide a certain pharmacokinetic profile in a subject (e.g., a human subject) in need thereof that is suitable (e.g., effective) for treating, for example, a disease or disorder of the subject (e.g., any of those described herein, such as PBA). PCT / US2018 / 054178 describes several such pharmacokinetic profiles, examples of which are provided in embodiments B1, B3-7, B9, B11-21, and B15-18 in the Exemplary Embodiments section. Additional pharmacokinetic profiles are described herein; see, e.g.,

[46] -

[62] in the Summary of the Invention.

[0094] The methods herein are not limited to a particular subject or class of subjects. In some embodiments, the subject is characterized as an extensive metabolizer. In some embodiments, the subject is characterized as a poor metabolizer. In some embodiments, the subject is not co-administered a CYP2D6 inhibitor. In some embodiments, the subject is not co-administered quinidine. In some embodiments, the subject is co-administered a CYP2D6 inhibitor, such as quinidine or bupropion. However, in any of the embodiments described herein, the subject does not suffer from a cough and / or does not require a cough suppressant.

[0095] In some embodiments, the subject (e.g., a human subject) is characterized as having a neurological disease or disorder. In some embodiments, the subject (e.g., a human subject) is characterized as having one or more diseases or disorders selected from an affective disorder, a psychiatric disorder, a brain dysfunction disorder, a movement disorder, dementia, a motor neuron disease, a neurodegenerative disease, a seizure disorder, and a headache. In some embodiments, the subject is suffering from one or more diseases or disorders selected from depression, major depressive disorder, treatment-resistant depression, treatment-resistant bipolar depression, bipolar disorder including cyclothymia, seasonal affective disorder, mood disorder, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), adjustment disorder, atypical depression, mania, anxiety disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH), attention deficit / hyperactivity disorder (AD / HD), bipolar and manic states, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, drug addiction or abuse, nicotine addiction, psychosexual dysfunction, emotion dysregulation, and mood lability. In some embodiments, the subject is afflicted with one or more diseases or disorders selected from Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar degeneration (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia. In any of the embodiments herein, the subject may be suffering from emotional dysregulation, depression (e.g., major depressive disorder or treatment-resistant depression), stroke, traumatic brain injury, seizures, pain (e.g., post-operative pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof.In any of the embodiments herein, the subject may suffer from an emotion dysregulation disorder.

[0096] Treatment method Dextromethorphan is known to be useful in treating various diseases or disorders. See, for example, Nguyen, L. et al., Pharmacology & Therapeutics 159:1022 (2016). Accordingly, in some embodiments, the present disclosure is also directed to a method of treating a disease or disorder in a subject in need of such treatment, where administration of dextromethorphan would be beneficial. In some embodiments, the method comprises transdermally administering a therapeutically effective amount of dextromethorphan to the subject. In some embodiments, the administering comprises applying a transdermal delivery device (e.g., those described herein in paragraphs

[18] -

[35] of the Summary of the Invention) to the skin of the subject. In some embodiments, the administration results in a PK profile described herein (e.g., those described herein in paragraphs

[46] -

[62] of the Summary of the Invention). In some embodiments, the subject does not suffer from a cough and / or does not require cough suppressants. In some embodiments, the subject is an extensive metabolizer of dextromethorphan. In some embodiments, the subject is a poor metabolizer of dextromethorphan. In some embodiments, the subject is sensitive or intolerant to a CYP2D6 inhibitor. In some embodiments, the subject is sensitive or intolerant to quinidine, e.g., experiencing QTc prolongation. In some embodiments, the subject has one or more side effects associated with quinidine. In some embodiments, the subject is co-administered with (or requires) a drug whose metabolism is affected by a CYP2D6 inhibitor.

[0097] A variety of diseases and disorders are suitable for treatment by the methods herein. In some embodiments, the disease or disorder is a neurological disorder. Non-limiting exemplary neurological diseases or disorders include affective disorders, psychiatric disorders, brain function disorders, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0098] Affective disorders that can be treated by the methods herein include, but are not limited to, depression, major depressive disorder, treatment-resistant depression and treatment-resistant bipolar depression, bipolar disorders including cyclothymia, seasonal affective disorder, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), adjustment disorder, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH) and attention deficit / hyperactivity disorder (AD / HD), bipolar and manic states, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, drug addiction or abuse, nicotine addiction, psychosexual dysfunction, affective dysregulation, and emotional lability.

[0099] Psychiatric disorders that can be treated by the methods herein include, but are not limited to, anxiety disorders, including but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic depression, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizophreniformity, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease.

[0100] Drug addictions and abuse that can be treated by the methods herein include, but are not limited to, addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, methamphetamine), nicotine, alcohol, opioids, anxiolytics and hypnotics, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as cigarette, cigar, and / or pipe smoking, and chewing tobacco addiction.

[0101] Brain dysfunction that can be treated by the methods herein includes, but is not limited to, disorders associated with intellectual disability, such as senile dementia, Alzheimer's dementia, memory loss, amnesia / amnestic syndrome, epilepsy, impaired consciousness, coma, impaired attention, speech disorders, vocal spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, attention deficit hyperactivity syndrome, and schizophrenia. Brain dysfunction also includes disorders caused by cerebrovascular diseases, including, but not limited to, stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, and head trauma, and symptoms include impaired consciousness, senile dementia, coma, impaired attention, and speech disorders.

[0102] Movement disorders that can be treated by the methods herein include, but are not limited to, akathisia, akinesia, dyskinesia, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, and Tourette's syndrome, and Wilson's disease.

[0103] Dementias that can be treated by the methods herein include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff syndrome, and Pick's disease.

[0104] Motor neuron diseases that can be treated by the methods herein include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophies, Tay-Sachs disease, Sandhoff disease, and hereditary spastic paraplegia.

[0105] Neurodegenerative diseases that can be treated by the methods herein include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar degeneration (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophies, Charcot-Marie-Tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0106] Seizure disorders that can be treated by the methods herein include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile convulsions; partial seizures, including but not limited to simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsy partialis continua; generalized seizures, including but not limited to generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0107] The types of headaches that can be treated by the methods herein include, but are not limited to, migraines, tension-type headaches, and cluster headaches.

[0108] Other neurological disorders that can be treated by the methods herein include, but are not limited to, Rett syndrome, autism, tinnitus, impaired consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; dysphonia due to uncontrollable laryngospasm, including, but not limited to, abductor spasmodic dysphonia, adductor spasmodic dysphonia, myotonic dysphonia, and voice tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity such as methotrexate neurotoxicity; incontinence, including, but not limited to, stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0109] In some embodiments, the disease or disorder is pain, joint pain, pain associated with sickle cell disease, emotional dysregulation, depression (including major depressive disorder, treatment-resistant depression, etc.), memory and cognition-related disorders, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), and the like.

[0110] The methods herein can also be used to treat or alleviate any type of pain, including, but not limited to, musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, inflammatory pain, arthritic pain, complex regional pain syndrome, and the like.

[0111] In some embodiments, the disease or disorder may be allodynia, refractory hyperalgesia, dermatitis, pain, inflammation, or an inflammatory condition such as Crohn's disease, including pain associated with psoriasis, cancer, viral infection, or as adjuvant therapy for multiple myeloma.

[0112] In any of the embodiments described herein, the method can be for treating emotion dysregulation, depression (e.g., major depressive disorder, treatment-resistant depression, etc.), stroke, traumatic brain injury, seizures, pain (e.g., post-operative pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof.

[0113] Suitable dosing regimens, dosages, durations, transdermal delivery devices, etc. include any of those described herein in any combination. In any of the embodiments described herein, the subject may be a human subject.

[0114] In some specific embodiments, a method for treating emotion dysregulation is provided, comprising applying a transdermal delivery device of the present specification (e.g., those described in

[18] to

[35] in the Summary of the Invention) to a subject in need thereof. In some embodiments, the transdermal delivery device contains about 5 mg to about 100 mg of dextromethorphan. In some embodiments, the transdermal delivery device is applied once daily, e.g., for up to 7 days, for at least 7 days, for one month, or for any desired period of time. In some embodiments, the transdermal delivery device contains about 50 mg to about 700 mg of dextromethorphan. In some embodiments, the transdermal delivery device is applied once weekly, e.g., for one week, one month, or for any desired period of time. In some embodiments, the transdermal delivery device is applied once, twice, three times, four times, five times, or six times weekly, e.g., for one week, one month, or for any desired period of time. In some embodiments, the transdermal delivery device is applied to achieve any of the pharmacokinetic profiles described herein (e.g., the pharmacokinetic profiles shown in

[46] -

[62] in the Summary of the Invention section, or the pharmacokinetic profiles shown in embodiments B1, B3-7, B9, B11-21, and B15-18 in the Exemplary Embodiments section). In some embodiments, the subject is not administered a CYP2D6 inhibitor. In some embodiments, the subject is not administered quinidine. In some embodiments, the subject does not suffer from cough or require antitussive effects. In some embodiments, the subject is characterized as a poor metabolizer. In some embodiments, the subject is characterized as an extensive metabolizer.

[0115] In some embodiments, the methods described herein can further include administering to the subject an active agent other than dextromethorphan. For example, in some embodiments, the methods described herein further include administering to the subject an antidepressant. In some embodiments, the antidepressant is selected from bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, metabolites or prodrugs of any of these compounds, and combinations thereof. Other suitable antidepressants are described, for example, in U.S. Patent No. 9,861,595, the entire contents of which are incorporated by reference. In some embodiments, the methods described herein further include administering to the subject quinidine. In some embodiments, the methods described herein further include administering to the subject a CYP2D6 inhibitor. In some embodiments, the methods described herein further include administering to the subject one or more additional active agents selected from amlodipine, capsaicinoids (e.g., capsaicin or its esters), opioid agonists (e.g., μ-opiate analgesics (e.g., tramadol)), adenosinergic agonists, 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, gabapentin, and pharmaceutically acceptable salts thereof. These additional agents can be administered simultaneously or sequentially. Furthermore, these additional agents can be administered via the same route or different routes. For example, in some embodiments, the additional agents can be administered transdermally or orally. However, in some embodiments, the additional agents may also be combined with dextromethorphan in the same transdermal delivery device.

[0116] Because the transdermal patches described herein bypass first-pass hepatic metabolism, the methods herein can provide dextromethorphan to subjects receiving medications that may interfere with hepatic metabolism of dextromethorphan. In some embodiments, the methods include administering to the subject desipramine, paroxetine, thioridazine, pimozide, digoxin, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, and combinations thereof. However, in some embodiments, the subject is not administered any of desipramine, paroxetine, thioridazine, pimozide, digoxin, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, and combinations thereof. In some embodiments, the methods do not require determining whether the subject is an extensive or poor metabolizer of dextromethorphan.

[0117] Exemplary Methods The present disclosure provides the following non-limiting exemplary methods of transdermally administering dextromethorphan.

[0118] Typically, the methods herein are for treating a disease or disorder that would benefit from the administration of dextromethorphan. Suitable diseases or disorders that can be treated by the methods herein are described herein. In some embodiments, the methods herein are for treating a neurological disease or disorder in a subject in need of such treatment. Such neurological diseases or disorders include, but are not limited to, affective disorders, psychiatric disorders, brain function disorders, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches. In some embodiments, the methods are for treating emotion dysregulation, depression (e.g., major depressive disorder or treatment-resistant depression), stroke, traumatic brain injury, seizures, pain, methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof. In some embodiments, the subject is not suffering from a cough and / or does not require antitussive medication.

[0119] NUEDEXTA® tablets have been approved by the FDA for the treatment of emotional dysregulation, or PBA. See the NUEDEXTA® prescribing information (June 2019), the contents of which are incorporated herein by reference in their entirety. As described in the NUEDEXTA prescribing information, PBA occurs secondary to a variety of usually unrelated neurological conditions and is characterized by involuntary, sudden, and frequent episodes of laughter and / or crying. Episodes of PBA typically occur out of proportion to or incongruent with the underlying emotional state. PBA is a unique condition, distinct from other types of emotional lability that can occur in patients with neurological disease or injury.

[0120] In some specific embodiments, the methods herein are for treating PBA in a subject in need thereof, hi some embodiments, the subject also suffers from a neurodegenerative disease such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and / or Alzheimer's disease, a stroke, or a brain injury such as a traumatic brain injury.

[0121] The methods herein generally involve transdermally delivering a therapeutically effective amount of dextromethorphan to a subject in need thereof. In some embodiments, the methods involve transdermally delivering a daily dose of dextromethorphan of about 15 mg to about 50 mg (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any range between the recited values, such as about 20-50 mg, about 30-50 mg, or about 20-40 mg) to a subject in need thereof. In some embodiments, the daily dose is about 20 mg to 40 mg, such as about 35 mg, of dextromethorphan. In some embodiments, the daily dose can also be greater than 50 mg, such as about 60 mg, up to about 100 mg, of dextromethorphan. In some embodiments, the daily dose can be less than 15 mg, such as about 5 mg, about 10 mg, or about 5-10 mg of dextromethorphan. The daily dose of dextromethorphan is typically delivered by applying to a subject a transdermal delivery device or transdermal patch described herein or an adhesive composition / adhesive formulation, such as any of those described herein (e.g., those shown in

[18] -

[35] in the Summary of the Invention).

