Methods of managing pain using dexmedetomidine transdermal delivery devices

Abstract

Aspects of the invention include methods of managing pain in a subject by applying a transdermal delivery device containing a dexmedetomidine composition that is formulated to deliver a pain-relieving effective amount of dexmedetomidine to the subject. In practicing methods according to certain embodiments, a transdermal delivery device having a dexmedetomidine composition is applied to a subject and maintained in contact with the subject in a manner sufficient to deliver an amount of dexmedetomidine effective to manage pain in the subject. In some embodiments, a method includes hydrating the subject, such as by administering a hydrated fluid composition to the subject. Methods according to certain embodiments may also include co-administering an opioid to the subject. Also provided is a transdermal delivery device configured to deliver dexmedetomidine sufficient for practicing the methods of the invention; and a kit containing the transdermal delivery device.

Description

[0001] Case Analysis

[0002] This application is a divisional application of Chinese patent application No. 2017800721755, filed on May 22, 2019, entitled "Method for managing pain using a dexmedetomidine transdermal delivery device".

[0003] Cross-reference to related applications

[0004] Pursuant to 35 USC §119(e), this application claims priority to the filing dates of U.S. Provisional Patent Application Serial No. 62 / 415,248, filed October 31, 2016, and U.S. Provisional Patent Application Serial No. 62 / 547,582, filed August 18, 2017, the disclosure of which is incorporated herein by reference. Technical Field

[0005] This application relates to a method for managing pain, and more specifically, to a method for managing pain using a dexmedetomidine transdermal delivery device. Background Technology

[0006] Pain is the most common reason for seeking medical advice in the United States. Pain is an unpleasant sensory and emotional experience associated with actual or potential damage to tissues, bones, nerves, or cells. Most pain subsides immediately and the body heals once the painful stimulus is removed, but sometimes the pain persists despite the removal of the stimulus and the apparent healing of the body. (Foye's Principles of Medicinal Chemistry (7th Edition, 2013), p. 660)

[0007] In the United States, approximately 20 million surgical procedures are performed annually under general anesthesia. Surgical pain or discomfort following surgery or traumatic injury is a serious and often difficult-to-treat medical problem. The pain is usually located near the surgical site. Surgical pain can have two clinically important aspects: resting pain, or pain that occurs when the patient is not moving, and mechanical pain that is exacerbated by movement (coughing / sneezing, getting out of bed, physical therapy, etc.). A major problem with the management of surgical pain in major surgeries is the variety of prominent side effects of currently used medications.

[0008] Dexmedetomidine is the S-enantiomer of medetomidine and is used as a sedative in intensive care units and by anesthesiologists as an α2-adrenergic receptor agonist in intubated or non-intubated patients requiring sedation for surgery or short procedures. α2-adrenergic receptors are G protein-coupled receptors associated with a Gi heterotrimeric G protein comprising three highly homologous subtypes, including α... 2a α 2b and α 2cAdrenergic receptors. Activators of α2-adrenergic receptors are involved in sedation, muscle relaxation, and analgesia through their effects on the central nervous system.

[0009] Dexmedetomidine is used clinically as a sedative administered intravenously and therefore requires close supervision by qualified medical professionals in the hospital. Dexmedetomidine is currently used for sedation of intubated or mechanically ventilated subjects during treatment in intensive care settings, and for sedation of non-intubated subjects before and / or during non-surgical procedures. Summary of the Invention

[0010] Aspects of the present invention include a method for managing pain in a subject by applying a percutaneous delivery device comprising a dexmedetomidine composition formulated to deliver an effective amount of dexmedetomidine to the subject for pain relief. In practicing the method according to certain embodiments, the percutaneous delivery device having the dexmedetomidine composition is applied to the subject and maintained in contact with the subject in a manner sufficient to deliver an amount of dexmedetomidine effective for managing the subject's pain. In some embodiments, the method includes hydrating the subject. The method according to certain embodiments may also include co-administering an opioid to the subject. A percutaneous delivery device configured to deliver dexmedetomidine sufficient for practicing the method of the present invention is also provided; and a kit containing said percutaneous delivery device. Attached Figure Description

[0011] Figure 1 An example is shown of a curve of the average dexmedetomidine flow rate over time when applied to a transdermal delivery device of a dexmedetomidine transdermal composition having polyisobutylene / polybutene and a crosslinked polyvinylpyrrolidone adhesive, according to one embodiment.

[0012] Figure 2 Figure A shows an example of the cumulative dexmedetomidine delivery over time according to one implementation scheme. Figure 2 Figure B shows an example of a curve of the average dexmedetomidine flow rate over time as applied by a transdermal delivery device to a dexmedetomidine transdermal composition having a nonfunctionalized acrylate adhesive, according to one embodiment. Figure 2 Figure C illustrates an example of dexmedetomidine utilization over time according to one implementation scheme.

[0013] Figure 3 An example is shown of a curve depicting the average dexmedetomidine flow rate over time when applied to a transdermal delivery device of a dexmedetomidine transdermal composition having a nonfunctionalized acrylate adhesive, according to one embodiment.

[0014] Figure 4An example is shown of the average dexmedetomidine flow rate over time as applied to a transdermal delivery device of a dexmedetomidine transdermal composition having a hydroxyl-functionalized acrylate adhesive containing vinyl acetate, according to one embodiment.

[0015] Figure 5 An example is shown of a curve depicting the average dexmedetomidine flow rate over time when applied to a transdermal delivery device of a dexmedetomidine transdermal composition with a hydroxyl-functionalized acrylate adhesive, according to another embodiment.

[0016] Figure 6 An example is shown of the average dexmedetomidine flow rate curve as applied over time to a transdermal delivery device of a dexmedetomidine transdermal composition having a hydroxyl-functionalized acrylate adhesive and a hydroxyl-functionalized acrylate adhesive containing vinyl acetate, according to another embodiment.

[0017] Figures 7A to 7B An example is shown of the average dexmedetomidine flow rate curve under time variation applied to a transdermal delivery device of a dexmedetomidine transdermal composition having a non-functionalized acrylate adhesive, a hydroxyl-functionalized acrylate adhesive, and a hydroxyl-functionalized acrylate adhesive containing vinyl acetate, according to one embodiment.

[0018] Figure 8 An example is shown of a curve depicting the average dexmedetomidine flow rate over time when applied to a transdermal delivery device of a dexmedetomidine transdermal composition of an acrylate adhesive with carboxylic acid functionalization, according to another embodiment.

[0019] Figure 9 An example is shown of the average dexmedetomidine flow rate over time when applied to a transdermal delivery device having an acrylic binder containing vinyl acetate and having carboxyl and hydroxyl groups as functional groups, according to another embodiment.

[0020] Figure 10 An example is shown of the average dexmedetomidine flow rate over time as applied to a transdermal delivery device of a dexmedetomidine transdermal composition having a polyisobutylene / polybutene adhesive and a carboxylic acid-functionalized acrylate adhesive, according to one embodiment.

[0021] Figure 11 An example is shown of the average dexmedetomidine flow rate over time as applied to a transdermal delivery device having a dexmedetomidine transdermal composition having a polyisobutylene / polybutylene binder and a solubilizing agent levulinic acid, according to one embodiment.

[0022] Figure 12An example is shown of the average dexmedetomidine flow rate over time as applied to a transdermal delivery device containing a dexmedetomidine transdermal composition of polyisobutylene / polybutene binder and solubilizer lauryl lactate, according to one embodiment.

[0023] Figure 13 An example is shown of a curve depicting the average dexmedetomidine flow rate over time as applied to a transdermal delivery device of a dexmedetomidine transdermal composition having a polyisobutylene / polybutylene binder and a propylene glycol monolaurate solubilizer, according to one embodiment.

[0024] Figure 14A An example is shown of a curve of the average dexmedetomidine flow rate over time applied to a transdermal delivery device having a hydroxyl-functionalized acrylate adhesive containing vinyl acetate and a dexmedetomidine transdermal composition containing levulinic acid, according to one embodiment.

[0025] Figure 14B An example is shown of a curve of the average dexmedetomidine flow rate over time applied to a transdermal delivery device having a dexmedetomidine transdermal composition containing vinyl acetate and hydroxyl-functionalized acrylate adhesive and polyvinylpyrrolidone, according to one embodiment.

[0026] Figure 14C An example is shown of a curve depicting the average dexmedetomidine flow rate over time when applied to a transdermal delivery device of a dexmedetomidine transdermal composition having a hydroxyl-functionalized acrylate adhesive containing vinyl acetate and a carboxylic acid-functionalized acrylate adhesive, according to one embodiment.

[0027] Figure 15 An example is shown of the average dexmedetomidine flow rate as applied over time by a transdermal delivery device to a dexmedetomidine transdermal composition having an acrylate pressure-sensitive adhesive in the absence and presence of an acrylate adhesive functionalized with levulinic acid, oleic acid, or carboxylic acid, according to one embodiment.

