Transdermal delivery of dextromethorphan

Abstract

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

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 413,836, filed October 6, 2022, the entire contents of which are incorporated herein by reference.

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

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

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

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

[0006] In various embodiments, the present disclosure is based, in part, on the unexpected discovery that dextromethorphan can be administered transdermally at a sustained high flux of dextromethorphan, for example, for periods of 7 days or more, from the transdermal delivery devices (patches) herein, which typically contain solid-state dextromethorphan dispersed in an adhesive layer and / or reservoir layer. The transdermal delivery of dextromethorphan herein achieves therapeutically effective plasma dextromethorphan concentrations for treating the diseases or disorders herein, such as PBA. Compared to currently available oral delivery via formulations such as Nuedexta®, the transdermal delivery of dextromethorphan herein offers many advantages and addresses many of the unmet medical needs of such oral formulations. For example, the transdermal delivery devices or formulations (e.g., adhesive compositions) herein can be administered to achieve therapeutically effective plasma concentrations, regardless of whether a CYP2D6 inhibitor, such as quinidine, is co-administered. Thus, the transdermal delivery devices or transdermal formulations herein can be administered to transdermally deliver dextromethorphan to subjects who are sensitive or intolerant to CYP2D6 inhibitors, such as quinidine. The transdermal delivery devices or transdermal formulations herein can be conveniently administered to transdermally deliver dextromethorphan to subjects, regardless of whether the subject is a poor, intermediate, or extensive metabolizer of dextromethorphan first. Administration of dextromethorphan using the transdermal delivery devices or transdermal formulations herein may also provide, for example, more accurate dosing, less frequent dosing, and reduced risk of quinidine-associated side effects and / or increased dextromethorphan exposure (e.g., C ) compared to Nuedexta®. max ), reducing the potential for side effects associated with steroids, reducing pill burden, and improving patient compliance may provide a superior clinical experience.

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

[0008] In some embodiments, the present disclosure provides: [1] i. a backing layer; ii. a drug-containing adhesive layer comprising: 1) dextromethorphan in an amount of at least 15% by weight, preferably about 15% to about 50% by weight; 2) isopropyl myristate in an amount of about 6% to about 12% by weight; 3) a pressure-sensitive adhesive, preferably an acrylate-based pressure-sensitive adhesive, in an amount of about 20% to about 60% by weight; and 4) a solubilizing agent in an amount of about 6% to about 25% by weight; A transdermal patch comprising: At least a portion of the dextromethorphan is in a solid state dispersed in the pressure sensitive adhesive, preferably The transdermal patch is about 30 cm 2 ~Approx. 150cm 2 The transdermal patch has an active surface area of

[0009] [2] The transdermal patch of [1], wherein the acrylate-based pressure-sensitive adhesive is a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as an acrylate copolymer adhesive, e.g., Duro-Tak 87-2287 adhesive and the like, having non-acidic hydroxyl functional groups, e.g., as described herein.

[0010] [3] The transdermal patch of [1] or [2], wherein the acrylate-based pressure-sensitive adhesive is present in an amount of about 20% by weight, about 30% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, or about 60% by weight, or any value or range therebetween, such as about 40-60% by weight, about 45-55% by weight, etc.

[0011] [4] The transdermal patch according to any one of [1] to [3], wherein the solubilizer is a vinylpyrrolidone homopolymer (or povidone), for example, a vinylpyrrolidone polymer such as povidone K30, plasdone K29 / 32, and the like.

[0012] [5] The transdermal patch according to any one of [1] to [4], wherein the solubilizer is present in an amount of about 6%, about 8%, about 10%, about 15%, about 20%, or about 25%, or any value or range therebetween, such as about 8-15% or about 6-20%.

[0013] [6] The transdermal patch according to any one of [1] to [5], wherein the isopropyl myristate is present in an amount of about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, or about 12% by weight, or any value or range therebetween, such as about 8 to 12% by weight.

[0014] [7] The transdermal patch according to any one of [1] to [6], wherein the dextromethorphan is present in an amount of about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight, or any value or range therebetween, such as about 20 to 40% by weight, about 25 to 35% by weight, etc.

[0015] [8] The transdermal patch according to any one of [1] to [7], wherein the drug-containing adhesive layer contains about 150 mg to about 1000 mg of dextromethorphan, for example, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 750 mg, about 900 mg, about 1000 mg, or any value or range therebetween, such as about 250 to 400 mg, about 300 to 400 mg, or about 350 to 450 mg, or about 300 to 800 mg, or about 350 to 900 mg of dextromethorphan.

[0016] [9] The transdermal patch according to any one of [1] to [8], wherein the drug-containing adhesive layer contains about 30 mg to about 350 mg of isopropyl myristate, for example, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or any value or range therebetween, for example, about 50 to 150 mg, or about 75 to 125 mg, about 75 to 300 mg, or about 50 to 250 mg of isopropyl myristate.

[0017]

[10] The transdermal patch according to any one of [1] to [9], wherein the drug-containing adhesive layer comprises about 150 mg to about 1800 mg of the pressure-sensitive adhesive, preferably an acrylate-based pressure-sensitive adhesive, for example, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1400 mg, about 1600 mg, about 1800 mg, or any value or range therebetween, for example, about 350 to 600 mg, about 400 to 650 mg, or about 450 to 700 mg, about 450 to 1200 mg, about 350 to 1000 mg, or about 400 to 1600 mg.

[0018]

[11] The transdermal patch according to any one of [1] to

[10] , wherein the drug-containing adhesive layer contains the solubilizer in an amount of about 30 mg to about 350 mg, for example, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or any value or range therebetween, for example, about 50 to 150 mg, or about 75 to 125 mg, about 75 to 300 mg, or about 50 to 250 mg.

[0019]

[12] The transdermal patch according to any one of [1] to

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

[0020]

[13] Approximately 70cm 2The transdermal patch according to any one of [1] to

[12] , having an active surface area of

[0021]

[14] Approximately 2mg / cm 2 ~about 25mg / cm 2 , for example, about 2.5 mg / cm 2 , about 3mg / cm 2 , about 4mg / cm 2 , about 5mg / cm 2 , about 6mg / cm 2 , about 7mg / cm 2 , about 8mg / cm 2 , approximately 9 mg / cm 2 , about 10mg / cm 2 , about 12mg / cm 2 , about 15mg / cm 2 , about 20mg / cm 2 , about 25mg / cm 2 etc., or any value or range therebetween, e.g., about 3 to 10 mg / cm 2 , about 4~7mg / cm 2 , about 5~12mg / cm 2 , about 8~25mg / cm 2 The transdermal patch according to any one of [1] to

[13] , having a total dextromethorphan loading amount of 100 or more.

[0022]

[15] The transdermal patch according to any one of [1] to

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

[0023]

[16] The transdermal patch according to any one of [1] to

[15] , which is in the form of a single-layer patch.

[0024]

[17] The transdermal patch has a vascularity of at least about 200 μg / cm for at least 7 days as measured in vitro using human cadaver skin. 2 / day, e.g., about 200ug / cm for 7 days or more 2 / day, about 300ug / cm 2 / day, about 400ug / cm 2 / day, about 500ug / cm 2 / day, about 600ug / cm2 / day, about 700ug / cm 2 / day, about 800ug / cm 2 / day, about 1000ug / cm 2 / day, or any value or range therebetween, e.g., about 200-800 ug / cm 2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2 The transdermal patch according to any one of [1] to

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

[0025]

[18] The transdermal patch according to any one of [1] to

[16] , wherein a single application of the transdermal patch to a human subject can transdermally deliver a daily dose of about 15 mg to about 50 mg of dextromethorphan (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any value or range therebetween, e.g., about 20 to 50 mg, about 30 to 50 mg, or about 20 to 40 mg) to the human subject for at least 7 days.

[0026]

[19] A transdermal patch described in any of [1] to

[16] , which can transdermally deliver a therapeutically effective daily dose for treating emotional dysregulation to a human subject for at least 7 days by applying the transdermal patch once to the human subject.

[0027]

[20] i. a backing layer; ii. a skin-contacting drug-containing adhesive layer comprising: 1) dextromethorphan in an amount of about 6% to about 12% by weight; 2) isopropyl myristate in an amount of about 6% to about 12% by weight; 3) a first pressure-sensitive adhesive, preferably an acrylate-based pressure-sensitive adhesive, in an amount of about 65% to about 85% by weight; and 4) a crystallization inhibitor in an amount of about 6% to about 12% by weight; iii. a reservoir layer comprising: 1) dextromethorphan in an amount of at least 15% by weight (e.g., from about 15% by weight to about 50% by weight); 2) isopropyl myristate in an amount of from about 6% by weight to about 12% by weight; 3) a second pressure-sensitive adhesive in an amount of from about 20% by weight to about 60% by weight; and 4) a solubilizing agent in an amount of from about 6% by weight to about 25% by weight; A transdermal patch comprising: at least a portion of the dextromethorphan in the reservoir layer is in a solid state dispersed in the second pressure-sensitive adhesive; The first pressure sensitive adhesive and the second pressure sensitive adhesive may be the same or different, preferably the same, and preferably The transdermal patch is about 30 cm 2 ~Approx. 150cm 2 The transdermal patch has an active surface area of

[0028]

[21] The transdermal patch of claim

[20] , wherein the first pressure-sensitive adhesive is an acrylate-based pressure-sensitive adhesive.

[0029]

[22] The transdermal patch of

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

[0030]

[23] The transdermal patch of

[21] or

[22] , wherein the acrylate-based pressure-sensitive adhesive is about 65%, about 70%, about 75%, about 80%, or about 85% by weight of the skin-contacting drug-containing adhesive layer, or any value or range therebetween, such as about 70-85% by weight, about 65-75% by weight, etc.

[0031]

[24] The transdermal patch according to any one of

[20] to

[23] , wherein the crystallization inhibitor is a vinylpyrrolidone homopolymer (or povidone), for example, a vinylpyrrolidone polymer such as povidone K30, plasdone K29 / 32, and the like.

[0032]

[25] The transdermal patch of any of

[20] to

[24] , wherein the crystallization inhibitor is present in an amount of about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% of the skin-contacting drug-containing adhesive layer, or any value or range therebetween, such as about 6-12% or 8-12%.

[0033]

[26] The transdermal patch of any of

[20] to

[25] , wherein the isopropyl myristate is present in an amount of about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% by weight of the skin-contacting drug-containing adhesive layer, or any value or range therebetween, such as about 8 to 12% by weight.

[0034]

[27] The transdermal patch of any of

[20] to

[26] , wherein the dextromethorphan in the skin-contacting drug-containing adhesive layer is about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% by weight of the skin-contacting drug-containing adhesive layer, or any value or range therebetween, such as about 6 to 10% by weight.

[0035]

[28] The transdermal patch according to any one of

[20] to

[27] , wherein the second pressure-sensitive adhesive is an acrylate-based pressure-sensitive adhesive.

[0036]

[29] The transdermal patch of any of

[20] to

[28] , wherein the second pressure-sensitive adhesive is a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as an acrylate copolymer adhesive, e.g., Duro-Tak 87-2287 adhesive and the like, having non-acidic hydroxyl functional groups, e.g., as described herein.

[0037]

[30] A transdermal patch according to any one of

[20] to

[29] , wherein the second pressure-sensitive adhesive is present in an amount of about 20%, about 30%, about 35%, about 40%, about 45%, about 50%, or about 60% by weight of the reservoir layer, or any value or range therebetween, such as about 35-45% by weight, about 30-50% by weight, etc.

[0038]

[31] The transdermal patch according to any one of

[20] to

[30] , wherein the solubilizer is a vinylpyrrolidone homopolymer (or povidone), for example, a vinylpyrrolidone polymer such as povidone K30, plasdone K29 / 32, and the like.

[0039]

[32] The transdermal patch according to any one of

[20] to

[31] , wherein the solubilizing agent is present in an amount of about 6%, about 8%, about 10%, about 15%, about 20%, or about 25% of the reservoir layer, or any value or range therebetween, such as about 15-25% or about 10-20%.

[0040]

[33] A transdermal patch according to any one of

[20] to

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

[0041]

[34] The transdermal patch according to any one of

[20] to

[33] , wherein the dextromethorphan in the reservoir layer is about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight of the reservoir layer, or any value or range therebetween, such as about 20 to 40% by weight, about 25 to 35% by weight, etc.

[0042]

[35] The transdermal patch described in any one of

[20] to

[34] , wherein the dextromethorphan in the reservoir layer has a concentration that is about 200 to 800% (preferably, about 300 to 500%) of the concentration in the skin-contacting drug-containing adhesive layer.

[0043]

[36] The transdermal patch described in any of

[20] to

[35] , wherein the amount of dextromethorphan in the reservoir layer is at least about 200%, preferably about 200 to 3000% (preferably about 300 to 1500%) of the amount of dextromethorphan in the skin-contacting drug-containing adhesive layer.

[0044]

[37] The transdermal patch described in any of

[20] to

[36] , wherein the skin-contacting drug-containing adhesive layer has a thickness of about 0.4 mil to about 5 mil, for example, about 0.4 to 3 mil.

[0045]

[38] The transdermal patch described in any one of

[20] to

[37] , wherein the reservoir layer has a thickness of about 2 mil to about 7.5 mil, for example, about 4 mil.

[0046]

[39] The transdermal patch described in any of

[20] to

[38] , wherein the reservoir layer has a thickness of at least about 100% of the thickness of the skin-contacting drug-containing adhesive layer, preferably about 100 to 800% (preferably 100 to 600%, or 120 to 300%).

[0047]

[40] A transdermal patch according to any one of

[20] to

[39] , wherein the total weight of the reservoir layer is at least about 100%, about 100 to 800% (preferably about 100 to 600%, or about 120 to 300%) of the total weight of the skin-contacting drug-containing adhesive layer.

[0048]

[41] The transdermal patch according to any one of

[20] to

[40] , wherein the total amount of dextromethorphan is about 150 mg to about 1000 mg, for example, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 750 mg, about 900 mg, about 1000 mg, or any value or range therebetween, for example, about 250 to 400 mg, about 300 to 400 mg, or about 350 to 450 mg, or about 300 to 800 mg, about 350 to 900 mg, etc.

[0049]

[42] The transdermal patch according to any one of

[20] to

[41] , wherein the total amount of the isopropyl myristate is about 30 mg to about 350 mg, for example, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or any value or range therebetween, for example, about 50 to 150 mg, or about 75 to 125 mg, about 75 to 300 mg, or about 50 to 250 mg.

[0050]

[43] The transdermal patch according to any one of

[20] to

[42] , wherein the total amount of the first pressure-sensitive adhesive and the second pressure-sensitive adhesive is about 150 mg to about 1800 mg, for example, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1400 mg, about 1600 mg, about 1800 mg, or any value or range therebetween, for example, about 350 to 600 mg, about 400 to 650 mg, or about 450 to 700 mg, about 450 to 1200 mg, about 350 to 1000 mg, about 400 to 1600 mg, etc.

[0051]

[44] A transdermal patch according to any one of

[20] to

[43] , containing dextromethorphan as the only active ingredient.

[0052]

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

[20] to

[44] , having an active surface area of

[0053]

[46] Approximately 2mg / cm 2 ~about 25mg / cm 2 , for example, about 2.5 mg / cm 2 , about 3mg / cm 2 , about 4mg / cm 2 , about 5mg / cm 2 , about 6mg / cm 2 , about 7mg / cm 2 , about 8mg / cm 2 , approximately 9 mg / cm 2 , about 10mg / cm 2 , about 12mg / cm 2 , about 15mg / cm 2 , about 20mg / cm 2 , about 25mg / cm 2 etc., or any value or range therebetween, e.g., about 3 to 10 mg / cm 2 , about 4~7mg / cm 2 , about 5~12mg / cm 2 , about 8~25mg / cm 2 The transdermal patch according to any one of

[20] to

[45] , having a total dextromethorphan loading amount of

[0054]

[47] A transdermal patch according to any one of

[20] to

[46] , comprising the backing layer, the skin-contacting drug-containing adhesive layer, the reservoir layer, and optionally a release liner.

[0055]

[48] ​​The transdermal patch according to any one of

[20] to

[47] , which is in the form of a two-layer patch.

[0056]

[49] The transdermal patch has a vascularity of at least about 200 μg / cm for at least 7 days as measured in vitro using human cadaver skin. 2 / day, e.g., about 200ug / cm for 7 days or more 2 / day, about 300ug / cm 2 / day, about 400ug / cm 2 / day, about 500ug / cm 2 / day, about 600ug / cm 2 / day, about 700ug / cm2 / day, about 800ug / cm 2 / day, about 1000ug / cm 2 / day, or any value or range therebetween, e.g., about 200-800 ug / cm 2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2 The transdermal patch according to any one of

[20] to

[48] , having a dextromethorphan flux of 1000 kJ / day or more.

[0057]

[50] The transdermal patch according to any one of

[20] to

[48] , which can transdermally deliver a daily dose of about 15 mg to about 50 mg of dextromethorphan (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any value or range therebetween, e.g., about 20 to 50 mg, about 30 to 50 mg, or about 20 to 40 mg) to a human subject for at least 7 days by applying the transdermal patch once to the human subject.

[0058]

[51] A transdermal patch described in any of

[20] to

[48] , which can transdermally deliver a therapeutically effective daily dose for treating emotional dysregulation to a human subject for at least 7 days by applying the transdermal patch once to the human subject.

[0059]

[52] A method for treating a neurological disease or disorder (e.g., any of those described herein) in a subject in need of such treatment, comprising applying to the subject a transdermal patch described in any one of [1] to

[51] .

[0060]

[53] The method of

[52] , comprising applying the transdermal patch to transdermally deliver a therapeutically effective amount of dextromethorphan to the subject.

[0061]

[54] The method of

[52] , comprising applying the transdermal patch to the subject to transdermally deliver a daily dose of about 15 mg to about 50 mg (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any value or range therebetween, e.g., about 20-50 mg, about 30-50 mg, or about 20-40 mg) of dextromethorphan.

[0062]

[55] The method of

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

[0063]

[56] The method according to any one of

[52] to

[55] , wherein the transdermal patch is applied to the subject at a dosing frequency ranging from once a day to once a week, preferably once a week or twice a week.

[0064]

[57] The method according to any one of

[52] to

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

[0065]

[58] The method according to

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

[0066]

[59] The method according to any one of

[52] to

[58] , wherein the subject does not cough and / or does not require antitussive medication.