[0122] In some embodiments, a daily dose of dextromethorphan is delivered to a subject by applying a transdermal delivery device comprising a drug-containing adhesive layer, the drug-containing adhesive layer comprising dextromethorphan in an amount of about 2% to about 12% by weight, preferably about 6% to about 12% by weight (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12% by weight, or any range therebetween, e.g., about 6-12%, 8-12%, etc.), a pressure-sensitive adhesive, and a skin permeation enhancer. The dextromethorphan and skin permeation enhancer are typically dispersed (e.g., uniformly dispersed) in the pressure-sensitive adhesive. In some embodiments, the dextromethorphan and skin permeation enhancer can be uniformly mixed with the pressure-sensitive adhesive. In some embodiments, the drug-containing adhesive layer is a uniform mixture. The pressure-sensitive adhesive is typically an acrylate adhesive, such as a polyacrylate vinyl acetate copolymer, e.g., one with non-acidic hydroxyl functionality, such as those described herein, e.g., Duro-Tak 87-2287 adhesive and its analogs. The pressure-sensitive adhesive is typically present in an amount of about 65% to about 85% by weight of the drug-containing adhesive layer (e.g., about 65%, about 70%, about 75%, about 80%, or about 85% by weight, or any range therebetween, e.g., about 70-85%, about 75-85%, etc.). The skin permeation enhancer is typically isopropyl myristate. The skin permeation enhancer is typically present in an amount of about 6% to about 12% by weight of the drug-containing adhesive layer (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any range between the recited values, such as about 8-12% by weight). Preferably, the drug-containing adhesive layer further comprises a crystallization inhibitor, such as a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), for example, povidone K30, plasdone K29 / 32, and the like. Preferably, the crystallization inhibitor is present in an amount of about 6% to about 12% by weight of the drug-containing adhesive layer (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any range between the recited values, such as about 8-12% by weight).As described herein, the inclusion of a vinylpyrrolidone polymer can significantly improve dextromethorphan flux both in vitro and in vivo compared to an otherwise identical patch without the vinylpyrrolidone polymer. Transdermal delivery devices are typically about 30 cm. 2 ~about 100cm 2 , for example, about 30 cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 70cm 2 , about 80cm 2 , about 90cm 2 , about 100cm 2 , or any range between the stated values, e.g., about 40-60 cm 2 , about 60~80cm 2 It has an effective surface area of

[0123] The transdermal delivery device is typically configured to contain a sufficient amount of dextromethorphan to deliver the desired daily dose. For example, in some embodiments, the transdermal delivery device contains about 0.2 mg / cm 2 ~about 5mg / cm 2 , for example, about 0.2 mg / cm 2 , about 0.3mg / cm 2 , about 0.4mg / cm 2 , about 0.5mg / cm 2 , about 0.6mg / cm 2 , about 0.7mg / cm 2 , about 0.8mg / cm 2 , approximately 0.9 mg / cm 2 , about 1mg / cm 2 , about 2mg / cm 2 , about 5mg / cm 2 or any range between the values ​​listed, e.g., about 0.2 to 1 mg / cm 2 , about 0.5~1mg / cm 2Typically, the transdermal delivery device can be applied to a subject in need thereof once daily, with each application lasting approximately 24 hours. In a once-daily dosing regimen, the total dextromethorphan loading is typically within a narrow range, e.g., about 0.2 to 1 mg / cm. 2 , about 0.5~1mg / cm 2 In some embodiments, the transdermal delivery device can be applied to a subject in need thereof at an administration frequency of more than once a day, such as once every 1.5 days, once every 2 days, once every 3 days, once every 4 days, once every 5 days, or once a week, and in such embodiments, to deliver the desired daily dose, the transdermal delivery device typically provides a dose of about 1-5 mg / cm. 2 , or 5 mg / cm 2 even larger, up to 8 mg / cm 2 It is possible to have a greater total dextromethorphan loading, such as

[0124] In some preferred embodiments, the transdermal delivery device is applied once daily to deliver a daily dose of about 15 mg to 40 mg of dextromethorphan to a subject in need thereof. Typically, the drug-containing adhesive layer of the transdermal delivery device contains about 20 mg to about 100 mg of dextromethorphan, e.g., about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range therebetween, e.g., about 40 to 60 mg, 50 to 60 mg, or about 50 to 70 mg of dextromethorphan. In some embodiments, the daily dose is about 20 mg to 40 mg (e.g., about 35 mg) of dextromethorphan, and the drug-containing adhesive layer contains about 50 mg to about 70 mg of dextromethorphan, e.g., about 56 mg of dextromethorphan. The drug-containing adhesive layer also typically contains about 30 mg to about 100 mg of isopropyl myristate, e.g., about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range therebetween, e.g., about 40-60 mg, 50-60 mg, or about 50-70 mg. The pressure-sensitive adhesive is typically contained in the drug-containing adhesive layer in an amount of about 150 mg to about 900 mg, e.g., about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or any range therebetween, e.g., about 300-500 mg, 350-450 mg, or about 300-550 mg. In some embodiments, the crystallization inhibitor is preferably included in the drug-containing adhesive layer in an amount of about 30 mg to about 100 mg, e.g., about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or any range between the recited values, e.g., about 40-60 mg, 50-60 mg, or about 50-70 mg, etc. While the components of the drug-containing adhesive layer are listed in absolute amount ranges, it should be understood that in some embodiments, the components may have relative weight percentages in the drug-containing adhesive layer, as described herein.Dextromethorphan and isopropyl myristate are typically dispersed (e.g., homogeneously dispersed) in the pressure-sensitive adhesive. In some embodiments, dextromethorphan and isopropyl myristate are homogeneously mixed with the pressure-sensitive adhesive. In some embodiments, the drug-containing adhesive layer is a homogeneous mixture. The pressure-sensitive adhesive is typically an acrylate adhesive, such as a polyacrylate vinyl acetate copolymer, such as one with non-acidic hydroxyl functionality, such as those described herein, e.g., Duro-Tak 87-2287 adhesive and the like. The crystallization inhibitor is typically a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like. In some embodiments, the transdermal delivery device is about 30 cm. 2 ~about 100cm 2 , for example, about 30 cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 70cm 2 , about 80cm 2 , about 90cm 2 , about 100cm 2 , or any range between the stated values, e.g., about 40-60 cm 2 , about 60~80cm 2 In some embodiments, the transdermal delivery device has an effective surface area of ​​about 50-70 mg of dextromethorphan and about 60-80 cm 2 , for example, about 70 cm 2 In some embodiments, the transdermal delivery device contains about 56 mg of dextromethorphan and about 70 cm 2 has an effective surface area of

[0125] The transdermal delivery devices herein typically have a densitometric value of at least about 200 ug / cm as measured in vitro using human cadaver skin. 2 / day, for example, about 200ug / cm 2 / day, about 300ug / cm 2 / day, about 400ug / cm2 / day, about 500ug / cm 2 / day, about 600ug / cm 2 / day, about 700ug / cm 2 / day, about 800ug / cm 2 / day, about 1000ug / cm 2 / day, or any range between the stated values, e.g., about 200-800 ug / cm 2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2 In some embodiments, the transdermal delivery devices herein comprise a vinylpyrrolidone polymer, e.g., vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like, in an amount of about 6% to about 12% by weight (e.g., about 10% by weight) in the drug-containing adhesive layer, and the transdermal delivery device typically has a dextromethorphan flux of, e.g., about 400 to 800 μg / cm, as measured in vitro using human cadaver skin. 2 / day or about 500-800ug / cm 2 / day dextromethorphan flux.

[0126] In some preferred embodiments, the methods herein can be characterized as having high transdermal bioavailability (i.e., dextromethorphan delivered divided by the initial dextromethorphan in the patch). For example, as shown in Example 4B, the initial (i.e., pre-application) amount of dextromethorphan in an exemplary patch (comprising Plasdone K29 / 32) was about 56 mg, and after 24 hours of application of this exemplary patch to a subject, about 32.4 mg to about 41.1 mg of dextromethorphan was delivered to the subject, resulting in a transdermal bioavailability from the patch of about 58% (32.4 / 56) to about 73% (41.1 / 56). This high delivery rate is made possible, in part, by the unexpected discovery that it is possible to achieve a continuously high flux of dextromethorphan from the transdermal patches herein. In some embodiments of the methods herein, a transdermal delivery device or transdermal patch (e.g., as described herein) is applied to a subject once daily, and the residual amount of dextromethorphan in the transdermal delivery device or transdermal patch, i.e., the residual amount of dextromethorphan in the device or patch after removal after about 24 hours of wear, is less than 50% (e.g., less than 40%) of the initial amount of dextromethorphan in the transdermal delivery device or transdermal patch. In some embodiments, the transdermal delivery device or transdermal patch is applied once daily, and the percentage of dextromethorphan delivered to the subject is about 50% to about 80% of the initial amount of dextromethorphan in the transdermal delivery device or transdermal patch. In some embodiments, the transdermal delivery device or transdermal patch is applied more than once a day, e.g., once every 1.5 days, once every 2 days, once every 3 days, or once a week, and the amount of dextromethorphan remaining in the transdermal delivery device or transdermal patch is less than the desired daily dose delivered to the subject, e.g., less than 90% (e.g., less than 80%, or less than 60%). In some embodiments, the transdermal delivery device or transdermal patch is applied once every 1.5 days, once every 2 days, once every 3 days, or once a week, and the percentage of dextromethorphan delivered to the subject is about 60% to about 90% of the initial amount of dextromethorphan in the transdermal delivery device or transdermal patch.Typically, the transdermal delivery device or transdermal patch comprises a drug-containing adhesive layer comprising: (1) dextromethorphan in an amount of about 6% to about 12% by weight (e.g., as described herein, e.g., about 10% by weight); (2) a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as one having non-acidic hydroxyl functionality, such as those described herein, e.g., Duro-Tak 87-2287 adhesive and the like, in an amount of about 65% to about 85% by weight (e.g., as described herein, e.g., about 70% by weight); (3) isopropyl myristate in an amount of about 6% to about 12% by weight (e.g., as described herein, e.g., about 10% by weight); and (4) a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like, in an amount of about 6% to about 12% by weight (e.g., as described herein, e.g., about 10% by weight). For a once-daily dosing regimen, the transdermal delivery device or transdermal patch typically contains about 30 mg to about 100 mg of dextromethorphan, and the patch is about 30 cm in size. 2 ~Approx. 100cm 2 is.

[0127] In some embodiments, the methods herein may also be characterized by the unique in vivo pharmacokinetic (PK) profiles described herein. As shown in more detail in the Examples section, once-daily application of exemplary patches to human subjects provided therapeutically effective plasma concentrations sustained over a period of time. Treatment of the diseases or disorders herein with the novel PK profiles described herein is itself a novel feature of the present disclosure. These unique PK profiles may result in more precise dosing, less frequent dosing, reduced side effects associated with quinidine and / or increased dextromethorphan exposure (e.g., C max ) associated side effects, reduced pill burden, and improved patient compliance.

[0128] Some embodiments of the methods herein are directed to the novel PK profiles described herein. As one skilled in the art will appreciate, while the present disclosure focuses primarily on transdermal delivery of dextromethorphan, similar PK profiles can be achieved by other delivery routes that bypass first-pass metabolism and deliver dextromethorphan to a subject, e.g., in a continuous or substantially continuous manner. Accordingly, the present disclosure also specifically contemplates such methods of delivering dextromethorphan, which can include, for example, administering dextromethorphan intravenously, subcutaneously, intramuscularly, or via a depot.

[0129] In some embodiments, the disclosure provides a method of treating a neurological disease or disorder (e.g., any of those described herein, such as PBA) in a subject in need of treatment, comprising applying a transdermal patch to the subject at a dosing frequency of once daily to once weekly, wherein the transdermal patch contains about 15 mg to about 700 mg of dextromethorphan (e.g., about 15 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or any range therebetween, such as about 15-100 mg, about 30-100 mg, about 30-75 mg, or about 150-500 mg), such that application provides the subject with a therapeutically effective plasma concentration of dextromethorphan at steady state. In some embodiments, the transdermal patch contains about 30 mg to about 100 mg of dextromethorphan, hi some embodiments, the dosing frequency is once daily.

[0130] In some embodiments, the method characterizes a PK profile resulting from application of the transdermal patch. For example, in some embodiments, the present disclosure provides a method of treating a neurological disease or disorder (e.g., any of those described herein, such as PBA) in a subject in need of treatment, the method comprising applying to the subject, preferably once daily, a transdermal patch containing about 30 mg to about 100 mg of dextromethorphan to deliver a daily dose of about 15 mg to about 50 mg of dextromethorphan, wherein application results in a pharmacokinetic profile in the subject characterized by one or more of the following: a) AUC on day 7 or in the steady-state phase of about 180 h*ng / mL to about 2000 h*ng / mL, for example, about 200 h*ng / mL to about 600 h*ng / mL or about 300 h*ng / mL to about 500 h*ng / mL 0-24,DXM , b) C at day 7 or steady state of about 8 ng / mL to about 100 ng / mL, for example, about 10 ng / mL to about 20 ng / mL, for example, about 15 ng / mL Avg,DXM , c) C at day 7 or steady state of about 6 ng / mL to about 65 ng / mL, for example, about 6 ng / mL to about 20 ng / mL min,DXM , d) C at day 7 or steady state of about 8 ng / mL to about 90 ng / mL, for example, about 10 ng / mL to about 30 ng / mL max,DXM , e) The variability of dextromethorphan at day 7 or steady state stage [(C max -C min ) / C avg ], f) a dextromethorphan amplitude ratio [(C max -C min ) / C min ], g) an AUC of about 1.5 to about 5, for example, about 1.5 to about 3, for example, about 1.5 to 2.5 0-24,DXM,D1 AUC at steady state phase 0-24,DXM The ratio of h) AUC at steady state of about 12 to about 35 0-24,DOR AUC for 0-24,DXM The ratio of i) C at the steady state stage of about 12 to about 35 max,DOR C against max,DXM The ratio of, and j) C at the steady state stage of about 12 to about 35 Avg,DOR C against Avg,DXM The ratio of is. It should be understood that dextrorphan (Dor) concentrations and related parameters are based on free dextrorphan, i.e., unconjugated. In some embodiments, application results in: a) an AUC of about 200 h*ng / mL to about 600 h*ng / mL at day 7 or steady state; 0-24,DXM b) C at day 7 or steady state of about 10 ng / mL to about 20 ng / mL, for example about 15 ng / mL Avg,DXM c) C at day 7 or steady state of about 6 ng / mL to about 20 ng / mL min,DXM and / or d) a C at day 7 or steady state of about 10 ng / mL to about 30 ng / mL. max,DXM These levels of dextromethorphan exposure can be advantageous. As shown in Example 4B, at day 7 or steady state after twice-daily oral administration of NUEDEXTA® tablets, dextromethorphan plasma concentrations were much higher than those noted above. Thus, the methods herein provide a pharmacokinetic profile characterized by at least high dextromethorphan exposure (e.g., C max In some embodiments, application of the patch is expected to result in a reduction in the incidence of side effects associated with dextromethorphan (e.g., AUC, etc.). ... fluctuation of dextromethorphan (C) at day 7 or steady state [C] of about 0.18 to about 1. max -C min ) / C avg], and / or f) a dextromethorphan amplitude ratio [(C max -C min ) / C min In some embodiments, the application provides the subject with a pharmacokinetic profile characterized by: g) an AUC of about 1.5 to about 3; 0-24,DXM,D1 AUC at steady state phase 0-24,DXM In some embodiments, administration provides the subject with a pharmacokinetic profile characterized by a ratio of AUC 0.01 to AUC 0.02 at steady state of about 12 to about 35. 0-24,DOR AUC for 0-24,DXM i) the ratio of C at the steady state stage between about 12 and about 35 max,DOR C against max,DXM and / or j) a C at the steady state stage of about 12 to about 35 Avg,DOR C against Avg,DXM Typically, for each application of the transdermal patch other than the first dose, the pre-dose plasma dextromethorphan concentration is approximately equal to the mean concentration (C) observed from the immediately preceding dose. Avg , DXM), e.g., the pre-dose concentration for the second dose is not less than about 20% of the average concentration observed from the first dose. In some embodiments, the dextromethorphan accumulation ratio is in the range of about 1 to about 5, e.g., about 1.2 to about 3, and the subject is an extensive or very extensive metabolizer. In some embodiments, application results in a dextromethorphan half-life at steady state of about 11 to about 29 hours, e.g., about 11 to about 24 hours, e.g., about 17 hours, in extensive or very extensive metabolizers, and / or a dextromethorphan half-life of about 0.018 hours in extensive or very extensive metabolizers. -1 ~about 0.065h -1 , for example, about 0.020h -1 ~approx. 0.06 hours -1 The apparent first-order terminal elimination rate constant (λ) after the final dose after achieving a steady-state phase zThe subject is provided with a pharmacokinetic profile characterized by a pharmacokinetic profile of 100% or more of the following: (a) a dextromethorphan flux rate (a rate of dextromethorphan release) (b) a dextromethorphan release rate (a rate of dextromethorphan release) (c) a dextromethorphan release rate (a rate of dextromethorphan release) (d) a dextromethorphan release rate (a rate of dextromethorphan release) (e.g., a rate of dextromethorphan release) (e.g., a rate of dextromethorphan release) (f) a dextromethorphan release rate (a rate of dextromethorphan release) (g) a dextromethorphan release rate (a rate of dextromethorphan release) (h) a dextromethorphan release rate (a rate of dextromethorphan release) (i.e., a ...