[0028] Figure 16 An example is shown of a curve depicting the average dexmedetomidine flow rate over time when applied to a transdermal delivery device of a dexmedetomidine transdermal composition having a hydroxyl-functionalized acrylate adhesive containing vinyl acetate and a carboxylic acid-functionalized acrylate adhesive, according to another embodiment.

[0029] Figure 17 An example is shown of a curve depicting the average dexmedetomidine flow rate over time when applied to a transdermal delivery device of a dexmedetomidine transdermal composition having a hydroxyl-functionalized acrylate adhesive containing vinyl acetate and an oleic acid or carboxylic acid-functionalized acrylate adhesive, according to another embodiment.

[0030] Figure 18An example is shown, according to another embodiment, of the average dexmedetomidine flow rate over time as applied to a transdermal delivery device of a dexmedetomidine transdermal composition having a hydroxyl-functionalized acrylate adhesive containing vinyl acetate and a solubilizer such as a carboxylic acid-functionalized acrylate adhesive, lauryl lactate, or oleic acid.

[0031] Figure 19 The average in vitro skin flow rate of dexmedetomidine from various formulations is shown relative to time.

[0032] Figures 20 to 21 The flow rates from various formulations are shown on two different skin samples.

[0033] Figure 22 This study describes a comparison of pain ratings in patients after administration of a percutaneous delivery device containing dexmedetomidine, based on one implementation scheme, compared to placebo.

[0034] Figure 23 The study describes, according to one implementation, the use of emergency medications by patients over time post-operatively after administration of a percutaneous delivery device containing dexmedetomidine, compared to placebo.

[0035] Figure 24A This describes a comparison of patients' pain ratings after administration of a percutaneous delivery device containing dexmedetomidine, according to another implementation scheme, compared to placebo.

[0036] Figure 24B The figure depicts, according to another embodiment, the plasma concentration of dexmedetomidine in a patient after the application of a percutaneous delivery device containing dexmedetomidine.

[0037] Figure 25 The study describes the sedation effect of a percutaneous delivery device containing dexmedetomidine in patients receiving a placebo patch, according to one implementation scheme and the Wilson Sedation Rating Scale. Detailed Implementation

[0038] Aspects of the present invention include a method for managing pain in a subject by applying a percutaneous delivery device comprising a dexmedetomidine composition formulated to deliver an effective amount of dexmedetomidine to the subject for pain relief. In practicing the method according to certain embodiments, the percutaneous delivery device having the dexmedetomidine composition is applied to the subject and maintained in contact with the subject in a manner sufficient to deliver an amount of dexmedetomidine effective for managing the subject's pain. In some embodiments, the method includes hydrating the subject. The method according to certain embodiments may also include co-administering an opioid to the subject. A percutaneous delivery device configured to deliver dexmedetomidine sufficient for practicing the method of the present invention is also provided; and a kit containing said percutaneous delivery device.

[0039] Before describing the invention in more detail, it should be understood that the invention is not limited to the specific embodiments described, as such embodiments are of course subject to variation. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the invention will be limited only by the appended claims.

[0040] When a range of values ​​is provided, it should be understood that each intervention value between the upper and lower limits of this range (accurate to one-tenth of the unit of the lower limit unless the context clearly indicates otherwise), and any other value or intervention value within this range, is covered by the invention. The upper and lower limits of these smaller ranges may be independently included within these smaller ranges and also covered by the invention, subject to any specific excluded limit value within the stated range. Where the range includes one or both of the included limits, the invention also includes ranges that exclude any one or both of those included limits.

[0041] In this document, certain ranges of numerical values ​​are preceded by the term "approximately". The term "approximately" is used here to precisely indicate the exact number that follows it, as well as numbers that are close to or approximate to the number following this term. In determining whether a numerical value is close to or approximate to a specifically listed numerical value, an unlisted numerical value that is close to or approximate to a value that is substantially equivalent to the specifically listed numerical value in the context in which it appears.

[0042] 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 pertains. While any methods and materials similar to or equivalent to those described herein may also be used in the practice or testing of this invention, representative exemplary methods and materials are described here.

[0043] All publications and patents referenced in this specification are incorporated herein by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and to disclose and describe the methods and / or materials combined in the referenced publication. Any reference to a publication refers to that prior to its filing date and should not be construed as an admission that the invention is not entitled to a prior publication due to prior art. Furthermore, the publication date provided may differ from the actual publication date, which may require independent verification.

[0044] It should be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple indicators unless the context clearly indicates otherwise. It should also be noted that claims may be drafted to exclude any optional elements. Therefore, such statements are intended to serve as a precondition for using exclusive terms such as “merely,” “only,” or using the restrictive term “negative” in conjunction with the elements of the claim.

[0045] Those skilled in the art will understand upon reading this disclosure that the individual embodiments described and illustrated herein have discrete components and features that can be readily separated from or combined with features of any other embodiments without departing from the scope or spirit of the invention. Any stated method may be performed in the order of the stated events or in any other logically possible order.

[0046] In further describing various embodiments of the invention, methods for administering a percutaneous delivery device containing a dexmedetomidine composition to a subject and maintaining contact between the percutaneous delivery device and the subject in a manner sufficient to deliver a non-sedating dose of dexmedetomidine are first reviewed in more detail. Next, percutaneous delivery devices suitable for practicing the methods of the invention are described. Kits comprising the percutaneous delivery device of interest are then reviewed.

[0047] Methods for managing pain with dexmedetomidine transcutaneous delivery devices

[0048] Aspects of the present invention include a method of managing pain by applying a percutaneous delivery device comprising a dexmedetomidine composition formulated to deliver an effective amount of dexmedetomidine to a subject experiencing pain. In practicing the method according to an embodiment of the invention, the percutaneous delivery device having the dexmedetomidine composition is applied to the subject and maintained in contact with the subject in a manner sufficient to deliver an effective amount of dexmedetomidine to the subject. The term “percutaneous” in its conventional sense refers to a route of administration in which an active agent (i.e., a drug) is delivered through the skin (e.g., topically) or mucous membrane for systemic distribution. Thus, the percutaneous dexmedetomidine composition as described herein comprises a composition formulated to deliver dexmedetomidine to a subject through the subcutaneous tissue, dermis, and epidermis, including one or more of the stratum corneum, stratum germinativum, stratum spinosum, and stratum basale. Therefore, an extended percutaneous delivery device containing a percutaneous dexmedetomidine composition can be applied to any convenient location, such as the arm, leg, buttocks, abdomen, back, neck, scrotum, vagina, face, behind the ear, cheek, and under the tongue. In describing the method of the invention, the term "subject" means a person or organism to which the percutaneous delivery device is applied and maintained in contact. Thus, the subject of the invention may include, but is not limited to, mammals, such as humans and other primates, such as chimpanzees and other ape and monkey species, wherein in some embodiments the subject is a human. The term "subject" also means a person or organism of any age, weight, or other physical characteristic, wherein the subject may be an adult, child, infant, or newborn.

[0049] Transdermal administration of dexmedetomidine can be passive or active. “Passive” transport means that the dexmedetomidine composition is delivered across the skin or mucous membrane in the absence of applied energy (e.g., friction or heat) and relies primarily on the permeability of the barrier (e.g., skin or mucous membrane) and by delivery entropy. However, transdermal administration according to certain embodiments may also include active transport of the dexmedetomidine composition across the skin or mucous membrane. Active transport can be any convenient method sufficient to transport the composition across the skin or mucous membrane in conjunction with applied energy and may include, but is not limited to, microneedle delivery, facilitated diffusion, electrochemically generated gradients, iontophoresis systems, and other methods.

[0050] In some embodiments, the method includes applying a percutaneous delivery device having a dexmedetomidine composition to a subject experiencing pain and maintaining contact between the percutaneous delivery device and the subject in a manner sufficient to deliver an effective amount of dexmedetomidine for pain relief. An effective amount for pain relief means an amount that provides at least some (if not most) pain relief as experienced by the subject, wherein in some cases the amount of pain relief is the complete cessation of the sensation or perception of pain. The amount of pain relief can be quantified using any convenient protocol or evaluated in another manner.

