Transdermal dexmedetomidine for the treatment of agitation

Abstract

The present invention relates to methods of treating agitation using transdermal delivery patches containing dexmedetomidine.

Description

Technical Field

[0001] This application relates to dexmedetomidine for the treatment of agitation. Background Technology

[0002] Acute agitation is a serious, devastating, and distressing complication of many chronic mental illnesses, including dementia. The current standard of care is pharmacological sedation with antipsychotics and / or benzodiazepines (benzodiazepines).

[0003] Igalmi TM (Containing 120 mcg or 180 mg dexmedetomidine, administered sublingually or buccally) is the latest product approved by the US Food and Drug Administration (FDA) for the acute treatment of agitation associated with schizophrenia or bipolar I or II affective disorder in adults. Lower doses are recommended for older individuals (i.e., ≥ 65 years) (120 mcg) or those with hepatic impairment (60–120 mcg depending on the severity of agitation). Igalmi TM The prescription information indicates that if agitation persists after the initial dose, up to two additional doses may be administered at least two hours apart.

[0004] In clinical studies (NCT04268303 and NCT04276883), compared to placebo, in patients treated with 180 mcg and 120 mcg, Igalmi showed improved efficacy two hours after the first dose. TM The mean change from baseline in the total score of the Positive and Negative Syndrome Scale - Excitation Component (PEC) was statistically greater. (This was observed when Igalmi was administered.) TM A decrease in agitation was observed 20-30 minutes later. Igalmi TM The safety and efficacy of the drug have not been determined 24 hours after the first dose.

[0005] Alternative methods for treating and preventing agitation are needed (e.g., methods to preventively minimize or eliminate the frequency and / or severity of agitation in patients with a history of agitation or symptoms characterized by paroxysmal agitation). For said patients (e.g., those with chronic conditions such as Alzheimer's disease), treatment should be safe and have sustained efficacy in reducing the frequency and severity of agitation over a prolonged (e.g., consecutive days) period. Summary of the Invention

[0006] This invention relates to a transdermal delivery patch for providing sustained release of dexmedetomidine for the treatment of agitation.

[0007] In one aspect, methods for treating agitation in individuals in need include applying one or more percutaneous delivery patches to the individual's skin surface while the individual does not exhibit acute agitation at the time of patch application (e.g., an individual who is not agitated at the time of application).

[0008] The transdermal delivery patches include pharmaceutical compositions containing dexmedetomidine; and

[0009] One or more transdermal delivery patches deliver a therapeutically effective, non-sedating dose of dexmedetomidine to an individual.

[0010] In some embodiments, agitation is associated with severe neurocognitive disorders (MNDs) such as Alzheimer's type dementia.

[0011] In some embodiments, one or more transdermal delivery patches remain on an individual's skin surface for a duration of at least 72 hours (e.g., 96 hours).

[0012] In some embodiments, the frequency or severity of agitation decreases after application of one or more transdermal delivery patches and maintenance on the skin surface for at least 72 hours (e.g., 96 hours). In some embodiments, the reduction in the frequency or severity of agitated behavior is determined by changes (i.e., modifications) in one or more of the following scales used to measure agitation:

[0013] Agitation Behavior Scale (ABS)

[0014] The Cohen-Mansfeld Agitation Inventory (CMAI)

[0015] Clinical overall impression (severity CGI-S) and changes (CGI-C),

[0016] Neuropsychiatric Questionnaire - Sanatorium Version (NPI-NH) and

[0017] Paroxysmal Agitation Scale - Sanatorium Version (EAS-NH).

[0018] In some embodiments, one or more transdermal delivery patches provide an individual with a reduction in agitation and non-sedation. Attached Figure Description

[0019] These and other features, aspects, and advantages of the invention will be better understood with reference to the following description and accompanying drawings, wherein:

[0020] Figure 1A - 1C shows a view of an exemplary transdermal delivery patch of the present invention. Figure 1A Showing top and side views of an example transdermal delivery patch. Figure 1B Example of a 6 cm2 Top view and dimensions of the transdermal delivery patch (dimensions are in inches). Figure 1C Example of a 9 cm 2 and 12 cm 2 Top view and dimensions of the transdermal delivery patch (dimensions are shown in inches). For Figure 1B and Figure 1C The image on the left shows the dimensions of the transdermal delivery patch. The inner square with rounded corners corresponds to the adhesive transdermal delivery patch. The larger, outer square corresponds to the release liner size. The image on the right shows the dimensions of the transdermal delivery patch package.

[0021] Figure 2 The timeline of events for the clinical trial shown in Example 2 is provided, where a day is defined as a 24-hour interval relative to the time of administration of the DMTS / matched placebo system.

[0022] Figure 3 The timeline of agitation assessment in the clinical trial of Example 2 is shown. Detailed Implementation

[0023] 4.1 Definition

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention applies.

[0025] Those skilled in the art will understand that, generally, the terms used herein and especially in the appended claims (e.g., the body of the appended claims) are intended to be “open-ended” terms (e.g., the term “including” should be interpreted as “including (but not limited to)”, the term “having” should be interpreted as “at least having”, the term “include” should be interpreted as “including (but not limited to)”, etc.). Those skilled in the art will further understand that if there is an intention to state a particular number in an introductory claim, then that intention will be explicitly stated in the claim, and without such a statement, that intention does not exist. For example, as an aid to understanding, the appended claims may contain the introductory phrases “at least one” and “one or more” to describe the claim statement. However, the use of such phrases should not be construed as implying that a claim statement introduced by the indefinite article "a (a / an)" limits any particular claim containing the introduced claim statement to an embodiment containing only one of the stated statements, even when the same claim contains the introductory phrases "a or more" or "at least one" and indefinite articles such as "a (a / an)" (e.g., "a (a and / or an)" should generally be interpreted as meaning "at least one" or "a or more"); the same applies to the use of definite articles used to introduce claim statements. Furthermore, even when a specific number of introduced claim statements is explicitly listed, those skilled in the art will recognize that the statements should generally be interpreted as meaning at least the listed number (e.g., the explicit statement "two statements" (without other modifiers) means at least two statements, or two or more statements). Furthermore, in examples where a convention similar to "at least one of A, B, and C" is used, generally, the construction is intended to mean that a person skilled in the art will understand the meaning of the convention (e.g., "a system having at least one of A, B, and C" would include (but is not limited to) systems having only A, only B, only C, both A and B, both A and C, both B and C, and / or both A, B, and C). In examples where a convention similar to "at least one of A, B, or C" is used, generally, the construction is intended to mean that a person skilled in the art will understand the meaning of the convention (e.g., "a system having at least one of A, B, or C" would include (but is not limited to) systems having only A, only B, only C, both A and B, both A and C, both B and C, and / or both A, B, and C). Those skilled in the art should further understand that any transition word and / or phrase (whether in the specification, claims or drawings) that substantially represents two or more alternative terms should be understood to cover the possibility of including one, any, or both of the terms.For example, the phrase “A or B” should be understood as including the possibility of “A” or “B” or “A and B”.

[0026] Furthermore, when the features or aspects of the invention are described in accordance with the Markush group, those skilled in the art will recognize that the invention is also described in accordance with any individual member or subgroup of the Markush group.

[0027] As those skilled in the art will understand, for any and all purposes, such as for providing a written description, all scopes disclosed herein also encompass any and all possible subscopes and combinations thereof. Any listed scope can be readily recognized as sufficient to describe the same scope and to make it possible to divide it into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope discussed herein can be readily divided into a lower third, a middle third, and an upper third, etc. As those skilled in the art will also understand, all language such as “at most,” “at least,” “greater than,” “less than,” and the like includes the cited quantity and refers to a scope that can subsequently be divided into subscopes as discussed above. Finally, as those skilled in the art will understand, a scope includes each individual member. Thus, for example, a group having 1-3 objects means a group having 1, 2, or 3 objects. Similarly, a group having 1-5 objects means a group having 1, 2, 3, 4, or 5 objects, etc.

[0028] As used in this article, "dexmedetomidine" refers to the S-enantiomer of medetomidine:

[0029]

[0030] Or pharmaceutically acceptable salts, hydrates, or complexes of dexmedetomidine. Dexmedetomidine may be in the form of pharmaceutically acceptable salts (including, but not limited to, methanesulfonates, maleates, fumarates, tartrates, hydrochlorides, hydrobromic acid salts, p-toluenesulfonates, benzoates, acetates, phosphates, or sulfates). In some embodiments, "dexmedetomidine" refers to the hydrochloride salt of dexmedetomidine, namely, (+)4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazolium monohydrochloride.

[0031] Dexmedetomidine is a relatively selective α2-adrenergic agonist. Dexmedetomidine is the S-enantiomer of medetomidine. Precedex® (dexmedetomidine hydrochloride) is FDA approved for (1) sedation of patients initially intubated and mechanically ventilated during treatment in the intensive care unit and (2) sedation of non-intubated patients before and / or during surgery and other procedures. Precedex® is administered by continuous infusion.

[0032] As used in this article, “dose interval” refers to the period of time during which the dexmedetomidine transdermal delivery patch described herein remains in contact with the individual’s skin surface.

[0033] As used herein, “non-sedative” refers to a dose of dexmedetomidine that does not induce complete sedation in an individual. Appropriate protocols for determining sedation levels may include (but are not limited to) the Ramsay Sedation Scale, the Vancouver Sedative Recovery Scale, the Glasgow Coma Scale modified by Cook and Palma, the Comfort Scale, the New Sheffield Sedation Scale, the Sedation-Agitation Scale, the Motor Activity Assessment Scale, and the Wilson Sedation Score. In some embodiments, the Wilson Sedation Score is used to assess sedation levels; details of this can be found at the URL obtained by entering http: / / www.sedationsolutions.co.uk / training-series6.php before “sedationsolutions.co.uk / training-series6.php” and below:

[0034] Wilson's calming rating:

[0035] 1. Fully awake and oriented

[0036] 2. Drowsiness

[0037] 3. Close your eyes but obey commands.

[0038] 4. Eyes closed, but can respond to gentle physical stimulation (earlobe tugging).

[0039] 5. Eyes closed but no response to mild physical stimuli.

[0040] As used herein, “individual” means a human or organism to which a transdermal delivery patch is applied. Therefore, the individual of this invention may include (but is not limited to) mammals (e.g., humans and other primates (e.g., chimpanzees and other ape and monkey species) and the like), wherein in some embodiments the individual is human. The term individual is also intended to include any human or organism of any age, weight, or other physical characteristic, wherein the individual may be an adult, adolescent, child, infant, or newborn.

[0041] As used herein, “transdermal” refers to a route of administration in which the active agent (i.e., the drug) is delivered systemically through the skin (e.g., local administration) or mucous membranes. Therefore, the transdermal delivery patches described herein are formulated to deliver dexmedetomidine to an individual through one or more of the subcutaneous tissue, dermis, and epidermis (including the stratum corneum, stratum germinativum, stratum spinosum, and stratum basale). Thus, transdermal delivery patches can be applied to any convenient location (e.g., arm, lower leg, thigh, hip, buttock, abdomen, back, neck, scrotum, vagina, face, forehead, and behind the ear).

[0042] As used in this article, “treating” refers to suppressing or improving symptoms associated with a condition troubling an individual, where suppression and improvement, in a broad sense, means at least reducing the magnitude of parameters (e.g., symptoms) associated with the treated condition (e.g., postoperative pain). Therefore, treatment also includes the complete suppression (e.g., prevention of occurrence) or cessation (e.g., termination) of the condition, so that the individual no longer experiences the condition. Thus, treatment encompasses both prevention and management of the condition.

[0043] As used in this article, “severe neurocognitive disorder” (MND) is a type of brain disorder characterized by a significant decline in at least one of the cognitive domains (including executive function, complex attention, language, learning, memory, perceptual-motor, or social cognition). The decline represents a persistent and progressive change in the patient’s previous cognitive abilities over time, and is not solely associated with delirium episodes. In addition to cognitive decline, the patient’s function and ability to perform daily tasks must also decline. Daily functioning is typically assessed based on the ability to perform IADL (instrumental activities of daily living) (e.g., managing assets or medication) or (if more severe) ADL (activities of daily living) (e.g., grooming or feeding oneself). It is usually a progressive disorder, and individuals often cannot fully understand their deficits.

[0044] MND was previously referred to as "dementia," but due to its limitations (i.e., it was generally associated only with older patients and was often used synonymously with Alzheimer's disease), the definition was updated in DSM-5. However, MND can affect young individuals and does not always imply that Alzheimer's disease is the cause of cognitive decline.

[0045] As used herein, the term "agitation" refers to irritability, emotional outbursts, thought disorders, or excessive motor and verbal activity that can occur due to dysfunction of specific brain regions (e.g., the frontal lobe) or due to dysfunction of neurotransmitter systems (e.g., dopamine and norepinephrine). In this invention, agitation also includes aggression and hypervigilance, rejection behavior, and restlessness. Agitation can be acute, chronic, or paroxysmal.

[0046] As used herein, the term "effective dose" is used interchangeably with "therapeutic effective dose" or "therapeutic effective dose" and refers to a dose sufficient to produce the desired effect. An effective dose is sufficient to induce a reduction in an individual's symptoms (e.g., agitation).

[0047] As used herein, the term “signs of agitation” includes excessive physical activity (e.g., pacing, swaying, gesturing, pointing, agitation, performing repetitive habits), verbal aggression (e.g., shouting, speaking loudly, using profane language, screaming, yelling, threatening others), physical aggression (e.g., grabbing, pushing, shoving, clenching fists, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting oneself, slamming doors, tearing things, damaging property), and resistance to care (refusing care, constantly demanding attention, being obstinate, not following instructions).

[0048] As used in this article, the term “irritable episode” refers to an acute onset of agitation, typically characterized by signs of agitation (e.g., agitated speech, restlessness, self-harm, harm to others or objects, or resistance to care).

[0049] As used in this article, the term “non-aggressive” means the absence of acute signs of agitation as described in this article.

[0050] As used herein, the terms “irritability susceptibility” and “irritability predisposition” refer to a combination of genetic, environmental, and developmental factors that can influence an individual’s behavior and mental health. In the context of this invention, “irritability susceptibility” refers to a genetic or psychological predisposition to certain behaviors characterized by signs of agitation.

[0051] As used in this article, the term "history of agitation" refers to a previously documented occurrence of signs or episodes of agitation. Individuals diagnosed with certain medical conditions (such as MND, traumatic brain injury, delirium, schizophrenia, bipolar disorder) typically have a history of agitation.

[0052] As used herein, the term “reduction” refers to a reduced level compared to a control. For example, in agitated situations, those skilled in the art will readily understand that the reduction can be measured using well-known agitation scales such as the Agitation Behavior Scale (ABS), the Cohen-Mansfield Agitation Inventory (CMAI), the Neuropsychiatric Questionnaire-Nursing Home Version (NPI-NH), the Paroxysmal Agitation Scale-Nursing Home Version (EAS-NH), and the PEC score (derived from the excitatory component of the Positive and Negative Syndrome Scales).

[0053] As used herein, the term “adverse reaction” (AE) is an AE caused by a drug or device. Adverse reactions are a subgroup of all suspected adverse reactions (those to which there is reason to conclude that the drug or device caused the event). A suspected adverse reaction is any AE for which the drug has a reasonable probability of causing the AE. For the purpose of reporting safety in an IND application, “reasonable probability” means that there is evidence of a causal relationship between the drug and the AE. Compared to an adverse reaction, a suspected adverse reaction implies a lower degree of certainty of causation. If an AE or suspected adverse reaction is not listed in the investigator’s brochure or is not listed in terms of observed specificity or severity, then the AE or suspected adverse reaction is considered unexpected; or if an investigator’s brochure is not required or available, then it is inconsistent with the risk information presented elsewhere in the general study plan or current administration (as amended). As used in this definition, unexpected also refers to an AE or suspected adverse reaction that occurs with a class of drugs as mentioned in the investigator’s brochure or that is expected according to the pharmacological properties of the drug but not explicitly mentioned in relation to the specific drug in the study.

[0054] As used herein, the term "flux" refers to the rate of penetration of the active agent through an individual's skin or mucous membranes after transdermal administration. In some cases, the flux of dexmedetomidine can be determined using the following equation:

[0055] J 皮肤通量 = P × C,

[0056] Where J is skin flux, C is the concentration gradient through the skin or mucous membrane, and P is the permeability coefficient. Skin flux is the change in the cumulative amount of drug entering the body through the skin or mucous membrane over time.

[0057] 4.2 Methods for treating agitation

[0058] In one aspect, the present invention provides a method for treating agitation in an individual.

[0059] In some embodiments, agitation is associated with an individual's severe neurocognitive disorder (MND). MND refers to a type of brain disorder characterized by a significant decline in at least one of the cognitive domains (including executive function, complex attention, language, learning, memory, perceptomotor, or social cognition). In some embodiments, MND is selected from neurocognitive disorder (NCD) caused by Alzheimer's disease, vascular NCD, Lewy body NCD, NCD caused by Parkinson's disease, frontotemporal NCD, NCD caused by traumatic brain injury, NCD caused by HIV infection, substance / drug-induced NCD, NCD caused by Huntington's disease, NCD caused by prion disease, NCD caused by medical conditions, NCD caused by multiple etiologies, and NCD caused by unknown etiologies.

[0060] In some embodiments, the MND is an NCD caused by Alzheimer's disease. In some embodiments, the MND is dementia (e.g., Alzheimer's type dementia). In some embodiments, the MND is an NCD caused by Alzheimer's disease. In some embodiments, the MND is dementia (e.g., Alzheimer's type dementia). A person skilled in the art may, for example, diagnose a possible Alzheimer's type dementia based on the National Institute on Aging and the Alzheimer's Association (NIA-AA) guidelines (2018). In some embodiments, an individual is diagnosed with possible Alzheimer's type dementia.

[0061] In some embodiments, the individual is prone to agitation. In some embodiments, the individual has a history of agitation.

[0062] In some embodiments, the individual is not hospitalized. In other embodiments, the individual is hospitalized.

[0063] In some embodiments, the individual resides in a care facility. In some embodiments, the care facility is a retirement community. In some embodiments, the care facility is medical foster care. In some embodiments, the care facility is a nursing home. In some embodiments, the care facility is a memory care unit. In some embodiments, the care facility is an adult family residence.

[0064] In some embodiments, the individual is at least 5 years old (e.g., at least 10 years old, at least 15 years old, at least 20 years old, at least 25 years old, at least 30 years old, at least 35 years old, at least 40 years old, at least 45 years old, at least 50 years old, at least 55 years old, at least 60 years old, at least 65 years old, at least 70 years old, at least 75 years old, at least 80 years old, or at least 85 years old). In some embodiments, the individual has a weight greater than 50 kg (e.g., greater than 55 kg, greater than 60 kg, greater than 65 kg, greater than 70 kg, greater than 75 kg, or greater than 80 kg).

[0065] In some embodiments, prior to the application of one or more transdermal patches, the individual experienced two or more agitated episodes (e.g., three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) during a 7-day review period. As used herein, agitated episodes can impair social activity, may require medical intervention, or may impair the ability to perform daily living activities.

[0066] In some embodiments, prior to the application of one or more transdermal patches, the individual experienced two or more agitated episodes (e.g., three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) during a 14-day review period. As used herein, agitated episodes can impair social activity, may require medical intervention, or may impair the ability to perform daily living activities.

[0067] In some embodiments, within 4 days prior to the application of one or more transdermal delivery patches, the individual had an ABS score of at least 22 at at least one evaluation.

[0068] In some embodiments, agitation can impair social functioning, where the individual exhibits signs of verbal aggression (e.g., shouting, speaking loudly, using profane language, screaming, yelling, and / or threatening others). In some embodiments, agitation may require medical intervention, such as if the individual exhibits signs of physical aggression (e.g., grabbing, pushing, shoving, clenching fists, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting oneself, slamming doors, tearing things) and property damage. In some embodiments, agitation can impair an individual's ability to perform functional activities of daily living, where the individual exhibits signs of excessive motor activity (e.g., pacing, swaying, gesturing, pointing, agitation, performing repetitive habits). In some embodiments, agitation can disrupt the delivery of medical care and / or functional activities of daily living, where the individual exhibits high resistance (e.g., refusing care, having difficulty, repeatedly demanding attention, not following instructions).

[0069] In some embodiments, individuals have an estimated glomerular filtration rate (eGFR) that is above the lower limit of the age- and sex-specific ranges provided in Table 11.

[0070] In some embodiments, a method of treating agitation includes applying one or more percutaneously delivered patches to the skin surface of an individual who is not agitated at the time of application. In some embodiments, a method of treating agitation includes applying one or more percutaneously delivered patches to the skin surface of an individual who does not exhibit signs of acute agitation. The percutaneously delivered patches comprise a pharmaceutical composition containing dexmedetomidine. In some embodiments, the patch remains on the patient's skin surface for at least 72 hours (e.g., at least 84 hours, at least 96 hours, or up to 120 hours). In some embodiments, one or more percutaneously delivered patches deliver a therapeutically effective, non-sedating dose of dexmedetomidine to the individual sufficient to treat the individual's agitation.

[0071] In some embodiments, one or more transdermal delivery patches are applied by the individual himself / herself. In some embodiments, one or more transdermal delivery patches are applied by someone other than the individual (e.g., a caregiver, nurse, or physician).

[0072] One or more transdermal delivery patches are applied to the skin surface of an individual. In some embodiments, the skin surface is not within the reach of the individual's manual touch.

[0073] In some embodiments, the skin surface is selected from the arms, lower legs, thighs, hips, buttocks, abdomen, back, neck, scrotum, vagina, face, forehead, and behind the ears. In some embodiments, the skin surface is the upper or lower back of an individual.

[0074] In some embodiments, one or more transdermal delivery patches remain on an individual's skin surface for a duration of at least 72 hours (e.g., at least 80 hours, at least 90 hours, at least 96 hours, or at least 100 hours). As used herein, "maintain" means that at least 90% of the one or more transdermal delivery patches remain in contact with the individual's skin surface. For example, one or more transdermal delivery patches cannot be removed or otherwise damaged to ensure at least 90% contact between the one or more transdermal delivery patches and the skin surface. In some embodiments, for proper maintenance, the individual should avoid activities that could lead to excessive sweating when applying one or more transdermal delivery patches to the skin surface. In some embodiments, the individual may shower up to once per day.

[0075] In some embodiments, one or more transdermal delivery patches remain on an individual's skin surface for 72 to 100 hours (e.g., 72 to 96 hours, 72 to 70 hours, 72 to 80 hours, 80 to 100 hours, 80 to 96 hours, 80 to 90 hours, 90 to 100 hours, 90 to 96 hours, or 96 to 100 hours). In some embodiments, one or more transdermal delivery patches remain on an individual's skin surface for 2 to 6 days (e.g., 2 to 5 days, 2 to 4 days, 2 to 3 days, 3 to 6 days, 3 to 5 days, 3 to 4 days, 4 to 6 days, or 4 to 5 days). In some embodiments, one or more transdermal delivery patches remain on an individual's skin surface for 4 days. In some embodiments, one or more transdermal delivery patches remain on an individual's skin surface for 96 hours ± 3 hours.

[0076] In some embodiments, the method further includes removing one or more transdermal delivery patches from the individual's skin surface. In some embodiments, the one or more transdermal delivery patches are removed by the individual. In some embodiments, the one or more transdermal delivery patches are removed by someone other than the individual.

[0077] In some embodiments, the method further includes applying one or more additional transdermal delivery patches to the individual's skin surface.

[0078] In some embodiments, the individual has an ABS score of ≥ 22 at least once after the removal of one or more transdermal delivery patches and before the application of another one or more transdermal delivery patches to the individual's skin surface.

[0079] In some embodiments, one or more additional transdermal delivery patches are applied at least 10 days (e.g., at least 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 days) after the previous application of one or more transdermal delivery patches to the individual's skin. In some embodiments, one or more additional transdermal delivery patches are applied at least 14 days after the previous application of one or more transdermal delivery patches to the individual's skin. In some embodiments, one or more additional transdermal delivery patches are applied 14 days after the previous application of one or more transdermal delivery patches to the individual's skin.

[0080] In some embodiments, one or more additional transdermal delivery patches remain on the individual's skin surface for a duration of at least 72 hours (e.g., at least 84 hours, at least 96 hours, at least 108 hours, at least 120 hours, or at least 132 hours). In some embodiments, one or more additional transdermal delivery patches remain on the individual's skin surface for a duration of at least 96 hours. In some embodiments, one or more additional transdermal delivery patches remain on the individual's skin surface for 84 to 108 hours, for example, 90 to 100 hours. In some embodiments, one or more additional transdermal delivery patches remain on the individual's skin surface for 96 hours. In some embodiments, one or more additional transdermal delivery patches remain on the individual's skin surface for 4 days. In some embodiments, one or more additional transdermal delivery patches remain on the individual's skin surface for 96 hours ± 3 hours.

