RU2795729C2 - Dextromethorphan transdermal delivery device - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to a method and device for transdermal delivery for the treatment of pseudobulbar affect. The method includes once daily applying a transdermal delivery device containing about 5 to about 100 mg of dextromethorphan to the subject's skin. The device for transdermal delivery is a single-layer patch with a drug in the adhesive, where the specified single layer contains dextromethorphan, homogeneously dispersed in the adhesive, where the adhesive layer contains the adhesive in an amount of about 65 to about 85 wt.%, the drug in an amount of about 2 to about 12 wt.%, the penetration enhancer, which is isopropyl myristate, in an amount of about 6 to about 12% of the mass. The transdermal delivery device contains dextromethorphan as the only drug. The adhesive is an acrylate copolymer adhesive selected from polyacrylate vinyl acetate copolymers.

EFFECT: group of inventions allows to deliver a sufficient amount of dextromethorphan to achieve a therapeutically effective plasma concentration of dextromethorphan, while minimizing the amount of dextrofan metabolite, without requiring the use of CYP2D6 inhibitors, such as quinidine, and without requiring a determination of whether the subject is a slow metabolizer, an intermediate metabolizer, or a fast metabolizer (that is, without requiring determination of the patient's genotype).

10 cl, 7 dwg, 11 tbl, 6 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims priority over U.S. Provisional Application No. 62/568028, filed Oct. 4, 2017, and U.S. Provisional Application No. 62/680182, filed June 4, 2018, the contents of each of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

Field of invention

[002] In various embodiments, the invention relates generally to transdermal delivery devices comprising dextromethorphan, and methods for their preparation and use, for example, for use in the treatment of a disease or disorder, such as a neurological disease.

Prior Art

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

[004] The recommended starting dose of NUEDEXTA® capsules (dextromethorphan hydrobromide and quinidine sulfate), 20 mg/10 mg is one capsule per day orally for the first seven days of therapy. On the eighth day of therapy and thereafter, the daily dose should be one capsule every 12 hours, for a total of two capsules per day. The need for continued treatment should be reassessed periodically as some patients experience spontaneous improvement in PBA.

[005] The most common adverse reactions (incidence ≥ 3% and twice that of placebo) in patients taking NUEDEXTA®, in descending order, are diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, urinary tract infection tracts, influenza, increased levels of gamma-glutamyltransferase and flatulence. The following adverse reactions have been reported with the individual components of dextromethorphan: drowsiness, dizziness, nervousness or restlessness, nausea, vomiting, and abdominal pain.

SUMMARY OF THE INVENTION

[006] In various embodiments, the invention relates to novel transdermal delivery devices that contain dextromethorphan, pharmaceutical compositions that contain dextromethorphan, and methods for transdermal administration of dextromethorphan. The transdermal delivery devices, pharmaceutical compositions, and methods described herein have therapeutic efficacy in the treatment of various diseases and disorders, such as neurological diseases or disorders (eg, PBA).

[007] The transdermal delivery devices described herein are new in various aspects. In some embodiments, the transdermal delivery device may be characterized by a patch design, such as having an adhesive layer and a reservoir layer. Typically, the reservoir layer may contain a concentration of dextromethorphan of at least 10% wt. reservoir layer. In some embodiments, the transdermal delivery device may be characterized by an adhesive layer containing a mixture of two adhesives, such as a mixture of an acrylate adhesive and a silicone adhesive. In some embodiments, the transdermal delivery device may be characterized by the presence of, for example, a transdermal penetration enhancer, which can provide a higher flux compared to another equivalent transdermal delivery device without a transdermal penetration enhancer. In some embodiments, the transdermal delivery device may have certain specific release profiles, such as in vitro flux profiles when tested using human cadaver skin and/or in vivo release profiles. In any of the embodiments described herein, the transdermal delivery device may be configured to provide one or more in vitro release profiles and/or one or more pharmacokinetic (PK) profiles described herein to a user. In some embodiments, the transdermal delivery device can provide a pharmacokinetic (PK) profile with a pharmaceutically effective plasma concentration of dextromethorphan in a subject in need (e.g., a subject having a PBA) for a desired period of time. In some embodiments, the transdermal delivery device may be configured for once daily use, for example, to provide a daily dose of about 2 to about 50 mg of dextromethorphan. In some embodiments of the invention, the transdermal delivery device can be configured to be used once every at least one day, for example, once every two days or more (for example, once a week), or 1, 2, 3, 4, 5 or 6 times a week, for example, to provide a daily dose of about 2 to about 50 mg of dextromethorphan. Any of these features/aspects may be combined with others and such combinations are specifically contemplated by the present invention.

[008] In some embodiments of the invention, the device for transdermal delivery may contain an adhesive layer containing an adhesive that optionally contains dextromethorphan dispersed in the adhesive, in an amount of from about 2% of the mass. up to about 12% wt. adhesive layer; and a reservoir layer containing dextromethorphan in an amount of at least 10 wt%. (for example, from about 20 wt. % to about 60 wt. %) of the reservoir layer. In some embodiments, the transdermal delivery device may comprise an adhesive layer containing dextromethorphan dispersed in an adhesive containing an acrylate adhesive and a silicone adhesive, wherein the weight ratio of acrylate adhesive to silicone adhesive may be, for example, from about 20:1 to about 1 :20. In some embodiments, the transdermal delivery device may comprise an adhesive layer containing dextromethorphan dispersed in the adhesive, wherein the adhesive layer contains a percutaneous penetration enhancer, e.g. 25% (e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any range in between) higher than an equivalent transdermal delivery device without a percutaneous penetration enhancer when tested in vitro with using human cadaver skin.

[009] In some embodiments, the present invention relates to a method of administering dextromethorphan to a subject (eg, human) in need. In some embodiments, the method includes applying a transdermal delivery device to the skin of a subject. In some embodiments of the invention, such use results in one or more of the pharmacokinetic profiles described herein. In some embodiments, the transdermal delivery device has a flow characteristic such that, when administered transdermally, dextromethorphan is delivered to a subject in an amount of from about 2 mg/day to about 50 mg/day. In some embodiments, the transdermal delivery device comprises an adhesive layer, wherein the adhesive layer comprises dextromethorphan dispersed in the adhesive, and a transdermal penetration enhancer, the transdermal penetration enhancer being in such an amount that its use provides an average cumulative value of dextromethorphan penetration after 24 hours after application, at least 25% (e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any range in between) higher than an equivalent transdermal delivery device without a transdermal enhancer penetration. In some embodiments, the transdermal delivery device is used once per day. In some embodiments, the transdermal delivery device is used once every at least one day, such as once a week, twice a week, or three times a week.

[0010] In some embodiments, the present invention relates to a method of treating a disease or disorder (eg, a neurological disease or disorder, such as PBA) in a subject (eg, a human) in need thereof. In some embodiments, the method includes applying a transdermal delivery device containing dextromethorphan to the skin of a subject, the application resulting in one or more of the pharmacokinetic profiles described herein. In some embodiments, the transdermal delivery device is used once per day. In some embodiments, the transdermal delivery device is used once every at least one day, such as once a week, twice a week, or three times a week.

[0011] The methods described herein are not limited to a particular subject or a particular class of subjects. In some embodiments of the invention, the subject is characterized as a fast metabolizer (a subject with a high metabolic rate). In some embodiments of the invention, the subject is characterized as a slow metabolizer (a subject with a low metabolic rate). In some embodiments, the subject is not co-administered with a CYP2D6 inhibitor. In some embodiments, the subject is not co-administered quinidine. In some embodiments, the subject is co-administered a CYP2D6 inhibitor such as quinidine, bupropion, etc. However, in any of the embodiments described herein, the subject does not suffer from cough and/or does not require an antitussive drug .

[0012] In some embodiments, the methods described herein may further include administering to the subject an active substance other than dextromethorphan. For example, in some embodiments, the method includes administering an antidepressant to a subject. In some embodiments, the method described herein further comprises administering to the subject one or more additional active ingredients selected from the group consisting of: amlodipine, a capsaicinoid (e.g., capsaicin or an ester thereof), an opioid agonist (e.g., a μ-opiate analgesic (eg tramadol)), adenosinergic agonist, 3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol, gabapentin and their pharmaceutically acceptable salts. These additional substances may be administered simultaneously or sequentially, by the same or different routes.

BRIEF DESCRIPTION OF GRAPHICS/SHAPES

[0013] FIG. 1 is a graph showing the results of an in vitro flow study for a formulation A and B transdermal delivery device with various adhesives, with the dextromethorphan (DXM) flux from the formulation A patch (acrylate adhesive) shown at the top with a faster flow than from the patch with composition B (silicone adhesive).

[0014] FIG. 2 is a graph showing the results of an in vitro flow study for C1-C3 formulation patches that contain various ratios of silicone adhesive to acrylic adhesive, 54:46 (center), 18:92 (bottom), and 9:91 (top).

[0015] FIG. 3 is a graph showing the effect of a percutaneous penetration enhancer (isopropyl myristate, IPM) on in vitro flux: 10% IPM (top), 7.7% IPM (center), and 0% IPM (bottom).

[0016] FIG. 4A shows 96-hour plasma dextromethorphan concentration for a human clinical study comparing the effect of 24-hour administration of dextromethorphan (DXM) from a transdermal patch (Test A) and oral administration of Neudexta (20 mg DXM/10 mg quinidine) (reference B) twice a day. In FIG. 4B shows the plasma concentration of the dextrorphan metabolite over 96 hours for the same study. For FIG. 4A and 4B, both test and control administrations were administered to the subject on an empty stomach. Plasma concentrations refer to mean plasma concentrations with N = 16.

[0017] FIG. 5 shows a multi-layer patch design. The top layer is a skin-contacting adhesive layer, the middle layer is a reservoir layer, and the bottom layer is a protective layer or adhesive layer, which may be the same or different from the top layer.

[0018] FIG. 6A and 6B show simulated plasma concentrations of dextromethorphan over time following administration of 45 cm ² (FIG. 6A), 60 cm ² (FIG. 6B), or 90 cm ² (FIG. 6B) transdermal DXM patches, one once a day for 7 days. Plasma concentrations of dextromethorphan (DM) over time are also shown for comparison following oral administration of Neudexta (20 mg DXM/10 mg quinidine) twice daily for 7 days.

[0019] FIG. 6C and 6D show simulated plasma concentrations of dextrorphan (Dor) over time following administration of 45 cm ² (FIG. 6C), 60 cm ² (FIG. 6D), or 90 cm ² (FIG. 6D) DXM transdermal patches (Fig. 6D). ), once a day for 7 days. Also shown for comparison are plasma concentrations of dextrorphan over time following oral administration of Neudexta (20 mg DXM/10 mg quinidine) twice daily for 7 days.

[0020] FIG. 7 shows a two-zone patch design.

DETAILED DESCRIPTION OF THE INVENTION

[0021] The unpredictability of transdermal administration is notorious. From the inventor's experience, testosterone can be delivered transdermally without an enhancer at a rate three orders of magnitude faster than beta-estradiol. Structurally and in terms of the logarithm of the substance partition coefficient (LogP), these compounds are very similar, so this difference could not be expected. See U.S. Provisional Application No. 62/568,028, filed October 4, 2017, the contents of which are incorporated herein by reference in its entirety.

[0022] Dextromethorphan (DXM) has been used orally to treat neurological disorders such as pseudobulbar affect (PBA), emotional lability, agitation in Alzheimer's disease, major depressive disorder, treatment resistant disorder, in the treatment of pain, other CNS disorders, and the like. But to be effective, it must be delivered with a substance that competitively inhibits the cytochrome P450 2D6 (CYP2D6) liver enzyme. This, in particular, suggests that it is administered together with quinidine. Otherwise, there is too little processing of food by enzymes with the participation of the liver. US Pat. No. 6,335,030 B1 describes some examples of patches that contain dextromethorphan. Pharmacokinetic data on transdermal administration of dextromethorphan were unknown.

[0023] As detailed herein, the present invention primarily shows that dextromethorphan can be delivered transdermally in a therapeutically effective amount. Transdermal delivery of dextromethorphan may be advantageous in many different ways. For example, because the transdermal route avoids first-pass metabolism (inactivation in the liver prior to entering the systemic circulation), the transdermal delivery devices described herein can be administered to achieve a therapeutically effective plasma concentration whether or not a CYP2D6 inhibitor is co-administered. like quinidine. Thus, the transdermal delivery device and methods described herein may be administered for transdermal delivery of dextromethorphan to subjects who, for example, are sensitive to or intolerant of CYP2D6 inhibitors, such as quinine (e.g., have one or more side effects). associated with quinidine or co-administered with a drug whose metabolism is dependent on CYP2D6 inhibitors such as quinidine). In addition, the transdermal delivery device and methods described herein can be conveniently used to deliver dextromethorphan to a subject without considering, for example, with or without prior determination whether the subject is a slow metabolizer, an intermediate metabolizer, or a rapid metabolizer of dextromethorphan. For brevity, as used herein, unless otherwise apparent from the context, the terms slow metabolizer (PM), intermediate metabolizer (IM), or rapid metabolizer (EM) refer to the subject's ability to metabolize dextromethorphan. The categorization of a subject as PM, IM, or EM (alternatively referred to as ultra-metabolizers or ultra-rapid metabolizers, or UM, ultrarapid metabolizers) is known in the art. See, for example, Treducu A.L.D. et al. Frontiers in Pharmacology, vol. 9, Article 305 (April 2018), which designates subjects as UM based on genotype if they contain "≥ 3 copies of normal function genes").

[0024] In addition, contrary to expectations, the use of the transdermal delivery devices described herein may provide a longer _half -life of dextromethorphan, a reduced amount of metabolite (as evidenced by a higher ratio of dextromethorphan to dextrorphan), and/or a lower ratio peak-trough, when compared with the corresponding parameters observed with oral administration of the drug Neudexta. These characteristics can provide a superior clinical experience compared to, for example, Neudexta, while providing more accurate dosing, less frequent dosing, and reduced potential for side effects. The transdermal delivery devices herein can also be configured as a 24-hour patch, 2-day patch, 3-day patch, 4-day patch, 5-day patch, 6-day patch, or 7-day patch which is appropriate for the frequency dosing in the range of once a day to once a week, for example, once for more than 24 hours, more than 36 hours, more than 48 hours, etc., or 1, 2, 3, 4, 5 or 6 times in Week. Thus, the use of the transdermal delivery devices described herein may provide improved patient compliance and treatment regimens, at least by eliminating the Neudexta twice daily dosing regimen.

Transdermal delivery device containing dextromethorphan

[0025] Some embodiments of the present invention relate to novel transdermal delivery devices containing dextromethorphan.

[0026] Various patch designs can be used in the transdermal delivery device described herein. The transdermal delivery device described herein typically comprises a backing layer, an adhesive layer (eg, a drug in the adhesive layer) which is the skin-contact layer during use, and optionally a reservoir layer. The adhesive layer typically contains dextromethorphan dispersed in an adhesive (eg, homogeneously dispersed, which also includes dissolved), preferably in a pressure-sensitive adhesive. More than one adhesive layer may be used in the transdermal delivery device described herein. The adhesive layer is typically formulated such that the transdermal delivery device can adhere to the user's skin for a desired period of time. For example, in some embodiments, the transdermal delivery device is capable of continuously adhering to the user's skin for about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days. , about 6 days or about 7 days or more.

[0027] In some embodiments, the transdermal delivery device may be a drug-in-adhesive patch (DIA). In some embodiments, the DIA patch is a single layer patch, for example, one layer contains dextromethorphan homogeneously dispersed in the adhesive. In some embodiments, the DIA patch is a multilayer patch. For example, two adhesive drug layers may be included in the patch, optionally separated by a membrane, such as a rate control membrane or reservoir layer. In some embodiments, one of the drug layers in the adhesive may be a reservoir layer, for example, with a higher concentration of dextromethorphan than the other layer. In some embodiments, the two drug-in-adhesive layers may form a reservoir layer.

[0028] A drug-in-reservoir (DIR) patch design can also be used in the transdermal delivery device described herein. In some embodiments of the invention, the reservoir layer and the adhesive layer can be layered on top of each other or separated, for example, by a rate-controlling membrane. For example, in some embodiments of the invention, a reservoir layer, such as a drug matrix, may be layered on the adhesive layer. Those skilled in the art will understand that such an adhesive layer can also contain a certain amount of drug, for example, by means of equilibrium.