[0051] In other embodiments, the method includes applying a percutaneous delivery device having a dexmedetomidine composition to a painless subject and maintaining contact between the percutaneous delivery device and the subject in a manner sufficient to deliver an amount of dexmedetomidine that effectively prevents a certain amount of pain in the subject. "Prevents a certain amount of pain" means that when the percutaneous delivery device is applied to a painless subject and maintained in contact with the subject, the subject will experience at least less pain in response to a pain-causing event (e.g., physical trauma such as surgery) compared to a subject without the application of the percutaneous delivery device containing dexmedetomidine of the present invention. For example, the percutaneous delivery device containing dexmedetomidine of the present invention may be applied to the skin surface of a painless subject and maintained in contact with the subject in a manner that reduces the amount of pain experienced by the subject in response to a pain-causing event (e.g., surgery) by: 5% or more, such as 10% or more, such as 15% or more, such as 25% or more, such as 50% or more, such as 75% or more, such as 90% or more, such as 95% or more, and including 99% or more. In some cases, the percutaneous delivery device of the present invention is configured to deliver an amount of dexmedetomidine sufficient to completely eliminate any pain experienced by the subject in response to a pain-causing event (i.e., reduce the amount of pain by 100%) to a subject who is not experiencing pain. As described in more detail below, the amount of time the percutaneous delivery device is applied to the subject prior to a pain-causing event (e.g., surgery) can vary and can depend on a variety of factors, such as the amount of dexmedetomidine present in the percutaneous delivery device or the type of pain-causing event. In some cases, the percutaneous delivery device may be applied to the subject's skin surface 1 hour or more, such as 2 hours or more, such as 3 hours or more, such as 4 hours or more, such as 6 hours or more, such as 8 hours or more, such as 12 hours or more, such as 16 hours or more, and including 24 hours or more, prior to a pain-causing event (e.g., surgery).

[0052] In some cases, the amount of dexmedetomidine delivered to the subject is a non-sedating dose. "Non-sedating" means that the dexmedetomidine composition is formulated to deliver an amount of dexmedetomidine to the subject that does not cause complete sedation. In other words, the subject remains conscious and responsive throughout the entire duration of the transdermal administration of dexmedetomidine. In some instances, the subject remains cooperative, oriented, and euthanized during the administration of the transdermal dexmedetomidine composition. In other instances, the subject remains alert and responsive to instructions (e.g., verbal or written instructions) during the administration of the transdermal dexmedetomidine composition. In still other instances, the subject is alert, cooperative, oriented, and euthanized and responsive to instructions (e.g., verbal or written instructions) during the administration of the transdermal dexmedetomidine composition. As used herein, non-sedation includes situations where some sedation is present, for example, as determined by using a suitable sedation scale (such as those described above). In some cases, the subject is not fully sedated. The term "incomplete sedation" means that the subject experiences at least some sedation but can be awakened by mild physical stimulation or verbal commands. For example, in cases of incomplete sedation, the subject's eyes may be closed while the body is relaxed, but can be awakened by one or more physical stimuli or by commands (such as those given by a healthcare professional).

[0053] 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, the Wilson Sedation Score, and other convenient protocols for determining sedation levels.

[0054] In some embodiments, the method may further include assessing the subject's level of sedation to determine whether any reduction in responsiveness or cognitive or motor activity is due to administration of a percutaneous delivery device formulated to deliver a non-sedating dose of dexmedetomidine. The level of sedation can be assessed using any convenient protocol, such as those mentioned above. In some embodiments, the Wilson Sedation Scale is used and the following methods are employed to assess the level of sedation; details of the Wilson Sedation Scale can be found at the website previously created at "http: / / www." followed by "sedationsolutions.co.uk / training-series6.php":

[0055] Wilson Sedation Rating

[0056] 1. Fully conscious and oriented

[0057] 2. Drowsiness

[0058] 3. Eyes closed but can be awakened by command.

[0059] 4. Eyes closed, but can be awakened by gentle physical stimulation (earlobe traction).

[0060] 5. Eyes closed but cannot be awakened by slight physical stimulation.

[0061] In some embodiments, during administration of the dexmedetomidine transdermal composition of the present invention, the level of sedation in the subject is assessed and the subject is assigned a Wilson score of 3 or less, such as 2 or less, including cases where the subject is assigned a Wilson score of 1. In these cases, during administration of dexmedetomidine via the transdermal delivery device, the subject shows a quick response to tapping between the eyebrows or a loud auditory stimulus. In other cases, during administration of the transdermal device, the subject responds to verbal commands. In still other cases, during administration of the transdermal device, the subject is cooperative, oriented, and calm. In still other cases, during administration of dexmedetomidine via the transdermal delivery device, the subject is anxious, agitated, or restless. In still other cases, during administration of dexmedetomidine via the transdermal device, the level of sedation in the subject is assessed and the subject is assigned a Wilson score of 4. In these cases, the subject may be identified as not fully sedated.

[0062] The level of sedation in the subject can be assessed at any time during the method. In some cases, while maintaining prolonged contact between the percutaneous delivery device and the subject, the level of sedation can be assessed at regular intervals, such as every 0.25 hours, every 0.5 hours, every 1 hour, every 2 hours, every 4 hours, or some other interval. For example, the level of sedation can be assessed while maintaining contact between the percutaneous delivery device and the subject, such as 15 minutes after application of the percutaneous delivery device, 30 minutes after application of the percutaneous delivery device, 1 hour after application of the percutaneous delivery device, 2 hours after application of the percutaneous delivery device, 4 hours after application of the percutaneous delivery device, including 8 hours after application of the percutaneous delivery device.

[0063] The sedation level of the subject may be assessed once or multiple times during the dose interval, such as two or more times before, during, or after the dose interval, such as three or more times, including five or more times. In some cases, the upper limit for the number of times the subject may be assessed during the dose interval is 10 times or less, such as seven times or less, such as five times or less, such as three times or less and including two times or less. In some embodiments, the range of the number of times the subject may be assessed during the dose interval is such as two to ten times, such as three to nine times, such as four to eight times and including five to seven times.

[0064] In some implementations, sedation levels can be monitored throughout the time the percutaneous delivery device remains in contact with the subject, such as by a heart rate monitor, a respiratory monitor, or by visual observation, including with the assistance of a video monitor.

[0065] In some implementations, the administered subject is in a non-sedated state and is awake, alert, directed, and responsive to verbal or written instructions, including questions or requests. For example, the subject may be in a non-sedated state at the start of administration. In other implementations, the subject is in a non-sedated state at the start of administration and remains in a non-sedated state for one or more dose intervals (i.e., the period during which the dexmedetomidine transdermal delivery device of interest remains in contact with the subject). In still other implementations, the subject is in a non-sedated state at the start of administration and remains in a non-sedated state throughout the administration protocol.

[0066] In yet another embodiment, the amount of dexmedetomidine delivered to the subject is a sedative dose. "Sedative" means that the dexmedetomidine composition is formulated to deliver to the subject an amount of dexmedetomidine that induces sedation. In such embodiments, the patient may have a Wilson score of 4 or higher, including 5, wherein, as described above, if a subject is assigned a score of 4, the subject may be considered a not fully sedated subject.

[0067] As summarized above, in practicing the method according to embodiments of the invention, a percutaneous delivery device having a dexmedetomidine composition is applied to a subject and contact with the subject is maintained in a manner sufficient to deliver an effective amount of dexmedetomidine to manage the subject's pain. The term "pain" is used in its conventional sense to refer to an unpleasant sensory and emotional experience associated with or described in relation to actual or potential tissue damage (e.g., as defined by the International Association for the Study of Pain). In some cases, pain includes any sensory experience that causes distress to the subject. In embodiments, pain may include, but is not limited to, acute pain, chronic pain, neuropathic pain, cancer-related pain, postoperative pain, moderate to severe pain, labor pain, perioperative pain, and other types of pain. In some embodiments, the method of the invention and the percutaneous delivery device containing dexmedetomidine are used as supplementary anesthesia, for preoperative and postoperative analgesia, and for obstetric analgesia during or after labor and delivery.

[0068] In some embodiments, pain is surgical pain. Surgical pain (which may be interchangeably referred to as "postoperative," "post-incision," or "post-traumatic pain") refers to pain caused or resulting from external trauma, such as cuts, punctures, incisions, tears, or wounds entering individual tissues (including pain caused by all surgical procedures, whether invasive or non-invasive). Surgical pain treatable according to embodiments of the invention includes perioperative pain, such as pain experienced during and / or after a surgical procedure, and postoperative pain, such as pain experienced after a surgical procedure. As used herein, "surgical pain" does not include pain that occurs without external physical trauma. In some embodiments, surgical pain is internal or external pain, and wounds, cuts, trauma, tears, or incisions may occur accidentally (e.g., traumatic wounds) or intentionally (e.g., surgical incisions). As used herein, "pain" includes nociceptive sensation and aches, and pain can be assessed objectively and subjectively using pain ratings and other methods (e.g., using protocols well known in the art). As used herein, surgical pain includes anomalous pain (i.e., pain caused by stimuli that do not normally cause pain) and hyperalgesia (i.e., an increased response to stimuli that normally cause pain), which can further be thermal or mechanical stimuli (tactile) in nature. In some embodiments, the pain is characterized by thermal sensitivity, mechanical sensitivity, and / or resting pain (e.g., persistent pain in the absence of external stimuli). In some embodiments, surgical pain includes mechanically induced pain or resting pain. In other embodiments, surgical pain includes resting pain. Pain can be primary (e.g., directly caused by an event that causes pain) or secondary (e.g., pain related to but not directly caused by an event that causes pain).