[0067]

[60] The method according to any one of

[52] to

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

[0068]

[61] The method according to any one of

[52] to

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

[0069]

[62] The method according to any one of

[52] to

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

[0070]

[63] The method according to any one of

[52] to

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

[0071]

[64] The method according to any one of

[52] to

[63] , wherein the subject is concurrently administered a drug whose metabolism is affected by a CYP2D6 inhibitor.

[0072]

[65] The method according to any one of

[52] to

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

[0073]

[66] The method of

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

[0074]

[67] The method according to any one of

[52] to

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

[0075]

[68] The method according to any one of

[52] to

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

[0076] It is to be understood that both the foregoing summary of the invention and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed. [Brief explanation of the drawings]

[0077] [Figure 1] 1 presents a graph showing the results of an in vitro flux study for transdermal delivery devices prepared according to Examples 1 and 2. DETAILED DESCRIPTION OF THE INVENTION

[0078] Dextromethorphan (DXM) is used orally to treat neurological disorders such as dysregulation of affect (PBA), emotional lability, agitation in Alzheimer's disease, major depressive disorder, treatment-resistant disorders, pain management, other CNS disorders, and the like. However, to be effective, DXM must be delivered with a competitive inhibitor of the hepatic enzyme cytochrome P450 2D6 (CYP2D6). Specifically, this means that DXM is coadministered with quinidine. Otherwise, small amounts of DXM will be subject to hepatic action on ingested food.

[0079] The present disclosure generally relates to the transdermal delivery of dextromethorphan using the transdermal delivery devices, formulations (e.g., adhesive compositions), and methods herein, which offer many advantages over currently available oral formulations (e.g., Nuedexta®) and address many unmet medical needs associated with such oral formulations. For example, the transdermal delivery devices or formulations herein can be administered to achieve therapeutically effective plasma concentrations regardless of whether a CYP2D6 inhibitor, such as quinidine, is co-administered. Thus, the transdermal delivery devices or formulations herein can be administered to transdermally deliver dextromethorphan to subjects who are sensitive to or intolerant of CYP2D6 inhibitors, such as quinidine (e.g., subjects who have one or more side effects associated with quinidine or who are co-administering a drug whose metabolism is affected by a CYP2D6 inhibitor, such as quinidine). Furthermore, the transdermal delivery device or transdermal formulation herein can be conveniently administered to transdermally deliver dextromethorphan to a subject, regardless of whether the subject is first determined to be a poor, intermediate, or extensive metabolizer of dextromethorphan. For brevity, as used herein, unless otherwise clear from the context, poor metabolizer (PM), intermediate metabolizer (IM), or extensive metabolizer (EM) refers to a subject's ability to metabolize dextromethorphan. Classifying subjects as PM, IM, or EM (also referred to as extreme metabolizers or ultrarapid metabolizers or UMs) is known in the art. See, for example, Treducu ALD et al., Frontiers in Pharmacology, Vol. 9, Article 305 (April 2018), which assigns subjects as UMs if they contain "three or more copies of the gene that function normally" based on genotype.

[0080] Administration of dextromethorphan using the transdermal delivery devices or transdermal formulations herein may also result in, for example, more accurate dosing, less frequent dosing, fewer quinidine-associated side effects and / or increased dextromethorphan exposure (e.g., Cmax ), reducing the potential for side effects associated with the administration of dextromethorphan, reducing pill burden, and improving patient compliance, may provide a superior clinical experience. Given this disclosure, one skilled in the art can select an appropriate patch to more precisely deliver a therapeutically effective amount of dextromethorphan to a treated subject. Furthermore, the PK profiles described herein and in WO 2021 / 202329 A1 indicate that transdermal delivery of dextromethorphan can achieve a much lower yet effective plasma exposure of dextromethorphan compared to twice-daily oral dosing of Nuedexta® tablets. Thus, the methods herein are intended to provide a therapeutically effective treatment for patients with at least high dextromethorphan exposure (e.g., C max It is expected that this will result in a reduced incidence of side effects associated with steroids (e.g., AUC). The transdermal delivery devices herein can be configured as a 1-day patch, 2-day patch, 3-day patch, 4-day patch, 5-day patch, 6-day patch, or 7-day patch, and are suitable for dosing frequencies ranging from once daily to once weekly, e.g., once over 24 hours, once over 36 hours, once over 48 hours, etc., or once weekly, twice weekly, three times weekly, four times weekly, five times weekly, or six times weekly. Use of the transdermal delivery devices herein can improve patient compliance by avoiding at least a twice-daily dosing regimen of Nuedexta®.

[0081] Prior to the applicant's research, it was unknown whether dextromethorphan could be delivered transdermally to achieve therapeutically effective plasma concentrations for treating neurological diseases or disorders such as PBA. The unpredictability of transdermal administration is well known. For example, testosterone can be delivered transdermally without enhancers at rates three orders of magnitude higher than beta-estradiol. This difference was unexpected because these compounds are similar structurally and based on LogP calculations. See U.S. Provisional Application No. 62 / 568,028, filed October 4, 2017, the contents of which are incorporated by reference in their entirety. U.S. Pat. No. 6,335,030 B1 describes several examples of dextromethorphan patches intended to achieve antitussive effects. However, prior to applicant's work described in U.S. Provisional Application No. 62 / 680,182 and International Application No. PCT / US2018 / 054178 (published as WO2019 / 070864), the contents of each of which are incorporated herein by reference in their entireties, no pharmacokinetic data were known regarding transdermal administration of dextromethorphan.

[0082] PCT / US2018 / 054178 demonstrated that transdermal delivery of dextromethorphan without quinidine can produce significant dextromethorphan blood concentrations in humans. PCT / US2018 / 054178 also included a study in which healthy subjects were given a 45cm dose containing approximately 35mg of dextromethorphan. 2 An exemplary patch of size 15 mg (designed to transdermally deliver 15 mg per day and containing about 80% by weight adhesive (Duro-Tak 87-2287), about 10% by weight dextromethorphan base, and about 10% by weight permeation enhancer isopropyl myristate in the adhesive layer (drug-containing adhesive layer)) applied for about 24 hours resulted in a mean C of about 6 ng / mL, which approaches, among other things, that observed following oral administration of Nuedexta® tablets (20 mg dextromethorphan and 10 mg quinidine) twice daily to human subjects. max and a mean AUC of approximately 92 h·ng / mL. 0-24hA human pharmacokinetic study has been described in which it was found that

[0083] A further development in WO 2021 / 202329, the contents of which are incorporated herein by reference in their entirety, as detailed herein, demonstrates that the inclusion of a crystallization inhibitor, vinylpyrrolidone polymer (Plasdone K29 / 32), in a dextromethorphan transdermal patch significantly enhances the permeability of dextromethorphan from the patch in vitro and in vivo. Specifically, a 70 cm 2 The patch, worn for 24 hours, can deliver a daily dose of about 32.4 mg to about 41.1 mg of dextromethorphan to a human subject, resulting in a dextromethorphan flux of about 0.46 mg / cm 2 / day ~ approx. 0.59mg / cm 2 This is a significantly greater flux compared to a similar patch without the vinylpyrrolidone polymer (which was replaced by the adhesive matrix Duro-Tak 87-2287), with an estimated flux of approximately 0.33 mg / cm. 2 Additional in vivo data also showed that patches with vinylpyrrolidone polymers reduced the per unit patch area (cm 2 ) and demonstrates improved delivery of dextromethorphan per 1000 mg / dose.

[0084] The examples presented in WO2019 / 070864 and WO2021 / 202329 primarily relate to transdermal patches that do not contain drug particles or dextromethorphan in a solid state, such as dextromethorphan crystals. These drug crystals are believed to impede the permeation of dextromethorphan, which is undesirable. However, as shown herein, it has been unexpectedly discovered that by combining certain ingredients, dextromethorphan can be included in a transdermal patch at high concentrations and present at least partially in a solid state (such as dextromethorphan crystals), and the transdermal patch can have the desired dextromethorphan permeability over an extended period of time, making the transdermal patch suitable for a once-weekly dosing regimen.

[0085] In various embodiments, the present disclosure provides transdermal delivery devices and transdermal formulations containing high concentrations of dextromethorphan, methods for preparing the same, methods for transdermal delivery of dextromethorphan using the transdermal delivery devices or transdermal formulations herein, and methods for treating a disease or disorder using the transdermal delivery devices or transdermal formulations herein.

[0086] Transdermal delivery devices containing dextromethorphan Certain embodiments of the present disclosure are directed to novel transdermal delivery devices containing dextromethorphan.

[0087] Various patch designs can be used for the transdermal delivery devices herein. The transdermal delivery devices herein typically include a backing layer, an adhesive layer (e.g., a drug-containing adhesive layer) that serves as the skin-contacting layer during use, and an optional reservoir layer. The adhesive layer typically contains dextromethorphan dispersed in an adhesive, preferably a pressure-sensitive adhesive. Multiple adhesive layers can be used in the transdermal delivery devices herein. The adhesive layer is generally formulated to allow the transdermal delivery device to adhere to the user's skin for a desired period of time. For example, in some embodiments, the transdermal delivery device can be continuously adhered to the user's skin for about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more.

[0088] In some embodiments, the transdermal delivery device can be a drug-in-adhesive (DIA) patch. In some embodiments, the DIA patch is a single-layer patch, e.g., the single layer comprises dextromethorphan dispersed in an adhesive, with at least a portion of the dextromethorphan being in a solid state, i.e., not completely dissolved in the adhesive, or alternatively, may be said to have dextromethorphan particles, which can be dextromethorphan crystals.

[0089] In some embodiments, the DIA patch is a multi-layer patch. For example, the patch may contain two drug-containing adhesive layers, optionally separated by a membrane, such as a rate-controlling membrane, or a reservoir layer. In some embodiments, the two drug-containing adhesive layers may sandwich a reservoir layer. In some embodiments, one of the drug-containing adhesive layers may be a skin-contacting drug-containing adhesive layer, and the other drug-containing adhesive layer may be, for example, a reservoir layer having a higher dextromethorphan concentration than the skin-contacting drug-containing adhesive layer. In such embodiments, the reservoir layer typically contains at least a portion of the solid-state dextromethorphan dispersed in the adhesive.

[0090] The transdermal delivery device can contain dextromethorphan as the sole drug or in combination with another drug. Unless clearly contradicted, in any of the embodiments described herein, dextromethorphan can be the sole drug in the transdermal delivery device. Dextromethorphan can exist in various forms, for example, as the free base or a pharmaceutically acceptable salt. As used herein, weight percentages, concentrations, fluxes, etc., referring to dextromethorphan should be understood as the measured and / or calculated total amount of dextromethorphan, and the values ​​are expressed in terms of the equivalent value relative to the dextromethorphan base. Furthermore, unless otherwise clear from the context, all weight percentages or thicknesses should refer to the weight percentage or thickness based on the final formulation (e.g., the final adhesive layer or final reservoir layer, etc.) or the final transdermal delivery device, as appropriate. In any of the embodiments described herein, dextromethorphan can exist in its free base form, except that it may be protonated through equilibrium with other component(s). For example, in any of the embodiments described herein, the transdermal delivery device or pharmaceutical composition described herein can be prepared by directly or indirectly mixing the described amount of dextromethorphan base with other ingredients.

[0091] In any of the embodiments described herein, dextromethorphan in the transdermal delivery device can be partially or completely replaced with deuterated dextromethorphan, such as a d3 analog (O-CD3, or N-CD3) or a d6 analog (N-CD3, O-CD3). See, e.g., claims 1 and 17 of U.S. Pat. No. 7,973,049, the contents of which are incorporated by reference in their entirety. In such embodiments, it will be apparent that the method of using a deuterated dextromethorphan patch provides deuterated dextromethorphan to the user. As used herein, deuterated dextromethorphan refers to a compound resulting from the replacement of one or more hydrogen atoms of dextromethorphan with deuterium, such that each replacement position has a deuterium content greater than the natural abundance, i.e., the replacement position is enriched with deuterium. In some embodiments, the deuterated dextromethorphan has at least one position enriched with deuterium to at least 10% deuterium, at least 50% deuterium, at least 90% deuterium, at least 95% deuterium, or at least 98% deuterium. In any of the embodiments described herein, the dextromethorphan in the transdermal delivery device can also be partially or completely replaced with a dextromethorphan analog, such as a fluorinated dextromethorphan or a skin-permeable prodrug of dextromethorphan.

[0092] The adhesive layer typically comprises a pressure-sensitive adhesive (PSA). Useful features of a pressure-sensitive adhesive include adequate tack, good adhesive strength, and cohesive strength. Further useful attributes include biocompatibility (e.g., non-irritating, non-sensitizing, non-toxic), formulation compatibility, delivery system compatibility, etc. Useful pressure-sensitive adhesives include, for example, polyacrylates, polyacrylic esters, silicones, polyisobutylene, etc.

[0093] PSAs are generally known in the art. See, for example, Tan et al., Pharm Sci & Tech Today, 2:60-69 (1999). Non-limiting examples of useful PSAs include polyisobutylene (PIB), silicone polymers, acrylate copolymers, and combinations thereof. In some embodiments, the pressure-sensitive adhesive comprises a polyisobutylene adhesive, a silicone polymer adhesive, an acrylate copolymer adhesive, or a combination thereof. In some embodiments, the pressure-sensitive adhesive comprises an acrylate copolymer adhesive. Non-limiting examples of useful acrylate copolymers include polyacrylate vinyl acetate copolymers, such as acrylic pressure-sensitive adhesives such as Duro-Tak 87-2287, Duro-Tak 87-4098, Duro-Tak 87-4287, or Duro-Tak 87-2516, Duro-Tak 87-2852, or Duro-Tak 87-2194 manufactured by Henkel Adhesives. PIB is an elastomeric polymer commonly used in PSAs as both the main base polymer and tackifier. PIB is a homopolymer of isobutylene, characterized by a regular structure of a carbon-hydrogen backbone with only terminal unsaturation. Non-limiting examples of useful PIBs include those sold by BASF under the trade name Oppanol. Silicone polymers are high-molecular-weight polydimethylsiloxanes containing residual silanol functionality (SiOH) at the ends of the polymer chain. Non-limiting examples of useful silicone PSAs for use in pharmaceutical applications include those available from Dow Corning Corporation under the trade name BIO-PSA, e.g., BIO-7-4202. In some embodiments, the adhesive layer is from about 0.1 mil to about 10 mil, e.g., from about 1.5 mil to about 10 mil (e.g., from about 1.5 mil to about 2 mil) thick.

[0094] In some embodiments, suitable adhesives include, for example, the following silicone adhesives manufactured by Dow Corning: BIO-PSA 7-410X, BIO-PSA 7-420X, BIO-PSA 7-430X, BIO-PSA 7-440X, BIO-PSA 7-450X, BIO-PSA 7-460X, and BIO-PSA hot melt adhesive. In some embodiments, suitable adhesives include, for example, the following polyacrylate / polyacrylic ester adhesives manufactured by Henkel Adhesives: Duro-Tak 87-900A, 87-9301, 87-4098, 87-2510, 87-2287, 87-2677, 87-4287, 87-2516, 87-2074, 87-235A, 87-2353, 87-2852, 87-2051, 87-2052, 87-2054, 87-2194, 87-2196, 87-6908, 387-2510, 387-2287, 387-2516, 387-2353, 387-2051, 387-2051, and 387-2054; GELVA Examples include GMS 3083, 3253, 788, and 9073. These may have, for example, hydroxyl functionality, carboxyl functionality, hydroxyl and carboxyl functionality, or no functionality (as previously described). They may or may not contain, for example, vinyl acetate monomers. In some embodiments, the pressure-sensitive adhesive may be a copolymer formed from acrylate monomers and vinyl acetate, including those containing non-acidic hydroxyl functionality, such as DuroTak® 2287 (87-2287, 387-2287, etc.) adhesive and the like. DuroTak® 87-2287 and 387-2287 have the same polymer composition, and are used interchangeably herein. A typical composition of DuroTak® 2287 may include a random copolymer formed from the following monomers: 2-ethylhexyl acrylate (e.g., about 68.2%), vinyl acetate (e.g., about 26.5%), hydroxyethyl acrylate (e.g., about 5.2%), and glycidyl methacrylate (e.g., about 0.15%).In some embodiments, the acrylate copolymer adhesive may be formed from monomers including about 5.2 wt% 2-hydroxyethyl acrylate, about 20-40 wt% vinyl acetate, and about 55-75 wt% 2-ethylhexyl acrylate. See also U.S. Published Application No. US20060257462A1 and U.S. Patent No. 5,693,335, the contents of each of which are incorporated herein by reference in their entirety.

[0095] Typically, the transdermal delivery device herein is supported by a backing layer, such as an impermeable backing film, and the adhesive surface is protected by a release liner before use. Various materials can be used as the backing layer of the transdermal delivery device herein. Typically, the backing layer is impermeable. For example, the backing layer can be composed of an impermeable polymer film, such as a polyester (PET) film or a polyethylene (PE) film. In some embodiments, the backing layer can comprise a polyester, such as Scotchpak 9736 or Scotchpak 1012, a polyurethane film, such as Scotchpak 9701, or a polyethylene film, such as CoTran 9720. In some embodiments, the backing is part of an overlay and can be a nonwoven fabric, a polyurethane film, or other flexible material that provides flexibility and better wear.

[0096] The release liner can be manufactured in any desired size for the present invention. The release liner can be made of silicone or fluoropolymer-coated polyester film. The release liner protects the transdermal delivery device during storage and is removed before use. Silicone-coated release liners include those manufactured by Mylan Corporation, Loparex Corporation, and 3M's Drug Delivery Systems. These include those manufactured and supplied by 3M's Drug Delivery Systems and Loparex. In some embodiments, the release liner comprises 3M's ScotchPak 9744 or ScotchPak 1022.

[0097] The transdermal delivery devices herein may also optionally include other suitable excipients, such as humectants, plasticizers, antioxidants, anti-irritants, gel-forming agents, crystallization inhibitors, drug-release modifiers, etc. These excipients are within the purview of those skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients, ( 7th ed. 2012), the entire contents of which are incorporated herein by reference. In some embodiments, additional active ingredient(s) may also be included in the transdermal delivery devices herein.

[0098] The transdermal delivery device herein can have different sizes (patch sizes) depending on its application. Typically, the patch size is about 5 cm 2 ~about 300cm 2 (For example, about 5 cm 2 , about 10cm 2 , about 20cm 2 , about 30cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 80cm 2 , about 100cm 2 , about 120cm 2 , about 150cm 2 , about 200cm2 or any value or range between the specified values), e.g., about 30 cm 2 ~Approx. 150cm 2 , about 10cm 2 ~about 100cm 2 , for example, about 70 cm 2 It could be.