[0081] In some embodiments, the method further includes removing one or more (e.g., two or more, three or more, four or more, or five or more) transdermal delivery patches from the individual's skin surface.

[0082] In some embodiments, the Folstein Mini-Mental State Exam (MMSE) is used to assess an individual's cognitive function to characterize the severity of Alzheimer's disease and evaluate treatment-related cognitive changes. The Folstein MMSE is a standard mental state test commonly used to assess cognition. Domains measured by the MMSE include orientation to time and place, roll call, attention and calculation, memory, naming, repetition, comprehension, reading, writing, and drawing. The maximum total score for this test is 30. In some embodiments, when administered on one day out of seven days prior to the application of one or more transdermal patches, the individual has an MMSE score greater than 20 (e.g., greater than 21, 22, 23, 24, or 25). In some embodiments, when administered on one day out of seven days prior to the application of one or more transdermal patches, the individual has an MMSE score greater than 23. In some embodiments, the MMSE may be administered on one day out of seven days prior to the application of one or more transdermal patches and again at the end of the study. In some embodiments, an individual’s MMSE score improved after treatment with one or more transdermal delivery patches.

[0083] In some embodiments, the Johns Hopkins Fall Risk Assessment Score is used to evaluate an individual's cognitive function to characterize the severity of Alzheimer's disease and assess treatment-related cognitive changes. In some embodiments, individuals exhibit a Johns Hopkins Fall Risk Assessment Score greater than 10 (e.g., greater than 11, 12, 13, 14, or 15).

[0084] In some embodiments, as described herein, the frequency or severity of an individual's agitation decreases after one or more transdermal delivery patches or other transdermal delivery patches are applied to and maintained on the skin surface.

[0085] In some embodiments, a reduction in the frequency or severity of agitated behavior is determined by changes in one or more of the following scales:

[0086] Agitation Behavior Scale (ABS)

[0087] The Cohen-Mansfeld Agitation Inventory (CMAI)

[0088] Clinical overall impression (severity CGI-S) and changes (CGI-C),

[0089] Neuropsychiatric Questionnaire - Sanatorium Version (NPI-NH), and

[0090] Paroxysmal Agitation Scale - Sanatorium Version (EAS-NH).

[0091] In some embodiments, the Agitation Behavior Scale (ABS) is used to assess agitated behaviors. The ABS is particularly useful for continuous assessment to evaluate interventions designed to reduce agitation. The ABS is a 14-item scale developed to objectively assess agitated behaviors, particularly for continuous assessment to evaluate interventions designed to reduce agitation. ABS items include: short attention span, easily distracted, inability to concentrate, impulsivity, impatience, low tolerance for pain or frustration, uncooperativeness, resistance to care or requests, strong and / or threatening violence against people or property, explosive or unpredictable anger, shaking, rubbing, groaning or other self-stimulatory behaviors, pulling on tubes or restraints, leaving the treatment area, restlessness, pacing or hyperactivity, repetitive behaviors (motor and / or verbal), rapid, loud or excessive talking, sudden mood swings, provoking or excessive crying and / or laughing, and self-harm (physical and / or verbal).

[0092] Use the following scales to assess behavior:

[0093] 1. Does not exist: The behavior does not exist.

[0094] 2. Mild presentation: The aforementioned behavior exists, but does not prevent the performance of appropriate behaviors in other situations (the individual can adjust on their own, or the persistent agitated behavior does not interfere with appropriate behavior).

[0095] 3. Moderate presentation: Individuals need to shift from an agitated state to appropriate behavior, but can benefit from the aforementioned cues.

[0096] 4. Extreme presentation: Individuals are unable to engage in appropriate behavior due to agitation, even when given external cues or redirection.

[0097] The total ABS score ranges from 14 to 56. A total score of 21 or below is classified as normal; 22 to 28 as mild; 29 to 35 as moderate; and 36 or above as severe agitation.

[0098] In some embodiments, treatment with one or more percutaneous delivery patches can improve an individual's ABS classification from severely altered (i.e., improved) to moderate, severely altered (i.e., improved) to mild, or severely altered (i.e., improved) to normal. In some embodiments, treatment with one or more percutaneous delivery patches can reduce an individual's ABS score from severely to moderate, from moderate to mild, or from mild to normal. In some embodiments, treatment with one or more percutaneous delivery patches can reduce an individual's ABS score from severely to mild, from severely to normal, or from moderate to normal.

[0099] In some embodiments, a reduction in the frequency or severity of agitation is determined by the change in the ABS score over time after treatment with one or more percutaneous delivery patches compared to a baseline ABS score prior to application of one or more percutaneous delivery patches. In some embodiments, an individual's baseline ABS score is the average score of daily ABS measurements taken 4 days prior to application of one or more percutaneous delivery patches (i.e., day -4 to day -1). In some embodiments, an individual has an ABS score of at least 22 at at least one evaluation within 4 days prior to application of one or more percutaneous delivery patches. In some embodiments, an individual has an ABS score of at least 22 at at least one evaluation within 4 days prior to application of another one or more percutaneous delivery patches. In some embodiments, an individual's ABS score is measured daily for 1–14 days after application and maintenance of one or more percutaneous delivery patches on the individual's skin surface. In some embodiments, an individual's ABS score is evaluated 96 hours after application and maintenance of one or more percutaneous delivery patches on the individual's skin surface (e.g., on the morning of day 5 of the treatment period).

[0100] In some embodiments, an individual’s ABS score was lower than the individual’s baseline ABS score 96 hours after application and maintenance of one or more transdermal delivery patches on the skin surface.

[0101] In some embodiments, after applying one or more transdermal delivery patches to the skin surface and maintaining the patch for 4 days, the individual's ABS score was lower than the individual's baseline ABS score at 168 hours.

[0102] In some embodiments, the NPI-NH is used to assess dementia-related behavioral symptoms (including Alzheimer's disease). Based on a series of scripted questions posed to the patient's caregiver, the NPI-NH assesses the severity and frequency of each neuropsychiatric symptom and the degree of distress caused to the caregiver / research partner by each neuropsychiatric symptom. The scale is administered by a certified clinician, with the patient's caregiver acting as the information provider. Follow-up questions are asked based on positive responses to screening questions, and yes / no responses are recorded. Frequency and severity are assessed based on the most aberrant behavior revealed in the follow-up questions. After determining frequency and severity, the information provider is asked to rate the level of disruption of the behavior. After determining frequency and severity, the caregiver is asked to rate the level of disruption of the behavior.

[0103] In some embodiments, a reduction in the frequency or severity of agitation is determined by a time-varying NPI-NH score after treatment with one or more percutaneous delivery patches being lower than a baseline NPI-NH score measured before application of one or more percutaneous delivery patches. In some embodiments, an individual's baseline NPI-NH score is assessed on the same day as and before application of one or more percutaneous delivery patches to the individual's skin surface (e.g., 30 minutes to 12 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or 11 hours before application of one or more percutaneous delivery patches). In some embodiments, an individual's NPI-NH score is assessed after application of one or more percutaneous delivery patches to the individual's skin surface and maintenance for 4 days (e.g., after application and maintenance for at least 4 days (e.g., 4 to 9 days, including 5, 6, 7, 8, or 9 days, especially 7 days)).

[0104] In some embodiments, an individual's NPI-NH is evaluated using a 7-day retrospective period (e.g., day -7 to day -1 for baseline NPI-NH treatment or day 1 to day 7 for NPI-NH treatment).

[0105] frequency:

[0106] 1. Rarely - less than once a week

[0107] 2. Sometimes - about once a week

[0108] 3. Frequently - several times a week but less than daily

[0109] 4. Very frequently - once or more per day

[0110] Severity:

[0111] 1. Mild-onset behavior causes stress to resident physicians but is manageable.

[0112] 2. Moderate-level behavior causes stress and distress to resident physicians and is difficult to control.

[0113] 3. Severe agitation causes immense stress and distress to resident physicians and is extremely difficult or impossible to manage. There is a possibility of self-harm, and medication is usually required.

[0114] Occupational disruption:

[0115] 0. No effect

[0116] 1. Minimal (daily work remains almost unchanged)

[0117] 2. Mild (some changes in daily operations but requiring a little time to revise the budget)

[0118] 3. Moderate (disruption of daily operations, requires time to revise the budget)

[0119] 4. Severe (causing disruptive impact and distress to staff and other resident physicians, consuming a significant amount of time)

[0120] 5. Extremely severe or extremely severe (highly destructive, a major source of distress for staff and other residents, often requiring time to be devoted to other residents or activities).

[0121] In some embodiments, an individual's NPI-NH score was lower than their baseline NPI-NH score 168 hours after application of one or more percutaneous delivery patches to the individual's skin surface and maintenance for 4 days (i.e., day 8 of the treatment period). In some embodiments, both NPI-NH scores were evaluated using a 7-day review period.

[0122] In some embodiments, the Cohen-Mansfield Agitation Questionnaire (CMAI) is used to assess agitation. The CMAI is a 29-item scale designed to systematically assess agitation. It is used to assess the frequency of physical aggression, non-physical aggression, and verbal agitation in older adults with limited self-care abilities. The CMAI is applied using a 14-day review, where the frequency of each item over the 14-day interval is assessed based on the following 7-point scale:

[0123] 1. Never

[0124] 2. Less than once a week

[0125] 3. Once or twice a week

[0126] 4. Several times a week

[0127] 5. Once or twice a day

[0128] 6. Several times a day

[0129] 7. Several times per hour

[0130] CMAI is performed by an accredited assessor through a formal interview with the information provider. The information provider is a staff member of the institution or premises who has at least 2 hours of cumulative daily contact with the individual and directly observes the individual's behavior at least 3 days a week.

[0131] In some embodiments, the CMAI baseline score is based on a 14-day review period prior to the application of one or more transdermal delivery patches to the individual's skin surface. In some embodiments, the CMAI follow-up score is obtained 15 days after the application of one or more transdermal delivery patches to the individual's skin surface. In some embodiments, the total CMAI score 15 days after the application of one or more transdermal delivery patches to the individual's skin surface and maintenance for 4 days (i.e., 96 hours) is less than the individual's baseline total CMAI score.

[0132] In some embodiments, the EAS-NH is used to assess the frequency and severity of agitation daily. In some embodiments, a decrease in the frequency or severity of agitation is determined by a decrease in the EAS-NH score over time. In some embodiments, the initial EAS-NH score is assessed daily at every 24-hour interval for 7 days prior to the application of one or more transdermal delivery patches. In some embodiments, subsequent EAS-NH scores are assessed at every 24-hour interval following the application of one or more transdermal delivery patches to the individual's skin surface (e.g., at 24, 48, 72, 96, 120, 168, 192, 216, 240, 264, 288, or 336 hours after application).

[0133] In some embodiments, after applying one or more transdermal delivery patches to an individual's skin surface and maintaining them for 4 days (i.e., 96 hours), the individual's EAS-NH score at one or more of the following time points was lower than the baseline EAS-NH score of the individual evaluated before the application of one or more transdermal delivery patches: 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 168 hours, 192 hours, 216 hours, 240 hours, 264 hours, 288 hours, or 336 hours after application.

[0134] In some embodiments, the Clinical Global Impression-Severity (CGI-S) scale is used to assess clinicians' impressions of the severity of an individual's agitation. The CGI-S scale is a graded scale based on the clinician's assessment of clinical severity. The review period for CGI-S scores obtained at screening is based on 4-day and 7-day periods prior to the application of one or more percutaneous delivery patches. The CGI-S is a 7-point (1-7) clinician-rated scale, where higher grades indicate greater severity of agitation. In some embodiments, an individual's CGI-S score after treatment with one or more percutaneous delivery patches is lower than the baseline CGI-S score measured before the application of one or more percutaneous delivery patches. In some embodiments, the individual's baseline CGI-S score is assessed on the same day but prior to the application of one or more percutaneous delivery patches to the individual's skin surface. In some embodiments, an individual’s CGI-S score is evaluated at 96, 120, 144 and / or 168 hours after application of one or more transdermal delivery patches, wherein the one or more transdermal delivery patches remain on the individual’s skin surface for 4 days.

[0135] In some embodiments, the Clinical Global Impression-Change (CGI-C) is used to assess clinicians’ impressions of changes in an individual’s agitation. CGI=C is a graded scale based on the clinician’s judgment of the change in agitation level. The CGI-C score is derived from a 7-point (1-7) rating scale, where changes in agitation (improvement or deterioration) are rated as no change, mild change, moderate change, or significant change. In some embodiments, the CGI-C score shows improvement (e.g., a grade of mild, moderate, or significant improvement compared to a specified review period) after treatment with one or more percutaneous delivery patches. In some embodiments, the CGI-C score is assessed at 96, 120, 144, and / or 168 hours after application of one or more percutaneous delivery patches, wherein the one or more percutaneous delivery patches remain on the individual’s skin surface for 4 days.

[0136] In some embodiments, one or more percutaneous delivery patches deliver a therapeutically effective non-sedating dose of dexmedetomidine to an individual for at least two, three, or four days. As used herein, “non-sedating” means an amount of dexmedetomidine that does not induce complete sedation in the individual. Suitable protocols for determining sedation levels may include (but are not limited to) the Ramsey Sedation Scale, the Vancouver Sedation Recovery Scale, the Glasgow Coma Scale modified by Cook and Palma, the Comfort Scale, the New Sheffield Sedation Scale, the Sedation-Agitation Scale, the Muscle Activity Assessment Scale, and the Wilson Sedation Score. In some embodiments, the Wilson Sedation Scale is used to assess sedation levels.

[0137] In some embodiments, one or more percutaneous delivery patches deliver a non-sedating amount of dexmedetomidine to an individual, as measured by, for example, the Wilson sedation score. In some embodiments, the individual's Wilson sedation score does not exceed 3 postoperatively when the percutaneous delivery patch adheres to the individual's skin surface for at least 96 hours postoperatively. In some embodiments, the individual's Wilson sedation score is less than 3 (e.g., 2 or 1). In some embodiments, the individual's Wilson sedation score is 1. In some embodiments, one or more percutaneous delivery patches or a percutaneous delivery patch system delivers a non-sedating amount of dexmedetomidine to the individual.

[0138] The flux of an active agent administered transdermally is the rate at which the active agent penetrates through an individual's skin or mucous membranes. In some cases, the flux of dexmedetomidine can be determined using the following equation:

[0139] J 皮肤通量 = P × C

[0140] Where J represents skin flux.

[0141] C represents the concentration gradient across the skin or mucous membranes; and

[0142] P is the permeability coefficient.

[0143] Skin flux is the change over time in the amount of drug accumulated per unit area (i.e., square centimeters) across the skin, other suitable skin sources (such as skin obtained during abdominoplasty procedures), or mucous membranes.

[0144] The transdermal dexmedetomidine flux can be determined using any convenient protocol (e.g., a protocol using human cadaver skin with the epidermal layers (stratum corneum and live epidermis) sandwiched between the donor and recipient sides in a Franzcell and a recipient solution containing phosphate buffer). In one example protocol, human cadaver skin is used, and the epidermal layers (stratum corneum and live epidermis) are separated from the full-thickness skin as a skin membrane. The sample is die-cut to approximately 2.0 cm using an arched punch. 2The final diameter was determined. The release paper of the percutaneous delivery patch was removed, and the adhesive surface was adhered to the top of the epidermis / stratum corneum, with the dexmedetomidine adhesive surface facing the outer surface of the stratum corneum. Slight pressure was applied to achieve good contact between the adhesive layer and the stratum corneum. The donor and acceptor sides of the Franz cell were sandwiched together, and a acceptor solution containing phosphate buffer at pH 6.5 and 0.01% gentamicin was added to the longitudinal diffusion cell. The cell was maintained at 32°C–35°C during the experiment. Samples of the acceptor solution were obtained at regular intervals, and the active agent concentration was measured by HPLC. Fresh solution was used instead of the removed acceptor solution to maintain the cell's condition. The flux was calculated from the slope of a plot of the cumulative amount of drug permeating into the acceptor chamber against time.

[0145] In some embodiments, at any time after one or more patches have been applied to the skin surface and contact between the skin surface and the one or more patches has been maintained (e.g., 24, 48, 72, 96, or 120 hours after application), one or more transdermal delivery patches provide 0.005 to 5 μg / cm³. 2 / hr of dexmedetomidine in vitro average flux.

[0146] In some embodiments, at any time after the application of one or more patches and maintenance of contact between the skin surface and the one or more patches (e.g., 24, 48, 72, 96, and / or 120 hours after application), one or more transdermal delivery patches provide 0.5 μg / cm³. 2 / hr to 3 μg / cm 2 / hr (e.g., 0.5 μg / cm) 2 / hr to 2 μg / cm 2 / hr or 0.5 μg / cm 2 / hr to 1 μg / cm 2 The in vitro average flux of dexmedetomidine ( / hr)

[0147] In some embodiments, after applying one or more transdermal delivery patches and maintaining contact between the skin surface and the one or more transdermal delivery patches for 24 hours, the one or more transdermal delivery patches provide 0.5 μg / cm³. 2 / hr to 3 μg / cm 2 / hr (e.g., 0.5 μg / cm) 2 / hr to 2 μg / cm 2 / hr or 0.5 μg / cm 2 / hr to 1 μg / cm 2 The in vitro average flux of dexmedetomidine ( / hr)

[0148] In some embodiments, after applying one or more transdermal delivery patches and maintaining contact between the skin surface and the one or more transdermal delivery patches for 48 hours, the one or more transdermal delivery patches provide 0.5 μg / cm³. 2 / hr to 3 μg / cm 2 / hr (e.g., 0.5 μg / cm) 2 / hr to 2 μg / cm 2 / hr or 0.5 μg / cm 2 / hr to 1 μg / cm 2 The in vitro average flux of dexmedetomidine ( / hr)

[0149] In some embodiments, after applying one or more transdermal delivery patches and maintaining contact between the skin surface and the one or more transdermal delivery patches for 72 hours, the one or more transdermal delivery patches provide 0.5 μg / cm³. 2 / hr to 3 μg / cm 2 / hr (e.g., 0.5 μg / cm) 2 / hr to 2 μg / cm 2 / hr or 0.5 μg / cm 2 / hr to 1 μg / cm 2 The in vitro average flux of dexmedetomidine ( / hr)

[0150] In some embodiments, after applying one or more transdermal delivery patches and maintaining contact between the skin surface and the one or more transdermal delivery patches for 96 hours, the one or more transdermal delivery patches provide 0.5 μg / cm³. 2 / hr to 3 μg / cm 2 / hr (e.g., 0.5 μg / cm) 2 / hr to 2 μg / cm 2 / hr or 0.5 μg / cm 2 / hr to 1 μg / cm 2 The in vitro average flux of dexmedetomidine ( / hr)

[0151] In some embodiments, after 120 hours following the application of one or more transdermal delivery patches and maintenance of contact between the skin surface and the one or more transdermal delivery patches, the one or more transdermal delivery patches provide 0.5 μg / cm³. 2 / hr to 3 μg / cm 2 / hr (e.g., 0.5 μg / cm) 2 / hr to 2 μg / cm 2 / hr or 0.5 μg / cm 2 / hr to 1 μg / cm 2The in vitro average flux of dexmedetomidine ( / hr)

[0152] In some embodiments, one or more transdermal delivery patches provide 0.1 μg / cm 2 / hr to 3 μg / cm 2 / hr (e.g., 0.1 μg / cm) 2 / hr to 2.5 μg / cm 2 / hr / 0.1 μg / cm 2 / hr to 2.0μg / cm 2 / hr, 0.1 μg / cm 2 / hr to 1.5 μg / cm 2 / hr, 0.1 μg / cm 2 / hr to 1 μg / cm 2 / hr or 0.1 μg / cm 2 / hr to 0.8μg / cm 2 Peak in vitro flux of dexmedetomidine ( / hr)

[0153] In some embodiments, one or more transdermal delivery patches provide 0.5 to 3 μg / cm 2 / hr (e.g., 0.5 μg / cm) 2 / hr to 2.5 μg / cm 2 / hr, 0.5 μg / cm 2 / hr to 2.0μg / cm 2 / hr, 0.5 μg / cm 2 / hr to 1.5 μg / cm 2 / hr or 0.5 μg / cm 2 / hr to 1 μg / cm 2 Peak in vitro flux of dexmedetomidine ( / hr)

[0154] In some embodiments, peak dexmedetomidine flux is reached 2 hours or longer after application of one or more transdermal delivery patches (e.g., 4 hours or longer, 6 hours or longer, 12 hours or longer, 18 hours or longer, or 24 hours or longer after application of one or more transdermal delivery patches and maintenance of contact between the skin surface and one or more transdermal delivery patches).

[0155] In embodiments where one or more transdermal delivery patches comprise a release paper covering an adhesive surface, the method further includes removing the release paper to expose the adhesive surface prior to applying one or more transdermal delivery patches to the skin surface of an individual.

[0156] In some embodiments, the target dose is the amount of dexmedetomidine that, when administered to an individual, provides a systemic amount to achieve a desired mean plasma concentration of dexmedetomidine at a specific time. In other embodiments, the target dose is the amount of dexmedetomidine that, when administered to an individual, provides a steady-state mean plasma concentration of dexmedetomidine throughout the dosing interval or control regimen. In still other embodiments, the target dose is the amount of dexmedetomidine that, when administered to an individual, provides delivery of dexmedetomidine to the individual in vivo at a specific rate.

[0157] In some embodiments, one or more transdermal delivery patches are applied and maintained to deliver a target amount of dexmedetomidine (e.g., the average cumulative amount of dexmedetomidine delivered over a dose interval (e.g., 4 days or longer). The term "target cumulative amount" refers to the total amount of dexmedetomidine delivered to an individual via the skin and can vary due to skin or mucosal permeability and metabolic activity at the application site. In some embodiments, the average cumulative amount of dexmedetomidine over a dose interval (e.g., 4 days or longer) may be 5 μg / cm³. 2 Or more (e.g., 25 μg / cm within the dosing interval) 2 or more, 50 μg / cm 2 or more, 75 μg / cm 2 or more, 100 μg / cm 2 or more, 125 μg / cm 2 or more, 200 μg / cm 2 or more or 300 μg / cm 2 (or more). In some embodiments, the average cumulative delivery range of dexmedetomidine over the dose interval is, for example, 5 μg / cm. 2 Up to 500 μg / cm 2 For example, 25 μg / cm 2 Up to 400 μg / cm 2 Or 50 μg / cm 2 Up to 350 μg / cm 2 In some embodiments, the average cumulative amount of dexmedetomidine over a dosing interval (e.g., 3 days or longer) can be 200 μg / cm³. 2 Or more (e.g., 225 μg / cm² within the dosing interval) 2 or more, 250 μg / cm 2 or more, 275 μg / cm 2 or more, 300 μg / cm 2 or more, 325 μg / cm 2 (or more). In some embodiments, the average cumulative amount of dexmedetomidine delivered over the dose interval is 250 μg / cm. 2 Up to 350 μg / cm 2275 μg / cm 2 Up to 350 μg / cm 2 300 μg / cm 2 Up to 350 μg / cm 2 325 μg / cm 2 Up to 350 μg / cm 2 250 μg / cm 2 Up to 325 μg / cm 2 275 μg / cm 2 Up to 325 μg / cm 2 300 μg / cm 2 Up to 325 μg / cm 2 250μg / cm 2 Up to 300 μg / cm 2 275 μg / cm 2 Up to 300 μg / cm 2 Or 250 μg / cm 2 Up to 300 μg / cm 2 .

[0158] 4.3 Transdermal delivery patches

[0159] The methods described herein utilize one or more transdermal delivery patches that provide extended release of dexmedetomidine formulated within the patch. In some embodiments, the transdermal delivery patches described herein release dexmedetomidine over a period of at least 4 days.

[0160] In some embodiments, dexmedetomidine is a pharmaceutically acceptable salt of dexmedetomidine. In some embodiments, dexmedetomidine is dexmedetomidine hydrochloride.