[0131] In some embodiments, the methods herein may be particularly useful and advantageous for treating certain subjects. Patients with neurological disorders often have multiple comorbidities and / or are receiving treatment with numerous other medications. For example, treatment trials (controlled or uncontrolled) for PBA have been based on patient populations with a variety of other underlying neurological disorders, including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and stroke and traumatic brain injury. Therefore, patients with PBA are typically also receiving treatment with other medications, such as medications for the treatment of ALS, MS, stroke, and traumatic brain injury. The use of NUEDEXTA® tablets or similar measures to increase dextromethorphan plasma concentrations using CYP2D6 inhibitors is limited and may pose various limitations and drug-drug interactions for such patients. Some of the side effects or drugs affected by CYP2D6 inhibitors are described in the NUEDEXTA® prescribing information (June 2019 edition), the contents of which are incorporated herein by reference in their entirety. For example, the NUEDEXTA® prescribing information lists the following contraindications: 1) patients with a history of hypersensitivity reactions, such as thrombocytopenia, hepatitis, or myelosuppression or lupus-like syndrome, caused by quinidine, quinine, or mefloquine; 2) patients with known hypersensitivity to dextromethorphan; and 3) use in combination with an MAOI or within 14 days of stopping an MAOI. Allow 14 days between stopping NUEDEXTA and starting an MAOI; 4) history suggestive of QT interval prolongation, congenital long QT syndrome, polymorphic ventricular tachycardia, or heart failure; 5) complete atrioventricular (AV) block or patients at high risk for AV block without an implanted pacemaker; and 6) concomitant use of drugs that prolong the QT interval and are metabolized by CYP2D6 (e.g., thioridazine or pimozide).Additionally, the prescribing information for NUEDEXTA® contains various warnings and precautions, including: a) thrombocytopenia or other hypersensitivity reactions, b) hepatitis, c) QT prolongation, d) left ventricular hypertrophy (LVH) or left ventricular dysfunction (LVD), e) CYP2D6 substrates, f) dizziness, g) serotonin syndrome, and h) anticholinergic effects of quinidine. Many of these contraindications, warnings, and precautions are associated with quinidine. For example, the prescribing information for NUEDEXTA® states that "quinidine can cause immune-mediated thrombocytopenia, which can be severe or fatal," "quinidine has also been associated with a lupus-like syndrome with polyarthritis," "other associations include rash, bronchospasm, lymphadenopathy, hemolytic anemia, vasculitis, uveitis, angioedema, agranulocytosis, sicca syndrome, myalgia, elevated serum levels of skeletal muscle enzymes, and pneumonitis," and "hepatitis, including granulomatous hepatitis, has been reported in patients receiving quinidine." Quinidine may also cause "the safety and / or efficacy of drugs used in combination with NUEDEXTA that are metabolized by CYP2D6 may be reduced due to accumulation of the parent drug and / or impaired formation of the active metabolite," and "quinidine exposure, which can occur from NUEDEXTA overdose, may result in fatal cardiac arrhythmias, including polymorphic ventricular tachycardia." Chronic quinidine toxicity is possible with NUEDEXTA treatment. Furthermore, various drugs may affect the pharmacological effects of quinidine, such as CYP3A4 inhibitors and P-glycoprotein blockers, which may have direct effects on QTc or be proarrhythmic themselves, and may decrease serum potassium in association with diuretics, resulting in a moderate decrease in potassium concentration and thereby limiting the use of NUEDEXTA. Because quinidine inhibits CYP2D6, various drug-drug interactions may also occur with CYP2D6 substrates such as desipramine and paroxetine.As stated in the prescribing information for NUEDEXTA®, "In the case of prodrugs whose action is mediated by CYP2D6-generated metabolites (e.g., codeine and hydrocodone, whose analgesic and antitussive effects are thought to be mediated by morphine and hydromorphone, respectively), quinidine-mediated CYP2D6 inhibition likely prevents the desired clinical benefit from being achieved in the presence of NUEDEXTA." Quinidine is also an inhibitor of P-glycoprotein and can significantly affect plasma concentrations of drugs that are substrates of P-glycoprotein, such as digoxin. In summary, due to the various potential side effects associated with quinidine, there exists an unmet medical need for the treatment of PBA, at least in patient populations with one or more limitations and / or side effects associated with quinidine or CYP2D6 inhibitors in general.

[0132] Because the transdermal delivery route described herein does not require the use of quinidine or other CYP2D6 inhibitors, it can be advantageously used to treat patients without the constraints associated with quinidine or CYP2D6 inhibitors. For example, in some embodiments, the methods herein can treat subjects who are sensitive or intolerant to quinidine, or CYP2D6 inhibitors in general. In some embodiments, the subject can be sensitive or intolerant to CYP2D6 inhibitors. In some embodiments, the subject can be sensitive or intolerant to quinidine. In some embodiments, the subject has one or more side effects associated with quinidine. In some embodiments, the subject is co-administered with a drug whose metabolism is affected by a CYP2D6 inhibitor. In some embodiments, the subject is co-administered with a drug whose metabolism is affected by quinidine. In some embodiments, the subject is co-administered a drug such as a CYP3A4 inhibitor (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) that may affect the pharmacological effects of quinidine. In some embodiments, the subject can be further treated with a selective serotonin reuptake inhibitor (such as fluoxetine), a tricyclic antidepressant (such as clomipramine and imipramine), and / or a monoamine oxidase inhibitor (MAOI).

[0133] Furthermore, because the transdermal delivery route described herein does not require the use of quinidine or other CYP2D6 inhibitors, the transdermal delivery device or transdermal formulation described herein can be conveniently administered to transdermally deliver dextromethorphan to a subject, regardless of whether the subject is a poor, intermediate, or extensive metabolizer of dextromethorphan. In poor metabolizers, the addition of quinidine or other CYP2D6 inhibitors is not expected to significantly affect plasma exposure to dextromethorphan, yet such addition would expose the subject to potential side effects associated with quinidine or other CYP2D6 inhibitors. The transdermal delivery method described herein does not suffer from such drawbacks. In some embodiments, the method described herein can treat a subject without first determining whether the subject is a poor, intermediate, or extensive metabolizer of dextromethorphan. In some embodiments, the method described herein can treat a subject who is an extensive metabolizer. In some embodiments, the method described herein can treat a subject who is a poor metabolizer. In some embodiments, the methods herein can also include determining whether a subject is a poor, intermediate, or extensive metabolizer of dextromethorphan and administering an appropriate daily dose of dextromethorphan to the subject. For example, in some embodiments, the daily dose can be adjusted so that transdermal delivery results in a therapeutically effective plasma concentration of dextromethorphan in the subject. In some embodiments, the daily dose can be adjusted so that transdermal delivery results in any of the PK profiles described herein (e.g., those shown in

[46] -

[62] in the Summary of the Invention).For example, in some embodiments, the present disclosure provides a method for treating a neurological disease or disorder (e.g., any of those described herein) in a subject in need of such treatment, comprising: (a) applying a first transdermal patch (e.g., one of those described in paragraphs

[18] to

[35] in the Summary of the Invention) to the subject at a dosing frequency of once daily to once weekly to deliver a first daily dose (typically about 15 mg to about 50 mg) of dextromethorphan to the subject; (b) determining whether the application results in any of the pharmacokinetic profiles disclosed herein (e.g., those described in paragraphs

[46] to

[62] in the Summary of the Invention); and, optionally, (c) adjusting the upper or lower limit of the first daily dose so that the application results in one or more of the pharmacokinetic profiles disclosed herein (e.g., those described in paragraphs

[46] to

[62] in the Summary of the Invention). Suitable transdermal patches and dosing regimens include any of those described herein.

[0134] As discussed herein, the methods herein are directed to at least high dextromethorphan exposure (e.g., C max , AUC, etc.). Thus, in some embodiments, the methods herein are intended to provide a method for treating high dextromethorphan exposure (e.g., C max The compounds can also be advantageously used to treat a subject having one or more side effects associated with the administration of steroids (e.g., AUC, etc.).

[0135] The methods herein can be used in conjunction with other drug therapies. For example, in some embodiments, the methods can further include administering an antidepressant to the subject. In some embodiments, the antidepressant is bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, metabolites or prodrugs of any of these compounds, and combinations thereof. In some embodiments, the methods can further include administering to the subject one or more additional active agents selected from amlodipine, capsaicinoids (e.g., capsaicin or its esters), opioid agonists (e.g., μ-opiate analgesics (e.g., tramadol)), adenosinergic agonists, 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, gabapentin, and pharmaceutically acceptable salts thereof. Typically, the methods herein do not administer quinidine to the subject. However, in some embodiments, quinidine may be administered. These additional agents can be administered simultaneously or sequentially. Furthermore, these additional agents can be administered via the same or different routes. For example, in some embodiments, the additional agents may be administered transdermally or orally. However, in some embodiments, the additional agents may also be combined with dextromethorphan in the same transdermal delivery device.

[0136] definition As used herein, the term "about" modifying a quantity in connection with the present invention refers to variations in numerical value that may occur due, for example, to routine testing and handling, inadvertent errors in such testing and handling, differences in the manufacture, source, or purity of the components / materials used in the present invention, and the like. As used herein, "about" a particular value is inclusive of that particular value, for example, about 10% includes 10%. Whether modified by the term "about," the claims include equivalents of the stated quantity. In one embodiment, the term "about" means within 20% of the reported numerical value.

[0137] As used herein, the term "cumulative drug permeation" refers to the total amount of drug permeated per square centimeter during a given period of time. Unless otherwise clear from the context, "cumulative drug permeation" at a given time (e.g., 24 hours after administration) refers to the total amount of drug permeated per square centimeter from time 0 (i.e., the time of administration) to that given time. Unless otherwise clear from the context, "cumulative drug permeation" refers to the arithmetic mean value measured and / or calculated according to the methods described herein. As used herein, the term "mean value," unless specified, also refers to the arithmetic mean value unless inconsistent with common practice in the art.

[0138] 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, "flux" refers to an arithmetic mean value measured and / or calculated according to the methods described herein. Common units of flux are milligrams per square centimeter per hour or per day. As used herein, dextromethorphan flux per day should be understood as the arithmetic mean cumulative dextromethorphan permeation 24 hours after application, measured and / or calculated according to the methods described herein.

[0139] The flux rates referred to in this patent application can refer to those measured by either in vivo or in vitro methods. One method for measuring flux is to place a transdermal delivery device or transdermal formulation on a known skin area of ​​a human volunteer and measure the amount of drug that can permeate the skin within a certain time constraint. Those skilled in the art will understand that, in some cases, absolute in vitro flux values ​​can vary by several fold when measured using different cadaveric sources. As used herein, when specifically referred to as measured by an in vitro method using human cadaveric skin, the flux rate should be understood to be measured according to the method described in Example 2. For example, the tested patch of Example 2 can be used as a reference patch, which, when tested according to the method described in Example 2, should produce the same flux as observed in Example 2 within experimental error generally accepted by those skilled in the art. Although in vitro methods use human epidermal membranes obtained from cadavers rather than human volunteers to measure drug flux through the skin, it is generally accepted by those skilled in the art that the results of a properly designed and executed in vitro test can be used to extrapolate or predict the results of an in vivo test with reasonable reliability.

[0140] As used herein, the terms "treat," "treating," "treatment," and the like refer to eliminating, alleviating, or ameliorating a disease or condition and / or its associated symptoms. Although not excluded, treating a disease or condition does not require that the disease, condition, or its associated symptoms be completely eliminated.

[0141] The term "therapeutically effective amount," as used herein, refers to an amount of a therapeutic agent (e.g., dextromethorphan) sufficient to result in the amelioration of one or more symptoms of a disorder or condition (e.g., PBA), or to prevent the onset or progression of the disorder or condition, or to cause regression or cure of the disorder or condition.

[0142] The term "subject" (alternatively referred to herein as "patient"), as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0143] As used herein, application or administration of a transdermal delivery device herein should be understood according to how such a transdermal delivery device is normally applied or administered to the skin of, for example, a human subject.