[0099] When the transdermal delivery device herein is applied to a subject's skin, theoretically, the entire adhesive surface may come into contact with the skin. Therefore, the area of ​​the adhesive surface defines the skin-contact area through which the active ingredient from the device can penetrate the skin, which is also referred to herein as the active surface area. In some embodiments, the adhesive surface is the only surface of the transdermal delivery device that contacts the skin upon application, and the active surface area is the same as the area of ​​the adhesive surface. In some embodiments, the adhesive surface and one or more other surfaces of the transdermal delivery device contact the skin upon application, and the entire skin-contact area is the active surface area. In a typical DIA patch, the patch size is the same as the active surface area. However, as will be understood by those skilled in the art, for example, when an overlay design (the overlay typically includes adhesive and / or other components, but essentially does not contain or does not contain an active ingredient) is used to secure the transdermal delivery device to the skin, the adhesive surface of the overlay contacts the skin but does not deliver the active ingredient from the transdermal delivery device. Therefore, such adhesive surface from the overlay design is not considered to be the active surface area. Unless otherwise clear from the context, the unit " / cm 2 " should be understood as per square centimeter of active surface area as defined herein.

[0100] The active surface area can determine the dose of drug to be delivered. Typically, the active surface area is about 5 cm 2 ~about 300cm 2 (For example, about 5 cm 2 , about 10cm 2 , about 20cm 2 , about 30cm 2 , about 40cm 2 , about 50cm 2, about 60cm 2 , about 80cm 2 , about 100cm 2 , about 120cm 2 , about 150cm 2 , about 200cm 2 or any value or range between the specified values), e.g., about 30 cm 2 ~Approx. 150cm 2 , about 10cm 2 ~about 100cm 2 , for example, about 70 cm 2 It could be.

[0101] In some embodiments, the transdermal delivery devices herein can be configured to provide dextromethorphan to a user (e.g., a human subject) at a dose of at least about 2 mg / day (e.g., about 2 mg / day to about 50 mg / day) for one or more days, e.g., 2, 3, 4, 5, 6, or 7 days. For example, in some embodiments, the transdermal delivery devices can be configured to transdermally deliver dextromethorphan to a user at a dose of about 5 mg / day to about 50 mg / day (e.g., about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, or any value or range therebetween) for one or more days (e.g., 1.5 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or any value or range therebetween).

[0102] In some preferred embodiments, the transdermal delivery devices herein (e.g., any of those described in [1]-

[51] of the Summary of the Invention section) can be configured to transdermally deliver a daily dose of about 15 mg to about 50 mg of dextromethorphan (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any value or range therebetween, e.g., about 20-50 mg, about 30-50 mg, or about 20-40 mg) to a human subject for a period of 7 days or more, upon a single application of the transdermal patch to the human subject. In such embodiments, the transdermal patch is typically applied to the skin of the human subject and remains attached to the skin of the human subject for a period of 7 days or more, i.e., the patch is worn for about 7 days or more until it is removed or replaced with another transdermal patch. Additionally, the transdermal patch can transdermally deliver dextromethorphan to the human subject at substantially the same daily dose throughout the period the patch is worn, e.g., the delivered daily dose does not vary by more than 15 mg / day, more preferably, does not vary by more than 10 mg / day, from the average daily dose.

[0103] In some preferred embodiments, the transdermal delivery devices herein (e.g., any of those described in [1] to

[51] in the Summary of the Invention section) are capable of delivering at least about 200 μg / cm 2 of a drug to a human subject for 7 days or more by applying a single transdermal patch to the human subject. 2 / day (where "ug" means micrograms, as used herein). For example, in some embodiments, a transdermal patch can be configured to achieve a dextromethorphan flux of at least about 200 ug / cm for at least 7 days after a single application to a human subject. 2 / day, for example, for 7 days or more, about 200ug / cm² / day, about 300ug / cm² 2 / day, about 400ug / cm 2 / day, about 500ug / cm 2 / day, about 600ug / cm 2 / day, about 700ug / cm 2 / day, about 800ug / cm 2 / day, about 1000ug / cm2 / day, or any value or range therebetween, e.g., about 200-800 ug / cm 2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2 In some embodiments, the transdermal patch can deliver dextromethorphan transdermally to a human subject at substantially the same rate over the period the patch is worn, e.g., the cumulative daily permeation of dextromethorphan can be increased from the average cumulative daily permeation of dextromethorphan to 350 ug / cm. 2 / day, preferably 250ug / cm 2 / day, more preferably 200ug / cm 2 Does not change for more than / day.

[0104] The total dextromethorphan loading of the transdermal delivery device can be adjusted based on the total desired dose. Typically, the total dextromethorphan loading is (e.g., at least 2 mg / cm 2 , at least 3 mg / cm 2 , at least 4 mg / cm 2 , at least 5 mg / cm 2 , at least 6 mg / cm 2 , at least 7 mg / cm 2 , at least 8 mg / cm 2 , at least 9 mg / cm 2 , at least 10 mg / cm 2 , at least 15 mg / cm 2 , at least 20 mg / cm 2 , at least 25 mg / cm 2 etc.) 2mg / cm 2 For example, in some embodiments, the transdermal delivery device may be greater than about 2 mg / cm 2 ~about 25mg / cm 2 , for example, about 2.5 mg / cm 2 , about 3mg / cm 2 , about 4mg / cm 2, about 5mg / cm 2 , about 6mg / cm 2 , about 7mg / cm 2 , about 8mg / cm 2 , approximately 9 mg / cm 2 , about 10mg / cm 2 , about 12mg / cm 2 , about 15mg / cm 2 , about 20mg / cm 2 , about 25mg / cm 2 etc., or any value or range between the listed values, e.g., about 3-10 mg / cm 2 , about 4~7mg / cm 2 , about 5~12mg / cm 2 , about 8~25mg / cm 2 In some embodiments, the transdermal delivery device may have a total dextromethorphan loading of 25 mg / cm or more. 2 Total dextromethorphan loading exceeding 30 mg / cm 2 , or up to 35 mg / cm 2 As used herein, the total dextromethorphan loading of a patch can be calculated by dividing the total amount of dextromethorphan in the patch by the active surface area of ​​the patch.

[0105] Exemplary Transdermal Delivery Devices and Transdermal Formulations In some embodiments, the present disclosure also provides the following non-limiting exemplary transdermal delivery devices, or what may alternatively be referred to herein as transdermal patches or simply patches, and transdermal formulations such as adhesive compositions:

[0106] In some embodiments, the present disclosure provides an adhesive composition comprising (1) dextromethorphan, (2) a pressure-sensitive adhesive, (3) a skin permeation enhancer (e.g., isopropyl myristate), and (4) an optional solubilizing agent, wherein at least a portion of the dextromethorphan is in a solid state dispersed in the pressure-sensitive adhesive (e.g., as dextromethorphan crystals). Although optional, the solubilizing agent is typically included in the adhesive composition or drug-containing adhesive layer herein.

[0107] In some embodiments, the present disclosure provides an adhesive composition comprising (1) dextromethorphan, (2) a pressure-sensitive adhesive, (3) a skin permeation enhancer (e.g., isopropyl myristate), and (4) a solubilizing agent (e.g., a vinylpyrrolidone homopolymer (or povidone), e.g., a vinylpyrrolidone polymer such as povidone K30, plasdone K29 / 32, and the like), wherein at least a portion of the dextromethorphan is in a solid state dispersed in the pressure-sensitive adhesive (e.g., as dextromethorphan crystals). As used herein, a solubilizing agent refers to any agent capable of promoting and / or improving the solubilization of dextromethorphan in the adhesive compositions described herein. The solubilizing agent can typically be mixed with the pressure-sensitive adhesive in the adhesive composition. In some embodiments, dextromethorphan is present in an amount of at least 15% by weight of the adhesive composition, preferably about 15% to about 50% by weight (e.g., about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight, or any value or range therebetween, e.g., about 20-40% by weight, about 25-35% by weight, etc.), and the skin permeation enhancer (e.g., isopropyl myristate) is present in an amount of about 6% to about 12% by weight of the adhesive composition (e.g., about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, or about 12% by weight, or any value or range therebetween, e.g., about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight, or any value or range therebetween, e.g., about 20-40% by weight, about 25-35% by weight, etc.). the pressure-sensitive adhesive is present in an amount of about 20% to about 60% by weight of the adhesive composition (e.g., about 30%, about 40%, about 45%, about 50%, about 55%, or about 60% by weight, or any value or range therebetween, such as about 40-60%, about 45-55% by weight), and the solubilizer is present in an amount of about 6% to about 25% by weight of the adhesive composition (e.g., about 6%, about 8%, about 10%, about 15%, about 20%, or about 25% by weight, or any value or range therebetween, such as about 8-15% or about 6-20% by weight).Although some dextromethorphan is present in the adhesive composition in a solid state without dissolving, the adhesive composition typically has a uniform composition; for example, the dextromethorphan content throughout the adhesive composition is typically the same. In some embodiments, the adhesive composition contains dextromethorphan as the only active ingredient. In some embodiments, the skin permeation enhancer is isopropyl myristate. The pressure-sensitive adhesive may be any of those described herein. Typically, the pressure-sensitive adhesive is an acrylate copolymer adhesive, such as a polyacrylate vinyl acetate copolymer having non-acidic hydroxyl functionality, e.g., as described herein, such as Duro-Tak 87-2287 adhesive from Henkel Adhesives and its analogs. In some embodiments, the pressure-sensitive adhesive comprises an acrylate copolymer adhesive and an additional adhesive. For example, in some embodiments, the pressure-sensitive adhesive can be a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios (e.g., a weight ratio of acrylate adhesive to silicone adhesive ranging from about 1:20 to about 20:1, e.g., from about 10:1 to about 1:10, e.g., about 10:1, about 4:1, about 1:1, about 1:4, etc., or any value or range therebetween). The solubilizer can be a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like. In some embodiments, the solubilizer is a vinylpyrrolidone polymer having a nominal K value of about 25 to 35, e.g., about 29 to 32. The K values ​​assigned to various grades of PVP polymers are a function of average molecular weight, degree of polymerization, and intrinsic viscosity. The K value is derived from viscosity measurements and calculated according to the Fikentscher formula. Those skilled in the art will appreciate that any nominal K value allows for a certain amount of variation from the nominal value, typically 90% to 108%. For example, for povidone K30, which has a nominal K value of 30, the United States Pharmacopoeia and the European Pharmacopoeia typically allow for a variation of 90% to 108% from the stated value.Thus, povidone having a K value in the range of 27.0 to 32.4 is within the specification range for povidone K30 polymer. Unless otherwise apparent from the context, K values ​​referred to herein should be understood as nominal K values. In any of the embodiments described herein, unless otherwise specified or contradicted by context, vinylpyrrolidone polymers, such as vinylpyrrolidone homopolymer (or povidone), can have a nominal K value of about 25 to 35, e.g., about 29 to 32. As used herein, vinylpyrrolidone polymers should be generally understood to encompass both homopolymers and copolymers. The adhesive composition is typically used as an adhesive layer (e.g., a drug-containing adhesive layer) in the transdermal delivery devices described herein.

[0108] In some embodiments, the present disclosure provides a transdermal patch comprising a) a backing layer (e.g., as described herein) and b) an adhesive composition or adhesive layer disclosed herein. The adhesive surface is typically protected with a release liner prior to use. Suitable release liners are described herein. In some embodiments, the transdermal patch comprises, consists essentially of, or consists of a) a backing layer, b) an adhesive composition or adhesive layer disclosed herein, and c) optionally a release liner.

[0109] In some embodiments, the transdermal patch herein is a single-layer transdermal patch comprising a drug-containing adhesive layer, the drug-containing adhesive layer comprising, consisting essentially of, or consisting of (1) dextromethorphan, (2) a pressure-sensitive adhesive, (3) a skin permeation enhancer (e.g., isopropyl myristate), and (4) a solubilizing agent (e.g., a vinylpyrrolidone homopolymer (or povidone), e.g., a vinylpyrrolidone polymer such as Povidone K30, Plasdone K29 / 32, and the like), wherein at least a portion of the dextromethorphan is in a solid state dispersed in the pressure-sensitive adhesive, and the dextromethorphan is at least 15% by weight, preferably about 15% to about 50% by weight (e.g., about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight, or any value or range therebetween, e.g., about 20% to about 50% by weight). the skin permeation enhancer (e.g., isopropyl myristate) is in an amount of about 6% to about 12% by weight (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% by weight, or any value or range therebetween, e.g., about 8-12% by weight); and the pressure-sensitive adhesive is in an amount of about 20% to about 60% by weight (e.g., about 30%, about 40%, about 40% by weight, ... The drug-containing adhesive layer may be present in an amount of about 5%, about 50%, about 55%, or about 60% by weight, or any value or range therebetween, e.g., about 40-60%, about 45-55%, etc., and the solubilizer may be present in an amount of about 6% to about 25% by weight (e.g., about 6%, about 8%, about 10%, about 15%, about 20%, or about 25% by weight, or any value or range therebetween, e.g., about 8-15% or about 6-20% by weight). In some embodiments, the drug-containing adhesive layer comprises dextromethorphan as the only active ingredient. In some embodiments, the skin permeation enhancer is isopropyl myristate. The pressure-sensitive adhesive may be any of those described herein.Typically, the pressure-sensitive adhesive is an acrylate copolymer adhesive, such as a polyacrylate vinyl acetate copolymer having non-acidic hydroxyl functionality, such as those described herein, such as Duro-Tak 87-2287 adhesive and its analogs manufactured by Henkel Adhesives. In some embodiments, the pressure-sensitive adhesive comprises an acrylate copolymer adhesive and an additional adhesive. For example, in some embodiments, the pressure-sensitive adhesive can be a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios (e.g., a weight ratio of acrylate adhesive to silicone adhesive ranging from about 1:20 to about 20:1, e.g., from about 10:1 to about 1:10, e.g., about 10:1, about 4:1, about 1:1, about 1:4, etc., or any value or range therebetween). The solubilizer may typically be a vinylpyrrolidone polymer such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like. In some embodiments, the solubilizer is a vinylpyrrolidone homopolymer polymer having a nominal K value of about 25-35, e.g., about 29-32.

[0110] In some embodiments, the drug-containing adhesive layer comprises, consists essentially of, or consists of: (1) dextromethorphan; (2) a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, e.g., those with non-acidic hydroxyl functionality as described herein, such as Duro-Tak 87-2287 adhesive and the like; (3) isopropyl myristate; and (4) a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like, wherein the ranges / amounts of each component can be any of those described herein as suitable in any combination.

[0111] Transdermal patches are typically about 30 cm 2 ~Approx. 150cm 2 , for example, about 30 cm2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 70cm 2 , about 80cm 2 , about 90cm 2 , about 100cm 2 , about 120cm 2 , about 150cm 2 , or any value or range between the stated values, e.g., about 30-100 cm 2 , about 40~60cm 2 , about 60~80cm 2 In some embodiments, the transdermal patch has an active surface area of ​​about 70 cm 2 In some embodiments, the transdermal patch has an active surface area of ​​about 150 cm 2 Larger than, for example, up to 300 cm 2 It may also have an active surface area of ​​up to 1000 nm.

[0112] The transdermal patches herein can also be configured to contain a desired amount of dextromethorphan. In some embodiments, the transdermal patch can contain (1) about 150 mg to about 1000 mg of dextromethorphan, e.g., about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 750 mg, about 900 mg, about 1000 mg, or any value or range therebetween, e.g., about 250-400 mg, about 300-400 mg, or about 350-450 mg, or about 300-800 mg, about 350-900 mg, etc. (2) about 30 mg to about 350 mg of isopropyl myristate, e.g., about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or any value or range therebetween, e.g., about 50 to 150 mg, or about 75 to 125 mg, about 75 to 300 mg, about 50 to 250 mg, etc.; and (3) about 150 mg to about 1800 mg of isopropyl myristate. Pressure-sensitive adhesives, for example, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1400 mg, about 1600 mg, about 1800 mg, or any value or range therebetween, for example, about 350-600 mg, about 400-650 mg, or about 450-700 mg, about 450-1200 mg, about 350-1000 mg, about 400-1600 mg, etc. and (4) the solubilizing agent in an amount of about 30 mg to about 350 mg, e.g., about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or any value or range therebetween, e.g., about 50 to 150 mg, or about 75 to 125 mg, about 75 to 300 mg, about 50 to 250 mg, etc. At least a portion of the dextromethorphan is present in a solid state dispersed in the pressure-sensitive adhesive.In some embodiments, the pressure-sensitive adhesive is an acrylate-based adhesive, such as an acrylate copolymer. In some embodiments, the pressure-sensitive adhesive is a polyacrylate vinyl acetate copolymer, such as those having non-acidic hydroxyl functionality, such as those described herein, such as Duro-Tak 87-2287 adhesive and its analogs. In some embodiments, the pressure-sensitive adhesive comprises an acrylate copolymer adhesive and an additional adhesive. For example, in some embodiments, the pressure-sensitive adhesive can be a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios (e.g., a weight ratio of acrylate adhesive to silicone adhesive ranging from about 1:20 to about 20:1, e.g., from about 10:1 to about 1:10, e.g., about 10:1, about 4:1, about 1:1, about 1:4, etc., or any value or range therebetween). In some embodiments, the solubilizing agent is a vinylpyrrolidone homopolymer (or povidone), e.g., a vinylpyrrolidone polymer such as povidone K30, plasdone K29 / 32, and the like. In some embodiments, the solubilizing agent is a vinylpyrrolidone homopolymer polymer having a nominal K value of about 25-35, e.g., about 29-32. Typically, the drug-containing adhesive layer comprises dextromethorphan in an amount of about 20% to about 40% by weight (e.g., about 30% by weight, as described herein), isopropyl myristate in an amount of about 6% to about 12% by weight (e.g., about 10% by weight, as described herein), pressure-sensitive adhesive in an amount of about 40% to about 60% by weight (e.g., about 50% by weight, as described herein), and solubilizing agent in an amount of about 6% to about 20% by weight (e.g., about 10% by weight, as described herein). In some embodiments, the drug-containing adhesive layer contains dextromethorphan as the only active ingredient. Transdermal patches are typically about 30 cm. 2 ~Approx. 150cm 2 , for example, about 30 cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 70cm 2, about 80cm 2 , about 90cm 2 , about 100cm 2 , about 150cm 2 , or any value or range between the stated values, e.g., about 40-60 cm 2 , about 60~80cm 2 In some embodiments, the transdermal patch has an active surface area of ​​about 70 cm 2 In some embodiments, the transdermal patch has an active surface area of ​​about 150 cm 2 Larger than, for example, up to 300 cm 2 In any of the embodiments described herein, the transdermal patch may be in the form of a single layer patch, unless the context clearly contradicts this.