[0161] In some embodiments, one or more transdermal delivery patches include 1 to 4 mg of dexmedetomidine. In some embodiments, one or more transdermal delivery patches include 1 mg to 3.5 mg of dexmedetomidine (e.g., 1 mg to 2.75 mg, 1 mg to 2.5 mg, 1 mg to 2.25 mg, 1 mg to 2 mg, 1 mg to 1.75 mg, 1 mg to 1.5 mg, 1 mg to 1.25 mg, 1.25 mg to 3.5 mg, 1.25 mg to 3 mg, 1.25 mg to 2.75 mg, 1.25 mg to 2.5 mg, 1.25 mg to 2.25 mg, 1.25 mg to 2 mg, 1.25 mg to 1.75 mg, 1.25 mg to 1.5 mg, 1.5 mg to 3.5 mg, 1.5 mg to 3 mg, 1.5 mg to 2.75 mg, 1.5 mg to 2.5 mg, 1.5 mg to 2.25 mg, 1.5 mg to 2 mg, 1.5 mg to 1.75 mg, 1.7 ... 1 mg to 3.5 mg, 1.75 mg to 3 mg, 1.75 mg to 2.75 mg, 1.75 mg to 2.5 mg, 1.75 mg to 2.25 mg, 1.75 mg to 2 mg, 2 mg to 3.5 mg, 2 mg to 3 mg, 2 mg to 2.75 mg, 2 mg to 2.5 mg, 2 mg to 2.25 mg, 2.25 mg to 3.5 mg, 2.25 mg to 3 mg, 2.25 mg to 2.75 mg, 2.25 mg to 2.5 mg, 2.5 mg to 3.5 mg, 2.5 mg to 3.5 mg, 2.5 mg to 2.75 mg, 2.5 mg to 3.0 mg, 2.5 mg to 2.75 mg, 2.75 mg to 3.5 mg, 2.75 mg to 3.5 mg or 3 mg to 3.5 mg).

[0162] In some embodiments, one or more transdermal delivery patches comprise a total of 1.3 mg to 1.6 mg of dexmedetomidine or 1.4 mg to 1.5 mg of dexmedetomidine. In some embodiments, one or more transdermal delivery patches comprise a total of 1.8 mg to 2.3 mg of dexmedetomidine or 2.0 mg to 2.1 mg of dexmedetomidine. In some embodiments, one or more transdermal delivery patches comprise a total of 2 mg to 2.4 mg of dexmedetomidine or 2.1 mg to 2.2 mg of dexmedetomidine. In some embodiments, one or more transdermal delivery patches comprise a total of 2.6 mg to 3.2 mg of dexmedetomidine or 2.9 mg to 3 mg of dexmedetomidine. In some embodiments, one or more transdermal delivery patches comprise a total of 3 mg to 4 mg of dexmedetomidine or 3.5 mg to 3.7 mg of dexmedetomidine.

[0163] In some embodiments, one or more transdermal delivery patches comprise a total of 1 to 2 mg of dexmedetomidine (e.g., 1.3 to 1.6 mg of dexmedetomidine or 1.4 to 1.5 mg of dexmedetomidine).

[0164] In some embodiments, the transdermal delivery patch includes a drug layer attached to a backing layer, wherein the drug layer includes 1 mg to 4 mg of dexmedetomidine and a pressure-sensitive adhesive, and the drug layer has an adhesive surface suitable for adhesion to the skin surface.

[0165] In some embodiments, the drug layer is a single layer comprising dexmedetomidine and a pressure-sensitive adhesive. In some embodiments, the drug layer is attached to a backing layer, for example, by lamination. The surface of the drug layer opposite the backing layer is an adhesive and adheres to the individual's skin surface.

[0166] In some embodiments, the drug layer comprises 1 mg to 4 mg of dexmedetomidine. In some embodiments, the drug layer comprises 1 mg to 3.5 mg of dexmedetomidine (e.g., 1 mg to 2.75 mg, 1 mg to 2.5 mg, 1 mg to 2.25 mg, 1 mg to 2 mg, 1 mg to 1.75 mg, 1 mg to 1.5 mg, 1 mg to 1.25 mg, 1.25 mg to 3.5 mg, 1.25 mg to 3 mg, 1.25 mg to 2.75 mg, 1.25 mg to 2.5 mg, 1.25 mg to 2.25 mg, 1.25 mg to 2 mg, 1.25 mg to 1.75 mg, 1.25 mg to 1.5 mg, 1.5 mg to 3.5 mg, 1.5 mg to 3 mg, 1.5 mg to 2.75 mg, 1.5 mg to 2.5 mg, 1.5 mg to 2.25 mg, 1.5 mg to 2 mg, 1.5 mg to 1.75 mg, 1.75 mg to 3.5 mg). mg, 1.75 mg to 3 mg, 1.75 mg to 2.75 mg, 1.75 mg to 2.5 mg, 1.75 mg to 2.25 mg, 1.75 mg to 2 mg, 2 mg to 3.5 mg, 2 mg to 3 mg, 2 mg to 2.75 mg, 2 mg to 2.5 mg, 2 mg to 2.25 mg, 2.25 mg to 3.5 mg, 2.25 mg to 3 mg, 2.25 mg to 2.75 mg, 2.25 mg to 2.5 mg, 2.5 mg to 3.5 mg, 2.5 mg to 3.0 mg, 2.5 mg to 2.75 mg, 2.75 mg to 3.5 mg, 2.75 mg to 3.5 mg or 3 mg to 3.5 mg).

[0167] In some embodiments, the drug layer comprises 1.3 mg to 1.6 mg of dexmedetomidine or 1.4 mg to 1.5 mg of dexmedetomidine. In some embodiments, the drug layer comprises 1.8 mg to 2.3 mg of dexmedetomidine or 2.0 mg to 2.1 mg of dexmedetomidine. In some embodiments, the drug layer comprises 2 mg to 2.4 mg of dexmedetomidine or 2.1 mg to 2.2 mg of dexmedetomidine. In some embodiments, the drug layer comprises 2.6 mg to 3.2 mg of dexmedetomidine or 2.9 mg to 3 mg of dexmedetomidine. In some embodiments, the drug layer comprises 1 mg to 2 mg of dexmedetomidine (e.g., 1.3 mg to 1.6 mg of dexmedetomidine or 1.4 mg to 1.5 mg of dexmedetomidine).

[0168] Pressure-sensitive adhesives include (but are not limited to) poly-isobutene adhesives, polyisobutylene adhesives, polyisobutylene / polyisobutylene adhesive mixtures, carboxylated polymers, and acrylic or acrylate copolymers (e.g., carboxylated acrylate copolymers).

[0169] In cases where the pressure-sensitive adhesive contains polybutene, the polybutene may be saturated polybutene. Alternatively, the polybutene may be unsaturated polybutene. Furthermore, the polybutene may be a mixture or combination of saturated and unsaturated polybutene. In some embodiments, the pressure-sensitive adhesive may comprise a composition that is the same as or substantially the same as a composition of Indopol® L-2, Indopol® L-3, Indopol® L-6, Indopol® L-8, Indopol® L-14, Indopol® H-7, Indopol® H-8, Indopol® H-15, Indopol® H-25, Indopol® H-35, Indopol® H-50, Indopol® H-100, Indopol® H-300, Indopol® H-1200, Indopol® H-1500, Indopol® H-1900, Indopol® H-2100, Indopol® H-6000, Indopol® H-18000, Panalane® L-14E, or Panalane® H-300E. In some embodiments, the polybutene pressure-sensitive adhesive is Indopol® H-1900. In other embodiments, the polybutene pressure-sensitive adhesive is Panalane® H-300E.

[0170] The acrylate copolymers of interest include copolymers of various monomers (e.g., “soft” monomers, “hard” monomers, or “functional” monomers). Acrylate copolymers can consist of copolymers comprising: binary polymers (i.e., made from two monomers), ternary polymers (i.e., made from three monomers), or tetrameric polymers (i.e., made from four monomers), or copolymers having more than one number of monomers. Acrylate copolymers can be crosslinked or non-crosslinked. The polymer can be crosslinked by known methods to provide the desired polymer. The monomers of the acrylate copolymer may contain at least two or more exemplary components selected from acrylic acid, alkyl acrylates, methacrylates, copolymerizable secondary monomers, and monomers having functional groups.

[0171] The monomers (“soft” and “hard” monomers) may be methoxyethyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, acrylonitrile, methoxyethyl acrylate, methoxyethyl methacrylate, and the like. Additional examples of acrylic adhesive monomers are described in Satas, “Acrylic Adhesives,” Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (edited by D. Satas), Van Nostrand Reinhold, New York (1989), the contents of which are incorporated herein by reference.

[0172] In some embodiments, the pressure-sensitive adhesive comprises a polyvinyl acetate copolymer. In some embodiments, the pressure-sensitive adhesive comprises an ethylene-vinyl acetate copolymer, vinyl acetate-acrylic acid, polyvinyl chloride acetate, or polyvinylpyrrolidone. In some embodiments, the pressure-sensitive adhesive is an acrylate-vinyl acetate copolymer. In some embodiments, the pressure-sensitive adhesive may comprise a composition that is the same as or substantially the same as the composition of Duro-Tak® 87-9301, Duro-Tak® 87-200A, Duro-Tak® 87-2353, Duro-Tak® 87-2100, Duro-Tak® 87-2051, Duro-Tak® 87-2052, Duro-Tak® 87-2194, Duro-Tak® 87-2677, Duro-Tak® 87-201A, Duro-Tak® 87-2979, Duro-Tak® 87-2510, Duro-Tak® 87-2516, Duro-Tak® 87-387, Duro-Tak® 87-4287, Duro-Tak® 87-2287, or Duro-Tak® 87-2074. In this context, the term "substantially identical" refers to compositions of acrylate-vinyl acetate copolymers in organic solvent solutions.

[0173] In some embodiments, the pressure-sensitive adhesive is an acrylate adhesive, which is a non-functionalized acrylate, a hydroxy-functionalized acrylate, or an acid-functionalized acrylate. For example, the acrylate adhesive may be an acrylic adhesive having one or more -OH functional groups. When the acrylic adhesive has one or more -OH functional groups, in some cases, the pressure-sensitive adhesive may be the same as or substantially the same as the compositions of Duro-Tak® 87-4287, Duro-Tak® 87-2287, Duro-Tak® 87-2510, or Duro-Tak® 87-2516. Alternatively, the acrylate adhesive may be an acrylic adhesive having one or more -COOH functional groups. When the acrylic adhesive has one or more -COOH functional groups, in some cases, the pressure-sensitive adhesive may be the same as or substantially the same as the composition of Duro-Tak® 87-387, Duro-Tak® 87-2979, or Duro-Tak® 87-2353. Furthermore, the acrylic adhesive may be a non-functionalized acrylic adhesive. When the acrylic adhesive is non-functionalized, in some cases, the pressure-sensitive adhesive may be the same as or substantially the same as the composition of Duro-Tak® 87-9301.

[0174] In some embodiments, the pressure-sensitive adhesive includes acrylic polymers, acrylate copolymers, acrylate-vinyl acetate copolymers, polyacrylonitrile, or combinations thereof.

[0175] In some embodiments, the pressure-sensitive adhesive comprises a hydroxyl-functionalized acrylate copolymer.

[0176] The amount of pressure-sensitive adhesive in the drug layer can vary, for example, from 0.1 mg to 2000 mg (e.g., 0.5 mg to 1500 mg, 1 to 1000 mg, 10 to 750 mg, or 10 mg to 500 mg). Therefore, in some embodiments, the amount of pressure-sensitive adhesive is in the range of 1% to 99% (w / w) (e.g., 5% to 95% (w / w), 10% to 95% (w / w), 15% to 90% (w / w), or 20% to 85% (w / w)). In other embodiments, the amount of pressure-sensitive adhesive in the drug layer is 70% by weight or more (e.g., 75% by weight or more, 80% by weight or more, 85% by weight or more, 90% by weight or more, 95% by weight or more, 97% by weight or more).

[0177] The weight ratio of pressure-sensitive adhesive to dexmedetomidine in the drug layer can be between or within the range of 1:2 and 1:2.5, 1:2.5 and 1:3, 1:3 and 1:3.5, 1:3.5 and 1:4, 1:4 and 1:4.5, 1:4.5 and 1:5, 1:5 and 1:10, 1:10 and 1:25, 1:25 and 1:50, 1:50 and 1:75, and 1:75 and 1:99. For example, the weight ratio of pressure-sensitive adhesive to dexmedetomidine in the drug layer can be between 1:1 and 1:5, 1:5 and 1:10, 1:10 and 1:15, 1:15 and 1:25, 1:25 and 1:50, 1:50 and 1:75, or 1:75 and 1:99. Alternatively, the weight ratio of dexmedetomidine to the pressure-sensitive adhesive in the drug layer may be between or within the range of 2:1 and 2.5:1, 2.5:1 and 3:1, 3:1 and 3.5:1, 3.5:1 and 4:1, 4:1 and 4.5:1, 4.5:1 and 5:1, 5:1 and 10:1, 10:1 and 25:1, 25:1 and 50:1, 50:1 and 75:1, and 75:1 and 99:1. For example, the ratio of dexmedetomidine to the pressure-sensitive adhesive in the drug layer may be between 1:1 and 5:1, 5:1 and 10:1, 10:1 and 15:1, 15:1 and 25:1, 25:1 and 50:1, 50:1 and 75:1, or 75:1 and 99:1.

[0178] In some embodiments, the drug layer may further comprise one or more crosslinked hydrophilic polymers. For example, the crosslinked polymer may be an amine-containing hydrophilic polymer. The amine-containing polymer includes (but is not limited to) polyethyleneimine, amine-terminated polyethylene oxide, amine-terminated polyethylene / polypropylene oxide, polymers of dimethylaminoethyl methacrylate, and copolymers of dimethylaminoethyl methacrylate and vinylpyrrolidone. In some embodiments, the crosslinked polymer is crosslinked polyvinylpyrrolidone (e.g., PVP-CLM).

[0179] In some embodiments, the drug layer may contain other additives, depending on the adhesive used. For example, materials that inhibit drug crystallization (e.g., PVP-CLM, PVP K17, PVP K30, PVP K90) have hygroscopic properties that improve wear duration and improve physical properties (e.g., cold flow, tackiness, and bond strength of the adhesive).

[0180] In some embodiments, the amount of crosslinked polymer in the drug layer may vary. For example, the amount of crosslinked polymer may range from 0.1 mg to 500 mg (e.g., 0.5 mg to 400 mg, 1 to 300 mg, 10 to 200 mg, or 10 mg to 100 mg). Therefore, in some embodiments, the amount of crosslinked polymer in the drug layer ranges from 2% to 30% (w / w) (e.g., 4% to 30% (w / w), 5% to 25% (w / w), 6% to 22.5% (w / w), or 10% to 20% (w / w)). In other embodiments, the amount of crosslinked polymer in the drug layer is 8% by weight or more (e.g., 10% by weight or more, 12% by weight or more, 15% by weight or more, 20% by weight or more, 25% by weight or more, or 30% by weight or more).

[0181] In some embodiments, the drug layer further includes a penetration enhancer. The penetration enhancer increases the solubility of dexmedetomidine (e.g.) to prevent undesirable crystallization of dexmedetomidine in the drug layer. The penetration enhancer may be incorporated into the drug layer in an amount ranging from 0.01% to 20% (w / w) (e.g., 0.05% to 15% (w / w), 0.1% to 10% (w / w), 0.5% to 8% (w / w), or 0.5% to 5% (w / w)).

[0182] Example penetration enhancers include (but are not limited to) acids containing linoleic acid, oleic acid, linolenic acid, stearic acid, isostearic acid, levulinic acid, palmitic acid, caprylic acid, capric acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, stearic acid, N-lauroyl sarcosine, L-pyroglutamic acid, lauric acid, succinic acid, pyruvic acid, glutaric acid, sebacic acid, cyclopentanecarboxylic acid, and acylated amino acids. Other penetration enhancers of interest include (but are not limited to) aliphatic alcohols (e.g., saturated or unsaturated higher alcohols having 12 to 22 carbon atoms, such as oleyl alcohol or lauryl alcohol); fatty acid esters (e.g., isopropyl myristate, diisopropyl adipate, lauryl lactate, propyl lauryl oleate, ethyl oleate, and isopropyl palmitate); alkanolamines (e.g., triethanolamine, triethanolamine hydrochloride, and diisopropanolamine); polyol alkyl ethers (e.g., polyols such as glycerol, ... Alkyl ethers of ethylene glycol, propylene glycol, 1,3-butanediol, diglycerol, polyglycerol, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, polypropylene glycol monolaurate, sorbitan, sorbitol, isosorbide, methyl glucoside, oligosaccharides, and reducing oligosaccharides, wherein the number of carbon atoms in the alkyl portion of the polyol alkyl ether is preferably 6 to 20; polyoxyethylene alkyl ethers (e.g., polyoxyethylene alkyl ethers (wherein the number of carbon atoms in the alkyl portion is 6 to 20 and the polyoxyethylene chain...) The number of repeating units (e.g., -O-CH2CH2-) is 1 to 9, such as (but not limited to) polyoxyethylene lauryl ether, polyoxyethylene hexadecyl ether, polyoxyethylene stearyl ether, and polyoxyethylene oleyl ether; glycerides (i.e., fatty acid esters of glycerol), such as glycerides of fatty acids having 6 to 18 carbon atoms, wherein the glycerides may be monoglycerides (i.e., glycerol molecules covalently bonded to one fatty acid chain by ester bonds), diglycerides (i.e., glycerol molecules covalently bonded to two fatty acid chains by ester bonds), triglycerides (i.e., glycerol molecules covalently bonded to three fatty acid chains by ester bonds) or combinations thereof, wherein the fatty acid components forming the glycerides include caprylic acid, capric acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, stearic acid (i.e., stearic acid), and oleic acid; medium-chain fatty acid esters of polyols; alkyl lactates; alkyl dicarboxylic acids; acylated amino acids; pyrrolidones; pyrrolidone derivatives and combinations thereof. Additional penetration enhancers may comprise lactic acid, tartaric acid, 1,2,6-hexanetriol, benzyl alcohol, lanolin, potassium hydroxide (KOH), tris(hydroxymethyl)aminomethane, glyceryl monooleate (GMO), sorbitan monolaurate (SML), sorbitan monooleate (SMO), lauryl ether-4 (LTH), and combinations thereof. In some embodiments, penetration enhancers include levulinic acid, lauryl lactate, oleic acid, propylene glycol monolaurate, or combinations thereof.

[0183] In some embodiments, the penetration enhancer includes lauryl lactate, oleic acid, or a combination thereof. In some embodiments, the penetration enhancer is lauryl lactate.

[0184] The drug layer of a transdermal delivery patch is attached (e.g., by lamination) to a backing layer. In other words, the backing layer is in direct contact with the drug layer. The backing can be flexible, allowing for close contact with the desired application site on an individual. In some embodiments, the backing is made of a material that does not absorb dexmedetomidine and does not allow dexmedetomidine to leach from the matrix. The backing layer of interest may comprise (but is not limited to) nonwoven fabrics, woven fabrics, membranes (including sheets), porous bodies, foams, paper, or composite materials obtained by laminating a membrane onto a nonwoven fabric or a combination of fabrics.

[0185] In some embodiments, the backing layer comprises a membrane containing polyolefin resin, polyacrylic resin, polyester resin, cellophane, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyvinyl chloride, polystyrene, polyurethane, polyacrylonitrile, fluoropolymer, styrene-isoprene-styrene copolymer, styrene-butadiene rubber, polybutadiene, ethylene-vinyl acetate copolymer, polyamide, polysulfone, or combinations thereof. In some embodiments, the membrane comprises a polyolefin resin selected from polyethylene and polypropylene. In some embodiments, the polyester resin is polyethylene terephthalate. In some embodiments, the membrane comprises polyethylene and polyethylene terephthalate.

[0186] Nonwoven fabrics may contain polyolefin resins (e.g., polyethylene and polypropylene); polyester resins (e.g., polyethylene terephthalate, polybutylene terephthalate and polyethylene naphthalate); rayon, polyamide, poly(ester ether), polyurethane, polyacrylic resin, polyvinyl alcohol, styrene-isoprene-styrene copolymer and styrene-ethylene-propylene-styrene copolymer; and combinations thereof.

[0187] Woven fabrics may contain cotton, rayon, polyacrylic resin, polyester resin, polyvinyl alcohol, and combinations thereof.

[0188] The membrane may comprise polyolefin resins (e.g., polyethylene and polypropylene); polyacrylic resins (e.g., polymethyl methacrylate and polyethyl methacrylate); polyester resins (e.g., polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate); and celova with polyvinyl alcohol, ethylene-vinyl alcohol copolymers, polyvinyl chloride, polystyrene, polyurethane, polyacrylonitrile, fluoropolymers, styrene-isoprene-styrene copolymers, styrene-butadiene rubber, polybutadiene, ethylene-vinyl acetate copolymers, polyamides, and polysulfones; and combinations thereof. In some embodiments, the membrane comprises polyethylene and polyethylene terephthalate.

[0189] Paper may include impregnated paper, coated paper, wood-free paper, kraft paper, Japanese paper, cellophane, synthetic paper, and combinations thereof.

[0190] The surface of the drug layer opposite the backing layer is an adhesive and adheres to the individual's skin surface. In some embodiments, the surface area of ​​the adhesive surface is 3 cm². 2 up to 20 cm 2 For example, 3 cm 2 Up to 19 cm 2 3 cm 2 up to 18 cm 2 3 cm 2 up to 17cm 2 3 cm 2 up to 16 cm 2 3 cm 2 up to 15 cm 2 3 cm 2 Up to 14 cm 2 3 cm 2 up to 13 cm 2 3 cm 2 up to 12 cm 2 3 cm 2 Up to 11 cm 2 3 cm 2 Up to 10 cm 2 3 cm 2 up to 9 cm 2 3 cm 2 up to 8 cm 2 3 cm 2 up to 7 cm 2 3 cm 2 up to 6 cm 2 3 cm 2 up to 5cm 2 3 cm 2 up to 4 cm 2 4 cm 2 up to 20 cm 2 4 cm 2 Up to 19 cm 2 4 cm 2 up to 18 cm 2 4 cm 2 Up to 17 cm 2 4 cm 2 up to 16 cm 2 4 cm 2 up to 15 cm 2 4 cm 2 Up to 14 cm 2 4 cm 2 up to 13 cm 2 4 cm 2 up to 12 cm 24 cm 2 Up to 11 cm 2 4cm 2 Up to 10 cm 2 4 cm 2 up to 9 cm 2 4 cm 2 up to 8 cm 2 4 cm 2 up to 7 cm 2 4 cm 2 up to 6 cm 2 4 cm 2 up to 5 cm 2 5cm 2 up to 20 cm 2 5 cm 2 Up to 19 cm 2 5 cm 2 up to 18 cm 2 5 cm 2 Up to 17 cm 2 5 cm 2 up to 16 cm 2 5 cm 2 up to 15cm 2 5 cm 2 Up to 14 cm 2 5 cm 2 up to 13 cm 2 5 cm 2 up to 12 cm 2 5 cm 2 Up to 11 cm 2 5 cm 2 Up to 10 cm 2 5 cm 2 up to 9 cm 2 5 cm 2 up to 8 cm 2 5 cm 2 up to 7 cm 2 5 cm 2 up to 6 cm 2 6 cm 2 up to 20 cm 2 6 cm 2 Up to 19 cm 2 6 cm 2 up to 18 cm 2 6 cm 2 Up to 17 cm 2 6 cm 2 up to 16 cm 2 6 cm2 up to 15 cm 2 6 cm 2 Up to 14 cm 2 6 cm 2 up to 13 cm 2 6cm 2 up to 12 cm 2 6 cm 2 Up to 11 cm 2 6 cm 2 Up to 10 cm 2 6 cm 2 up to 9 cm 2 6 cm 2 up to 8 cm 2 6 cm 2 up to 7 cm 2 7cm 2 up to 20 cm 2 7 cm 2 Up to 19 cm 2 7 cm 2 up to 18 cm 2 7 cm 2 Up to 17 cm 2 7 cm 2 up to 16 cm 2 7 cm 2 up to 15cm 2 7 cm 2 Up to 14 cm 2 7 cm 2 up to 13 cm 2 7 cm 2 up to 12 cm 2 7 cm 2 Up to 11 cm 2 7 cm 2 Up to 10 cm 2 7 cm 2 up to 9 cm 2 7 cm 2 up to 8 cm 2 8 cm 2 up to 20 cm 2 8 cm 2 Up to 19 cm 2 8 cm 2 up to 18 cm 2 8 cm 2 Up to 17 cm 2 8 cm 2 up to 16 cm 2 8 cm 2up to 15 cm 2 8 cm 2 Up to 14 cm 2 8 cm 2 up to 13 cm 2 8 cm 2 up to 12 cm 2 8 cm 2 Up to 11 cm 2 8cm 2 Up to 10 cm 2 8 cm 2 up to 9 cm 2 9 cm 2 up to 20 cm 2 9 cm 2 Up to 19 cm 2 9 cm 2 up to 18 cm 2 9 cm 2 Up to 17 cm 2 9 cm 2 up to 16 cm 2 9 cm 2 up to 15 cm 2 9 cm 2 Up to 14 cm 2 9 cm 2 up to 13 cm 2 9 cm 2 up to 12 cm 2 9 cm 2 up to 11cm 2 9 cm 2 Up to 10 cm 2 10 cm 2 up to 20 cm 2 10 cm 2 Up to 19 cm 2 10 cm 2 up to 18 cm 2 10 cm 2 Up to 17 cm 2 10cm 2 up to 16 cm 2 10 cm 2 up to 15 cm 2 10 cm 2 Up to 14 cm 2 10 cm 2 up to 13 cm 2 10 cm 2 up to 12 cm 2 10 cm2 Up to 11 cm 2 11 cm 2 up to 20 cm 2 11 cm 2 Up to 19 cm 2 11 cm 2 up to 18 cm 2 11 cm 2 Up to 17 cm 2 11 cm 2 up to 16cm 2 11 cm 2 up to 15 cm 2 11 cm 2 Up to 14 cm 2 11 cm 2 up to 13 cm 2 11 cm 2 up to 12 cm 2 12 cm 2 up to 20 cm 2 12cm 2 Up to 19 cm 2 12 cm 2 up to 18 cm 2 12 cm 2 Up to 17 cm 2 12 cm 2 up to 16 cm 2 12 cm 2 up to 15 cm 2 12 cm 2 Up to 14 cm 2 12 cm 2 up to 13 cm 2 13 cm 2 Up to 14 cm 2 14 cm 2 up to 20 cm 2 14 cm 2 Up to 19 cm 2 14 cm 2 up to 18cm 2 14 cm 2 Up to 17 cm 2 14 cm 2 up to 16 cm 2 14 cm 2 up to 15 cm 2 15 cm 2 up to 20 cm 2 15 cm 2Up to 19 cm 2 15cm 2 up to 18 cm 2 15 cm 2 Up to 17 cm 2 15 cm 2 up to 16 cm 2 16 cm 2 up to 20 cm 2 16 cm 2 Up to 19 cm 2 16 cm 2 up to 18 cm 2 16 cm 2 Up to 17 cm 2 17 cm 2 up to 20 cm 2 17 cm 2 Up to 19 cm 2 17 cm 2 up to 18 cm 2 18 cm 2 up to 20cm 2 18 cm 2 Up to 19 cm 2 Or 19 cm 2 up to 20 cm 2 .