[0144] Exemplary Embodiments Exemplary Embodiments A1-55 Non-limiting exemplary embodiments A1 to A55 are given below. 1.a. an adhesive layer comprising an adhesive, optionally comprising dextromethorphan dispersed in the adhesive in an amount of about 2% to about 12% by weight of the adhesive layer; and optionally b. a reservoir layer comprising dextromethorphan in an amount of at least 10% by weight (e.g., about 20% to about 60% by weight) of the reservoir layer; A transdermal delivery device comprising: 2. The transdermal delivery device of embodiment A1, configured to transdermally deliver about 2 mg / day to about 50 mg / day of dextromethorphan to a user. 3. The transdermal delivery device of embodiment A1 or embodiment A2, wherein the transdermal delivery device is configured to transdermally deliver about 5 mg / day to about 50 mg / day (e.g., about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, or any ranges between said recited values) of dextromethorphan to a user for one or more days (e.g., 1.5 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or any ranges between said recited values). 4.About 0.5mg / cm 2 ~about 8mg / cm 2 A transdermal delivery device according to any one of embodiments A1-3, having a total dextromethorphan loading of 5.About 2mg / cm 2 ~about 6mg / cm 2(For example, about 2 mg / cm 2 , about 3mg / cm 2 , about 4mg / cm 2 , about 5mg / cm 2 , about 6mg / cm 2 A transdermal delivery device described in any one of embodiments A1 to A4 having a total dextromethorphan loading of 0.01 to 0.01% (0.01 to 0.01%), or any range therebetween. 6. Approximately 5cm 2 ~about 200cm 2 The transdermal delivery device of any one of embodiments A1-5, having an effective surface area of 7.About 10cm 2 ~Approx. 150cm 2 The transdermal delivery device of any one of embodiments A1-6, having an effective surface area of 8.About 30cm 2 ~Approx. 100cm 2 (For example, about 30 cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 70cm 2 , about 80cm 2 , about 90cm 2 , about 100cm 2 The transdermal delivery device of any one of embodiments A1-7, having an effective surface area of ​​0.05 mm, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 10 mm, 12 mm, 14 mm, 16 mm, 18 ... 9. The transdermal delivery device of any one of embodiments A1-8, wherein the adhesive layer comprises dextromethorphan in an amount from about 6% to about 12% by weight of the adhesive layer (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12% by weight, or any range therebetween). 10. The transdermal delivery device of any one of embodiments A1-9, wherein the adhesive layer further comprises a skin permeation enhancer. 11. The skin permeation enhancer is selected from the group consisting of isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, and a carbon chain length of C 12 ~C 18The transdermal delivery device of embodiment A10, wherein the fatty acid is selected from other fatty acids and fatty acid esters of the formula: 12. The transdermal delivery device of embodiment A10 or embodiment 11, wherein the skin permeation enhancer is present in an amount of about 2% to about 15% by weight of the adhesive layer. 13. A transdermal delivery device described in any one of embodiments A10-12, wherein the skin permeation enhancer is present in an amount of about 6% to about 12% by weight of the adhesive layer (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any range therebetween). 14. The transdermal delivery device of any one of embodiments A1-13, wherein the adhesive layer further comprises an agent for improving the cohesive strength of the adhesive layer. 15. The transdermal delivery device of any one of embodiments A1-13, wherein the adhesive layer further comprises an agent selected from a vinylpyrrolidone polymer (e.g., vinylpyrrolidone-vinyl acetate copolymer), Kollidon (e.g., Kollidon 30 LP, Kollidon 90, or Kollidon VA64), silicon dioxide, titanium dioxide, and combinations thereof. 16. The transdermal delivery device of embodiment A14 or embodiment 15, wherein the agent is present in an amount of about 1% to about 20% by weight of the adhesive layer. 17. A transdermal delivery device described in any one of embodiments A14 to A16, wherein the drug is present in an amount of about 2% to about 20% by weight of the adhesive layer (e.g., about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, about 10%, about 15%, about 20%, or any range between the recited values), for example, about 2% to about 6% by weight (e.g., about 2%, about 2.5%, about 3%, about 4%, about 5%, or any range between the recited values). 18. The transdermal delivery device of any one of embodiments A1-17, wherein the adhesive comprises a pressure-sensitive adhesive. 19. The transdermal delivery device of embodiment A18, wherein the pressure-sensitive adhesive comprises a polyisobutylene adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive (e.g., a polyacrylate vinyl acetate copolymer, such as one having non-acidic hydroxyl functional groups, such as those described herein, e.g., Duro-Tak 87-2287 adhesive and the like), or a combination thereof. 20. The transdermal delivery device of embodiment A18 or embodiment A19, wherein the pressure-sensitive adhesive is present in an amount of about 50% to about 90% by weight of the adhesive layer. 21. A transdermal delivery device described in any one of embodiments A18-20, wherein the pressure-sensitive adhesive is present in an amount of about 60% to about 85% by weight of the adhesive layer (e.g., about 60% by weight, about 70% by weight, about 75% by weight, about 80% by weight, about 85% by weight, or any range between the recited values). 22. A transdermal delivery device described in any one of embodiments A1-21, wherein the adhesive layer is capable of continuously adhering to the user's skin for at least 1 day (e.g., at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days). 23. The transdermal delivery device of any one of embodiments A1-22, wherein the adhesive layer is about 0.1 mil to about 10 mil thick (e.g., about 0.5 mil to about 10 mil, about 1 mil to 10 mil). 24. A transdermal delivery device described in any one of embodiments A1-23, wherein the reservoir layer comprises dextromethorphan in an amount of about 30% to about 50% by weight of the reservoir layer (e.g., about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, or any range between the recited values). 25. The transdermal delivery device of any one of embodiments A1-24, wherein the reservoir layer further comprises a skin permeation enhancer. 26. The skin permeation enhancer is selected from the group consisting of isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, and a carbon chain length of C 12 ~C 18The transdermal delivery device of embodiment A25, wherein the fatty acid is selected from other fatty acids and fatty acid esters of the formula: 27. The transdermal delivery device of embodiment A25 or embodiment A26, wherein the skin permeation enhancer is present in an amount of about 2% to about 15% by weight of the reservoir layer. 28. A transdermal delivery device described in any one of embodiments A25-27, wherein the skin permeation enhancer is present in an amount of about 6% to about 12% by weight of the reservoir layer (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any range therebetween). 29. The transdermal delivery device of any one of embodiments A1-28, wherein the reservoir layer further comprises an agent for improving the cohesion of the reservoir layer. 30. The transdermal delivery device of any one of embodiments A1-28, wherein the reservoir layer further comprises an agent selected from a vinylpyrrolidone polymer (e.g., vinylpyrrolidone-vinyl acetate copolymer), Kollidon (e.g., Kollidon 30 LP, Kollidon 90, or Kollidon VA64), silicon dioxide, titanium dioxide, and combinations thereof. 31. The transdermal delivery device of embodiment A29 or embodiment A30, wherein the agent is present in an amount of about 1% to about 20% by weight of the reservoir layer. 32. A transdermal delivery device described in any one of embodiments A29 to A31, wherein the drug is present in an amount of about 2% to about 20% by weight of the reservoir layer (e.g., about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, about 10%, about 15%, about 20%, or any range between the recited values), for example, about 2% to about 6% by weight (e.g., about 2%, about 2.5%, about 3%, about 4%, about 5%, or any range between the recited values). 33. The transdermal delivery device of any one of embodiments A1-32, wherein the reservoir layer comprises dextromethorphan dispersed, e.g., uniformly dispersed, in a pressure-sensitive adhesive. 34. The transdermal delivery device of embodiment A33, wherein the pressure-sensitive adhesive comprises a polyisobutylene adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive (e.g., a polyacrylate vinyl acetate copolymer, such as one having non-acidic hydroxyl functional groups, such as those described herein, Duro-Tak 87-2287 adhesive and the like), or a combination thereof. 35. The transdermal delivery device of embodiment A33 or embodiment A34, wherein the pressure-sensitive adhesive is present in an amount of about 20% to about 80% by weight of the reservoir layer. 36. A transdermal delivery device described in any one of embodiments A33-35, wherein the pressure-sensitive adhesive is present in an amount of about 20% to about 65% by weight of the reservoir layer (e.g., about 20% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 50% by weight, about 60% by weight, about 65% by weight, or any range between the recited values). 37. The transdermal delivery device of any one of embodiments A1-36, wherein the reservoir layer is about 0.1 mil to about 10 mil thick (e.g., about 0.5 mil to about 10 mil, about 1 mil to about 10 mil). 38. The transdermal delivery device of any one of embodiments A1-37, wherein the adhesive layer and the reservoir layer are separated by a rate-controlling membrane. 39. A method for administering dextromethorphan to a subject in need thereof, comprising applying to the subject a transdermal delivery device / patch described in any one of embodiments A1 to 38, C1 to 21, and those set forth in

[18] to

[35] in the Summary of the Invention, or applying to the subject a transdermal delivery device comprising an adhesive layer having the same or substantially the same ingredients as those in formulations A, B, C1, C2, C3, D0, D1, D2, or E1 in the preceding examples. 40. The method of embodiment A39, wherein the subject is not suffering from a cough and / or does not require antitussive medication. 41. The method of embodiment A39 or embodiment A40, wherein the subject is characterized as an extensive metabolizer. 42. The method of any one of embodiments A39-41, wherein the subject is suffering from a neurological disease or disorder. 43. The method of any one of embodiments A39-41, wherein the subject is suffering from one or more diseases or disorders selected from an affective disorder, a psychiatric disorder, a brain dysfunction disorder, a movement disorder, dementia, a motor neuron disease, a neurodegenerative disease, a seizure disorder, and a headache. 44. The method of any one of embodiments A39-41, wherein the subject is suffering from one or more diseases or disorders selected from depression, major depressive disorder, treatment-resistant depression, treatment-resistant bipolar depression, bipolar disorder including cyclothymia, seasonal affective disorder, mood disorder, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), adjustment disorder, atypical depression, mania, anxiety disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH), attention deficit / hyperactivity disorder (AD / HD), bipolar and manic states, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, drug addiction or abuse, nicotine addiction, psychosexual dysfunction, emotion dysregulation, and emotional lability. 45. The subject is diagnosed with Alzheimer's disease, prion-related disease, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menke's disease, or The method of any one of embodiments A39-41, wherein the patient is suffering from one or more diseases or disorders selected from: Amyloidosis, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia. 46. ​​The method of any one of embodiments A39-41, wherein the subject is suffering from emotional dysregulation, depression (e.g., major depressive disorder or treatment-resistant depression), stroke, traumatic brain injury, seizures, pain (e.g., postoperative pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof. 47. The method of any one of embodiments A39-46, further comprising administering to the subject an antidepressant. 48. The method of embodiment A47, wherein said antidepressant is selected from bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, metabolites or prodrugs of any of these compounds, and combinations thereof. 49. The method of any one of embodiments A39-46, further comprising administering quinidine to the subject. 50. The method of any one of embodiments A39-46, wherein said subject is not administered a CYP2D6 inhibitor. 51. The method of any one of embodiments A39-46, wherein the subject is not administered quinidine. 52. The method of any one of embodiments A39-46, wherein the subject is not administered any of desipramine, paroxetine, thioridazine, pimozide, digoxin, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, and combinations thereof. 53. The method of any one of embodiments A39-46, further comprising administering to the subject one or more additional active agents selected from amlodipine, capsaicinoids (e.g., capsaicin or its esters), opioid agonists (e.g., μ-opiate analgesics (e.g., tramadol)), adenosinergic agonists, 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, gabapentin, and pharmaceutically acceptable salts thereof. 54. The method of any one of embodiments A39-53, wherein the transdermal delivery device is applied once daily, for example, for up to 7 days or more, or for at least 7 days, or any desired period of time. 55. The method of any one of embodiments A39-53, wherein the transdermal delivery device is applied once a week, or two, three, four, five, or six times a week.