[0069] Aspects of the present invention include methods for treating pain in a subject. In some embodiments, the method includes treating surgical pain in a subject, such as one or more of the following: abnormal pain, hyperalgesia, heat-induced pain, mechanically induced pain, or resting pain. For example, surgical pain may include mechanically induced pain and / or resting pain. In some cases, surgical pain includes resting pain. “treating” or “treatment” means at least suppressing or improving symptoms associated with a symptom causing pain in the subject, wherein the broad terms of suppression and improvement are used to refer to at least reducing the magnitude of parameters (e.g., symptoms) associated with the treated symptom (such as pain). Thus, treatment also includes situations where symptoms are completely suppressed, for example, prevented from occurring or stopped, such as termination, so that the subject no longer experiences said symptom. Thus, treatment also includes both prevention and management of the symptom. In some embodiments, abnormal pain is suppressed, improved, and / or prevented, and in some embodiments, hyperalgesia is suppressed, improved, and / or prevented. In some cases, the pain is chronic pain. In other cases, the pain is located proximal to and / or near one or more sites of external trauma, wound, or incision. Other aspects of the subject method include methods for improving and / or preventing the development or progression of surgical pain by administering dexmedetomidine of the present invention via a percutaneous delivery device.

[0070] As discussed above, in some cases, the method includes applying a percutaneous delivery device having a dexmedetomidine composition comprising dexmedetomidine and a pressure-sensitive adhesive to the skin surface of a subject (which may be non-sedated), and maintaining the percutaneous delivery device in contact with the subject in a manner sufficient to deliver an effective amount of dexmedetomidine for a period of time to manage the subject's pain. As discussed above, the amount may be non-sedated or sedated as needed. A non-sedated amount may allow the patient to be reactive or alert and may be associated with a score of no more than 3, including 2 or lower, according to the Wilson Sedation Scale. "Managing pain" or "pain management" means at least suppressing or improving pain, where suppression and improvement mean at least reducing the magnitude of pain.

[0071] In some embodiments, the method includes extended percutaneous delivery of dexmedetomidine to a subject. "Extended percutaneous delivery" means that the percutaneous administration is formulated to provide delivery of the dexmedetomidine composition over an extended period of time, such as over a process of hours, days, and including weeks, including 1 hour or longer, such as 2 hours or longer, such as 4 hours or longer, such as 8 hours or longer, such as 12 hours or longer, such as 24 hours or longer, such as 48 hours or longer, such as 72 hours or longer, such as 96 hours or longer, such as 120 hours or longer, such as 144 hours or longer and including 168 hours or longer. For the above ranges, in some cases, the upper limit of the time period is 168 hours or less, such as 144 hours or less, such as 120 hours or less, such as 96 hours or less, such as 72 hours or less, such as 48 hours or less and including 24 hours or less. In some implementations, the extended transdermal delivery range is, for example, 0.5 hours to 168 hours, 1 hour to 144 hours, 1.5 hours to 120 hours, 2 hours to 96 hours, 2.5 hours to 72 hours, or 3 hours to 72 hours.

[0072] In some embodiments, sustained-release transdermal administration of the dexmedetomidine composition comprises multi-day delivery of a therapeutically effective amount of the active dexmedetomidine agent applied to the skin of a subject. Multi-day delivery means that the transdermal composition is formulated to provide a therapeutically effective amount to a subject for a sustained period of time (1 day or longer, such as 2 days or longer, such as 4 days or longer, such as 7 days or longer, such as 14 days and including 30 days or longer) while the transdermal delivery device is applied to the skin of the subject. For multi-day delivery, in some cases, the time period is capped at 30 days or less, such as 28 days or less, such as 21 days or less, such as 14 days or less, such as 7 days or less and including 3 days or less. In some embodiments, the range of multi-day transdermal delivery is such as 2 to 30 days, such as 2 to 15 days, such as 2 to 7 days, such as 2 to 4 days and including 2 to 4 days, for example, 3 days or 4 days.

[0073] Depending on the specific approach employed, pain management according to embodiments of the invention may include one or more administration dose intervals. The term "dose interval," in its conventional sense herein, refers to the duration of a single application of a percutaneous delivery device and the maintenance of contact between the percutaneous delivery device and the subject. In other words, a dose interval begins with the application of a percutaneous dexmedetomidine composition to the skin or mucous membrane of the subject and ends with the removal of contact between the percutaneous dexmedetomidine composition and the subject. Thus, a dose interval is the period of time during which a certain amount of dexmedetomidine is in contact with the skin or mucous membrane of the subject, and can last for approximately 0.5 hours or longer, such as 1 hour or longer, such as 2 hours or longer, such as 4 hours or longer, such as 8 hours or longer, such as 12 hours or longer, such as 16 hours or longer, such as 20 hours or longer, such as 24 hours or longer, such as 30 hours or longer, such as 36 hours or longer, such as 48 hours or longer, such as 72 hours or longer, such as 96 hours or longer, such as 120 hours or longer, such as 144 hours or longer, and includes 168 hours or longer. In some cases, the upper limit for the duration of the dose interval is 168 hours or less, such as 144 hours or less, such as 120 hours or less, such as 96 hours or less, such as 72 hours or less, such as 48 hours or less and including 40 hours or less. In some embodiments, the duration of the dose interval ranges from 0.5 hours to 168 hours, such as 24 hours to 144 hours, such as 30 hours to 120 hours, such as 36 hours to 96 hours, such as 48 hours to 84 hours, such as 60 hours to 84 hours, such as 66 hours to 78 hours, for example 72 hours.

[0074] As used herein, the term "administration regimen" refers to one or more sequential dosing intervals sufficient to produce the desired therapeutic effect of a dexmedetomidine percutaneous delivery device. In some embodiments, the regimen may include a single dosing interval such that only one dose consisting of one or more percutaneous devices is administered to the subject. In such cases, a single percutaneous delivery device may be administered to the subject. In other cases of such embodiments, two or more different percutaneous delivery devices may be administered to the subject at substantially the same time. In these cases, two or more, such as three or more, including four or more, are administered to the subject substantially simultaneously. In some of these cases, the number of different percutaneous delivery devices administered to the subject is ten or less, such as eight or less, including six or less, for example five or less. "Substantially the same time" means that multiple percutaneous delivery devices are administered to the subject at the same time (i.e., simultaneously) or sequentially with a minimum time interval between the administration of each percutaneous delivery device, wherein the minimum time interval may vary, but in some cases, the range is ten minutes or less, such as five minutes or less, including two minutes or less, such as one minute or less, for example 30 seconds or less, including 15 seconds or less. Therefore, if there is any time interval between the application of multiple transdermal delivery devices in these embodiments, the interval has almost no practical effect on the delivery curve of the active agent from the transdermal delivery device to the subject.

[0075] In some embodiments, the administration protocol may include multiple dosing intervals. "Multiple dosing intervals" means applying more than one percutaneous delivery device sequentially while maintaining contact with the subject. Then, the contact between the percutaneous delivery device and the subject is removed, and a new percutaneous delivery device is re-applied to the subject. In the methods of practicing the present invention, the administration protocol may include two or more dosing intervals, such as three or more dosing intervals, such as four or more dosing intervals, such as five or more dosing intervals, including ten or more dosing intervals.

[0076] In multi-dose interval management protocols, the duration between dose intervals can vary depending on the subject's physiological function or the management protocol (as determined by a healthcare professional). For example, the duration between dose intervals in a multi-dose management protocol can be predetermined and followed at regular intervals. Therefore, the time between dose intervals can vary and can be 1 day or longer, such as 2 days or longer, such as 3 days or longer, such as 4 days or longer, such as 5 days or longer, such as 6 days or longer, such as 7 days or longer, such as 10 days or longer, including 30 days or longer. In some cases, the upper limit for the time period between dose intervals is 30 days or less, such as 28 days or less, such as 21 days or less, such as 14 days or less, such as 7 days or less and including 3 days or less. In some embodiments, the range of time between dose intervals is such as 2 to 30 days, such as 3 to 28 days, such as 4 to 21 days, such as 5 to 14 days and including 6 to 10 days.

[0077] In some cases, the duration between dose intervals may depend on the plasma concentration of dexmedetomidine during the time between dose intervals when the percutaneous delivery device is not in contact with the subject. For example, a subsequent dose interval may begin when the plasma concentration of dexmedetomidine falls below a specific threshold.