[0191] In some embodiments, the surface area of ​​the adhesive surface is 3 cm². 2 up to 15 cm 2 The drug layer comprises 1 mg to 4 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 4 cm². 2 up to 15 cm 2 The drug layer includes 1 mg to 4 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 5 cm². 2 up to 15 cm 2 The drug layer includes 1 mg to 4 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 6 cm². 2 up to 15 cm 2 The drug layer includes 1 mg to 4 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 7 cm². 2 up to 15 cm 2 The drug layer includes 1 mg to 4 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 8 cm². 2 up to 15 cm 2 The drug layer includes 1 mg to 4 mg of dexmedetomidine.

[0192] In some embodiments, the surface area of ​​the adhesive surface is 3 cm². 2 up to 8 cm 2 The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 4 cm². 2 up to 8 cm 2 The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 5 cm². 2 up to 8 cm 2 The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 6 cm². 2 up to 8 cm 2 The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 7 cm². 2 up to 8 cm 2 The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 3 cm². 2 up to 7 cm 2 The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 4 cm². 2 up to 7cm 2 The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 5 cm². 2 up to 7 cm 2 The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 6 cm². 2 up to 7 cm 2 The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 3 cm². 2 up to 6 cm 2 The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 4 cm². 2 up to 6 cm 2 The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 5 cm². 2 up to 6 cm 2 The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 3 cm². 2 up to 5 cm 2The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 4 cm². 2 up to 5 cm 2 The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 3 cm². 2 up to 4 cm 2 The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 6 cm². 2 The drug layer includes 1 mg to 3.5 mg of dexmedetomidine.

[0193] In some embodiments, the surface area of ​​the adhesive surface is 3 cm². 2 up to 15 cm 2 The drug layer includes 1 mg to 4 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 3 cm². 2 up to 15 cm 2 The drug layer includes 1 mg to 2 mg of dexmedetomidine. In some embodiments, the surface area of ​​the adhesive surface is 3 cm². 2 up to 15 cm 2 The drug layer includes 1.3 mg to 1.6 mg of dexmedetomidine.

[0194] In some embodiments, the surface area of ​​the adhesive surface is 6 cm². 2 up to 7 cm 2 The drug layer includes 1.4 mg to 1.5 mg of dexmedetomidine (e.g., 1.46 mg dexmedetomidine). In some embodiments, the surface area of ​​the adhesive surface is 9 cm². 2 Up to 10 cm 2 The drug layer includes 1.4 mg to 1.5 mg of dexmedetomidine (e.g., 1.46 mg dexmedetomidine). In some embodiments, the surface area of ​​the adhesive surface is 12 cm². 2 up to 13 cm 2 The drug layer includes 1.4 mg to 1.5 mg of dexmedetomidine (e.g., 1.46 mg of dexmedetomidine).

[0195] In some embodiments, the surface area of ​​the adhesive surface is 6 cm². 2 up to 7 cm 2 The drug layer includes 2 mg to 3 mg of dexmedetomidine (e.g., 2.92 mg dexmedetomidine). In some embodiments, the surface area of ​​the adhesive surface is 9 cm². 2 Up to 10 cm 2The drug layer includes 2 to 3 mg of dexmedetomidine (e.g., 2.92 mg dexmedetomidine). In some embodiments, the surface area of ​​the adhesive surface is 12 cm². 2 up to 13 cm 2 The drug layer includes 2 to 3 mg of dexmedetomidine (e.g., 2.92 mg dexmedetomidine). In some embodiments, the surface area of ​​the adhesive surface is 15 cm². 2 up to 16 cm 2 The drug layer includes 3 mg to 4 mg of dexmedetomidine (e.g., 3.65 mg dexmedetomidine).

[0196] The transdermal delivery patch can be of any shape and size, provided that the surface area of ​​the adhesive surface is as provided herein. In some embodiments, the transdermal delivery patch is rectangular. In some embodiments, the transdermal delivery patch is rectangular with rounded corners. In some embodiments, the transdermal delivery patch is square. In some embodiments, the transdermal delivery patch is square with rounded corners. In some embodiments, the transdermal delivery patch is circular. In some embodiments, the transdermal delivery patch is elliptical. Exemplary transdermal delivery patches are illustrated in... Figure 1A -C

[0197] In some embodiments, the transdermal delivery patch has a length of 0.5 inches to 4 inches and a width of 0.5 inches to 4 inches (e.g., a length of 1 inch to 4 inches and a width of 0.5 inches to 4 inches, a length of 1.5 inches to 4 inches and a width of 0.5 inches to 4 inches, a length of 2 inches to 4 inches and a width of 0.5 inches to 4 inches, a length of 2.5 inches to 4 inches and a width of 0.5 inches to 4 inches, a length of 3 inches to 4 inches and a width of 0.5 inches to 4 inches, a length of 3.5 inches to 4 inches and a width of 0.5 inches to 4 inches, a length of 0.5 inches to 4 inches and a width of 0.5 inches to 3.5 inches, a length of 1 inch to 4 inches and a width of 0.5 inches to 3.5 inches, 1. 5 inches to 4 inches in length and 0.5 inches to 3.5 inches in width; 2 inches to 4 inches in length and 0.5 inches to 3.5 inches in width; 2.5 inches to 4 inches in length and 0.5 inches to 3.5 inches in width; 3 inches to 4 inches in length and 0.5 inches to 3.5 inches in width; 3.5 inches to 4 inches in length and 0.5 inches to 3.5 inches in width; 0.5 inches to 4 inches in length and 0.5 inches to 3.5 inches in width; 1 inch to 4 inches in length and 0.5 inches to 3 inches in width; 1.5 inches to 4 inches in length and 0.5 inches to 3 inches in width; 2 inches to 4 inches in length and 0.5 inches to 3 inches in width; 2.5 inches to 4 inches in length and 0.5 inches to 3 inches in width. Width from 1 inch to 3 inches, length from 3 inches to 4 inches and width from 0.5 inches to 3 inches, length from 3.5 inches to 4 inches and width from 0.5 inches to 3 inches, length from 0.5 inches to 4 inches and width from 0.5 inches to 2.5 inches, length from 1 inch to 4 inches and width from 0.5 inches to 2.5 inches, length from 1.5 inches to 4 inches and width from 0.5 inches to 2.5 inches, length from 1.5 inches to 4 inches and width from 0.5 inches to 2.5 inches, length from 2 inches to 4 inches and width from 0.5 inches to 2.5 inches, length from 2.5 inches to 4 inches and width from 0.5 inches to 2.5 inches, length from 3 inches to 4 inches and width from 0.5 inches to 2.5 inches, length from 3.5 inches to 4 inches and width from 0.5 inches to 2.5 inches. 0.5 inches to 4 inches in length and 0.5 inches to 2 inches in width, 1 inch to 4 inches in length and 0.5 inches to 2 inches in width, 1.5 inches to 4 inches in length and 0.5 inches to 2 inches in width, 2 inches to 4 inches in length and 0.5 inches to 2 inches in width, 2.5 inches to 4 inches in length and 0.5 inches to 2 inches in width, 3 inches to 4 inches in length and 0.5 inches to 2 inches in width, 3.5 inches to 4 inches in length and 0.5 inches to 2 inches in width, 0.5 inches to 4 inches in length and 0.5 inches to 1.5 inches in width, 1 inch to 4 inches in length and 0.5 inches to 1.5 inches in width, 1.5 inches to 4 inches in length and 0.5 inches to 1.5 inches in width.5 inches wide, 2 inches to 4 inches long and 0.5 inches to 1.5 inches wide, 2.5 inches to 4 inches long and 0.5 inches to 1.5 inches wide, 3 inches to 4 inches long and 0.5 inches to 1.5 inches wide, 3.5 inches to 4 inches long and 0.5 inches to 1.5 inches wide, 0.5 inches to 4 inches long and 0.5 inches to 1 inch wide, 1 inch to 4 inches long and 0.5 inches to 1 inch wide, 1.5 inches to 4 inches long and 0.5 inches to 1 inch wide, 2 inches to 4 inches long and 0.5 inches to 1 inch wide, 2.5 inches to 4 inches long and 0.5 inches to 1 inch wide, 3 inches to 4 inches... Length and width from 0.5 inches to 1 inch, length from 3.5 inches to 4 inches and width from 0.5 inches to 1 inch, length from 0.5 inches to 4 inches and width from 1 inch to 4 inches, length from 0.5 inches to 4 inches and width from 1.5 inches to 4 inches, length from 0.5 inches to 4 inches and width from 2 inches to 4 inches, length from 0.5 inches to 4 inches and width from 2.5 inches to 4 inches, length from 0.5 inches to 4 inches and width from 3 inches to 4 inches, length from 0.5 inches to 4 inches and width from 3.5 inches to 4 inches, length from 0.5 inches to 3.5 inches and width from 0.5 inches to 4 inches, length from 0.5 inches to 3.5 inches and width from 1 inch to 4 inches, 0.5 inches Lengths from 1 inch to 3.5 inches and widths from 1.5 inches to 4 inches; lengths from 0.5 inches to 3.5 inches and widths from 2 inches to 4 inches; lengths from 0.5 inches to 3.5 inches and widths from 2.5 inches to 4 inches; lengths from 0.5 inches to 3.5 inches and widths from 3 inches to 4 inches; lengths from 0.5 inches to 3 inches and widths from 1 inch to 4 inches; lengths from 0.5 inches to 3 inches and widths from 1.5 inches to 4 inches; lengths from 0.5 inches to 3 inches and widths from 2 inches to 4 inches; lengths from 0.5 inches to 3 inches and widths from 2 inches to 4 inches; lengths from 0.5 inches to 3 inches and widths from 2.5 inches. 4 inches in width, 0.5 inches to 3 inches in length and 3 inches to 4 inches in width, 0.5 inches to 3 inches in length and 3.5 inches to 4 inches in width, 0.5 inches to 2.5 inches in length and 0.5 inches to 4 inches in width, 0.5 inches to 2.5 inches in length and 1 inch to 4 inches in width, 0.5 inches to 2.5 inches in length and 1.5 inches to 4 inches in width, 0.5 inches to 2.5 inches in length and 2 inches to 4 inches in width, 0.5 inches to 2.5 inches in length and 2.5 inches to 4 inches in width, 0.5 inches to 2.5 inches in length and 3 inches to 4 inches in width, 0.5 inches to 2.5 inches in length and 3.5 inches to 4 inches in width, 0.5 inches to 2 inches in length and 0.5 inches to 4 inches in width; 0.5 inches to 2 inches in length and 1 inch to 4 inches in width; 0.5 inches to 2 inches in length and 1.5 inches to 4 inches in width; 0.5 inches to 2 inches in length and 2 inches to 4 inches in width; 0.5 inches to 2 inches in length and 2.5 inches to 4 inches in width; 0.5 inches to 2 inches in length and 3 inches to 4 inches in width; 0.5 inches to 2 inches in length and 3.5 inches to 4 inches in width; 0.5 inches to 1.5 inches in length and 0.5 inches to 4 inches in width; 0.5 inches to 1.5 inches in length and 1 inch to 4 inches in width; 0.5 inches to 1.5 inches in length and 1.5 inches to 4 inches in width; 0.5 inches to 1.5 inches in length. (And widths from 2 inches to 4 inches, lengths from 0.5 inches to 1.5 inches and widths from 2.5 inches to 4 inches, lengths from 0.5 inches to 1.5 inches and widths from 3 inches to 4 inches, lengths from 0.5 inches to 1 inch and widths from 0.5 inches to 4 inches, lengths from 0.5 inches to 1 inch and widths from 1 inch to 4 inches, lengths from 0.5 inches to 1 inch and widths from 1.5 inches to 4 inches, lengths from 0.5 inches to 1 inch and widths from 2 inches to 4 inches, lengths from 0.5 inches to 1 inch and widths from 2.5 inches to 4 inches, lengths from 0.5 inches to 1 inch and widths from 3 inches to 4 inches, lengths from 0.5 inches to 1 inch and widths from 3.5 inches to 4 inches).

[0198] In some embodiments, the transdermal delivery patch has a length of 0.5 cm to 1 cm and a width of 0.5 cm to 1 cm.

[0199] In some embodiments, the transdermal delivery patch has a length of 1 to 1.5 inches and a width of 1 to 1.5 inches.

[0200] In some embodiments, the transdermal delivery patch has a length of 1.5 to 2 inches and a width of 1 to 1.5 inches.

[0201] In some embodiments, the adhesive surface of the transdermal delivery patch is adhered to a release liner. In these embodiments, the drug layer is substantially sandwiched between the backing layer and the release liner. The release liner can be manually removed, thereby exposing the adhesive surface of the drug layer of the transdermal delivery patch, which can then be adhered to the skin surface.

[0202] In some embodiments, the adhesive surface of the transdermal delivery patch has a length of 0.5 inches to 4 inches and a width of 0.5 inches to 4 inches (e.g., a length of 1 inch to 4 inches and a width of 0.5 inches to 4 inches, a length of 1.5 inches to 4 inches and a width of 0.5 inches to 4 inches, a length of 2 inches to 4 inches and a width of 0.5 inches to 4 inches, a length of 2.5 inches to 4 inches and a width of 0.5 inches to 4 inches, a length of 3 inches to 4 inches and a width of 0.5 inches to 4 inches, a length of 3.5 inches to 4 inches and a width of 0.5 inches to 4 inches, a length of 0.5 inches to 4 inches and a width of 0.5 inches to 3.5 inches, a length of 1 inch to 4 inches and a width of 0.5 inches to 3.5 inches). Width, length 1.5 inches to 4 inches and width 0.5 inches to 3.5 inches, length 2 inches to 4 inches and width 0.5 inches to 3.5 inches, length 2.5 inches to 4 inches and width 0.5 inches to 3.5 inches, length 3 inches to 4 inches and width 0.5 inches to 3.5 inches, length 3.5 inches to 4 inches and width 0.5 inches to 3.5 inches, length 0.5 inches to 4 inches and width 0.5 inches to 3 inches, length 1 inch to 4 inches and width 0.5 inches to 3 inches, length 1.5 inches to 4 inches and width 0.5 inches to 3 inches, length 2 inches to 4 inches and width 0.5 inches to 3 inches, length 2.5 inches to 4 inches and width 0.5 inches to 3 inches, width 2.5 inches to 4 inches Length and width from 0.5 inches to 3 inches, 3 inches to 4 inches in length and 0.5 inches to 3 inches in width, 3.5 inches to 4 inches in length and 0.5 inches to 3 inches in width, 0.5 inches to 4 inches in length and 0.5 inches to 2.5 inches in width, 1 inch to 4 inches in length and 0.5 inches to 2.5 inches in width, 1.5 inches to 4 inches in length and 0.5 inches to 2.5 inches in width, 1.5 inches to 4 inches in length and 0.5 inches to 2.5 inches in width, 2 inches to 4 inches in length and 0.5 inches to 2.5 inches in width, 2.5 inches to 4 inches in length and 0.5 inches to 2.5 inches in width, 3 inches to 4 inches in length and 0.5 inches to 2.5 inches in width, 3.5 inches to 4 inches in length and 0.5 inches to 2.5 inches in width. The following are measurements related to the length and width of a given size: 1 inch to 4 inches, 0.5 inches to 4 inches, 0.5 inches to 2 inches, 1 inch to 4 inches, 0.5 inches to 2 inches, 1.5 inches to 4 inches, 0.5 inches to 2 inches, 2 inches to 4 inches, 0.5 inches to 2 inches, 2.5 inches to 4 inches, 0.5 inches to 2 inches, 3 inches to 4 inches, 0.5 inches to 2 inches, 3.5 inches to 4 inches, 0.5 inches to 2 inches, 0.5 inches to 4 inches, 0.5 inches to 1.5 inches, 1 inch to 4 inches, 0.5 inches to 1.5 inches, and 1.5 inches to 4 inches.5 inches to 1.5 inches in width, 2 inches to 4 inches in length and 0.5 inches to 1.5 inches in width, 2.5 inches to 4 inches in length and 0.5 inches to 1.5 inches in width, 3 inches to 4 inches in length and 0.5 inches to 1.5 inches in width, 3.5 inches to 4 inches in length and 0.5 inches to 1.5 inches in width, 0.5 inches to 4 inches in length and 0.5 inches to 1 inch in width, 1 inch to 4 inches in length and 0.5 inches to 1 inch in width, 1.5 inches to 4 inches in length and 0.5 inches to 1 inch in width, 2 inches to 4 inches in length and 0.5 inches to 1 inch in width, 2.5 inches to 4 inches in length and 0.5 inches to 1 inch in width, 3 1 inch to 4 inches in length and 0.5 inches to 1 inch in width, 3.5 inches to 4 inches in length and 0.5 inches to 1 inch in width, 0.5 inches to 4 inches in length and 1 inch to 4 inches in width, 0.5 inches to 4 inches in length and 1.5 inches to 4 inches in width, 0.5 inches to 4 inches in length and 2 inches to 4 inches in width, 0.5 inches to 4 inches in length and 2.5 inches to 4 inches in width, 0.5 inches to 4 inches in length and 3 inches to 4 inches in width, 0.5 inches to 4 inches in length and 3.5 inches to 4 inches in width, 0.5 inches to 3.5 inches in length and 0.5 inches to 4 inches in width, 0.5 inches to 3.5 inches in length and 1 inch to 4 inches in width. Width of 1 inch, length of 0.5 inches to 3.5 inches and width of 1.5 inches to 4 inches, length of 0.5 inches to 3.5 inches and width of 2 inches to 4 inches, length of 0.5 inches to 3.5 inches and width of 2.5 inches to 4 inches, length of 0.5 inches to 3.5 inches and width of 3 inches to 4 inches, length of 0.5 inches to 3 inches and width of 3 inches to 4 inches, length of 0.5 inches to 3 inches and width of 0.5 inches to 4 inches, length of 0.5 inches to 3 inches and width of 1 inch to 4 inches, length of 0.5 inches to 3 inches and width of 1.5 inches to 4 inches, length of 0.5 inches to 3 inches and width of 2 inches to 4 inches, width of 0.5 inches to 3 inches. 1 inch in length and 2.5 inches to 4 inches in width, 0.5 inches to 3 inches in length and 3 inches to 4 inches in width, 0.5 inches to 3 inches in length and 3.5 inches to 4 inches in width, 0.5 inches to 2.5 inches in length and 0.5 inches to 4 inches in width, 0.5 inches to 2.5 inches in length and 1 inch to 4 inches in width, 0.5 inches to 2.5 inches in length and 1.5 inches to 4 inches in width, 0.5 inches to 2.5 inches in length and 2 inches to 4 inches in width, 0.5 inches to 2.5 inches in length and 2.5 inches to 4 inches in width, 0.5 inches to 2.5 inches in length and 3 inches to 4 inches in width, 0.5 inches to 2.5 inches in length and 3 inches to 4 inches in width.Width from 5 inches to 4 inches, length from 0.5 inches to 2 inches and width from 0.5 inches to 4 inches, length from 0.5 inches to 2 inches and width from 1 inch to 4 inches, length from 0.5 inches to 2 inches and width from 1.5 inches to 4 inches, length from 0.5 inches to 2 inches and width from 2 inches to 4 inches, length from 0.5 inches to 2 inches and width from 2 inches to 4 inches, width from 0.5 inches to 2 inches and width from 2 inches to 4 inches, length from 0.5 inches to 2 inches and width from 3 inches to 4 inches, length from 0.5 inches to 2 inches and width from 3.5 inches to 4 inches, length from 0.5 inches to 1.5 inches and width from 0.5 inches to 1.5 inches, width from 0.5 inches to 1.5 inches, width from 1 inch to 4 inches, length from 0.5 inches to 1.5 inches and width from 1.5 inches to 4 inches, width from 0.5 inches to 1.5 inches. (5 inches in length and 2 to 4 inches in width; 0.5 to 1.5 inches in length and 2.5 to 4 inches in width; 0.5 to 1.5 inches in length and 3 to 4 inches in width; 0.5 to 1.5 inches in length and 3.5 to 4 inches in width; 0.5 to 1 inch in length and 0.5 to 4 inches in width; 0.5 to 1 inch in length and 1 to 4 inches in width; 0.5 to 1 inch in length and 1.5 to 4 inches in width; 0.5 to 1 inch in length and 2 to 4 inches in width; 0.5 to 1 inch in length and 2.5 to 4 inches in width; 0.5 to 1 inch in length and 3 to 4 inches in width; 0.5 to 1 inch in length and 3.5 to 4 inches in width).

[0203] In some embodiments, the adhesive surface of the transdermal delivery patch has a length of 0.5 cm to 1 cm and a width of 0.5 cm to 1 cm.

[0204] In some embodiments, the adhesive surface of the transdermal delivery patch has a length of 1 to 1.5 inches and a width of 1 to 1.5 inches.

[0205] In some embodiments, the adhesive surface of the transdermal delivery patch has a length of 1.5 to 2 inches and a width of 1 to 1.5 inches.

[0206] In some embodiments, the release paper is silicone-coated or fluoropolymer-coated. In some embodiments, the release paper comprises a polyester sheet. In some embodiments, the release paper comprises a silicone-coated polyester sheet. In some embodiments, the release paper comprises a fluoropolymer-coated polyester sheet.

[0207] In some embodiments, one or more transdermal delivery patches are packaged within a pouch. Any suitable pouch material (e.g., single-layer or multi-layer pouch) can be used. Example pouch materials include (but are not limited to) polyester, polyethylene, foil, and combinations thereof. In some embodiments, the pouch comprises polyester (e.g., polyethylene terephthalate). In some embodiments, the pouch comprises polyethylene. In some embodiments, the pouch comprises foil. In some embodiments, one or more transdermal delivery patches are packaged within a multi-layer pouch.

