Dextromethorphan Transdermal Delivery Device

Abstract

To provide transdermal delivery devices containing dextromethorphan for use in the treatment of diseases or disorders such as neurological diseases, and to provide methods of preparing and using the same.SOLUTION: Provided is a method of treating a neurological disease or disorder in a human subject in need thereof, the neurological disease or disorder being pseudobulbar affect, depression, stroke, traumatic brain injury, seizure, pain, methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof, the method comprising applying a transdermal delivery device comprising dextromethorphan to the skin of the subject. The transdermal delivery device can be characterized by the novel design, for example, with an adhesive layer and a reservoir layer, with an adhesive layer comprising a mixture of two adhesives, and / or with a skin permeation enhancer, e.g., in an amount that can significantly enhance the flux of dextromethorphan.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 568,028, filed October 4, 2017, and U.S. Provisional Application No. 62 / 680,182, filed June 4, 2018, the contents of each of which are incorporated by reference in their entirety herein.

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

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

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

[0005] The most common adverse reactions in patients taking NUEDEXTA® (≥ 3%) The most common side effects (incidence and 2-fold greater than placebo) were, in order of frequency, diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, urinary tract infection, influenza, increased gamma glutamyltransferase, and flatulence. The following side effects have been reported with the use of the individual components of dextromethorphan: drowsiness, dizziness, nervousness or restlessness, nausea, vomiting, and stomach pain. Summary of the Invention

[0006] In various embodiments, the present invention is directed to novel transdermal delivery devices comprising dextromethorphan, pharmaceutical compositions comprising dextromethorphan, and methods of transdermally administering dextromethorphan. The transdermal delivery devices, pharmaceutical compositions, and methods herein are useful for treating a variety of diseases and disorders, such as neurological diseases or disorders (e.g., PBA).

[0007] The transdermal delivery device herein is novel in various aspects. In some embodiments, the transdermal delivery device can be characterized by a patch design, for example, having an adhesive layer and a reservoir layer. Typically, the reservoir layer can include dextromethorphan at a concentration of at least 10% by weight of the reservoir layer. In some embodiments, the transdermal delivery device can be characterized by an adhesive layer that includes a mixture of two adhesives, such as a mixture of an acrylate adhesive and a silicone adhesive. In some embodiments, the transdermal delivery device can be characterized by having a skin permeation enhancer that can provide a higher flux, for example, compared to an otherwise comparable transdermal delivery device that does not include a skin permeation enhancer. In some embodiments, the transdermal delivery device can be characterized by having a certain particular release profile, such as an in vitro flux profile and / or an in vivo release profile when tested using human cadaver skin. In any of the embodiments described herein, the transdermal delivery device can be configured to provide the user with one or more in vitro release profiles and / or one or more PK profiles described herein. In some embodiments, the transdermal delivery device can provide a pharmacokinetic ("PK") profile of a pharmacologic effective plasma concentration of dextromethorphan for a desired period of time in a subject in need thereof (e.g., a subject with PBA). In some embodiments, the transdermal delivery device can be configured for use once per day to provide a daily dose of dextromethorphan, e.g., from about 2 mg to about 50 mg. In some embodiments, the transdermal delivery device can be configured for use at least once per day, e.g., once every two or more days (e.g., once per week), or 1, 2, 3, 4, 5, or 6 times per week, to provide a daily dose of dextromethorphan, e.g., from about 2 mg to about 50 mg. Any of these features / aspects can be combined with the others, and such combinations are specifically contemplated by the present disclosure.

[0008] In some embodiments, the transdermal delivery device can include 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 a reservoir layer comprising dextromethorphan in an amount of at least 10% by weight of the reservoir layer (e.g., about 20% to about 60%). In some embodiments, the transdermal delivery device can include an adhesive layer comprising dextromethorphan dispersed in an adhesive comprising an acrylate adhesive and a silicone adhesive, the weight ratio of the acrylate adhesive to the silicone adhesive can range, for example, from about 20:1 to about 1:20. In some embodiments, the transdermal delivery device can include an adhesive layer comprising dextromethorphan dispersed in the adhesive, the adhesive layer comprising a skin permeation enhancer in an amount that provides 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) higher than the average cumulative dextromethorphan of an otherwise comparable transdermal delivery device that does not contain the skin permeation enhancer, when tested in vitro using, for example, human cadaver skin.

[0009] In some embodiments, the disclosure provides a method of administering dextromethorphan to a subject (e.g., a human subject) in need thereof. In some embodiments, the method includes applying a transdermal delivery device to the skin of the subject. In some embodiments, application results in one or more PK profiles described herein. In some embodiments, the transdermal delivery device is configured to have flux characteristics such that application transdermally delivers from about 2 mg / day to about 50 mg / day of dextromethorphan to the subject. In some embodiments, the transdermal delivery device includes an adhesive layer, the adhesive layer including dextromethorphan dispersed in the adhesive and a skin permeation enhancer, the skin permeation enhancer being in an amount such that 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) higher than the average cumulative dextromethorphan resulting from application of an otherwise equivalent transdermal delivery device without the skin permeation enhancer. In some embodiments, the transdermal delivery device is applied once a day. In some embodiments, the transdermal delivery device is applied at least once a day, for example, once a week, twice a week, or three times a week.

[0010] In some embodiments, the disclosure provides a method of treating a disease or disorder in a subject (e.g., a human subject) in need of treatment of the disease or disorder (e.g., a neurological disease or disorder such as PBA). In some embodiments, the method includes applying a transdermal delivery device comprising dextromethorphan to the skin of the subject, where the application results in one or more PK profiles described herein. In some embodiments, the transdermal delivery device is applied once a day. In some embodiments, the transdermal delivery device is applied at least once a day, for example, once a week, twice a week, or three times a week.

[0011] 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 with a CYP2D6 inhibitor. In some embodiments, the subject is not co-administered with quinidine. In some embodiments, the subject is co-administered with a CYP2D6 inhibitor, such as quinidine, bupropion, etc. However, in any of the embodiments described herein, the subject does not suffer from a cough and / or does not require a cough suppressant.

[0012] In some embodiments, the methods herein may further comprise administering to the subject an active agent other than dextromethorphan. For example, in some embodiments, the methods herein comprise administering to the subject an antidepressant. In some embodiments, the methods herein further comprise 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 pharma- ceutically acceptable salts thereof. These additional agents may be administered simultaneously or sequentially via the same or different routes. [Brief description of the drawings]

[0013] [Figure 1] 1 shows a graph illustrating in vitro flux test results of transdermal delivery devices having formulations A and B with different adhesives, with the flux of dextromethorphan (DXM) from the patch containing formulation A (acrylate adhesive) shown at the top with a faster flux than the patch containing formulation B (silicone adhesive). [Diagram 2]FIG. 13 is a graph showing in vitro flux test results of patches using formulations C1-C3, containing different ratios of silicone adhesive to acrylic adhesive: 54:46 (middle), 18:92 (bottom), and 9:91 (top). [Diagram 3] 1 is a graph 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 4] FIG. 4A shows dextromethorphan plasma concentrations over 96 hours in a human clinical trial comparing the effects of a 24-hour DXM transdermal patch (Study A) with twice-daily oral administration of Neudexta (20 mg DXM / 10 mg quinidine) (Reference B). FIG. 4B shows the plasma concentrations of the metabolite dextrorphan over 96 hours in the same study. In FIGS. 4A and 4B, both test and reference doses were administered to subjects under fasting conditions. Plasma concentrations refer to the average plasma concentrations for N=16. [Diagram 5] 1 shows a multi-layer patch design: 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] Figures 6A and 6B show simulated plasma concentrations of dextromethorphan over time following administration of a DXM transdermal patch of 45 cm2 (Figure 6A), 60 cm2 (Figure 6B), or 90 cm2 (Figure 6B) once daily for 7 days. For comparison, plasma concentrations of dextromethorphan (DM) over time following oral administration of Neudexta (20 mg DXM / 10 mg quinidine) twice daily for 7 days are also shown. [Figure 6B] Figures 6A and 6B show simulated plasma concentrations of dextromethorphan over time following administration of a DXM transdermal patch of 45 cm2 (Figure 6A), 60 cm2 (Figure 6B), or 90 cm2 (Figure 6B) once daily for 7 days. For comparison, plasma concentrations of dextromethorphan (DM) over time following oral administration of Neudexta (20 mg DXM / 10 mg quinidine) twice daily for 7 days are also shown. [Figure 6C] Figures 6C and 6D show simulated plasma concentrations of dextrorphan (Dor) over time following administration of a DXM transdermal patch of 45 cm2 (Figure 6C), 60 cm2 (Figure 6D), or 90 cm2 (Figure 6D) once per day for 7 days. For comparison, plasma concentrations of dextrorphan over time following oral administration of Neudexta (20 mg DXM / 10 mg quinidine) twice per day for 7 days are also shown. [Figure 6D] Figures 6C and 6D show simulated plasma concentrations of dextrorphan (Dor) over time following administration of a DXM transdermal patch of 45 cm2 (Figure 6C), 60 cm2 (Figure 6D), or 90 cm2 (Figure 6D) once per day for 7 days. For comparison, plasma concentrations of dextrorphan over time following oral administration of Neudexta (20 mg DXM / 10 mg quinidine) twice per day for 7 days are also shown. [Figure 7] A two-zone patch design is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Detailed Description of the Invention The unpredictability of transdermal administration is notorious. In the inventors' experience, testosterone can be delivered transdermally at a rate three orders of magnitude higher than beta-estradiol without enhancers. This difference could not have been predicted, as the compounds are very similar in structure and calculated LogP. See U.S. Provisional Application No. 62 / 568,028, filed October 4, 2017, the contents of which are incorporated by reference in their entirety.

[0015] 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, and other central nervous system disorders. However, to be effective, DXM must be delivered with a substance that competitively inhibits the liver enzyme cytochrome P450 2D6 (CYP2D6). In particular, this means that dextromethorphan is co-administered with quinidine. Otherwise, there is too little dextromethorphan and dextromethorphan passes through the liver's metabolism of digested food. U.S. Patent No. 6,335,030 B1 describes several examples of dextromethorphan patches. No pharmacokinetic data were known for transdermal administration of dextromethorphan.

[0016] As detailed herein, the present disclosure is the first to show that dextromethorphan can be delivered transdermally in therapeutically effective amounts. Delivering dextromethorphan transdermally can be advantageous in many different aspects. For example, the transdermal route avoids first-pass metabolism, so the transdermal delivery device herein can be administered to achieve a therapeutically effective plasma concentration regardless of whether a CYP2D6 inhibitor such as quinidine is co-administered. Thus, the transdermal delivery device and method herein can be administered to deliver dextromethorphan transdermally, for example, to a subject sensitive or intolerant to a CYP2D6 inhibitor such as quinine (e.g., having one or more side effects associated with quinidine or co-administering a drug whose metabolism is affected by a CYP2D6 inhibitor such as quinidine). Furthermore, the transdermal delivery device and method herein can be conveniently administered to deliver dextromethorphan transdermally to a subject, for example, regardless of whether the subject is a poor, intermediate, or extensive metabolizer of dextromethorphan, for example, without first determining this. For the sake of brevity, as used herein, unless otherwise clear from the context, poor metabolizer (PM), intermediate metabolizer (IM), or extensive metabolizer (EM) refers to the ability of a subject to metabolize dextromethorphan. The classification of a subject as a PM, IM, or EM (or labeled as an ultra-extensive or ultra-rapid metabolizer or UM) is known in the art. See, for example, Treducu ALD et al. Frontiers in Pharmacology, vol. 9, Article 305 (April 2018), in which a subject is assigned as a UM based on genotype if it contains "three or more copies of the normal functioning gene."