[0078] In some embodiments, dexmedetomidine may be administered via a percutaneous delivery device prior to activities that may cause external trauma, wounds, or incisions (such as surgery). For example, dexmedetomidine may be administered via a percutaneous delivery device 30 minutes or longer, 1 hour or longer, 2 hours or longer, 5 hours or longer, 10 hours or longer, 15 hours or longer, 24 hours or longer, or even 1 day or longer, prior to activities that may cause external trauma, wounds, or incisions (such as before surgery). In other embodiments, dexmedetomidine may be administered via a percutaneous delivery device during and / or after surgery or activities that cause external trauma, wounds, or incisions. In some cases, dexmedetomidine is administered via a percutaneous delivery device 1 hour or longer, 2 hours or longer, 3 hours or longer, 4 hours or longer, 6 hours or longer, 8 hours or longer, 12 hours or longer, 18 hours or longer, 24 hours or longer, 30 hours or longer, or 36 hours or longer after surgery or activity that results in external trauma, wound, or incision.

[0079] In some cases, the active agent from the composition is administered to the subject perioperatively. As used herein, the term perioperative means before, during, and after a procedure, such as a surgical procedure. Therefore, the percutaneous delivery device is applied to the subject before the surgical procedure and then maintained on the subject during and for a period of time after the procedure. For example, dexmedetomidine may be applied via a percutaneous delivery device for 30 minutes or more, 1 hour or more, 2 hours or more, 5 hours or more, 8 hours or more, 9 hours or more, 10 hours or more, 11 hours or more, 12 hours or more, 15 hours or more, 18 hours or more, 24 hours or more, such as 1 day or more, before the surgical procedure and maintained on the subject during the surgical procedure. In some cases, the percutaneous delivery device is applied at any time from 0.50 to 30 hours before the procedure, such as from 1 to 24 hours before the procedure. The composition of the present invention is then maintained on the subject for a period of time after the surgical procedure, wherein this postoperative maintenance period can vary and is, in some cases, 1 hour or longer, such as 2 hours or longer, such as 4 hours or longer, such as 8 hours or longer, such as 12 hours or longer, such as 24 hours or longer, such as 48 hours or longer, such as 72 hours or longer, such as 96 hours or longer, such as 120 hours or longer, such as 144 hours or longer, and including 168 hours or longer. For the above ranges, in some cases, the upper limit of the time period is 168 hours or less, such as 144 hours or less, such as 120 hours or less, such as 96 hours or less, such as 72 hours or less, such as 48 hours or less, and including 24 hours or less. In some embodiments, the extended percutaneous delivery range is, for example, 0.5 hours to 168 hours, 1 hour to 144 hours, 1.5 hours to 120 hours, 2 hours to 96 hours, 2.5 hours to 72 hours, or 3 hours to 72 hours. In some embodiments, the perioperative delivery protocol is a multi-day perioperative percutaneous delivery protocol that spans a period before and after the surgical procedure, wherein in some cases, this protocol ranges from 2 days to 30 days, such as 2 days to 15 days, 2 days to 7 days, 2 days to 4 days, and includes 2 days to 4 days, for example, 3 days.

[0080] In some implementations, the percutaneous delivery device is applied and maintained in contact with the subject for a total duration of 72 hours. In one example, the percutaneous delivery device is applied 4 hours before the start of the procedure, maintained in contact with the subject during the procedure, and removed after a total duration of 72 hours. In another example, the percutaneous delivery device is applied 6 hours before the start of the procedure, maintained in contact with the subject during the procedure, and removed after a total duration of 72 hours. In yet another example, the percutaneous delivery device is applied 12 hours before the start of the procedure, maintained in contact with the subject during the procedure, and removed after a total duration of 72 hours. In yet another example, the percutaneous delivery device is applied 18 hours before the start of the procedure, maintained in contact with the subject during the procedure, and removed after a total duration of 72 hours. In yet another example, the percutaneous delivery device is applied 24 hours before the start of the procedure, maintained in contact with the subject during the procedure, and removed after a total duration of 72 hours. In yet another example, the percutaneous delivery device is applied 24 hours before the start of the procedure, maintained in contact with the subject during the procedure, and removed after a total duration of 84 hours. In yet another instance, a percutaneous delivery device was applied 24 hours before the start of the surgical procedure, maintained in contact with the subject during the procedure, and removed after a total duration of 96 hours.

[0081] In other embodiments, one or more percutaneous delivery devices of the present invention are applied to the subject for a predetermined period of time (e.g., 4 hours, 6 hours, 12 hours, 18 hours, 24 hours, etc.) before the start of the surgical procedure and maintained in contact with the subject for 72 hours or more after the procedure. Therefore, the total duration of contact between the percutaneous delivery device and the subject can be 76 hours or more, such as 80 hours or more, such as 84 hours or more, such as 90 hours or more, and including 96 hours or more. In one example, the percutaneous delivery device is applied 4 hours before the start of the surgical procedure, maintained in contact with the subject during the procedure, and maintained in contact with the subject for 72 hours or more after the procedure. In another example, the percutaneous delivery device is applied 6 hours before the start of the surgical procedure, maintained in contact with the subject during the procedure, and maintained in contact with the subject for 72 hours or more after the procedure. In yet another example, the percutaneous delivery device is applied 12 hours before the start of the surgical procedure, maintained in contact with the subject during the procedure, and maintained in contact with the subject for 72 hours or more after the procedure. In yet another example, the percutaneous delivery device was applied 18 hours before the start of the surgical procedure, and contact was maintained with the subject during the procedure and for 72 hours or more after the procedure. In yet another example, the percutaneous delivery device was applied 24 hours before the start of the surgical procedure, and contact was maintained with the subject during the procedure and for 72 hours or more after the procedure. In yet another example, the percutaneous delivery device was applied 24 hours before the start of the surgical procedure, and contact was maintained with the subject during the procedure and for 84 hours or more after the procedure. In yet another example, the percutaneous delivery device was applied 24 hours before the start of the surgical procedure, and contact was maintained with the subject during the procedure and for 96 hours or more after the procedure.

[0082] As described above, aspects of the present invention include managing pain in a subject by applying a percutaneous delivery device containing a dexmedetomidine composition formulated to deliver an effective amount of dexmedetomidine. In some cases, aspects of the present invention include perioperative pain management, which in some cases results in the treatment of postoperative pain and in some cases results in the treatment of perioperative pain, wherein perioperative pain includes postoperative pain and pain experienced during surgery. In some embodiments, the method includes maintaining contact between the percutaneous delivery device and the subject in a manner sufficient to deliver a target dose of dexmedetomidine to manage the subject's pain, for example, as if delivering a target dose that would manage pain, as determined by total drug exposure or by average daily drug exposure. The term target dose means the amount of dexmedetomidine required to be absorbed. The target drug exposure for managing pain can vary depending on the desired therapeutic effect of the percutaneous dexmedetomidine composition, the management regimen, the subject's physiological function, and the subject's level of sedation at the time of administration. In some embodiments, the target drug exposure of dexmedetomidine is an amount within a non-sedating therapeutic window.

[0083] The term "non-sedating therapeutic window" is used herein to refer to the range of dexmedetomidine doses that are therapeutically effective in managing pain in a subject and produce little (if any) sedation. In other words, for a specific individual subject managing pain, the non-sedating therapeutic window of dexmedetomidine is the range of dexmedetomidine concentrations considered to be "completely sedative" or "completely sedative-inducing" as defined below and considered "ineffective" for managing pain in the subject as defined above. In some embodiments of the invention, the non-sedating therapeutically effective amount provides a systemic dose of dexmedetomidine that achieves the desired management in the subject while maintaining a Wilson score of 3 or lower. For example, in managing pain in a subject, the target non-sedating dose of dexmedetomidine can range from 50 μg / day to 350 μg / day over a dose interval (e.g., a 168-hour dose interval), such as 100 μg / day to 340 μg / day, such as 145 μg / day to 330 μg / day, such as 155 μg / day to 320 μg / day, such as 165 μg / day to 310 μg / day, such as 175 μg / day to 300 μg / day, such as 185 μg / day to 290 μg / day, such as 195 μg / day to 280 μg / day, and includes 50 μg / day to 250 μg / day. In some embodiments, the target dose of dexmedetomidine ranges from 147 μg / day to 290 μg / day over a dose interval (e.g., a 168-hour or longer dose interval).

[0084] In some embodiments, the target dose is the amount of systemic quantity that provides the desired mean plasma concentration of dexmedetomidine administered at a specific time during pain management when administered to a subject. In other embodiments, the target dose is the amount that provides a steady-state mean plasma concentration of dexmedetomidine throughout the dosing interval or management regimen when administered to a subject. In other embodiments, the target dose is the amount that provides a specific rate of dexmedetomidine delivery to a subject in vivo when administered to a subject.