[0208] In embodiments, the package has a length of 1 inch to 4 inches and a width of 1 inch to 4 inches (e.g., a length of 1.5 inches to 4 inches and a width of 1 inch to 4 inches, a length of 2 inches to 4 inches and a width of 1 inch to 4 inches, a length of 2.5 inches to 4 inches and a width of 1 inch to 4 inches, a length of 3 inches to 4 inches and a width of 1 inch to 4 inches, a length of 3.5 inches to 4 inches and a width of 1 inch to 4 inches, a length of 1 inch to 3.5 inches and a width of 1 inch to 4 inches, a length of 1.5 inches to 3.5 inches and a width of 1 inch to 4 inches, a length of 2 inches to 3.5 inches and a width of 1 inch to 4 inches, a length of 2 inches to 3.5 inches and a width of 1 inch to 4 inches, a length of 2.5 inches to 4 inches and a width of 1 inch to 4 inches, a length of 2.5 inches to 4 inches and a width of 1 inch to 4 inches, a length of 1 inch ... 3.5 inches in length and 1 to 4 inches in width, 3 inches to 3.5 inches in length and 1 to 4 inches in width, 1 inch to 3 inches in length and 1 to 4 inches in width, 1.5 inches to 3 inches in length and 1 to 4 inches in width, 2 inches to 3 inches in length and 1 to 4 inches in width, 2.5 inches to 3 inches in length and 1 to 4 inches in width, 1 inch to 2.5 inches in length and 1 to 4 inches in width, 1.5 inches to 2.5 inches in length and 1 to 4 inches in width, 2 inches to 2.5 inches in length and 1 to 4 inches in width, 1 inch to 2 inches in length and 1 to 4 inches in width. 1.5 inches to 2 inches in length and 1 inch to 4 inches in width, 1 inch to 1.5 inches in length and 1 inch to 4 inches in width, 1 inch to 4 inches in length and 1 inch to 3.5 inches in width, 1.5 inches to 4 inches in length and 1 inch to 3.5 inches in width, 1 inch to 4 inches in length and 1 inch to 3.5 inches in width, 1 inch to 4 inches in length and 1.5 inches to 3.5 inches in width, 1 inch to 4 inches in length and 2 inches to 3.5 inches in width, 1 inch to 4 inches in length and 2.5 inches to 3.5 inches in width, 1 inch to 4 inches in length and 3 inches to 3.5 inches in width, 1 inch to 4 inches in length and 3 inches to 3.5 inches in width, 1 inch to 4 inches in length and 3 inches to 3.5 inches in width, 1 inch to 4 inches in length and 2.5 inches to 3.5 inches in width, 1 inch to 4 inches in length and 2.5 inches to 3.5 inches in width, 1 inch to 4 inches in length and 3 ... (Length and width of 1 inch to 3 inches, length of 1 inch to 4 inches and width of 1.5 inches to 3 inches, length of 1 inch to 4 inches and width of 2 inches to 3 inches, length of 1 inch to 4 inches and width of 2.5 inches to 3 inches, length of 1 inch to 4 inches and width of 1 inch to 2.5 inches, length of 1 inch to 4 inches and width of 1.5 inches to 2.5 inches, length of 1 inch to 4 inches and width of 2 inches to 2.5 inches, length of 1 inch to 4 inches and width of 1 inch to 2 inches, length of 1 inch to 4 inches and width of 1.5 inches to 2 inches, length of 1 inch to 4 inches and width of 1 inch to 1.5 inches).

[0209] In some embodiments, the package has a length of 2.75 to 3.5 inches and a width of 2 to 2.75 inches. In some embodiments, the package has a length of 3.25 to 4 inches and a width of 2.5 to 3 inches.

[0210] In some embodiments, the transdermal delivery patch includes a drug layer attached to a backing layer, wherein:

[0211] The drug layer includes 1 mg to 2 mg of dexmedetomidine (e.g., 1.3 mg to 1.6 mg of dexmedetomidine or 1.4 mg to 1.5 mg of dexmedetomidine), a pressure-sensitive adhesive containing a hydroxyl-functionalized acrylate polymer, and lauryl lactate.

[0212] The drug layer has an adhesive surface suitable for adhesion to the skin surface, wherein the adhesive surface has a 3 cm depth. 2 up to 9 cm 2 (e.g., 6 cm) 2 up to 7 cm 2 ) surface area; and

[0213] The backing layer comprises polyethylene and polyethylene terephthalate.

[0214] In some embodiments, the transdermal delivery patch includes a drug layer attached to a backing layer, wherein:

[0215] The drug layer includes 1 mg to 2 mg of dexmedetomidine (e.g., 1.3 mg to 1.6 mg of dexmedetomidine or 1.4 mg to 1.5 mg of dexmedetomidine), a pressure-sensitive adhesive containing a hydroxyl-functionalized acrylate polymer, and lauryl lactate.

[0216] The drug layer is adhered to a release paper coated with a silicone or fluoropolymer, wherein, upon removal, the release paper exposes an adhesive surface suitable for adhesion to the skin surface of the drug layer, wherein the adhesive surface has a depth of 3 cm. 2 up to 9 cm 2 (e.g., 6 cm) 2 up to 7cm 2 ) surface area; and

[0217] The backing layer comprises polyethylene and polyethylene terephthalate.

[0218] In some embodiments, the transdermal delivery patch includes a drug layer attached to a backing layer, wherein:

[0219] The drug layer includes 2.5 mg to 3.5 mg of dexmedetomidine (e.g., 2.6 mg to 3.2 mg of dexmedetomidine), a pressure-sensitive adhesive containing a hydroxyl-functionalized acrylate polymer, and lauryl lactate;

[0220] The drug layer has an adhesive surface suitable for adhesion to the skin surface, wherein the adhesive surface has a 7 cm depth. 2 Up to 11 cm 2 (e.g., 9 cm) 2 Up to 10 cm 2 ) surface area; and

[0221] The backing layer comprises polyethylene and polyethylene terephthalate.

[0222] In some embodiments, the transdermal delivery patch includes a drug layer attached to a backing layer, wherein:

[0223] The drug layer includes 2.5 mg to 3.5 mg of dexmedetomidine (e.g., 2.6 mg to 3.2 mg of dexmedetomidine), a pressure-sensitive adhesive containing a hydroxyl-functionalized acrylate polymer, and lauryl lactate;

[0224] The drug layer is adhered to a release paper coated with a silicone or fluoropolymer, wherein, upon removal, the release paper exposes an adhesive surface suitable for adhesion to the skin surface of the drug layer, wherein the adhesive surface has a 7 cm² area. 2 Up to 11 cm 2 (e.g., 9 cm) 2 Up to 10 cm 2 ) surface area; and

[0225] The backing layer comprises polyethylene and polyethylene terephthalate.

[0226] In some embodiments, the transdermal delivery patch includes a drug layer attached to a backing layer, wherein:

[0227] The drug layer includes 2.5 mg to 3.5 mg of dexmedetomidine (e.g., 2.6 mg to 3.2 mg of dexmedetomidine), a pressure-sensitive adhesive containing a hydroxyl-functionalized acrylate polymer, and lauryl lactate;

[0228] The drug layer has an adhesive surface suitable for adhesion to the skin surface, wherein the adhesive surface has an 11 cm² area. 2 up to 14cm 2 (e.g., 12 cm) 2 up to 13 cm 2 ) surface area; and

[0229] The backing layer comprises polyethylene and polyethylene terephthalate.

[0230] In some embodiments, the transdermal delivery patch includes a drug layer attached to a backing layer, wherein:

[0231] The drug layer includes 2.5 mg to 3.5 mg of dexmedetomidine (e.g., 2.6 mg to 3.2 mg of dexmedetomidine), a pressure-sensitive adhesive containing a hydroxyl-functionalized acrylate polymer, and lauryl lactate;

[0232] The drug layer is adhered to a release paper coated with a silicone or fluoropolymer, wherein, upon removal, the release paper exposes an adhesive surface suitable for adhesion to the skin surface of the drug layer, wherein the adhesive surface has an area of ​​11 cm. 2 Up to 14 cm 2 (e.g., 12 cm) 2 up to 13 cm 2 ) surface area; and

[0233] The backing layer comprises polyethylene and polyethylene terephthalate.

[0234] In some embodiments, a transdermal delivery patch described herein is applied to the surface of an individual's skin. In other embodiments, one or more transdermal delivery patches (e.g., two, three, four, or five or more transdermal delivery patches) are applied to the surface of an individual's skin.

[0235] In embodiments utilizing multiple transdermal delivery patches, the total dose of dexmedetomidine (e.g., 1 mg to 3.5 mg) may be divided equally or unequally among the transdermal delivery patches. In some embodiments, the total dose of dexmedetomidine is divided equally. For example, a total dose of 2.92 mg of dexmedetomidine can be achieved using two transdermal delivery patches described herein, wherein each patch includes 1.3 mg to 1.6 mg of dexmedetomidine (e.g., 1.46 mg of dexmedetomidine).

[0236] In some embodiments, when using at least two transdermal delivery patches, they may be applied adjacent to each other onto an individual's skin surface. As used herein, "adjacent" means that the transdermal delivery patches are close together or adjacent to each other.

[0237] 5. Examples

[0238] The following abbreviations used in the examples have the definitions stated below:

[0239]

[0240] Example 1: Preparation of an exemplary transdermal delivery patch

[0241] A formulation is prepared by mixing dexmedetomidine and a pressure-sensitive adhesive in an organic solvent (e.g., ethyl acetate, isopropyl alcohol, hexane, or heptane with a solid content of 30-60 wt%), followed by further mixing. Once a homogeneous mixture is formed, the solution is poured onto release paper (2-3 mils of silicone-coated or fluoropolymer-coated polyester sheet) and dried at 60-80°C for 10-90 minutes. A single-layer adhesive film is then laminated onto a backing (e.g., PET and / or polyethylene), cut to the desired size, and packaged. In some cases, lauryl lactate (LL) is added to the adhesive composition during the initial mixing step. An illustration of an exemplary DMTS (dexmedetomidine transdermal system) patch of the present invention is provided. Figure 1A -C

[0242] DMTS and matched placebo systems are stored in their original packaging until dispensing. Packaged DMTS / matched placebo systems are stored at controlled room temperature (15°C to 30°C).

[0243] Example 2: A phase 2 clinical trial of agitation associated with Alzheimer's type dementia

[0244] 1. Research Overview

[0245] The study was designed to evaluate the efficacy of DMTS against the frequency and severity of agitation associated with dementia compared to placebo. This phase 2 study will be conducted in individuals residing in care facilities who have agitation associated with Alzheimer's type of dementia.

[0246] • Main objectives To evaluate the efficacy of DMTS compared with placebo on the frequency and severity of agitation associated with Alzheimer's type dementia.

[0247] • Secondary objectives Evaluation of (1) the safety and tolerability of DMTS (including evaluation of skin irritation), (2) the adhesiveness of DMTS and (3) the sedative effect of DMTS.

[0248] The primary outcome measure was the change in the ABS (Corrigan JD.) score from baseline (mean score from day -4 to day -1) to 96 hours after administration (day 1 to day 4).

[0249] Secondary outcome indicators are:

[0250] • Clinical Global Impression Scale-Severity (CGI-S) score at 96 hours post-administration (day 5) relative to baseline before randomization (day 1).

[0251] • Changes in ABS scores from baseline (average score from day -4 to day -1) to 168 hours after first administration (day 1 to day 7).

[0252] • Change in CGI-S score 168 hours after administration (day 8) relative to baseline before randomization on day 1.

[0253] • Percentage of individuals who met the DTMS / placebo administration guidelines on day 15.

[0254] • Changes in the Neuropsychiatric Questionnaire-Nursing Home Version (NPI-NH) from baseline score before randomization on day 1 (reviewed from day -7 to day -1) to score 168 hours after administration (reviewed from day 1 to day 7).

[0255] Other secondary outcome indicators are:

[0256] • The incidence and severity of adverse events (AEs) that occur during treatment.

[0257] • Clinically significant changes in safety assessment results (including, as needed, changes in vital signs, Mini-Mental State Examination (MMSE), clinical laboratory tests, electrocardiogram (ECG), and physical examination (PE)).

[0258] • Adhesion score.

[0259] • The sedation effect based on the Wilson Sedation Scale.

[0260] • Assess the severity and frequency of agitation in DMTS compared to placebo using the Paroxysmal Agitation Scale-Nursing Home Version (EAS-NH) at specified time points.

[0261] • Clinical Global Impression Scale-Change (CGI-C) scores at 96, 120, 144, and 168 hours after administration for each treatment period.

[0262] • Clinical Global Impression Scale-Change (CGI-C) score at 96 hours after the second administration (day 19) relative to baseline (score before randomization on day 1) and before administration (score before administration on day 15).

[0263] • Changes in the total ABS score from baseline (average score from day 01 to day -1) and from before administration (average score from day 11 to day 14) to 96 hours after the second administration (average score from day 15 to day 18).

[0264] • Change in CMAI total score from baseline (day -1) to day 15.

[0265] Phase 2 is a randomized, double-blind, placebo-controlled dual-administration study of DMTS or matched placebo during a 4-day treatment period (day 1 time 0 occurs when the first DMTS or matched placebo system is administered), followed by an additional 4-day treatment period using the same treatment (or matched placebo) 14 days later.

[0266] Eligible individuals were screened up to 21 days prior to the start of the study. Eligible individuals were randomized in a 1:1:1 ratio to receive treatment with 1 DMTS (1.46 mg dexmedetomidine) and 1 matched placebo, 2 DMTS (2.92 mg dexmedetomidine), or 2 matched placebos. Individuals in each treatment group received a total of 2 patches / systems per treatment period (see Table 1), for a total of 4 patches / systems during the study period. For the second treatment period beginning on day 15, if an individual continued to meet the agitation criteria (i.e., exhibiting an ABS score ≥22 at least once between days 11 and 14), the individual would receive the same treatment as in the first treatment period. Individuals who are not suitable for DTMS / placebo administration on day 15 will remain in the study without receiving any other treatment and will be evaluated in the same way as individuals who received any other treatment and will be evaluated in the same way as individuals who received DTMS / placebo administration on day 15 (except for PK sampling, sedation evaluation and evaluations directly related to the patch (e.g., adhesion evaluation)).

[0267] First, six individuals will be recruited and will receive DMTS / matched placebo. Safety data from these first six individuals will be reviewed (blinded or unblinded, as needed) and monitored.

[0268] Individuals will reside in their care facilities during the duration of the trial. This will be based on the event schedule ( Figure 2 The following assessments will be performed: agitation assessment (frequency and severity), sedation level assessment, safety assessment (including vital signs such as oxygen saturation [SpO2]); DMTS / matched placebo adhesion assessment, and skin irritation assessment. Additionally, blood samples will be collected to determine plasma dexmedetomidine concentrations.

[0269] Table 1: Treatment Group

[0270]

[0271] If an individual experiences any of the following conditions, the individual's medication will be discontinued and the DMTS removed at any point during the trial:

[0272] Wilson's sedation score was 5.

[0273] • Clinically significant symptomatic bradycardia.

[0274] • Clinically significant symptomatic hypotension.

[0275] • Falls are believed to be related to DMTS.

[0276] • Severe local adverse reactions (AEs) at the DMTS application site.

[0277] • Any SAE or severe AE.

[0278] 2. Individual choice and exit

[0279] Approximately 150 individuals will be randomized to receive treatment.

[0280] An individual is considered eligible to participate in this study if all of the following inclusion criteria are met:

[0281] • Voluntarily provide written informed consent.

[0282] • Male or female residing in a nursing home.

[0283] • Dementia diagnosed as probable Alzheimer's disease (AD) based on the National Association on Aging and Alzheimer's Disease (NIA-AA) guidelines (2018). The clinical diagnosis of "probable Alzheimer's disease (AD)" will be based on the 2018 NIA-AA diagnostic guidelines, which include patient biomarker data as part of the study diagnosis (Jack et al., 2018). If patient biomarker data is unavailable, the clinical diagnosis of probable AD will be based on the 2011 NIA-AA guidelines (McKhann et al., 2011), according to the 2018 NIA-AA diagnostic guidelines.

[0284] • Two or more episodes of agitation (impairing social activity, requiring staff or medical intervention, or impairing the ability to perform daily living activities) at the time of screening (using a 7-day review period).

[0285] • When assessing eligibility before randomization on day 1, the total ABS score must be ≥22 at least once between day -4 and day -1.

[0286] • The medication must remain unchanged for at least one week prior to screening.

[0287] • The Mini-Mental State Examination (MMSE) score is ≤ 23 at the time of screening.

[0288] • Female individuals should meet the following conditions:

[0289] ○ Not pregnant, not lactating, and not planning to become pregnant during or within one menstrual cycle after the study; and

[0290] Surgical sterilization; or postmenopause (i.e., amenorrhea for ≥2 years, as reported by the individual / caregiver; FSH testing will be used to confirm postmenopausal status); or a surgically sterilized monogamous partner; or a same-sex sexual partner; or using double-barrier contraception; or abstaining from sex; or using insertable, injectable, transdermal, or combination oral contraceptives for 3 months prior to the study, during the study, and 1 month after the study.

[0291] • Males who have female sexual partners of reproductive age during the study and one month after the study must undergo surgical sterilization or commit to using a reliable method of contraception.

[0292] • Weight > 50 kg and BMI between 20 and 38 kg / m² 2 (Include).

[0293] • Be able to understand the research procedures, comply with all research procedures, and agree to participate in the research process for its entire duration.

[0294] • Must have resided in the institution for at least 7 days prior to screening and will remain there until the evaluation is completed.

[0295] An individual is considered ineligible to participate in this study if any of the following exclusion criteria are met:

[0296] • Known hypersensitivity to either dexmedetomidine or DMTS / placebo.

[0297] • Based on the investigator’s examination at the clinic before screening or before surgery, the DMTS / matched placebo system application site has skin abnormalities (e.g., scars, tattoos) or unhealthy skin conditions (e.g., burns, wounds).

[0298] • Has clinically significant abnormal clinical laboratory test values ​​as determined by investigators.

[0299] • Suffering from agitation caused by acute poisoning.

[0300] • Patients who have a significant risk of suicide or homicide according to the investigator’s assessment, or who answered “yes” to item 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS).

[0301] • History of deep vein thrombosis or Leiden factor V deficiency.

[0302] • A history of positive test results for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.

[0303] • If, as determined by the investigator, a patient has a clinically significant history or clinical presentation of any of the following: renal, hepatic, cardiovascular, metabolic, neurological, or psychotic symptoms; congestive heart failure, peptic ulcer, gastrointestinal bleeding, or other conditions that may prevent participation in the study.

[0304] • A history of physician-diagnosed migraines, frequent nonvascular headaches (>5 times per month), epilepsy, or taking anticonvulsants.

[0305] • History of syncope or other syncope episodes.

[0306] • The presence and / or significant history of orthostatic hypotension (as determined by the investigator or the assignee) or, according to the investigator, a history of severe dizziness or syncope upon standing.

[0307] • There is clinically significant evidence of abnormalities in 12-lead ECG.

[0308] • Average heart rate (HR) < 60 or > 100 bpm, systolic blood pressure (BP) < 90 or 140 mmHg or systolic BP < 60 or > 90 mmHg, measured in three sequential positions (after 5 minutes of supine; after 2 minutes of sitting; and after 2 minutes of standing) and after repeating the sequence 3 times.

[0309] • Has a history of alcohol abuse or prescription drug abuse within the previous 5 years.

[0310] • A positive result in a urine drug screening or alcohol breath test indicates drug abuse or alcohol consumption at the time of screening and / or clinic registration.

[0311] • Concurrent therapy that is being evaluated for efficacy or safety that may interfere with the efficacy evaluation, such as any drug that, according to investigators, may have a significant synergistic interaction with dexmedetomidine.

[0312] • Use of any natural health product (including sage, comfrey, caddisfly, basil, kava, peppermint oil, scutellaria, St. John's wort, or valerian, excluding vitamin or mineral supplements) within 14 days prior to and throughout the study, unless advised by the investigator or assigner, does not interfere with the study procedures or data integrity or impair individual safety. Use of medications with potential cardiac effects (e.g., hypotension, bradycardia) may be permitted if the individual has been consistently taking such medications for at least 30 days prior to screening. Sedative medications (e.g., quetiapine) may or may not be permitted based on a possible evaluation of the study intervention interaction.

[0313] • Had symptoms of an upper respiratory tract infection within 14 days prior to administering the study drug.

[0314] • Administer oral or injectable corticosteroids within 14 days prior to administration of the investigational drug (intranasal and topical corticosteroids are permitted during this period).

[0315] • Accept any research and development product within 30 days prior to administering the investigational drug.

[0316] • Johns Hopkins Fall Risk Assessment Score >13.

[0317] • Based on the opinion of the researcher or the assigner, for any reason, they are deemed unsuitable to participate in the study and / or unable to comply with the study protocol.

[0318] In addition to the inclusion and exclusion criteria listed above, each individual agrees to comply with each of the following restrictions:

[0319] • Individuals cannot remove or tamper with the DMTS / matching placebo.

[0320] • If the DMTS / matched placebo becomes <90% sticky, the individual will alert the appropriate staff in the clinical research unit.

[0321] • When administering the DMTS / matched placebo system, individuals should avoid strenuous exercise, bathing, sauna, steam room, or any other activity or environment that may lead to excessive sweating.

[0322] • During treatment, individuals may need to shower once a day, provided that the shower lasts for ≤ 10 minutes.

[0323] • One week before the first dose of the study drug until the final PK sample is obtained, individuals should avoid the following foods: grapefruit juice or products, pomegranate juice or products, foods containing poppy seeds and / or beverages or foods containing quinine (e.g., quinine water) or lime (e.g., orange marmalade).

[0324] • No alcoholic beverages are permitted starting two days before surgery and during residence at the clinical research unit.

[0325] If an individual completes all screening procedures, receives the study drug as expected during treatment period 1, completes the follow-up period to day 14 and is not suitable for treatment period 2, and completes the study end (EOS) assessment; or if an individual completes all screening procedures, receives the study drug as expected during treatment periods 1 and 2 and completes the assessments for both treatment periods, and completes the study end (EOS) assessment, then the individual will complete the study.

[0326] Any individual with a TEAE will be followed until the AE subsides, returns to baseline, or is deemed stable by the investigator. Any individual who voluntarily withdraws from the study (e.g., withdraws consent) or interrupts the study for study-related reasons (e.g., due to TEAE) before all evaluations (Treatment Phase 1 or Treatment Phase 2) are completed will be considered to have prematurely discontinued the study.

[0327] Under any of the circumstances listed below, an individual may discontinue the study or decide to withdraw from the study voluntarily (or through LAR). The reason for early discontinuation should be detailed on the appropriate Case Report Form (CRF).

[0328] • die

[0329] • Adverse events

[0330] • Protocol violations that necessitate early termination of research, as assessed by the researcher, assigner, or commissioner.

[0331] • Loss to follow-up

[0332] • Noncompliance

[0333] • Pregnancy

[0334] • Individual decision (withdrawal of consent when the reason is unknown)

[0335] • The client terminates the research for any reason.

[0336] • Other: Researcher or individual decisions that cannot be categorized into one of the above categories (in this case, the reasons should be detailed in the relevant CRF).

[0337] 3. Research Procedures

[0338] Individuals will be randomized in a 1:1:1 ratio via an interactive network response system (IWRS) to receive 1 DMTS (1.46 mg dexmedetomidine) and 1 matched placebo, 2 DMTS (2.92 mg dexmedetomidine), or 2 matched placebos.

[0339] The commissioner, researchers, personnel directly involved in monitoring and / or performing research procedures and evaluations within the clinical research unit, as well as individuals and information providers, will not be aware of the treatment assignment.

[0340] In emergency situations, researchers may learn about treatment if and only if it is necessary to know the treatment assignment in order to properly guide medical management.

[0341] The investigational drug (i.e., DMTS / matched placebo) will be administered by qualified and trained personnel from a clinical research unit. Following administration, a mark (e.g., a line) will be made on the adjacent skin from the DMTS / matched placebo using indelible ink. The integrity of these marks will be visually inspected to assess for signs of tampering or removal of the DMTS or matched placebo and to evaluate individual adherence to proper wearing guidelines.

[0342] Personnel at clinical research units will retain a logbook for all investigational drugs.

[0343] Blood samples used to determine the plasma concentration of dexmedetomidine will be obtained at the following time points during the two treatment periods: before application and 24, 48, and 96 hours after application (before patch removal).

[0344] The study lasted 36 days. The screening period was 14 days. In the treatment phase 1, individuals received medication for 4 days and were followed up for 10 days. In the treatment phase 2, eligible individuals received medication for 4 days, were followed up for 3 days, and underwent the study termination procedure for 1 day. Uneligible individuals received medication were followed up for 7 days and underwent the study termination procedure for 1 day.

[0345] All the preprocessing procedures outlined in this section are summarized in the event timeline. Figure 2 )middle.