[0145] Exemplary embodiments B1 to B26 Non-limiting exemplary embodiments B1 to B26 are shown below. 1. A method of administering dextromethorphan to a human subject in need thereof, comprising applying a transdermal delivery device comprising dextromethorphan to the skin of the subject once daily, wherein said application results in the following pharmacokinetic profile in the human subject: a. One day after application, a mean C of at least about 3 ng / ml (e.g., about 3 ng / ml to about 12 ng / ml) of dextromethorphan max ; b. A mean AUC of at least about 40 ng*h / ml (e.g., about 40 ng*h / ml to about 150 ng*h / ml) of dextromethorphan one day after application 0-24 ; c. One day after application, the C of dextromethorphan is about 1.5 or less (e.g., about 1 to about 1.5). 24h / C 12h Average ratio of ; d. One day after application, the C of dextromethorphan is at least about 1.2 (e.g., about 1.5 to about 2.5). 24h / C 6h Average ratio of ; e. One day after application, the C of dextromethorphan is approximately 0.85 to approximately 1.3. 24h / C 18h Average ratio of ; f. One day after application, a mean C of dextrorphan of 2 ng / ml or less (e.g., 2 ng / ml or less, 1 ng / ml or less, or 0.5 ng / ml or less) max ; g. Mean AUC of dextrorphan of 10 ng*h / ml or less (e.g., 10 ng*h / ml or less, or 5 ng*h / ml or less) one day after application 0-24 ; h. One day after application, a C of dextromethorphan of at least about 5 (at least about 10, at least about 15, at least about 20) max C against dextrorphan max the average ratio of i. an AUC of dextromethorphan of at least about 5 (at least about 10, at least about 15, at least about 20, or at least about 25) at day 1 after application; 0-24 AUC vs. dextrorphan 0-24 Average ratio of The method according to any one of the preceding claims, wherein one or more of the following results: 2. The method of embodiment B1, wherein the human subject is not suffering from a cough and / or does not require antitussive medication. 3. The method of embodiment B1 or embodiment B2, wherein the human subject is characterized as an extensive metabolizer. 4. The mean C of dextromethorphan observed from the application of the patch to the human subject orally administering a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily, when measured one day after application. max At least about 30% (e.g., about 30% to about 80%) of the mean C of dextromethorphan max The method of any one of embodiments B1-3, wherein 5. The mean AUC of dextromethorphan observed from administering orally twice daily to the human subject a combination of 20 mg dextromethorphan and 10 mg quinidine via said patch, measured one day after application. 0-24 At least about 30% (e.g., about 30% to about 80%) of the mean AUC of dextromethorphan 0-24 The method of any one of embodiments B1-4, wherein 6. The mean C of dextromethorphan observed from the oral administration of a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily to the human subject when measured one day after application. max About 50% or less (e.g., about 10% to about 30%) of the mean C of dextrorphan max The method of any one of embodiments B1 to B5, wherein 7. The mean AUC of dextromethorphan observed from administering orally twice daily to the human subject a combination of 20 mg dextromethorphan and 10 mg quinidine via said patch, measured one day after application. 0-24 About 50% or less (e.g., about 10% to about 30%) of the mean AUC of dextrorphan 0-24 The method of any one of embodiments B1 to B6, wherein 8. The method of any one of embodiments B1-7, wherein the human subject is suffering from emotional dysregulation, depression (e.g., major depressive disorder or treatment-resistant depression), stroke, traumatic brain injury, seizures, pain (e.g., post-operative pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof. 9. Applying the transdermal delivery device once daily for a period of up to 7 days, or for at least 7 days, or any desired period, wherein said application results in the following pharmacokinetic profile in the human subject: a. 7 days after application, a mean C of at least about 8 ng / ml (e.g., about 8 ng / ml to about 20 ng / ml) of dextromethorphan max and b. A mean C of dextrorphan of 2 ng / ml or less (e.g., 2 ng / ml or less, 1 ng / ml or less, or 0.5 ng / ml or less) 7 days after application max , The method of any one of embodiments B1 to B8, wherein one or both of: 10. The method of any one of embodiments B1-9, wherein the transdermal delivery device comprises from about 5 mg to about 100 mg of dextromethorphan. 11. A method of administering dextromethorphan to a human subject in need thereof, comprising applying a transdermal delivery device comprising dextromethorphan to the skin of the subject once weekly, or two, three, four, five, or six times weekly, wherein said application results in the following pharmacokinetic profile in the human subject: a. On the first day after application, a mean C of at least about 3 ng / ml (e.g., about 3 ng / ml to about 12 ng / ml) of dextromethorphan max ; b. A mean AUC of at least about 40 ng*h / ml (e.g., about 40 ng*h / ml to about 150 ng*h / ml) of dextromethorphan one day after application 0-24 ; c. One day after application, the C of dextromethorphan is about 1.5 or less (e.g., about 1 to about 1.5). 24h / C 12h Average ratio of ; d. One day after application, the C of dextromethorphan is at least about 1.2 (e.g., about 1.5 to about 2.5). 24h / C 6h Average ratio of ; e. One day after application, the C of dextromethorphan is approximately 0.85 to approximately 1.3. 24h / C 18h Average ratio of ; f. One day after application, a mean C of dextrorphan of 2 ng / ml or less (e.g., 2 ng / ml or less, 1 ng / ml or less, or 0.5 ng / ml or less) max ; g. Mean AUC of dextrorphan of 10 ng*h / ml or less (e.g., 10 ng*h / ml or less, or 5 ng*h / ml or less) one day after application 0-24 ; h. One day after application, a C of dextromethorphan of at least about 5 (at least about 10, at least about 15, at least about 20) max C against dextrorphan max the average ratio of i. an AUC of dextromethorphan of at least about 5 (at least about 10, at least about 15, at least about 20, or at least about 25) at day 1 after application;0-24 AUC vs. dextrorphan 0-24 Average ratio of The method according to any one of the preceding claims, wherein one or more of the following results: 12. The application results in the following pharmacokinetic profile in the human subject: a. 7 days after application, a mean C of at least about 8 ng / ml (e.g., about 8 ng / ml to about 20 ng / ml) of dextromethorphan max and b. A mean C of dextrorphan of 2 ng / ml or less (e.g., 2 ng / ml or less, 1 ng / ml or less, or 0.5 ng / ml or less) 7 days after application max , The method of embodiment B11, wherein one or both of: 13. The method of embodiment B11 or embodiment B12, wherein the human subject is not suffering from a cough and / or does not require antitussive medication. 14. The method of any one of embodiments B11-13, wherein the human subject is characterized as an extensive metabolizer. 15. The mean C of dextromethorphan observed from orally administering a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily for 7 days to the human subject using the patch, when measured 7 days after application. max At least about 30% (e.g., about 30% to about 80%) of the mean C of dextromethorphan max The method of any one of embodiments B11 to B14, wherein 16. The mean AUC of dextromethorphan observed from administering orally to the human subject a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily for 7 days using the patch, when measured 7 days after application. 0-24 At least about 30% (e.g., about 30% to about 80%) of the mean AUC of dextromethorphan 0-24 The method of any one of embodiments B11 to B15, wherein 17. The mean C of dextromethorphan observed from administering a combination of 20 mg of dextromethorphan and 10 mg of quinidine orally twice daily for 7 days to the human subject using the patch, when measured 7 days after application. max About 50% or less (e.g., about 10% to about 30%) of the mean C of dextrorphan max The method of any one of embodiments B11-16, wherein 18. The mean AUC of dextromethorphan observed from administering orally to the human subject a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily for 7 days using the patch, when measured 7 days after application. 0-24 About 50% or less (e.g., about 10% to about 30%) of the mean AUC of dextrorphan 0-24 The method of any one of embodiments B11 to B17, wherein 19. The method of any one of embodiments B11-18, wherein the human subject suffers from an emotion dysregulation disorder. 20. The method of any one of embodiments B11-19, wherein the transdermal delivery device comprises from about 50 mg to about 700 mg of dextromethorphan. 21. A method of treating a disease or disorder in a subject in need thereof, comprising applying to the skin of the subject once daily a transdermal delivery device comprising dextromethorphan, wherein said applying results in one or more of the pharmacokinetic profiles described in embodiments B1, B3-7, and B9, and wherein the disease or disorder is any of those described herein. 22. The method of embodiment B21, wherein said disease or disorder is a neurological disease or disorder, such as an emotional dysregulation disorder. 23. A method of treating a disease or disorder in a subject in need thereof, comprising applying a transdermal delivery device comprising dextromethorphan to the skin of the subject once per week, or two, three, four, five, or six times per week, wherein said applying results in one or more of the pharmacokinetic profiles described in embodiments B11-12 and B15-18, and wherein said disease or disorder is any of those described herein. 24. The method of embodiment 21, wherein the disease or disorder is a neurological disease or disorder, such as an emotional dysregulation disorder. 25. The method of any one of embodiments B1 to B24, wherein the transdermal delivery device is selected from the transdermal delivery devices described in any of embodiments A1 to A38, C1 to C21, and those set forth in

[18] to

[35] in the Summary of the Invention. 26. The method of any one of embodiments B1-24, wherein the transdermal delivery device comprises an adhesive layer having the same or substantially the same components as those in formulation A, B, C1, C2, C3, D0, D1, D2, or E1 in the preceding examples.

[0146] Exemplary embodiments C1 to C32 Non-limiting exemplary embodiments C1 to C32 are shown below. 1. A transdermal delivery device comprising an adhesive layer comprising dextromethorphan dispersed in an adhesive comprising an acrylate adhesive and a silicone adhesive, The transdermal delivery device, wherein the weight ratio of the acrylate adhesive to the silicone adhesive ranges from about 20:1 to about 1:20. 2. The transdermal delivery device of embodiment C1, wherein the weight ratio of the acrylate adhesive to the silicone adhesive is in the range of about 10:1 to about 1:10 (e.g., about 10:1, about 4:1, about 1:1, about 1:4, or any range between the recited values). 3. When tested in vitro using human cadaver skin, the drug has a saturation of at least about 200 μg / cm 24 hours after application. 2 (For example, about 200ug / cm 2 ~About 2000ug / cm2 The transdermal delivery device of embodiment C1 or embodiment C2, wherein the transdermal delivery device is configured to provide an average cumulative permeation of dextromethorphan of 1000 kJ / kg. 4. In vitro testing using human cadaver skin demonstrated a dose of at least approximately 5 μg / cm from 8 to 24 hours after application. 2 *h (e.g., about 5ug / cm 2 *h~about 20ug / cm 2 *h, about 10ug / cm 2 *h~about 18ug / cm 2 *The transdermal delivery device of any one of embodiments C1-3, configured to provide an average flux of dextromethorphan of h). 5. The transdermal delivery device of any one of embodiments C1-4, wherein the adhesive layer further comprises a skin permeation enhancer in an amount to provide an average cumulative permeation of dextromethorphan at 24 hours after application that is at least about 25% (e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any range between said recited values) greater than the average cumulative permeation of dextromethorphan of an otherwise equivalent transdermal delivery device but that does not contain the skin permeation enhancer, when tested in vitro using human cadaver skin. 6. The transdermal delivery device of any one of embodiments C1-5, wherein the adhesive layer comprises a skin permeation enhancer in an amount to provide an average flux of dextromethorphan from 8 to 24 hours after application that is at least about 25% (e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any range between the recited values) greater than the average flux of dextromethorphan of an otherwise equivalent transdermal delivery device that does not contain the skin permeation enhancer, when tested in vitro using human cadaver skin. 7. The transdermal delivery device of any one of embodiments C1-6, wherein the adhesive layer comprises a skin permeation enhancer in an amount to provide an average flux of dextromethorphan from 4 to 8 hours after application that is at least about 2 times (e.g., about 3 times, about 4 times, about 5 times, about 8 times, about 10 times, or any ranges between the recited values) the average flux of dextromethorphan of an otherwise equivalent transdermal delivery device that does not contain the skin permeation enhancer, when tested in vitro using human cadaver skin. 8. The transdermal delivery device of any one of embodiments C1-7, wherein the adhesive layer comprises a skin permeation enhancer in an amount to provide an average flux of dextromethorphan from 0 to 4 hours after application that is at least about 5 times (e.g., about 5 times, about 8 times, about 10 times, about 20 times, or any range between the recited values) the average flux of dextromethorphan of an otherwise equivalent transdermal delivery device that does not contain the skin permeation enhancer, when tested in vitro using human cadaver skin. 9. A transdermal delivery device of any one of embodiments C1-8 suitable for 1-day, 2-day, 3-day, 4-day, 5-day, 6-day, or 7-day application. 10. At least about 200ug / cm per day 2 (For example, about 200ug / cm 2 ~About 20000ug / cm 2 The transdermal delivery device of embodiment C9 is configured to provide a dose of dextromethorphan of 100 mg / kg to a user. 11.About 5cm 2 ~about 200cm 2 The transdermal delivery device of any one of embodiments C1-10, having a size of 12.About 10cm 2 ~about 100cm 2 The transdermal delivery device of any one of embodiments C1-11, having a size of 13. A transdermal delivery device comprising an adhesive layer comprising dextromethorphan dispersed in an adhesive, The transdermal delivery device, wherein the adhesive layer comprises a skin permeation enhancer in an amount that provides an average cumulative permeation of dextromethorphan at 24 hours after application that is at least about 25% (e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any range between the recited values) greater than the average cumulative permeation of dextromethorphan from an otherwise equivalent transdermal delivery device that does not contain the skin permeation enhancer, when tested in vitro using human cadaver skin. 14. The transdermal delivery device of embodiment C13, wherein the skin permeation enhancer is in an amount that provides an average flux of dextromethorphan from 8 to 24 hours after application that is at least about 25% (e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any ranges between the recited values) greater than the average flux of dextromethorphan of an otherwise equivalent transdermal delivery device but not the skin permeation enhancer, when tested in vitro using human cadaver skin. 15. The transdermal delivery device of embodiment C13 or embodiment C14, wherein the skin permeation enhancer is in an amount to provide an average flux of dextromethorphan from 4 to 8 hours after application that is at least about 2 times (e.g., about 3 times, about 4 times, about 5 times, about 8 times, about 10 times, or any ranges between the recited values) the average flux of dextromethorphan of an otherwise equivalent transdermal delivery device but not including the skin permeation enhancer, when tested in vitro using human cadaver skin. 16. The transdermal delivery device of any one of embodiments C13-15, wherein the skin permeation enhancer is in an amount that provides an average flux of dextromethorphan from 0 to 4 hours after application that is at least about 5 times (e.g., about 5 times, about 8 times, about 10 times, about 20 times, or any range between the recited values) the average flux of dextromethorphan of an otherwise equivalent transdermal delivery device but not the skin permeation enhancer, when tested in vitro using human cadaver skin. 17. A transdermal delivery device of any one of embodiments C13-16 suitable for 1-day, 2-day, 3-day, 4-day, 5-day, 6-day, or 7-day application. 18. At least about 200ug / cm per day 2 (For example, about 200ug / cm 2 ~About 2000ug / cm 2 The transdermal delivery device described in embodiment C17, wherein the transdermal delivery device is configured to provide the user with dextromethorphan in an amount of 1000 mg / kg or more. 19. Approximately 5cm 2 ~about 200cm 2 The transdermal delivery device of any one of embodiments C13-18, having a size of 20.About 10cm 2 ~about 100cm 2 The transdermal delivery device of any one of embodiments C13-19, having a size of 21. The skin permeation enhancer is selected from the group consisting of isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, and a carbon chain length of C 12 ~C 18 The transdermal delivery device of any one of embodiments C13-20, wherein the hydroxybenzoates are selected from the group consisting of hydroxybenzoates, ... 22. A method of administering dextromethorphan to a subject in need thereof, comprising applying a transdermal delivery device to the skin of the subject, the transdermal delivery device comprising an adhesive layer, the adhesive layer comprising dextromethorphan dispersed in an adhesive, and a skin permeation enhancer in an amount such that the application results in an average cumulative dextromethorphan permeated 24 hours after application that is at least about 25% (e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any range between the recited values) greater than the average cumulative dextromethorphan resulting from application of an otherwise equivalent transdermal delivery device without the skin permeation enhancer. 23. The method of embodiment C22, wherein the skin permeation enhancer is in an amount such that the application results in an average flux of dextromethorphan from 8 to 24 hours after application that is at least about 25% (e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any range between the recited values) greater than the average flux of dextromethorphan resulting from application of an otherwise equivalent transdermal delivery device that does not contain the skin permeation enhancer. 24. The method of embodiment C22 or embodiment C23, wherein the skin permeation enhancer is in an amount such that the application results in an average flux of dextromethorphan from 4 to 8 hours after application that is at least about 2 times (e.g., about 3 times, about 4 times, about 5 times, about 8 times, about 10 times, or any range between the recited values) the average flux of dextromethorphan resulting from application of an otherwise equivalent transdermal delivery device that does not contain the skin permeation enhancer. 25. The method of any one of embodiments C22-24, wherein the skin permeation enhancer is in an amount such that the application results in an average flux of dextromethorphan from 0 to 4 hours after application that is at least about 5 times (e.g., about 5 times, about 8 times, about 10 times, about 20 times, or any range between the recited values) the average flux of dextromethorphan resulting from application of an otherwise equivalent transdermal delivery device that does not contain the skin permeation enhancer. 26. The method of any one of embodiments C22-25, wherein the transdermal delivery device is applied once daily for one or more days (e.g., 1, 2, 3, 4, 5, 6, or 7 days or more). 27. At least about 200ug / cm per day 2 (For example, about 200ug / cm 2 ~About 20000ug / cm 2 The method of embodiment C26, wherein dextromethorphan of 28. The transdermal delivery device is about 5 cm 2 ~about 200cm 2The method of any one of embodiments C22 to C27, having a size of 29. The transdermal delivery device is about 10 cm 2 ~Approx. 100cm 2 The method of any one of embodiments C22 to C28, having a size of 30. The skin permeation enhancer is selected from the group consisting of isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, and a carbon chain length of C 12 ~C 18 The method of any one of embodiments C22 to C29, wherein the fatty acid is selected from other fatty acids and fatty acid esters, and combinations thereof. 31. A method of administering dextromethorphan to a subject in need thereof, comprising applying a transdermal delivery device to the skin of the subject, wherein the transdermal delivery device is configured to have flux characteristics such that said application transdermally delivers between about 2 mg / day and about 50 mg / day of dextromethorphan to the subject. 32. The method of embodiment C31, wherein the transdermal delivery device is configured to have flux characteristics such that the application transdermally delivers about 5 mg / day to about 50 mg / day (e.g., about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, or any ranges between the recited values) of dextromethorphan to the subject for one or more days (e.g., 1.5 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or any ranges between the recited values). [Example]

[0147] Example 1. Preparation of a dextromethorphan transdermal patch This example demonstrates one procedure for preparing a dextromethorphan drug-in-adhesive patch. Dextromethorphan base is generally commercially available. Alternatively, dextromethorphan base can be prepared by converting dextromethorphan hydrobromide to the free base using, for example, a 1:1 molar ratio of NaOH.