[0017] Additionally, unexpectedly, administration of the transdermal delivery device herein resulted in a longer T of dextromethorphan compared to the corresponding parameters observed from oral administration of Neudexta. 1 / 2, reduced amounts of metabolites (as evidenced by a higher ratio of dextromethorphan to dextrorphan), and / or a lower peak-to-trough ratio. These properties can provide a superior clinical experience compared to Neudexta, such as, for example, more accurate dosing, less frequent dosing, and reduced potential for side effects. The transdermal delivery device herein can also 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, which is suitable for dosing frequencies ranging from once a day to once a week, such as once every 24 hours, more than 36 hours, more than 48 hours, etc., or 1, 2, 3, 4, 5, or 6 times a week. Thus, the use of the transdermal delivery device herein can improve patient compliance by avoiding at least the twice-daily dosing regimen of Neudexta.

[0018] Transdermal Delivery Devices Containing Dextromethorphan Certain embodiments of the present disclosure are directed to novel transdermal delivery devices containing dextromethorphan.

[0019] A variety of patch designs can be used for the transdermal delivery device herein. The transdermal delivery device herein typically includes a backing layer, an adhesive layer (e.g., a drug-in-adhesive layer) that is the skin contact layer during use, and an optional reservoir layer. The adhesive layer typically includes dextromethorphan dispersed (e.g., evenly dispersed, including dissolved) in an adhesive, preferably a pressure-sensitive adhesive. Multiple adhesive layers can be used for the transdermal delivery device herein. The adhesive layer is typically formulated to allow the transdermal delivery device to adhere to the skin of the user for a desired period of time. For example, in some embodiments, the transdermal delivery device can be continuously adhered to the skin of the user for about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days, or more.

[0020] 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, for example, the single layer contains dextromethorphan evenly 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, which are optionally separated by a membrane, for example, a rate-controlling membrane, or a reservoir layer. In some embodiments, one of the drug-in-adhesive layers can be, for example, a reservoir layer that contains a higher dextromethorphan concentration than the other layer. In some embodiments, the two drug-in-adhesive layers can sandwich a reservoir layer.

[0021] The transdermal delivery device herein may also use a drug-containing reservoir (DIR) design. In some embodiments, the reservoir layer and the adhesive layer may be laminated to each other 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 to an adhesive layer. Those skilled in the art will appreciate that such an adhesive layer may also contain a certain amount of drug, for example, by equilibrium.

[0022] Other patch designs can also be used for the transdermal delivery device herein. For example, in some embodiments, the transdermal delivery device can be an active patch, such as an iontophoretic patch. In some embodiments, the transdermal delivery device can be a minimally invasive patch, such as a microneedle-based patch.

[0023] The transdermal delivery device may contain dextromethorphan as the only drug or in combination with another drug. Unless clearly contradicted, in any of the embodiments described herein, dextromethorphan may be the only drug in the transdermal delivery device. Dextromethorphan may be present in various forms, for example, as a free base or a pharma- ceutically acceptable salt. As used herein, weight percentages, concentrations, fluxes, etc., relating to dextromethorphan are measured and / or calculated as the total amount of dextromethorphan, and values ​​should be understood to be expressed in equivalent value relative to dextromethorphan base. Furthermore, unless otherwise clear from the context, all weight percentages should refer to weight percentages based on the final formulation (e.g., final adhesive layer or reservoir layer, etc.) or transdermal delivery device, as appropriate. In any of the embodiments described herein, dextromethorphan may be present in its free base form, except that it may be protonated through equilibrium with other components. 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 amounts of dextromethorphan base with other ingredients.

[0024] In any of the embodiments described herein, the dextromethorphan in the transdermal delivery device is deuterated dextromethorphan, such as the d3 analog (O-CD 3 , or N-CD 3 ) or d6 analogue (N-CD 3 , O-CD 3), see, for example, claims 1 and 17 of U.S. Patent No. 7,973,049, the contents of which are incorporated by reference in their entirety. Obviously, in such an embodiment, the method of using a deuterated dextromethorphan patch will provide the user with deuterated dextromethorphan. As used herein, deuterated dextromethorphan refers to a compound resulting from the replacement of one or more hydrogen atoms of dextromethorphan with deuterium, with each replacement position having a deuterium content above the natural abundance, i.e., the replacement position is enriched with deuterium. In some embodiments, the deuterated dextromethorphan has at least one position with deuterium enriched 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.

[0025] The adhesive layer typically comprises a pressure sensitive adhesive (PSA). Useful features of a pressure sensitive adhesive include adequate tackiness, good adhesion and cohesion. Further useful attributes include biocompatibility (e.g., non-irritating, non-sensitizing, non-toxic), formulation compatibility, and delivery system compatibility. Useful pressure sensitive adhesives include, for example, polyacrylates, polyacrylic esters, silicones, polyisobutylenes, and the like.

[0026] PSAs are generally known in the art. See, for example, Tan et al., Pharm Sci & Tech Today, 2:60-69 (1999). Non-limiting useful PSAs include polyisobutylene (PIB), silicone polymers, acrylate copolymers, and combinations thereof. In some embodiments, the pressure sensitive adhesive comprises a polyisobutylene adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some embodiments, the pressure sensitive adhesive comprises an acrylate copolymer adhesive. Non-limiting examples of useful acrylate copolymers include poly(acrylate / vinyl acetate) copolymers, such as acrylic pressure sensitive adhesives such as Duro-Tak 87-2287, Duro-Tak 87-4098, Duro-Tak 87-4287, or Duro-Tak 87-2516, Duro-Tak 87-2852, or Duro-Tak 87-2194 manufactured by Henkel Adhesives. PIB is an elastomeric polymer commonly used in PSAs as both the primary 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 functional groups (SiOH) at the ends of the polymer chains. Non-limiting useful silicone PSAs for use in pharmaceutical applications include, for example, those available from Dow Corning Corporation under the trade name BIO-PSA, 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.

[0027] In some embodiments, suitable adhesives include, for example, the following silicone adhesives from 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 adhesives. In some embodiments, suitable adhesives include, for example, the following polyacrylate / polyacrylic ester adhesives from Henkel Adhesives: Duro-Tak 87-900A, 87-9301, 87-4098, 87-2510, 87-2287, 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 GMS Examples of such functional groups include 3083, 3253, 788, and 9073. These may or may not have functional groups (as active materials, as described above), such as hydroxyl, carboxyl, hydroxyl and carboxyl functional groups. These may or may not include vinyl acetate monomer, for example.

[0028] 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 include polyester, such as Scotchpak 9736 or Scotchpak 1012, polyurethane film, such as Scotchpak 9701, or polyethylene film, such as CoTran 9720. In some embodiments, the backing is part of the overlay and can be a nonwoven fabric, polyurethane film, or other flexible material that provides flexibility and better wear.

[0029] The release liner can be manufactured in the desired size of the present invention. The release liner can be composed of silicone or fluoropolymer coated polyester film. The release liner protects the transdermal delivery device during storage and is removed before use. Silicone coated release liners include those manufactured by Mylan Corporation, Loparex Corporation, and 3M's Drug Delivery Systems. 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.

[0030] The transdermal delivery devices herein may also optionally include other suitable excipients, such as humectants, plasticizers, antioxidants, anti-irritants, gel formers, crystallization inhibitors, drug release modifiers, etc. These excipients are within the knowledge 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) can also be included in the transdermal delivery devices herein.

[0031] The transdermal delivery device (e.g., DIA patch) of the present invention 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 120cm 2 , about 150cm 2 , about 200cm 2 or any range between the specified values), e.g., about 10 cm 2 ~Approx. 100cm 2 It could be.

[0032] When a transdermal delivery device (e.g., a DIA patch) of the present specification 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, which is also referred to herein as the active surface area. In some embodiments, the adhesive surface is the only surface of the transdermal delivery device that contacts the skin upon application, and the active surface area is the same as the area of ​​the adhesive surface. In some embodiments, the adhesive surface and one or more other surfaces of the transdermal delivery device are in contact with the skin upon application, and the entire skin contact area is the active surface area. In a typical DIA patch, the patch size is the same as the active surface area. Unless otherwise clear from the context, the units " / cm 2 " should be understood as per square centimeter of active surface area as defined herein.

[0033] The active surface area can determine the dose of drug delivered. Typically, the active surface area is about 5 cm 2 ~about 300cm 2 (For example, 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 ~Approx. 100cm 2 It could be.

[0034] In some embodiments, the transdermal delivery device herein can be configured to provide at least about 2 mg / day (e.g., about 2 mg / day to about 50 mg / day) of dextromethorphan to a user for a period of one or more days, e.g., 2, 3, 4, 5, 6, or 7 days. For example, in some embodiments, the transdermal delivery device is configured to transdermally deliver dextromethorphan to a user at 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) 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).

[0035] The total dextromethorphan loading of the transdermal delivery device can be adjusted based on the total dose desired. Typically, the total dextromethorphan loading is 0.5 mg / cm 2 (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 For example, in some embodiments, the transdermal delivery device provides a 2 ~about 8mg / cm 2 , for example, about 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 active surface area of ​​the patch.

[0036] TDD with reservoir layer In some embodiments, a reservoir layer can be optionally included in the transdermal delivery devices herein. For example, for high daily doses and / or long term (e.g., one or more days) applications, the reservoir layer can provide a more sustained flux of dextromethorphan to the user.

[0037] In some embodiments, the transdermal delivery device includes an adhesive layer that includes an adhesive and a reservoir layer that includes dextromethorphan. In some embodiments, the adhesive layer optionally includes dextromethorphan dispersed in the adhesive. In some embodiments, the adhesive layer does not include dextromethorphan except through equilibration with the reservoir layer. In some embodiments, the adhesive layer includes dextromethorphan dispersed in the adhesive. In some embodiments, the reservoir layer includes 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 that 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, they can also have the same thickness. However, in some embodiments, the two adhesive layers can have different ingredients, different concentrations of the same ingredient, or different thicknesses, etc. An exemplary configuration can be seen in FIG. 3, where the adhesive layer is the top layer, the backing layer or adhesive layer, which may be the same or different from the top layer, is the bottom layer, and the reservoir layer is the middle layer.