[0085] In some embodiments, applying a percutaneous delivery device containing a dexmedetomidine composition and maintaining contact between the percutaneous delivery device and the subject includes delivering a target amount of dexmedetomidine, such as the average cumulative amount of dexmedetomidine delivered over a dosing interval (e.g., 7 days or longer). The term "target cumulative amount" refers to the total amount of dexmedetomidine delivered to the subject through the skin and can vary due to skin or mucous membrane permeability and metabolic activity at the application site. In some embodiments, the average cumulative amount of dexmedetomidine over a 7-day delivery interval may be 5 μg / cm³. 2 Or even higher, such as 25 μg / cm 2 Or even higher, such as 50 μg / cm 2 Or even higher, such as 75 μg / cm² within the dose interval. 2 Or even higher, such as 100 μg / cm 2 Or even higher, such as 125 μg / cm 2 or larger and including 200 μg / cm 2 Or higher. For the average cumulative amount of dexmedetomidine delivered within a dosing interval, in some cases, the upper limit is 500 μg / cm³. 2 Or even smaller, such as 400 μg / cm 2 Or even smaller, such as 300 μg / cm 2 Or even smaller, such as 200 μg / cm 2 Or even smaller, such as 100 μg / cm 2 or smaller and including 50 μg / cm 2 In some embodiments, the average cumulative amount of dexmedetomidine delivered over the dosing interval is in the range of, for example, 5 μg / cm³. 2 Up to 500 μg / cm 2 Such as 25 μg / cm 2 Up to 400 μg / cm 2 And including 50 μg / cm 2 Up to 300 μg / cm 2 .

[0086] A method according to certain embodiments may include applying one or more percutaneous delivery devices containing a dexmedetomidine composition to a subject, such as two to four, such as three percutaneous delivery devices, and maintaining contact between the percutaneous dexmedetomidine composition and the subject in a manner sufficient to provide an average plasma concentration in the range of 0.05 ng / mL to 0.5 ng / mL, such as 0.1 ng / mL to 0.45 ng / mL, such as 0.15 ng / mL to 0.4 ng / mL, such as 0.2 ng / mL to 0.35 ng / mL, and including 0.25 ng / mL to 0.3 ng / mL over a dose interval. For example, contact between the percutaneous delivery device and the subject may be maintained in a manner sufficient to provide an average plasma concentration in the range of 0.16 ng / mL to 0.36 ng / mL over a dose interval (e.g., 168 hours or longer). In other embodiments, the method includes maintaining contact between the dexmedetomidine composition and the subject in a manner sufficient to provide an average plasma concentration in the range of 0.05 ng / mL to 0.5 ng / mL throughout the course of administration (i.e., within one or more dosing intervals), such as 0.1 ng / mL to 0.45 ng / mL, such as 0.15 ng / mL to 0.4 ng / mL, such as 0.2 ng / mL to 0.35 ng / mL, and including 0.25 ng / mL to 0.3 ng / mL throughout the course of administration. For example, contact between the percutaneous delivery device and the subject may be maintained in a manner sufficient to provide an average plasma concentration in the range of 0.16 ng / mL to 0.36 ng / mL throughout the course of administration.

[0087] As discussed above, methods include delivering dexmedetomidine to a subject to manage prolonged durations of surgical pain, such as longer than 6 hours, longer than 12 hours, longer than 24 hours, longer than 48 hours, longer than 72 hours, longer than 96 hours, longer than 120 hours, longer than 144 hours, and including longer than 168 hours. In some embodiments, the method includes maintaining the percutaneous dexmedetomidine composition in contact with the subject's skin surface sufficient to provide a target-average amount of absorbed dexmedetomidine over 72 hours. This depends on the surface area of ​​the percutaneous delivery device (e.g., 6 cm²). 2 4 cm 2 2 cm 2The average absorption of dexmedetomidine over 72 hours can vary, such as 150 mcg to 600 mcg, such as 175 mcg to 575 mcg, such as 100 mcg to 400 mcg, such as 125 mcg to 375 mcg, such as 50 mcg to 200 mcg, and including 60 mcg to 190 mcg. In some cases, the transdermal delivery device has a 6 cm... 2 The surface area is such that the transdermal dexmedetomidine composition maintains contact with the subject's skin surface in a manner sufficient to provide the following average absorbed amounts of dexmedetomidine over 72 hours: 192.7 mcg to 551.7 mcg, such as 224 mcg to 437 mcg, such as 278 mcg to 384 mcg, such as 304 mcg to 357 mcg, and including 320 mcg to 341 mcg. In other cases, the transdermal delivery device has a 4 cm² surface area. 2 The surface area is such that the transdermal dexmedetomidine composition maintains contact with the subject's skin surface in a manner sufficient to provide the following average absorbed amounts of dexmedetomidine over 72 hours: 100 mcg to 400 mcg, such as 125 mcg to 375 mcg, such as 128.5 mcg to 367.8 mcg, such as 150 mcg to 292 mcg, such as 185 mcg to 256 mcg, such as 203 mcg to 238 mcg, and including 213 mcg to 228 mcg. In other cases, the transdermal delivery device has a 2 cm² surface area. 2 The surface area, and maintains contact between the transdermal dexmedetomidine composition and the subject's skin surface in a manner sufficient to provide the following average absorbed amounts of dexmedetomidine over 72 hours: 50 mcg to 200 mcg, such as 60 mcg to 190 mcg, such as 64 mcg to 184 mcg, such as 75 mcg to 146 mcg, such as 93 mcg to 128 mcg, such as 101 mcg to 119 mcg, and including 107 mcg to 114 mcg.

[0088] In other embodiments, the method may include maintaining contact between the transdermal dexmedetomidine composition and the skin surface of the subject sufficient to provide average dexmedetomidine absorption over 72 hours. This depends on the surface area of ​​the transdermal delivery device (e.g., 6 cm²). 2 4 cm 2 2 cm 2(etc.), the average absorption of dexmedetomidine over 72 hours can vary, in some cases ranging from 1 mcg / h to 10 mcg / h, 2 mcg / h to 8 mcg / h, 0.5 mcg / h to 6 mcg / h, 1 mcg / h to 5.5 mcg / h, 0.1 mcg / h to 5 mcg / h, and including 0.5 mcg / h to 3 mcg / h. In some cases, the transdermal delivery device has a 6 cm 2 The surface area is sufficient to maintain contact between the transdermal dexmedetomidine composition and the subject's skin surface in a manner adequate to provide the following average dexmedetomidine absorption over 72 hours: 1 mcg / h to 10 mcg / h, such as 2 mcg / h to 8 mcg / h, such as 3.1 mcg / h to 6.1 mcg / h, such as 3.9 mcg / h to 5.3 mcg / h, such as 4.2 mcg / h to 5.0 mcg / h, and including 4.4 mcg / h to 4.7 mcg / h. In some cases, the transdermal delivery device has a 4 cm² surface area. 2 The surface area is such that the transdermal dexmedetomidine composition maintains contact with the subject's skin surface in a manner sufficient to provide the following average dexmedetomidine absorption over 72 hours: 0.5 mcg / h to 6 mcg / h, such as 1 mcg / h to 5.5 mcg / h, such as 1.8 mcg / h to 5.1 mcg / h, such as 2.1 mcg / h to 4.1 mcg / h, such as 2.6 mcg / h to 3.6 mcg / h, such as 2.8 mcg / h to 3.3 mcg / h, and including 3.0 mcg / h to 3.2 mcg / h. In other cases, the transdermal delivery device has a 2 cm² surface area. 2 The surface area is sufficient to maintain the contact between the transdermal dexmedetomidine composition and the subject's skin surface in a manner adequate to provide the following average dexmedetomidine absorption over 72 hours: 0.1 mcg / h to 5 mcg / h, such as 0.5 mcg / h to 3 mcg / h, such as 0.9 mcg / h to 2.6 mcg / h, such as 1.0 mcg / h to 2.0 mcg / h, such as 1.3 mcg / h to 1.8 mcg / h, such as 1.4 mcg / h to 1.7 mcg / h, and including 1.5 mcg / h to 1.6 mcg / h.