[0029] Other patch designs may also be used in the transdermal delivery device described herein. For example, in some embodiments, the transdermal delivery device may be an active patch, such as an iontophoresis patch. In some embodiments, the transdermal delivery device may be a minimally invasive patch, such as a microneedle patch.

[0030] The transdermal delivery device may contain dextromethorphan alone or in combination with another drug. Unless explicitly contradicted, in any of the embodiments described herein, dextromethorphan may be the only drug in the transdermal delivery device. Dextromethorphan may be in various forms, for example as a free base or a pharmaceutically acceptable salt. As used herein, the terms mass percent, concentration, flux, etc., in relation to dextromethorphan should be understood as the total amount of dextromethorphan measured and/or calculated with a value expressed in terms of the equivalent value for the dextromethorphan base. In addition, all weight percentages, unless otherwise clear from the context, should refer to a weight percentage based on the final composition (e.g., final adhesive layer or reservoir layer, etc.) or transdermal delivery device, as the case may be. In any of the embodiments of the invention described herein, dextromethorphan may exist in its free base form, except that it may be protonated through equilibrium with other ingredient(s). For example, in any of the embodiments of the invention described herein, the transdermal delivery device or pharmaceutical compositions described herein can be obtained by mixing directly or indirectly the specified amount of dextromethorphan base with other ingredients.

[0031] In any of the embodiments described herein, the dextromethorphan in the transdermal delivery device may be partially or completely replaced by a deuterated dextromethorphan, for example, a d3 analog (O-CD ₃ , or N-CD ₃ ) or a d6 analog (N- CD ₃ , O-CD ₃ ), see, for example, paragraphs 1 and 17 of US Pat. No. 7,973,049, the contents of which are incorporated by reference in their entirety. Obviously, in such embodiments, methods using deuterated dextromethorphan patches will provide the user with deuterated dextromethorphan. As used herein, the term "deuterated dextromethorphan" refers to a compound obtained by replacing one or more hydrogen atoms of dextromethorphan with deuterium, resulting in a higher deuterium content at each substituted position, i.e., the substituted position is enriched in deuterium. In some embodiments, 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. % deuterium. In any of the embodiments described herein, the dextromethorphan in the transdermal delivery device may also be partially or completely replaced by a dextromethorphan analog such as fluorinated dextromethorphan or a skin-permeable dextromethorphan prodrug, etc.

[0032] The adhesive layer typically contains a pressure sensitive adhesive (PSA). Useful characteristics for a pressure sensitive adhesive include adequate tack, good adhesion, and cohesive strength. Other useful properties include biocompatibility (such as non-irritant, non-sensitizing, non-toxic properties), formulation compatibility, delivery system compatibility, and the like. Suitable pressure sensitive adhesives include, for example, polyacrylates, polyacrylic esters, silicones, polyisobutylenes, and the like.

[0033] 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 polyisobutylenes (PIB), silicone polymers, acrylate copolymers, and combinations thereof. In some embodiments, the pressure-sensitive adhesive comprises a polyisobutylene adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some embodiments, the pressure sensitive adhesive comprises an acrylate copolymer adhesive. Non-limiting useful acrylate copolymers include, for example, acrylic pressure-sensitive adhesives such as polyacrylate vinyl acetate copolymer, e.g. Duro-Tak 87-2852 or Duro-Tak 87-2194), which are manufactured by Henkel Adhesives. PIBs are elastomeric polymers that are commonly used in PSA, both as primary base polymers and as tackifiers. PIBs are homopolymers of isobutylene and have a regular carbon-hydrogen backbone structure with only terminal unsaturation. Non-limiting applicable PIBs include those sold under the trade name Oppanol from BASF. Silicone polymers are high molecular weight polydimethylsiloxane that contain residual silanol functional groups (SiOH) at the ends of the polymer chains. Non-limiting, suitable silicone PSAs for pharmaceutical use include those available from Dow Corning Corporation, eg under the trade name BIO-PSA, eg BIO-7-4202. In some embodiments, the adhesive layer has a thickness of from about 0.1 mil (2.54 microns) to about 10 mils (254 microns), for example, from about 1.5 mils (38.1 microns) to about 10 mils (254 microns). microns), (for example, from about 1.5 mils (38.1 microns) to about 2 mils (50.8 microns)).

[0034] 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 adhesive. 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 3083, 3253, 788 and 9073. They may, for example, have hydroxy functional groups, carboxyl groups, hydroxyl and carboxyl groups or have no functional groups (as active as above). They may, for example, contain vinyl acetate monomer or not.

[0035] Typically, a transdermal delivery device (eg, a DIA patch) is supported by a protective layer, such as an impervious protective film, and the adhesive surface is protected by a protective coating prior to use. Various materials can be used as a protective layer for the transdermal delivery device. As a rule, the protective layer is impermeable. For example, the protective layer may consist of impervious polymeric films such as polyester (PET) or polyethylene (PE) films. In some embodiments, the protective layer may comprise a polyester such as Scotchpak 9736 or Scotchpak 1012, a polyurethane film such as Scotchpak 9701, or a polyethylene film such as CoTran 9720. In some embodiments, the protective layer is part of the coating and may be a non-woven fabric, polyurethane film or other pliable material for flexibility and better wear.

[0036] For the present invention, the protective coating can be made in the required size. The protective coating may consist of a silicone or fluoropolymer coated polyester film. The protective cover protects the transdermal delivery device during storage and is removed prior to use. Silicone coated protective covers include those manufactured by Mylan Corporation, Loparex Corporation, and 3M Drug Delivery Systems. Fluoropolymer coated protective coatings include those manufactured and supplied by 3M Drug Delivery Systems and Loparex. In some embodiments, the protective coating comprises 3M ScotchPak 9744 or Scotchpak 1022.

[0037] The transdermal delivery devices described herein may also optionally contain other suitable excipients such as humectants, plasticizers, antioxidants, emollients, gelling agents, crystallization inhibitors, drug release modifiers, etc. These excipients are known to those skilled in the art and can be found, for example, in the Handbook of Pharmaceutical Excipients ( ^7th ed. 2012), the entire contents of which are incorporated herein by reference. In some embodiments, an additional active ingredient(s) may also be included in the transdermal delivery device described herein.

[0038] The transdermal delivery devices (eg, DIA patches) described herein may have different sizes (patch sizes) depending on their application. Typically, the dimensions of the patch may be from about 5 cm ² to about 300 cm ² (for example, about 5 cm ² , about 10 cm ² , about 20 cm 2 , about 30 cm ² , about 40 cm ^{2 ,} about 50 cm ² , about 60 cm ² , about 80 cm ² , about 100 cm ² , about 120 cm ² , about 150 cm ² , about 200 cm ² or any range in between), for example, from about 10 cm ² to about 100 cm ² .

[0039] When applying the transdermal delivery devices (eg, DIA patches) described herein to the skin of a subject, the entire adhesive surface could theoretically come into contact with the skin. Thus, the area of the adhesive surface determines the area of contact with the skin, which is also referred to in this document as the area of the active surface. 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 adhesive surface area. In some embodiments, the adhesive surface and one or more other surfaces of the transdermal delivery device are in contact with the skin upon application, and the entire skin contact area is the active surface area. In a typical DIA patch, the size of the patch is the same as the active surface area. Unless otherwise clear from the context, the unit "/cm ² "should be understood per square centimeter of active surface area, as defined herein.

[0040] The active surface area may determine the doses of drug to be delivered. Typically, the active surface area may be from about 5 cm ² to about 300 cm ² (eg, about 5 cm ² , about 10 cm ² , about 20 cm 2 , about 30 cm ² , about 40 cm ^{2 ,} about 50 cm ² , about 60 cm ² , about 80 cm ² , about 100 cm ² , about 120 cm ² , about 150 cm ² , about 200 cm ² or any range in between), for example, from about 10 cm ² to about 100 cm ² .

[0041] In some embodiments, the transdermal delivery device described herein may be configured to provide the user with at least about 2 mg/day of dextromethorphan (e.g., about 2 mg/day to about 50 mg/day ) over a time period of 1 day or more, such as 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. For example, in some embodiments, the transdermal delivery device is configured to transdermally deliver dextromethorphan to a user in an amount of 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 in between) for 1 day or more (e.g., 1.5 days, 2 days, 3 days, 4 days , 5 days, 6 days, 7 days, or any range in between).

[0042] The total amount of dextromethorphan in the transdermal delivery device can be adjusted based on the desired total dose. As a rule, the total content of dextromethorphan exceeds 0.5 mg/cm ² (for example, at least 2 mg/cm ² , at least 3 mg/cm ² , at least 4 mg/cm ² , at least 5 mg/cm ² , at least 6 mg/cm ² etc.). For example, in some embodiments, the transdermal delivery device may have a total dextromethorphan content of from about 0.5 mg/cm ² to about 8 mg/cm ² , for example, from about 2 mg/cm ² to about 6 mg/cm ² (for example , about 2 mg/cm ² , about 3 mg/cm ² , about 4 mg/cm ² , about 5 mg/cm ² , about 6 mg/cm ^{2 ,} or within any ranges in between). In this context, the total amount of dextromethorphan in a patch can be calculated by dividing the total amount of dextromethorphan in the patch by the active surface area of the patch.

Transdermal Delivery Device (TDD) with reservoir layer

[0043] In some embodiments, a reservoir layer may be included in the transdermal delivery device described herein. For example, for high daily doses and/or use over an extended period of time (eg, 1 day or more), the reservoir layer may provide the user with a more sustained flow of dextromethorphan.

[0044] In some embodiments, the transdermal delivery device comprises an adhesive layer containing an adhesive and a reservoir layer containing dextromethorphan. In some embodiments of the invention, the adhesive layer optionally contains dextromethorphan dispersed in the adhesive. In some embodiments of the invention, the adhesive layer does not contain dextromethorphan, if not to take into account the equilibrium with the reservoir layer. In some embodiments of the invention, the adhesive layer contains dextromethorphan dispersed in the adhesive. In some embodiments, the reservoir layer contains dextromethorphan in an adhesive. In some embodiments of the invention, the reservoir layer and the adhesive layer are the same layer. In some embodiments of the invention, the reservoir layer is located between the adhesive layer and the protective layer. In some embodiments of the invention, the reservoir layer may be located between two adhesive layers, which may be the same or different. For example, in some embodiments, the two adhesive layers may have the same ingredients at the same concentrations, and in some embodiments, the invention may also have the same thickness. However, in some embodiments, the two adhesive layers may have different ingredients, or the same ingredients at different concentrations, or different thicknesses, etc. An exemplary configuration is shown in FIG. 3, where the adhesive layer is the top layer, and 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.

[0045] In some embodiments, the reservoir layer is separated from the adhesive layer by a membrane, such as a rate control membrane such as a microporous membrane. The reservoir layer preferably contains an adhesive; however, other reservoir layer layer designs are also suitable when compatible with the adhesive layer and the backing layer. For example, in some embodiments of the invention, the reservoir layer may be a woven/nonwoven material saturated with dextromethorphan, or containing dextromethorphan dispersed in another suitable carrier/base.

[0046] Dextromethorphan may be present in the adhesive layer and the reservoir layer at various concentrations. As a rule, the concentration of dextromethorphan in the reservoir layer is higher than in the adhesive layer. For example, in some embodiments of the invention, the adhesive layer may contain dextromethorphan in an amount of from about 2% to about 12% (for example, about 2%, about 4%, about 6%, about 8%, about 10%, about 12%, or any range between the indicated values) by weight of the adhesive layer; while the reservoir layer may contain dextromethorphan in an amount of about 20% or more, for example, about 30% or more, about 40% or more, about 50% or more, for example, from about 20% to about 60%, from about 30% up to about 50% wt. reservoir layer. In some embodiments, the adhesive layer contains about 6% to about 12% dextromethorphan (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or in any range between the indicated values) by weight of the adhesive layer. In some embodiments of the invention, the adhesive layer contains dextromethorphan at or near saturation concentration in the adhesive, for example, about 10 wt%. in acrylate adhesive. In some embodiments of the invention, the reservoir layer contains dextromethorphan above the saturation concentration in the adhesive. In other words, the dextromethorphan in the reservoir layer is supersaturated and therefore may include solid dextromethorphan which can serve as a drug depot.

[0047] Suitable adhesives for the adhesive layer and reservoir layer, as the case may be, include any of those described herein, preferably pressure-sensitive adhesives. The adhesives included in the adhesive layer and the reservoir layer may be the same or different. In some embodiments, the adhesives included in the adhesive layer and the reservoir layer are the same, for example, acrylate-based adhesives. Other suitable adhesives include a polyisobutylene adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive (eg, a polyacrylate vinyl acetate copolymer such as Duro-Tak 87-2287), or a combination thereof. In any of the embodiments of the invention described herein, the adhesive layer may be configured to adhere permanently to the user's skin for at least 1 day (e.g., at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days).

[0048] An adhesive (eg, a pressure-sensitive adhesive) is typically the main ingredient for the adhesive layer and the reservoir layer (as the case may be). For example, in some embodiments of the invention, the adhesive layer contains a pressure-sensitive adhesive in an amount of from about 50% to about 90% of the mass. adhesive layer. In some embodiments, the pressure-sensitive adhesive is present in an amount of from about 60% to about 85% (e.g., about 60%, about 70%, about 75%, about 80%, about 85%, or any range in between) by weight of the adhesive layer. For example, in some embodiments of the invention, the reservoir layer may contain a pressure-sensitive adhesive in an amount of from about 20% to about 80% of the mass. reservoir layer. For example, in some embodiments, the pressure-sensitive adhesive is present in an amount of from about 20% to about 65% (e.g., about 20%, about 30%, about 35%, about 40%, about 50%, about 60%, about 65% or any range between the indicated values) by weight of the reservoir layer.

[0049] Suitable device sizes for transdermal delivery are described herein. In some embodiments, the transdermal delivery device has an active surface area of from about 5 cm ² to about 200 cm ² . In some embodiments, the transdermal delivery device has an active surface area of from about 10 cm ² to about 150 cm ² . In some embodiments, the transdermal delivery device has an active surface area of from about 30 cm ² to about 100 cm ² (e.g., about 30 cm ² , about 40 cm ² , about 50 cm ² , about 60 cm ² , about 70 cm ² , about 80 cm ² , about 90 cm ² , about 100 cm ² or any range in between).

[0050] The adhesive layer and the reservoir layer may have different thicknesses. For example, in some embodiments, the adhesive layer has a thickness of from about 0.1 mil (2.54 µm) to about 10 mil (254 µm) (for example, from about 0.5 mil (12.7 µm) to about 10 mil (254 µm), about 1 mil (25.4 µm) to about 10 mil (254 µm)). In some embodiments of the invention, the reservoir layer has a thickness of from about 0.1 mil (2.54 microns) to about 10 mils (254 microns), (for example, from about 0.5 mils (12.7 microns) to about 10 mils ( 254 µm), from about 1 mil (25.4 µm) to about 10 mil (254 µm)).

[0051] Transdermal penetration enhancers may also be included in the adhesive layer and reservoir layer. For example, in some embodiments of the invention, the adhesive layer contains a transdermal penetration enhancer selected from the group consisting of: isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, other fatty acids and esters of fatty acids with carbon chain lengths from C ₁₂ to C _18, as well as their combinations. In some embodiments, the adhesive layer contains isopropyl myristate. Similarly, in some embodiments of the invention, the reservoir layer contains a transdermal penetration enhancer selected from the group consisting of: isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, other fatty acids and esters of fatty acids with carbon chain lengths from C ₁₂ to C _{18 ,} as well as their combinations. In some embodiments, the reservoir layer contains isopropyl myristate.

[0052] Different amounts of transdermal penetration enhancers can be used for the adhesive layer and the reservoir layer. Typically, the percutaneous penetration enhancer may be present in an amount of from about 2% to about 15% by weight. adhesive layer or reservoir layer. For example, in some embodiments, the percutaneous penetration enhancer is present in an amount of about 6% to about 12% (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12 % or in any range between the indicated values) by weight of the adhesive layer. In some embodiments, the percutaneous penetration enhancer is present in an amount of from about 6% to about 12% (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or in any range between the indicated values) by the mass of the reservoir layer. However, in some embodiments, the adhesive layer and/or reservoir layer may also be substantially free of a percutaneous penetration enhancer selected from the group consisting of: isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, other fatty acids, and complex esters of fatty acids with carbon chain lengths from C ₁₂ to C _18, as well as combinations thereof.