[0038] 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 comprises an adhesive. However, other designs of the reservoir layer are suitable if compatible with the adhesive layer and the backing layer. For example, in some embodiments, the reservoir layer can be a scrim / nonwoven saturated with dextromethorphan, or other suitable support / substrate with dextromethorphan dispersed therein.

[0039] Dextromethorphan can be included in the adhesive layer and the reservoir layer in various concentrations. 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% by weight, about 4% by weight, about 6% by weight, about 8% by weight, about 10% by weight, about 12% by weight, or any range between the recited values); while the reservoir layer can include dextromethorphan in an amount of about 20% by weight or more of the reservoir layer, such as about 30% by weight or more, about 40% by weight or more, about 50% by weight or more, such as about 20% by weight to about 60% by weight, about 30% by weight to about 50% by weight. 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 between the recited values). In some embodiments, the adhesive layer contains dextromethorphan at or near the saturation concentration in the adhesive, for example, about 10% by weight in an acrylate adhesive. In some embodiments, the reservoir layer contains dextromethorphan in excess of the saturation concentration in the adhesive. In other words, the reservoir layer can contain dextromethorphan in a supersaturated state, and thus solid dextromethorphan, which can function as a drug depot.

[0040] Suitable adhesives for the adhesive layer and reservoir layer, if applicable, include any of those described herein, preferably pressure-sensitive adhesives. The adhesives included in the adhesive layer and reservoir layer may be the same or different. In some embodiments, the adhesives included in the adhesive layer and reservoir layer are the same, for example, an acrylate-based adhesive. Other suitable adhesives include polyisobutylene adhesives, silicone polymer adhesives, acrylate copolymer adhesives (e.g., poly(acrylate / vinyl acetate) copolymers such as Duro-Tak 87-2287), or combinations thereof. In any of the embodiments described herein, the adhesive layer can be configured to adhere to the skin of a user continuously 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, at least seven days).

[0041] The adhesive (e.g., pressure sensitive adhesive) is typically a major component of the adhesive layer and the 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).

[0042] Suitable sizes for the transdermal delivery device 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 active surface area of ​​about 10 cm 2~Approx. 150cm 2 In some embodiments, the transdermal delivery device has an active surface area 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 between the recited values).

[0043] 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).

[0044] Skin permeation enhancers may also be included in the adhesive layer and the reservoir layer. For example, in some embodiments, the adhesive layer may include isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate ... 12 ~C 18 In some embodiments, the adhesive layer comprises an isopropyl myristate. Similarly, in some embodiments, the reservoir layer comprises an isopropyl myristate, an oleyl oleate, an oleic acid, a glycerol monooleate ... 12 ~C 18 and other fatty acids and fatty acid esters, and combinations thereof. In some embodiments, the reservoir layer comprises isopropyl myristate.

[0045] Various amounts of the skin permeation enhancer can be used in the adhesive layer and the reservoir layer. Typically, the skin permeation enhancer can be present in an amount of about 2% to about 15% by weight of the adhesive layer or the 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 layer and / or the reservoir layer can also be an isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate ... 12 ~C 18 and combinations thereof.

[0046] In some embodiments, the adhesive layer and / or reservoir layer may include an agent selected from vinylpyrrolidone polymers (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 may be present in an amount of about 2% to about 20% by weight of the adhesive layer 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 between the recited values). Without wishing to be bound by theory, it is believed that such agents may improve the cohesive strength of the adhesive layer or reservoir layer. Additionally, such agents may 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.

[0047] It should be noted that the identity and amounts of the components, such as adhesive, skin permeation enhancer, drug, etc. for the adhesive layer and reservoir layer are independently selected and may be the same or different. Typically, the identity may be the same, but the amount may vary. The thickness of the adhesive layer and reservoir layer may also be the same or different.

[0048] TDD with adhesive mixture As detailed in the Examples section, varying the adhesive components can affect the flux properties of a transdermal delivery device that includes dextromethorphan. Thus, in some embodiments, the present disclosure also provides a transdermal delivery device that includes an adhesive layer, the adhesive layer including two or more adhesives. Typically, the adhesive layer includes dextromethorphan dispersed in two or more adhesives.

[0049] In some embodiments, the adhesive layer can include a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios (e.g., weight ratios 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 between the recited values). Other ingredients and suitable amounts that can be optionally included in the adhesive layer, such as a skin permeation enhancer, include those described herein.

[0050] An adhesive layer having two or more adhesives may be included / used in any of the transdermal delivery devices herein. For example, in some embodiments, a transdermal delivery device including a reservoir layer as described herein may have an adhesive layer that includes a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios.

[0051] TDD containing a skin permeation enhancer Skin permeation enhancers (transdermal enhancers) can enhance the skin permeability of dextromethorphan through the skin and can be optionally included in the transdermal delivery device herein. Various skin permeation enhancers can be included. Non-limiting useful skin permeation enhancers include, for example, sulfoxides (e.g., dimethyl sulfoxide, DMSO), Azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), esters, glycols (e.g., propylene glycol (PG)), surfactants (e.g., Tween 80), terpenes, and combinations thereof. See, 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 dimethylsulfoxide (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 dermal permeation enhancer comprises isopropyl myristate, oleyl oleate, oleic acid, glycerol mono ... 12 ~C 18 and other fatty acids and fatty acid esters, and combinations thereof. In some particular embodiments, the skin permeation enhancer is isopropyl myristate.

[0052] The skin permeation enhancer is present in an amount of about 1% to about 25% by weight of the adhesive layer, such as about 2%, about 5%, about 10%, about 15%, about 20%, about 25% by weight of the adhesive layer, or any range between the recited 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, where the amount of potential such enhancer is about 20% or less of the minimum amount shown to enhance transdermal flux by about 50% or more.

[0053] In some embodiments, the skin permeation enhancer and its amount are selected to provide certain improved flux properties. For example, in some embodiments, the present disclosure provides a transdermal delivery device comprising an adhesive layer comprising dextromethorphan dispersed in an adhesive, the adhesive layer comprising a skin permeation enhancer in an amount that provides 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) higher than an otherwise comparable transdermal delivery device that does not comprise a skin permeation enhancer, when tested in vitro using human cadaver skin. The term "an otherwise comparable transdermal delivery device that does not comprise a skin permeation enhancer" should be understood as a control transdermal delivery device in which the content of the skin permeation enhancer in the adhesive layer is replaced with an adhesive, with all other aspects being the same. For example, a transdermal delivery device may include 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 may include a corresponding 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.

[0054] The skin permeation enhancer and its amount can also be adjusted to enhance flux at different times after application. For example, in some embodiments, the permeation enhancer can be adjusted to provide the following: 1) an average flux of dextromethorphan 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 of an otherwise comparable 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, or about 5 times) higher than the average flux of dextromethorphan of an otherwise comparable transdermal delivery device without the skin permeation enhancer; fold, about 5 times, about 8 times, about 10 times, or any range between the recited values); 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, or any range between the recited values) the average flux of dextromethorphan of an otherwise comparable transdermal delivery device without the skin permeation enhancer, when tested in vitro using human cadaver skin. As detailed in the Examples, in one example, a significant enhancement in flux was observed both at or before 4 hours after application when the amount of the permeation enhancer isopropyl myristate was increased to about 10% by weight.

[0055] An adhesive layer comprising a skin permeation enhancer may be included / used in any of the transdermal delivery devices herein. For example, in some embodiments, a transdermal delivery device comprising a reservoir layer as described herein may have an adhesive layer comprising a skin permeation enhancer. Adhesive Other ingredients that may optionally be included in the agent layer and suitable amounts include those described herein.

[0056] In some particular embodiments, the transdermal delivery device can include an adhesive layer and a reservoir layer, which can have, for example, the ingredients and amounts shown in the table below. JPEG0007609943000001.jpg88166

[0057] All amounts in the table refer to the weight percentage 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 Above, for example, about 70 cm 2 For example, in some embodiments, the transdermal delivery device is configured to provide dextromethorphan to the user at about 15 mg / day to about 40 mg / day, 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 that protects the adhesive surface prior to use. Typically, these patches can be used at a dosing frequency of less than once a day, such as once a day, or once every two or more days, such as once a week, or 2, 3, 4, 5, or 6 times a week, such as twice a week.

[0058] In some particular embodiments, the transdermal delivery device can include an adhesive layer, which can have, for example, the ingredients and amounts shown in the table below. JPEG0007609943000002.jpg50166

[0059] All amounts in the table refer to the weight percentage of the final adhesive layer, with the total being 100%. In some embodiments, the transdermal delivery device is about 10 cm 2 Above, for example, about 30 cm 2 , about 45cm 2 , about 60cm2 , about 75cm 2 , about 90cm 2 For example, in some embodiments, the transdermal delivery device is configured to provide the 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 more than once a day, e.g., once a day or once every 12 hours.

[0060] In vitro flux properties In some embodiments, the transdermal delivery devices herein are configured to provide a certain in vitro dextromethorphan flux profile when tested in vitro, for example, using human cadaver skin. For example, in some embodiments, any of the transdermal delivery devices herein, when tested in vitro using human cadaver skin, provide: 1) a 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 ) the average cumulative dextromethorphan permeated; and / or 2) at least about 5ug / cm2 permeation at 8-24 hours after application when tested in vitro using human cadaver skin. 2 *h (for example, about 5ug / cm 2 *h~about 20ug / cm 2 *h, about 10ug / cm 2 *h~approx.18ug / cm 2 *h) an average flux of dextromethorphan.

[0061] In some embodiments, the transdermal delivery device is administered to a subject in need thereof at least about 200 ug / cm per day. 2 (For example, about 200ug / cm 2 ~About 2000ug / cm 2 ) 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 to the subject. 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 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 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 It is.

[0062] A transdermal delivery device having the above flux characteristics can be made by one of skill in the art in light of this disclosure. The preparation of some transdermal delivery devices is also illustrated in the Examples section. The cumulative drug permeated (dextromethorphan, deuterated dextromethorphan, or a combination thereof) can be adjusted, for example, by varying the composition of the adhesive layer (e.g., drug concentration, permeation enhancer, drug loading, adhesive type, etc.).

[0063] 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.

[0064] The transdermal delivery device herein can also be characterized by a certain in vivo release profile, for example, to provide a desired pharmacokinetic (PK) profile, for example, any of those described herein. In some embodiments, the transdermal delivery device can be configured to provide a PK profile, for example, any of the PK profiles described herein, in a subject in need thereof. In some embodiments, the transdermal delivery device is configured to provide a PK profile effective for treating, for example, a disease or disorder in a subject (such as, for example, PBA, as described herein).

[0065] TDD with two different zones In some embodiments, the transdermal delivery device can include two different zones having different release rates.

[0066] Shown in Figure 7 is a diagram of a matrix transdermal device 100. The central matrix 20 can be configured, for example, to provide a more rapid onset (selected drug amount and adhesive or adhesive mixture). In an exemplary embodiment, the amount of pharmaceutical active added to the central matrix 20 can reduce adhesive forces. Nevertheless, the adhesive forces from the surrounding matrix 30 hold the device in place. The surrounding matrix 30 can be configured, for example, to provide a more prolonged delivery of the pharmaceutical active.