[0148] Formulation A was prepared using an acrylate adhesive without a skin permeation enhancer. In a 150 mL beaker, 10 g of ethyl acetate was added, followed by 2.5 g of DXM. The blend was mixed to dissolve the DXM. While mixing, the blend was added to 50 g of DuroTak 87-2287 (Henkel Adhesives), an acrylic PSA with 50.5% solids. The contents of the batch were mixed for 30 minutes or until the contents were uniform. The resulting wet solution was then cast onto a release liner (Loparex Corp.) using a 10 mil casting applicator. The casting was dried in a forced air oven at 80°C for 10 minutes. After drying, the dried casting was laminated to a patch backing film, Scotchpak 1012 (3 M Drug Delivery Systems). The patch was then coated to a 30 cm 2 The resulting transdermal patches had an adhesive matrix thickness of 2.5 mil (approximately 180 mg adhesive matrix weight per patch) and contained 9% DXM. HPLC analysis confirmed that the patches contained approximately 16 mg DXM. The patches had good skin adhesion and adhered tightly to the skin for over 48 hours. The patches were die-cut and mounted in Franz cells for skin permeation testing. No crystals were observed on the patches for 6 months at 25°C, indicating good stability of the transdermal patch formulation.

[0149] Formulation B uses a silicone adhesive without a skin permeation enhancer. In a 150 mL beaker, 10 g of ethyl acetate was added, followed by 2.5 g of DXM. The blend was mixed to dissolve the DXM. While mixing, the blend was added to 50 g of a silicone PSA, Bio-PSA DC7-4502 (Dow Corning), 60.0% solids. The contents of the batch were mixed for 30 minutes or until the contents were uniform. The resulting wet solution was cast onto a fluoropolymer-coated release liner (3M 1022) using a 15 mil casting applicator. The casting was dried in a forced air oven at 80°C for 10 minutes. After drying, the dried casting was laminated to a patch backing film, Scotchpak 1012 (3M Drug Delivery Systems). The patch was then coated to a 30 cm 2 The resulting transdermal patch had an adhesive matrix thickness of 3.5 mils. The patch had good skin adhesion and adhered tightly to the skin for more than 48 hours. The patch was die-cut and mounted in a Franz cell for skin permeation testing. No crystals were observed on the patch at 25°C for 6 months, indicating good stability of the transdermal patch formulation.

[0150] Formulation C was prepared using a mixture of acrylate adhesive and silicone adhesive, without a skin permeation enhancer, and maintaining the dextromethorphan concentration at 9%. Following the same procedure as above, three formulations, Formulations C1-C3, were prepared using silicone / acrylic PSA blends in ratios of 54 / 46, 18 / 82, and 9 / 91, respectively.

[0151] Preparation of Formulation D Following the same procedure as above, formulations containing various amounts of permeation enhancers were also prepared. Formulation D1 contained 7.7% isopropyl myristate, and formulation D2 contained 10% isopropyl myristate. As a control, formulation D0 was also prepared without isopropyl myristate.

[0152] Table 1 below summarizes the weight percentages of the ingredients of the different formulations prepared above. (The percentages in the table refer to dry weight.)

[0153] TIFF0007798361000003.tif46165

[0154] Preparation of Formulation E Formulations containing a crystallization inhibitor were also prepared using the same procedure as above. Formulation E1 contained, by dry weight, approximately 10% dextromethorphan base, approximately 10% isopropyl myristate, approximately 70% polyacrylate adhesive (DuroTak 387-2287), and approximately 10% crystallization inhibitor Plasdone K-29 / 32 (polyvinylpyrrolidone). These ingredients were blended with isopropanol to form a homogeneous solution. This wet formulation contained the following ingredients: approximately 63.1% polyacrylate adhesive (DuroTak 387-2287, approximately 50% solids), approximately 4.5% Plasdone K-29 / 32 (polyvinylpyrrolidone), approximately 4.5% isopropyl myristate, approximately 4.5% dextromethorphan base, and approximately 23.4% isopropyl alcohol. This wet formulation was cast onto a release liner (3MilPET8310, silicone-coated polyester film) and allowed to dry. The dried casting was then laminated onto a patch backing film, Scotchpak 9733 PET film. The patch was die-cut to the desired size. In one example, this formulation was used to produce a patch containing, for example, about 56 mg of dextromethorphan base, about 70 cm 2 Transdermal patches measuring 100 μg / ml were prepared.

[0155] Example 2. Transdermal flux test The transdermal flux of dextromethorphan from the patch was tested using human cadaver skin by the Franz diffusion cell method.

[0156] Patch formulations A, B, and C prepared in Example 1 were used in skin permeation studies using the following protocol: Franz Cell Assembly - Logan Instruments (6-cell unit) Each cell has a volume of 12 mL and an orifice with a diameter of 1.5 cm. The receptor medium is phosphate buffer solution (PBS) pH 7.4 Maintain cell temperature at 37°C Sampling method: Take 1.5 mL for HPLC assay, empty the cell, and replace with fresh medium. Sampling time points: 4 hours, 8 hours, 12 hours, 24 hours, and 48 hours Cadaver skin was used and obtained from the New York Fire Fighters Skin Bank. Skin number MM07116, Caucasian, 58 years old, male, skin location: left hind leg. · Media assay method: HPLC based.

[0157] The test results for Formulations A and B are shown in Table 1 below (see also Figure 1). Skin permeation studies were carried out for up to 48 hours (2 days). The values ​​presented are for permeation depths of 1 cm. 2 The cumulative amount of DXM permeated per 100 μg / cm 2 )

[0158] TIFF0007798361000004.tif62165

[0159] The test results for formulations C1 to C3 are shown in Table 3 below (see also Figure 2). Skin permeation experiments were carried out for up to 7 days. The values ​​presented are for 1 cm 2 The cumulative amount of DXM permeated per 100 μg / cm 2 )

[0160] TIFF0007798361000005.tif76165

[0161] Example 3A. Dextromethorphan Transdermal Patch with Permeation Enhancer Formulations D0-D2 were also tested for their in vitro skin flux properties following the same protocol as described in Example 2. The results are shown in Table 4A (see also Figure 3A).

[0162] TIFF0007798361000006.tif31165

[0163] The results clearly show that increasing the level of IPM up to 10% significantly enhances the skin permeation of DXM.

[0164] Example 3B. Dextromethorphan Transdermal Patch with Plasdone (PVP) Formulation E1 was also tested for its in vitro skin flux properties using dermatome-harvested human cadaver skin. Apparatus: Vertical diffusion cell Skin type: Human cadaver skin (dermatome harvest) Dosing area: 1.767cm 2 (1 cm diameter opening of the diffusion cell) Diffusion cell volume: 12 mL Acceptor medium: Phosphate buffered saline pH 7.4 Medium temperature: 37℃±1.0℃ Sampling intervals: 4 hours, 8 hours, 24 hours, and 48 hours Sampling volume: 1.5 to 2.0 mL

[0165] The permeability of formulation E1 was tested according to the protocol described in Example 2. The amount of drug permeated into the receptor compartment per unit area (i.e., μg / cm) (calculated from the concentration of drug permeated in each cell) at various time points was measured. 2 ) to report.

[0166] The results are shown in Table 4B (see also Figure 3B).

[0167] TIFF0007798361000007.tif41165

[0168] It was surprising to observe that the in vitro permeation of dextromethorphan was significantly enhanced by the addition of plasdone. According to Example 3A, the same formulation without plasdone achieved a 24-hour flux of approximately 334 μg / cm. 2Thus, the incorporation of Plasdone more than doubled the cumulative in vitro permeation of dextromethorphan over 24 hours. Both studies were performed on freshly prepared patches. This permeation enhancement was also observed in in vivo studies (see Example 4).

[0169] Example 4. In vivo pharmacokinetic studies Example 4A. Single-Dose Pharmacokinetic Study This example describes an open-label, randomized, two-treatment, two-period, two-sequence crossover study conducted in 16 healthy adult men and women to evaluate the relative bioavailability of an experimental dextromethorphan patch (15 mg / 24 hr) compared to that of NUEDEXTA® (dextromethorphan hydrobromide and quinidine sulfate) capsules, 20 mg / 10 mg (Avanir Pharmaceuticals, Inc.) under fasting conditions. All 16 subjects in this study were genotyped to determine their CYP2D6 genotype. All 16 subjects can be characterized as extensive metabolizers of dextromethorphan. For example, see Treducu ALD et al., Frontiers in Pharmacology, Vol. 9, Article 305 (April 2018), where subjects were assigned as UM if they contained "three or more copies of the normal functioning gene" based on genotype.

[0170] This study measured the pharmacokinetic profiles of both dextromethorphan and dextrorphan (one of the metabolites of dextromethorphan).

[0171] During one period of the study, one dextromethorphan patch, 45 cm, containing 35 mg of DXM 2A patch, a drug-in-adhesive patch with a DIA layer containing approximately 80% adhesive (Duro-Tak 87-2287) by weight, approximately 10% dextromethorphan base by weight, and approximately 10% permeation enhancer isopropyl myristate by weight, designed to transdermally deliver approximately 15 mg / 24 hours, was applied to the lateral left upper arm of healthy subjects for 24 hours after at least a 10-hour overnight fast. In another study period, one NUEDEXTA® (dextromethorphan hydrobromide and quinidine sulfate) capsule, 20 mg / 10 mg, was administered every 12 hours (at hours 0 and 12) (for a total dose of 40 mg / 20 mg over 24 hours) after at least a 10-hour overnight fast (hour 0).

[0172] For NUEDEXTA treatment, subjects fasted overnight for at least 10 hours only before the 0-hour dose. The dosing sequence followed a two-stage randomization schedule. Blood samples were collected pre-dose and at intervals of 96 hours after study drug administration (0 hours) in each study period. Subjects were confined to the clinical facility from at least 10 hours before dosing (0 hours) until after the 36-hour blood sample collection in each study period, and returned to the clinical facility for blood sample collection at 48 hours, 72 hours, and 96 hours. The dosing (0 hours) interval was at least 10 days.

[0173] Plasma concentrations of dextromethorphan and its active metabolite, dextrorphan, were measured by well-validated analytical procedures. Statistical analysis using mean bioequivalence methodology was performed to evaluate the bioavailability of the test formulations relative to the dextromethorphan and dextrorphan-only reference products.

[0174] The study design was based on the known pharmacokinetics of NUEDEXTA® (dextromethorphan hydrobromide and quinidine sulfate) capsules, the FDA draft guidance for dextromethorphan hydrobromide and quinidine sulfate capsules, and generally accepted standards of practice for conducting bioavailability / bioequivalence studies under fasting conditions and adherence testing. A washout period of at least 10 days was selected for this study to minimize potential carryover effects.

[0175] This study was also designed to minimize potential drug-drug interactions that could affect the results of this study. For example, subjects were screened and monitored for the use of medications such as MAO inhibitors, tricyclic antidepressants, SSRIs, drugs implicated in TdP or cardiac arrhythmias, and inducers or inhibitors of CYP3A4 or CYP2D6.

[0176] Pharmacokinetic results Blood samples were collected (relative to the dose) at the following time points: pre-dose (hour 0) and 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 9.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 20.0, 24.0, 24.5, 25.0, 26.0, 30.0, 36.0, 48.0*, 72.0*, and 96.0* hours post-dose (*return samples). Samples were then processed and analyzed for both dextromethorphan and dextrorphan concentrations using validated analytical methods. SAS®, version 9.4 or later, was used for all pharmacokinetic and statistical calculations.

[0177] Tables 5A-5D show the results of this study. Tables 5A and 5C show the plasma concentrations of dextromethorphan and dextrorphan, respectively, in subjects who received oral administration of NUEDEXTA (reference) twice daily. Tables 5B and 5D show the plasma concentrations of dextromethorphan and dextrorphan, respectively, in subjects who received 24-hour treatment with a dextromethorphan patch.

[0178] TIFF0007798361000008.tif196165

[0179] TIFF0007798361000009.tif198165

[0180] TIFF0007798361000010.tif201165

[0181] TIFF0007798361000011.tif192165

[0182] Based on this study, subjects treated with the DXM patch had an observed AUC of DXM with patch treatment. 0-24 , AUC 0-t , and C max It was also unexpectedly revealed that the ratios of DXM to DRP observed with patch treatment were significantly higher than the respective ratios observed with NUEDEXTA treatment. For example, the AUC of DXM to DRP observed with patch treatment was significantly higher than the respective ratios observed with NUEDEXTA treatment. 0-24 The mean ratio of 24.54:9.03 was nearly three times the mean ratio observed with the NUEDEXTA treatment, see Table 6 below.

[0183] TIFF0007798361000012.tif177165

[0184] 4A and 4B show graphs of dextromethorphan and dextrorphan concentrations from 0 to 96 hours.