[0113] The transdermal patches herein typically contain about 2 mg / cm 2 ~about 25mg / cm 2 , for example, about 2.5 mg / cm 2 , about 3mg / cm 2 , about 4mg / cm 2 , about 5mg / cm 2 , about 6mg / cm 2 , about 7mg / cm 2 , about 8mg / cm 2 , approximately 9 mg / cm 2 , about 10mg / cm 2 , about 12mg / cm 2 , about 15mg / cm 2 , about 20mg / cm 2 , about 25mg / cm 2 etc., or any value or range between the listed values, e.g., about 3 to 10 mg / cm 2 , about 4~7mg / cm 2 , about 5~12mg / cm 2 , about 8~25mg / cm 2 The total dextromethorphan loading is as follows:

[0114] Typically, the amount of dextromethorphan contained in the transdermal patch herein is sufficient to deliver a therapeutically effective amount of dextromethorphan to a subject in need thereof. In some embodiments, the amount of dextromethorphan contained in the transdermal patch herein is sufficient to transdermally deliver a daily dose of about 15 mg to about 50 mg of dextromethorphan (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any value or range therebetween, e.g., about 20-50 mg, about 30-50 mg, or about 20-40 mg) to a subject in need thereof for at least 7 days. Preferably, a single patch is used herein to deliver the daily dose.

[0115] The transdermal patches herein typically have a dextromethorphan flux suitable for delivering a therapeutically effective amount to a subject in need thereof. For example, in some embodiments, the transdermal patch has a dextromethorphan flux of at least about 200 μg / cm for at least 7 days as measured in vitro using human cadaver skin. 2 / day, e.g., about 200ug / cm for 7 days or more 2 / day, about 300ug / cm 2 / day, about 400ug / cm 2 / day, about 500ug / cm 2 / day, about 600ug / cm 2 / day, about 700ug / cm 2 / day, about 800ug / cm 2 / day, about 1000ug / cm 2 / day, or any value or range therebetween, e.g., about 200-800 ug / cm 2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2In some embodiments, the transdermal patch can transdermally deliver dextromethorphan to a human subject at substantially the same rate over the period the patch is worn, e.g., the cumulative daily permeation of dextromethorphan is greater than or equal to 350 ug / cm2, for example, from the average cumulative daily permeation of dextromethorphan. 2 / day, preferably 250ug / cm 2 / day, more preferably 200ug / cm 2 / day. As discussed in WO 2021 / 202329 A1, the use of a vinylpyrrolidone polymer (Plasdone K29 / 32) as a crystallization inhibitor has been found to significantly enhance the flux of dextromethorphan from the transdermal patches herein both in vitro and in vivo. Unexpectedly, the use of a vinylpyrrolidone polymer (Plasdone K29 / 32) does not prevent dextromethorphan crystallization, but it does enable the transdermal patches herein to achieve desirable dextromethorphan permeation even when some dextromethorphan is present in the solid state, which is generally believed to hinder drug permeation from transdermal patches.

[0116] In some embodiments, the present disclosure also provides a method for selecting a transdermal patch for a method herein (e.g., a method for treating PBA), the method comprising measuring dextromethorphan flux from a transdermal patch disclosed herein (e.g., those shown in [1] to

[51] in the Summary of the Invention) in vitro using, for example, human cadaver skin, and determining that the transdermal patch exhibits a dextromethorphan flux of at least about 200 μg / cm for at least 7 days as measured in vitro using human cadaver skin. 2 / day, e.g., about 200ug / cm for 7 days or more 2 / day, about 300ug / cm 2 / day, about 400ug / cm 2 / day, about 500ug / cm 2 / day, about 600ug / cm 2 / day, about 700ug / cm 2 / day, about 800ug / cm2 / day, about 1000ug / cm 2 / day, or any value or range between the listed values, e.g., about 200-800 ug / cm 2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2 and selecting a transdermal patch with a dextromethorphan flux of 100 mg / day or more.

[0117] In some specific embodiments, the transdermal patch comprises, consists essentially of, or consists of: a) a backing layer (e.g., as described herein); b) a drug-containing adhesive layer; and c) an optional release liner, wherein the drug-containing adhesive layer comprises: (1) dextromethorphan in an amount of about 15% to about 50% by weight (e.g., as described herein, such as about 30% by weight); and (2) Duro-Tak (3) a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as those having non-acidic hydroxyl functional groups, as described herein, such as 87-2287 adhesive and the like, in an amount of about 20% to about 60% by weight (e.g., as described herein, e.g., about 50% by weight); (4) a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like, in an amount of about 6% to about 20% by weight (e.g., as described herein, e.g., about 10% by weight). In some embodiments, the transdermal patch has at least a portion of the dextromethorphan in a solid state. In some embodiments, the transdermal patch has a dextromethorphan content of at least about 300 μg / cm for 7 days or more, as measured in vitro using human cadaver skin. 2 / day (e.g., about 300ug / cm 2 / day~about 650ug / cm 2 / day) dextromethorphan flux.

[0118] In some specific embodiments, the present disclosure provides a monolithic transdermal patch comprising, consisting essentially of, or consisting of: a) a backing layer (e.g., as described herein); b) a drug-containing adhesive layer; and c) an optional release liner, wherein the drug-containing adhesive layer contains: (1) about 150 mg to about 1000 mg of dextromethorphan (e.g., as described herein); and (2) Duro-Tak (1) from about 150 mg to about 1800 mg (e.g., as described herein) of a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as those having non-acidic hydroxyl functionality, e.g., as described herein, such as 87-2287 adhesive and the like; (2) from about 30 mg to about 350 mg (e.g., as described herein) of isopropyl myristate; and (3) from about 30 mg to about 350 mg (e.g., as described herein) of a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like. In some embodiments, the transdermal patch has at least a portion of the dextromethorphan in a solid state. In some embodiments, the weight percentages of the components in the drug-containing adhesive layer can be: (1) dextromethorphan in an amount of about 15% to about 50% by weight (e.g., as described herein, such as about 30% by weight); (2) a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as those having non-acidic hydroxyl functional groups, e.g., as described herein, such as Duro-Tak 87-2287 adhesive and the like, in an amount of about 20% to about 60% by weight (e.g., as described herein, such as about 50% by weight); (3) isopropyl myristate in an amount of about 6% to about 12% by weight (e.g., as described herein, such as about 10% by weight); and (4) a vinylpyrrolidone polymer, such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like, in an amount of about 6% to about 20% by weight (e.g., as described herein, such as about 10% by weight). In some embodiments, the transdermal patch is about 30 cm2 ~Approx. 150cm 2 (e.g., as described herein, e.g., about 70 cm 2 In some embodiments, the transdermal patch has an active surface area of ​​at least about 300 ug / cm for at least 7 days as measured in vitro using human cadaver skin. 2 / day (e.g., about 300ug / cm 2 / day~about 650ug / cm 2 / day) dextromethorphan flux.

[0119] Preferably, transdermal patches and formulations are shelf-stable when stored at room temperature (25±2°C) and 60%±5% relative humidity (RH) for approximately 1 month, 3 months, 6 months, or longer. Shelf-stable results in a transdermal patch or formulation that would be accepted by one of ordinary skill in the art as being equivalent to the original transdermal patch or formulation, i.e., equivalent to the initial state at the start of storage. Shelf-stable is typically characterized by one or more of the following: (1) substantially the same amounts of drug-related impurities, with no significant increase in either individual or total impurities; (2) substantially the same amount of dextromethorphan; (3) substantially the same physical properties, such as peel adhesion, shear hold, tack, and peel strength; and (4) substantially the same drug release rate and / or dextromethorphan permeation rate. "Substantially the same" should be understood to mean within 80-125% or within the measurement tolerances. For example, patches prepared according to Examples 1 and 2 herein were found to be storage stable after being stored at room temperature (25±2°C) and a relative humidity (RH) of 60%±5% RH, or at 40°C and 75% RH for at least one month.

[0120] In some embodiments, the present disclosure also provides a method for preparing a transdermal delivery device or adhesive composition. In some embodiments, the method includes: a) mixing dextromethorphan, an adhesive (e.g., a pressure-sensitive adhesive described herein, such as Duro-Tak 87-2287), a permeation enhancer (e.g., isopropyl myristate), and a solubilizer (e.g., a vinylpyrrolidone homopolymer (or povidone), e.g., a vinylpyrrolidone polymer, such as povidone K30, plasdone K29 / 32, and the like, as described herein) in a suitable solvent (e.g., an organic solvent, such as an ester solvent or an alcohol solvent, typically a volatile substance, e.g., ethyl acetate or isopropanol, or a combination thereof) to form a homogeneous mixture; b) casting the homogeneous mixture onto a release liner; and c) drying the casting to remove the solvent, thereby forming an adhesive composition on the release liner. In some embodiments, dextromethorphan and an adhesive (e.g., a pressure-sensitive adhesive described herein, e.g., Duro-Tak 87-2287) are mixed separately and then mixed with the remaining ingredients. In some embodiments, a permeation enhancer and solubilizer are mixed separately and then mixed with the mixture of dextromethorphan and an adhesive (e.g., a pressure-sensitive adhesive described herein, such as Duro-Tak 87-2287). In some embodiments, the method further includes laminating the adhesive composition to a backing layer. Suitable amounts of dextromethorphan and suitable adhesives, solubilizers, permeation enhancers, and their respective amounts can include any of those described herein, in any combination. Adhesive compositions with or without release liners and transdermal delivery devices prepared by the methods herein are also novel aspects of the present disclosure. Some exemplary procedures are described in the Examples section herein.

[0121] TDD with reservoir layer In some embodiments, the transdermal delivery devices herein include a reservoir layer, which can provide a more sustained flux of dextromethorphan to the user, for example, in the case of high daily doses and / or long-term (e.g., 7 days or more) applications.

[0122] In some embodiments, the transdermal delivery device includes an adhesive layer containing an adhesive and a reservoir layer containing dextromethorphan. In some embodiments, the adhesive layer contains dextromethorphan dispersed in the adhesive. In some embodiments, the adhesive layer does not contain dextromethorphan except through equilibrium with the reservoir layer. In some embodiments, the adhesive layer contains dextromethorphan dispersed in the adhesive. In some embodiments, the reservoir layer contains dextromethorphan in the adhesive. In some embodiments, the reservoir layer contains dextromethorphan in the adhesive. In some embodiments, the reservoir layer is sandwiched between an adhesive layer and a backing layer, and the adhesive layer is the skin-contacting layer (preferably the skin-contacting drug-containing adhesive layer). In some embodiments, the reservoir layer may be sandwiched between two adhesive layers, which may be the same or different. For example, in some embodiments, the two adhesive layers can have the same concentration of the same ingredient, and in some embodiments, can have the same thickness. However, in some embodiments, the two adhesive layers can have different ingredients, or different concentrations of the same ingredient, or different thicknesses, etc.

[0123] In some embodiments, the reservoir layer is separated from the adhesive layer by a membrane, e.g., a rate-controlling membrane such as a microporous membrane. The reservoir layer preferably contains an adhesive. However, other reservoir layer designs are suitable if they are compatible with the adhesive layer and backing layer. For example, in some embodiments, the reservoir layer can be a scrim / nonwoven saturated with dextromethorphan, or dextromethorphan dispersed in another suitable carrier / substrate.

[0124] Dextromethorphan can be included in various concentrations in the adhesive layer and the reservoir layer. Typically, the concentration of dextromethorphan in the reservoir layer is higher than the concentration of dextromethorphan in the adhesive layer. For example, in some embodiments, the adhesive layer can include dextromethorphan in an amount of about 2% to about 12% by weight of the adhesive layer (e.g., about 2%, about 4%, about 6%, about 8%, about 10%, about 12%, or any range therebetween), while the reservoir layer can include dextromethorphan in an amount of about 20% or more by weight of the reservoir layer, e.g., about 30% or more, about 40% or more, about 50% or more by weight, e.g., about 20% to about 60% by weight, about 30% to about 50% by weight, etc. In some embodiments, the adhesive layer can contain dextromethorphan in an amount of about 6% to about 12% by weight of the adhesive layer (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any value or range therebetween). In some embodiments, the adhesive layer contains dextromethorphan at or near a saturated concentration in the adhesive, e.g., about 10% by weight in an acrylate adhesive. In some embodiments, the reservoir layer contains dextromethorphan above a saturated concentration in the adhesive. In other words, the reservoir layer can be supersaturated with dextromethorphan and thus contain solid dextromethorphan, which can function as a drug depot.

[0125] Suitable adhesives for the adhesive layer and reservoir layer, where applicable, include any of those described herein, preferably pressure-sensitive adhesives. The adhesives included in the adhesive layer and reservoir layer can be the same or different. In some embodiments, the adhesive included in the adhesive layer and reservoir layer is the same, e.g., an acrylate adhesive. Other suitable adhesives include polyisobutylene adhesives, silicone polymer adhesives, acrylate copolymer adhesives (e.g., polyacrylate vinyl acetate copolymers, such as those having non-acidic hydroxyl functionality, e.g., as described herein, such as Duro-Tak 87-2287 adhesive and the like), or combinations thereof. For example, in any of the embodiments described herein, unless directly contrary to the context, the pressure-sensitive adhesive can be a polyacrylate vinyl acetate copolymer containing non-acidic hydroxyl functionality, e.g., as described herein, such as DuroTak® 2287 adhesive. In some embodiments, the adhesive can be a mixture of an acrylate copolymer adhesive (e.g., Durotak 87-2287) and a silicone adhesive (e.g., BIO-7-4202) in various ratios (e.g., a weight ratio of acrylate adhesive to silicone adhesive ranging from about 1:20 to about 20:1). In some embodiments, the weight ratio of acrylate adhesive to silicone adhesive ranges from about 10:1 to about 1:10 (e.g., about 10:1, about 4:1, about 1:1, about 1:4, or any value or range therebetween). In any of the embodiments described herein, the adhesive layer can be configured to continuously adhere to a user's skin for at least 7 days.

[0126] In some embodiments, the adhesive layer comprises a pressure-sensitive adhesive in an amount of about 50% to about 90% by weight of the adhesive layer. In some embodiments, the pressure-sensitive adhesive is present in an amount of about 60% to about 85% by weight of the adhesive layer (e.g., about 60%, about 70%, about 75%, about 80%, about 85%, or any value or range therebetween). In some embodiments, the reservoir layer can comprise a pressure-sensitive adhesive in an amount of about 20% to about 60% by weight of the reservoir layer. For example, in some embodiments, the pressure-sensitive adhesive is present in an amount of about 20% to about 50% by weight of the reservoir layer (e.g., about 20%, about 30%, about 35%, about 40%, about 50%, or any value or range therebetween).

[0127] Suitable sizes for transdermal delivery devices are described herein. In some embodiments, the transdermal delivery device is about 5 cm 2 ~about 200cm 2 In some embodiments, the transdermal delivery device has an active surface area of ​​about 10 cm 2 ~Approx. 150cm 2 In some embodiments, the transdermal delivery device has an active surface area of ​​about 30 cm 2 ~Approx. 150cm 2 (For example, about 30 cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 70cm 2 , about 80cm 2 , about 90cm 2 , about 100cm 2 , about 120cm 2 , about 150cm 2 , or any value or range therebetween).

[0128] The adhesive layer and reservoir layer can be of various thicknesses. For example, in some embodiments, the adhesive layer is about 0.1 mil to about 10 mils thick (e.g., about 0.5 mil to about 10 mils, about 1 mil to 10 mils). In some embodiments, the reservoir layer can also be about 0.1 mil to about 10 mils thick (e.g., about 0.5 mil to about 10 mils, about 1 mil to 10 mils). For example, in preferred embodiments, the adhesive layer is about 0.4 mil to about 3 mils thick. In some preferred embodiments, the adhesive layer is about 0.4 mil to about 5 mils thick. In some embodiments, the reservoir layer is about 2 mil to about 7.5 mils thick, such as about 4 mils. In some embodiments, the reservoir layer has a thickness of at least about 100% of the thickness of the adhesive layer, preferably about 100 to 500% (preferably 100 to 600%, or 100 to 300%). In some embodiments, the amount of dextromethorphan in the reservoir layer is at least about 200%, preferably about 200-3000% (preferably about 300-1500%, e.g., about 300-800% or about 400-600%) of the amount of dextromethorphan in the adhesive layer. In some embodiments, the total weight of the reservoir layer is at least about 100%, preferably about 100-800% (preferably 100-600%, or 120-300%) of the total weight of the adhesive layer.

[0129] The adhesive layer and reservoir layer can also contain a skin permeation enhancer. For example, in some embodiments, the adhesive layer contains a compound selected from the group consisting of isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate, and hydroxypropyl methylcellulose with a carbon chain length of C. 12 ~C 18 In some embodiments, the adhesive layer comprises a skin permeation enhancer selected from isopropyl myristate. Similarly, in some embodiments, the reservoir layer comprises a soluble polymer selected from isopropyl myristate, oleyl oleate, oleic acid, glycerol monooleate ... 12 ~C 18and other fatty acids and fatty acid esters thereof, and combinations thereof. In some embodiments, the reservoir layer comprises isopropyl myristate.

[0130] Various amounts of skin permeation enhancer can be used in the adhesive layer and reservoir layer. Typically, the skin permeation enhancer can be present in an amount of about 2% to about 15% by weight of the adhesive or reservoir layer. For example, in some embodiments, the skin permeation enhancer is present in an amount of about 6% to about 12% by weight of the adhesive layer (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any value or range therebetween). In some embodiments, the skin permeation enhancer is present in an amount of about 6% to about 12% by weight of the reservoir layer (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any value or range therebetween).

[0131] In some embodiments, the adhesive layer may include a crystallization inhibitor, such as a vinylpyrrolidone homopolymer (or povidone), e.g., a vinylpyrrolidone polymer such as povidone K30, plasdone K29 / 32, and the like. In some embodiments, the crystallization inhibitor may be present in an amount of about 6% to about 12% by weight (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, or any value or range therebetween, such as about 6-12% by weight). In some embodiments, the adhesive layer does not include a crystallization inhibitor.