[0067] In an embodiment having two distinct zones, the rapid release portion of the device may be, for example, about 5 cm 2 ~Approx. 150cm 2 , for example, about 5 cm 2 ~Approx. 100cm 2 , or about 5 cm 2 ~about 40cm 2 , etc. The slower releasing portion may be, for example, about 5 cm 2 ~Approx. 150cm 2 , for example, about 5 cm 2 ~Approx. 100cm 2 , or about 7.5 cm 2~55cm 2 may be an area of

[0068] Dextromethorphan administration method and PK profile In various embodiments, the present invention 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 a disease or disorder described herein.

[0069] Some embodiments are directed to a method of administering dextromethorphan to a subject (e.g., a human subject) in need thereof. In some embodiments, the subject is sensitive or otherwise intolerant to quinidine, e.g., with QTc prolongation. In some embodiments, the method includes applying either a transdermal delivery device or a pharmaceutical composition to the subject, e.g., the skin of the subject. In some embodiments, the subject is not administered dextromethorphan via another source, e.g., via oral administration. However, in some embodiments, the subject can also be supplemented with another source of dextromethorphan, e.g., by co-administering an oral formulation of dextromethorphan to the subject. In some embodiments, the user is characterized as an extensive metabolizer. In some embodiments, the user is characterized as a poor metabolizer. In some embodiments, the user is not co-administered with a CYP2D6 inhibitor. In some embodiments, the user is not co-administered with quinidine. In some embodiments, the user is co-administered with a CYP2D6 inhibitor, such as quinidine, bupropion, etc.

[0070] Various dosing regimens are suitable for the methods herein. For example, in some embodiments, the method includes administering a transdermal delivery device (e.g., as described herein) to a subject once a day for a desired period of time. In some embodiments, the transdermal delivery device includes about 5 mg to about 100 mg of dextromethorphan. In some embodiments, the method may also include 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 a week, etc.) for a desired period of time. In some embodiments, the method may also include administering a transdermal delivery device (e.g., as described herein) to a subject at least once a day for a desired period of time, for example, once every two or more days (e.g., once a week), or 1, 2, 3, 4, 5, or 6 times a week. In some embodiments, the method may include administering a transdermal delivery device (e.g., as described herein) to a subject once a week. In some embodiments, the transdermal delivery device comprises about 50 mg to about 700 mg of dextromethorphan. In the methods herein, typically, the transdermal delivery device is applied to the subject once per day or more than once per day, although in some embodiments, the methods may also involve applying the transdermal delivery device to the subject less than once per day, such as, for example, twice per day or three times per day.

[0071] The methods of administering dextromethorphan herein typically provide a certain pharmacokinetic profile that is suitable (e.g., effective) for treating, e.g., a disease or disorder (e.g., any of those described herein, such as PBA) in a subject (e.g., a human subject) in need thereof.

[0072] In some embodiments, the method includes administering to a subject a transdermal delivery device herein to increase a mean blood C of dextromethorphan from about 6 ng / mL to about 21 ng / mL (e.g., from about 8 ng / mL to about 17 ng / mL, or from about 10 ng / mL to about 15 ng / mL). maxover a period of 12 hours or more, the AUC of dextromethorphan is approximately equivalent (normalized to the period of measurement) to a 12-hour value of about 52 ng·h / mL to about 144 ng·h / mL (e.g., about 65 ng·h / mL to about 125 ng·h / mL, or about 75 ng·h / mL to about 110 ng·h / mL).

[0073] As described in detail in the Examples section, 2 An exemplary patch containing about 35 mg of dextromethorphan in a size of about 1.5 mm and designed to transdermally deliver 15 mg per day, with an adhesive layer (drug-containing adhesive layer) containing about 80% by weight adhesive (Duro-Tak 87-2287), about 10% by weight dextromethorphan base, and about 10% by weight of the permeation enhancer isopropyl myristate, was applied to healthy humans for about 24 hours to, among other things, produce a mean C max and a mean AUC of approximately 92 h·ng / mL. 0-24h This achieves a PK profile that approaches that observed from oral administration of a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily to human subjects. This demonstrates for the first time that transdermal delivery of dextromethorphan without quinidine can provide significant blood levels of dextromethorphan in humans. Furthermore, the human PK data will enable those skilled in the art to adjust patch design to achieve the desired PK profile.

[0074] For example, in some embodiments, the method consists essentially of, or consists of, applying a transdermal delivery device (e.g., as described herein) comprising dextromethorphan to the skin of a subject (e.g., a human subject) once per day (e.g., for up to seven days or more, or for at least seven days, or any period of time), whereby application results in the following pharmacokinetic profile in the subject: 1) a mean C of at least about 3 ng / ml (e.g., from about 3 ng / ml to about 12 ng / ml) of dextromethorphan 1 day after application (i.e., measured over the period 0 to 24 hours after application). max2) 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 3) A C of dextromethorphan of about 1.5 or less (e.g., about 1 to about 1.5) one day after application. 24h / C 12h 4) a C of dextromethorphan of at least about 1.2 (e.g., about 1.5 to about 2.5) one day after application 24h / C 6h 5) One day after application, the C of dextromethorphan was about 0.85 to about 1.3. 24h / C 18h 6) 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) 1 day after application max 7) Mean AUC of dextrorphan below 10 ng*h / ml (e.g., below 10 ng*h / ml or below 5 ng*h / ml) on the first day after application 0-24 8) a C of dextrorphan of at least about 5 (at least about 10, at least about 15, at least about 20) one day after application. max C of dextromethorphan against max and 9) an AUC of dextrorphan of at least about 5 (at least about 10, at least about 15, at least about 20, or at least about 25) one day after application. 0-24 AUC of dextromethorphan 0-24 in any combination. In some embodiments, the application results in a PK profile in the subject that includes: a). 1) and / or 2); b). 3), 4), and / or 5); c). 6) and / or 7); d). 8) and / or 9); or e). any combination of a), b), c), and d).

[0075] In some embodiments, the method may include, consist essentially of, or consist of applying a transdermal delivery device (e.g., as described herein) comprising dextromethorphan to the skin of a subject (e.g., a human subject) at least once per day (e.g., 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.) (e.g., for up to seven days or more, or for at least seven days or any period of time), whereby application results in the following pharmacokinetic profile in the subject: 1) a mean C of at least about 3 ng / ml (e.g., from about 3 ng / ml to about 12 ng / ml) of dextromethorphan 1 day after application. max 2) 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 3) A C of dextromethorphan of about 1.5 or less (e.g., about 1 to about 1.5) one day after application. 24h / C 12h 4) a C of dextromethorphan of at least about 1.2 (e.g., about 1.5 to about 2.5) one day after application 24h / C 6h 5) One day after application, the C of dextromethorphan was about 0.85 to about 1.3. 24h / C 18h 6) 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) 1 day after application max 7) Mean AUC of dextrorphan below 10 ng*h / ml (e.g., below 10 ng*h / ml or below 5 ng*h / ml) on the first day after application 0-24 8) a C of dextrorphan of at least about 5 (at least about 10, at least about 15, at least about 20) one day after application. max C of dextromethorphan against max 9) an AUC of dextrorphan of at least about 5 (at least about 10, at least about 15, at least about 20, or at least about 25) one day after application. 0-24 AUC of dextromethorphan 0-24In some embodiments, the application results in a PK profile in the subject that includes: a). 1) and / or 2); b). 3), 4), and / or 5); c). 6) and / or 7); d). 8) and / or 9); or e). any combination of a), b), c), and d). In some embodiments, the method involving at least once-daily application results in a PK profile after one day of application that is substantially the same as that observed with the once-daily method described herein.

[0076] Plasma concentrations from the transdermal delivery devices herein can be maintained substantially constant, with peak-to-trough ratios typically lower than those observed from orally administering Neudexta twice daily. For example, in some embodiments, the method includes applying a transdermal delivery device to the skin of a subject (e.g., a human subject) once a week, whereby application results in: i) a C of dextromethorphan of 2 or less (e.g., about 0.85 to about 1.3) 7 days after application; 24h / C 12h ii) a C of dextromethorphan of 2 or less (e.g., about 0.85 to about 1.3) 7 days after application 24h / C 6h and / or iii) a C of dextromethorphan of 2 or less (e.g., about 0.85 to about 1.3) at 7 days after application. 24h / C 18h In some embodiments, administration results in an average ratio of at least two of i)-iii). In some embodiments, administration results in all of i)-iii). The once-daily methods described herein can also result in relatively low peak-to-trough ratios, which are typically lower than the corresponding ratios observed from twice-daily oral administration of Neudexta, e.g., when measured during a period after steady state is reached.

[0077] In some embodiments, the methods herein provide for the determination of the C of dextromethorphan according to different needs, e.g., to match (or approach) that observed when a combination of 20 mg dextromethorphan and 10 mg quinidine is orally administered twice daily. max and / or AUC.

[0078] For example, in some embodiments, the method includes applying a transdermal delivery device herein to a subject (e.g., a human subject) once daily or once weekly for up to seven days or more, or at least seven days, or any desired period of time, where the application results in: i) a mean C of at least about 8 ng / ml (e.g., about 8 ng / ml to about 20 ng / ml) of dextromethorphan at 7 days after application; max and / or ii) 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 In some embodiments, the application results in the following PK profile, when measured 7 days after application: a) Mean C of dextromethorphan observed from orally administering a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily for 7 days to a subject (e.g., a human subject). max At least about 30% (e.g., about 30% to about 80%) of the mean C of dextromethorphan max and b) the mean AUC of dextromethorphan observed from orally administering a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily to subjects (e.g., human subjects) for 7 days. 0-24 At least about 30% (e.g., about 30% to about 80%) of the mean AUC of dextromethorphan 0-24 and c) the mean C of dextromethorphan observed from orally administering to subjects (e.g., human subjects) a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily for 7 days. max About 50% or less (e.g., about 10% to about 30%) of the mean C of dextromethorphan maxand d) the mean AUC of dextromethorphan observed from orally administering to subjects (e.g., human subjects) a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily for 7 days. 0-24 About 50% or less (e.g., about 10% to about 30%) of the mean AUC of dextromethorphan 0-24 , one or more of are provided.

[0079] 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 with a CYP2D6 inhibitor. In some embodiments, the subject is not co-administered with quinidine. In some embodiments, the subject is co-administered with a CYP2D6 inhibitor, such as quinidine, bupropion, etc. However, in any of the embodiments described herein, the subject does not suffer from a cough and / or does not require a cough suppressant.

[0080] 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 emotional disorder, a psychiatric disorder, a brain dysfunction disorder, a movement disorder, a 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 depression, 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. 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-Barre syndrome, and spastic paraplegia. In any of the embodiments herein, the subject may suffer from emotion dysregulation, depression, stroke, traumatic brain injury, seizures, pain (e.g., postoperative pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's disease, autism, or combinations thereof.In any of the embodiments herein, the subject may suffer from emotion dysregulation.