[0185] Example 4B. Multiple-Dose Pharmacokinetic Study This example describes an open-label, randomized, multi-dose, two-treatment, two-period, two-sequence crossover study conducted in 20 healthy adult men and women to evaluate the bioavailability of an experimental dextromethorphan patch (35 mg / 24 hr) (where applicable, one patch applied / replaced every 24 hours for 7 days (7 times) on Days 1 through 7 [final application on the morning of Day 8]) compared with that of NUEDEXTA® (dextromethorphan hydrobromide and quinidine sulfate) capsules, 20 mg / 10 mg (Avanir Pharmaceuticals, Inc.; one capsule administered every 12 hours for 7 days (14 times) on Days 1 through 7 for a total daily dose of 40 mg / 20 mg over 24 hours). The experimental dextromethorphan patch had a drug-containing adhesive layer according to Formulation E1. Each test dextromethorphan patch contained approximately 56 mg of dextromethorphan base, approximately 392 mg of Duro-Tak polyacrylate (Duro-Tak 387-2287) adhesive, approximately 56 mg of Plasdone K-29 / 32, and approximately 56 mg of isopropyl myristate, and measured approximately 70 cm. 2 It is the size of.

[0186] Both dextromethorphan and dextrorphan were measured in this study.

[0187] During one period of the study, subjects received Treatment A, where applicable, with 1x study dextromethorphan patch 35 mg / 24 hr applied / replaced every 24 hours for 7 days (7 times) on days 1 through 7 (with final patch removal on the morning of day 8). Time 0 on day 1 was administered after an overnight fast of at least 10 hours, and subsequent doses were administered after a fast of at least 6 hours. Blood samples were collected before each patch application, at 24-hour intervals after patch application on days 1 and 7, and at 72-hour intervals after patch removal on day 7.

[0188] In another study period, subjects received Treatment B, which consisted of one 20 mg / 10 mg capsule of NUEDEXTA® (dextromethorphan hydrobromide and quinidine sulfate) every 12 hours for 7 days (14 doses) on Days 1 through 7 (total daily dose of 40 mg / 20 mg, equivalent to 29.31 mg of dextromethorphan base over a 24-hour period). The Time 0 dose on Day 1 was administered after an overnight fast of at least 10 hours, with subsequent doses administered after at least a 4-hour fast. Blood samples were collected prior to the Time 0 dose on Day 1, at intervals throughout the first 12-hour dosing interval on Day 1, prior to the morning (Time 0) and evening (12-hour) doses on Days 5 and 6, prior to the morning (Time 0) dose on Day 7, and over two 12-hour dosing intervals on Day 7 (i.e., 24 hours after the morning dose on Day 7).

[0189] Subjects were confined to the clinical facility for each study period from at least 10 hours prior to the 0-hour dose on Day 1 until at least 36 hours after the 0-hour dose on Day 7 (i.e., 180 hours after the 0-hour dose on Day 1). Subjects receiving Treatment A returned to the clinical facility for blood sample collection at 48, 72, and 96 hours. The interval between the last dose in Period I and the first dose in Period II was 16 days.

[0190] Plasma concentrations of dextromethorphan and its active metabolite, dextrorphan (unconjugated), were measured using a well-validated analytical procedure. After 7 days of administration of the two medications, statistical analysis was performed using analysis of variance (ANOVA) techniques to assess the bioavailability of the test formulations relative to the reference product on day 7.

[0191] The patch was applied to the subject's upper outer arm, anterior chest, or upper back. The patch was removed 24 hours (±5 minutes) after application.

[0192] Pharmacokinetic sample collection Treatment A: On Day 1, 7 mL of venous blood was collected in a chilled K3EDTA vacutainer within 60 minutes prior to patch application at time 0 and at 1.0, 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, 14.0, 16.0, 18.0, 20.0, 22.0, and 23.0 hours after patch application. On Day 2, a predose sample was collected before patch application†. This sample corresponded to the 24.0-hour sample on Day 1. On Days 3 through 6, predose samples were collected before each patch application†. On Day 7, pre-dose samples were collected within 5 minutes before patch application and at 1.0, 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, 14.0, 16.0, 18.0, 20.0, 22.0, 23.0, 24.0 (within 5 minutes before patch removal), 24.5, 25.0, 26.0, 28.0, 30.0, 32.0, 36.0, 48.0*, 72.0*, and 96.0* hours post-dose (*return samples). †Samples are collected immediately before each dose with a -5-minute margin to accommodate dosing activity, if necessary.

[0193] Treatment B: On Day 1, 7 mL of venous blood was collected in chilled K3EDTA vacutainers within 60 minutes before the 0-hour AM dose and at 1.0, 2.0, 3.0, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0, 8.0, 10.0, and 12.0 hours post-dose. On Days 5 and 6, pre-dose samples were collected before each dose administration (0-hour and 12-hour doses on Days 5 and 6). On Day 7, pre-dose samples were collected within 5 minutes pre-dose and at 1.0, 2.0, 3.0, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 12.0 hours post-dose. On Day 7, pre-dose samples were collected within 5 minutes pre-dose and at 1.0, 2.0, 3.0, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 12.0 hours, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 20.0, and 24.0 hours post-dose. †Samples are collected immediately prior to each dose, with a -5 minute tolerance to accommodate dosing activity if necessary.

[0194] All times are relative to the dose. After collection, samples were processed and analyzed. Pharmacokinetic and statistical services performed all pharmacokinetic and statistical calculations using SAS®, version 9.4 or later.

[0195] The following pharmacokinetic parameters were determined for each subject and each analyte for the test and reference articles: AUC 0-12,D1 : Area under the plasma concentration-time curve from time zero (0) to the end of the 12-hour morning dosing interval on Day 1 after the first dose of Treatment B AUC 0-24,D1 : Area under the plasma concentration-time curve from time zero (0) to the end of the 24-hour dosing interval on Day 1 after the first dose of Treatment A AUC 0-12,D7 : Area under the plasma concentration-time curve from time zero (0) to the end of the 12-hour morning dosing interval on Day 7 of Treatment B AUC 0-24,D7 : Area under the plasma concentration-time curve over two 12-hour dosing intervals, from time zero (0) to the end of the 24-hour dosing interval on Day 7 for Treatment A and from the morning (0 hour) dose to the end of the 12-hour afternoon dosing on Day 7 for Treatment B. AF 治療A : Accumulation rate of Treatment A Treatment A (AUC 0-24,D7 AUC 0-24,D1 (divided by AF 治療B : Accumulation rate of Treatment B Treatment B (AUC 0-12,D7 AUC 0-12,D1 (divided by C avg,D7 :AUC 0-24,D7 Observed mean plasma concentrations on day 7 calculated as / 24 hours C max,D1 : Maximum observed plasma concentration on Day 1 across the 24-hour dosing interval for Treatment A and the first 12-hour dosing interval for Treatment B C max,D7 : Maximum observed plasma concentration on day 7 C min,D7 :Minimum observed plasma concentration on day 7 C pre,Dx : Plasma concentrations observed in the morning and afternoon on days 1 to 7, where x = 1 to 7 refers to Treatment A and x = 1M, 5M, 5E, 6M, 6E, 7M, 7E (M = morning, and E = afternoon) refers to Treatment B. C 12,D1 Predose plasma concentrations observed at the end of the first 12-hour dosing interval for Treatment B on Day 1 C24,D7 : The plasma concentration fluctuation observed at the end of the last dosing interval (i.e., 24 hours after patch application on Day 7 for Treatment A, and 12 hours after the 12-hour afternoon dose on Day 7, which is 24 hours after the midnight dose on Day 7 for Treatment B): [(C max,D7 -C min,D7 ) / C avg,D7 ] is calculated as Variability: [(C max,D7 -C min,D7 ) / C ave,D7 On day 7, treatment B had C max,D7 and C min,D7 and may result in different dosing intervals. Amplitude rate: [(C max,D7 -C min,D7 ) / C min,D7 On day 7, treatment B had a C max,D7 and C min,D7 and may result in different dosing intervals. T max,D1 : Time to reach maximum observed plasma concentration on Day 1 over a 24-hour dosing interval for Treatment A and over the first 12-hour dosing interval for Treatment B T max,D7 : Time to reach maximum observed plasma concentration on day 7 λ z,D7 Apparent first-order terminal elimination rate constant after the last dose on day 7 (Treatment A only) t 1 / 2,D7 Apparent terminal elimination half-life after the last dose on Day 7 (Treatment A only) MR Dx Metabolic ratio, treatment A on day 1 (MR D1 ) and Day 7 (MR D7 ) Dextromethorphan AUC 0-24 and dextrorphan AUC 0-24 In Treatment B, the ratio of D1 ) and Day 7 (MR D7 ) Dextromethorphan AUC 0-12 and dextrorphan AUC 0-12 It is expressed as the ratio of ;MR D7 / MR D1 Ratio is MR D7 / D1 Expressed as CLTD Apparent transdermal clearance (CL) of dextromethorphan on day 7 of treatment A TD =CL / F=Dose / AUC 0-24,D7 , but dose = 35 mg) CLo Apparent oral clearance of dextromethorphan on day 7 of Treatment B (CLo = CL / F = dose / AUC 0-12,D7 , where dose = 14.66 mg, and = dose / AUC 0-24,D7 , where dose = 2 x 14.66 mg)

[0196] Summary tables of arithmetic means (untransformed) of pharmacokinetic parameters are shown in Table 7 for dextromethorphan and Table 8 for dextrorphan. Geometric means, ratios of geometric means, their associated 90% confidence intervals, and within-subject CV (ISCV%) values ​​based on ANOVA (ln-transformed) are shown in Table 9 for dextromethorphan and Table 10 for dextrorphan. Analysis results for steady-state assessment by Helmert contrasts are shown in Table 11 for dextromethorphan and Table 12 for dextrorphan.

[0197] In Treatment A (Study A, patch), mean plasma concentrations of dextromethorphan increased over 16 hours after initial patch application, after which concentrations averaged C max,D1 of 10990 pg / mL (median T max,D1The concentration remained near 18.0 hours after application, with little fluctuation until patch removal at 24 hours after application. In most subjects, concentrations reached a plateau by 10-14 hours after administration. Concentrations stabilized by Day 3 and remained relatively constant over the next 4 days, as indicated by assessment of predose concentrations over that period using the Helmert contrast method for steady-state attainment. From Day 3 onward, the least-squares geometric mean (LSGM) ratio of morning predose dextromethorphan concentrations in the Helmert contrast was greater than 90% (p=0.0941 for Day 3 vs. Days 4-7). By Day 7, dextromethorphan concentration variability (mean variability: 0.41) and dextrorphan concentration variability (mean variability: 0.43) were small over the 24-hour application period of the final patch, with the mean peak dextromethorphan concentration reaching a median T of 11.9 hours. max,D7 The AUC accumulation ratios from days 1 to 7 were 2.1 for dextromethorphan and 2.5 for dextrorphan, similar for both analytes. After patch removal on day 8, dextromethorphan and dextrorphan concentrations decreased, with mean terminal half-lives of 17 and 18 hours, respectively.

[0198] In Treatment B (Reference B, NUEDEXTA® capsules), the mean peak dextromethorphan plasma exposure on Day 1 (9691 pg / mL) was similar to the mean peak in Study A (10990 pg / mL). However, quinidine inhibited dextromethorphan metabolism to dextrorphan to a greater extent, with a mean dextromethorphan accumulation ratio of 8.5 and a significantly lower mean dextrorphan accumulation ratio of 1.9, resulting in a metabolic AUC 0-12 The ratio is approximately 5-fold higher on day 7 compared to day 1 (i.e., the geometric mean MR D7 / MR D1 = 4.81; see Table 9), the effect of reference B was more pronounced on day 7 compared to day 1. max Similar results were observed for the data from days 1 and 7.

[0199] The maximum inhibitory effect of quinidine was observed with a mean CL of 27.0 L / hr for a 0-12 hour AM dosing interval and 26.8 L / hr for a combined 0-24 hour AM and PM dosing interval. o The values ​​were similar, and in the steady-state analysis, the morning pre-dose dextromethorphan concentration on Day 6 (C pre,D6M ) on the 7th day (C pre,D7M and C 24,D7 The LSGM ratio of 93.3% for β-hemoglobin (β) indicated that at least 90% of the theoretical steady state was achieved by day 6, indicating stabilization by day 7. The p-values ​​for the three Helmert contrasts were highly statistically significant (p<0.001; see Table 11), suggesting that steady state was not reached by day 7. However, the small residual variation in the ANOVA increased the likelihood of detecting statistically significant differences among small differences (<10%) in the Helmert contrast means.

[0200] CL o (Reference B geometric mean: 25.8 L / h) is the CL on day 7. TD This was approximately 4.4-fold lower than the geometric mean for Test A (113.9 L / h). Due to the difference in the multiple-dose characteristics of the test and reference products, the dextromethorphan bioavailability over 24 hours on Day 7 for Test A was approximately 75% lower than that for Reference B, resulting in a Test / Reference (A / B) ratio of C max,D7 is 25.56%, C 24,D7 is 27.60%, AUC 0-24,D7 All but one of the 20 subjects had low dextromethorphan concentrations in Test A on Day 7. This subject had the highest dextromethorphan concentrations in Test A on Days 1 and 7 and was a poor CYP2D6 metabolizer, as confirmed by genetic analysis.

[0201] Metabolic genotyping revealed that one subject was genetically identified as a poor CYP2D6 metabolizer, while the remaining subjects were characterized as either extensive metabolizers (N=3), heterozygous extensive metabolizers (N=13), or intermediate metabolizers (N=3).

[0202] TIFF0007798361000013.tif186165

[0203] TIFF0007798361000014.tif216165

[0204] TIFF0007798361000015.tif155165

[0205] TIFF0007798361000016.tif161165

[0206] TIFF0007798361000017.tif110165

[0207] TIFF0007798361000018.tif164165

[0208] TIFF0007798361000019.tif161165

[0209] TIFF0007798361000020.tif153165

[0210] TIFF0007798361000021.tif119165

[0211] TIFF0007798361000022.tif109165

[0212] TIFF0007798361000023.tif92165

[0213] TIFF0007798361000024.tif122165

[0214] TIFF0007798361000025.tif122165

[0215] Overall, the pharmacokinetic results indicate that drug release from the patch was consistent over 7 days, with a steady-state drug accumulation ratio of 2.1 and low fluctuations in dextromethorphan concentrations.