[0346] Filter (day -21 to day -1)

[0347] Individuals will undergo screening procedures during the screening period. Written informed consent will be obtained before any protocol-specific procedure is performed.

[0348] The following evaluations and procedures are required during the screening process to determine eligibility:

[0349] • Sign the Informed Consent Form (ICF).

[0350] • Starting from day -7, the ABS will be completed daily by the field staff (which will be used to assess compliance with the agitation criteria and calculate the baseline ABS score [average score from day -4 to day -1] before randomization on day 1).

[0351] • Abuse of drugs and alcohol testing.

[0352] • Medical history.

[0353] • Demography.

[0354] • Complete PE (including height and weight measurements) and BMI calculation.

[0355] • Review inclusion and exclusion criteria.

[0356] • Accompanying drug review.

[0357] • Vital signs: Blood pressure (BP), respiratory rate (RR), heart rate (HR), and pulse oximetry SpO2 were measured as follows: BP, RR, HR, and SpO2 were measured after the individual had been supine for at least 5 minutes, BP and HR were measured after the individual had been sitting for 1 minute, and BP and HR were measured after the individual had been standing for 2 minutes. This procedure was repeated twice more to obtain BP and HR in triplicate. Oral or infrared temperature was also measured once. Screening vital signs were reviewed for any events that might disqualify an individual from participating in the study (e.g., clinically significant bradycardia, arrhythmia, or other cardiovascular events).

[0358] • Liver function classification.

[0359] • Serological tests (Hepatitis B surface antigen [HBsAg], Hepatitis C antibody [HCV Ab], and HIV).

[0360] • Serum pregnancy test for women of reproductive age.

[0361] • Follicle-stimulating hormone (FSH) test in females.

[0362] • Results of clinical safety laboratory tests (hematology, serum chemistry, coagulation, and urine analysis) should be obtained before day -7.

[0363] • 12-lead ECG. Review the ECG to identify any events that might prevent an individual from participating in the study (e.g., clinically significant bradycardia, arrhythmia, or other cardiovascular events).

[0364] • MMSE.

[0365] • Complete EAS-NH daily starting from day -7.

[0366] • Columbia Suicide Severity Rating Scale (C-SSRS).

[0367] • Johns Hopkins Fall Risk Assessment.

[0368] • Review the Account Executive (AE).

[0369] Before randomization (Day 1)

[0370] The pre-randomization period is the final screening time and will be used as the baseline. The pre-randomization procedure is performed on day 1 before randomization to the treatment group and administration of study treatment. Individuals are randomized using IWRS after the following procedures have been performed and the individuals meet the entry criteria:

[0371] • Review inclusion and exclusion criteria. Examine the individual's agitation history to determine if the individual meets the medication criteria: two or more agitated episodes (e.g., kicking, biting, hitting, shouting) that impair social activity, require staff or medical intervention, or impair daily living functioning. Episodes should have occurred between day -7 and day -1 prior to medication. Confirm that the individual had at least one ABS total score ≥22 between day -1 and day -4.

[0372] • Vital signs: BP, RR, HR, and SpO2 measured using a pulse oximeter, as described below: BP, RR, HR, and SpO2 are measured after the individual has been supine for at least 5 minutes, then BP and HR are measured after the individual has been sitting for 1 minute, and then BP and HR are measured after the individual has been standing for 2 minutes. This procedure is repeated twice more to obtain BP and HR in triplicate. Oral or infrared temperature is also measured once. Review pre-randomization vital signs to identify any events that might disqualify the individual from participating in the study (e.g., clinically significant bradycardia, arrhythmia, or other cardiovascular events).

[0373] • Simplified PE includes evaluation of the HEENT, heart, lungs, and skin.

[0374] • Urine pregnancy test for women of reproductive age.

[0375] • 12-lead ECG. Review the pre-randomization ECG to identify any events that might disqualify an individual from participating in the study (e.g., clinically significant bradycardia, arrhythmia, or other cardiovascular events).

[0376] • CGI-S.

[0377] • NPI-NH.

[0378] • CMAI.

[0379] • Accompanying drug review.

[0380] • Review the Account Executive (AE).

[0381] Treatment Procedure

[0382] Treatment period 1 (day 1 to day 14)

[0383] During the treatment period, individuals will receive a single 4-day (96-hour) application of either DMTS or a matched placebo. Each application will consist of two systems (patches) applied to the same side of the back. The treatment period will begin when the DMTS and / or matched placebo system is applied (day 1, time 0). During treatment period 1, the patches will remain on the individual for four consecutive days (days 1 through 4; removed 96 hours after application on the morning of day 5). Follow-up procedures will be performed for the following 10 days (days 5 through 14) after the patches are removed 96 hours (4 days) after treatment period 1.

[0384] All research procedures during treatment phase 1 are summarized in the event timeline. Figure 2 ), and the timetable for agitation assessment ( Figure 3 The schedules for vital signs assessment (Table 2), PK assessment (Table 3), clinical safety laboratory testing (Table 4), and sedation assessment (Table 5) are as follows. When multiple procedures or assessments are performed simultaneously, the sequence is as follows: sedation, vital signs, PK, skin irritation, and adhesion.

[0385] Table 2. Timetable for vital sign assessment.

[0386]

[0387] Resting vital signs will be obtained after the individual has been supine for at least 5 minutes, then sitting for 1 minute, and then standing for 2 minutes. In the screening prior to randomization (Day 1), BP and HR will be measured in the supine, sitting, and standing sequence; this sequence will be repeated a total of 3 times. At all other time points, single BP and HR measurements will be obtained in the supine, sitting, and standing sequence. For individuals in wheelchairs who cannot stand, measurements in the supine and sitting positions are required only.

[0388] a. The values ​​before screening and randomization (day 1) will be used to study eligibility.

[0389] b. Use the randomized values ​​from day 1 as the baseline.

[0390] c. At 6, 12, 16, 36, 60, 84, 112, and 132 hours after DMTS / matched placebo administration / time 0:

[0391] • If the individual is already in bed and asleep, then vital signs cannot be measured.

[0392] • If the individual is awake, vital signs will be measured in supine, sitting, and standing positions.

[0393] The timing of vital sign assessment is as follows:

[0394] • The evaluation should be performed within ± 30 minutes of the specified nominal time.

[0395] • An evaluation that matches the PK blood draw should be performed before the PK blood draw.

[0396] • An evaluation consistent with patch removal should be performed before removal.

[0397] Table 3: Timeline of PK Evaluation

[0398]

[0399] All samples were obtained within the specified nominal time ± 30 minutes. A total of 8 samples will be collected for PK analysis. At each collection time point, 8 mL of blood will be drawn (6 mL for PK analysis + 2 mL for flushing the tubing (if necessary)). Based on this, a total of approximately 32 mL (for individuals treated in Treatment Phase 1 only) or 64 mL (for individuals treated in two Treatment Phases) of blood will be collected for PK. Evaluation of compatibility with patch removal should be performed prior to removal.

[0400] Table 4. Laboratory tests for clinical safety.

[0401]

[0402] In addition, pregnancy tests will be performed on women of childbearing age.

[0403] Table 5. Schedule for sedation assessment.

[0404]

[0405] Evaluations consistent with patch removal should be performed before removal. If the individual is asleep and has gone to bed, a sedation evaluation will not be obtained.

[0406] Treatment period 1 medication administration procedure (days 1 to 4)

[0407] The following procedures will be implemented during treatment phase 1:

[0408] Day 1:

[0409] • Use IWRS randomization.

[0410] • Assess vital signs before administration and at 6, 12, and 16 hours after administration.

[0411] • Obtain a PK sample prior to application.

[0412] • The DMTS / matched placebo system was administered to the hairless area of ​​the upper back within 3 hours of randomization.

[0413] • EAS-NH is completed by on-site staff.

[0414] • ABS is completed by on-site staff.

[0415] • The Wilson Sedation Scale was used to assess the patient before and 12 hours after administration.

[0416] • Adhesion scores were obtained 6 and 12 hours after application.

[0417] Day 2:

[0418] • Assess vital signs 24 and 36 hours after administration.

[0419] • Obtain PK samples 24 hours after application.

[0420] •ECG.

[0421] • EAS-NH is completed by on-site staff.

[0422] • ABS is completed by on-site staff.

[0423] • The Wilson Sedation Scale was used to evaluate the patient 24 and 36 hours after administration.

[0424] • Adhesion scores were obtained 24 and 36 hours after application.

[0425] Day 3:

[0426] • Assess vital signs at 48 and 60 hours after administration.

[0427] • Obtain PK samples 48 hours after application.

[0428] •ECG.

[0429] • EAS-NH is completed by on-site staff.

[0430] • ABS is completed by on-site staff.

[0431] • The Wilson Sedation Scale was used to evaluate the patient at 48 and 60 hours after administration.

[0432] • Adhesion scores were obtained 48 and 60 hours after application.

[0433] Day 4:

[0434] • Assess vital signs at 72 and 84 hours after administration.

[0435] • EAS-NH is completed by on-site staff.

[0436] • ABS is completed by on-site staff.

[0437] • The Wilson Sedation Scale was used to evaluate the patient 72 hours after administration.

[0438] • Adhesion scores were obtained 72 and 84 hours after application.

[0439] Phase 1 after medication (days 5 to 14)

[0440] Day 5:

[0441] • Obtain an adhesion evaluation at 96 hours (before removal).

[0442] • Remove DTMS / matching placebo system.

[0443] • Wipe the application site to check for any drug residue.

[0444] • Assess vital signs at 96 (before removal), 104 and 112 hours after administration.

[0445] • Obtain a PK sample 96 hours after application (before removal).

[0446] • Conduct clinical safety laboratory testing 96 hours after application (before removal).

[0447] • ABS is completed by on-site staff.

[0448] • CGI-S is obtained after the patch is removed.

[0449] • Obtain CGI-C after the patch is removed.

[0450] • EAS-NH is completed by on-site staff.

[0451] • Wilson sedation scores were obtained at 96 (before removal), 104, and 108 hours after application.

[0452] • Skin irritation assessment should be performed 1 hour after removal of the DMTS / placebo system.

[0453] Day 6:

[0454] • Assess vital signs at 120 and 132 hours after administration.

[0455] • ABS is completed by on-site staff.

[0456] • CGI-S.

[0457] • CGI-C.

[0458] • EAS-NH is completed by on-site staff.

[0459] • Wilson sedation scores were obtained at 120 and 132 hours after administration.

[0460] • Skin irritation should be evaluated 24 hours after removal of the DMTS / placebo system.

[0461] Day 7:

[0462] • Assess vital signs 144 hours after administration.

[0463] • ABS is completed by on-site staff.

[0464] • CGI-S.

[0465] • CGI-C.

[0466] • EAS-NH is completed by on-site staff.

[0467] • A Wilson sedation score was obtained 144 hours after administration.

[0468] Day 8:

[0469] • Assess vital signs 168 hours after administration.

[0470] • ABS is completed by on-site staff.

[0471] • CGI-S.

[0472] • CGI-C.

[0473] • EAS-NH is completed by on-site staff.

[0474] • A Wilson sedation score was obtained 168 hours after administration.

[0475] Day 9:

[0476] • Assess vital signs 192 hours after administration.

[0477] • ABS is completed by on-site staff.

[0478] • EAS-NH is completed by on-site staff.

[0479] • Wilson sedation score was obtained 192 hours after administration.

[0480] Day 10:

[0481] • Assess vital signs 216 hours after administration.

[0482] • ABS is completed by on-site staff.

[0483] • EAS-NH is completed by on-site staff.

[0484] • Wilson sedation score was obtained 216 hours after administration.

[0485] Day 11:

[0486] • Assess vital signs 240 hours after administration.

[0487] • ABS is completed by on-site staff.

[0488] • EAS-NH is completed by on-site staff.

[0489] • A Wilson sedation score was obtained 240 hours after administration.

[0490] Day 12:

[0491] • Assess vital signs 264 hours after administration.

[0492] • ABS is completed by on-site staff.

[0493] • EAS-NH is completed by on-site staff.

[0494] • A Wilson sedation score was obtained 264 hours after administration.

[0495] Day 13:

[0496] • Assess vital signs 288 hours after administration.

[0497] • ABS is completed by on-site staff.

[0498] • EAS-NH is completed by on-site staff.

[0499] • A Wilson sedation score was obtained 288 hours after administration.

[0500] Day 14:

[0501] • Assess vital signs 3-12 hours after administration.

[0502] • ABS is completed by on-site staff.

[0503] • EAS-NH is completed by on-site staff. SS

[0504] • Wilson sedation score was obtained 12 hours after SS3 administration.

[0505] All study procedures during post-administration period 1 are summarized in the event timeline ( Figure 2 ), and the timetable for agitation assessment ( Figure 3 The schedules for vital sign assessment (Table 2), PK assessment (Table 3), clinical safety laboratory testing (Table 4), and sedation assessment (Table 5) are included.

[0506] Treatment period 2 (days 15 to 21)

[0507] During the second treatment period, if an individual meets the criterion of having a total ABS score of ≥22 at least once during the period from day 11 to day 14 on day 15, then the individual will receive the same treatment administered during the first treatment period, with the patch placed on the opposite dorsal side of the first treatment period.

[0508] Individuals who are not suitable for DMTS / placebo administration on day 15 will remain in the study without receiving any other treatment and will undergo the same evaluations as those who receive DMTS / placebo administration on day 15 (except for PK sampling, sedation evaluation, and evaluations directly related to the patch (e.g., adhesion evaluation).

[0509] Review pre-treatment vital signs and ECG to identify any events that might prevent the individual from continuing the study (e.g., clinically significant bradycardia, arrhythmia, or other cardiovascular events).

[0510] Treatment period 2 will begin (day 15, time 0) on the morning of day 15 if DMTS or matched placebo has been administered (for individuals receiving DMTS / placebo on day 15), or on the morning of day 15 if inappropriate for DMTS / placebo on day 15 (for individuals not receiving DMTS / placebo on day 15). During treatment period 2, the patch will remain on the individual for four consecutive days (days 15 through 18; removed on the morning of day 19, 96 hours after application). Follow-up will be performed for the following three days (days 19 through 21) after the patch is removed four days after treatment period 2.

[0511] All study procedures during and after treatment phase 2 are summarized in the event timeline. Figure 2 In the context of multiple procedures or evaluations performed simultaneously, the sequence is as follows: sedation, vital signs, pharmacokinetic (PK), skin irritation, and adhesion.

[0512] Treatment schedule for Phase 2 (days 15 to 18)

[0513] Day 15:

[0514] The following procedures will be implemented during treatment phase 2:

[0515] • Use IWRS to obtain the drug / reagent number for each individual (only for individuals who received DMTS / placebo administration on day 15).

[0516] • Assess vital signs before administration / at time 0 and at 6, 12, and 16 hours after administration / at time 0.

[0517] • Obtain a PK sample before administering the DTMS / matched placebo system (only for individuals who received DMTS / placebo administration on day 15).

[0518] • Administer the DMTS / matched placebo system to the hairless area of ​​the upper back that was not used in treatment period 1 (only for individuals who received DMTS / placebo administration on day 15).

[0519] • Record the time when an individual is considered unsuitable for DMTS / placebo administration on day 15 and define this time as time 0 of treatment period 2 (only for individuals who did not receive DMTS / placebo administration on day 15).

[0520] • EAS-NH is completed by on-site staff.

[0521] • Complete CMAI before patch application / time 0.

[0522] • ABS is completed by on-site staff.

[0523] • Complete NPI-NH before patch application / time 0.

[0524] • Complete CGI-S before patch application / time 0.

[0525] • The Wilson Sedation Scale was used to assess individuals before and 12 hours after administration (only for individuals who received the DMTS / placebo on day 15).

[0526] • Adhesion scores were obtained 6 and 12 hours after administration (only for individuals who received DMTS / placebo administration on day 15).

[0527] Day 16:

[0528] • Assess vital signs 24 and 36 hours after administration / time 0.

[0529] • Obtain a PK sample 24 hours after administration (only for individuals who received DMTS / placebo administration on day 15).

[0530] •ECG.

[0531] • EAS-NH is completed by on-site staff.

[0532] • ABS is completed by on-site staff.

[0533] • The Wilson Sedation Scale was used to assess individuals 24 and 36 hours after administration (only for individuals who received the DMTS / placebo on day 15).

[0534] • Adhesion scores were obtained 24 and 36 hours after administration (only for individuals who received DMTS / placebo administration on day 15).

[0535] Day 17:

[0536] • Assess vital signs at 48 and 60 hours after administration / time 0.

[0537] • Obtain a PK sample 48 hours after administration (only for individuals who received DMTS / placebo administration on day 15).

[0538] • EAS-NH is completed by on-site staff.

[0539] • ABS is completed by on-site staff.

[0540] • The Wilson Sedation Scale was used to assess individuals 48 and 60 hours after administration (only individuals who received the DMTS / placebo on day 15 were assessed).

[0541] • Adhesion scores were obtained at 48 and 60 hours after administration (only for individuals who received DMTS / placebo administration on day 15).

[0542] Day 18:

[0543] • Assess vital signs at 72 and 84 hours after administration / time 0.

[0544] • EAS-NH is completed by on-site staff.

[0545] • ABS is completed by on-site staff.

[0546] • The Wilson Sedation Scale was used to assess individuals 72 hours after administration (only for individuals who received the DMTS / placebo on day 15).

[0547] • Adhesion scores were obtained at 72 and 84 hours after administration (only for individuals who received DMTS / placebo administration on day 15).

[0548] Phase 2 after medication (days 19 to 21)

[0549] Unless otherwise stated, all procedures were performed on both individuals who received DMTS / placebo administration on day 15 and individuals who did not receive treatment administration on day 15.

[0550] Day 19:

[0551] • Adhesion assessment was performed 96 hours (before removal) (only for individuals who received DMTS / placebo on day 15).

[0552] • Remove the DMTS / matched placebo system (only for individuals who received DMTS / placebo administration on day 15).

[0553] • Wipe the application site to check for drug residues (only for individuals who received DMTS / placebo on day 15).

[0554] • Evaluate vital signs at 96 (before removal), 104, and 112 hours after administration / time 0.

[0555] • Obtain a PK sample 96 hours after administration (before removal) (only for individuals who received DMTS / placebo administration on day 15).

[0556] • Clinical safety laboratory testing should be performed 96 hours after administration (before removal) / 96 hours after time 0.

[0557] • EAS-NH is completed by on-site staff.

[0558] • ABS is completed by on-site staff.

[0559] • Complete CGI-C 96 hours after patch removal / time 0.

[0560] • Complete CGI-S 96 hours after patch removal / time 0.

[0561] • Wilson sedation scores were obtained at 96 (before removal), 104, and 108 hours after administration (only for individuals who received DMTS / placebo administration on day 15).

[0562] • Skin irritation assessment should be performed 1 hour after removal of the DMTS / placebo system (only for individuals who received DMTS / placebo on day 15).

[0563] Day 20:

[0564] • Evaluate vital signs at 120 and 132 hours after administration / time 0.

[0565] • EAS-NH is completed by on-site staff.

[0566] • ABS is completed by on-site staff.

[0567] • CGI-C.

[0568] • CGI-S.

[0569] • The Wilson Sedation Scale was used to assess individuals 120 and 132 hours after administration (only individuals who received the DMTS / placebo on day 15 were assessed).

[0570] • Skin irritation assessment should be performed 24 hours after DTMS / placebo system removal (only for individuals who received DTMS / placebo on day 15).

[0571] Day 21:

[0572] • Assess vital signs 144 hours after administration / time 0.

[0573] • EAS-NH is completed by on-site staff.

[0574] • ABS is completed by on-site staff.

[0575] • CGI-C.

[0576] • CGI-S.

[0577] • The Wilson Sedation Scale was used to assess individuals 72 hours after administration (only for individuals who received the DMTS / placebo on day 15).

[0578] • Skin irritation assessment should be performed 144 hours after removal of the DTMS / placebo system (only for individuals who received DTMS / placebo on day 15).

[0579] Study ended (Day 22 or ET)

[0580] All individuals completing this study will complete the EOS procedure on day 22. Individuals who prematurely discontinue the study should complete the EOS procedure before termination.

[0581] The individual will complete the EOS procedure described below:

[0582] • PE

[0583] • Accompanying drug review

[0584] • AE Evaluation

[0585] • Vital signs (including oral or infrared temperature)

[0586] • Clinical safety laboratory tests (hematology, serum chemistry, and urine analysis)

[0587] •12-lead ECG

[0588] • MMSE

[0589] • Urine pregnancy test

[0590] • ABS completed by on-site staff

[0591] • NPI-NH

[0592] • EAS-NH is completed by on-site staff.

[0593] • CGI-C

[0594] • CGI-S

[0595] • Wilson Sedation Score

[0596] Individuals who prematurely discontinue the study drug should be encouraged to remain in the study and according to the event timeline ( Figure 2 The evaluation of the corresponding treatment period and follow-up should be completed, even after the DTMS / placebo system has been removed in advance.

[0597] In addition, the following evaluations should be performed before removing DTMS:

[0598] • Adhesion evaluation

[0599] • Vital signs

[0600] • Wilson Sedation Scale

[0601] • Blood samples used for PK analysis

[0602] After removing DMTS in advance:

[0603] • Skin irritation was evaluated 1 and 24 hours after removal of the DMTS / placebo system.

[0604] • Continue post-administration evaluation according to the event timeline.

[0605] Visually assess DMTS / matched placebo adhesion at the following time points (± 15 min): 6, 12, 24, 36, 48, 60, 72, and 84 hours after each application and ≤ 15 minutes before removal (96 hours after patch application). Evaluate DTMA / placebo system adhesion according to the scoring system described in Table 6.

[0606] Table 6. DMTS Adhesion Scale

[0607]

[0608] Research on drug materials and administration

[0609] DMTS provides prolonged release of dexmedetomidine over a 4-day administration period. Each DMTS has a 6 cm³ content. 2 It has a surface area and contains 1.46 mg of dexmedetomidine. The excipients include lauryl lactate and an acrylate-based copolymer.

[0610] The placebo-matched transdermal system is the same as that of DMTS, except that it does not contain dexmedetomidine.

[0611] Each DMTS or matched placebo system is individually packaged in a sealed package. Each package is labeled with study characteristics information to meet all applicable regulatory requirements. All shipments of DMTS / matched placebo systems will include a temperature monitoring device that records the environmental conditions of the product at regular intervals throughout the shipment. The study drug will not be dispensed until the client has verified that no temperature deviation has occurred during shipment.

[0612] Upon receiving the investigational product, staff at the clinical research unit will inspect the shipment to verify that the product was received under acceptable conditions. Once inspected, the investigational product will be immediately transferred to a suitable, environmentally controlled storage area.

[0613] DMTS and matched placebo systems will be stored in their original packaging until dispensing. Packaged DMTS / matched placebo systems will be stored at controlled room temperature.

[0614] All research products will be stored and handled strictly in accordance with the protocol, packaging markings, and instructions for supply to clinical research units and their designated pharmacies.

[0615] Individuals will receive two DMTS / matched placebo patches (as shown in Table 1) up to two times. Each DMTS / matched placebo patch will be applied to a hairless area of ​​the individual's upper back by a trained clinical investigator. If the individual's entire upper back is hairy, a portion of the upper back may be trimmed to facilitate patch application (the application site should not be shaved). The DMTS / matched placebo patches will be worn for four days (96 hours from the time of application).

[0616] Monitor the following steps to ensure proper maintenance of the DMTS / matched placebo patch:

[0617] 1. DMTS / matched placebo should not be removed or destroyed (unless this is not necessary to resolve AEs or other tolerability issues).

[0618] 2. If the DMTS / matching placebo becomes less than 90% sticky, the relevant field staff should be alerted.

[0619] 3. When administering the DMTS / matched placebo system, individuals should avoid strenuous exercise, bathing, sauna, steam room, or any other activity or environment that may lead to excessive sweating.

[0620] 4. During treatment, individuals may take one shower per day, provided that the shower lasts for ≤ 10 minutes.

[0621] 5. One week before the first dose of the study drug until the final PK sample has been obtained, individuals must avoid the following foods: grapefruit juice or products, pomegranate juice or products, foods containing poppy seeds and / or beverages or foods containing quinine (e.g., quinine water) or lime (e.g., orange marmalade).

[0622] 6. Do not consume alcoholic beverages starting 2 days before the first dose and during the study period.

[0623] After removal, each recovered DMTS will be stored in its original package to ensure drug attribution. The date of administration, individual identification, and location of administration will be marked on the appropriate label. Specific instructions will be provided. Recovered DMTS will be returned to the client.