[0081] Treatment Dextromethorphan is known to be useful in treating a variety of diseases or disorders. See, e.g., Nguyen, L. et al., Pharmacology & Therapeutics 159:1022 (2016). Thus, 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. In some embodiments, the method comprises transdermally administering a therapeutically effective amount of dextromethorphan to a subject. In some embodiments, the administration comprises applying a transdermal delivery device to the skin of the subject. In some embodiments, the administration results in a PK profile described herein. In some embodiments, the subject does not suffer from cough and / or does not require a cough suppressant. 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 otherwise intolerant to quinidine, e.g., with QTc prolongation.

[0082] A variety of diseases and disorders are suitable for treatment by the methods herein. In some embodiments, the neurological disease or disorder is a neurological disorder. Non-limiting exemplary neurological diseases or disorders include emotional disorders, psychiatric disorders, brain function disorders, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0083] Affective disorders that can be treated by the methods herein include depression, major depression, These conditions include, but are not limited to, treatment-resistant depression and treatment-resistant bipolar depression, bipolar disorder 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, emotion dysregulation, and emotional lability.

[0084] 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 disorder, somatoform disorder, personality disorder, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizophreniality, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease.

[0085] Substance addiction abuse that can be treated by the methods herein includes, but is not limited to, drug addiction, 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.

[0086] Brain dysfunction that can be treated by the method of the present specification includes, but is not limited to, disorders associated with intellectual disability, such as senile dementia, Alzheimer's dementia, memory loss, amnesia / amnesic syndrome, epilepsy, impaired consciousness, coma, impaired attention, speech disorder, vocal spasm, Parkinson's disease, Lennox-Gastaut syndrome, autism, 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, head trauma, etc., and symptoms include impaired consciousness, senile dementia, coma, impaired attention, and speech disorder.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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-Barre syndrome, and spastic paraplegia.

[0091] Seizure disorders that can be treated by the methods herein include, but are not limited to, epileptic seizures, non-epileptic 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.

[0092] 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.

[0093] 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.

[0094] In some embodiments, the disease or disorder is pain, joint pain, pain associated with sickle cell disease, emotional dysregulation, depression (including treatment-resistant depression), memory and cognition related disorders, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), and the like.

[0095] 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, arthritis pain, complex regional pain syndrome, and the like.

[0096] 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 an adjuvant treatment for multiple myeloma.

[0097] In any of the embodiments herein, the method may be for treating emotional dysregulation, depression, stroke, traumatic brain injury, seizures, pain (e.g., post-operative pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof.

[0098] Suitable dosing regimens, dosages, durations, transdermal delivery devices, and the like include any of those described herein in any combination. In any of the embodiments herein, the subject may be a human subject.

[0099] In some specific embodiments, a method of treating emotion dysregulation is provided, comprising applying the transdermal delivery device herein to a subject in need thereof. In some embodiments, the transdermal delivery device comprises about 5 mg to about 100 mg of dextromethorphan. In some embodiments, the transdermal delivery device is applied once a day, for example, for up to 7 days, at least 7 days, one month, or any period of time. In some embodiments, the transdermal delivery device comprises about 50 mg to about 700 mg of dextromethorphan. In some embodiments, the transdermal delivery device is applied once a week, for example, for one week, one month, or any period of time desired. In some embodiments, the transdermal delivery device is applied 1, 2, 3, 4, 5, or 6 times a week, for example, for one week, one month, or any period of time desired. In some embodiments, the transdermal delivery device is applied to achieve any of the pharmacokinetic profiles described herein. 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 is not suffering from a cough and is not in need of a cough suppressant. In some embodiments, the subject is characterized as a poor metabolizer. In some embodiments, the subject is characterized as an extensive metabolizer.

[0100] Combination therapy In some embodiments, the method herein can further comprise administering to the subject an active agent other than dextromethorphan. For example, in some embodiments, the method further comprises 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 method further comprises administering to the subject quinidine. In some embodiments, the method further comprises 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 esters thereof), opioid agonists (e.g., μ-opiate analgesics (e.g., tramadol)), adenosinergic agonists, 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, gabapentin, and pharma- ceutically acceptable salts thereof. 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 can be administered transdermally or orally. However, in some embodiments, the additional agents can also be combined with dextromethorphan in the same transdermal delivery device.

[0101] Since the transdermal application described herein avoids first-pass hepatic metabolism, the method herein can provide dextromethorphan to a subject undergoing drug therapy that may interfere with the hepatic metabolism of dextromethorphan. In some embodiments, the method includes 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 method does not require and / or is independent of determining whether the subject is an extensive or poor metabolizer of dextromethorphan.

[0102] definition As used herein, the term "about" modifying amounts related to the present invention refers to variations in quantity that may occur, for example, through routine testing and handling; through inadvertent errors in such testing and handling; through differences in the manufacture, source, or purity of the components / materials used in the present invention; and the like. As used herein, "about" a particular value also includes the particular value, for example, about 10% includes 10%. Whether or not modified by the term "about", the claims include the equivalent of the recited amount. In one embodiment, the term "about" means within 20% of the reported numerical value.

[0103] As used herein, the term "cumulative drug permeated" refers to the total amount of drug permeated per square centimeter during a given period of time. Unless otherwise clear from the context, "cumulative drug permeated" at a given time (e.g., 24 hours after administration) refers to the total amount of drug permeated per square centimeter from time 0 (i.e., time of administration) to the given time. Unless otherwise clear from the context, "cumulative drug permeated" refers to the arithmetic mean value measured and / or calculated according to the methods described herein. As used herein, the term "mean value" also refers to the arithmetic mean value unless otherwise specified and consistent with common practice in the art.

[0104] As used herein, the term "flux" refers to the amount of drug permeating the skin per unit area per unit time. Unless otherwise clear from the context, "flux" refers to the arithmetic mean value measured and / or calculated according to the methods described herein. A typical unit of flux is milligrams per square centimeter per hour.

[0105] The flux rates referred to in this patent application can refer to those measured by either in vivo or in vitro methods. One method of measuring flux is to place a transdermal delivery device or formulation on a known skin area of ​​a human volunteer and measure the amount of drug that can permeate across the skin within a certain time constraint. Those skilled in the art will understand that in some cases, the absolute value of in vitro flux may differ by several fold when measured using different cadaveric sources. As used herein, when specifically referred to as being 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 patch tested in Example 2 can be used as a reference patch, which, when tested according to the method according to Example 2, should yield the same flux 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 using 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.

[0106] As used herein, the terms "treat," "treating," "treatment," and the like refer to eliminating, reducing, or ameliorating a disease or condition, and / or symptoms associated therewith. Although not excluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.

[0107] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent (e.g., dextromethorphan) sufficient to result in amelioration of one or more symptoms of a disorder or condition (e.g., PBA), or to prevent the progression or occurrence of the disorder or condition, or to cause regression or cure of the disorder or condition.

[0108] As used herein, the term "subject" (also referred to herein as "patient") refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0109] As used herein, application or administration of a transdermal delivery device herein should be understood according to the way such a transdermal delivery device is normally applied or administered to the skin, for example, of a human subject.

[0110] Exemplary embodiments Exemplary embodiments A1 to A55 1.a. an adhesive layer comprising an adhesive and optionally comprising dextromethorphan dispersed in the adhesive in an amount of about 2% to about 12% by weight of the adhesive layer; 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.

[0111] 2. The transdermal delivery device of embodiment A1, configured to transdermally deliver from about 2 mg / day to about 50 mg / day of dextromethorphan to a subject.

[0112] 3. The transdermal delivery device of embodiment A1 or 2, 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 range between the 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 range between the recited values).

[0113] 4.About 0.5mg / cm 2 ~about 8mg / cm 2 The transdermal delivery device of any one of embodiments A1-3, having a total dextromethorphan loading of

[0114] 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 The transdermal delivery device of any one of embodiments A1-4, having a total dextromethorphan loading of 0.01 to 0.05 (or any range therebetween).

[0115] 6. Approximately 5cm 2 ~about 200cm 2 The transdermal delivery device of any one of embodiments A1-5, having an active surface area of

[0116] 7.About 10cm 2 ~Approx. 150cm 2 The transdermal delivery device of any one of embodiments A1-6, having an active surface area of

[0117] 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 active surface area of ​​0.01 to 0.1 mmHg (or any range therebetween).

[0118] 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% 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).

[0119] 10. The transdermal delivery device of any one of embodiments A1-9, wherein the adhesive layer further comprises a skin permeation enhancer.

[0120] 11. The skin permeation enhancer is selected from the group consisting of isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, and glycerol monooleate with a carbon chain length of C 12 ~C 18 The transdermal delivery device of embodiment A10, wherein the fatty acid or fatty acid ester is selected from the group consisting of:

[0121] 12. The transdermal delivery device of embodiment A10 or 11, wherein the skin permeation enhancer is present in an amount of about 2% to about 15% by weight of the adhesive layer.

[0122] 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% 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).

[0123] 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.

[0124] 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.

[0125] 16. The transdermal delivery device of embodiment A14 or 15, wherein the agent is present in an amount of about 1% to about 20% by weight of the adhesive layer.

[0126] 17. A transdermal delivery device according to any one of embodiments A14-16, 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).

[0127] 18. A transdermal delivery device according to any one of embodiments A1-17, wherein the adhesive comprises a pressure sensitive adhesive.

[0128] 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 poly(acrylate / vinyl acetate) copolymer such as Duro-Tak 87-2287), or a combination thereof.

[0129] 20. The transdermal delivery device of embodiment A18 or 19, wherein the pressure sensitive adhesive is present in an amount of about 50% to about 90% by weight of the adhesive layer.

[0130] 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).

[0131] 22. A transdermal delivery device described in any one of embodiments A1-21, wherein the adhesive layer is capable of adhering to the skin of a user continuously 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).

[0132] 23. A transdermal delivery device according to any one of embodiments A1-22, wherein the adhesive layer is from about 0.1 mil to about 10 mil thick (e.g., from about 0.5 mil to about 10 mil, from about 1 mil to 10 mil).

[0133] 24. A transdermal delivery device according to any one of embodiments A1-23, wherein the reservoir layer comprises dextromethorphan in an amount from about 30% to about 50% by weight of the reservoir layer (e.g., about 30%, about 35%, about 40%, about 45%, about 50% by weight, or any range between the recited values).

[0134] 25. The transdermal delivery device of any one of embodiments A1-24, wherein the reservoir layer further comprises a skin permeation enhancer.

[0135] 26. The skin permeation enhancer is selected from the group consisting of isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, and glycerol monooleate with a carbon chain length of C 12 ~C 18 The transdermal delivery device of embodiment A25, wherein the fatty acid or fatty acid ester is selected from the group consisting of:

[0136] 27. The transdermal delivery device of embodiment A25 or 26, wherein the skin permeation enhancer is present in an amount of about 2% to about 15% by weight of the reservoir layer.

[0137] 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% 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).

[0138] 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.