[0053] In some embodiments of the invention, the adhesive layer and / or reservoir layer may contain a substance selected from the group consisting of: polymer vinylpyrrolidone (for example, vinylpyrrolidone-vinyl acetate copolymers), kollidon (for example, Kollidon 30 LP, Kollidon 90 or Kollidon VA64) , silicon dioxide, titanium dioxide, and combinations thereof. In some embodiments, the substance may be present in an amount of from about 2% to about 20% (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 indicated values) by weight of the adhesive layer or reservoir layer. Without wishing to be limited by theory, it is believed that such substances can improve the cohesive strength of the adhesive layer or reservoir layer. In addition, such substances may have other functions such as inhibition of crystallization. In some embodiments of the invention, the adhesive layer contains a substance that is effective to improve the cohesive strength of the adhesive layer. In some embodiments of the invention, the reservoir layer contains a substance that is effective to improve the cohesive strength of the reservoir layer.

[0054] It should be noted that the identification characteristics of ingredients such as adhesives, transdermal penetration enhancers, substances and amounts thereof for the adhesive layer and the reservoir layer are independently selected and may be the same or different. As a rule, the quantities may vary while the identification characteristic may be the same. The thickness of the adhesive layer and the reservoir layer can also be the same or different.

Device for transdermal delivery with a mixture of adhesives

[0055] As detailed in the Examples section, changing the adhesive components can affect the flow characteristics of a transdermal delivery device containing dextromethorphan. Therefore, in some embodiments, the present invention also provides a transdermal delivery device comprising an adhesive layer, wherein the adhesive layer comprises two or more adhesives. Typically, the adhesive layer contains dextromethorphan dispersed in two or more adhesives.

[0056] In some embodiments of the invention, the adhesive layer may contain a mixture of acrylate copolymer adhesive (for example, Durotak 87-2287) and silicone adhesive (for example, BIO-7-4202) in various ratios (for example, the weight ratio of acrylate adhesive to silicone adhesive is in the range from 1:20 to 20:1). In some embodiments, the weight ratio of acrylate adhesive to 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 ranges between the specified values). Other ingredients and suitable amounts that may optionally be included in the adhesive layer, such as transdermal penetration enhancers, include those described herein.

[0057] An adhesive layer with two or more adhesives can be included/used in any transdermal delivery device described herein. For example, in some embodiments, the transdermal delivery device comprising the reservoir layer described herein may have an adhesive layer with a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios.

Transdermal delivery device with percutaneous penetration enhancer

[0058] Percutaneous penetration enhancers (transdermal enhancers) can improve the penetration of dextromethorphan through the skin and can be included in the transdermal delivery device described herein, if desired. Various percutaneous penetration enhancers may be included. Non-limiting useful percutaneous penetration enhancers include, for example, sulfoxides (eg, dimethyl sulfoxide, DMSO), azones (eg, laurocapram), pyrrolidones (eg, 2-pyrrolidone, 2P), alcohols and alkanols (eg, ethanol or decanol), esters, glycols (eg, propylene glycol (PG)), surfactants (eg, Tween 80), terpenes, and combinations thereof. See, for example, Williams et al., Adv Drug Deliv Rev. 27; 56(5): 603-18 (2004). In some embodiments, the transdermal penetration enhancers comprise one or more compounds selected from sulfoxides, alcohols, alkanols, esters, glycols, and surfactants. In some embodiments, percutaneous penetration enhancers comprise one or more compounds selected from the group consisting of: dimethyl sulfoxide (DMSO), oleic alcohol, oleyl oleate, oleic acid, levulinic acid, other fatty acids and fatty acid esters, propylene glycol, dipropylene glycol, ethanol and surfactants such as tween 80. In some embodiments, the transdermal device may contain one or more compounds selected from the group consisting of: DMSO, N-methyl-2-pyrolidone, azone, myristic acid, sesquiterpene oil, 4-decyloxazolidin-2-one, urea and the like. In some embodiments, the transdermal penetration enhancer is selected from the group consisting of: isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, other fatty acids and fatty acid esters with carbon chain lengths from C ₁₂ to C _18, as well as combinations thereof. In some specific embodiments, the transdermal penetration enhancer is isopropyl myristate.

[0059] The transdermal penetration enhancer is typically present in an amount of from about 1% to about 25% by weight. adhesive layer, for example, about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, or in any ranges between the indicated values by weight of the adhesive layer. In some embodiments, the transdermal device may be substantially free of a transdermal enhancer. In some embodiments, a transdermal device is substantially free of a transdermal enhancer if the amount of any potential such enhancers is about 20% or less than the smallest amount shown to increase transdermal flow by about 50% or more.

[0060] In some embodiments of the invention, the percutaneous penetration enhancer and its amount is selected to provide certain improved flow characteristics. For example, in some embodiments, the present invention provides a transdermal delivery device comprising an adhesive layer containing dextromethorphan dispersed in the adhesive, wherein the adhesive layer contains a percutaneous penetration enhancer in an amount that provides an average cumulative penetration value of dextromethorphan 24 hours after application of at least about 25% (e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any range in between) higher than an equivalent transdermal delivery device without a percutaneous penetration enhancer when tested in vitro using human cadaver skin. The term "equivalent transdermal delivery device without transdermal penetration enhancer" should be understood as a control transdermal delivery device in which the content of the transdermal penetration enhancer in the adhesive layer is replaced with an adhesive, all other aspects being the same. For example, a transdermal delivery device contains an adhesive layer containing 10% wt. transdermal penetration enhancer and 10% wt. dextromethorphan, dispersed in 80% wt. acrylate adhesive, while another equivalent device will contain the appropriate adhesive layer with 10% wt. dextromethorphan, dispersed in 90% wt. the same acrylate adhesive, while all other aspects of the two devices are the same.

[0061] The transdermal penetration enhancer and its amount can also be adjusted to achieve an increase in flux at various time points after application. For example, in some embodiments of the invention, the percutaneous penetration enhancer is in an amount that provides one or more of the following: 50%, about 100%, about 150%, about 200%, or any range in between) higher than other equivalent transdermal delivery device without a percutaneous penetration enhancer; 2) mean dextromethorphan flux from 4 hours to 8 hours after administration of 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 these values) greater than that of another equivalent transdermal delivery device without a percutaneous penetration enhancer; and 3) an average dextromethorphan flux from 0 hours to 4 hours after administration of at least about 5 times (e.g., about 5 times, about 8 times, about 10 times, about 20 times, or any ranges between these value) greater than that of another equivalent transdermal delivery device without a percutaneous penetration enhancer in in vitro tests using human cadaver skin. As detailed in the examples, in one example, when the amount of penetration enhancer, isopropyl myristate, is increased to about 10% by weight, a significant improvement in flow is observed even up to 4 hours after application.

[0062] A transdermal penetration enhancer adhesive layer can be included/used in any transdermal delivery device described herein. For example, in some embodiments, a transdermal delivery device comprising the reservoir layer described herein may have a transdermal penetration enhancer adhesive layer. Other ingredients and suitable amounts that may optionally be included in the adhesive layer include those described herein.

[0063] In some specific embodiments, the transdermal delivery device may comprise an adhesive layer and a reservoir layer, wherein the adhesive layer and reservoir layer may, for example, contain the ingredients and amounts shown in the table below.

Adhesive layer ingredients Example Typical amount Preferred Quantity adhesive DuroTak 287-2287 from about 65% to about 85% from about 75% to about 77.5% Medicine Dextromethorphan as base from about 2% to about 12% about 10% Penetration enhancer isopropyl myristate from about 6% to about 12% about 10% Other Kollidon, e.g. Kollidon VA64 from about 1% to about 20% from about 2.5% to about 5% Reservoir Ingredients adhesive DuroTak 287-2287 from about 20% to about 70% from about 20% to about 57.5% Medicine Dextromethorphan as base from about 20% to about 60% from about 30% to about 50% Penetration enhancer isopropyl myristate from about 6% to about 12% about 10% Other Kollidon, e.g. Kollidon VA64 from about 1% to about 20% from about 2.5% to about 20%

All amounts in the table refer to the weight percentage of the respective layer (based on the final composition), with the total amount of each layer being 100%. In some embodiments, the transdermal delivery device may have an active surface area of about 60 cm ² or more, such as about 70 cm ² . In some embodiments, the transdermal delivery device is configured to provide the user with dextromethorphan in an amount of from about 15 mg/day to about 40 mg/day, for example, 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 in between. In some embodiments, the transdermal delivery device contains dextromethorphan in an amount of about 50 mg to about 700 mg (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 in between). In some embodiments of the invention, the reservoir layer may be located between two adhesive layers, which may be the same or different. Typically, such a transdermal delivery device also contains a protective layer and a protective coating that protects the adhesive surface prior to use. Typically, these patches can be used for a dosing frequency of less than once a day, for example, once every day or every two days or more, for example, once a week or 2, 3, 4, 5 or 6 times a week, for example, twice a week.

[0064] In some specific embodiments, the transdermal delivery device may comprise an adhesive layer, which may, for example, contain the ingredients and amounts shown in the table below.

Adhesive layer ingredients Example Typical amount Preferred Quantity adhesive DuroTak 287-2287 from about 65% to about 85% about 80%, or from about 75% to about 77.5% Medicine Dextromethorphan as base from about 2% to about 12% about 10% Penetration enhancer isopropyl myristate from about 6% to about 12% about 10% Other Kollidon, e.g. Kollidon VA64 0% to about 20% 0%, or about 2.5% to about 5%

All amounts in the table refer to the weight percent of the final composition of the adhesive layer, with the total amount being 100%. In some embodiments, the transdermal delivery device may have an active surface area of about 10 cm² or more, such as about 30cm², about 45 cm², about 60 cm², about 75 cm², about 90 cm². In some embodiments, the transdermal delivery device is configured to provide the user with dextromethorphan in an amount of from about 15 mg/day to about 40 mg/day, for example, 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 in between. In some embodiments, the transdermal delivery device contains dextromethorphan in an amount of about 5 mg to about 100 mg (e.g., about 15 mg, about 30 mg, about 45 mg, about 60 mg, about 90 mg, or any range in between. ). Typically, such a transdermal delivery device also contains a protective layer and a protective coating that protects the adhesive surface prior to use. Typically, these patches can be used for a dosing frequency of at least once a day, such as once a day or once every 12 hours, etc.

Flow characteristics in vitro

[0065] In some embodiments, the transdermal delivery device described herein is configured to provide a defined in vitro flux profile of dextromethorphan, such as when tested using human cadaver skin. For example, in some embodiments, any of the transdermal delivery devices described herein can be configured to provide 1) an average cumulative penetration of dextromethorphan of at least about 200 μg/cm ² (μg refers to micrograms) (e.g., from about 200 μg/cm ² to about 2000 μg/cm ² ) 24 hours after application; and/or 2) the mean dextromethorphan flux is at least about 5 µg/cm ² h (e.g., about 5 µg/cm ² h to about 20 µg/cm ² h, from about 10 µg/cm ² ×h to about 18 μg/cm ² ×h) from 8 hours to 24 hours after application, when tested in vitro using human cadaver skin.

[0066] In some embodiments, a transdermal delivery device can transdermally deliver to a subject in need at least about 200 µg/cm ² (e.g., about 200 µg/cm ² to about 2000 µg/cm ² ) per day. In some embodiments, the transdermal delivery device is configured with a flow characteristic such that application of the transdermal delivery device to a subject in need transdermally delivers dextromethorphan to the subject in an amount of about 2 mg/day to about 50 mg/day. In some embodiments, a transdermal delivery device may transdermally deliver a substance to a subject in an amount of 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 in between) for 1 day or more (e.g., 1.5 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or any range in between). The size of the transdermal delivery device is typically from about 5 cm ² to about 200 cm ² , for example, from about 10 cm ² to about 100 cm ² .

[0067] Devices for transdermal delivery with the above flow characteristics can be prepared by experts in the art in view of the present invention. Several device preparations for transdermal delivery are also provided as an example in the Examples section. The overall penetration of the drug (dextromethorphan, deuterated dextromethorphan, or a combination thereof) can be adjusted, for example, by varying the composition of the adhesive layer (e.g., drug concentration, penetration enhancer, drug loading, types of adhesives, etc.).

[0068] It should be noted that the pharmaceutical composition formulated for the adhesive layer and/or reservoir layer described herein is also a new aspect of the present invention.

[0069] The transdermal delivery device described herein may also have a defined in vivo release profile, eg, to provide a desired pharmacokinetic (PK) profile, eg, any of those described herein. In some embodiments, the transdermal delivery device may be configured to provide a PK profile in a subject in need, such as any of the PK profiles described herein. In some embodiments, the transdermal delivery device is configured to provide a PK profile effective, for example, for treating a disease or disorder (eg, as described herein, such as PBA) in a subject.

Transdermal delivery device with two different areas

[0070] In some embodiments, the transdermal delivery device may comprise two different zones with different release rates.

[0071] In FIG. 7 illustrates a view of a transdermal matrix device 100. The central matrix 20 may, for example, be configured (amount of drug and adhesive or adhesive mixture selected) to provide a faster onset of action. In an illustrative example, the added amount of pharmaceutically active substance in the Central matrix 20 may reduce adhesion. However, adhesion from the surrounding matrix 30 holds the device in place. The surrounding matrix 30 may be configured to, for example, provide longer delivery of the pharmaceutically active substance.

[0072] In embodiments of the invention with two different zones, the faster release portion of the device may be in area, for example, from about 5 cm ² to about 150 cm ² , for example, from about 5 cm ² to about 100 cm ² or from about 5 cm ² to about 40 cm ^{2 ,} etc. The slower release portion may be in area, for example, from about 5 cm ² to about 150 cm ² , for example, from about 5 cm ² to about 100 cm ² or from about 7.5 ^cm2 to about 55 ^cm2 , etc.

Methods for administering dextromethorphan and providing PK profiles.

[0073] In various embodiments, this invention provides a method of using the transdermal delivery device or pharmaceutical compositions described herein, for example, to administer dextromethorphan to a subject in need, such as those suffering from any of the diseases or disorders, described in this document.

[0074] Some embodiments of the invention relate to a method of administering dextromethorphan to a subject (eg, human) in need. In some embodiments of the invention, the subject is sensitive to quinidine or otherwise intolerant of it, for example, due to prolongation of the QTc interval. In some embodiments, the method includes applying any of the transdermal delivery devices or pharmaceutical compositions to the subject, eg, to the subject's skin. In some embodiments, the subject is not administered dextromethorphan from another source, such as by oral administration. However, in some embodiments, the subject may also be supplemented from another source of dextromethorphan, such as by co-administering an oral composition of dextromethorphan to the subject. In some embodiments of the invention, the user is characterized as a fast metabolizer. In some embodiments of the invention, the user is characterized as a slow metabolizer. In some embodiments, the user is not co-administered a CYP2D6 inhibitor. In some embodiments, the user is not co-administered quinidine. In some embodiments, a CYP2D6 inhibitor such as quinidine, bupropion, etc. is co-administered to the user.

[0075] Various dosing regimens are suitable for the methods described herein. For example, in some embodiments, the method includes administering a transdermal delivery device (eg, as described herein) to a subject once daily for a desired period of time. In some embodiments, the transdermal delivery device contains from 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 days or more (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 the required period of time. In some embodiments, the method may also include administering a transdermal delivery device (e.g., as described herein) to a subject once on at least one day, e.g., once every two days or more (e.g., once a week), or 1, 2, 3, 4, 5, or 6 times per week for the required period of time. In some embodiments, the method may also include administering a transdermal delivery device (eg, as described herein) to a subject once a week. In some embodiments, the transdermal delivery device contains from about 50 mg to about 700 mg of dextromethorphan. Although the methods described herein typically use a transdermal delivery device to a subject at a frequency of once per day or once every more than 1 day, in some embodiments the methods may also use a transdermal delivery device to a subject. with a frequency of once in a period of less than 1 day, for example, twice a day or three times a day.

[0076] The methods of administering dextromethorphan described herein generally provide a defined pharmacokinetic profile in a subject in need (e.g., a human) that is appropriate (e.g., effective), e.g., for treating the subject's disease or disorder (e.g., , any of those described in this document, such as PBA).