[0132] In some embodiments, the reservoir layer can include a solubilizing agent, such as a vinylpyrrolidone homopolymer (or povidone), e.g., a vinylpyrrolidone polymer such as povidone K30, plasdone K29 / 32, and the like. In some embodiments, the solubilizing agent is present in an amount of about 6%, about 8%, about 10%, about 15%, about 20%, or about 25% of the reservoir layer, or any value or range therebetween, such as about 15-25% or about 10-20%. In some embodiments, the reservoir layer does not include a solubilizing agent.

[0133] It should be noted that the identities of the adhesive layer and reservoir layer components, such as adhesive, skin permeation enhancer, drug, etc., and their amounts are independently selected and can be the same or different. Generally, the amounts can be varied while the identities remain the same.

[0134] Exemplary Transdermal Delivery Devices Having a Reservoir Layer In some embodiments, the present disclosure also provides the following non-limiting exemplary transdermal patches having an adhesive layer and a reservoir layer, and related transdermal formulations.

[0135] In some embodiments, the transdermal patch comprises (1) a backing layer, (2) a skin-contacting drug-containing adhesive layer (e.g., any of those described herein), and (3) a reservoir layer. In some embodiments, the transdermal patch may be characterized as having a two-layer structure or two-layer batch, in which the reservoir layer is sandwiched between the backing layer and the skin-contacting drug-containing adhesive layer. For clarity, the skin-contacting drug-containing adhesive layer refers to the drug-containing adhesive layer in the transdermal patch that contacts the skin when applied to the intended user's skin. The skin-contacting drug-containing adhesive layer is typically protected by a release liner before use. In some embodiments, the transdermal patch consists of a backing layer, a skin-contacting drug-containing adhesive layer, a reservoir layer, and optionally a release liner.

[0136] In some embodiments, the skin-contacting drug-containing adhesive layer comprises 1) dextromethorphan in an amount of about 6% to about 12% by weight, 2) isopropyl myristate in an amount of about 6% to about 12% by weight, 3) a first pressure-sensitive adhesive, preferably an acrylate-based pressure-sensitive adhesive, in an amount of about 65% to about 85% by weight, and 4) a crystallization inhibitor in an amount of about 6% to about 12% by weight; and the reservoir layer comprises 1) dextromethorphan in an amount of at least 15% by weight, 2) isopropyl myristate in an amount of about 6% to about 12% by weight, 3) a second pressure-sensitive adhesive in an amount of about 20% to about 60% by weight, and 4) a solubilizing agent in an amount of about 6% to about 25% by weight, wherein at least a portion of the dextromethorphan in the reservoir layer is in a solid state dispersed in the second pressure-sensitive adhesive. In some alternative embodiments, the reservoir layer does not include a solubilizing agent and / or the skin-contacting drug-in-adhesive layer does not include a crystallization inhibitor.

[0137] The first and second pressure-sensitive adhesives can be the same or different, preferably the same. Typically, both the first and second pressure-sensitive adhesives are acrylate-based pressure-sensitive adhesives. In some embodiments, the first pressure-sensitive adhesive is a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as an acrylate copolymer adhesive, e.g., a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive having non-acidic hydroxyl functionality, e.g., as described herein, such as Duro-Tak 87-2287 adhesive and the like. In some embodiments, the second pressure-sensitive adhesive is a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as an acrylate copolymer adhesive, e.g., a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive having non-acidic hydroxyl functionality, e.g., as described herein, such as Duro-Tak 87-2287 adhesive and the like.

[0138] The first pressure-sensitive adhesive is typically present in the skin-contacting drug-containing adhesive layer in an amount of about 65%, about 70%, about 75%, about 80%, or about 85% by weight of the skin-contacting drug-containing adhesive layer, or any value or range therebetween, such as about 65-75%, about 70-85% by weight.

[0139] The second pressure-sensitive adhesive is typically present in the reservoir layer in an amount of about 20%, about 30%, about 35%, about 40%, about 45%, about 50%, or about 60% by weight of the reservoir layer, or any value or range therebetween, such as about 35-45%, about 30-50%, etc.

[0140] Isopropyl myristate is typically present in an amount of about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% by weight of the skin-contacting drug-containing adhesive layer, or any value or range between the recited values, such as about 8-12% by weight. The concentration of isopropyl myristate in the reservoir layer is typically similar to the concentration of isopropyl myristate in the skin-contacting drug-containing adhesive layer. For example, in some embodiments, the reservoir layer also contains isopropyl myristate in an amount of about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% by weight of the reservoir layer, or any value or range between the recited values, such as about 8-12%.

[0141] The dextromethorphan in the skin-contacting drug-containing adhesive layer is typically below its saturation concentration in the adhesive layer; in other words, the skin-contacting drug-containing adhesive layer usually does not contain dextromethorphan in the solid state. In some embodiments, the dextromethorphan in the skin-contacting drug-containing adhesive layer is at or near the saturation concentration of dextromethorphan in the adhesive layer. In some embodiments, the dextromethorphan in the skin-contacting drug-containing adhesive layer is about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% by weight of the skin-contacting drug-containing adhesive layer, or any value or range therebetween, such as about 6-10% by weight.

[0142] In some embodiments, the skin-contacting drug-containing adhesive layer comprises a crystallization inhibitor in an amount effective to prevent dextromethorphan solid formation in the skin-contacting drug-containing adhesive layer. In some embodiments, the crystallization inhibitor is a vinylpyrrolidone polymer such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like. In some embodiments, the crystallization inhibitor is present in an amount of about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% of the skin-contacting drug-containing adhesive layer, or any value or range therebetween, such as about 6-12% or 8-12%.

[0143] The dextromethorphan in the reservoir layer typically exceeds its saturation concentration in the reservoir layer, with at least a portion of the dextromethorphan being in a solid state. In some embodiments, the dextromethorphan in the reservoir layer is about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight of the reservoir layer, or any value or range therebetween, such as about 20-40%, about 25-35%, etc.

[0144] The solubilizer in the reservoir layer is typically a vinylpyrrolidone homopolymer (or povidone), e.g., a vinylpyrrolidone polymer such as povidone K30, plasdone K29 / 32, and the like. The amount of solubilizer is not particularly limited and is typically about 6%, about 8%, about 10%, about 15%, about 20%, or about 25%, or any value or range therebetween, such as about 15-25% or about 10-20%.

[0145] The transdermal patches herein may also be characterized by different configurations of the skin-contacting drug-containing adhesive layer and reservoir layer, which are believed to contribute to the desired permeation of dextromethorphan over an extended period of time, such as 7 days or more.

[0146] For example, in some embodiments, the dextromethorphan concentration in the reservoir layer may be about 200-800% (preferably about 300-500%) of the dextromethorphan concentration in the skin-contacting drug-containing adhesive layer. For example, in some embodiments, the skin-contacting drug-containing adhesive layer may have a dextromethorphan concentration of about 8% by weight, while the reservoir layer may have a dextromethorphan concentration of about 30% by weight, i.e., about 3.75 times, or 375%, the dextromethorphan concentration in the skin-contacting drug-containing adhesive layer.

[0147] In some embodiments, the amount of dextromethorphan in the reservoir layer can be at least about 200%, preferably about 200-3000% (preferably about 300-1500%, e.g., about 300-800% or about 400-600%) of the amount of dextromethorphan in the skin-contacting drug-containing adhesive layer. For example, in some embodiments, the skin-contacting drug-containing adhesive layer can have about 56 mg of dextromethorphan, while the reservoir layer can have about 120 mg to about 900 mg of dextromethorphan or more. In some embodiments, the ratio of the amount of dextromethorphan in the reservoir layer to the amount of dextromethorphan in the skin-contacting drug-containing adhesive layer is from about 2:1 to about 30:1, e.g., about 3:1, about 4:1, about 5:1, about 8:1, about 10:1, about 15:1, about 20:1, about 30:1, etc., or any value or range therebetween.

[0148] Typically, the skin-contacting drug-containing adhesive layer is thinner than the reservoir layer. In some embodiments, the skin-contacting drug-containing adhesive layer has a thickness of about 0.4 mil to about 3 mil. In some embodiments, the skin-contacting drug-containing adhesive layer has a thickness of about 0.4 mil to about 5 mil. In some embodiments, the reservoir layer has a thickness of about 2 mil to about 7.5 mil, such as about 4 mil. In some embodiments, the reservoir layer has a thickness of at least about 100%, preferably about 100 to 800% (preferably 100 to 600% or 120 to 300%) of the thickness of the skin-contacting drug-containing adhesive layer. In some embodiments, the total weight of the reservoir layer is at least about 100%, preferably about 100 to 800% (preferably 100 to 600% or 120 to 300%) of the total weight of the skin-contacting drug-containing adhesive layer. In some embodiments, the ratio of the thickness of the reservoir layer to the thickness of the skin-contacting drug-containing adhesive layer is about 1:1 to about 10:1, e.g., about 1:1, about 1.3:1, about 1.5:1, about 2:1, about 3:1, about 5:1, about 8:1, about 10:1, etc., or any value or range between the recited values. In some embodiments, the ratio of the total weight of the reservoir layer to the total weight of the skin-contacting drug-containing adhesive layer is about 1:1 to about 10:1, e.g., about 1:1, about 1.3:1, about 1.5:1, about 2:1, about 3:1, about 5:1, about 8:1, about 10:1, etc., or any value or range between the recited values.

[0149] The total amount of dextromethorphan in the transdermal patches herein, i.e., the total amount including dextromethorphan in both the skin-contacting drug-containing adhesive layer and the reservoir layer, is typically in the range of about 150 mg to about 1000 mg, e.g., about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 750 mg, about 900 mg, about 1000 mg, or any value or range therebetween, e.g., about 250-400 mg, about 300-400 mg, or about 350-450 mg, or about 300-800 mg, about 350-900 mg, etc. In some embodiments, the transdermal patches herein provide a dextromethorphan concentration of about 2 mg / cm. 2 ~about 25mg / cm 2, for example, about 2.5 mg / cm 2 , about 3mg / cm 2 , about 4mg / cm 2 , about 5mg / cm 2 , about 6mg / cm 2 , about 7mg / cm 2 , about 8mg / cm 2 , approximately 9 mg / cm 2 , about 10mg / cm 2 , about 12mg / cm 2 , about 15mg / cm 2 , about 20mg / cm 2 , about 25mg / cm 2 etc., or any value or range between the listed values, e.g., about 3 to 10 mg / cm 2 , about 4~7mg / cm 2 , about 5~12mg / cm 2 , about 8~25mg / cm 2 The total dextromethorphan loading is as follows:

[0150] The total amount of isopropyl myristate in the transdermal patches herein, i.e., the total amount including isopropyl myristate in both the skin-contacting drug-containing adhesive layer and the reservoir layer, is typically in the range of about 30 mg to about 350 mg, e.g., about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or any value or range therebetween, e.g., about 50-150 mg, or about 75-125 mg, about 75-300 mg, about 50-250 mg, etc.

[0151] The total amount of the first pressure-sensitive adhesive and the second pressure-sensitive adhesive is typically in the range of about 150 mg to about 1800 mg, e.g., about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1400 mg, about 1600 mg, about 1800 mg, or any value or range therebetween, e.g., about 350 to 600 mg, about 400 to 650 mg, or about 450 to 700 mg, about 450 to 1200 mg, about 350 to 1000 mg, about 400 to 1600 mg, etc.

[0152] Preferably, the transdermal patch is about 30 cm 2 ~Approx. 150cm 2 In some embodiments, the transdermal patch typically has an active surface area of ​​about 30 cm 2 ~Approx. 150cm 2 , for example, about 30 cm 2 , about 40cm 2 , about 50cm 2 , about 60cm 2 , about 70cm 2 , about 80cm 2 , about 90cm 2 , about 100cm 2 , about 120cm 2 , about 150cm 2 , or any value or range between the stated values, e.g., about 30-100 cm 2 , about 40~60cm 2 , about 60~80cm 2 In some embodiments, the transdermal patch has an active surface area of ​​about 70 cm 2 In some embodiments, the transdermal patch has an active surface area of ​​about 150 cm 2 Larger than, for example, up to 300 cm 2 It may also have an active surface area of ​​up to 1000 nm.

[0153] Typically, the amount of dextromethorphan contained in a transdermal patch herein, such as a bilayer patch herein, is sufficient to deliver a therapeutically effective amount of dextromethorphan to a subject in need thereof. In some embodiments, the amount of dextromethorphan contained in a transdermal patch herein is sufficient to transdermally deliver a daily dose of about 15 mg to about 50 mg of dextromethorphan (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any value or range therebetween, such as about 20-50 mg, about 30-50 mg, or about 20-40 mg) to a subject in need thereof for at least 7 days. Preferably, a single patch is used herein to deliver the daily dose.

[0154] The transdermal patches herein typically have a dextromethorphan flux suitable for delivering a therapeutically effective amount to a subject in need thereof. Unexpectedly, in patches having a reservoir layer, such as the bilayer patch herein, the use of a vinylpyrrolidone polymer (Plasdone K29 / 32) in both the skin-contacting drug-containing adhesive layer and the reservoir layer enables the transdermal patches herein to achieve desirable dextromethorphan permeation even when some dextromethorphan is present in the solid state within the reservoir layer, which is generally believed to hinder drug permeation from transdermal patches. For example, in some embodiments, a transdermal patch, such as the bilayer patch herein, achieves a dextromethorphan flux of at least about 200 μg / cm for at least 7 days as measured in vitro using human cadaver skin. 2 / day, e.g., about 200ug / cm for 7 days or more 2 / day, about 300ug / cm 2 / day, about 400ug / cm 2 / day, about 500ug / cm 2 / day, about 600ug / cm 2 / day, about 700ug / cm 2 / day, about 800ug / cm 2 / day, about 1000ug / cm 2 / day, or any value or range between the listed values, e.g., about 200-800 ug / cm 2 / day, about 300~800ug / cm 2 / day, about 400~800ug / cm 2 / day, about 500~800ug / cm 2 In some embodiments, the transdermal patch has a dextromethorphan flux of at least about 300 μg / cm for 7 days or more, as measured in vitro using human cadaver skin. 2 / day (e.g., about 300ug / cm 2 / day~about 650ug / cm 2 / day) dextromethorphan flux.

[0155] Preferably, the transdermal patch having a reservoir layer is shelf stable when stored at room temperature (25±2°C) and a relative humidity (RH) of 60%±5% RH for about 1 month, 3 months, 6 months or more.

[0156] In some embodiments, the present disclosure also provides a method for preparing a transdermal delivery device having a reservoir layer. In some embodiments, the method includes 1) preparing a skin-contacting drug-containing adhesive layer, 2) preparing a reservoir layer, and 3) laminating the skin-contacting drug-containing adhesive layer to the reservoir layer. Typically, the reservoir layer is sandwiched between the skin-contacting drug-containing adhesive layer and a backing layer. The skin-contacting drug-containing adhesive layer and the reservoir layer can be prepared according to the methods herein. For example, the reservoir layer can be prepared by a process including: a) mixing dextromethorphan, an adhesive (e.g., a pressure-sensitive adhesive described herein, such as Duro-Tak 87-2287), a permeation enhancer (e.g., isopropyl myristate), and a solubilizer (e.g., a vinylpyrrolidone homopolymer (or povidone), e.g., a vinylpyrrolidone polymer, such as Povidone K30, Plasdone K29 / 32, and the like, as described herein) in a suitable solvent (e.g., an organic solvent, such as an ester solvent or an alcohol solvent, typically a volatile material, e.g., ethyl acetate or isopropanol, or a combination thereof) to form a homogeneous mixture; b) casting the homogeneous mixture onto a release liner; and c) drying the casting to remove the solvent, thereby forming a reservoir adhesive composition on the release liner.Similarly, the skin contact drug-containing adhesive layer can be prepared by a process comprising: a) mixing dextromethorphan, an adhesive (e.g., a pressure-sensitive adhesive described herein such as Duro-Tak 87-2287), a permeation enhancer (e.g., isopropyl myristate), and a crystallization inhibitor (e.g., a vinylpyrrolidone homopolymer (or povidone), e.g., a vinylpyrrolidone polymer, such as Povidone K30, Plasdone K29 / 32, and the like) in a suitable solvent (e.g., an organic solvent such as an ester solvent or an alcohol solvent, typically a volatile material, e.g., ethyl acetate or isopropanol, or a combination thereof) to form a homogeneous mixture; b) casting the homogeneous mixture onto a release liner; and c) drying the casting to remove the solvent, thereby forming a skin contact drug-containing adhesive adhesive composition on the release liner. In some embodiments, dextromethorphan and an adhesive (e.g., a pressure-sensitive adhesive described herein, e.g., Duro-Tak 87-2287) are mixed separately and then mixed with the remaining ingredients. In some embodiments, a permeation enhancer and a solubilizer or crystallization inhibitor are mixed separately and then mixed with the mixture of dextromethorphan and an adhesive (e.g., a pressure-sensitive adhesive described herein, such as Duro-Tak 87-2287). In some embodiments, the method further includes laminating the reservoir adhesive composition to a backing layer. The suitable amounts of dextromethorphan and suitable adhesives, solubilizers, crystallization inhibitors, permeation enhancers, and their respective amounts can include any of those described herein, in any combination. The reservoir adhesive composition and the skin-contact drug-containing adhesive adhesive composition, with or without a release liner, as well as the transdermal delivery devices prepared by the methods herein, are also novel aspects of the present disclosure. Some exemplary procedures are described in the Examples section herein.

[0157] Transdermal delivery devices having the flux characteristics described herein can be prepared by those skilled in the art in light of this disclosure. The Examples section also illustrates the preparation of several transdermal delivery devices. The cumulative permeation of drug (dextromethorphan, deuterated dextromethorphan, or a combination thereof) can be adjusted, for example, by varying the composition of the adhesive layer (e.g., drug concentration, permeation enhancer, drug loading, adhesive type, etc.).

[0158] It should be noted that pharmaceutical compositions formulated for the adhesive layer and / or reservoir layer described herein are also novel aspects of the present disclosure.

[0159] The transdermal delivery devices herein can also be characterized by a certain in vivo release profile that provides, for example, a desired pharmacokinetic (PK) profile, for example, any of those described herein. In some embodiments, the transdermal delivery device can be configured to provide a PK profile, for example, any of the PK profiles described herein, in a subject in need thereof. In some embodiments, the transdermal delivery device is configured to provide, for example, a PK profile that is effective for treating a disease or disorder (e.g., PBA, as described herein) in a subject.

[0160] The various aspects of the transdermal delivery devices and transdermal formulations of the present disclosure can be combined in all possible combinations.