[0139] 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 0, or Kollidon VA64), silicon dioxide, titanium dioxide, and combinations thereof.

[0140] 31. The transdermal delivery device of embodiment A29 or 30, wherein the agent is present in an amount of about 1% to about 20% by weight of the reservoir layer.

[0141] 32. A transdermal delivery device according to any one of embodiments A29-31, 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).

[0142] 33. The reservoir layer is a pressure-sensitive adhesive, for example a uniformly dispersed dextran. A transdermal delivery device described in any one of embodiments A1-32, comprising lomethorphan.

[0143] 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 poly(acrylate / vinyl acetate) copolymer such as Duro-Tak 87-2287), or a combination thereof.

[0144] 35. The transdermal delivery device of embodiment A33 or 34, wherein the pressure-sensitive adhesive is present in an amount of about 20% to about 80% by weight of the reservoir layer.

[0145] 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).

[0146] 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).

[0147] 38. A transdermal delivery device according to any one of embodiments A1-37, wherein the adhesive layer and the reservoir layer are separated by a rate-controlling membrane.

[0148] 39. A method of administering dextromethorphan to a subject in need thereof, comprising applying to the subject a transdermal delivery device described in any one of embodiments A1-38 or C1-21, or comprising applying to the subject a transdermal delivery device comprising an adhesive layer having the same or substantially the same ingredients as in formulation A, B, C1, C2, C3, D0, D1, or D2 in the preceding examples.

[0149] 40. The method of embodiment A39, wherein the subject is not suffering from cough and / or does not require cough suppressants.

[0150] 41. The method of embodiment A39 or 40, wherein the subject is characterized as an extensive metabolizer.

[0151] 42. The method of any one of embodiments A39-41, wherein the subject is suffering from a neurological disease or disorder.

[0152] 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 function disorder, a movement disorder, dementia, a motor neuron disease, a neurodegenerative disease, a seizure disorder, and a headache.

[0153] 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 depression, 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, affective dysregulation disorder, and emotional lability.

[0154] 45. The subject is diagnosed with Alzheimer's disease, prion-related disease, 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, or Menkes disease. The method of any one of embodiments A39-41, wherein the patient is suffering from one or more diseases or disorders selected from: 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.

[0155] 46. ​​The method of any one of embodiments A39-41, wherein the subject is suffering from emotional dysregulation, depression, stroke, traumatic brain injury, seizures, pain (e.g., post-operative pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof.

[0156] 47. The method of any one of embodiments A39-46, further comprising administering to the subject an antidepressant.

[0157] 48. The method of embodiment A47, wherein the antidepressant is selected from bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, metabolites or prodrugs of any of these compounds, and combinations thereof.

[0158] 49. The method of any one of embodiments A39-46, further comprising administering to the subject quinidine.

[0159] 50. The method of any one of embodiments A39-46, wherein the subject is not administered a CYP2D6 inhibitor.

[0160] 51. The method of any one of embodiments A39-46, wherein the subject is not administered quinidine.

[0161] 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.

[0162] 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 an ester thereof), opioid agonists (e.g., μ-opiate analgesics (e.g., tramadol)), adenosinergic agonists, 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, gabapentin, and pharma- ceutically acceptable salts thereof.

[0163] 54. The method of any one of embodiments A39-53, wherein the transdermal delivery device is applied once a day for up to 7 days or more, or for at least 7 days, or any desired period of time.

[0164] 55. The method of any one of embodiments A39-53, wherein the transdermal delivery device is applied once a week, or 2, 3, 4, 5, or 6 times a week.

[0165] Exemplary embodiments B1 to B26 1. A method of administering dextromethorphan to a human subject in need thereof, comprising applying a transdermal delivery device containing dextromethorphan to the skin of the subject once daily, wherein said application results in the following pharmacokinetic profile in the human subject: a. A mean C of at least about 3 ng / ml (e.g., about 3 ng / ml to about 12 ng / ml) of dextromethorphan one day after application. max ; b. A mean AUC of dextromethorphan of at least about 40 ng*h / ml (e.g., about 40 ng*h / ml to about 150 ng*h / ml) one day after application. 0-24 ; 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 The average ratio of; 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 The average ratio of; d. A C of dextromethorphan of at least about 1.2 (e.g., about 1.5 to about 2.5) one day after application. 24h / C 6h The average ratio of; e. One day after application, the C of dextromethorphan is about 0.85 to about 1.3. 24h / C 18h The average ratio of; f. 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) one day after application. max ; g. Mean AUC of dextrorphan at 10 ng*h / ml (e.g., 10 ng*h / ml or less, or 5 ng*h / ml or less) on the first day after application 0-24 ; h. A C of dextrorphan of at least about 5 (at least about 10, at least about 15, at least about 20) one day after application. max C of dextromethorphan against max The average ratio of; i. an AUC of dextrorphan of at least about 5 (at least about 10, at least about 15, at least about 20, or at least about 25) one day after application; 0-24 AUC of dextromethorphan 0-24 Average ratio of The method of claim 1, wherein one or more of the following results:

[0166] 2. The method of embodiment B1, wherein the human subject is not suffering from a cough and / or does not require a cough suppressant.

[0167] 3. The method of embodiment B1 or 2, wherein the human subject is characterized as an extensive metabolizer.

[0168] 4. The mean C of dextromethorphan observed from orally administering a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily to said human subjects by said application, when measured one day after application. max At least about 30% (e.g., about 30% to about 80%) of the mean C of dextromethorphanmax The method of any one of embodiments B1-3, wherein

[0169] 5. The mean AUC of dextromethorphan observed from orally administering a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily to said human subjects according to said application, when 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

[0170] 6. The mean C of dextrorphan observed from orally administering a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily to said human subjects 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 B1-5, wherein

[0171] 7. The mean AUC of dextrorphan observed from orally administering a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily to said human subjects according to said application, when 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 B1-6, wherein

[0172] 8. The method of any one of embodiments B1-7, wherein the human subject is suffering from emotional dysregulation, depression, stroke, traumatic brain injury, seizures, pain (e.g., post-operative pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof.

[0173] 9. applying the transdermal delivery device once a day for a period of up to 7 days or for at least 7 days or any desired period, wherein the application results in the following pharmacokinetic profile in the human subject: a. A mean C of at least about 8 ng / ml (e.g., about 8 ng / ml to about 20 ng / ml) of dextromethorphan 7 days after application 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 B1-8, wherein one or both of the following is achieved:

[0174] 10. The method of any one of embodiments B1-9, wherein the transdermal delivery device contains from about 5 mg to about 100 mg of dextromethorphan.

[0175] 11. A method of administering dextromethorphan to a human subject in need thereof, comprising applying a transdermal delivery device containing dextromethorphan to the skin of the subject once a week, or 2, 3, 4, 5, or 6 times a week, wherein said application results in the following pharmacokinetic profile in the human subject: a. A mean C of at least about 3 ng / ml (e.g., about 3 ng / ml to about 12 ng / ml) of dextromethorphan one day after application. max ; b. A mean AUC of dextromethorphan of at least about 40 ng*h / ml (e.g., about 40 ng*h / ml to about 150 ng*h / ml) one day after application. 0-24 ; c. One day after application, a C of dextromethorphan of about 1.5 or less (e.g., about 1 to about 1.5) 24h / C 12h The average ratio of; d. A C of dextromethorphan of at least about 1.2 (e.g., about 1.5 to about 2.5) one day after application. 24h / C 6h The average ratio of; e. One day after application, the C of dextromethorphan is about 0.85 to about 1.3. 24h / C 18h The average ratio of; f. 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) one day after application. max ; g. Mean AUC of dextrorphan below 10 ng*h / ml (e.g., below 10 ng*h / ml or below 5 ng*h / ml) on the first day after application 0-24 ; h. A C of dextrorphan of at least about 5 (at least about 10, at least about 15, at least about 20) one day after application. max C of dextromethorphan against max the average ratio of i. an AUC of dextrorphan of at least about 5 (at least about 10, at least about 15, at least about 20, or at least about 25) one day after application; 0-24 AUC of dextromethorphan 0-24 The average ratio of The method of claim 1, wherein the method results in one or more of the following:

[0176] 12. The application results in the following pharmacokinetic profile in the human subject: a. A mean C of at least about 8 ng / ml (e.g., about 8 ng / ml to about 20 ng / ml) of dextromethorphan 7 days after application 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, further comprising providing one or both of:

[0177] 13. The method of embodiment B11 or 12, wherein the human subject is not suffering from cough and / or does not require antitussive medication.

[0178] 14. The method of any one of embodiments B11-13, wherein the human subject is characterized as an extensive metabolizer.

[0179] 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 said human subjects 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 B11-14, wherein

[0180] 16. The mean AUC of dextromethorphan observed from orally administering a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily for 7 days to said human subjects according to said application, 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 B11-15, wherein

[0181] 17. The mean C of dextrorphan observed from orally administering a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily for 7 days to said human subjects 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

[0182] 18. The mean AUC of dextrorphan observed from orally administering a combination of 20 mg dextromethorphan and 10 mg quinidine twice daily for 7 days to said human subjects according to said application, when measured 7 days after application. 0-24h About 50% or less (e.g., about 10% to about 30%) of the mean AUC of dextrorphan 0-24hThe method of any one of embodiments B11-17, wherein

[0183] 19. The method of any one of embodiments B11-18, wherein the human subject suffers from an emotion dysregulation disorder.

[0184] 20. The method of any one of embodiments B11-19, wherein the transdermal delivery device contains from about 50 mg to about 700 mg of dextromethorphan.

[0185] 21. A method of treating a disease or disorder in a subject in need thereof, comprising administering once daily to the skin of the subject a transdermal delivery device comprising dextromethorphan, wherein said application results in one or more pharmacokinetic profiles described in embodiments B1, B3-7, and B9, and wherein the disease or disorder is any of those described herein.

[0186] 22. The method of embodiment 21, wherein the disease or disorder is a neurological disease or disorder, such as an emotional dysregulation disorder.

[0187] 23. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the skin of the subject a transdermal delivery device comprising dextromethorphan once a week or 2, 3, 4, 5, or 6 times a week, wherein said application results in one or more pharmacokinetic profiles as described in embodiments B11-12 and B15-18, wherein said disease or disorder is any of those described herein.

[0188] 24. The method of embodiment 21, wherein the disease or disorder is a neurological disease or disorder, such as an emotional dysregulation disorder.

[0189] 25. The method of any one of embodiments B1-24, wherein the transdermal delivery device is selected from the transdermal delivery device of any one of embodiments A1-38 and C1-21.

[0190] 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 in formulation A, B, C1, C2, C3, D0, D1, or D2 in the preceding examples.

[0191] Exemplary embodiments C1 to C32 1. An adhesive layer comprising dextromethorphan dispersed in an adhesive comprising an acrylate adhesive and a silicone adhesive; The weight ratio of the acrylate adhesive to the silicone adhesive ranges from about 20:1 to about 1:20. Transdermal delivery devices.

[0192] 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).