[0624] After removal, each application site of the DMTS applied to the individual's back was tested for drug residue. Using a TX714K α sampling rapid swab (ITW Texwipe, Kernersville, NC), the swab was soaked in a 70% isopropyl alcohol / water mixture. Excess liquid was tapped off and the individual's back was gently swabbed along one direction (horizontal or vertical) where the DMTS was applied. The swab was flipped over and the application site area was swabbed a second time in the same direction as the first. The separate handle was broken off and the swab head was placed in an empty glass vial (20 mL or less, empty of liquid).

[0625] 4. Evaluation of efficacy, pharmacodynamics and pharmacokinetics

[0626] Effectiveness will be assessed by measuring agitation frequency, severity, and improvement. Figure 3 ).

[0627] Agitated Behavior Scale

[0628] The Abnormal Activity Scale (ABS) is a 14-item scale developed to objectively evaluate agitated behavior, particularly through continuous assessment, to evaluate interventions aimed at reducing agitation. The ABS items are as follows:

[0629] 1. Short attention span, easily distracted, and unable to concentrate.

[0630] 2. Impulsive, impatient, and with low tolerance for pain or frustration.

[0631] 3. Uncooperative, resistant to care or requests.

[0632] 4. Strong and / or threatening violence against people or property

[0633] 5. Explosive or unpredictable anger

[0634] 6. Shaking, rubbing, groaning, or other self-stimulatory behaviors

[0635] 7. Pulling on pipes or restraint devices

[0636] 8. Leave the treatment area

[0637] 9. Restlessness, pacing, or excessive movement

[0638] 10. Repetitive behaviors (motor and / or verbal)

[0639] 11. Speaking quickly, loudly, or excessively.

[0640] 12. Sudden change in mood.

[0641] 13. Excessive crying or laughing

[0642] 14. Self-harm (physical and / or verbal)

[0643] Use the following scales to assess behavior:

[0644] 1. Does not exist: The behavior does not exist.

[0645] 2. Mild: The behavior exists, but does not prevent the performance of appropriate behaviors in other situations (the individual can adjust on their own, or the persistent agitation does not interfere with appropriate behaviors).

[0646] 3. Moderate: The individual needs to shift from an agitated state to appropriate behavior, but can benefit from the cues provided.

[0647] 4. Extreme: Individuals are unable to engage in appropriate behavior due to agitation, even when given external cues or redirection.

[0648] For projects 10-14, a scoring guideline based on the number of events has been developed:

[0649]

[0650] The total ABS score ranges from 14 to 56. A total score of 21 or below is considered normal; 22 to 28 is considered mild; 29 to 35 is considered moderate; and 36 or above is considered severe agitation. ABS will be completed daily by field staff starting from day -7. ABS assessments should be completed at approximately the same time each day. During each assessment period, individual behavior in the 24 hours preceding the final assessment day will be evaluated.

[0651] Neuropsychiatric Questionnaire - Sanatorium Version (NPI-NH)

[0652] The Neuropsychiatric Inventory (NPI) was developed by Cummings et al. (Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J, The Neuropsychiatric Inventory: comprehensive assessment of psychopathology indementia., Neurology. 1994 Dec;44(12):2308-14.) to assess relevant behavioral symptoms (including AD). In cases where caregivers are professionals (e.g., in nursing homes), an interview with the NPI-NH version was conducted. The scale was provided to the individual's designated information provider through a certified clinician. The information provider was a staff member of the institution who had at least two hours of cumulative daily contact with the individual, at least three days a week, and directly observed the individual's behavior. Based on a series of scripted questions posed to an individual's designated information provider, NPI-NH uses a 7-day review period to assess the severity and frequency of each neuropsychiatric symptom and the degree of distress caused to the caregiver / research partner by each neuropsychiatric symptom. Follow-up questions are asked based on positive responses to screening questions, and yes / no responses are recorded. Frequency and severity are assessed based on the most aberrant behavior revealed in the follow-up questions. After determining frequency and severity, information providers are asked to rate the level of disruption of the behavior. After determining frequency and severity, caregivers are asked to rate the level of disruption of the behavior.

[0653] frequency:

[0654] 1. Rarely - less than once a week

[0655] 2. Sometimes - about once a week

[0656] 3. Frequently - several times a week but less than daily

[0657] 4. Very frequently - once or more per day

[0658] Severity:

[0659] 1. Mild-onset behavior causes stress to resident physicians but is manageable.

[0660] 2. Moderate-level behavior causes stress and distress to resident physicians and is difficult to control.

[0661] 3. Severe agitation causes immense stress and distress to resident physicians and is extremely difficult or impossible to manage. There is a possibility of self-harm, and medication is usually required.

[0662] Occupational disruption:

[0663] 0. No effect

[0664] 1. Minimal (daily work remains almost unchanged)

[0665] 2. Mild (some changes in daily operations but requiring a little time to revise the budget)

[0666] 3. Moderate (disruption of daily operations, requires time to revise the budget)

[0667] 4. Severe (causing disruptive impact and distress to staff and other resident physicians, consuming a significant amount of time)

[0668] 5. Extremely severe or extremely severe (highly destructive, a major source of distress for staff and other residents, often requiring time to be devoted to other residents or activities).

[0669] Complete NPI-NH was provided before randomization, on days 1, 8, 15, or before time 0, and on EOS (day 22) / ET (each with a 7-day review period).

[0670] Clinical Global Impression Severity (CGI-S) and Clinical Global Impression Change (CGI-C)

[0671] The overall clinical impression is based on the clinician's assessment of the clinical severity and variability of agitation. Both CGI-S and CGI-C will focus on the severity of agitation rather than the overall severity of dementia. CGI-C will refer to the relevant pre-treatment CGI-S (before randomization on day 1 for treatment period 1 and day 15 for treatment period 2) and will be evaluated at designated time points. The schedule for CGI-C and CGI-S assessments is shown below. Figure 3 middle.

[0672] The CGI-S is a 7-point (1-7) clinician-assessed scale, where higher grades indicate higher severity of agitation. The CGI-S is assessed based on the severity of agitation as follows:

[0673] 0. No rating

[0674] 1. Completely calm and undisturbed

[0675] 2. On the verge of agitation

[0676] 3. Mild agitation

[0677] 4. Moderate agitation

[0678] 5. Significant agitation

[0679] 6. Severe agitation

[0680] 7. Among the most severely agitated patients

[0681] Changes in agitation will be assessed using CGI-C. CGI-C scores range from 1 to 7.

[0682] 0. No rating (missing)

[0683] 1. Significant improvements,

[0684] 2. Moderate improvement.

[0685] 3. Slight improvements,

[0686] 4. No change.

[0687] 5. Mild deterioration,

[0688] 6. Moderate deterioration,

[0689] 7. Significantly worsened.

[0690] Paroxysmal Agitation Scale - Nursing Home Version (EAS-NH)

[0691] EAS-NH is designed to assess the frequency and severity of agitation daily. For each agitated behavior, the frequency and severity are recorded over a 24-hour period. EAS-NH provides daily assessments of agitation frequency and severity. EAS-NH is completed from day -7 until EOS. Field staff will record the frequency of agitated behaviors (i.e., resistance, self-harm or harm to others, agitated speech, and agitation / nervousness) daily. For each of these agitated behaviors, the assessor records the following:

[0692] A: There was no agitated behavior.

[0693] B: The behavior exists, but it does not affect daily life and does not require additional attention from caregivers.

[0694] C: The patient has difficulty controlling their behavior, which has a certain impact on daily life, but does not require extensive attention from caregivers.

[0695] D: Poor behavioral control significantly impacts daily life, requiring continuous attention from caregivers.

[0696] E: Extreme behavior; safety precautions should be taken.

[0697] EAS-NH should be completed at approximately the same time each day. During each assessment period, assess individual behavior in the 24 hours preceding the last day of assessment. EAS-NH data can be flexibly aggregated and scaled to indicate the frequency and severity of agitation during a specified review period (e.g., day-4 to day-1, day-7 to day-1, day 1 to day-4, day 1 to day 7, etc.).

[0698] The Cohen-Mansfield Agitation Inventory (CMAI)

[0699] The CMAI is a 29-item scale that systematically assesses agitation. It is used to assess the frequency of physical aggression, non-physical aggression, and verbal agitation in older adults with limited self-care abilities.

[0700] The CMAI was applied using a 14-day review, where the frequency of each item within this 14-day interval was assessed based on the following 7-point scale:

[0701] 1. Never

[0702] 2. Less than once a week

[0703] 3. Once or twice a week

[0704] 4. Several times a week

[0705] 5. Once or twice a day

[0706] 6. Several times a day

[0707] 7. Several times per hour

[0708] CMAI is performed by researchers or their appointees on Day 1 (before randomization) and Day 15 through formal interviews with designated information providers. Information providers are staff members of the stated institution or facility who have had at least 2 hours of cumulative daily contact with the individual, at least 3 days per week, and directly observe the individual's behavior.

[0709] According to the sedation assessment schedule (Table 5), the sedation level will be assessed by field personnel at least once a day. The Wilson sedation scale presented in Table 7 will be used to assess the sedation level (Némethy M, Paroli L, Williams-Russo PG, Blank TJ). Sedation will be assessed using regional anesthesia: inter-rater agreement on a modified Wilson sedation scale. (Anesth. Analg. 2002;94:723-8).

[0710] Table 7. Original Wilson Sedation Scale

[0711]

[0712] A sedation assessment consistent with patch removal should be performed before removal.

[0713] Use MMSE to assess cognitive function.

[0714] Mini-Mental State Examination (MMSE)

[0715] The Folstein Mental State Examination (MMSE) is a standard mental state test commonly used to assess cognition. The domains measured by the MMSE include orientation to time and place, roll call, attention and counting, memory, naming, repetition, comprehension, reading, writing, and drawing. The maximum total score for this test is 30. The MMSE will be administered during screening and again at EOS.

[0716] 5. Safety assessment

[0717] Safety assessment included evaluating adverse events (AEs) from the time of informed consent signing to the end of the study, clinical laboratory tests (hematology, serum chemistry, coagulation, and urinalysis), vital signs, ECG, and physical examination. Skin irritation was assessed using the modified Draize scoring system.

[0718] An AE is any adverse medical event related to the use of a drug in humans, whether or not it is considered to be related to the drug. An AE can be any adverse and unexpected sign (including clinically significant laboratory abnormalities), symptom, or illness that is temporarily related to the use of a drug or investigational product, without any determination of causation. An AE can be caused by the use of any drug and any route of administration, formulation, or dosage (including overdose).

[0719] All adverse events (AEs) occurring between the individual's ICF signing and the EOS visit will be recorded on the corresponding CRF. AEs will be determined based on voluntarily provided signs or symptoms and clinical observation and evaluation during the study visit. Spontaneously reported AEs will be recorded accurately, and AEs will be elicited by clinical study staff at designated time points using non-leading questions. Any AE occurring at the application site of the DMTS / matched placebo system will be designated as an application site reaction on the source documentation and CRF.

[0720] All SAEs and non-regressed AEs will be subject to appropriate medical management until the investigator or assignee confirms that regression has been achieved, the patient has returned to baseline, or the patient has reached a stable state.

[0721] Unless the intensity, frequency, or quality of the drug changes after administration, a pre-existing condition, disease, or symptom is not considered a TEAE.

[0722] The severity of adverse events (AEs) is summarized in Table 8.

[0723] Table 8. Classification of the severity of adverse events

[0724]

[0725] For each AE, the investigator or assigner will evaluate the causal relationship (i.e., the relationship between the AE and the investigational drug) according to the definition provided in Table 9.

[0726] Table 9. Classification of Causal Relationships of Adverse Events (Relationship with Study Drug)

[0727]

[0728] A SAE is defined as an AE that results in any of the following:

[0729] •die

[0730] • Life-threatening AEs (that is, AEs that put an individual at immediate risk of death; according to this criterion, it is assumed that AEs that could cause death (if more serious) are not SAEs)

[0731] • Hospitalization of inpatients or extension of their existing hospital stay

[0732] • Permanent or significant impairment or substantial disruption of the ability to perform normal daily functions

[0733] • Congenital abnormalities / birth defects

[0734] • Important medical events that may not lead to death, may not endanger life, or may not require hospitalization, but may endanger an individual or require medical or surgical intervention to prevent the outcomes listed above, based on appropriate medical judgment.

[0735] Skin irritation at each DMTS / matched placebo site will be evaluated at 1 hour (± 5 min) and 24 hours (± 2 h) after removal of the DMTS / matched placebo. Skin irritation evaluation will include assessing the presence and severity of erythema, edema, papules, and vesicles (if present) using the scales in Table 7.

[0736] Whenever a skin irritation assessment produces a non-zero score, the symptoms will be recorded and tracked as a TEAE (Training-Effective Acute Relapse). Any individual with a skin irritation score ≥ 1 will be tracked until the irritation subsides or stabilizes.

[0737] Any skin irritation or other local effects at the drug application site (which are not included in the Skin Irritation Scale (Table 10) and / or identified outside the predetermined skin irritation evaluation time point) will be recorded as TEAE and designated as an application site reaction.

[0738] Table 10. Skin Irritation Rating Scale

[0739]

[0740] Clinical safety laboratory tests will include hematology, fasting, serum chemistry, coagulation, and urinalysis, as described in Table 4. Hematology, serum chemistry, coagulation, and urinalysis will be performed at screening. Although the screening period will be extended from day -14 to before randomization on day 1, the screening clinical safety laboratory tests must be performed before randomization—within 7 days prior to day 1 (i.e., no earlier than day -7) and early enough to obtain results promptly for randomization on day 1. Hematology, serum chemistry, and urinalysis will be performed on day 5, day 19, and at the EOS visit or at the time of early study interruption. FSH testing will be performed only at screening in postmenopausal females.

[0741] The results of all laboratory tests will be reviewed by the investigator or assignee. For clinical safety laboratory tests, a maximum of approximately 71 mL of blood will be obtained from each individual. If the result of any test is outside the reference range or if additional testing is required to ensure safety due to clinical symptoms, additional samples may be obtained upon the advice of the investigator or assignee.

[0742] The total volume of blood to be drawn during this study for hematological, serological, coagulation serological and PK sampling is approximately 135 mL per individual.

[0743] Blood will be collected only during screening, following standard procedures for viral serological testing to screen for HBsAg, HCV Ab, and HIV. Individuals will be provided with counseling before and after hepatitis and HIV testing. Only individuals with negative viral serological tests are eligible for the study.

[0744] During screening, tests for alcohol and drug abuse will be performed on-site. Only individuals with negative results for both tests will be eligible for the study. Test results will be recorded in the source file. Urine will be tested for opioids, amphetamines, cocaine, benzodiazepines, and cannabinoids. A breathalyzer test will be performed for alcohol.

[0745] All medications (prescription and over-the-counter, herbal remedies, or investigational drugs) taken by an individual during the period prior to screening and 30 days before drug administration will be documented in the source file. The reported medications will be reviewed and evaluated by the investigator or assignee to determine whether they affect an individual's eligibility to participate in the study.

[0746] For females of reproductive age, serum pregnancy testing will be performed during screening, and urine pregnancy testing will be performed before randomization (day 1) and on EOS. Individuals with positive pregnancy tests will be excluded from the study.

[0747] All medications (prescription and over-the-counter, herbal remedies, or investigational drugs) taken by an individual during the period prior to screening and 30 days before drug administration will be documented in the source file. The reported medications will be reviewed and evaluated by the investigator or assignee to determine whether they affect an individual's eligibility to continue participating in the study.

[0748] All medications administered to recruited individuals from screening to EOS will be documented and recorded on the corresponding CRF. Reported medications will be reviewed and evaluated by the investigator or assignee to determine whether they affect an individual's eligibility to continue participating in the study.

[0749] If an individual has been taking a medication with potential cardiac effects (e.g., hypotension, bradycardia) for at least 30 days prior to screening, then the medication may be permitted for use.

[0750] Based on the investigator's and medical monitor's assessment of the potential interaction of the research intervention, sedative agents (such as quetiapine (Seroquel)) may or may not be permitted.

[0751] Individuals may receive rescue medications for agitation. The criteria for care determining whether treatment for agitation is appropriate will be followed. All rescue medications administered to recruited individuals from screening to EOS will be documented and recorded on the relevant CRF.

[0752] The following therapies will be prohibited during the designated screening period and throughout the study:

[0753] • Chronic opioid therapy for >2 weeks within one month prior to the administration of the study drug.

[0754] • Use of natural health products (containing sage, comfrey, caddisfly, basil, kava, peppermint oil, scutellaria, St. John's wort, or valerian, excluding vitamin or mineral supplements) within 14 days prior to drug administration and throughout the study, unless advised by the investigator or appointer, does not interfere with the study procedures or data integrity or compromise individual safety.

[0755] • Opium preparations, amphetamines, cocaine, benzodiazepines, and cannabinoids, as determined by a positive urine drug screening test.

[0756] • Concurrent therapy that may interfere with the assessment of efficacy or safety, such as any drug that the investigator deems to have significant sedative properties or to act synergistically with the investigational drug. The investigator's evaluation of the potential interaction with the investigational intervention may or may not permit on-demand treatment with sedative agents.

[0757] A physical examination (PE) will be performed (excluding breast, urinary tract, and rectal examinations) to assess an individual's overall health and physical condition at screening and EOS visits. The PE will include an assessment of the following body systems: head, ears, eyes, nose and throat (HEENT), lymph nodes, heart, lungs, limbs, peripheral blood vessels, abdomen, nerves, chest / back, and skin. Only at the screening visit will the PE also include height and weight measurements (and BMI calculation).

[0758] A simplified physical examination will be performed upon clinic registration and will include evaluations of the following body systems: HEENT, heart, lungs, and skin.

[0759] Any new or worsening physical finding that meets the definition of an AE (observed after administration of DMTS / matched placebo) should be reported as an AE.

[0760] A 12-lead ECG will be obtained during screening, clinic registration, and EOS. Each ECG will be obtained after the individual has rested in a supine position for at least 5 minutes. The ECG will be electronically measured, and ventricular rate and PR, QRS, QT, and QTc intervals will be calculated. The investigator will review all ECG findings to assess whether any value outside the corresponding normal range is clinically significant. All clinically significant abnormalities that meet the definition of AE will be reported as AEs and recorded on the AE CRF.

[0761] According to Figure 2Vital signs consisting of blood pressure (BP), respiratory rate (RR), heart rate (HR), and SpO2 were measured according to the schedule provided in Table 2. Resting vital signs were obtained after the individual was in a supine position for at least 5 minutes, then in a sitting position for 1 minute, and then in a standing position for 2 minutes. In the screening prior to randomization (Day 1), BP and HR were measured in the supine, sitting, and standing sequence; this sequence was repeated a total of 3 times. At all other time points, a single BP and HR measurement was obtained in the supine, sitting, and standing sequence.

[0762] Oral or infrared body temperature will be measured before screening, randomization (day 1), and at EOS.

[0763] When rising from a supine or sitting position, individuals should be advised to be cautious of orthostatic hypotension symptoms (dizziness, postural instability, vertigo, etc.). Generally, it is recommended that individuals transition slowly from a supine to a sitting position or from a sitting to a standing position. When sitting, the individual's legs should be suspended and not crossed. When rising to a standing position, the individual should avoid holding their breath. If the individual experiences dizziness or other symptomatic orthostatic hypotension after rising or during the initiation of a standing BP measurement, they should immediately return to a supine position and remain supine until the symptoms subside. Repeat supine BP measurements should be obtained.

[0764] If the time of vital sign measurement coincides with the time of PK sampling, then the vital sign measurement should be obtained before the PK blood draw.

[0765] If symptomatic adverse events (AEs) are potentially related to changes in vital signs, then vital signs should also be measured and recorded. Any clinically significant abnormal vital signs will be recorded on the AE CRF.

[0766] Clinically significant bradycardia in a given individual is defined as an absolute HR < 45 bpm or a decrease of > 30% relative to the mean HR value obtained before DMTS / matched placebo administration, and this value lasts for 1 minute.

[0767] Clinically significant symptomatic bradycardia will be accompanied by one or more of the following persistent symptoms: syncope, dizziness, fatigue, chest pain, dyspnea, and hypoxemia (SpO2 < 90%).

[0768] Clinically significant hypotension in a given individual is defined as an absolute blood pressure (systolic blood pressure < 80 mmHg or diastolic blood pressure < 50 mmHg) or a lower value (absolute or relative to baseline) that is > 30% lower than the corresponding mean blood pressure obtained before administration of DMTS / matched placebo, and this value (absolute or relative to baseline) lasts for 1 minute.

[0769] Clinically significant symptomatic hypotension will be accompanied by one or more of the following persistent symptoms: syncope, dizziness, fatigue, chest pain, difficulty breathing, hypoxemia (SpO2 < 90%), and cold, clammy skin.

[0770] If an individual experiences a symptomatic, clinically significant cardiovascular event (e.g., bradycardia or hypotension), DMTS should be removed, and the following measures may be implemented as needed based on the investigator's judgment:

[0771] • Administer fluids (orally or intravenously).

[0772] • If the individual has low blood pressure and bradycardia, then administer a small dose of atropine.

[0773] • If the individual has low blood pressure, then administer a vasopressor.

[0774] Columbia Suicide Severity Rating Scale (C-SSRS)

[0775] The Columbia Suicide Severity Rating Scale (C-SSRS) is a suicidal ideation rating scale. This scale identifies behaviors and thoughts associated with an increased risk of future suicidal behavior. C-SSRS assessments will be administered during screening.

[0776] Johns Hopkins Fall Risk Assessment

[0777] The Johns Hopkins Fall Risk Assessment Tool helps staff determine an individual's fall risk level. The scale uses various score-based criteria to derive an overall risk score. A score <6 is considered low fall risk, 6-13 indicates moderate fall risk, and >13 indicates high fall risk. The Johns Hopkins Fall Risk Assessment will be administered during screening. Individuals with a Johns Hopkins Fall Risk Assessment score >13 will be excluded from the study.

[0778] Liver function grading and liver injury assessment

[0779] Liver function grading is a measure of overall liver damage calculated based on multiple clinical liver disease indicators. Liver function grading will be determined during the screening period. Individuals with a liver function grading score >5 will be excluded from the study.

[0780] 6. Evaluation of efficacy, pharmacokinetics and pharmacodynamic data

[0781] The primary efficacy outcome measure is the change in the total ABS score from baseline (mean score from day -4 to day -1) to 96 hours after the first treatment administration (day 1 to day 4). The estimate of the primary efficacy outcome measure is the difference in the mean change from baseline (mean score from day -4 to day -1) to 96 hours after the first treatment administration (day 1 to day 4) between individuals in the ITT population randomized to placebo and those randomized to DMTS dose groups, where treatment policy strategies are appropriate for the comorbidity of concern (e.g., non-adherence, treatment interruption, or use of prohibited agents). Analysis of the primary efficacy outcome measure will be performed using a repeated measures mixed model (MMRM) based on a restricted maximum likelihood approach, with the change from baseline on each day of the first treatment administration as the response variable and including treatment group, baseline, center of study, date, baseline-date interaction, and treatment group-date interaction as model terms. The population-level summary will be the difference in equally weighted treatment differences from day 1 to day 4 in the mixed model.

[0782] Similarly, the ITT population will be the target population for evaluating key secondary outcome measures, and treatment policies and strategies will be adapted to the occurrence of the comorbidities of concern. The same MMRM for the primary outcome measure will be used to analyze changes in ABS scores from baseline (mean score from day -4 to day -1) to 168 hours after first treatment administration (day 1 to day 7). CGI-S scores at 96 hours post-administration and at 168 hours post-administration relative to baseline (score before randomization on day 1) will be analyzed in a similar manner. Changes in NPI-NH scores from baseline before randomization on day 1 to 168 hours post-administration will be analyzed using an ANCOVA model, with treatment, score before randomization on day 1, and center of study as model terms. The methodology for analyzing the percentage of individuals meeting the DTMS / placebo administration criteria on day 15, any supplemental agitation analyses using ABS, CGI-S, CGI-C, NPI-NH, and CMAI at additional time points during treatment period 1 and treatment period 2, and the methodology for controlling for Type I error associated with multiple tests will be specified in SAP.

[0783] Venous blood samples for PK analysis were obtained according to the schedule outlined in Table 3. The total eight PK sampling times for Treatment Phases 1 and 2 were scheduled as follows: before administration and 24, 48, and 96 hours after administration. Sample collection at 96 hours was performed prior to patch removal. All samples were obtained within the specified nominal time ± 30 minutes. Treatment Phase 2 PK samples were not collected from individuals unsuitable for Treatment Phase 2 administration.