[0089] In other embodiments, the method may include maintaining contact between the transdermal dexmedetomidine composition and the subject's skin surface sufficient to deliver the mean maximum plasma concentration of dexmedetomidine over 72 hours. This depends on the surface area of ​​the transdermal delivery device (e.g., 6 cm²). 2 4 cm 2 2 cm 2(etc.), the mean maximum plasma concentration of dexmedetomidine absorbed over 72 hours can vary, ranging from 50 pg / mL to 250 pg / mL, 70 pg / mL to 225 pg / mL, 25 pg / mL to 150 pg / mL, 40 pg / mL to 140 pg / mL, 10 pg / mL to 80 pg / mL, and including 20 pg / mL to 70 pg / mL. In some cases, the percutaneous delivery device has a 6 cm... 2 The surface area is such that the percutaneous dexmedetomidine composition maintains contact with the subject's skin surface in a manner sufficient to provide the following average maximum plasma concentrations of dexmedetomidine over 72 hours: 50 pg / mL to 250 pg / mL, such as 70 pg / mL to 225 pg / mL, such as 70.1 pg / mL to 205 pg / mL, such as 77 pg / mL to 153 pg / mL, such as 96 pg / mL to 134 pg / mL, such as 106 pg / mL to 125 pg / mL, and including 111 pg / mL to 119 pg / mL. In other cases, the percutaneous delivery device has a 4 cm² surface area. 2 The surface area is such that the percutaneous dexmedetomidine composition maintains contact with the subject's skin surface in a manner sufficient to provide the following average maximum plasma concentrations of dexmedetomidine over 72 hours: 25 pg / mL to 150 pg / mL, such as 40 pg / mL to 140 pg / mL, such as 47 pg / mL to 137 pg / mL, such as 51 pg / mL to 102 pg / mL, such as 64 pg / mL to 90 pg / mL, such as 70 pg / mL to 83 pg / mL, and including 74 pg / mL to 79 pg / mL. In other cases, the percutaneous delivery device has a 2 cm² surface area. 2 The surface area, and maintains contact between the transdermal dexmedetomidine composition and the subject's skin surface in a manner sufficient to provide the following average maximum plasma concentrations of dexmedetomidine over 72 hours: 10 pg / mL to 80 pg / mL, such as 20 pg / mL to 70 pg / mL, such as 23.4 pg / mL to 68.3 pg / mL, such as 26 pg / mL to 51 pg / mL, such as 32 pg / mL to 45 pg / mL, and including 35 pg / mL to 42 pg / mL.

[0090] In other embodiments, the method may include maintaining contact between the transdermal dexmedetomidine composition and the subject's skin surface sufficient to provide the average area under a plasma dexmedetomidine concentration curve from the time of application up to infinity. This depends on the surface area of ​​the transdermal delivery device (e.g., 6 cm²). 2 4 cm 2 2 cm2 (etc.), the mean area under the plasma dexmedetomidine concentration curve can vary over 72 hours, ranging from 3000 hx pg / mL to 10000 hx pg / mL, 3500 hx pg / mL to 9000 hx pg / mL, 2000 hx pg / mL to 7500 hx pg / mL, 2250 hx pg / mL to 6000 hx pg / mL, 1000 hx pg / mL to 3500 hx pg / mL, and including 1100 hx pg / mL to 3000 hx pg / mL. In some cases, the percutaneous delivery device has a 6 cm 2 The surface area is such that the percutaneous dexmedetomidine composition maintains contact with the subject's skin surface in a manner sufficient to provide the following average area under the plasma dexmedetomidine concentration curve over 72 hours: 3517 h x pg / mL to 8954 h x pg / mL, such as 4548 h x pg / mL to 7712 h x pg / mL, such as 5339 h x pg / mL to 6921 h x pg / mL, such as 5735 h x pg / mL to 6525 h x pg / mL, and including 5972 h x pg / mL to 6288 h x pg / mL. In other cases, the percutaneous delivery device has a 4 cm² surface area. 2 The surface area is such that the percutaneous dexmedetomidine composition maintains contact with the subject's skin surface in a manner sufficient to provide the following average area under the plasma dexmedetomidine concentration curve over 72 hours: 2345 hx pg / mL to 5969 hx pg / mL, such as 3032 hx pg / mL to 5141 hx pg / mL, such as 3559 hx pg / mL to 4614 hx pg / mL, such as 3823 hx pg / mL to 4350 hx pg / mL, and including 3981 hx pg / mL to 4192 hx pg / mL. In yet another embodiment, the percutaneous delivery device has a 2 cm² surface area. 2 The surface area, and maintains contact between the transdermal dexmedetomidine composition and the subject's skin surface in such a manner as to provide the following average area under the plasma dexmedetomidine concentration curve over 72 hours: 1172 hx pg / mL to 2985 hx pg / mL, such as 1516 hx pg / mL to 2571 hx pg / mL, such as 1780 hx pg / mL to 2307 hx pg / mL, such as 1912 hx pg / mL to 2175 hx pg / mL, and including 1991 hx pg / mL to 2096 hx pg / mL.

[0091] In some embodiments, the method may further include determining the plasma concentration of dexmedetomidine in the subject during the management of the subject's pain. The plasma dexmedetomidine concentration can be determined using any convenient protocol, such as liquid chromatography-mass spectrometry (LCMS). The plasma concentration of dexmedetomidine can be determined at any desired time. In some embodiments, the plasma concentration of dexmedetomidine can be monitored throughout the duration of contact between the percutaneous delivery device and the subject, such as through real-time data acquisition. In other cases, the plasma concentration of dexmedetomidine is monitored while maintaining contact between the percutaneous delivery device and the subject by acquiring data at regular intervals, such as every 0.25 hours, every 0.5 hours, every 1 hour, every 2 hours, every 4 hours, every 12 hours, every 24 hours, including every 72 hours, or some other interval. In still other cases, the plasma concentration of dexmedetomidine is monitored while maintaining contact between the percutaneous delivery device and the subject by acquiring data according to a specific schedule after the percutaneous delivery device has been applied to the subject. For example, plasma concentrations of dexmedetomidine can be determined at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 76 hours, 80 hours, 84 hours, 96 hours, 120 hours, and including 168 hours after the percutaneous delivery device is applied to the subject.

[0092] In some embodiments, the plasma concentration of dexmedetomidine is determined, for example, before the percutaneous delivery device is applied to the subject, to determine the baseline plasma concentration of dexmedetomidine. For example, the plasma concentration may be determined 5 minutes, such as 10 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, and up to 480 minutes before the application of the percutaneous delivery device. As described in detail below, the method may include multiple dosing intervals, wherein the percutaneous delivery device can be repeatedly applied and the percutaneous delivery device remains in contact with the subject. In these embodiments, the plasma concentration may be determined after the removal of the first percutaneous delivery device and before the application of the second percutaneous delivery device.

[0093] The plasma concentration of dexmedetomidine can be determined once or multiple times in any given measurement period, such as two or more times, three or more times, including five or more times in each measurement period. In some cases, the upper limit for the number of times the plasma concentration of dexmedetomidine can be determined in any given measurement period is 10 times or fewer, such as seven times or fewer, such as five times or fewer, such as three times or fewer and including two times or fewer. In some embodiments, the range of the number of times the plasma concentration of dexmedetomidine can be determined in any given measurement period is such as two to ten times, such as three to nine times, such as four to eight times and including five to seven times.

[0094] Methods for managing pain according to certain embodiments may include applying a percutaneous delivery device containing a dexmedetomidine composition to a subject and maintaining contact between the percutaneous dexmedetomidine composition and the subject in a manner sufficient to maintain a percutaneous dexmedetomidine flow rate of 30% or more of the peak percutaneous dexmedetomidine flow rate after reaching peak percutaneous flow. Thus, once the percutaneous delivery device of interest reaches peak percutaneous dexmedetomidine flow, the percutaneous delivery device is configured to maintain a dexmedetomidine flow rate to the subject at at least 30%, such as at least 35%, such as at least 40%, and including at least 50% of the peak flow rate during any given dose interval. In other words, according to these specific embodiments, once the percutaneous delivery device reaches peak flow, the percutaneous flow rate of dexmedetomidine to the subject does not drop below 30% or more of the peak flow rate at any time during the dose interval.

[0095] For example, the percutaneous dexmedetomidine composition may be kept in contact with the subject in a manner sufficient to maintain the percutaneous dexmedetomidine flow rate within 50% or more, such as 55% or more, such as 60% or more, such as 65% or more, such as 70% or more, such as 75% or more, such as 80% or more, such as 85% or more, such as 90% or more, such as 95%, and including 99% of the peak percutaneous dexmedetomidine flow rate. In some embodiments, the percutaneous dexmedetomidine flow rate does not decrease at all after reaching peak flow and maintains a rate of 100% of the peak dexmedetomidine flow rate from the time it reaches peak flow until the end of a given dosing interval.

[0096] The flow rate of a transdermal active agent is the rate at which the active agent penetrates the skin or mucous membranes of a subject. In some cases, the flow rate of dexmedetomidine can be determined using the following equation:

[0097]

[0098] Where J is skin flow rate, C is the concentration gradient across the skin or mucous membrane, and P is the permeability coefficient. Skin flow rate is the change in the cumulative amount of drug that passes through the skin or mucous membrane into the body relative to time.