[0193] 3. When tested in vitro using human cadaver skin, it has a concentration of at least about 200ug / cm2 24 hours after application. 2 (For example, about 200ug / cm 2 ~About 2000ug / cm 2 The transdermal delivery device of embodiment C1 or 2, wherein the transdermal delivery device is configured to provide an average cumulative permeated dextromethorphan of 100%.

[0194] 4. When tested in vitro using human cadaver skin, it has been shown to produce a concentration of at least about 5ug / cm2 8-24 hours after application. 2 *h (for example, about 5ug / cm 2 *h~about 20ug / cm 2 *h, about 10ug / cm 2 *h~approx.18ug / cm 2*The transdermal delivery device of any one of embodiments C1-3, configured to provide an average flux of dextromethorphan of h).

[0195] 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 that provides 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) higher than the average cumulative dextromethorphan of an otherwise comparable transdermal delivery device but not comprising the skin permeation enhancer, when tested in vitro using human cadaver skin.

[0196] 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 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 of an otherwise comparable transdermal delivery device but not containing the skin permeation enhancer, when tested in vitro using human cadaver skin.

[0197] 7. The transdermal delivery device of any one of embodiments C1-6, wherein the adhesive layer comprises a skin permeation enhancer in an amount that provides an average flux of dextromethorphan 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) greater than the average flux of dextromethorphan of an otherwise equivalent transdermal delivery device without the skin permeation enhancer, when tested in vitro using human cadaver skin.

[0198] 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) greater than the average flux of dextromethorphan of an otherwise equivalent transdermal delivery device without the skin permeation enhancer, when tested in vitro using human cadaver skin.

[0199] 9. A transdermal delivery device according to any one of embodiments C1-8, which is suitable for a 1-day, 2-day, 3-day, 4-day, 5-day, 6-day, or 7-day application.

[0200] 10. 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 C9, wherein the transdermal delivery device is configured to provide dextromethorphan of 0.1 mg / kg or more to a user.

[0201] 11.About 5cm 2 ~about 200cm 2 The transdermal delivery device of any one of embodiments C1-10, having a size of

[0202] 12.About 10cm 2 ~Approx. 100cm 2 The transdermal delivery device of any one of embodiments C1-11, having a size of

[0203] 13. An adhesive layer comprising dextromethorphan dispersed in the adhesive; the adhesive layer comprises a skin permeation enhancer in an amount that provides 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 of an otherwise comparable transdermal delivery device that does not contain the skin permeation enhancer, when tested in vitro using human cadaver skin. Transdermal delivery devices.

[0204] 14. The transdermal delivery device of embodiment C13, wherein the skin permeation enhancer is in an amount that provides an average flux of dextromethorphan 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 of an otherwise comparable transdermal delivery device but not containing the skin permeation enhancer, when tested in vitro using human cadaver skin.

[0205] 15. The transdermal delivery device of embodiment C13 or 14, wherein the skin permeation enhancer is in an amount to provide an average flux of dextromethorphan 4 to 8 hours after application that is at least about 2-fold (e.g., about 3-fold, about 4-fold, about 5-fold, about 8-fold, about 10-fold, or any range between the recited values) greater than the average flux of an otherwise comparable transdermal delivery device without the skin permeation enhancer, when tested in vitro using human cadaver skin.

[0206] 16. The transdermal delivery device of any one of embodiments C13-15, wherein the skin permeation enhancer is 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) greater than the average flux of dextromethorphan of an otherwise equivalent transdermal delivery device but not comprising the skin permeation enhancer, when tested in vitro using human cadaver skin.

[0207] 17. A transdermal delivery device according to any one of embodiments C13-16, which is suitable for application for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days.

[0208] 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 dextromethorphan of 0.1 mg / kg or more to a user.

[0209] 19. Approximately 5cm 2 ~about 200cm 2 The transdermal delivery device of any one of embodiments C13-18, having a size of

[0210] 20.About 10cm 2 ~Approx. 100cm 2 The transdermal delivery device of any one of embodiments C13-19, having a size of

[0211] 21. The skin permeation enhancer is selected from the group consisting of isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, and glycerol monooleate with a carbon chain length of C 12 ~C 18 The transdermal delivery device of any one of embodiments C13-20, wherein the fatty acid and fatty acid ester are selected from the group consisting of , , and other fatty acids and fatty acid esters, and combinations thereof.

[0212] 22. 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 comprises an adhesive layer, the adhesive layer comprising dextromethorphan dispersed in an adhesive, and a skin permeation enhancer, wherein the skin permeation enhancer is 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.

[0213] 23. The method of embodiment C22, wherein the skin permeation enhancer is in an amount such that said application results in an average cumulative dextromethorphan permeated 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 cumulative dextromethorphan resulting from application of an otherwise equivalent transdermal delivery device without the skin permeation enhancer.

[0214] 24. The method of embodiment C22 or 23, wherein the skin permeation enhancer is in an amount such that said application results in a mean flux of dextromethorphan 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 mean flux of dextromethorphan resulting from application of an otherwise equivalent transdermal delivery device without the skin permeation enhancer.

[0215] 25. The method of any one of embodiments C22-24, wherein the skin permeation enhancer is in an amount such that said application results in a mean 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 mean flux of dextromethorphan resulting from application of an otherwise equivalent transdermal delivery device without the skin permeation enhancer.

[0216] 26. The method of any one of embodiments C22-25, wherein the transdermal delivery device is applied once a day for one or more days (e.g., 1, 2, 3, 4, 5, 6, or 7 days or more).

[0217] 27. At least about 200ug / cm per day 2 (For example, about 200ug / cm 2 ~About 2000ug / cm 2 The method of embodiment C26, wherein dextromethorphan of

[0218] 28. The transdermal delivery device is approximately 5 cm 2 ~about 200cm 2 The method of any one of embodiments C22 to C27, having a size of

[0219] 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

[0220] 30. The skin permeation enhancer is selected from the group consisting of isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, and glycerol monooleate with a carbon chain length of C 12 ~C 18 The method of any one of embodiments C22-29, wherein the fatty acid and fatty acid ester of the formula (I) is selected from the group consisting of fatty acids and fatty acid esters of the formula (I), and combinations thereof.

[0221] 31. A method for 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 upon application, about 2 mg / day to about 50 mg / day of dextromethorphan is transdermally delivered to the subject.

[0222] 32. The method of embodiment C31, wherein the transdermal delivery device is configured to have flux characteristics such that, upon application, the transdermal delivery device 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). EXAMPLES

[0223] Example 1. Preparation of dextromethorphan transdermal patch This example shows one procedure for preparing dextromethorphan drug-containing adhesive patch.Dextromethorphan base is generally commercially available.Alternatively, dextromethorphan base can be prepared by converting dextromethorphan hydrobromide to free base, for example, using NaOH in a molar ratio of 1:1.

[0224] Preparation of Formulation A 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, 50 g of an acrylic PSA, DuroTak 87-2287 (Henkel Adhesives), 50.5% solids, was added. The contents of the batch were mixed for 30 minutes or until the contents were uniform. The resulting wetting solution was then cast onto a release liner (Loparex Corp.) using a 10 mil casting applicator. The casting was dried at 80° C. for 10 minutes in a forced air oven. After drying, the dried casting was laminated to a patch backing film Scotchpak 012 (3 M Drug Delivery Systems). The patch was then molded to a 30 cm 2 The resulting transdermal patch 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 patch contained approximately 16 mg DXM. The patch had good skin adhesion and adhered closely 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.

[0225] Preparation of Formulation B using 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 a silicone PSA, 50 g of Bio-PSA DC7-4502 with 60.0% solids (Dow Corning). The contents of the batch were mixed for 30 minutes or until the contents were uniform. The resulting wetting solution was cast onto a fluoropolymer coated release liner (3M's 1022) using a 15 mil casting applicator. The casting was dried at 80° C. for 10 minutes in a forced air oven. After drying, the dried casting was laminated to a patch backing film Scotchpak 1012 (3 M Drug Delivery Systems). The patch was then coated with a 30 cm 2 The resulting transdermal patch had an adhesive matrix thickness of 3.5 mil. The patch had good skin adhesion and adhered closely 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.

[0226] Preparation of Formulation C, which used a mixture of acrylate and silicone adhesives, did not use a skin permeation enhancer, and maintained the concentration of dextromethorphan at 9%. Following a similar 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.

[0227] Preparation of Formulation D: Following the same procedure as above, formulations containing different amounts of permeation enhancers are also prepared. Formulation D1 contains isopropyl myristate in an amount of 7.7%, and formulation D2 contains isopropyl myristate in an amount of 10%. As a control, formulation D0 without isopropyl myristate was also prepared.

[0228] Table 1 below summarizes the components of the different formulations prepared above in weight percentages (the percentages in the table refer to dry weights). (Table 1) JPEG0007609943000003.jpg38166

[0229] Example 2. Transdermal flux test The transdermal flux of dextromethorphan from the patch was examined using human cadaver epidermis by the Franz diffusion cell method.

[0230] 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 buffered saline (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 times: 4, 8, 12, 24, 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.

[0231] The test results for Formulations A and B are shown in Table 1 below (see also Figure 1). Values ​​presented are in cm 2 The cumulative amount of DXM transmitted per unit area (i.e., μg / cm 2 ). (Table 2) JPEG0007609943000004.jpg46166

[0232] The test results for formulations C1-C3 are shown in Table 3 below (see also Figure 2). The values ​​presented are in cm 2The cumulative amount of DXM transmitted per unit area (i.e., μg / cm 2 ). (Table 3) JPEG0007609943000005.jpg61166

[0233] Example 3. Dextromethorphan transdermal patch containing a permeation enhancer Formulations D0-D2 were also tested for their in vitro flux properties following the same protocol as described in Example 2. The results are shown in Table 4 (see also Figure 3). (Table 4) JPEG0007609943000006.jpg19166

[0234] The results clearly show that increasing the level of IPM by up to 10% significantly enhances the skin permeation of DXM.

[0235] Example 4. In vivo pharmacokinetic studies This example relates to an open-label, randomized, two-treatment, two-period, two-sequence crossover study conducted in 16 healthy adult male and female subjects to evaluate the comparative bioavailability of an experimental dextromethorphan patch, 15 mg / 24 hours, versus 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 CYP2D6 genotype. All 16 subjects can be characterized as extensive metabolizers of dextromethorphan. See, for example, Treducu ALD et al. Frontiers in Pharmacology, vol. 9, Article 305 (April 2018).

[0236] This study measured the pharmacokinetic profiles of both dextromethorphan and dextrorphan (one metabolite of dextromethorphan).

[0237] During one period of the study, a drug-in-adhesive patch was used, consisting of a 45 cm patch containing 35 mg of DXM, with a DIA layer containing approximately 80 wt% adhesive (Duro-Tak 87-2287), approximately 10 wt% dextromethorphan base, and approximately 10 wt% of the permeation enhancer isopropyl myristate, designed to deliver approximately 15 mg / 24 hours transdermally. 2 One dextromethorphan patch was applied to the left lateral upper arm of healthy subjects for 24 hours after an overnight fast of at least 10 hours. In the other study period, a single NUEDEXTA® (dextromethorphan hydrobromide and quinidine sulfate) capsule, 20 mg / 10 mg, was administered every 12 hours (hours 0 and 12) (for a total dose of 40 mg / 20 mg over 24 hours) after an overnight fast of at least 10 hours (hour 0).