[0077] In some embodiments, the methods include administering the transdermal delivery device described herein to a subject to achieve a mean blood _Cmax of dextromethorphan from about 6 ng/mL to about 21 ng/mL (e.g., from about 8 ng/mL). /ml to about 17 ng/ml or from about 10 ng/ml to about 15 ng/ml), and that for twelve hours or more, the AUC of dextromethorphan approximately corresponds to (normalized to the measurement period) a 12-hour value of about 52 ng × h/ml to about 144 ng*h/ml (eg, from about 65 ng*h/ml to about 125 ng*h/ml, or from about 75 ng*h/ml to about 110 ng*h/ml).

[0078] As detailed in the Examples section, use in a healthy individual of an exemplary patch containing about 35 mg of dextromethorphan, a 45 ^cm adhesive) about 80% wt. adhesive (Duro-Tak 87-2287), about 10% wt. dextromethorphan in the form of a base, and about 10% of the mass. penetration enhancer of isopropyl myristate, within about 24 hours, in particular, a mean C _max of about 6 ng/ml and a mean AUC _0-24h of about 92 h ng/ml are achieved, which are close to those observed when taken orally in humans combinations of dextromethorphan 20 mg and quinidine 10 mg twice daily. This shows for the first time that transdermal delivery of dextromethorphan without the use of quinidine can provide significant levels of dextromethorphan in human blood. In addition, the human PK data allows the practitioner to adjust the design of the patch to achieve the desired PK profile.

[0079] For example, in some embodiments, the method comprises, consists essentially of, or consists of applying a transdermal delivery device (e.g., described herein) containing dextromethorphan to the skin of a subject (e.g., human) once daily (for example, for a period of up to 7 days or more, or for at least 7 days, or any desired period of time), while the application results in one or more (1, 2, 3, 4, 5, 6, 7 , 8, or all), in any combination of the following pharmacokinetic profile in a subject: 1) Mean _Cmax of dextromethorphan is at least about 3 ng/mL (e.g., about 3 ng/mL to about 12 ng/mL) at Day 1 after application (i.e. measured over a period of 0 to 24 hours after application); 2) the mean AUC _0-24 of dextromethorphan is at least about 40 ng×h/ml (eg, from about 40 ng×h/ml to about 150 ng×h/ml) 1 day after application; 3) the average value of the ratio C _24h /C _12h dextromethorphan is no more than about 1.5 (for example, from about 1 to about 1.5) 1 day after application; 4) the average value of the ratio C _24h /C _6h dextromethorphan is at least about 1.2 (for example, from 1.5 to 2.5) 1 day after application; 5) the average value of the ratio C _24h /C _18h dextromethorphan is from about 0.85 to about 1.3 in 1 day after application; 6) the average value of C _max dextrorphan is not more than 2 ng/ml (for example, not more than 2 ng/ml, not more than 1 ng/ml or not more than 0.5 ng/ml) 1 day after application; 7) the average AUC _0-24 of dextrorphan is not more than 10 ng×h/ml (for example, not more than 10 ng×h/ml or not more than 5 ng×h/ml) 1 day after application; 8) the average value of the ratio of C _max dextromethorphan to C _max dextrofan is at least about 5 (for example, at least about 10, at least about 15, at least about 20) at 1 day after application; and 9) the average ratio of AUC _0-24 dextromethorphan to AUC _0-24 dextrophan is at least about 5 (e.g., at least about 10, at least about 15, at least about 20, or at least about 25) 1 day after application. In some embodiments, the application results in a subject in a PK profile containing: 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).

[0080] In some embodiments, the method may comprise, consist essentially of, or consist of applying a transdermal delivery device (e.g., described herein) containing dextromethorphan to the skin of a subject (e.g., human) once at least per day (for example, once every two days or more (for example, once every two days, once every three days, once every four days, once every five days, once every six days, once a week etc.) (for example, for a period of up to 7 days or more, or for at least 7 days or any required period of time), while the application results in one or more (1, 2, 3, 4 , 5, 6, 7, 8, or all), any combination of the following pharmacokinetic profile in a subject: 1) Mean _Cmax of dextromethorphan is at least about 3 ng/mL (e.g., from about 3 ng/mL to about 12 ng /ml) 1 day after application; 2) the mean AUC _0-24 of dextromethorphan is at least about 40 ng×h/ml (eg, from about 40 ng×h/ml to about 150 ng×h/ml) 1 day after application; 3) the average value of the ratio C _24h /C _12h dextromethorphan is no more than about 1.5 (for example, from about 1 to about 1.5) 1 day after application; 4) the average value of the ratio C _24h /C _6h dextromethorphan is at least about 1.2 (for example, from 1.5 to 2.5) 1 day after application; 5) the average value of the ratio C _24h /C _18h dextromethorphan is from about 0.85 to about 1.3 in 1 day after application; 6) the average value of C _max dextrorphan is not more than 2 ng/ml (for example, not more than 2 ng/ml, not more than 1 ng/ml or not more than 0.5 ng/ml) 1 day after application; 7) the average AUC _0-24 of dextrorphan is not more than 10 ng×h/ml (for example, not more than 10 ng×h/ml or not more than 5 ng×h/ml) 1 day after application; 8) the average value of the ratio of C _max dextromethorphan to C _max dextrofan is at least about 5 (for example, at least about 10, at least about 15, at least about 20) at 1 day after application; and 9) the average ratio of AUC _0-24 dextromethorphan to AUC _0-24 dextrophan is at least about 5 (e.g., at least about 10, at least about 15, at least about 20, or at least about 25) 1 day after application. In some embodiments, the application results in a subject in a PK profile containing: 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, a method using at least once within 1 day results in essentially the same PK profile for 1 day after application as that observed after applying the method described herein once a day .

[0081] Plasma concentration from the transdermal delivery device described herein can be maintained substantially constant and the peak-to-trough ratio is generally lower than that observed with twice-daily oral dosing of Neudexta. For example, in some embodiments, the method includes applying a transdermal delivery device to the skin of a subject (e.g., human) once a week, the application resulting in i) an average C _24h /C _12h dextromethorphan ratio of no more than 2 (e.g., from about 0.85 to about 1.3) on day 7 after application; ii) an average C _24h /C _6h dextromethorphan ratio of no more than 2 (eg, about 0.85 to about 1.3) on day 7 after application; and/or iii) an average C _24h /C _18h dextromethorphan ratio of not more than 2 (eg, about 0.85 to about 1.3) on day 7 after administration. In some embodiments of the invention, the application leads to at least two of the results listed in paragraphs i)-iii). In some embodiments of the invention, the application leads to all the results listed in points i)-iii). The once-daily methods described herein can also result in a relatively low peak-to-trough ratio, which is typically below the corresponding ratio seen with twice-daily oral administration of Neudexta, e.g. period of time after reaching steady state.

[0082] In some embodiments of the invention, the methods described herein can be adjusted to achieve C _max and / or AUC of dextromethorphan in accordance with various needs, for example, to match (or approximate) those observed with oral administration of combination 20 mg dextromethorphan and quinidine 10 mg twice daily.

[0083] For example, in some embodiments, the method includes administering the transdermal delivery device described herein to a subject (e.g., human) once a day or once a week, for up to 7 days or more, or for for at least 7 days, or any desired period of time, while the application results in the following: i) the average value of C _max dextromethorphan is at least about 8 ng/ml (for example, from about 8 ng/ml to about 20 ng/ml ml) on the 7th day after application; and/or ii) the mean _Cmax of dextrorphan is no more than 2 ng/ml (eg, no more than 2 ng/ml, no more than 1 ng/ml, or no more than 0.5 ng/ml) on day 7 after application. In some embodiments, use results in one or more of the following PK profiles: a) the mean C _max for dextromethorphan is at least about 30% (e.g., about 30% to about 80%) of that observed when oral administration of a combination of 20 mg of dextromethorphan and 10 mg of quinidine twice a day in a subject (eg, human) for 7 days; b) the mean AUC _0-24 for dextromethorphan is at least about 30% (e.g., about 30% to about 80%) of that observed with an oral combination of dextromethorphan 20 mg and quinidine 10 mg twice daily in a subject (e.g., , person) within 7 days; c) the mean C _max for dextrorphan is no more than about 50% (e.g., about 10% to about 30%) of that observed with a combination of dextromethorphan 20 mg and quinidine 10 mg administered orally twice daily in a subject ( for example, a person) within 7 days; and d) the mean AUC _{of 0-24} dextrorphan is no greater than about 50% (e.g., about 10% to about 30%) of that observed with oral dosing of a combination of dextromethorphan 20 mg and quinidine 10 mg twice daily in a subject (e.g., , human) within 7 days when measured on the 7th day after application.

[0084] The methods described herein are not limited to a particular subject or a particular class of subjects. In some embodiments of the invention, the subject is characterized as a fast metabolizer (a subject with a high metabolic rate). In some embodiments of the invention, the subject is characterized as a slow metabolizer (a subject with a low metabolic rate). In some embodiments, the subject is not co-administered with a CYP2D6 inhibitor. In some embodiments, the subject is not co-administered quinidine. In some embodiments, the subject is co-administered a CYP2D6 inhibitor such as quinidine, bupropion, etc. However, in any of the embodiments described herein, the subject does not suffer from cough and/or does not require an antitussive drug .

[0085] In some embodiments of the invention, the subject (eg, human) is characterized as suffering from a neurological disease or disorder. In some embodiments, the subject (e.g., human) is characterized by having one or more diseases or disorders selected from the group consisting of: affective disorders, psychiatric disorders, cerebral function disorders, movement disorders, dementias, motor neuron diseases, neurodegenerative diseases, seizure disorders and headaches. In some embodiments of the invention, the subject suffers from one or more diseases or disorders selected from the group that includes: depression, major depression, treatment-resistant depression, treatment-resistant bipolar depression, bipolar disorders, including cyclothymia, seasonal affective disorders, disorders mood, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH), deficit disorder attention/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 drug abuse, nicotine addiction, psychosexual dysfunction, pseudobulbar affect and emotional lability. In some embodiments of the invention, the subject suffers from one or more diseases or disorders selected from the group that includes: Alzheimer's disease, prion diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, ataxia Friedrich disease, Huntington's disease, Levy's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shye-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 paraparesis, neurofibromatosis, olivopontocerebellar atrophy or degeneration, strionigral degeneration, Guillain-B syndrome arre, spastic paraplegia . In any of the embodiments described herein, the subject may be suffering from pseudobulbar affect, depression, stroke, traumatic brain injury, epileptic seizure, pain (eg, postoperative pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's disease, autism, or their combinations. In any of the embodiments of the invention described herein, the subject may suffer from pseudobulbar affect.

TREATMENT METHODS

[0086] Dextromethorphan is known to be useful in the treatment of various diseases or disorders. See, for example, Nguyen, L. et al.; Pharmacology & Therapeutics 159:1022 (2016). Thus, in some embodiments, the present invention also relates to a method of treating a disease or disorder in a subject in need thereof. In some embodiments, the method comprises transdermally administering to a subject a therapeutically effective amount of dextromethorphan. In some embodiments of the invention, the term "introduction" includes the use of a transdermal delivery device on the skin of a subject. In some embodiments, the administration results in a PK profile as described herein. In some embodiments of the invention, the subject does not suffer from a cough and/or does not need an antitussive substance. In some embodiments, the subject is a rapid metabolizer of dextromethorphan. In some embodiments, the subject is a poor dextromethorphan metabolizer. In some embodiments of the invention, the subject is sensitive to quinidine or otherwise intolerant of it, for example, due to prolongation of the QTc interval.

[0087] The methods described herein are suitable for the treatment of various diseases and disorders. In some embodiments, the disease or disorder is a neurological disorder. Non-limiting exemplary neurological diseases or disorders include mood disorders, psychiatric disorders, cerebral function disorders, movement disorders, dementias, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0088] Mood disorders that can be treated by the methods described herein include, but are not limited to: depression, major depression, treatment-resistant depression, treatment-resistant bipolar depression, bipolar disorders including cyclothymia, seasonal affective disorders, mood disorders , chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH), attention deficit disorder /hyperactivity (AD/HD), bipolar and manic states, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, drug addiction or drug abuse, nicotine dependence, psychosexual dysfunction, pseudobulbar affect and emotional lability .

[0089] Mental disorders that can be treated using the methods described 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-depressive illness, hypomania, unipolar depression, depression, stress disorders, psychosomatic disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer's disease, agitation and excitation in Alzheimer's disease.

[0090] Drug dependence that can be treated using the methods described herein includes, but is not limited to, drug dependence, dependence on cocaine, on psychostimulants (for example, crack, cocaine, amphetamine, methamphetamine), nicotine, alcohol, opioids , anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents and volatile nitrites. Nicotine addiction includes nicotine addiction in all known forms such as smoking cigarettes, cigars and/or pipes, as well as dependence on chewing tobacco.

[0091] Impairments of cerebral function that can be treated using the methods described herein include, but are not limited to, intellectual deficit disorders such as senile dementia, Alzheimer's dementia, memory loss, amnesia/amnestic syndrome , epilepsy, impaired consciousness, coma, decreased attention, speech disorders, vocal spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome and schizophrenia. Cerebral function disorders also include disorders caused by cerebrovascular diseases, including, but not limited to, stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral vein thrombosis, head trauma, and the like, in which symptoms include impaired consciousness, senile dementia, coma , decreased attention and speech disorders.

[0092] Movement disorders that can be treated using the methods described herein include, but are not limited to: akathisia, akinesia, associated movements, 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, Tourette's syndrome, and Wilson's disease.

[0093] Dementias that can be treated by the methods described herein include, but are not limited to: Alzheimer's disease, Parkinson's disease, vascular dementia, Lewy body dementia, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normotensive hydrocephalus , Huntington's disease, Wernicke-Korsakoff syndrome and Pick's disease.

[0094] Motor neuron diseases that can be treated using the methods described herein include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome ( SMA), spinal muscular atrophy (SMA), spinal motor atrophy, Tay-Sachs disease, Sandhoff disease, and hereditary spastic paraplegia.

[0095] Neurodegenerative diseases that can be treated using the methods described herein include, but are not limited to: Alzheimer's disease, prion diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Levy's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shye-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 paraparesis, neurofibromatosis, olivopontocerebellar atrophy or degeneration, strionigral degeneration, Guillain syndrome — Barre, spastic paraplegia.

[0096] Epileptic disorders that can be treated as described 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, Jackson's seizures, complex partial seizures, and continuous partial epilepsy; generalized seizures, including, but not limited to, generalized tonic-clonic seizures, petit mal seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0097] Types of headaches that can be treated with the methods described herein include, but are not limited to, migraine, tension headaches, and cluster headaches.

[0098] Other neurological disorders that can be treated by the methods described herein include, but are not limited to: Rett syndrome, autism, tinnitus, mental disorders, sexual dysfunction, persistent cough, narcolepsy, cataplexy; voice disturbances due to uncontrolled spasms of the laryngeal muscles, including, but not limited to, spastic abduction-type dysphonia, adduction-type spastic dysphonia, muscle tension 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; as well as erectile dysfunction.

[0099] In some embodiments, the disease or disorder is pain, joint pain, pain associated with sickle cell anemia, pseudobulbar affect, depression (including treatment-resistant depression), memory and cognitive disorders, schizophrenia, disease Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett's syndrome, convulsions, cough (including chronic cough), etc.

[00100] The methods described 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, pain inflammation, arthritis pain, complex regional pain syndrome, etc.

[00101] In some embodiments, the disease or disorder may be allodynia, refractory hyperalgesia, dermatitis, pain, inflammation, or inflammatory conditions such as Crohn's disease, including pain associated with inflammation, psoriasis, cancer, viral infection, or as an adjuvant in the treatment of multiple myeloma.

[00102] In any of the embodiments of the invention described herein, the method can be used to treat pseudobulbar lesions, depression, stroke, traumatic brain injury, epileptic seizure, pain (for example, postoperative pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's disease, autism, or combinations thereof.

[00103] Suitable dosing regimens, number of doses, duration, transdermal delivery devices, etc. include any of those described herein in any combination. In any of the embodiments described herein, the subject may be a human.