[0161] Dextromethorphan administration and treatment methods In various embodiments, the present disclosure also provides methods of using a transdermal delivery device or pharmaceutical composition described herein, e.g., to administer dextromethorphan to a subject in need thereof, e.g., a subject suffering from any of the diseases or disorders described herein.

[0162] Some embodiments are directed to methods of administering dextromethorphan to a subject (e.g., a human subject) in need thereof. In some embodiments, the subject is sensitive to or intolerant of a CYP2D6 inhibitor, such as quinidine, e.g., has one or more side effects associated with quinidine, and / or is co-administered with (or requires) a drug whose metabolism is affected by a CYP2D6 inhibitor, such as quinidine. In some embodiments, the subject is sensitive to or intolerant of quinidine, e.g., has QTc prolongation. In some embodiments, the method includes applying either a transdermal delivery device (e.g., those shown in [1]-

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

[0163] Various dosing regimens are suitable for the methods herein. For example, in some embodiments, the method comprises administering to the subject a transdermal delivery device (e.g., as described herein, e.g., as shown in [1]-

[51] in the Summary of the Invention) once a week (e.g., replaced every other week) for a desired period of time. In some embodiments, the transdermal delivery device comprises about 150 mg to about 1000 mg of dextromethorphan. In some embodiments, the method can also comprise administering to the subject a transdermal delivery device (e.g., as described herein) at least once a day for a desired period of time, e.g., once a week, or once, twice, three times, four times, five times, or six times a week, with a dosing frequency ranging from once a day to once a week; preferably, a transdermal patch is applied to the subject once or twice a week. In some embodiments, the method can also comprise administering to the subject a transdermal delivery device (e.g., as described herein, e.g., as shown in [1]-

[51] in the Summary of the Invention) once a week. For the avoidance of doubt, when it is said that a transdermal delivery device is applied to a subject once a week, it should be understood that each application of the transdermal delivery device has a duration of about one week, i.e., it is continuously attached to the subject's skin for about one week, and it can be replaced once a week during the treatment period. Other expressions should be understood similarly.

[0164] The methods of administering dextromethorphan herein typically provide a certain pharmacokinetic profile in a subject (e.g., a human subject) in need thereof that is suitable (e.g., effective) for treating, e.g., a disease or disorder of the subject (e.g., any of those described herein, such as PBA), as described herein and in WO 2021 / 202329 A1.

[0165] The methods herein are not limited to a particular subject or class of subjects. In some embodiments, the subject is characterized as an extensive metabolizer. In some embodiments, the subject is characterized as a poor metabolizer. In some embodiments, the subject is not co-administered a CYP2D6 inhibitor. In some embodiments, the subject is not co-administered quinidine. In some embodiments, the subject is co-administered a CYP2D6 inhibitor, such as quinidine or bupropion. However, in any of the embodiments described herein, the subject does not cough and / or does not require antitussive medication.

[0166] In some embodiments, the subject (e.g., a human subject) is characterized as having a neurological disease or disorder. In some embodiments, the subject (e.g., a human subject) is characterized as having one or more diseases or disorders selected from an affective disorder, a psychiatric disorder, a brain dysfunction disorder, a movement disorder, dementia, a motor neuron disease, a neurodegenerative disease, a seizure disorder, and a headache. In some embodiments, the subject is suffering from one or more diseases or disorders selected from depression, major depressive disorder, treatment-resistant depression, treatment-resistant bipolar depression, bipolar disorder including cyclothymia, seasonal affective disorder, mood disorder, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), adjustment disorder, atypical depression, mania, anxiety disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH), attention deficit / hyperactivity disorder (AD / HD), bipolar and manic states, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, drug addiction or abuse, nicotine addiction, psychosexual dysfunction, emotion dysregulation, and mood lability. In some embodiments, the subject is afflicted with one or more diseases or disorders selected from Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar degeneration (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia. In any of the embodiments herein, the subject may be suffering from emotional dysregulation, depression (e.g., major depressive disorder or treatment-resistant depression), stroke, traumatic brain injury, seizures, pain (e.g., post-operative pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof.In any of the embodiments herein, the subject may suffer from an emotion dysregulation disorder.

[0167] Treatment method Dextromethorphan is known to be useful in treating various diseases or disorders. See, for example, Nguyen, L. et al., Pharmacology & Therapeutics 159:1022 (2016). Accordingly, in some embodiments, the present disclosure is also directed to a method of treating a disease or disorder in a subject in need of such treatment, where administration of dextromethorphan would be beneficial. In some embodiments, the method comprises transdermally administering a therapeutically effective amount of dextromethorphan to the subject. In some embodiments, the administering comprises applying a transdermal delivery device (e.g., those described herein, such as those shown in [1]-

[51] in the Summary of the Invention) to the skin of the subject. In some embodiments, the administration results in a PK profile described herein or any of the PK profiles described in WO 2021 / 202329 A1. In some embodiments, the subject does not cough and / or does not require cough suppressants. In some embodiments, the subject is an extensive metabolizer of dextromethorphan. In some embodiments, the subject is a poor metabolizer of dextromethorphan. In some embodiments, the subject is sensitive or intolerant to a CYP2D6 inhibitor. In some embodiments, the subject is sensitive or intolerant to quinidine, e.g., experiencing QTc prolongation. In some embodiments, the subject has one or more side effects associated with quinidine. In some embodiments, the subject is co-administered with (or requires) a drug whose metabolism is affected by a CYP2D6 inhibitor.

[0168] A variety of diseases and disorders are suitable for treatment by the methods herein. In some embodiments, the disease or disorder is a neurological disorder. Non-limiting exemplary neurological diseases or disorders include affective disorders, psychiatric disorders, brain function disorders, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0169] Affective disorders that can be treated by the methods herein include, but are not limited to, depression, major depressive disorder, treatment-resistant depression and treatment-resistant bipolar depression, bipolar disorders including cyclothymia, seasonal affective disorder, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), adjustment disorder, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH) and attention deficit / hyperactivity disorder (AD / HD), bipolar and manic states, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, drug addiction or abuse, nicotine addiction, psychosexual dysfunction, affective dysregulation, and emotional lability.

[0170] Psychiatric disorders that can be treated by the methods herein include, but are not limited to, anxiety disorders, including but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic depression, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizophreniformity, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease.

[0171] Drug addictions and abuse that can be treated by the methods herein include, but are not limited to, addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, methamphetamine), nicotine, alcohol, opioids, anxiolytics and hypnotics, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as cigarette, cigar, and / or pipe smoking, and chewing tobacco addiction.

[0172] Brain dysfunction that can be treated by the methods herein includes, but is not limited to, disorders associated with intellectual disability, such as senile dementia, Alzheimer's dementia, memory loss, amnesia / amnestic syndrome, epilepsy, impaired consciousness, coma, impaired attention, speech disorders, vocal spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, attention deficit hyperactivity syndrome, and schizophrenia. Brain dysfunction also includes disorders caused by cerebrovascular diseases, including, but not limited to, stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, and head trauma, and symptoms include impaired consciousness, senile dementia, coma, impaired attention, and speech disorders.

[0173] Movement disorders that can be treated by the methods herein include, but are not limited to, akathisia, akinesia, dyskinesia, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, and Tourette's syndrome, and Wilson's disease.

[0174] Dementias that can be treated by the methods herein include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff syndrome, and Pick's disease.

[0175] Motor neuron diseases that can be treated by the methods herein include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophies, Tay-Sachs disease, Sandhoff disease, and hereditary spastic paraplegia.

[0176] Neurodegenerative diseases that can be treated by the methods herein include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar degeneration (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophies, Charcot-Marie-Tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0177] Seizure disorders that can be treated by the methods herein include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile convulsions; partial seizures, including but not limited to simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsy partialis continua; generalized seizures, including but not limited to generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0178] The types of headaches that can be treated by the methods herein include, but are not limited to, migraines, tension-type headaches, and cluster headaches.

[0179] Other neurological disorders that can be treated by the methods herein include, but are not limited to, Rett syndrome, autism, tinnitus, impaired consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; dysphonia due to uncontrollable laryngospasm, including, but not limited to, abductor spasmodic dysphonia, adductor spasmodic dysphonia, myotonic dysphonia, and voice tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity such as methotrexate neurotoxicity; incontinence, including, but not limited to, stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0180] In some embodiments, the disease or disorder is pain, joint pain, pain associated with sickle cell disease, emotional dysregulation, depression (including major depressive disorder, treatment-resistant depression, etc.), memory and cognition-related disorders, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), and the like.

[0181] The methods herein can also be used to treat or alleviate any type of pain, including, but not limited to, musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, inflammatory pain, arthritic pain, complex regional pain syndrome, and the like.

[0182] In some embodiments, the disease or disorder may be allodynia, refractory hyperalgesia, dermatitis, pain, inflammation, or an inflammatory condition such as Crohn's disease, including pain associated with psoriasis, cancer, viral infection, or as adjuvant therapy for multiple myeloma.

[0183] In any of the embodiments described herein, the method can be for treating emotion dysregulation, depression (e.g., major depressive disorder, treatment-resistant depression, etc.), stroke, traumatic brain injury, seizures, pain (e.g., post-operative pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof.

[0184] Suitable dosing regimens, dosages, durations, transdermal delivery devices, etc. include any of those described herein in any combination. In any of the embodiments described herein, the subject may be a human subject.

[0185] In some specific embodiments, a method for treating emotion dysregulation is provided, comprising applying a transdermal delivery device described herein (e.g., those described in [1] to

[51] in the Summary of the Invention) to a subject in need thereof. In some embodiments, the transdermal delivery device contains about 150 mg to about 1000 mg of dextromethorphan. In some embodiments, the transdermal delivery device is applied once a week, for example, for one week, one month, or any desired period. In some embodiments, the transdermal delivery device is applied once, twice, three times, four times, five times, or six times a week, for example, for one week, one month, or any desired period. In some embodiments, the transdermal delivery device is applied to achieve any of the pharmacokinetic profiles described herein. In some embodiments, the subject is not administered a CYP2D6 inhibitor. In some embodiments, the subject is not administered quinidine. In some embodiments, the subject does not cough or require antitussive effects. In some embodiments, the subject is characterized as a poor metabolizer. In some embodiments, the subject is characterized as an extensive metabolizer.

[0186] In some embodiments, the methods described herein can further include administering to the subject an active agent other than dextromethorphan. For example, in some embodiments, the methods described herein further include administering to the subject an antidepressant. In some embodiments, the antidepressant is selected from bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, metabolites or prodrugs of any of these compounds, and combinations thereof. Other suitable antidepressants are described, for example, in U.S. Patent No. 9,861,595, the entire contents of which are incorporated by reference. In some embodiments, the methods described herein further include administering to the subject quinidine. In some embodiments, the methods described herein further include administering to the subject a CYP2D6 inhibitor. In some embodiments, the methods described herein further include administering to the subject one or more additional active agents selected from amlodipine, capsaicinoids (e.g., capsaicin or its esters), opioid agonists (e.g., μ-opiate analgesics (e.g., tramadol)), adenosinergic agonists, 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, gabapentin, and pharmaceutically acceptable salts thereof. These additional agents can be administered simultaneously or sequentially. Furthermore, these additional agents can be administered via the same route or different routes. For example, in some embodiments, the additional agents can be administered transdermally or orally. However, in some embodiments, the additional agents may also be combined with dextromethorphan in the same transdermal delivery device.

[0187] Because the transdermal patches described herein bypass first-pass hepatic metabolism, the methods herein can provide dextromethorphan to subjects receiving medications that may interfere with hepatic metabolism of dextromethorphan. In some embodiments, the methods include administering to the subject desipramine, paroxetine, thioridazine, pimozide, digoxin, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, and combinations thereof. However, in some embodiments, the subject is not administered any of desipramine, paroxetine, thioridazine, pimozide, digoxin, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, and combinations thereof. In some embodiments, the methods do not require determining whether the subject is an extensive or poor metabolizer of dextromethorphan.

[0188] The present disclosure also provides the following non-limiting exemplary methods of transdermally administering dextromethorphan.

[0189] Typically, the methods herein are for treating a disease or disorder that would benefit from the administration of dextromethorphan. Suitable diseases or disorders that can be treated by the methods herein are described herein. In some embodiments, the methods herein are for treating a neurological disease or disorder in a subject in need of such treatment. Such neurological diseases or disorders include, but are not limited to, affective disorders, psychiatric disorders, brain function disorders, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches. In some embodiments, the methods are for treating emotion dysregulation, depression (e.g., major depressive disorder or treatment-resistant depression), stroke, traumatic brain injury, seizures, pain, methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof. In some embodiments, the subject does not cough and / or does not require antitussive medication.

[0190] Nuedexta® tablets have been approved by the FDA for the treatment of emotional dysregulation, or PBA. See Nuedexta® prescribing information (June 2019), the contents of which are incorporated herein by reference in their entirety. As described in the Nuedexta prescribing information, PBA occurs secondary to a variety of usually unrelated neurological conditions and is characterized by involuntary, sudden, and frequent episodes of laughter and / or crying. Episodes of PBA typically occur out of proportion to or incongruent with the underlying emotional state. PBA is a unique condition, distinct from other types of emotional lability that can occur in patients with neurological disease or injury.

[0191] In some specific embodiments, the methods herein are for treating PBA in a subject in need thereof, hi some embodiments, the subject also suffers from a neurodegenerative disease such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and / or Alzheimer's disease, a stroke, or a brain injury such as a traumatic brain injury.

[0192] The methods herein generally involve transdermally delivering a therapeutically effective amount of dextromethorphan to a subject in need thereof. In some embodiments, the methods involve transdermally delivering a daily dose of dextromethorphan of about 15 mg to about 50 mg (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any value or range therebetween, such as about 20-50 mg, about 30-50 mg, or about 20-40 mg) to a subject in need thereof. In some embodiments, the daily dose is about 20 mg to 40 mg, such as about 35 mg, of dextromethorphan. In some embodiments, the daily dose can also be greater than 50 mg, such as about 60 mg, up to about 100 mg, of dextromethorphan. In some embodiments, the daily dose can be less than 15 mg, such as about 5 mg, about 10 mg, or about 5-10 mg of dextromethorphan. The daily dose of dextromethorphan is typically delivered by applying to a subject a transdermal delivery device or transdermal patch described herein or an adhesive composition / adhesive formulation, such as any of those described herein (e.g., those shown in [1]-

[51] in the Summary of the Invention). As discussed herein, the transdermal patches described herein are advantageous in that each patch can provide the desired daily dose of dextromethorphan for seven or more days. Thus, the methods described herein may provide better patient compliance and convenience through an advantageous once-weekly dosing regimen.

[0193] In some embodiments, the methods herein may also be characterized by the unique in vivo pharmacokinetic (PK) profiles described herein. As shown in more detail in the Examples section, application of exemplary patches to human subjects once a week resulted in therapeutically effective plasma concentrations for 7 days or more, similar to a reference patch applied once daily. See also WO2021 / 202329A1. Treatment of the diseases or disorders herein with the novel PK profiles described herein is itself a novel feature of the present disclosure. These unique PK profiles may allow for more precise dosing, less frequent dosing, and reduced risk of quinidine-associated side effects and / or increased dextromethorphan exposure (e.g., C max ), reducing the potential for side effects associated with steroid use, reducing pill burden, and improving patient compliance. In some embodiments, the PK profile is characterized by the following characteristics: (1) AUC at day 7 or steady state 0-24,DXM (2) C on day 7 or during the steady state phase is about 180 h*ng / mL to about 2000 h*ng / mL, for example, about 200 h*ng / mL to about 600 h*ng / mL, or about 300 h*ng / mL to about 500 h*ng / mL. Avg,DXM (3) C on day 7 or during the steady state phase is about 8 ng / mL to about 100 ng / mL, for example, about 10 ng / mL to about 20 ng / mL, for example, about 15 ng / mL. min,DXM (4) the C on day 7 or during the steady-state phase is about 6 ng / mL to about 65 ng / mL, for example, about 6 ng / mL to about 20 ng / mL. max,DXM In some embodiments, the PK profile is characterized by one or more of the following characteristics: a) AUC at day 7 or steady state 0-24,DXM b) C on day 7 or during the steady-state phase Avg,DXM c) C on day 7 or during the steady state phase min,DXMand / or d) C on day 7 or during the steady-state phase. max,DXM is about 10 ng / mL to about 30 ng / mL.

[0194] In some embodiments, the methods herein may be particularly useful and advantageous for treating certain subjects. Patients with neurological disorders often have multiple comorbidities and / or are receiving treatment with numerous other medications. For example, treatment trials (controlled or uncontrolled) for PBA have been based on patient populations with a variety of other underlying neurological disorders, including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and stroke and traumatic brain injury. Therefore, patients with PBA are typically also receiving treatment with other medications, such as medications for the treatment of ALS, MS, stroke, and traumatic brain injury. The use of Nuedexta® tablets or similar measures to increase dextromethorphan plasma concentrations using CYP2D6 inhibitors is limited and may pose various limitations and drug-drug interactions for such patients. Some of the side effects or drugs affected by CYP2D6 inhibitors are described in the Nuedexta® prescribing information (June 2019 edition), the contents of which are incorporated herein by reference in their entirety. For example, the Nuedexta® prescribing information lists the following contraindications: 1) patients with a history of hypersensitivity reactions, such as thrombocytopenia, hepatitis, or bone marrow suppression or lupus-like syndrome, caused by quinidine, quinine, or mefloquine; 2) patients with known hypersensitivity to dextromethorphan; and 3) use in combination with an MAOI or within 14 days of stopping an MAOI. Allow 14 days between stopping NUEDEXTA and starting an MAOI; 4) history suggestive of QT interval prolongation, congenital long QT syndrome, polymorphic ventricular tachycardia, or heart failure; 5) complete atrioventricular (AV) block or patients at high risk for AV block without an implanted pacemaker; and 6) concomitant use of drugs that prolong the QT interval and are metabolized by CYP2D6 (e.g., thioridazine or pimozide).Additionally, the prescribing information for Nuedexta® contains various warnings and precautions, including: a) thrombocytopenia or other hypersensitivity reactions, b) hepatitis, c) QT prolongation, d) left ventricular hypertrophy (LVH) or left ventricular dysfunction (LVD), e) CYP2D6 substrates, f) dizziness, g) serotonin syndrome, and h) anticholinergic effects of quinidine. Many of these contraindications, warnings, and precautions are associated with quinidine. For example, the prescribing information for Nuedexta® states that "quinidine can cause immune-mediated thrombocytopenia, which can be severe or fatal," "quinidine has also been associated with a lupus-like syndrome with polyarthritis," "other associations include rash, bronchospasm, lymphadenopathy, hemolytic anemia, vasculitis, uveitis, angioedema, agranulocytosis, sicca syndrome, myalgia, elevated serum levels of skeletal muscle enzymes, and pneumonitis," and "hepatitis, including granulomatous hepatitis, has been reported in patients receiving quinidine." Quinidine may also cause "the safety and / or efficacy of drugs used in combination with Nuedexta that are metabolized by CYP2D6 may be reduced due to accumulation of the parent drug and / or impaired formation of the active metabolite," and "quinidine exposure, which may result from Nuedexta overdose, may result in fatal cardiac arrhythmias, including polymorphic ventricular tachycardia." Chronic quinidine toxicity is possible with Nuedexta treatment. Furthermore, various drugs may affect the pharmacological effects of quinidine, such as CYP3A4 inhibitors and P-glycoprotein blockers, which may have direct effects on QTc or be proarrhythmic themselves, and may decrease serum potassium in association with diuretics, resulting in a moderate decrease in potassium concentration and thereby limiting the use of NUEDEXTA. Because quinidine inhibits CYP2D6, various drug-drug interactions may also occur with CYP2D6 substrates such as desipramine and paroxetine.As stated in the Nuedexta® prescribing information, "In the case of prodrugs whose action is mediated by CYP2D6-generated metabolites (e.g., codeine and hydrocodone, whose analgesic and antitussive effects are thought to be mediated by morphine and hydromorphone, respectively), quinidine-mediated CYP2D6 inhibition likely prevents the desired clinical benefit from being achieved in the presence of Nuedexta." Quinidine is also an inhibitor of P-glycoprotein and can significantly affect plasma concentrations of drugs that are P-glycoprotein substrates, such as digoxin. In summary, due to the various potential side effects associated with quinidine, there exists an unmet medical need for the treatment of PBA, at least in patient populations with one or more limitations and / or side effects associated with quinidine or CYP2D6 inhibitors in general.