[0238] For NUEDEXTA treatment, subjects fasted overnight for at least 10 hours only before the 0-hour dose. The order of dosing followed a 2-sequence randomization schedule. Blood samples were collected before dosing and at intervals of more than 96 hours after dosing with study drug (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 the 48-hour, 72-hour, and 96-hour blood sample collections. The dosing (0 hours) interval was at least 10 days.

[0239] Plasma concentrations of dextromethorphan and its active metabolite dextrorphan were measured by fully validated analytical procedures. Statistical analysis using mean bioequivalence methodology was performed to evaluate the bioavailability of the test formulations compared to that of the dextromethorphan and dextrorphan-only reference products.

[0240] The study was designed 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 for conducting bioavailability / bioequivalence and adhesion studies under fasting conditions. A washout period of at least 10 days was selected for the study to minimize potential carryover effects.

[0241] The study was also designed to minimize potential drug interactions that may have affected the results of this study: for example, subjects were screened and monitored for taking medications such as MAO inhibitors, tricyclic antidepressants, SSRIs, drugs involved in TdP or arrhythmias, and inducers or inhibitors of CYP3A4 or CYP2D6.

[0242] Pharmacokinetic results Blood samples were collected at these time points (for small doses): pre-dose (0 hours) 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 sample). 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.

[0243] Tables 5A-5D show the results from this study. Tables A and C show the plasma concentrations of dextromethorphan and dextrorphan, respectively, in subjects who received Neudextra (reference) orally twice daily. Tables B and D show the plasma concentrations of dextromethorphan and dextrorphan, respectively, in subjects who received a 24-hour treatment with a dextromethorphan patch.

[0244] Table 5A. Dextromethorphan PK profile in Neudexta-treated subjects JPEG0007609943000007.jpg145166

[0245] Table 5B. Dextromethorphan PK profile in subjects receiving DXM patch treatment JPEG0007609943000008.jpg148166

[0246] Table 5C. Dextrorphan PK profile in Neudexta-treated subjects JPEG0007609943000009.jpg153166

[0247] Table 5D. Dextrorphan PK profile in subjects receiving DXM patch treatment JPEG0007609943000010.jpg150166

[0248] Based on this study, subjects treated with the DXM patch had a significantly lower AUC of DXM vs. DRP observed with patch treatment. 0-24 , AUC 0-t , and C max The ratios of DXM to DRP observed with the patch treatment were significantly higher than the respective ratios observed with the Neudexta treatment. 0-24 was nearly three times (24.54:9.03) the mean ratio observed with Neudexta treatment, see Table 6 below.

[0249] Table 6. Comparison of PK profiles of patch and Neudexta treatments JPEG0007609943000011.jpg128166

[0250] 4A and 4B show graphs of dextromethorphan and dextrorphan concentrations from 0 to 96 hours.

[0251] Example 5. Multi-layer patch design In this example, a novel multi-layer design is described.

[0252] An exemplary patch design useful for 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 287-2287): 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 287-2287): 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 that refers to 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.

[0253] In one example, a multi-layer patch may be 60 cm 2 More than, for example, about 60 cm 2 ~Approx. 150cm 2 The size of the slit may be 0.01 to 0.01 mm.

[0254] 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 a patch is suitable for a 7-day application and can transdermally deliver about 20 mg or more of dextromethorphan per day for 7 days (a total delivery of about 140 mg or more over the 7-day period).

[0255] Example 6. Pharmacokinetic simulation This example shows a simulation of dextromethorphan (DXM or DM) plasma profiles and dextrorphan (DOR) plasma profiles over a 7 day period following daily application of patches of different sizes.

[0256] The method used to simulate the plasma profile after daily dosing of different sized patches over a 7-day period is called superposition. It involves iteratively adding the concentration of the next dose to the profile of the previous dose without the need for compartmental modeling or knowing the PK parameters. First, the 70 cm 2 The mean plasma profiles of dextromethorphan (abbreviated DXM or DM) and dextrorphan (abbreviated DOR or DRP) after a single 24-hour patch application were 2 The results obtained using the patch are shown in Example 4. It is assumed that the rate of absorption of DXM increases proportionally with patch size, but the rate of conversion of DXM to DRP, the rate of DXM clearance, and the rate of DRP clearance remain unchanged.

[0257] Next, apply 60cm once a day for 7 days. 2 and 90cm 2 DXM and DRP plasma profiles from the patch were predicted using predicted single-dose profiles and the principle of superposition, assuming that each dose after day 1 causes no changes in the clearance of DXM, DRP, or the conversion of DXM and DRP.

[0258] The results of the pharmacokinetic simulation are shown in Figures 6A to 6D. As shown in Figure 6B, 2Daily administration of DXM patches of these sizes produces DXM plasma levels that fall within the peak and trough DXM concentrations from 7 days of oral administration of Neudexta BID (20 mg DXM / 10 mg quinidine). Furthermore, the DXM plasma levels obtained from daily administration of the DXM patch are less variable, with peak-to-trough ratios lower than those observed from 7 days of oral administration of Neudexta BID (20 mg DXM / 10 mg quinidine).

[0259] It should be understood that the Detailed Description section, and not the Summary and Abstract sections, are 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 inventors, and thus are not intended to be in any way limiting of the scope of the invention and the appended claims.

[0260] The present invention has been described above using functional components that illustrate implementation of specified functions and their relationships. The boundaries of these functional components have been arbitrarily defined in this specification for the convenience of description. Alternative boundaries can be defined as long as the specified functions and their relationships are appropriately performed.

[0261] 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.

[0262] The foregoing description of the specific embodiments fully discloses the general nature of the invention, so that others, by applying knowledge within the art, may easily 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 or terminology used herein is for the purpose of description rather than limitation, and thus may be interpreted by those skilled in the art in light of the teaching and guidance.

[0263] 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.

[0264] All of the various aspects, embodiments, and options described herein can be combined in any and all variations.

[0265] 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. In the event that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall control.

Claims

1. 1. A transdermal delivery device for use in treating a neurological disease or disorder in a human subject in need thereof, comprising: the neurological disease or disorder is an emotional dysregulation disorder, the transdermal delivery device is a drug-in-adhesive patch having a single drug-in-adhesive layer and containing dextromethorphan only in the drug-in-adhesive layer, the dextromethorphan being uniformly dispersed in the adhesive in the drug-in-adhesive layer; The transdermal delivery device contains dextromethorphan base as the only drug, the drug-containing adhesive layer comprises an adhesive in an amount of about 65% to about 85%, a drug in an amount of about 2% to about 12%, a permeation enhancer in an amount of about 6% to about 12%, and any other components in an amount of about 0% to 20%, wherein the adhesive is an acrylate copolymer adhesive selected from polyacrylate vinyl acetate copolymers, and the permeation enhancer is isopropyl myristate; The transdermal delivery device comprises about 15 mg to about 100 mg of dextromethorphan, the transdermal delivery device is applied to the skin of the subject once daily; the subject is not administered a CYP2D6 inhibitor, the human subject is not suffering from cough and / or does not require cough suppressants; Said application resulted in the following pharmacokinetic profile in said human subjects: a. Mean C of about 3 ng / ml to about 12 ng / ml of dextromethorphan on day 1 of application ｍａｘ ; b. Mean AUC of dextromethorphan from about 40 ng*h / ml to about 150 ng*h / ml on day 1 of application ０－２４ ; c. One day after application, a C of dextromethorphan of about 1 to about 1.5 ２４ｈ / C １２ｈ The average ratio of d. One day after application, a C of dextromethorphan of about 1.5 to about 2.5 ２４ｈ / C ６ｈ The average ratio of e. One day after application, a C of dextromethorphan of about 0.85 to about 1.3 ２４ｈ / C １８ｈ The average ratio of f. Mean C of dextrorphan below 2 ng / ml on day 1 of application ｍａｘ ; g. Mean AUC of dextrorphan below 10 ng*h / ml on day 1 of application ０－２４ ; h. A C of dextrorphan of at least about 5 one day after application. ｍａｘ C of dextromethorphan against ｍａｘ The average ratio of i. AUC of dextrorphan of at least about 5 on day 1 of application. ０－２４ AUC of dextromethorphan ０－２４ Average ratio of The transdermal delivery device is provided with one or more of:

2. By the above application, a) Mean C of about 3 ng / ml to about 12 ng / ml of dextromethorphan on day 1 of application ｍａｘ and / or b) Mean AUC of dextromethorphan from about 40 ng*h / ml to about 150 ng*h / ml on day 1 of application ０－２４ The transdermal delivery device of claim 1 , which provides a PK profile comprising:

3. By the above application, c) One day after application, a C of dextromethorphan of about 1 to about 1.5 ２４ｈ / C １２ｈ The average ratio of d) One day after application, a C of dextromethorphan of about 1.5 to about 2.5 ２４ｈ / C ６ｈ and / or the average ratio of e) One day after application, a C of dextromethorphan of about 0.85 to about 1.3 ２４ｈ / C １８ｈ Average ratio of 3. The transdermal delivery device of claim 1 or 2, which provides a PK profile comprising:

4. By the above application, f) Mean C of 2 ng / ml or less of dextrorphan on the first day of application ｍａｘ and / or g) Mean AUC of dextrorphan below 10 ng*h / ml on day 1 of application ０－２４ The transdermal delivery device of any one of claims 1 to 3, which provides a PK profile comprising:

5. By the above application, h) A C of dextrorphan of at least about 5 one day after application. ｍａｘ C of dextromethorphan against ｍａｘ and / or the average ratio of i) AUC of dextrorphan of at least about 5 after 1 day of application. ０－２４ AUC of dextromethorphan ０－２４ Average ratio of The transdermal delivery device of any one of claims 1 to 4, which provides a PK profile comprising:

6. The transdermal delivery device is applied once daily for a period of up to seven days or for at least seven days or any desired period, and said application results in the following pharmacokinetic profile in the human subject: a. A mean C of at least about 8 ng / ml of dextromethorphan at 7 days after application ｍａｘ and b. Mean C of 2 ng / ml or less of dextrorphan 7 days after application ｍａｘ The transdermal delivery device of any one of claims 1 to 5, wherein one or both of the following are provided:

7. The transdermal delivery device of any one of claims 1 to 6, wherein the human subject is characterized as an extensive metabolizer.

8. 8. The transdermal delivery device of any one of claims 1 to 7, wherein the human subject is not administered any of desipramine, paroxetine, thioridazine, pimozide, digoxin, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, and combinations thereof.

9. 9. The transdermal delivery device of any one of claims 1 to 8, providing a daily dose of about 15 mg to about 50 mg of dextromethorphan.

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