[00104] In some specific embodiments, the present invention relates to a method for treating a pseudobulbar lesion, which includes administering the transdermal delivery device described herein to a subject in need thereof. In some embodiments, the transdermal delivery device contains from about 5 mg to about 100 mg of dextromethorphan. In some embodiments of the invention, the transdermal delivery device is used once a day, for example, for a period of time up to 7 days, at least 7 days, 1 month, or any desired period of time. In some embodiments, the transdermal delivery device contains from about 50 mg to about 700 mg of dextromethorphan. In some embodiments, the transdermal delivery device is used once per week, such as for 1 week, 1 month, or whatever period of time is required. In some embodiments, the transdermal delivery device is used 1, 2, 3, 4, 5, or 6 times per week, such as for 1 week, 1 month, or whatever period of time is required. In some embodiments, a transdermal delivery device is used to achieve any pharmacokinetic profile 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 coughing or in need of an antitussive effect. In some embodiments of the invention, the subject is characterized as a slow metabolizer. In some embodiments of the invention, the subject is characterized as a rapid metabolizer.

Combination Therapy

[00105] In some embodiments, the methods described herein may further comprise administering to the subject an active substance other than dextromethorphan. For example, in some embodiments, the method described herein further comprises administering an antidepressant to the subject. In some embodiments, the antidepressant is selected from the group consisting of: bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, a metabolite or prodrug of any of these compounds, and combinations thereof. Other suitable antidepressants are described, for example, in US patent No. 9 861 595, the contents of which are incorporated into this description by reference in its entirety. In some embodiments, the method described herein further comprises administering quinidine to the subject. In some embodiments, the method described herein further comprises administering a CYP2D6 inhibitor to the subject. In some embodiments, the method described herein further comprises administering to the subject one or more additional active ingredients selected from the group consisting of: amlodipine, a capsaicinoid (e.g., capsaicin or an ester thereof), an opioid agonist (e.g., a μ-opiate analgesic (eg tramadol)), adenosinergic agonist, 3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol, gabapentin and their pharmaceutically acceptable salts. These additional substances may be administered simultaneously or sequentially. In addition, these additional substances can be administered in the same or different ways. For example, in some embodiments of the invention, the additional substance may be administered transdermally or orally. However, in some embodiments, the additional agent may also be combined with dextromethorphan in the same transdermal delivery device.

[00106] Because the transdermal application described herein bypasses hepatic first pass metabolism, the methods described herein may provide dextromethorphan to subjects who are taking medications that can impair hepatic metabolism of dextromethorphan. In some embodiments, the method includes administering desipramine, paroxetine, thioridazine, pimozide, digoxin, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, and combinations thereof to the subject. However, in some embodiments, the subject is not administered any drug from the group consisting of: desipramine, paroxetine, thioridazine, pimozide, digoxin, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, and combinations thereof. In some embodiments of the invention, the method does not require a determination, and/or is applied without regard to whether the subject is a fast metabolizer or a slow metabolizer of dextromethorphan.

Definitions

[00107] Used in this context, the term "about", modifying the amount related to the invention, refers to a change in the numerical amount that can occur, for example, as a result of routine testing and processing; due to an unintentional error in such testing and processing; due to differences in manufacturing, source or purity of the ingredients/materials used in the invention; etc. As used herein, the term "about" a specific value also includes the specific value, for example, about 10% includes 10%. Whether or not the term "about" is modified, the claims include equivalents of the amounts listed. In one embodiment of the invention, the term "about" means a value within 20% of the reported numerical value.

[00108] As used herein, the term "cumulative drug penetration" refers to the total amount of drug penetrating per square centimeter during a given time period. Unless otherwise clear from the context, "cumulative drug penetration" at a given time (e.g., 24 hours after administration) refers to the total amount of drug that has penetrated per square centimeter from time 0 (i.e. time of administration) to the value of the given time. Unless otherwise clear from the context, "cumulative drug penetration" refers to the arithmetic mean value measured and/or calculated in accordance with the methods described herein. Used in this document, the term "average", if not specified, also refers to the arithmetic mean, unless it is contrary to common practice in this area.

[00109] As used herein, the term "flux" refers to the amount of drug permeated through the skin per unit area per unit time. Unless otherwise apparent from the context, the term "flux" refers to the arithmetic mean value measured and/or calculated in accordance with the methods described herein. A typical flow measurement is milligrams per square centimeter per hour.

[00110] The flow rate referred to in this patent application may mean that it is measured by in vivo or in vitro methods. One way to measure flux is to place a transdermal delivery device or formulation on a known area of the skin of a human volunteer and measure the amount of drug that can permeate the skin within certain time limits. Those skilled in the art will appreciate that in some cases the absolute in vitro flux may differ by several times when measured using a different source from a cadaver. As used herein, the term "flux" is to be understood as measured in accordance with the method described in Example 2, where it is specifically indicated as being measured in vitro using human cadaver skin. For example, the patch tested in Example 2 can be used as a control patch which, when tested by the method of Example 2, should produce the same flux as observed in Example 2, within the experimental error generally accepted by those skilled in the art. Although the in vitro method uses a human cadaver-derived epidermal membrane instead of measuring drug flux through the skin using human volunteers, it is generally recognized by those skilled in the art that results from a properly designed and executed in vitro test can be used. to evaluate or predict the results of an in vivo test with reasonable certainty.

[00111] As used herein, the terms "treat," "treatment," "treatment," and the like, refer to the elimination, reduction, or amelioration of a disease or condition and/or associated symptoms. While not excluded, treatment of a disease or condition does not require complete elimination of the disease, condition, or associated symptoms.

[00112] As used herein, the term "therapeutically effective amount" refers to an amount of a drug (e.g., dextromethorphan) that is sufficient to result in the reduction of one or more symptoms of a disorder or condition (e.g., PBA) or to prevent the onset or further development disorder or condition, or cause regression or cure of the disorder or condition.

[00113] As used herein, the term "subject" (alternatively referred to herein as "subject") refers to an animal, preferably a mammal, most preferably a human, who has been the subject of treatment, observation, or experiment.

[00114] As used herein, the term "use or administration of the transdermal delivery device described herein" should be understood in accordance with the way in which such a transdermal delivery device is routinely used or administered to, for example, human skin.

Exemplary Embodiments of the Invention

[00115] Exemplary Embodiments A1-55

A transdermal delivery device comprising

an adhesive layer containing an adhesive, which optionally contains dextromethorphan dispersed in the adhesive, in an amount of from about 2% to about 12% of the mass. adhesive layer; And

a reservoir layer containing dextromethorphan in an amount of at least 10% (eg, from about 20% to about 60%) by weight of the reservoir layer.

The transdermal delivery device of Embodiment A1, wherein the transdermal delivery device is configured to transdermally deliver dextromethorphan to a user in an amount of from about 2 mg/day to about 50 mg/day.

The transdermal delivery device of Embodiment A1 or 2, wherein the transdermal delivery device is configured to transdermally deliver dextromethorphan to a user in an amount of 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 in between) for 1 day or more (e.g., 1.5 days , 2 days, 3 days, 4 days, 5 days , 6 days, 7 days, or any range in between).

The transdermal delivery device according to any of the embodiments of the invention A1-3, which has a total content of dextromethorphan from about 0.5 mg/cm ² to about 8 mg/cm ² .

The transdermal delivery device of any one of embodiments A1-4, which has a total dextromethorphan content of about 2 mg/cm ² to about 6 mg/cm ² (e.g., about 2 mg/cm ² , about 3 mg/cm ² , about 4 mg/cm ² about 5 mg/cm ² , about 6 mg/cm ² , or within any ranges in between).

The transdermal delivery device according to any of the embodiments of the invention A1-5, which has an active surface area from about 5 cm ² to about 200 cm ² .

The transdermal delivery device according to any of the embodiments of the invention A1-6, which has an active surface area from about 10 cm ² to about 150 cm ² .

The transdermal delivery device of any one of embodiments A1-7, which has an active surface area of from about 30 cm ² to about 100 cm ² (e.g., about 30 cm ² , about 40 cm ² , about 50 cm ² , about 60 cm ² , about 70 cm ² , about 80 cm ² , about 90 cm ² , about 100 cm ² , or any range in between).

The transdermal delivery device of any one of Embodiments A1-8, wherein the adhesive layer contains about 6% to about 12% dextromethorphan (e.g., about 6%, about 7%, about 8%, about 9% , about 10%, about 11%, about 12% or in any range between the indicated values) (wt.) of the adhesive layer.

The transdermal delivery device according to any one of the embodiments of the invention A1-9, characterized in that the adhesive layer further comprises a transdermal penetration enhancer.

A transdermal delivery device according to embodiment A10, characterized in that the percutaneous penetration enhancer is selected from the group consisting of: isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, other fatty acids and fatty acid esters with carbon chain lengths from C ₁₂ to From _18, as well as their combinations.

The device for transdermal delivery according to an embodiment of the invention A10 or 11, characterized in that the percutaneous penetration enhancer is present in an amount of from about 2% to about 15% of the mass. adhesive layer.

The transdermal delivery device of any one of embodiments A10-12, wherein the percutaneous penetration enhancer is present at about 6% to about 12% (e.g., about 6%, about 7%, about 8%, about 9% , about 10%, about 11%, about 12% or any range between the values indicated) by weight of the adhesive layer.

The transdermal delivery device according to any one of the embodiments of the invention A1-13, characterized in that the adhesive layer further comprises a substance to improve the cohesive strength of the adhesive layer.

A transdermal delivery device according to any one of the embodiments of the invention A1-13, characterized in that the adhesive layer further comprises a substance selected from the group consisting of: polymer vinylpyrrolidone (for example, vinylpyrrolidone-vinyl acetate copolymers), Kollidon (for example, Kollidon 30 LP, Kollidon 90 or Kollidon VA64), silicon dioxide, titanium dioxide and combinations thereof.

Device for transdermal delivery according to the embodiment of the invention A14 or 15, characterized in that the substance is present in an amount of from about 1% to about 20% of the mass. adhesive layer.

The transdermal delivery device of any one of embodiments A14-16, wherein the substance is present in an amount of from about 2% to about 20% (e.g., about 2%, about 2.5%, about 3%, about 4% , about 5%, about 6%, about 10% about 15%, about 20%, or any range in between), e.g., about 2% to about 6% (e.g., about 2%, about 2.5% , about 3%, about 4%, about 5%, or any range between the indicated values) by weight of the adhesive layer.

The transdermal delivery device according to any of the embodiments of the invention A1-17, characterized in that the adhesive contains a pressure-sensitive adhesive.

The transdermal delivery device of embodiment A18, wherein the pressure-sensitive adhesive comprises a polyisobutylene adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive (e.g., a polyacrylate vinyl acetate copolymer such as Duro-Tak 87-2287), or a combination thereof.

The device for transdermal delivery according to the embodiment of the invention A18 or 19, characterized in that the pressure-sensitive adhesive is present in an amount of from about 50% to about 90% of the mass. adhesive layer.

The transdermal delivery device of any one of embodiments A18-20, wherein the pressure-sensitive adhesive is present in an amount of from about 60% to about 85% (e.g., about 60%, about 70%, about 75%, about 80 %, about 85% or any range between the indicated values) by weight of the adhesive layer.

The transdermal delivery device according to any one of the embodiments of the invention A1-21, characterized in that the adhesive layer is adapted to adhere permanently to the skin of the user for at least 1 day (for example, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days).

The transdermal delivery device of any one of embodiments A1-22, wherein the adhesive layer has a thickness of about 0.1 mil (2.54 microns) to about 10 mils (254 microns) (e.g., about 0.5 mil (12.7 µm) to about 10 mil (254 µm), from about 1 mil (25.4 µm) to about 10 mil (254 µm)).

The transdermal delivery device of any one of embodiments A1-23, wherein the reservoir layer contains about 30% to about 50% dextromethorphan (e.g., about 30%, about 35%, about 40%, about 45% , about 50% or in any range between the indicated values) by weight of the reservoir layer.

The transdermal delivery device according to any of the embodiments of the invention A1-24, characterized in that the reservoir layer further comprises a transdermal penetration enhancer.

A transdermal delivery device according to embodiment A25, characterized in that the percutaneous penetration enhancer is selected from the group consisting of: isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, other fatty acids and fatty acid esters with carbon chain lengths from C ₁₂ to From _18, as well as their combinations.

The transdermal delivery device according to embodiment A25 or 26, characterized in that the transdermal penetration enhancer is present in an amount of from about 2% to about 15% by weight. reservoir layer.

The transdermal delivery device of any one of embodiments A25-27, wherein the percutaneous penetration enhancer is present at about 6% to about 12% (e.g., about 6%, about 7%, about 8%, about 9% , about 10%, about 11%, about 12% or any range between the indicated values) by weight of the reservoir layer.

The transdermal delivery device according to any of the embodiments of the invention A1-28, characterized in that the reservoir layer further comprises a substance to improve the cohesive strength of the reservoir layer.

A transdermal delivery device according to any of the embodiments of the invention A1-28, characterized in that the reservoir layer further comprises a substance selected from the group consisting of: polymer vinylpyrrolidone (for example, vinylpyrrolidone-vinyl acetate copolymers), Kollidon (for example, Kollidon 30 LP, Kollidon 90 or Kollidon VA64), silicon dioxide, titanium dioxide and combinations thereof.

Device for transdermal delivery according to the embodiment of the invention A29 or 30, characterized in that the substance is present in an amount of from about 1% to about 20% of the mass. reservoir layer.

The transdermal delivery device of any one of embodiments A29-31, wherein the substance is present in an amount of from about 2% to about 20% (e.g., about 2%, about 2.5%, about 3%, about 4% , about 5%, about 6%, about 10% about 15%, about 20%, or any range in between), e.g., about 2% to about 6% (e.g., about 2%, about 2.5% , about 3%, about 4%, about 5%, or any range between the indicated values) by weight of the reservoir layer.

The transdermal delivery device according to any one of the embodiments of the invention A1-32, characterized in that the reservoir layer contains dextromethorphan dispersed, for example, homogeneously dispersed, in a pressure-sensitive adhesive.

The transdermal delivery device of Embodiment A33, wherein the pressure-sensitive adhesive comprises a polyisobutylene adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive (e.g., a polyacrylate vinyl acetate copolymer such as Duro-Tak 87-2287), or a combination thereof.

The device for transdermal delivery according to an embodiment of the invention A33 or 34, characterized in that the pressure-sensitive adhesive is present in an amount of from about 20% to about 80% of the mass. reservoir layer.

The transdermal delivery device of any one of embodiments A33-35, wherein the pressure-sensitive adhesive is present in an amount of from about 20% to about 65% (e.g., about 20%, about 30%, about 35%, about 40% %, about 50%, about 60%, about 65% or any range between the indicated values) by weight of the reservoir layer.

The transdermal delivery device of any one of embodiments A1-36, wherein the reservoir layer has a thickness of about 0.1 mil (2.54 microns) to about 10 mils (254 microns) (e.g., about 0.5 mil (12.7 µm) to about 10 mil (254 µm), from about 1 mil (25.4 µm) to about 10 mil (254 µm)).

The transdermal delivery device according to any one of the embodiments of the invention A1-37, characterized in that the adhesive layer and the reservoir layer are separated by a release rate controlling membrane.

A method of administering dextromethorphan to a subject in need thereof, the method comprising administering a transdermal delivery device according to any one of embodiments A1-38 or C1-21 to the subject, or the method comprising administering to the subject a transdermal delivery device comprising an adhesive layer having the same, or essentially the same, ingredients as in Formulation A, B, C1, C2, C3, D0, D1 or D2 in the examples.

The method according to embodiment A39, wherein the subject does not suffer from a cough and/or does not require an antitussive.

The method of embodiment A39 or 40 wherein the subject is characterized as a rapid metabolizer.

The method according to any one of the embodiments of the invention A39-41, characterized in that the subject suffers from a neurological disease or disorder.

The method according to any one of the embodiments of the invention A39-41, characterized in that the subject suffers from one or more diseases or disorders selected from the group consisting of: affective disorders, mental disorders, disorders of cerebral function, movement disorders, dementias, motor neuron diseases , neurodegenerative diseases, seizure disorders and headaches.

The method according to any of the embodiments of the invention A39-41, characterized in that the subject suffers from one or more diseases or disorders selected from the group consisting of: depression, major depression, treatment-resistant depression, treatment-resistant bipolar depression, bipolar disorders including cyclothymia, seasonal affective disorders, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, 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, addiction or drug abuse, nicotine addiction, psychosexual dysfunction, pseudobulbar affect and emotional lability.