[0195] Because the transdermal delivery route described herein does not require the use of quinidine or other CYP2D6 inhibitors, it can be advantageously used to treat patients without the constraints associated with quinidine or CYP2D6 inhibitors. For example, in some embodiments, the methods herein can treat subjects who are sensitive or intolerant to quinidine, or CYP2D6 inhibitors in general. In some embodiments, the subject can be sensitive or intolerant to CYP2D6 inhibitors. In some embodiments, the subject can be sensitive or intolerant to quinidine. In some embodiments, the subject has one or more side effects associated with quinidine. In some embodiments, the subject is co-administered with a drug whose metabolism is affected by a CYP2D6 inhibitor. In some embodiments, the subject is co-administered with a drug whose metabolism is affected by quinidine. In some embodiments, the subject is co-administered a drug such as a CYP3A4 inhibitor (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) that may affect the pharmacological effects of quinidine. In some embodiments, the subject can be further treated with a selective serotonin reuptake inhibitor (such as fluoxetine), a tricyclic antidepressant (such as clomipramine and imipramine), and / or a monoamine oxidase inhibitor (MAOI).

[0196] Furthermore, because the transdermal delivery route described herein does not require the use of quinidine or other CYP2D6 inhibitors, the transdermal delivery device or transdermal formulation described herein can be conveniently administered to transdermally deliver dextromethorphan to a subject, regardless of whether the subject is a poor, intermediate, or extensive metabolizer of dextromethorphan. In poor metabolizers, the addition of quinidine or other CYP2D6 inhibitors is not expected to significantly affect plasma exposure to dextromethorphan, yet such addition would expose the subject to potential side effects associated with quinidine or other CYP2D6 inhibitors. The transdermal delivery method described herein does not suffer from such drawbacks. In some embodiments, the method described herein can treat a subject without first determining whether the subject is a poor, intermediate, or extensive metabolizer of dextromethorphan. In some embodiments, the method described herein can treat a subject who is an extensive metabolizer. In some embodiments, the method described herein can treat a subject who is a poor metabolizer. In some embodiments, the methods herein can also include determining whether a subject is a poor, intermediate, or extensive metabolizer of dextromethorphan and administering an appropriate daily dose of dextromethorphan to the subject. For example, in some embodiments, the daily dose can be adjusted so that transdermal delivery results in a therapeutically effective plasma dextromethorphan concentration in the subject. In some embodiments, the daily dose can be adjusted so that transdermal delivery results in any of the PK profiles described herein.For example, in some embodiments, the present disclosure provides a method for treating a neurological disease or disorder (e.g., any of those described herein) in a subject in need of such treatment, the method comprising: (a) applying a first transdermal patch (e.g., one of those shown in [1]-

[51] in the Summary of the Invention) to the subject at a dosing frequency of once daily to once weekly to deliver a first daily dose (typically about 15 mg to about 50 mg) of dextromethorphan to the subject; (b) determining whether the application results in any of the pharmacokinetic profiles disclosed herein; and, optionally, (c) adjusting the upper or lower limit of the first daily dose so that the application results in one or more of the pharmacokinetic profiles disclosed herein. Suitable transdermal patches and dosing regimens include any of those described herein.

[0197] As discussed herein, the methods herein are directed to at least high dextromethorphan exposure (e.g., C max , AUC, etc.). Thus, in some embodiments, the methods herein are intended to provide a method for treating high dextromethorphan exposure (e.g., C max The compounds can also be advantageously used to treat a subject having one or more side effects associated with the administration of steroids (e.g., AUC, etc.).

[0198] The methods herein can be used in conjunction with other drug therapies. For example, in some embodiments, the methods can further include administering an antidepressant to the subject. In some embodiments, the antidepressant is bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, metabolites or prodrugs of any of these compounds, and combinations thereof. In some embodiments, the methods can further include administering to the subject one or more additional active agents selected from amlodipine, capsaicinoids (e.g., capsaicin or its esters), opioid agonists (e.g., μ-opiate analgesics (e.g., tramadol)), adenosinergic agonists, 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, gabapentin, and pharmaceutically acceptable salts thereof. Typically, the methods herein do not administer quinidine to the subject. However, in some embodiments, quinidine may be administered. These additional agents can be administered simultaneously or sequentially. Furthermore, these additional agents can be administered via the same or different routes. For example, in some embodiments, the additional agents may be administered transdermally or orally. However, in some embodiments, the additional agents may also be combined with dextromethorphan in the same transdermal delivery device.

[0199] definition As used herein, the term "about" modifying a quantity in connection with the present invention refers to variations in the quantity that may occur, for example, through routine testing and handling; through inadvertent errors in such testing and handling; through differences in the manufacture, source, or purity of the components / materials used in the present invention; etc. As used herein, "about" a particular value is inclusive of the specific value, for example, about 10% includes 10%. Whether or not modified by the term "about," the claims include the equivalent of the recited amount. In one embodiment, the term "about" means within 20% of the reported numerical value.

[0200] As used herein, the term "cumulative drug permeated" refers to the total amount of drug permeated per square centimeter during a given period of time. Unless otherwise clear from the context, "cumulative drug permeated" at a given time (e.g., 24 hours after administration) means the total amount of drug permeated per square centimeter from time 0 (i.e., the time of administration) to that given time. Unless otherwise clear from the context, "cumulative drug permeated" refers to the arithmetic mean value measured and / or calculated according to the methods described herein. As used herein, the term "mean value" also refers to the arithmetic mean value unless otherwise specified and consistent with common practice in the art.

[0201] As used herein, the term "flux" refers to the amount of drug permeated through the skin per unit area per unit time. Unless otherwise apparent from the context, "flux" refers to the arithmetic mean value measured and / or calculated according to the methods described herein. Typical units of flux are milligrams per square centimeter per hour or per day. As used herein, dextromethorphan flux per day should be understood as the arithmetic mean value of cumulative dextromethorphan permeation 24 hours after application, measured and / or calculated according to the methods described herein.

[0202] The flux rates referred to in this patent application can refer to those measured by either in vivo or in vitro methods. One method for measuring flux is to place a transdermal delivery device or transdermal formulation on a known skin area of ​​a human volunteer and measure the amount of drug that can permeate the skin within a certain time constraint. Those skilled in the art will understand that, in some cases, absolute in vitro flux values ​​can vary by several fold when measured using different cadaveric sources. As used herein, when specifically referred to as measured by an in vitro method using human cadaveric skin, the flux rate should be understood to be measured according to the method described in Example 4. For example, the tested patch of Example 4 can be used as a reference patch, which, when tested according to the method described in Example 4, should produce the same flux as observed in Example 4 within experimental error generally accepted by those skilled in the art. Although in vitro methods use human epidermal membranes obtained from cadavers rather than human volunteers to measure drug flux through the skin, it is generally accepted by those skilled in the art that the results of a properly designed and executed in vitro test can be used to extrapolate or predict the results of an in vivo test with reasonable reliability.

[0203] As used herein, the terms "treat," "treating," "treatment," and the like refer to eliminating, alleviating, or ameliorating a disease or condition and / or its associated symptoms. Although not excluded, treating a disease or condition does not require that the disease, condition, or its associated symptoms be completely eliminated.

[0204] The term "therapeutically effective amount," as used herein, refers to an amount of a therapeutic agent (e.g., dextromethorphan) sufficient to result in the amelioration of one or more symptoms of a disorder or condition (e.g., PBA), or to prevent the onset or progression of the disorder or condition, or to cause regression or cure of the disorder or condition.

[0205] The term "subject" (alternatively referred to herein as "patient"), as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0206] As used herein, application or administration of a transdermal delivery device herein should be understood according to how such a transdermal delivery device is normally applied or administered to the skin of, for example, a human subject. [Example]

[0207] Example 1. Preparation of a dextromethorphan transdermal patch This example demonstrates one procedure for preparing a single-layer dextromethorphan drug-in-adhesive patch. Dextromethorphan base ("DXM") is commonly available commercially. Alternatively, dextromethorphan base can be prepared by converting dextromethorphan hydrobromide to the free base using, for example, a 1:1 molar ratio of NaOH.

[0208] Preparation of Formulation A: Formulation A has the following ingredients (weight percentages are on a dry weight basis): [Table 1]

[0209] Patches based on Formulation A were prepared according to the following general procedure. Add isopropyl alcohol (IPA) to disposable beaker 1, add Plasdone K29 / 32 and stir for 30 minutes or until dissolved. Add weighed IPM (isopropyl myristate). Mix until dissolved. Weigh out the ethyl acetate and add it to disposable beaker 2. Add the DXM and mix until the dispersion is well mixed. Then weigh out and add the DuroTak® 387-2287. Add the contents of beaker 1 to beaker 2 while stirring. Mix until homogenous. ·Cast onto backing film (3M Beige Film 9723NR). Drying - The cast adhesive film is dried in an oven at 85°C for 10 minutes. · Lamination - Laminating a release liner to the dried adhesive film. ·(70cm 2 Die cut to size and place in a bag.

[0210] Example 2. Preparation of a dextromethorphan transdermal patch containing a reservoir layer This example demonstrates one procedure for preparing a dextromethorphan drug-in-adhesive patch having a skin-contacting drug-in-adhesive layer and a reservoir layer.

[0211] The components of the skin-contacting drug-containing adhesive layer and reservoir layer are listed below, with weight percentages based on dry weight. [Table 2]

[0212] The patches in this example were prepared according to the following general procedure.

[0213] Reservoir layer: Add IPA to disposable beaker 1, add Plasdone K29 / 32 and stir for 30 minutes or until dissolved. Add weighed IPM (Isopropyl Myristate). Mix until dissolved. Weigh out the ethyl acetate and add it to disposable beaker 2. Add the DXM and mix until the dispersion is well mixed. Then weigh out and add the DuroTak® 387-2287. Add the contents of beaker 1 to beaker 2 while stirring. Mix until homogenous. ·Cast onto backing film (3M Beige Film 9723NR). Drying - The cast adhesive film is dried in an oven at 85°C for 10 minutes.

[0214] Skin contact drug-containing adhesive layer: Add IPA to disposable beaker 1, add Plasdone K29 / 32 and stir for 30 minutes or until dissolved. Add weighed IPM (Isopropyl Myristate). Mix until dissolved. Weigh out ethyl acetate and add to disposable beaker 2. Add DXM and mix until DXM is dissolved. Next, weigh out and add DuroTak® 387-2287. Add the contents of beaker 1 to beaker 2 while stirring. Mix until homogenous. ·Cast onto backing film (3M Beige Film 9723NR). Drying - The cast adhesive film is dried in an oven at 85°C for 10 minutes.

[0215] Building a two-layer patch: The skin-contacting drug-containing adhesive layer is laminated onto the reservoir layer film. The skin-contacting drug-containing adhesive layer is approximately 3 mils thick, and the reservoir layer is approximately 4 mils thick. For every 100 mg, the reservoir layer is approximately 57.14 mg, and the skin-contacting drug-containing adhesive layer is approximately 42.86 mg. A release liner is laminated onto the dried adhesive two-layer film. ·(70cm 2 Die cut to size and place in a bag.

[0216] Example 3. Preparation of a Reference Dextromethorphan Transdermal Patch A single-layer drug-in-adhesive patch was prepared as a reference patch according to the procedure described in WO2021 / 202329, published October 7, 2021. Formulation E1 contains, by dry weight, approximately 10% dextromethorphan base, approximately 10% isopropyl myristate, approximately 70% polyacrylate adhesive (DuroTak® 387-2287), and approximately 10% crystallization inhibitor Plasdone K-29 / 32 (polyvinylpyrrolidone). These components were blended with isopropanol to form a homogeneous solution. This wet formulation contains the following ingredients: approximately 63.1% polyacrylate adhesive (DuroTak® 387-2287, approximately 50% solids), approximately 4.5% Plasdone K-29 / 32 (polyvinylpyrrolidone), approximately 4.5% isopropyl myristate, approximately 4.5% dextromethorphan base, and approximately 23.4% isopropyl alcohol. This wet formulation was cast onto a release liner (3Mil PET 8310, silicone-coated polyester film) and allowed to dry. The dried casting was then laminated to a patch backing film, Scotchpak 9733 PET film. Patches were die-cut to the desired size. In one example, this formulation was used to produce, for example, a patch containing approximately 56 mg of dextromethorphan base and measuring approximately 70 cm. 2 Transdermal patches measuring 100 μg / ml were prepared.

[0217] Example 4. Transdermal flux test The transdermal flux of dextromethorphan from the patch was tested using human cadaver skin by the Franz diffusion cell method, see e.g., WO2021 / 202329.

[0218] The patches prepared in Examples 1 and 2 were used in skin permeation studies using the following protocol.

[0219] Franz Cell Assembly - Logan Instruments (6-cell unit) Each cell has a volume of 12 mL and an orifice with a diameter of 1.5 cm. The receptor medium is phosphate buffer solution (PBS) pH 7.4 Maintain cell temperature at 37°C Sampling method: Take 1.5 mL for HPLC assay, empty the cell, and replace with fresh medium. Sampling time points: 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, and 192 hours · Media assay method: HPLC based.

[0220] The test results are shown in Table 1 below (see also Figure 1). Skin permeation experiments were carried out for up to 8 days. The values ​​presented are for 1 cm 2 The cumulative amount of DXM permeated per 100 μg / cm 2 ) [Table 3]

[0221] Example 5. Stability Test The patches prepared in Examples 1 and 2 were also tested for storage stability under two conditions: 25°C / 60% RH (relative humidity) and 40°C / 75% RH. The results are shown in Tables 2 and 3 below.

[0222] [Table 4]

[0223] As shown in Table 2, the single-layer patch prepared according to Example 1 was found to have good storage stability, good peel adhesion, and release liner removal ability. Furthermore, the content of dextromethorphan remained unchanged for at least one month under the two storage conditions.

[0224] [Table 5]

[0225] As shown in Table 3, the bilayer patch prepared according to Example 2 was also found to have good storage stability, good peel adhesion, and release liner removal ability. Furthermore, the content of dextromethorphan remained unchanged for at least one month under the two storage conditions.

[0226] Example 6. In vivo pharmacokinetic studies This example relates to an open-label, randomized, three-treatment, three-period, three-sequence, crossover, comparative bioavailability study of test products (T1 and T2), a single dose of a 35 mg / 24-hour delivery dextromethorphan sustained-release transdermal patch (once weekly) with multiple doses of a 35 mg / 24-hour delivery reference (®) dextromethorphan transdermal patch (once daily) in healthy adult males under fasting conditions. T1 was a single-layer patch (70 cm) according to Example 1. 2 , 35 mg / day with weekly dosing). T2 refers to a bilayer patch according to Example 2 (70 cm 2 , 35 mg / day with once-weekly dosing). The reference patch refers to the patch prepared according to Example 3 (70 cm 2 The study involved 12 subjects.

[0227] Plasma concentrations of dextromethorphan and its active metabolite, dextrorphan, were measured using a well-validated analytical procedure. Statistical analysis was performed to evaluate the bioavailability of the test formulations compared to that of the reference product for dextromethorphan and dextrorphan only. For details of the analytical procedure and statistical analysis, see WO 2021 / 202329.

[0228] Tables 4A-4C show the results of this study.

[0229] [Table 6]

[0230] [Table 7]

[0231] [Table 8]

[0232] In addition to the pharmacokinetic study, safety observations were also conducted. All subjects were confirmed to be in normal health during post-study medical examinations. No serious / significant adverse events were reported throughout the entire study period.

[0233] Based on the study results, it was concluded that the test products (T1 and T2) [dextromethorphan sustained-release transdermal patch (once weekly) 35 mg / 24-hour delivery] and the multi-dose reference product (R) [dextromethorphan transdermal patch (once daily) 35 mg / 24-hour delivery] were equivalent with respect to dextromethorphan.

[0234] It was unexpected that these test products with drug particles in the adhesive layer showed similar results to the reference product, demonstrating for the first time that a once-weekly dosing regimen can deliver therapeutically effective amounts of dextromethorphan transdermally, and that these patches should be easier for patients to use because they only need to be changed weekly instead of daily.

[0235] It should be recognized that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections may set forth one or more, but not all, exemplary embodiments of the invention as contemplated by the inventor(s) and are not intended to limit the scope of the invention and the appended claims in any way.

[0236] The present invention has been described above using functional components that illustrate the implementation of certain functions and their relationships. The boundaries of these functional components have been arbitrarily defined herein for the convenience of the description. Alternative boundaries may be defined so long as the specified functions and their relationships are appropriately performed.