[0216] Due to differences in the multiple-dose characteristics of the test and reference products, the 24-hour bioavailability of dextromethorphan on Day 7 was approximately 75% lower in Test A compared to Reference B, and the test-to-reference ratio for LSGM was C. max,D7 is 25.56%, C 24,D7 is 27.60%, AUC 0-24,D7 The difference in dextromethorphan concentrations between the patch and NUEDEXTA® capsules was 26.89%. All 20 subjects except one had low dextromethorphan concentrations in Study A on Day 7. This subject had the highest dextromethorphan concentrations in Study A on Days 1 and 7 and was a phenotypically and genotypically poor CYP2D6 metabolizer. These data suggest that the relative bioavailability of dextromethorphan from the patch compared with the NUEDEXTA® capsules under multiple-dose conditions may be affected by the subject's CYP2D6 metabolizer status.

[0217] In summary, the relative bioavailability of dextromethorphan was approximately one-quarter lower after application of a 35 mg / 24-hour dextromethorphan patch once daily for 7 days compared with oral administration of 1 x 20 mg / 10 mg NUEDEXTA® (dextromethorphan hydrobromide and quinidine sulfate) capsules every 12 hours for 7 days under fasting conditions. The lower relative bioavailability from the patch compared with the oral capsule on day 7 is due to greater inhibition of dextromethorphan metabolism to dextrorphan by quinidine on day 7 compared with day 1 for the reference product.

[0218] The geometric mean CL from this study (dextromethorphan patch, 35 mg / 24 hour once-daily application on day 7, 113.9 L / h) and the study following Example 4A (dextromethorphan patch, 15 mg / 24 hour daily application, 93.4 L / h) TDBased on the similarity of the (patch) values, the pharmacokinetics of dextromethorphan from the patch appear to be linear (i.e., dose- and time-independent), whereas the pharmacokinetics of dextromethorphan from NUEDEXTA® (dextromethorphan hydrobromide and quinidine sulfate) capsules are nonlinear as a result of the time-dependent inhibition of dextromethorphan metabolism by quinidine.

[0219] CL on Day 1 in the study shown in Example 4A TD and CL o The value was a dose-normalized AUC of 1.07. 0-∞ The geometric mean ratios are very similar, implying that the total plasma exposure (AUC) of dextromethorphan should be similar for the patch and capsule over 24 hours on Day 1 at similar daily doses. o In this study, CL was administered on day 7. TD The quinidine inhibitory effect on the CYP2D6 metabolism of dextromethorphan was approximately 4.4-fold lower than that of the quinidine inhibitor. This indicates that the inhibitory effect of quinidine on the CYP2D6 metabolism of dextromethorphan is time-dependent, increasing in magnitude from Day 1 to Day 7. Thus, increasing the dose from 15 mg / 24 h to 35 mg / 24 h based on the Day 1 pharmacokinetic data from the study shown in Example 4A to achieve similar plasma exposures for the patch and capsule over the initial 24 hours of dosing, followed by a reduction in peak and total plasma exposure by approximately fourfold compared to the capsule during the subsequent multiple-dose regimen (Day 7), is not predictable given the nonlinear time-dependent pharmacokinetic properties of dextromethorphan from the capsule. Therefore, it is not possible to consistently achieve similar systemic exposures of dextromethorphan in the patch and capsule from a single dose (Day 1) to multiple doses (Day 7) without changing the patch dosing regimen.

[0220] Residual dextromethorphan analysis Dextromethorphan content in applied patches returned from clinical sites was assessed. A well-validated HPLC method was used to identify and measure dextromethorphan content in transdermal delivery systems.

[0221] Each patch was extracted by sonication without heating in the extraction solvent methanol / water, and the extracted dextromethorphan was then quantified by isocratic reverse-phase HPLC with UV detection. Elution was performed with a mobile phase containing mobile phase A:acetonitrile:methanol (80:20) and mobile phase B:water. The ratio of mobile phase A:mobile phase B was 78:22 (containing 0.1% trifluoroacetic acid). The column was a Gemini C18, 5 μm, 150 × 4.6 mm, 110 A, maintained at 40 °C, and the UV detector was set at 360 nm.

[0222] The results (Tables 13A / 13B) show that the mean residual dextromethorphan in the worn patches ranged from about 14.9 mg to about 23.6 mg. Thus, the daily delivery of dextromethorphan was about 32.4 mg to about 41.1 mg, consistent with the predicted delivery of 35 mg based on the in vitro flux data.

[0223] TIFF0007798361000026.tif94165

[0224] TIFF0007798361000027.tif89165

[0225] Example 5. Multilayer patch design In this example, a novel multi-layer design is described.

[0226] An exemplary patch design useful in embodiments herein can include a contact layer and a reservoir layer, as shown in Figure 5. The contact layer (top layer in Figure 5) can have the following components: 1) adhesive (e.g., DURO-TAK 87-2287): about 77.5% to about 75%; 2) drug (dextromethorphan base): about 10%; 3) enhancer (e.g., isopropyl myristate-IPM): about 10%; and 4) Kollidon, e.g., Kollidon VA64: about 2.5% to about 5%. The reservoir layer can have the following components: 1) adhesive (e.g., DURO-TAK 87-2287): about 57.5% to about 20%; 2) drug (dextromethorphan base): about 30% to about 50%; 3) enhancer (e.g., isopropyl myristate-IPM): about 10%; and 4) Kollidon, e.g., Kollidon VA64: about 2.5% to about 20%. The lower layer can be a backing layer or an adhesive layer similar to the upper layer. Suitable backing layers are described herein. Kollidon is a trade name for a vinylpyrrolidone polymer (e.g., vinylpyrrolidone-vinyl acetate copolymer, e.g., Kollidon VA64). Prior to application, the contact layer is typically protected with a release liner. Suitable release liners are also described herein.

[0227] In one example, a multi-layer patch may be 60 cm 2 For example, about 60 cm 2 ~Approx. 150cm 2 The size of the slit may be:

[0228] In one example, a multi-layer patch may be 70 cm 2 and is designed to contain a total of about 370 mg of dextromethorphan base. Such patches are suitable for 7-day wear and can transdermally deliver at least about 20 mg of dextromethorphan per day for 7 days (a total of at least about 140 mg delivered over 7 days).

[0229] It should be understood that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections may describe one or more, but not all, exemplary embodiments of the invention contemplated by the inventor(s), and therefore are not intended to limit the scope of the invention and the appended claims in any way.

[0230] The present invention has been described above using functional components that illustrate the implementation of specified functions and relationships thereof. The boundaries of these functional components have been arbitrarily defined herein for the convenience of description. Alternative boundaries may be defined as long as the specified functions and relationships thereof are appropriately performed.

[0231] For aspects of the invention described as genus, all individual species are considered individually as separate aspects of the invention. When an aspect of the invention is described as "comprising" a feature, the embodiment is also considered to "consist of" or "consisting essentially of" that feature.

[0232] The foregoing description of specific embodiments fully discloses the general nature of the invention, so that others, applying knowledge within the skill of the art, can readily modify and / or adapt such specific embodiments for various applications without undue experimentation and without departing from the general concept of the invention. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It should be understood that the terminology used herein is for the purpose of description rather than limitation, and may be interpreted by those skilled in the art in light of the teaching and guidance.

[0233] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0234] All of the various aspects, embodiments, and options described herein can be combined in any and all variations.

[0235] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. If any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall control.

Claims

1. A transdermal patch for treating a neurological disease or disorder in a subject in need thereof, the transdermal patch being used by being attached to the subject, the transdermal patch comprising: a. a backing layer; b. a drug-in-adhesive layer comprising: (1) dextromethorphan in an amount of 6% to 12% by weight; (2) isopropyl myristate in an amount of 6% to 12% by weight; (3) a pressure-sensitive adhesive in an amount of 65% to 80% by weight; and (4) a crystallization inhibitor in an amount of 6% to 12% by weight. Including, The transdermal patch is 30 cm ２ ~100cm ２ and having an effective surface area of the pressure sensitive adhesive is a polyacrylate vinyl acetate copolymer pressure sensitive adhesive having non-acidic hydroxyl functional groups; The crystallization inhibitor is a vinylpyrrolidone homopolymer. The transdermal patch.

2. 10. The transdermal patch of claim 1, wherein the pressure sensitive adhesive is a random copolymer of the following monomers: 2-ethylhexyl acrylate, vinyl acetate, hydroxyethyl acrylate, and glycidyl methacrylate.

3. 3. The transdermal patch of claim 1, wherein the drug-containing adhesive layer comprises a crystallization inhibitor in an amount of 8% to 12% by weight.

4. 4. The transdermal patch of claim 3, wherein the crystallization inhibitor is a vinylpyrrolidone homopolymer having a nominal K value of 25-35.

5. 5. The transdermal patch of any one of claims 1 to 4, wherein the drug-in-adhesive layer comprises: 1) 20 mg to 100 mg of dextromethorphan; 2) 30 mg to 100 mg of isopropyl myristate; 3) 150 mg to 900 mg of the pressure-sensitive adhesive; and 4) the crystallization inhibitor in an amount of 30 mg to 100 mg.

6. The transdermal patch of any one of claims 1 to 5, wherein the drug-containing adhesive layer contains dextromethorphan as the sole active ingredient.

7. 7. The transdermal patch of any one of claims 1 to 6, wherein the transdermal patch is applied to transdermally deliver a daily dose of 15 mg to 50 mg of dextromethorphan to the subject.

8. 8. The transdermal patch of any one of claims 1 to 7, wherein the neurological disease or disorder is emotional dysregulation, depression, stroke, traumatic brain injury, seizures, pain, methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof.

9. A transdermal patch described in any one of claims 1 to 8, further comprising an antidepressant.

10. A transdermal patch for treating a neurological disease or disorder in a subject in need thereof, the transdermal patch being applied to the subject at a dosing frequency of once daily to once weekly, the transdermal patch containing 15 mg to 700 mg of dextromethorphan, the application of which produces a therapeutically effective plasma concentration of dextromethorphan in the subject at steady state; The transdermal patch comprises: a. a backing layer; b. a drug-in-adhesive layer comprising: (1) dextromethorphan in an amount of 6% to 12% by weight; (2) isopropyl myristate in an amount of 6% to 12% by weight; (3) a pressure-sensitive adhesive in an amount of 65% to 80% by weight; and (4) a crystallization inhibitor in an amount of 6% to 12% by weight. Including, the transdermal patch has an effective surface area of ​​30 cm 2 to 100 cm 2 ; the pressure sensitive adhesive is a polyacrylate vinyl acetate copolymer pressure sensitive adhesive having non-acidic hydroxyl functional groups; The crystallization inhibitor is a vinylpyrrolidone homopolymer. The transdermal patch.

11. The transdermal patch contains 30 mg to 100 mg of dextromethorphan, and by applying the patch, a) AUC at day 7 or steady state from 180h*ng / mL to 2000h*ng / mL ０－２４，ＤＸＭ , b) C at day 7 or steady state stage of 8 ng / mL to 100 ng / mL Ａｖｇ，ＤＸＭ , c) C at day 7 or steady state stage of 6 ng / mL to 65 ng / mL ｍｉｎ，ＤＸＭ , d) C at day 7 or steady state stage of 8 ng / mL to 90 ng / mL ｍａｘ，ＤＸＭ , e) Dextromethorphan variability at day 7 or steady state stage [(C ｍａｘ -C ｍｉｎ ) / C ａｖｇ ], f) Dextromethorphan amplitude ratio [(C ｍａｘ -C ｍｉｎ ) / C ｍｉｎ ], g) AUC of 1.5 to 5 ０－２４，ＤＸＭ，Ｄ１ AUC at steady state phase ０－２４，ＤＸＭ The ratio of h) AUC at steady state from 12 to 35 ０－２４，ＤＯＲ AUC for ０－２４，ＤＸＭ The ratio of i) C at steady state stage of 12-35 ｍａｘ，ＤＯＲ C against ｍａｘ，ＤＸＭ The ratio of, and j) C at steady state stage from 12 to 35 Ａｖｇ，ＤＯＲ C against Ａｖｇ，ＤＸＭ The ratio of The transdermal patch of claim 10, wherein the transdermal patch provides the subject with a pharmacokinetic profile characterized by one or more of the following:

12. (1) For each application of the transdermal patch other than the first administration, the plasma dextromethorphan concentration before administration was determined to be equal to or greater than the mean concentration (C Ａｖｇ，ＤＸＭ ) not to be less than 20% of the (2) The dextromethorphan accumulation ratio is in the range of 1 to 5, and the subject is an extensive metabolizer or an ultra-extensive metabolizer; (3) By applying the patch, k) the half-life of dextromethorphan at steady state is reduced to 11 to 29 hours in extensive metabolizers or very extensive metabolizers, and / or l) the half-life of dextromethorphan at steady state is reduced to 0.018 hours in extensive metabolizers or very extensive metabolizers. －１ ~0.065h －１ The apparent first-order terminal elimination rate constant (λ) after the final dose after achieving a steady-state phase ｚ ), and / or (4) The transdermal patch according to any one of claims 10 to 11, wherein the application transdermally delivers a daily dose of 15 mg to 50 mg of dextromethorphan to the subject.

13. 13. The transdermal patch of any one of claims 10 to 12, wherein the neurological disease or disorder is emotional dysregulation, depression, stroke, traumatic brain injury, seizures, pain, methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof.

14. The transdermal patch is applied once daily, and the residual amount of dextromethorphan in the transdermal patch is less than 50% of the initial amount of dextromethorphan in the transdermal patch; or 14. The transdermal patch of any one of claims 1 to 13, wherein the percentage of dextromethorphan delivered to the subject is 50% to 80% of the initial amount of dextromethorphan in the patch.

15. A transdermal patch comprising: i. a backing layer; ii. a drug-in-adhesive layer comprising: 1) dextromethorphan in an amount of 2% to 12% by weight, 2) isopropyl myristate in an amount of 6% to 12% by weight, 3) a pressure-sensitive adhesive in an amount of 65% to 80% by weight, and 4) a crystallization inhibitor in an amount of 6% to 12% by weight; Including, 30 cm ２ ~100cm ２ and having an effective surface area of the pressure sensitive adhesive is a polyacrylate vinyl acetate copolymer pressure sensitive adhesive having non-acidic hydroxyl functional groups; The crystallization inhibitor is a vinylpyrrolidone homopolymer. The transdermal patch.

16. 16. The transdermal patch of claim 15, wherein the pressure sensitive adhesive is a random copolymer of the following monomers: 2-ethylhexyl acrylate, vinyl acetate, hydroxyethyl acrylate, and glycidyl methacrylate.

17. The transdermal patch of claim 15 or claim 16, wherein the crystallization inhibitor is a vinylpyrrolidone homopolymer having a nominal K value of 25-35.

Images