The method according to any of the embodiments of the invention A39-41, characterized in that the subject suffers from one or more diseases or disorders selected from the group consisting of: Alzheimer's disease, prion diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Levy's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shye-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 paraparesis, neurofibromatosis, olivopontocerebellar atrophy or de generation, strionigral degeneration, Guillain-Barré syndrome and spastic paraplegia.

The method according to any one of the embodiments of the invention A39-41, characterized in that the subject suffers from pseudobulbar affect, depression, stroke, traumatic brain injury, epileptic seizure, pain (for example, postoperative pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's disease, autism or combinations thereof.

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

The method of embodiment A47 wherein the antidepressant is selected from the group consisting of: bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, a metabolite or prodrug of any of these compounds, and combinations thereof.

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

The method according to any one of the embodiments of the invention A39-46, characterized in that the subject is not administered a CYP2D6 inhibitor.

The method according to any one of the embodiments of the invention A39-46, characterized in that the subject is not administered quinidine.

The method according to any of the embodiments of the invention A39-46, characterized in that the subject is not administered any drug from the group that includes: desipramine, paroxetine, thioridazine, pimozide, digoxin, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole and their combinations.

The method of any one of embodiments A39-46 further comprising administering to the subject one or more additional active ingredients selected from the group consisting of: amlodipine, a capsaicinoid (e.g., capsaicin or an ester thereof), an opioid agonist (e.g., μ- an opiate analgesic (such as tramadol)), an adenosinergic agonist, 3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol, gabapentin, and pharmaceutically acceptable salts thereof.

The method of any one of Embodiments A39-53, wherein the transdermal delivery device is used once daily, e.g., for a period of up to 7 days or more, or for at least 7 days, or any desired period time.

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

[00116] Exemplary Embodiments of the Invention B1-26

A method of administering dextromethorphan to a human in need, the method comprising applying a transdermal delivery device containing dextromethorphan to the subject's skin once daily, the use resulting in one or more of the following pharmacokinetic profiles in humans:

the mean C _max of dextromethorphan is at least about 3 ng/ml (eg, from about 3 ng/ml to about 12 ng/ml) 1 day after application;

the mean AUC _0-24 of dextromethorphan is at least about 40 ng×h/ml (eg, from about 40 ng×h/ml to about 150 ng×h/ml) 1 day after application;

the mean C _24h /C _12h dextromethorphan ratio is no more than about 1.5 (eg, about 1 to about 1.5) at 1 day post-application;

the average value of the ratio C _24h /C _6h dextromethorphan is at least about 1.2 (for example, from 1.5 to 2.5) 1 day after application;

the average value of the ratio C _24h /C _18h dextromethorphan is from about 0.85 to about 1.3 in 1 day after application;

the average value of C _max dextrorphan is not more than 2 ng/ml (for example, not more than 2 ng/ml, not more than 1 ng/ml or not more than 0.5 ng/ml) 1 day after application;

the mean AUC _0-24 of dextrorphan is not more than 10 ng×h/ml (for example, not more than 10 ng×h/ml or not more than 5 ng×h/ml) 1 day after application;

the average value of the ratio of C _max dextromethorphan to C _max dextrofan is at least about 5 (for example, at least about 10, at least about 15, at least about 20) 1 day after application; And

the mean ratio of AUC _0-24 dextromethorphan to AUC _0-24 dextrophan is at least about 5 (e.g., at least about 10, at least about 15, at least about 20, or at least about 25) per day after application.

Method according to embodiment B1, characterized in that the person does not suffer from a cough and/or does not require an antitussive.

Method according to embodiment B1 or 2, characterized in that the person is characterized as a rapid metabolizer.

The method of any one of embodiments B1-3, wherein use results in a mean _Cmax of dextromethorphan of at least about 30% (e.g., about 30% to about 80%) of that observed with oral administration of the combination dextromethorphan 20 mg and quinidine 10 mg twice daily in humans, measured 1 day post-application.

The method of any one of embodiments B1-4, wherein use results in a mean AUC _0-24 of dextromethorphan of at least about 30% (e.g., about 30% to about 80%) of that observed with oral application of a combination of dextromethorphan 20 mg and quinidine 10 mg twice a day in humans, when measured 1 day after application.

The method of any one of embodiments B1-5, wherein use results in a mean _Cmax of dextrorphan of no more than about 50% (e.g., about 10% to about 30%) of that observed with oral administration of the combination dextromethorphan 20 mg and quinidine 10 mg twice daily in humans, measured 1 day post-application.

The method of any of embodiments B1-6, wherein administration results in a mean AUC _0-24 of dextrorphan of no more than about 50% (e.g., about 10% to about 30%) of that observed with oral application of a combination of dextromethorphan 20 mg and quinidine 10 mg twice a day in humans, when measured 1 day after application.

The method according to any of the embodiments of the invention B1-7, characterized in that the person suffers from pseudobulbar affect, depression, stroke, traumatic brain injury, epileptic seizure, pain (for example, postoperative pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's disease, autism or combinations thereof.

The method of any one of embodiments B1-8, comprising administering the transdermal delivery device once a day for up to seven days, or for at least 7 days, or any desired period of time, wherein administration results in one or both of the following pharmacokinetic profiles in humans:

the mean C _max of dextromethorphan is at least about 8 ng/ml (eg, from about 8 ng/ml to about 20 ng/ml) on day 7 after administration; And

the average value of C _max dextrorphan is not more than 2 ng/ml (for example, not more than 2 ng/ml, not more than 1 ng/ml or not more than 0.5 ng/ml) on the 7th day after application.

The method of any of embodiments B1-9, wherein the transdermal delivery device contains about 5 mg to about 100 mg of dextromethorphan.

A method of administering dextromethorphan to a person in need thereof, the method comprising applying a transdermal delivery device containing dextromethorphan to the subject's skin once a week or 2, 3, 4, 5, or 6 times a week, the application resulting in one or more of the following pharmacokinetic profiles in humans:

the mean C _max of dextromethorphan is at least about 3 ng/ml (eg, from about 3 ng/ml to about 12 ng/ml) 1 day after application;

the mean AUC _0-24 of dextromethorphan is at least about 40 ng×h/ml (eg, from about 40 ng×h/ml to about 150 ng×h/ml) 1 day after application;

the mean C _24h /C _12h dextromethorphan ratio is no more than about 1.5 (eg, about 1 to about 1.5) at 1 day post-application;

the average value of the ratio C _24h /C _6h dextromethorphan is at least about 1.2 (for example, from 1.5 to 2.5) 1 day after application;

the average value of the ratio C _24h /C _18h dextromethorphan is from about 0.85 to about 1.3 in 1 day after application;

the average value of C _max dextrorphan is not more than 2 ng/ml (for example, not more than 2 ng/ml, not more than 1 ng/ml or not more than 0.5 ng/ml) 1 day after application;

the mean AUC _0-24 of dextrorphan is not more than 10 ng×h/ml (for example, not more than 10 ng×h/ml or not more than 5 ng×h/ml) 1 day after application;

the average value of the ratio of C _max dextromethorphan to C _max dextrofan is at least about 5 (for example, at least about 10, at least about 15, at least about 20) 1 day after application; And

the mean ratio of AUC _0-24 dextromethorphan to AUC _0-24 dextrophan is at least about 5 (e.g., at least about 10, at least about 15, at least about 20, or at least about 25) per day after application.

The method of embodiment B11, wherein the use further results in one or both of the following pharmacokinetic profiles in humans:

the mean C _max of dextromethorphan is at least about 8 ng/ml (eg, from about 8 ng/ml to about 20 ng/ml) on day 7 after administration; And

the average value of C _max dextrorphan is not more than 2 ng/ml (for example, not more than 2 ng/ml, not more than 1 ng/ml or not more than 0.5 ng/ml) on the 7th day after application.

Method according to embodiment B11 or 12, wherein the person does not suffer from a cough and/or does not require an antitussive.

The method according to any of the embodiments of the invention B11-13, characterized in that the person is characterized as a rapid metabolizer.

The method of any of embodiments B11-14, wherein use results in a mean _Cmax of dextromethorphan of at least about 30% (e.g., about 30% to about 80%) of that observed with oral administration of the combination 20 mg dextromethorphan and 10 mg quinidine twice daily in humans for 7 days as measured 7 days after administration.

The method of any one of embodiments B11-15, wherein use results in a mean AUC _0-24 of dextromethorphan of at least about 30% (e.g., about 30% to about 80%) of that observed with oral taking a combination of dextromethorphan 20 mg and quinidine 10 mg twice a day in humans for 7 days when measured on day 7 after application.

The method of any one of embodiments B11-16, wherein use results in a mean _Cmax of dextrorphan of no more than about 50% (e.g., about 10% to about 30%) of that observed with oral administration of the combination 20 mg dextromethorphan and 10 mg quinidine twice daily in humans for 7 days as measured 7 days after administration.

The method of any one of embodiments B11-17, wherein administration results in a mean AUC _0-24 of dextrorphan of no more than about 50% (e.g., about 10% to about 30%) of that observed with oral taking a combination of dextromethorphan 20 mg and quinidine 10 mg twice a day in humans for 7 days when measured on day 7 after application.

The method according to any of the embodiments of the invention B11-18, characterized in that the person suffers from a pseudobulbar lesion.

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.

A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a transdermal delivery device containing dextromethorphan to the subject's skin once daily, the use resulting in one or more of the following pharmacokinetic profiles described in the embodiments of the invention B1, B3-7 and B9, in which the disease or disorder is any of those described herein.

The method of embodiment 21, wherein the disease or disorder is a neurological disease or disorder, such as pseudobulbar lesion.

A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a transdermal delivery device comprising dextromethorphan to the subject's skin once a week or 2, 3, 4, 5, or 6 times a week, the application resulting in one or more of the following pharmacokinetic profiles described in Embodiments B11-12 and B15-18, wherein the disease or disorder is any of those described herein.

The method of embodiment 21, wherein the disease or disorder is a neurological disease or disorder, such as pseudobulbar lesion.

The method according to any one of embodiments B1-24, wherein the transdermal delivery device is selected from the transdermal delivery devices according to any one of embodiments A1-38 and C1-21.

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, ingredients as in formulation A, B, C1, C2, C3, D0, D1 or D2 in examples.

[00117] Exemplary Embodiments C1-32

1. Device for transdermal delivery, containing:

an adhesive layer containing dextromethorphan dispersed in an adhesive containing an acrylate adhesive and a silicone adhesive,

wherein the weight ratio of acrylate adhesive to silicone adhesive is from about 20:1 to about 1:20.

2. The transdermal delivery device of Embodiment C1, wherein the weight ratio of acrylate adhesive to 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 anywhere in between).

3. The transdermal delivery device of embodiment C1 or 2, which is configured to provide an average cumulative penetration of dextromethorphan in an amount of at least about 200 µg/cm ² (e.g., from about 200 µg/cm ² to about 2000 µg/cm ² ) 24 hours after application, when tested in vitro using human cadaver skin.

4. The transdermal delivery device of any one of embodiments C1-3, which is configured to provide an average dextromethorphan flux that is at least about 5 μg/cm ² h (e.g., from about 5 μg/cm ² h up to about 20 μg/cm ² h, from about 10 μg/cm ² h to about 18 μg/cm ² h) from 8 hours to 24 hours after application, when tested in vitro using human cadaver skin.

5. A transdermal delivery device according to any of embodiments C1-4, wherein the adhesive layer further comprises a percutaneous penetration enhancer in an amount to provide an average cumulative penetration of dextromethorphan 24 hours after application by at least 25% (e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any range in between) higher than an equivalent transdermal delivery device without a percutaneous penetration enhancer when tested in vitro using human cadaver skin.

6. The device for transdermal delivery according to any of the embodiments of the invention C1-5, characterized in that the adhesive layer contains a percutaneous penetration enhancer in an amount that provides an average value of the flow of dextromethorphan from 8 hours to 24 hours after application by at least about 25% ( e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any range in between) higher than another equivalent transdermal delivery device without a percutaneous penetration enhancer when tested in vitro using skin human corpse.

7. A device for transdermal delivery according to any of the embodiments of the invention C1-6, characterized in that the adhesive layer contains a percutaneous penetration enhancer in an amount that provides an average value of the flow of dextromethorphan from 4 hours to 8 hours after application of 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 in between) above the value of another equivalent transdermal delivery device without a percutaneous penetration enhancer when tested in vitro using human cadaver skin.

8. A transdermal delivery device according to any one of embodiments of the invention C1-7, characterized in that the adhesive layer contains a transdermal penetration enhancer in an amount that provides an average value of the flow of dextromethorphan from 0 hours to 4 hours after application of at least about 5 times ( e.g., about 5 times, about 8 times, about 10 times, about 20 times, or any range in between) above that of another equivalent transdermal delivery device without a percutaneous penetration enhancer when tested in vitro using cadaver skin person.

9. A transdermal delivery device according to any one of embodiments C1-8 which is suitable for use within 1, 2, 3, 4, 5, 6 or 7 days.

10. The transdermal delivery device of Embodiment C9, which is configured to provide the user with at least about 200 µg/cm ² (e.g., about 200 µg/cm ² to about 2000 µg/cm ² ) of dextromethorphan per day.

11. The transdermal delivery device of any one of embodiments C1-10, which is about 5 cm ² to about 200 cm ² in size.

12. The transdermal delivery device of any one of embodiments C1-11, which is about 10 cm ² to about 100 cm ² in size.

13. Device for transdermal delivery, containing:

an adhesive layer containing dextromethorphan dispersed in an adhesive,

wherein the adhesive layer contains a percutaneous penetration enhancer in an amount that provides an average cumulative value of penetration of dextromethorphan 24 hours after application by at least 25% (for example, about 25%, about 50%, about 100%, about 150%, about 200% or any range between the specified value) higher than another equivalent transdermal delivery device without a percutaneous penetration enhancer when tested in vitro using human cadaver skin.

14. The transdermal delivery device of Embodiment C13, wherein the transdermal penetration enhancer is in an amount to provide an average flux of dextromethorphan from 8 hours to 24 hours after application by at least about 25% (e.g., about 25%, about 50%, about 100%, about 150%, about 200%, or any range in between) higher than another equivalent transdermal delivery device without a percutaneous penetration enhancer when tested in vitro using human cadaver skin.

15. The transdermal delivery device of embodiment C13 or 14, wherein the percutaneous penetration enhancer is in an amount to provide an average dextromethorphan flux of 4 hours to 8 hours after application of at least about 2 times (e.g., about 2 times 3-fold, about 4-fold, about 5-fold, about 8-fold, about 10-fold, or any range in between) above that of another equivalent transdermal delivery device without a percutaneous penetration enhancer, when tested in vitro using skin of a human corpse.

16. The transdermal delivery device of any one of C13-15 embodiments, wherein the percutaneous penetration enhancer is in an amount to provide an average 0 hour to 4 hour dextromethorphan flux after application of at least about 5 times (e.g., about 5-fold, about 8-fold, about 10-fold, about 20-fold, or any range in between) above that of another equivalent transdermal delivery device without a percutaneous penetration enhancer when tested in vitro using human cadaver skin.

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

18. The transdermal delivery device of embodiment C17, which is configured to provide the user with at least about 200 µg/cm ² (e.g., about 200 µg/cm ² to about 2000 µg/cm ² ) of dextromethorphan per day.

19. The transdermal delivery device of any one of embodiments C13-18, which is about 5 cm ² to about 200 cm ² in size.

20. The transdermal delivery device of any one of embodiments C13-19, which is about 10 cm ² to about 100 cm ² in size.

21. The transdermal delivery device according to any one of embodiments of the invention C13-20, characterized in that the percutaneous penetration enhancer is selected from the group consisting of: isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, other fatty acids and fatty acid esters with lengths carbon chains from C ₁₂ to C _18, as well as combinations thereof.

22. A method of administering dextromethorphan to a subject in need thereof, the method comprising applying a transdermal delivery device to the subject's skin, the transdermal delivery device comprising an adhesive layer, the adhesive layer comprising dextromethorphan dispersed in an adhesive, and a transdermal penetration enhancer, the transdermal delivery enhancer penetration is in such an amount that its use provides an average cumulative value of penetration of dextromethorphan 24 hours after application by at least 25% (for example, about 25%, about 50%, about 100%, about 150%, about 200% or in ranges between the specified value) is higher than any other equivalent transdermal delivery device without a percutaneous penetration enhancer.