[0237] For aspects of the invention described as genus, all individual species are separate aspects of the invention considered individually. When aspects of the invention are described as "comprising" an element, embodiments "consisting of" or "consisting essentially of" that element are also contemplated.

[0238] The above specific descriptions of specific embodiments fully illustrate the general nature of the invention, so that others, applying knowledge within the skill of those skilled in the art, can easily modify and / or adapt such specific embodiments for various uses without undue experimentation and without departing from the general concept of the invention. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. The words and terms used herein are for the purpose of description and not of limitation, and the words and terms used herein would be understood by one of ordinary skill in the art in light of the teaching and guidance provided herein.

[0239] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0240] Any of the various aspects, embodiments, and options described herein can be combined in any and all variations.

[0241] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, and patent application was specifically and individually indicated to be incorporated by reference. If any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition of the term in this document shall control.

Claims

1. i. a backing layer; ii. a drug-containing adhesive layer comprising: 1) dextromethorphan in an amount of at least 15% by weight, preferably about 15% to about 50% by weight, 2) isopropyl myristate in an amount of about 6% to about 12% by weight, 3) a pressure-sensitive adhesive, preferably an acrylate-based pressure-sensitive adhesive, in an amount of about 20% to about 60% by weight, and 4) a solubilizing agent in an amount of about 6% to about 25% by weight; A transdermal patch comprising: At least a portion of the dextromethorphan is in a solid state dispersed in the pressure sensitive adhesive, preferably The transdermal patch is approximately 30 cm ２ ~Approx. 150cm ２ The transdermal patch has an active surface area of

2. 10. The transdermal patch of claim 1, wherein the acrylate-based pressure-sensitive adhesive is a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as an acrylate copolymer adhesive, e.g., Duro-Tak 87-2287 adhesive and the like, having non-acidic hydroxyl functional groups, e.g., as described herein.

3. 3. The transdermal patch of claim 1 or claim 2, wherein the acrylate-based pressure-sensitive adhesive is in an amount of about 30%, about 40%, about 45%, about 50%, about 55%, or about 60% by weight, or any value or range therebetween, such as about 40-60%, about 45-55%, etc.

4. The transdermal patch of any of claims 1 to 3, wherein the solubilizer is a vinylpyrrolidone polymer such as vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like.

5. 5. The transdermal patch of any of claims 1-4, wherein the solubilizing agent is present in an amount of about 6%, about 8%, about 10%, about 15%, about 20%, or about 25%, or any value or range between said recited values, such as about 8-15% or about 6-20%.

6. 6. The transdermal patch of any one of claims 1 to 5, wherein the isopropyl myristate is in an amount of about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% by weight, or any value or range therebetween, such as about 8-12% by weight.

7. 7. The transdermal patch of any one of claims 1 to 6, wherein the dextromethorphan is in an amount of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight, or any value or range therebetween, such as about 20-40% by weight, about 25-35% by weight, etc.

8. 8. The transdermal patch of any of claims 1-7, wherein the drug-containing adhesive layer comprises about 150 mg to about 1000 mg of dextromethorphan, e.g., about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 750 mg, about 900 mg, about 1000 mg, or any value or range therebetween, such as about 250-400 mg, about 300-400 mg, or about 350-450 mg, or about 300-800 mg, about 350-900 mg, etc.

9. 9. The transdermal patch of any of claims 1-8, wherein the drug-containing adhesive layer comprises about 30 mg to about 350 mg of isopropyl myristate, e.g., about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or any value or range therebetween, e.g., about 50-150 mg or about 75-125 mg, about 75-300 mg, about 50-250 mg, etc.

10. 10. The transdermal patch of any of claims 1 to 9, wherein the drug-containing adhesive layer comprises about 150 mg to about 1800 mg of the pressure-sensitive adhesive, preferably an acrylate-based pressure-sensitive adhesive, for example, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1400 mg, about 1600 mg, about 1800 mg, or any value or range between said recited values, such as about 350-600 mg, about 400-650 mg, or about 450-700 mg, about 450-1200 mg, about 350-1000 mg, about 400-1600 mg, etc.

11. 11. The transdermal patch of any of claims 1 to 10, wherein the drug-containing adhesive layer comprises the solubilizer in an amount of about 30 mg to about 350 mg, e.g., about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or any value or range therebetween, such as about 50-150 mg or about 75-125 mg, about 75-300 mg, about 50-250 mg, etc.

12. The transdermal patch of any one of claims 1 to 11, wherein the drug-containing adhesive layer contains dextromethorphan as the sole active ingredient.

13. Approximately 70cm ２ The transdermal patch according to any one of claims 1 to 12, having an active surface area of

14. Approximately 2mg / cm ２ ~Approx. 25mg / cm ２ , e.g., about 2.5 mg / cm ２ , about 3mg / cm ２ , about 4mg / cm ２ , about 5mg / cm ２ , about 6mg / cm ２ , about 7mg / cm ２ , about 8mg / cm ２ , about 9 mg / cm ２ , about 10mg / cm ２ , about 12mg / cm ２ , about 15mg / cm ２ , about 20mg / cm ２ , about 25mg / cm ２ etc., or any value or range therebetween, e.g., about 3 to 10 mg / cm ２ , about 4-7mg / cm ２ , about 5-12mg / cm ２ , about 8-25mg / cm ２ The transdermal patch according to any one of claims 1 to 13, having a total dextromethorphan loading of

15. The transdermal patch of any one of claims 1 to 14, comprising the backing layer, the drug-containing adhesive layer, and optionally a release liner.

16. The transdermal patch according to any one of claims 1 to 15, which is in the form of a single layer patch.

17. The transdermal patch has a densitometric value of at least about 200 ug / cm for at least 7 days as measured in vitro using human cadaver skin. ２ / day, e.g., about 200 ug / cm for 7 days or more ２ / day, approximately 300ug / cm ２ / day, approximately 400ug / cm ２ / day, approximately 500ug / cm ２ / day, approximately 600ug / cm ２ / day, approximately 700ug / cm ２ / day, approximately 800ug / cm ２ / day, approximately 1000ug / cm ２ / day, or any value or range therebetween, e.g., about 200-800 ug / cm ２ / day, about 300-800ug / cm ２ / day, approximately 400-800ug / cm ２ / day, about 500-800ug / cm ２ 17. The transdermal patch of any one of claims 1 to 16, having a dextromethorphan flux of 1000 mg / day or more.

18. 17. The transdermal patch of any one of claims 1 to 16, wherein a single application of the transdermal patch to a human subject is capable of transdermally delivering a daily dose of about 15 mg to about 50 mg of dextromethorphan (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any value or range therebetween, such as about 20-50 mg, about 30-50 mg, or about 20-40 mg) to the human subject for at least 7 days.

19. 17. The transdermal patch of any one of claims 1 to 16, wherein a single application of the transdermal patch to a human subject transdermally delivers to the human subject a therapeutically effective daily dose for treating emotional dysregulation for at least seven days.

20. i. a backing layer; ii. a skin-contacting drug-containing adhesive layer comprising: 1) dextromethorphan in an amount from about 6% to about 12% by weight, 2) isopropyl myristate in an amount from about 6% to about 12% by weight, 3) a first pressure-sensitive adhesive, preferably an acrylate-based pressure-sensitive adhesive, in an amount from about 65% to about 85% by weight, and 4) a crystallization inhibitor in an amount from about 6% to about 12% by weight; iii. a reservoir layer comprising: 1) dextromethorphan in an amount of at least 15% by weight; 2) isopropyl myristate in an amount from about 6% to about 12% by weight; 3) a second pressure-sensitive adhesive in an amount from about 20% to about 60% by weight; and 4) a solubilizing agent in an amount from about 6% to about 25% by weight; A transdermal patch comprising: at least a portion of the dextromethorphan in the reservoir layer is in a solid state dispersed in the second pressure-sensitive adhesive; the first pressure-sensitive adhesive and the second pressure-sensitive adhesive are the same or different, preferably the same; Preferably, the transdermal patch is about 30 cm ２ ~Approx. 150cm ２ The transdermal patch has an active surface area of

21. 21. The transdermal patch of claim 20, wherein the first pressure-sensitive adhesive is an acrylate-based pressure-sensitive adhesive.

22. 22. The transdermal patch of claim 21, wherein the acrylate-based pressure-sensitive adhesive is an acrylate copolymer adhesive, e.g., a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as those having non-acidic hydroxyl functional groups, e.g., as described herein, such as Duro-Tak 87-2287 adhesive and the like.

23. 23. The transdermal patch of claim 21 or claim 22, wherein the acrylate-based pressure-sensitive adhesive is in an amount of about 65%, about 70%, about 75%, about 80%, or about 85% by weight of the skin-contacting drug-containing adhesive layer, or any value or range therebetween, such as about 70-85%, about 65-75%, etc.

24. The transdermal patch of any of claims 20 to 23, wherein the crystallization inhibitor is a vinylpyrrolidone polymer such as a vinylpyrrolidone homopolymer (or povidone), e.g., povidone K30, plasdone K29 / 32, and the like.

25. 25. The transdermal patch of claim 24, wherein the crystallization inhibitor is present in an amount of about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% of the skin-contacting drug-containing adhesive layer, or any value or range therebetween, such as about 6-12% or 8-12%.

26. 26. The transdermal patch of any of claims 20-25, wherein the isopropyl myristate is in an amount of about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% by weight of the skin-contacting drug-containing adhesive layer, or any value or range therebetween, such as about 8-12% by weight.

27. 27. The transdermal patch of any of claims 20-26, wherein the dextromethorphan is in an amount of about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% by weight of the skin-contacting drug-containing adhesive layer, or any value or range therebetween, such as about 6-10% by weight.

28. The transdermal patch of any one of claims 20 to 27, wherein the second pressure-sensitive adhesive is an acrylate-based pressure-sensitive adhesive.

29. 29. The transdermal patch of any of claims 20-28, wherein the second pressure-sensitive adhesive is an acrylate copolymer adhesive, e.g., a polyacrylate vinyl acetate copolymer pressure-sensitive adhesive, such as those having non-acidic hydroxyl functionality, e.g., as described herein, such as Duro-Tak 87-2287 adhesive and the like.

30. 30. The transdermal patch of any of claims 20-29, wherein the second pressure-sensitive adhesive is in an amount of about 20%, about 30%, about 35%, about 40%, about 45%, about 50%, or about 60% by weight of the reservoir layer, or any value or range therebetween, such as about 35-45%, about 30-50%, etc.

31. The transdermal patch of any of claims 20 to 30, wherein the solubilizer is a vinylpyrrolidone polymer such as a vinylpyrrolidone homopolymer (or povidone), for example, povidone K30, plasdone K29 / 32, and the like.

32. 32. The transdermal patch of any of claims 20-31, wherein the solubilizing agent is present in an amount of about 6%, about 8%, about 10%, about 15%, about 20%, or about 25% of the reservoir layer, or any value or range therebetween, such as about 15-25% or about 10-20%.

33. 33. The transdermal patch of any of claims 20-32, wherein the isopropyl myristate of the reservoir layer is in an amount of about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% by weight of the reservoir layer, or any value or range therebetween, such as about 8-12% by weight.

34. 34. The transdermal patch of any of claims 20-33, wherein the dextromethorphan in the reservoir layer is in an amount of about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight of the reservoir layer, or any value or range therebetween, e.g., about 20-40%, about 25-35%, etc.

35. 35. The transdermal patch of any one of claims 20 to 34, wherein the dextromethorphan in the reservoir layer has a concentration that is about 200-800% (preferably about 300-500%) of the concentration in the skin-contacting drug-containing adhesive layer.

36. 36. The transdermal patch of any one of claims 20 to 35, wherein the amount of dextromethorphan in the reservoir layer is about 200 to 800% (preferably about 300 to 500%) of the amount of dextromethorphan in the skin-contacting drug-containing adhesive layer.

37. 37. The transdermal patch of any of claims 20 to 36, wherein the skin-contacting drug-containing adhesive layer has a thickness of from about 0.4 mil to about 5 mil, such as from about 0.4 to 3 mil.

38. The transdermal patch of any of claims 20 to 37, wherein the reservoir layer has a thickness of about 2 mil to about 7.5 mil, such as about 4 mil.

39. 39. The transdermal patch of any of claims 20 to 38, wherein the reservoir layer has a thickness of at least about 100%, preferably about 100-800% (preferably 100-600%, or 120-300%) of the thickness of the skin-contacting drug-containing adhesive layer.

40. 40. The transdermal patch of any one of claims 20 to 39, wherein the total weight of the reservoir layer is at least about 100%, preferably about 100-800% (preferably 100-600%, or 120-300%) of the total weight of the skin-contacting drug-containing adhesive layer.

41. 41. The transdermal patch of any of claims 20-40, wherein the total amount of dextromethorphan is about 150 mg to about 1000 mg, e.g., about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 750 mg, about 900 mg, about 1000 mg, or any value or range therebetween, e.g., about 250-400 mg, about 300-400 mg, or about 350-450 mg, or about 300-800 mg, about 350-900 mg, etc.

42. 42. The transdermal patch of any one of claims 20 to 41, wherein the total amount of isopropyl myristate is about 30 mg to about 350 mg, e.g., about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or any value or range therebetween, e.g., about 50 to 150 mg, or about 75 to 125 mg, about 75 to 300 mg, about 50 to 250 mg, etc.

43. 43. The transdermal patch of any of claims 20-42, wherein the combined amount of the first pressure-sensitive adhesive and the second pressure-sensitive adhesive is from about 150 mg to about 1800 mg, e.g., about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1400 mg, about 1600 mg, about 1800 mg, or any value or range therebetween, e.g., about 350-600 mg, about 400-650 mg, or about 450-700 mg, about 450-1200 mg, about 350-1000 mg, about 400-1600 mg, etc.

44. 44. The transdermal patch of any one of claims 20 to 43, comprising dextromethorphan as the only active ingredient.

45. Approximately 70cm ２ The transdermal patch of any one of claims 20 to 44, having an active surface area of

46. Approximately 2mg / cm ２ ~Approx. 25mg / cm ２ , e.g., about 2.5 mg / cm ２ , about 3mg / cm ２ , about 4mg / cm ２ , about 5mg / cm ２ , about 6mg / cm ２ , about 7mg / cm ２ , about 8mg / cm ２ , about 9 mg / cm ２ , about 10mg / cm ２ , about 12mg / cm ２ , about 15mg / cm ２ , about 20mg / cm ２ , about 25mg / cm ２ etc., or any value or range therebetween, e.g., about 3 to 10 mg / cm ２ , about 4-7mg / cm ２ , about 5-12mg / cm ２ , about 8-25mg / cm ２ The transdermal patch of any one of claims 20 to 45, having a total dextromethorphan loading of

47. 47. The transdermal patch of any one of claims 20 to 46, comprising the backing layer, the skin-contacting drug-containing adhesive layer, the reservoir layer, and optionally a release liner.

48. The transdermal patch according to any one of claims 20 to 47, which is in the form of a two-layer patch.

49. The transdermal patch has a densitometric value of at least about 200 ug / cm for at least 7 days as measured in vitro using human cadaver skin. ２ / day, e.g., about 200 ug / cm for 7 days or more ２ / day, approximately 300ug / cm ２ / day, approximately 400ug / cm ２ / day, approximately 500ug / cm ２ / day, approximately 600ug / cm ２ / day, approximately 700ug / cm ２ / day, approximately 800ug / cm ２ / day, approximately 1000ug / cm ２ / day, or any value or range therebetween, e.g., about 200-800 ug / cm ２ / day, about 300-800ug / cm ２ / day, approximately 400-800ug / cm ２ / day, about 500-800ug / cm ２ 49. The transdermal patch of any one of claims 20 to 48, having a dextromethorphan flux of 1000 mg / day or more.

50. 49. The transdermal patch of any of claims 20-48, wherein a single application of the transdermal patch to a human subject is capable of transdermally delivering a daily dose of about 15 mg to about 50 mg of dextromethorphan (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any value or range therebetween, such as about 20-50 mg, about 30-50 mg, or about 20-40 mg) to the human subject for at least 7 days.

51. 49. The transdermal patch of any one of claims 20 to 48, wherein a single application of the transdermal patch to a human subject transdermally delivers to the human subject a therapeutically effective daily dose for treating emotional dysregulation for at least seven days.

52. 52. A method of treating a neurological disease or disorder in a subject in need thereof, comprising applying to the subject a transdermal patch according to any one of claims 1 to 51.

53. 53. The method of claim 52, comprising applying the transdermal patch to transdermally deliver a therapeutically effective amount of dextromethorphan to the subject.

54. 53. The method of claim 52, comprising applying the transdermal patch to transdermally deliver to the subject a daily dose of about 15 mg to about 50 mg (e.g., about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or any value or range between said recited values, such as about 20-50 mg, about 30-50 mg, or about 20-40 mg).

55. 55. The method of claim 54, wherein the daily dose is about 35 mg of dextromethorphan.

56. 56. The method of any one of claims 52 to 55, wherein the transdermal patch is applied to the subject with a dosing frequency ranging from once a day to once a week, preferably the transdermal patch is applied to the subject once a week or twice a week.

57. 57. The method of any one of claims 52 to 56, wherein the neurological disease or disorder is emotional dysregulation, depression such as major depressive disorder or treatment-resistant depression, stroke, traumatic brain injury, seizures, pain, methotrexate neurotoxicity, Parkinson's disease, autism, or a combination thereof.

58. 58. The method of claim 57, wherein the neurological disease or disorder is an emotional dysregulation disorder.

59. 59. The method of any one of claims 52 to 58, wherein the subject does not cough and / or does not require antitussive medication.

60. 60. The method of any one of claims 52-59, wherein the subject is characterized as an extensive metabolizer of dextromethorphan.

61. 60. The method of any one of claims 52-59, wherein the subject is characterized as a poor metabolizer of dextromethorphan.

62. 62. The method of any one of claims 52 to 61, wherein the subject is sensitive or intolerant to a CYP2D6 inhibitor.

63. 63. The method of any one of claims 52-62, wherein the subject has one or more side effects associated with quinidine.

64. 64. The method of any one of claims 52 to 63, wherein the subject is co-administered a drug whose metabolism is affected by a CYP2D6 inhibitor.

65. 65. The method of any one of claims 52 to 64, further comprising administering to the subject an antidepressant.

66. 66. The method of claim 65, wherein the antidepressant is selected from bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, metabolites or prodrugs of any of these compounds, and combinations thereof.

67. 67. The method of any one of claims 52 to 66, wherein the subject is not administered quinidine.

68. 68. The method of any one of claims 52 to 67, wherein the subject is a human subject.

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