[0784] For each PK sample, approximately 8 mL of blood will be drawn (6 mL for PK analysis + 2 mL for flushing the tubing (if necessary)). Therefore, a total of up to approximately 32 mL (for individuals receiving treatment period 1 only) or 64 mL (for individuals receiving two treatment periods) of blood will be drawn from each individual for PK evaluation.

[0785] The plasma concentrations of dexmedetomidine at each time point will be summarized using arithmetic and geometric means, SD, median, range, and coefficient of variation. The time history of the plasma concentration data will be plotted as needed.

[0786] The sedation score will be summarized over time.

[0787] 7. Analysis of security data

[0788] Clinical safety laboratory testing includes hematology, fasting serum chemistry, coagulation, and urinalysis. Hematological, serum chemistry, coagulation, and urinalysis are performed at screening. Although the screening period will be extended from day -21 to before randomization on day 1, screening laboratory tests should be performed and results obtained before the start of ABS screening evaluation from day -7 to day -1. Serological, serum chemistry, and urinalysis are also performed on day 5, day 19, and at the EOS visit, or if the study is interrupted early. FSH testing is performed only at screening in postmenopausal women.

[0789] The results of all laboratory tests will be reviewed by the investigator or assignee. For clinical safety laboratory tests, a maximum of approximately 71 mL of blood will be obtained from each individual. If the result of any test is outside the reference range or if additional testing is required to ensure safety due to clinical symptoms, additional samples may be obtained upon the advice of the investigator or assignee. The total volume of blood drawn during this study for hematological, serological, coagulation, serological, and PK sampling will be approximately 135 mL per individual.

[0790] All individuals receiving the study treatment will be included in the summary and list of safety data. AEs will be coded using the MedDRA (Medical Dictionary of Regulatory Activities) and tabulated by System Organ Classification (SOC) and Priority Item (PT). Individual events (PTs) within each SOC will be presented in descending order of frequency. AEs will be presented by maximum severity and their relationship to the study treatment. SAEs will be summarized separately.

[0791] Descriptive statistics (mean, median, SD, and range) of vital signs, MMSE, ECG data, and clinical laboratory data over time will be presented, along with changes from baseline. For clinical laboratory data, the number (percentage) of individuals with results below, within, and above the normal range will be tabulated by visit. Quantitative changes from baseline will be summarized, and a transition table indicating changes from normal status will be presented (if appropriate). Abnormal findings in the laboratory data will be listed.

[0792] Termination data (including reasons for early interruption) will be summarized by overall treatment. Concomitant medications, PE findings, and medical history will be listed. Skin irritation data will be summarized. Adhesion scores at each evaluation time point will be summarized.

[0793] During screening, estimated glomerular filtration rate (eGFR) should be calculated. To meet study eligibility requirements, an individual's eGFR should be higher than the lower limit of the age- and sex-specific ranges shown in Table 11. The ranges in this table were obtained from approximately 3,000 potential kidney donors aged between 20 and 80 years.

[0794] Table 11: Age- and sex-specific normal GFR reference ranges

[0795]

[0796] GFR = Glomerular Filtration Rate

[0797] Note: The ranges in this table are based on GFR measurements from 2,974 prospective living kidney donors.

[0798] 8. Statistics

[0799] The full details of the statistical analysis will be documented in the Statistical Analysis Plan (SAP), which will include estimates of key performance indicators, the analysis population, the summarization strategy, sensitivity analysis, and details of any variations presented in the analysis (if applicable).

[0800] Determination of sample quantity

[0801] The study plans to randomize approximately 150 individuals. Individuals will be randomly assigned in a 1:1:1 ratio to either the treatment group (1 DMTS 1.46 mg dexmedetomidine and 1 matched placebo, or 2 DMTS 2.92 mg dexmedetomidine and 2 matched placebos), requiring a sample size of approximately 47 evaluable individuals per treatment group to achieve at least 85% efficacy in detecting a 2.0-point difference in the change from baseline in the total ABS score from baseline to 96 hours after the first administration (day 1 to day 4) between the DMTS and placebo groups. This calculation is based on the assumption of a two-sample t-test (two-sided α set at the 0.05 level and a common standard deviation (SD) of 3.2 points for the change in score). Assuming a 6% dropout rate, approximately 150 individuals (50 per treatment group) will be needed for randomization to retain 141 evaluable individuals.

[0802] Randomization

[0803] IWRS will be used to randomly assign individuals equally to treatment groups.

[0804] Analysis of groups

[0805] The intention-to-treat (ITT) cohort consists of all randomized individuals. The ITT cohort will be the target cohort for primary and key secondary efficacy assessments, with the randomized treatment group used in the analysis. A subgroup of the ITT cohort will include all individuals receiving a second treatment. This subgroup will be the target cohort for an exploratory evaluation of efficacy related to second treatment administration.

[0806] The safety cohort includes all individuals who have been randomized and treated. The safety cohort will be used to aggregate safety data based on the treatment received.

[0807] Statistical analysis will be performed using SAS.

[0808] Demographic and other baseline characteristics of all individuals at the start of the study will be summarized. Continuous variables will be summarized as mean, SD, median, and range; categorical characteristics will be presented as the percentage of individuals belonging to each relevant category.

[0809] The study confirmed, through one or more measures, that patient agitation decreased after treatment. The study also confirmed that patients did not become substantially sedated as a result of treatment.

[0810] 6. Equivalent forms and incorporation by reference

[0811] Although the provided disclosure has been shown and illustrated, especially with reference to preferred embodiments and various alternative embodiments, those skilled in the art will understand that various changes may be made to its form and details without departing from the spirit and scope of the provided disclosure.

[0812] For all purposes, all references, patents and patent applications (including U.S. Provisional Application No. 63 / 698,171) cited in the text of this specification are incorporated herein by reference in their entirety.

Claims

1. A method for treating agitation in an individual in need, comprising applying one or more transdermal delivery patches to the skin surface of the individual, wherein the individual is not agitated at the time of application, wherein: The transdermal delivery patch comprises a pharmaceutical composition containing dexmedetomidine; and The one or more transdermal delivery patches deliver a therapeutically effective, non-sedating dose of dexmedetomidine to the individual.

2. The method of claim 1, wherein the agitation is associated with the individual’s severe neurocognitive disorder (MND).

3. The method according to claim 2, wherein the MND is selected from neurocognitive disorders (NCDs) caused by Alzheimer's disease, vascular NCDs, Lewy body NCDs, NCDs caused by Parkinson's disease, frontotemporal NCDs, NCDs caused by traumatic brain injury, NCDs caused by HIV infection, substance / drug-induced NCDs, NCDs caused by Huntington's disease, NCDs caused by prion diseases, NCDs caused by medical conditions, NCDs caused by multiple etiologies, and NCDs caused by unknown etiologies.

4. The method of claim 2, wherein the MND is NCD caused by Alzheimer's disease.

5. The method of claim 2, wherein the MND is dementia (e.g., Alzheimer's type dementia).

6. The method according to any one of claims 1 to 5, wherein the individual is not hospitalized.

7. The method of claim 6, wherein the individual resides in a care facility.

8. The method according to any one of claims 1 to 5, wherein the individual is hospitalized.

9. The method according to any one of claims 1 to 8, wherein the individual is at least 60 years old, at least 65 years old, at least 70 years old, or at least 75 years old.

10. The method according to any one of claims 1 to 9, wherein the individual is diagnosed with dementia, possibly Alzheimer's disease.

11. The method according to any one of claims 1 to 10, wherein the individual had two or more agitated episodes during a 7-day review period prior to the application of one or more transdermal delivery patches.

12. The method of claim 11, wherein the two or more episodes of agitation impair social activity, require medical intervention, or impair the ability to perform daily living activities.

13. The method according to any one of claims 1 to 12, wherein when performed on one of seven days prior to the application of one or more transdermal patches, the individual has a Mini-Mental State Examination (MMSE) score of ≤ 23.

14. The method according to any one of claims 1 to 13, wherein when performed on one of four days prior to the application of one or more transdermal patches, the individual has at least one agitated behavior scale (ABS) score of at least 22.

15. The method according to any one of claims 1 to 13, wherein the skin surface is selected from the arm, lower leg, thigh, hip, buttock, abdomen, back, neck, scrotum, vagina, face, forehead and behind the ear.

16. The method according to any one of claims 1 to 15, wherein the one or more transdermal delivery patches are applied by the individual himself / herself.

17. The method according to any one of claims 1 to 15, wherein the one or more transdermal delivery patches are applied by someone other than the individual.

18. The method of claim 17, wherein the skin surface is not within the reach of the individual's manual touch.

19. The method of claim 18, wherein the skin surface is the upper or lower back of the individual.

20. The method according to any one of claims 1 to 19, wherein the one or more transdermal delivery patches are maintained on the skin surface of the individual for a duration of at least 72 hours, for example 96 hours ± 3 hours.

21. The method of claim 20, further comprising removing the one or more transdermal delivery patches from the skin surface of the individual.

22. The method of claim 21, wherein when the individual experiences two or more episodes of agitation within a 7-day review after removal of the one or more transdermal delivery patches, the method further comprises applying another one or more transdermal delivery patches to the skin surface of the individual.

23. The method of claim 21, wherein when the individual experiences two or more episodes of agitation within a 14-day review period after removal of the one or more transdermal delivery patches, the method further comprises applying another one or more transdermal delivery patches to the skin surface of the individual.

24. The method of claim 22 or 23, wherein at least 10 days after the application of the one or more transdermal delivery patches to the skin surface of the individual, the other one or more transdermal delivery patches are applied to the skin surface of the individual.

25. The method of claim 24, wherein at least 14 days after the application of the one or more transdermal delivery patches to the skin surface of the individual, the other one or more transdermal delivery patches are applied to the skin surface of the individual.

26. The method according to any one of claims 22 to 25, wherein the additional one or more transdermal delivery patches are maintained on the skin surface of the individual for a duration of at least 72 hours, for example 96 hours ± 3 hours.

27. The method according to any one of claims 22 to 26, further comprising removing the additional one or more transdermal delivery patches from the skin surface of the individual.

28. The method according to any of the preceding claims, wherein after applying the one or more transdermal delivery patches or the other one or more transdermal delivery patches to the skin surface and maintaining them on the skin surface for at least 72 hours, for example 96 hours ± 3 hours, the frequency or severity of the individual's agitation is reduced.

29. The method of claim 28, wherein a reduction in the frequency or severity of agitation is determined by changes in one or more of the following scales: The Agitation Behavior Scale (ABS) Cohen-Mansfield Agitation Inventory (CMAI) Clinical Global Impression (CGI) severity (S) and change in CGI (CGI) Neuropsychiatric Questionnaire - Sanatorium Version NPI-NH, and Paroxysmal Agitation Scale - Sanatorium Version EAS-NH 30. The method of claim 29, wherein 96 hours after applying and maintaining the one or more transdermal delivery patches on the skin surface of the individual, the individual's ABS score is less than the baseline ABS score of the individual evaluated before the application of the one or more transdermal delivery patches.

31. The method of claim 29 or 30, wherein 168 hours after applying the one or more transdermal delivery patches to the skin surface of the individual and maintaining them for 4 days (i.e., 96 hours), the individual's ABS score is less than the baseline ABS score of the individual evaluated before the application of the one or more transdermal delivery patches.

32. The method of claim 29, wherein the individual's ABS classification changes from severe to moderate, from severe to mild, from severe to normal, from moderate to mild, from moderate to normal, or from mild to normal.

33. The method according to any one of claims 29 to 32, wherein the CMAI baseline score is based on a 14-day review period prior to the application of the one or more transdermal delivery patches to the skin surface of the individual.

34. The method according to any one of claims 29 to 33, wherein the CMAI follow-up score is obtained 15 days after application of one or more transdermal delivery patches to the skin surface of the individual.

35. The method according to any one of claims 29 to 34, wherein, 15 days after the application of the one or more transdermal delivery patches to the skin surface of the individual and maintenance for 4 days (i.e., 96 hours), the total CMAI score is less than the individual's baseline total CMAI score.

36. The method according to any one of claims 29 to 35, wherein 168 hours after the application of the one or more transdermal delivery patches to the skin surface of the individual and maintenance for 4 days (i.e., 96 hours), the individual's NPI-NH score is less than the individual's baseline NPI-NH score.

37. The method of claim 36, wherein both NPI-NH scores are evaluated using a 7-day review period.

38. The method according to any one of claims 29 to 37, wherein after applying the one or more transdermal delivery patches to the skin surface of the individual and maintaining them for 4 days (i.e., 96 hours), the individual's EAS-NH score is lower than the baseline EAS-NH score of the individual evaluated before application of the one or more transdermal delivery patches at one or more of the following time points: 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 168 hours, 192 hours, 216 hours, 240 hours, 264 hours, 288 hours, or 336 hours after application.

39. The method according to any one of claims 29 to 38, wherein when the individual is evaluated at least 96 hours after the application of the one or more transdermal delivery patches to the skin surface of the individual and maintenance for 4 days (i.e., 96 hours), the individual's Clinical Global Impression Scale-Change CGI-C score is 1 to 3.

40. The method according to any one of claims 29 to 39, wherein after applying the one or more transdermal delivery patches to the skin surface of the individual and maintaining them for 4 days (i.e., 96 hours), at 96 hours, 120 hours, 144 hours and / or 168 hours, the individual's CGI-C score is less than the individual's baseline CGI-S score measured before the application of the one or more transdermal delivery patches.

41. The method according to any one of claims 29 to 40, wherein after applying the one or more transdermal delivery patches to the skin surface of the individual and maintaining them for 4 days (i.e., 96 hours), at 96 hours, 120 hours, 144 hours and / or 168 hours, the individual's Clinical Global Impression Scale-Severity (CGI-S) score is less than the individual's baseline CGI-S score measured before the application of the one or more transdermal delivery patches.

42. The method according to any one of the preceding claims, wherein the one or more transdermal delivery patches comprise 1 mg to 3.5 mg of dexmedetomidine, for example 1 mg to 3 mg, 1 mg to 2 mg or 2 mg to 3 mg, preferably 1.46 mg or 2.92 mg.

43. The method according to any of the preceding claims, wherein the transdermal delivery patch comprises a drug layer attached to a backing layer, wherein The drug layer comprises 1 mg to 3.5 mg of dexmedetomidine and a pressure-sensitive adhesive, wherein the drug layer has an adhesive surface suitable for adhesion to the skin surface.

44. The method of claim 40, wherein the adhesive surface has a 3 cm² area. 2 up to 20 cm 2 Surface area.

45. The method according to claim 40 or 41, wherein the drug layer comprises 1 mg to 2 mg of dexmedetomidine, for example 1.3 mg to 1.6 mg of dexmedetomidine, preferably 1.4 mg to 1.5 mg of dexmedetomidine.

46. ​​The method according to claim 40 or 41, wherein the drug layer comprises 2.5 mg to 3.5 mg dexmedetomidine, preferably 2.92 mg dexmedetomidine.

47. The method of claim 41, wherein the adhesive surface has a 3 cm... 2 Up to 10 cm 2 Preferably 6cm 2 up to 7 cm 2 Surface area.

48. The method of claim 41, wherein the adhesive surface has a 7 cm² area. 2 Up to 11 cm 2 Preferably 9cm 2 Up to 10 cm 2 Surface area.

49. The method of claim 41, wherein the adhesive surface has an 11 cm² area. 2 Up to 14 cm 2 Preferably 12cm 2 up to 13 cm 2 Surface area.

50. The method of any one of claims 40 to 46, wherein the transdermal delivery patch has a length of 0.5 to 4 inches and a width of 0.5 to 4 inches.

51. The method according to any one of claims 40 to 47, wherein the pressure-sensitive adhesive comprises an acrylic polymer, an acrylate copolymer, an acrylate-vinyl acetate copolymer, polyacrylonitrile, or a combination thereof.

52. The method of claim 48, wherein the pressure-sensitive adhesive comprises a hydroxyl-functionalized acrylate copolymer.

53. The method according to any one of claims 40 to 49, wherein the drug layer further comprises a penetration enhancer.

54. The method of claim 50, wherein the penetration enhancer comprises lauryl lactate, oleic acid, or a combination thereof.

55. The method of claim 51, wherein the penetration enhancer is lauryl lactate.

56. The method according to any one of claims 40 to 52, wherein the transdermal delivery patch further comprises a backing layer.

57. The method of claim 53, wherein the backing layer comprises a film containing polyolefin resin, polyacrylic resin, polyester resin, cerova, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyvinyl chloride, polystyrene, polyurethane, polyacrylonitrile, fluoropolymer, styrene-isoprene-styrene copolymer, styrene-butadiene rubber, polybutadiene, ethylene-vinyl acetate copolymer, polyamide, polysulfone, or combinations thereof.

58. The method of claim 54, wherein the membrane comprises a polyolefin resin selected from polyethylene and polypropylene.

59. The method of claim 54, wherein the membrane comprises a polyester resin, wherein the polyester resin is polyethylene terephthalate.

60. The method of claim 54, wherein the membrane comprises polyethylene and polyethylene terephthalate.

61. The method according to any one of claims 40 to 57, wherein the transdermal delivery device further comprises release paper adhered to the adhesive surface of the drug layer.

62. The method of claim 58, wherein the release paper comprises a silicon or fluoropolymer coating.

63. The method of claim 40, wherein the transdermal delivery patch comprises a drug layer containing 1 mg to 2 mg of dexmedetomidine (e.g., 1.4 mg to 1.6 mg, preferably 1.46 mg), a pressure-sensitive adhesive comprising a hydroxyl-functionalized acrylate polymer, and lauryl lactate; wherein The drug layer has an adhesive surface suitable for adhesion to the skin surface, wherein the adhesive surface has a depth of 3 cm. 2 up to 9cm 2 Preferably 6 cm 2 up to 7 cm 2 Surface area; and The backing layer comprises polyethylene and polyethylene terephthalate.

64. The method of claim 40, wherein the transdermal delivery patch comprises a drug layer containing 2.5 mg to 3.5 mg dexmedetomidine (e.g., 2.92 mg dexmedetomidine), a pressure-sensitive adhesive comprising a hydroxyl-functionalized acrylate polymer, and lauryl lactate; wherein The drug layer has an adhesive surface suitable for adhesion to the skin surface, wherein the adhesive surface has a 7 cm diameter. 2 up to 11cm 2 Preferably 9 cm 2 Up to 10 cm 2 Surface area; and The backing layer comprises polyethylene and polyethylene terephthalate.

65. The method of claim 40, wherein the transdermal delivery patch comprises a drug layer containing 2.5 mg to 3.5 mg dexmedetomidine (preferably 2.92 mg dexmedetomidine), a pressure-sensitive adhesive comprising a hydroxyl-functionalized acrylate polymer, and lauryl lactate; wherein The drug layer has an adhesive surface suitable for adhesion to the skin surface, wherein the adhesive surface has an area of ​​11 cm. 2 Up to 14 cm 2 Preferably 12 cm 2 up to 13 cm 2 Surface area; and The backing layer comprises polyethylene and polyethylene terephthalate.

66. The method according to any one of claims 40 to 62, wherein the transdermal delivery device further comprises release paper adhered to the adhesive surface of the drug layer.

67. The method of claim 63, wherein the release paper comprises a silicone-coated polyester.

68. The method according to any of the preceding claims, wherein the one or more percutaneous delivery patches deliver a therapeutically effective, non-sedating dose of dexmedetomidine to the individual for at least two days.

69. The method according to any of the preceding claims, wherein at any time after applying one or more transdermal delivery patches to a skin surface and maintaining contact between the skin surface and the one or more transdermal delivery patches (e.g., 24 hours, 48 ​​hours, 72 hours, and 96 hours after application), the one or more transdermal delivery patches provide 0.005 to 5 μg / cm³. 2 / hr of dexmedetomidine in vitro average flux.

70. The method according to any of the preceding claims, wherein at any time after application of the one or more patches and maintenance of contact between the skin surface and the one or more patches (e.g., 24 hours, 48 ​​hours, 72 hours, 96 hours and / or 120 hours after application), the one or more transdermal delivery patches provide 0.5 μg / cm³. 2 / hr to 3 μg / cm 2 / hr, for example 0.5 μg / cm 2 / hr to 2 μg / cm 2 / hr or 0.5 μg / cm 2 / hr to 1 μg / cm 2 / hr of dexmedetomidine in vitro average flux.

71. The method according to any of the preceding claims, wherein, 24 hours after application of the one or more transdermal delivery patches and maintenance of contact between the skin surface and the one or more transdermal delivery patches, the one or more transdermal delivery patches provide 0.5 μg / cm 2 / hr to 3 μg / cm 2 / hr, for example 0.5 μg / cm 2 / hr to 2 μg / cm 2 / hr or 0.5 μg / cm 2 / hr to 1 μg / cm 2 / hr of dexmedetomidine in vitro average flux.

72. The method according to any of the preceding claims, wherein, 48 hours after application of the one or more transdermal delivery patches and maintenance of contact between the skin surface and the one or more transdermal delivery patches, the one or more transdermal delivery patches provide 0.5 μg / cm 2 / hr to 3 μg / cm 2 / hr, for example 0.5 μg / cm 2 / hr to 2 μg / cm 2 / hr or 0.5 μg / cm 2 / hr to 1 μg / cm 2 / hr of dexmedetomidine in vitro average flux.

73. The method according to any of the preceding claims, wherein, 72 hours after application of the one or more transdermal delivery patches and maintenance of contact between the skin surface and the one or more transdermal delivery patches, the one or more transdermal delivery patches provide 0.5 μg / cm 2 / hr to 3 μg / cm 2 / hr, for example 0.5 μg / cm 2 / hr to 2 μg / cm 2 / hr or 0.5 μg / cm 2 / hr to 1 μg / cm 2 / hr of dexmedetomidine in vitro average flux.

74. The method according to any of the preceding claims, wherein, 96 hours after application of the one or more transdermal delivery patches and maintenance of contact between the skin surface and the one or more transdermal delivery patches, the one or more transdermal delivery patches provide 0.5 μg / cm 2 / hr to 3 μg / cm 2 / hr, for example 0.5 μg / cm 2 / hr to 2 μg / cm 2 / hr or 0.5 μg / cm 2 / hr to 1 μg / cm 2 / hr of dexmedetomidine in vitro average flux.

75. The method according to any of the preceding claims, wherein, 120 hours after application of the one or more transdermal delivery patches and maintenance of contact between the skin surface and the one or more transdermal delivery patches, the one or more transdermal delivery patches provide 0.5 μg / cm 2 / hr to 3 μg / cm 2 / hr, for example 0.5 μg / cm 2 / hr to 2 μg / cm 2 / hr or 0.5 μg / cm 2 / hr to 1 μg / cm 2 / hr of dexmedetomidine in vitro average flux.

76. The method according to any one of the preceding claims, wherein the one or more transdermal delivery patches provide 0.1 μg / cm 2 / hr to 3 μg / cm 2 / hr, for example 0.1 μg / cm 2 / hr to 2.5 μg / cm 2 / hr, 0.1 μg / cm 2 / hr to 2.0μg / cm 2 / hr, 0.1 μg / cm 2 / hr to 1.5 μg / cm 2 / hr, 0.1 μg / cm 2 / hr to 1 μg / cm 2 / hr or 0.1 μg / cm 2 / hr to 0.8μg / cm 2 / hr of in vitro dexmedetomidine peak flux.

77. The method according to any one of the preceding claims, wherein the one or more transdermal delivery patches provide 0.5 μg / cm 2 / hr to 3 μg / cm 2 / hr, for example 0.5 μg / cm 2 / hr to 2.5 μg / cm 2 / hr, 0.5 μg / cm 2 / hr to 2.0μg / cm 2 / hr, 0.5 μg / cm 2 / hr to 1.5 μg / cm 2 / hr or 0.5 μg / cm 2 / hr to 1 μg / cm 2 / hr of in vitro dexmedetomidine peak flux.

78. The method according to any of the preceding claims, wherein the peak dexmedetomidine flux is reached 2 hours or longer after application of the one or more transdermal delivery patches, for example, 4 hours or longer, 6 hours or longer, 12 hours or longer, 18 hours or longer, or 24 hours or longer after application of the one or more transdermal delivery patches and maintenance of contact between the skin surface and the one or more transdermal delivery patches.

79. The method according to any of the preceding claims, wherein at least two transdermal delivery patches are applied to the skin surface of the individual.

80. The method of claim 76, wherein the at least two transdermal delivery patches are applied adjacent to each other onto the skin surface of the individual.

81. The method according to any of the preceding claims, wherein the estimated glomerular filtration rate (eGFR) of the individual is above the lower limit of the age- and sex-specific ranges provided in Table 11.

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