23. The method of embodiment C22, wherein the percutaneous penetration enhancer is in such an amount that the application provides an average flux of dextromethorphan from 8 hours to 24 hours after application by at least about 25% (for example, about 25 %, about 50%, about 100%, about 150%, about 200%, or any range in between) higher than other equivalent transdermal delivery device without a percutaneous penetration enhancer.

24. The method according to embodiment C22 or 23, wherein the percutaneous penetration enhancer is in such an amount that the application results in an average dextromethorphan flux from 4 hours to 8 hours after application of at least about 2 times (for example, about 3-fold, about 4-fold, about 5-fold, about 8-fold, about 10-fold, or any range in between) above that of another equivalent transdermal delivery device without a percutaneous penetration enhancer.

25. The method according to any one of the embodiments of the invention C22-24, characterized in that the percutaneous penetration enhancer is in such an amount that as a result of application, an average value of the flow of dextromethorphan from 0 hours to 4 hours after application is at least about 5 times ( for example, about 5-fold, about 8-fold, about 10-fold, about 20-fold, or any range in between) above that of another equivalent transdermal delivery device without a percutaneous penetration enhancer.

26. The method according to any one of embodiments of the invention C22-25, characterized in that the device for transdermal delivery is applied once a day for 1 day or more, (for example, 1 day, 2 days, 3 days, 4 days, 5 days , 6 days or 7 days or more).

27. The method of Embodiment C26 which transdermally delivers dextromethorphan to the subject at least about 200 μg/cm ² (eg, from about 200 μg/cm ² to about 2000 μg/cm ² ) per day.

28. The method of any one of embodiments C22-27, wherein the transdermal delivery device has a size of from about 5 cm ² to about 200 cm ² .

29. The method of any one of embodiments C22-28, wherein the transdermal delivery device has a size of from about 10 cm ² to about 100 cm ² .

30. The method according to any one of the embodiments of the invention C22-29, characterized in that the percutaneous penetration enhancer is selected from the group containing: isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, other fatty acids and esters of fatty acids with carbon chain lengths from From ₁₂ to C _18, as well as their combinations.

31. A method of administering dextromethorphan to a subject in need thereof, the method comprising applying a transdermal delivery device to the subject's skin, the transdermal delivery device having a flow characteristic such that, when administered, dextromethorphan is delivered transdermally to the subject in an amount of from about 2 mg/day to about 50 mg/day.

32. The method of Embodiment C31, wherein the transdermal delivery device is configured with a flow characteristic such that, when administered, dextromethorphan is delivered transdermally to the subject in an amount of 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 in between) for 1 day or more (e.g., 1 , 5 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or any range between the indicated values).

Examples

Example 1 Preparation of a transdermal patch containing dextromethorphan

[00118] This example shows one procedure for preparing a patch containing a drug such as dextromethorphan in an adhesive. The base of dextromethorphan is generally commercially available. Alternatively, dextromethorphan base can be prepared by converting dextromethorphan hydrobromide to the free base, for example using a 1:1 molar ratio of NaOH.

[00119] Preparation of formulation A using an acrylate adhesive without skin penetration enhancers. To a 150 ml beaker was added 10 g of ethyl acetate followed by 2.5 g of DXM. The mixture was stirred to dissolve the DXM. With stirring, it was added to acrylic PSA, 50 g DuroTak 87-2287 (Henkel Adhesives), which contains 50.5% solids. The contents of the mixture were mixed for 30 minutes or until the contents became homogeneous. The resulting slurry was then poured onto the protective coating (Loparex Corp.) using a 10 mil (254 µm) casting applicator. The casting was dried in a furnace with forced air supply at 80°C for 10 min. After drying, the dried casting was laminated onto a protective film of Scotchpak 1012 patch (3 M Drug Delivery Systems). The patch was cut into a 30 cm ² shape. The resulting transdermal patch has an adhesive matrix thickness of 2.5 mils (dosage by weight of about 180 mg of adhesive matrix per patch) and contains 9% DXM. HPLC analysis confirmed that the patch contained approximately 16 mg of DXM. The patch has good adhesion to the skin and adheres tightly to the skin for more than 48 hours. The patch was cut to attach to the Franz cells for skin penetration studies. No crystals were observed on the patch for 6 months at 25°C, indicating good stability of the formulation for the transdermal patch.

[00120] Preparation of composition B, which uses a silicone adhesive without skin penetration enhancers. To a 150 ml beaker was added 10 g of ethyl acetate followed by 2.5 g of DXM. The mixture was stirred to dissolve the DXM. With stirring, it was added to silicone PSA, 50 g Bio-PSA DC7-4502 (Dow Corning), which contains 60.0% solids. The contents of the mixture were mixed for 30 minutes or until the contents became homogeneous. The resulting slurry was then poured onto a fluoropolymer coated protective coating (3M 1022) using a 15 mil (254 micron) casting applicator. The casting was dried in a furnace with forced air supply at 80°C for 10 min. After drying, the dried casting was laminated onto a protective film of Scotchpak 1012 patch (3 M Drug Delivery Systems). The patch was cut into a 30 cm ² shape. The resulting transdermal patch has a 3.5 mil (88.9 micron) adhesive matrix. The patch has good adhesion to the skin and adheres tightly to the skin for more than 48 hours. The patch was cut to attach to the Franz cells for skin penetration studies. No crystals were observed on the patch for 6 months at 25°C, indicating good stability of the formulation for the transdermal patch.

[00121] Formulation C, which uses a mixture of acrylate and silicone adhesive without skin penetration enhancers, while maintaining the concentration of dextromethorphan at 9%. Three formulations were prepared according to the procedures described above, formulations C1-C3, with a silicone/acrylic PSA blend of 54/46, 18/82 and 9/91, respectively.

[00122] Formulation D, following the same procedures described above, formulations were also prepared with varying amounts of penetration enhancers. Composition D1 contains isopropyl myristate in an amount of 7.7%; composition D2 contains isopropyl myristate in an amount of 10%. As a control, composition D0 was also prepared, which does not contain isopropyl myristate.

[00123] The following Table 1 summarizes the ingredients of the various formulations prepared as above in weight percent. (Percentages in the table refer to dry weight.)

Table 1. Composition No. A B C1 C2 C3 D0 D1 D2 DXM 9 8 9 9 9 10 10 10 DuroTak 87-2287 91 92 49 16 8 90 82.3 80 DC 7-4502 42 75 83 IPM 0 7.7 10 Total 100 100 100 100 100 100 100 100

Example 2 Transdermal Flow Test

[00124] Transdermal flow of dextromethorphan from the patch was tested using human cadaveric epidermis by the Franz diffusion cell method.

[00125] Patches A, B and C prepared in Example 1 were used to study skin penetration using the following protocol:

• Franz Diffusion Cell Set - Logan Instruments (block of 6 cells)

• Each cell has a volume of 12 ml, a hole with a diameter of 1.5 cm.

• Receptor medium is phosphate buffered saline (PBS) pH 7.4

• Cell temperature maintained at 37°C

• Sampling method: take 1.5 ml for HPLC analysis, empty well, replace with fresh medium

• Selection time: 4, 8, 12, 24 and 48 hours

• Cadaver skin is used and sourced from the New York Fire Fighters Skin Bank. Skin no. MM07116, age 58, male, skin patch: posterior surface of left tibia.

• Method of analysis for medium: based on HPLC.

[00126] The study results for formulations A and B are shown in Table 1 below (see also FIG. 1). Values shown are the cumulative amount of DXM per cm ² (ie, µg/cm ² ).

Table 2. Compound A B Watch Acrylic PSA
DuroTak 87-2287 Silicone PSA DC7-4502 0 0.0 0.0 4 48.6 25.8 8 124.9 79.8 12 201.3 138.1 24 424.3 294.4 48 625.1 597.0

[00127] The results of the study for formulations C1-C3 are presented in Table 3 below (see also FIG. 2). Values shown are the cumulative amount of DXM per cm ² (ie, µg/cm ² ).

Table 3 Compound C1 C2 C3 Day/
silicone/acrylic ratio 54/46 18/82 9/91 0.33 71.0 34.8 159.5 1 308.1 215.9 487.0 2 536.5 433.3 768.8 3 667.8 584.1 902.6 4 755.2 703.7 979.1 5 815.8 784.0 1023.5 6 866.3 854.6 1060.6 7 906.7 910.2 1086.1

Example 3 Transdermal patch containing dextromethorphan with penetration enhancers

[00128] Formulations D0-D2 were also tested for their in vitro flow characteristics following the same protocol as described in Example 2. The results are shown in Table 4 (see also FIG. 3).

Table 4 Compound D0 D1 D2 Isopropyl myristate (IPM) % 0 7.7 10.0 24 hour stream 141.3 240.0 334.6

[00129] The results clearly show that increased levels of IPM, up to 10%, significantly improve the penetration of DXM into the skin.

Example 4 In Vivo Pharmacokinetic Studies

[00130] This example relates to an open-label, randomized, two-treatment, two-sequence, two-period, crossover study that was conducted in 16 healthy adult males and females to evaluate the comparative bioavailability of the dextromethorphan test patch, 15 mg/24 hours. relative to NUEDEXTA® (dextromethorphan hydrobromide and quinidine sulfate) capsules, 20 mg/10 mg (Avanir Pharmaceuticals, Inc.) on an empty stomach. All 16 participants in this study were genotyped to determine the CYP2D6 genotype. All 16 subjects can be characterized as a rapid metabolizer of dextromethorphan. See, for example, Treducu A.L.D. et al. Frontiers in Pharmacology, vol. 9, Article 305 (April 2018).

[00131] In this study, the pharmacokinetic profile was measured for both dextromethorphan and dextrorphan (one metabolite of dextromethorphan).

[00132] In one study period, one (1) 45 ^cm2 dextromethorphan patch containing 35 mg DXM was presented, which was a drug-in-adhesive (DIA) patch with a DIA layer containing about 80 wt. adhesive (Duro-Tak 87-2287), about 10% wt. bases of dextromethorphan and about 10% of the mass. an isopropyl myristate penetration enhancer that was designed for transdermal delivery at about 15 mg/24 hours and was applied to the upper outer left arm of healthy subjects for 24 hours after an overnight fast of at least 10 hours. In another study period, one capsule of NUEDEXTA® (dextromethorphan hydrobromide and quinidine sulfate), 20 mg/10 mg, was administered every 12 hours (at 00:00 and 12:00) (for a total dose of 40 mg/20 mg for 24 hours) after an overnight abstaining from eating for at least 10 hours (0-hours).

[00133] For treatment with NUEDEXTA®, subjects were fasted overnight for at least 10 hours up to the 0-hour dose only. The order of administration follows the randomization plan in two sequences. Blood samples were collected pre-dose and at intervals up to 96 hours post-dose (0 hours) with study drug at each study period. Subjects were at the clinical facility from at least 10 hours pre-dose (0 hours) until blood samples were taken at 36 hours in each study period, and returned to the clinical facility for blood sampling at 48, 72, and 96 hours. The interval between doses (0 hours) was at least 10 days.

[00134] Plasma concentrations of dextromethorphan and its active metabolite dextrorphan were measured using a fully validated analytical procedure. Statistical analysis using the mean bioequivalence methodology was performed to evaluate the bioavailability of the test formulation compared to the reference product for dextromethorphan and dextrorphan only.

[00135] The study was designed based on the known pharmacokinetics of NUEDEXTA® capsules (Dextromethorphan Hydrobromide and Quinidine Sulfate), the FDA Draft Guidelines for Dextromethorphan Hydrobromide and Quinidine Sulfate Capsules, and generally accepted standards for fasting bioavailability/bioequivalence and adhesion studies. To minimize any possibility of a carryover effect, a washout period of at least 10 days was chosen for this study.

[00136] The study was also designed to minimize potential drug interactions that could affect the results of this study. For example, subjects were examined and monitored for medications such as monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), drugs that cause torsades de pointes (TdP) ventricular tachycardia. or cardiac arrhythmias, inducers or inhibitors of CYP3A4 or CYP2D6, etc.

Pharmacokinetic results

[00137] Blood samples were collected at the following time points (relative to the time of dosing): pre-dose (0 hours) and after 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 for blood sampling). The samples were then processed and analyzed for both dextromethorphan and dextrophan concentrations using approved analytical methods. SAS® software version 9.4 or higher was used for all pharmacokinetic and statistical calculations.

[00138] Tables 5A-5D show the results of this study. Tables A and C show the plasma concentrations of dextromethorphan and dextrophan, respectively, in subjects who took Neudextra (comparator) orally twice a day. Tables B and D show the plasma concentrations of dextromethorphan and dextrofan, respectively, in subjects who received a dextromethorphan patch within 24 hours.

[00139] Table 5A. PK profile of dextromethorphan in subjects treated with Neudexta

AUC 0-t / AUC 0-∞ AUC 0-t AUC 0-24 Cmax Tmax Patient Period Subsequence AUC 0-∞ (h×ng/ml) (ng/ml) (h) 2001 1 2 0.993 351.9471 349.606 184.0613 16.601 15 2002 2 1 0.964 195.315 188.2605 125.9288 10.095 18 2003 1 2 0.968 678.6678 657.1278 261.3503 18.961 15 2004 2 1 0.925 1179.091 1090.282 413.963 25.246 18 2005 1 2 0.985 241.7969 238.2765 139.581 10.527 16 2006 2 1 0.988 113.702 112.3683 71.981 5.179 18 2007 1 2 0.988 212.503 209.9133 120.7003 9.266 16 2008 2 1 0.987 199.7647 197.2488 115.1745 8.949 17 2009 1 2 0.977 61.9881 60.5778 41.9003 3.009 17 2010 2 1 0.992 420.076 416.5713 198.18 14.367 16 2011 2 1 0.991 146.6518 145.3553 94.6668 7.912 16 2012 1 2 0.987 630.2464 622.358 258.1298 17.371 18 2013 2 1 0.96 1127.656 1082.814 391.2635 27.377 17 2014 1 2 0.99 209.3143 207.2588 119.782 9.519 18 2015 2 1 0.989 203.16 200.8948 123.0515 11.967 15 2016 1 2 0.994 413.279 410.8915 188.3373 13.428 16 N 16 16 16 16 16 16 Average 0.98 399.0725 386.8627 178.0032 13.1109 16.625 Standard deviation 0.0182 341.34 321.0667 106.3368 6.6888 1.1475 The coefficient of variation (%) 1.8534 85.5333 82.9924 59.7387 51.0169 6.902 Min. 0.9247 61.9881 60.5778 41.9003 3.009 15 Median 0.9876 227.15 224.0949 132.7549 11.247 16.5 Max. 0.9942 1179.091 1090.282 413.963 27.377 18 geometric mean - 293.6809 287.7623 151.5212 11.4739 - Geometric coefficient of variation (%) - 96.1162 94.5644 65.4088 60.9954 -

[00140] Table 5B. PK profile of dextromethorphan in subjects treated with DXM patch

AUC 0-t / AUC 0-∞ AUC 0-t AUC 0-24 Cmax Tmax Kel Patient Period Subsequence AUC 0-∞ (h×ng/ml) (ng/ml) (h) (h-1) 2001 2 2 0.995 343.5848 341.9338 225.8408 12.168 13 0.0521 2002 1 1 0.979 157.7533 154.4763 83.966 5.918 24 0.0598 2003 2 2 0.993 254.6006 252.7 138.4305 7.924 13 0.0558 2004 1 1 0.909 762.9419 693.3915 227.2223 15.069 25 0.028 2005 2 2 0.981 108.1344 106.0843 39.8225 3.565 24 0.0449 2006 1 1 0.976 155.7666 152.0265 76.285 5.39 24 0.0406 2007 2 2 0.974 76.1848 74.1835 37.4935 2.768 24 0.0655 2008 1 1 0.953 160.8027 153.2865 101.7265 5.729 9 0.089 2009 2 2 0.983 135.951 133.5808 60.496 5.299 24.5 0.0464 2010 1 1 0.989 170.5676 168.6183 93.6805 5.488 24.5 0.0487 2011 1 1 0.981 150.6617 147.8318 88.5355 5.359 13 0.0594 2012 2 2 0.991 175.1153 173.5208 89.2915 5.41 24 0.0583 2013 1 1 0.972 135.1146 131.3655 59.5475 5.058 24.5 0.0501 2014 2 2 0.988 103.1524 101.9025 51.8775 3.747 13 0.0448 2015 1 1 0.99 89.5274 88.629 49.1685 3.503 24.5 0.0601 2016 2 2 0.98 118.201 115.859 56.2235 3.982 24.5 0.0418 N 16 16 16 16 16 16 16 Average 0.9771 193.6287 186.8369 92.4755 6.0236 20.5313 0.0528 Standard deviation 0.0208 165.2082 149.9839 58.4479 3.2516 5.8807 0.0135 The coefficient of variation (%) 2.1321 85.3221 80.2753 63.2036 53.9815 28.6425 25.5494 Min. 0.9088 76.1848 74.1835 37.4935 2.768 9 0.028 Median 0.9811 153.2141 149.9291 80.1255 5.3745 24 0.0511 Max. 0.9952 762.9419 693.3915 227.2223 15.069 25 0.089 Geometric mean - 160.6092 156.8942 79.6881 5.4375 - - Geometric coefficient of variation (%) - 60.1868 58.6836 58.0178 46.2616 - -

[00141] Table 5C. PK profile of dextrorphan in subjects treated with Neudexta

AUC 0-t / AUC 0-∞ AUC 0-t AUC 0-24 Cmax Tmax Patient Period Subsequence AUC 0-∞ (h×ng/ml) (ng/ml) (h) 2001 1 2 0.91 54.6319 49.7395 37.0408 2.508 15 2002 2 1 0.95 54.7694 52.0113 44.3253 4.736 3 2003 1 2 0.79 44.4308 35.1195 19.2823 1.375 3 2004 2 1 0.758 45.5979 34.5633 16.5818 0.997 18 2005 1 2 0.933 49.1071 45.8165 37.2095 2.842 2 2006 2 1 0.846 21.7259 18.3733 17.4788 1.763 2 2007 1 2 0.923 34.5947 31.9278 25.6383 1.927 15 2008 2 1 0.863 27.3844 23.634 20.3403 1.463 3 2009 1 2 0.977 61.0768 59.6648 50.6268 4.251 16 2010 2 1 0.88 47.2853 41.614 29.7973 2.385 5 2011 2 1 0.944 44.4111 41.9088 38.2585 4.014 2 2012 1 2 0.773 35.9404 27.7748 18.5353 1.369 4 2013 2 1 - - 24.2913 9.816 0.709 18 2014 1 2 0.907 33.6648 30.522 24.7718 1.804 3 2015 2 1 0.872 42.554 37.1155 29.618 2.482 2 2016 1 2 0.877 37.8946 33.2445 26.2825 2.035 4 N 15 15 16 16 16 16 Average 0.8802 42.338 36.7075 27.8502 2.2913 7.1875 Standard deviation 0.0657 10.6596 11.2148 11.1675 1.1676 6.5138 The coefficient of variation (%) 7.469 25.1775 30.5518 40.0985 50.9602 90.6263 Min. 0.758 21.7259 18.3733 9.816 0.709 2 Median 0.8801 44.4111 34.8414 25.9604 1.981 3.5 Max. 0.9769 61.0768 59.6648 50.6268 4.736 18 Geometric mean - 40.9614 35.0859 25.6926 2.0294 - Geometric coefficient of variation (%) - 28.0586 32.3114 44.7726 55.4075 -

[00142] Table 5D. PK profile of dextrorphan in subjects treated with DXM patch

AUC 0-t / AUC 0-∞ AUC 0-t AUC 0-24 Cmax Tmax Kel Patient Period Subsequence AUC 0-∞ (h×ng/ml) (ng/ml) (h) (h-1) 2001 2 2 0.816 23.5515 19.2253 9.77 0.665 26 0.0495 2002 1 1 - - 13.3518 7.81 0.658 13 - 2003 2 2 0.786 15.0118 11.7988 7.563 0.478 20 0.071 2004 1 1 - - 16.3933 6.348 0.58 24.5 - 2005 2 2 - - 1.5003 0 0.279 thirty - 2007 2 2 - - 2.594 0.955 0.286 thirty - 2008 1 1 - - 7.8075 5.6295 0.431 24 - 2009 2 2 - - 4.7703 3.265 0.354 12 - 2010 1 1 - - 11.3405 6.759 0.539 26 - 2011 1 1 - - 1.6505 1.102 0.312 26 - 2012 2 2 - - 4.957 2.741 0.401 24 - 2013 1 1 - - 13.1663 6.377 0.683 24 - 2014 2 2 - - 6.6303 4.4165 0.393 26 - 2015 1 1 - - 10.327 5.9315 0.588 14 - 2016 2 2 - - 4.1193 2.386 0.319 26 - N 2 2 15 15 15 15 2 Average 0.8011 19.2816 8.6421 4.7369 0.4644 23.0333 0.0602 Standard deviation 0.0215 6.0384 5.5101 2.8797 0.1446 5.7273 0.0152 The coefficient of variation (%) 2.6783 31.317 63.7586 60.7921 31.1453 24.8654 25.2412 Min. 0.786 15.0118 1.5003 0 0.279 12 0.0495 Median 0.8011 19.2816 7.8075 5.6295 0.431 24.5 0.0602 Max. 0.8163 23.5515 19.2253 9.77 0.683 thirty 0.071 Geometric mean - 18.8029 6.7033 4.1953 0.4433 - - Geometric coefficient of variation (%) - 32.6691 96.3776 82.6752 32.64 - -

[00143] Based on this study, it was also surprisingly found that for subjects treated with a DXM (dextromethorphan) patch, the ratios of AUC _0-24 , AUC _0-t , and C _max DXM to DRP (dextrorphan) observed during patch treatment were significantly higher than the corresponding ratios observed with Neudexta treatment. For example, the average ratio of AUC _0-24 DXM to DRP observed with patch treatment is about 3 times that observed with Neudexta treatment (24.54:9.03), see Table 6 below.

Treatment with Neudexta Band-Aid Treatment AUC 0-t AUC 0-24 Cmax AUC 0-t AUC 0-24 Cmax Patient Period Sequential
validity (DXM/DRP) (DXM/DRP) (DXM/DRP) Period Subsequence (DXM/DRP) (DXM/DRP) (DXM/DRP) 2001 1 2 7.03 4.97 6.62 2 2 17.79 23.12 18.30 2002 2 1 3.62 2.84 2.13 1 1 11.57 10.75 8.99 2003 1 2 18.71 13.55 13.79 2 2 21.42 18.30 16.58 2004 2 1 31.54 24.96 25.32 1 1 42.30 35.79 25.98 2005 1 2 5.20 3.75 3.70 2 2 70.71 - 12.78 2006 2 1 6.12 4.12 2.94 1 1 - - - 2007 1 2 6.57 4.71 4.81 2 2 28.60 39.26 9.68 2008 2 1 8.35 5.66 6.12 1 1 19.63 18.07 13.29 2009 1 2 1.02 0.83 0.71 2 2 28.00 18.53 14.97 2010 2 1 10.01 6.65 6.02 1 1 14.87 13.86 10.18 2011 2 1 3.47 2.47 1.97 1 1 89.57 80.34 17.18 2012 1 2 22.41 13.93 12.69 2 2 35.01 32.58 13.49 2013 2 1 44.58 39.86 38.61 1 1 9.98 9.34 7.41 2014 1 2 6.79 4.84 5.28 2 2 15.37 11.75 9.53 2015 2 1 5.41 4.15 4.82 1 1 8.58 8.29 5.96 2016 1 2 12.36 7.17 6.60 2 2 28.13 23.56 12.48 N 16 16 16 15 16 Average 12.07 9.03 8.88 29.43 24.54 13.12 Standard deviation 11.78 10.15 9.96 22.93 18.82 5.06 The coefficient of variation (%) 97.60% 112.45% 112.10% 77.89% 76.70% 38.60%

[00144] Table 6. Comparison of PK profiles for Neudexta and patch treatment

[00145] FIG. 4A and 4B are graphs of dextromethorphan and dextrorphan concentrations over 0-96 hours.

Example 5 Laminated Patch Construction

[00146] This example describes a new layered design.

[00147] As illustrated in FIG. 5, an exemplary patch design suitable for the embodiments described herein may include a contact layer and a reservoir layer. The contact layer (top layer in Fig. 5) may have the following ingredients: 1) adhesive (eg DURO-TAK 287-2287): about 77.5% - about 75%; 2) drug (dextromethorphan base): about 10%; 3) enhancer (for example, isopropyl myristate - IPM): about 10%; and 4) Kollidon, eg Kollidon VA64: from about 2.5% to about 5%. The reservoir layer may contain the following ingredients: 1) adhesive (eg DURO-TAK 287-2287): about 57.5% - about 20%; 2) drug (dextromethorphan base): from about 30% to about 50%; 3) enhancer (for example, isopropyl myristate - IPM): about 10%; and 4) Kollidon, eg Kollidon VA64: from about 2.5% to about 20%. The bottom layer may be a protective layer or may be an adhesive layer, the same as the top layer. Suitable protective layers are described in this document. Kollidon is a registered trade name that refers to the vinylpyrrolidone polymer (eg vinylpyrrolidone-vinyl acetate copolymers, eg Kollidon VA64). Before application, the contact layer is usually a protected protective coating. Suitable protective coatings are also described in this document.

[00148] In one example, the multilayer patch may have a size of 60 cm ² or more, such as from about 60 cm ² to about 150 cm ² .

[00149] In one example, the multilayer patch may have a size of 70 cm ² , which is designed to contain a total of about 370 mg of dextromethorphan base. Such a patch is suitable for use within 7 days, which can deliver transdermally about 20 mg or more of dextromethorphan per day for 7 days (total delivery is about 140 mg or more) for 7 days).

Example 6 Pharmacokinetic Modeling

[00150] This example shows the modeling of plasma profiles of dextromethorphan (DXM or DM) and dextrorphan (DOR) for 7 days after daily application of patches of different sizes.

[00151] The method used to mimic the plasma profile after daily dosing for 7 days for patches of different sizes is called overlay. This involves re-adding the next dose concentration to the previous dose profile without the need for any compartmental modeling or the need to know any PK parameters. First, dextromethorphan (abbreviated as DXM or DM) and dextrorphan (abbreviated as DOR or DRP) denote plasma profiles after a single application for 24 hours of a 70 cm ² patch with a 45 cm ² patch, as shown in Example 4. Assumptions are in that the DXM uptake rate increased proportionally with patch size, while the DXM to DRP conversion rate, DXM clearance rate, and DRP clearance rate did not change.

[00152] In this case, the plasma profiles of DXM and DRP from a 60 cm ² and 90 cm ² patch with a single application for 7 days were predicted using predicted single dose profiles and an overlap principle with the assumptions that each subsequent dosing after 1 day will not cause changes in DXM clearance, DRP and DXM and DRP conversion.

[00153] The results of pharmacokinetic modeling are shown in FIG. 6A-6D. As illustrated in FIG. 6B, daily administration of a DXM patch of about 60 cm ² and above will result in a drop in plasma DXM levels within the peak and trough of DXM concentrations with twice-daily oral dosing of Neudexta (20 mg DXM/10 mg quinidine) for 7 days. Moreover, plasma levels of DXM obtained with daily DXM patches are less variable with a lower peak-to-trough ratio than with twice-daily oral dosing of Neudexta (20 mg DXM/10 mg quinidine) for 7 days.

[00154] It should be understood that the "Detailed Description" section, and not the "Summary" and "Abstract" sections, is for use in interpreting the claims. The Summary and Abstract sections may set forth one or more, but not all, exemplary embodiments of the present invention as intended by the inventor(s), and thus are not intended to be limiting in any way. of the present invention and the appended claims.

[00155] The invention has been described above in terms of functional building blocks illustrating the implementation of certain functions and their relationships. The boundaries of these functional building blocks have been arbitrarily defined herein for convenience of description. Alternative boundaries may be defined provided that the specified functions and their relationships are properly performed.

[00156] With respect to aspects of the invention described as a genus, all distinct species are individually considered to be separate aspects of the invention. If aspects of the invention are described as "comprising" a feature, embodiments of the invention are also intended to "consist of" or "consist essentially of" the feature.

[00157] The foregoing description of specific embodiments of the invention will so fully disclose the general nature of the invention that others can easily modify and/or adapt for various applications such specific embodiments of the invention, without undue experimentation, without deviating from general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments of the invention based on the instructions and guidelines provided herein. It should be understood that the phraseology or terminology described herein is for the purpose of description and not limitation, as a result of which the terminology or phraseology of the present description must be interpreted by a person skilled in the art in light of the instructions and guidelines.

[00158] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiment of the invention, but should be defined only in accordance with the following claims and their equivalents.

[00159] All of the various aspects, embodiments of the invention, and options described herein may be combined in any and all embodiments.

[00160] All publications, patents, and patent applications referred to in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application were specifically and separately indicated for inclusion by reference. To the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

Claims (18)

1. A method of treating a neurological disease or disorder in a human subject in need thereof, wherein the neurological disease or disorder is a pseudobulbar affect, the method comprising administering once daily a transdermal delivery device containing about 5 to about 100 mg dextromethorphan, on the skin of the subject, and the device for transdermal delivery is a single-layer patch with a drug in the adhesive, where the specified single layer contains dextromethorphan, homogeneously dispersed in the adhesive, where the adhesive layer contains the adhesive in an amount of from about 65 to about 85 wt.%, a drug in an amount of from about 2 to about 12 wt.%, an isopropyl myristate penetration enhancer in an amount of from about 6 to about 12 wt.%, and the transdermal delivery device contains dextromethorphan as the only drug, where the adhesive is an acrylate copolymer adhesive selected from polyacrylate vinyl acetate copolymers. 2. The method of claim 1, wherein the transdermal delivery device is used for up to seven days. 3. The method of claim 1, wherein the transdermal delivery device is used for at least 7 days. 4. The method according to any one of paragraphs. 1-3, characterized in that the subject, which is a human, does not suffer from cough and/or does not need an antitussive drug. 5. The method according to any one of paragraphs. 1-4, characterized in that the person is characterized as a fast metabolizer. 6. The method according to any one of paragraphs. 1-5, characterized in that the subject is not administered quinidine. 7. The method according to any one of paragraphs. 1-6, characterized in that the subject is not administered any drug from the group that includes: desipramine, paroxetine, thioridazine, pimozide, digoxin, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole and combinations thereof. 8. The method according to any one of paragraphs. 1-7, characterized in that the person is additionally administered an antidepressant selected from the group that includes: bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, metabolite or prodrug of any of these compounds and combinations thereof. 9. The method according to any one of paragraphs. 1-8, characterized in that the transdermal delivery device provides a daily dose of dextromethorphan from about 2 to about 50 mg. 10. Device for transdermal delivery for the treatment of pseudobulbar affect, containing an adhesive layer containing an adhesive that contains dextromethorphan dispersed in the adhesive, in an amount of from about 6 to about 12% of the mass. adhesive layer; and a reservoir layer containing dextromethorphan in an amount of from about 10 to about 60% of the mass. reservoir layer where the adhesive layer contains (a) transdermal penetration enhancer, which is isopropyl myristate, in an amount of from about 6 to about 12% of the mass. adhesive layer; And (b) pressure-sensitive adhesive containing acrylate copolymer adhesive, in an amount of from about 50 to about 90% of the mass. adhesive layer; where the reservoir layer contains (a) transdermal penetration enhancer, which is isopropyl myristate, in an amount of from about 6 to about 12% of the mass. reservoir layer; And (b) dextromethorphan dispersed in a pressure-sensitive adhesive containing an acrylate copolymer adhesive, where the pressure-sensitive adhesive is present in an amount of from about 20 to about 80% of the mass. reservoir layer; where the adhesive layer has a thickness of from about 2.54 to about 254 microns, corresponding to about 0.1 to about 10 mils, and the reservoir layer has a thickness of from about 2.54 to about 254 microns, which corresponds to from about 0.1 to about about 10 mil; And wherein the transdermal delivery device contains dextromethorphan as the sole drug, wherein the acrylate copolymer adhesive is selected from polyacrylate vinyl acetate copolymers.

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