[0099] In some cases, it is sufficient to provide 0.05 μg / cm 2 / hr or higher, such as 0.1 μg / cm 2 / hr or higher, such as 0.5 μg / cm 2 / hr or higher, such as 1 μg / cm 2 / hr, such as 2 μg / cm 2 / hr, such as 3 μg / cm 2 / hr or higher, such as 5 μg / cm 2 / hr or higher, such as 7.5 μg / cm 2 Maintaining contact between the transdermal dexmedetomidine delivery device and the subject at a peak flow rate of / hr or greater, and including providing a peak flow rate sufficient to deliver 10 μg / cm³. 2 Maintain contact between the transdermal dexmedetomidine delivery device and the subject at a peak flow rate of / hr or higher. In some cases, the upper limit for the peak flow rate of transdermal dexmedetomidine delivery is 10 μg / cm³. 2 / hr or less, such as 9 μg / cm 2 / hr or less, such as 8 μg / cm 2 / hr or less, such as 7 μg / cm 2 / hr or less, 6 μg / cm 2 / hr or less, such as 5 μg / cm 2 / hr or less and including 2 μg / cm 2 / hr or less. In some implementations, the peak flow rate of transdermal dexmedetomidine delivery ranges from 0.05 μg / cm³. 2 / hr to 10 μg / cm 2 / hr, such as 1 μg / cm 2 / hr to 9 μg / cm 2 / hr and includes 2 μg / cm 2 / hr to 8 μg / cm 2 / hr.

[0100] Therefore, by maintaining contact between the transdermal dexmedetomidine delivery device and the subject in a manner sufficient to provide at least 30% of the peak transdermal dexmedetomidine flow rate, it is sufficient to provide a flow rate of up to 0.5 μg / cm³. 2 After the peak transdermal flow rate of / hr, it was 0.15 μg / cm. 2 / hr or greater, such as reaching 0.6 μg / cm 2 The peak transdermal flow rate was 0.18 μg / cm³ / hr. 2 / hr or greater, such as reaching 0.75 μg / cm 2 The peak transdermal flow rate was 0.225 μg / cm³ / hr. 2 / hr or greater, such as reaching 0.9 μg / cm 2 After the peak flow rate of / hr, it reached 0.27 μg / cm. 2 / hr or greater, such as reaching 1.0 μg / cm 2 After the peak flow rate of / hr, 0.3 μg / cm 2 / hr or greater, such as reaching 5 μg / cm 2 1.5 μg / cm³ after a peak flow rate of / hr or greater. 2 The transdermal delivery device is kept in contact with the subject at a flow rate of / hr, and includes a flow rate sufficient to provide up to 10.0 μg / cm³. 2 After the peak flow rate of / hr, it reached 3.0 μg / cm. 2 The transdermal dexmedetomidine delivery device is kept in contact with the subject at a flow rate of / hr or higher.

[0101] The time required to reach peak dexmedetomidine flow can vary depending on the amount of dexmedetomidine present in the dexmedetomidine composition of the percutaneous delivery device, the subject's physiological function, and the target application site. In some cases, peak dexmedetomidine flow is reached 2 hours or more after application of the percutaneous delivery device to the subject, such as 4 hours or more, 6 hours or more, 12 hours or more, 18 hours or more, and including 24 hours or more after application of the percutaneous delivery device to the subject. In other cases, peak dexmedetomidine flow is reached at 168 hours or earlier, such as 144 hours or earlier, 120 hours or earlier, 96 hours or earlier, 72 hours or earlier, 48 hours or earlier, 24 hours or earlier, 12 hours or earlier, 8 hours or earlier, 4 hours or earlier, and including 2 hours or earlier. In some implementations, peak dexmedetomidine flow is reached 24 hours after the percutaneous delivery device is applied to the subject.

[0102] In some embodiments, during pain management of a subject, the percutaneous composition is maintained in contact with the subject to provide a steady-state mean dexmedetomidine flow rate to the subject. The term "steady-state" in its conventional sense refers to a mean dexmedetomidine flow rate in which the amount of dexmedetomidine released from the percutaneous delivery device remains substantially constant. Thus, while maintaining contact between the percutaneous delivery device and the subject, the flow rate of dexmedetomidine from the percutaneous delivery device of interest increases or decreases by 50% or less at any time, such as increasing or decreasing by 45% or less, such as 40% or less, such as 35% or less, such as 30% or less, such as 25% or less, such as 20% or less, such as 15% or less, such as 12% or less, such as 10% or less, such as 6% or less, such as 5% or less, such as 4% or less and including 1% or less.

[0103] While maintaining contact between the dexmedetomidine transdermal delivery device and the subject to provide a steady-state mean dexmedetomidine flow rate, the steady-state mean dexmedetomidine flow rate may be maintained for 0.5 hours or longer, such as 1 hour or longer, such as 2 hours or longer, such as 3 hours or longer, such as 4 hours or longer, such as 8 hours or longer, 12 hours or longer, such as 24 hours or longer, such as 36 hours or longer, such as 48 hours or longer, such as 72 hours or longer, such as 96 hours or longer, such as 120 hours or longer, such as 144 hours or longer, and including 168 hours or longer. For maintaining a steady-state mean dexmedetomidine flow rate, in some cases, the upper limit is a duration of 168 hours or less, such as 144 hours or less, such as 120 hours or less, such as 96 hours or less, such as 72 hours or less, such as 48 hours or less, such as 24 hours or less, such as 12 hours or less, such as 8 hours or less, such as 4 hours or less and including 2 hours or less.

[0104] In these embodiments, the percutaneous delivery device is configured to provide a constant flow rate, such as by introducing a concentration gradient across the skin or mucous membrane or by providing an excess of the amount of dexmedetomidine. For example, a percutaneous dexmedetomidine composition of interest may contain an excess of 5% or more of the normal dose, such as 10% or more, such as 15% or more, such as 20% or more, and including an excess of 25% or more of the normal dose. For the amount of excess dexmedetomidine present in the percutaneous delivery device to provide a constant flow rate, in some cases, the upper limit is 50% or less of the normal dose, such as 45% or less, such as 25% or less, such as 20% or less, and including 10% or less. While a percutaneous dexmedetomidine composition of interest may contain an excess to provide a constant flow rate, the amount of the excess dose is not absorbed as part of the dosing interval and is insufficient to produce a dose that is fully sedative (i.e., the dose of dexmedetomidine delivered to the subject remains a non-sedative dose). Therefore, in some embodiments of the transdermal dexmedetomidine delivery device maintained in a manner sufficient to provide a constant flow rate, 25% or less (such as 20% or less, 15% or less, 10% or less, 5% or less) of the available dexmedetomidine in the transdermal composition may not be utilized during the dose interval, and 1% or less of the available dexmedetomidine in the transdermal composition may not be utilized.

[0105] Methods for managing pain (e.g., surgical pain) in a subject according to certain embodiments may include administering to the subject a percutaneous delivery device containing a dexmedetomidine composition configured to deliver a non-sedating amount of dexmedetomidine, and providing approximately 0.005 to approximately 5 μg / cm at any time after administration of the percutaneous delivery device. 2 •hr, such as about 0.01 to about 4 μg / cm 2 •hr, such as about 0.02 to about 3 μg / cm 2 •hr, such as about 0.05 to about 2.5 μg / cm 2 •hr, such as about 0.1 to about 2 μg / cm 2 •hr and includes about 0.1 to about 1 μg / cm 2 The percutaneous dexmedetomidine composition is kept in contact with the subject in a manner consistent with the mean in vivo dexmedetomidine flow rate over 24 hours. In some embodiments, the method includes applying the percutaneous dexmedetomidine composition to the subject at a concentration sufficient to provide approximately 0.005 to approximately 2.0 μg / cm³ at a concentration sufficient to provide such a concentration ... 2 •hr, such as about 0.01 to about 1.75 μg / cm 2 •hr, such as about 0.02 to about 1.5 μg / cm 2•hr, such as about 0.05 to about 1.25 μg / cm 2 •hr and includes providing approximately 0.1 to approximately 1 μg / cm² within 24 hours after application. 2 The percutaneous delivery device is kept in contact with the subject in a manner that maintains the mean in vivo flow rate of dexmedetomidine for approximately 1 hour. In yet another embodiment, the method includes applying the percutaneous dexmedetomidine delivery device to the subject and providing approximately 0.005 to approximately 2.0 μg / cm³ at a dose sufficient to deliver the dose 168 hours after application. 2 •hr, such as about 0.01 to about 1.75 μg / cm 2 •hr, such as about 0.02 to about 1.5 μg / cm 2 •hr, such as about 0.05 to about 1.25 μg / cm 2 •hr and includes providing approximately 0.1 to approximately 1 μg / cm³ 168 hours after application. 2 The percutaneous delivery device is kept in contact with the subject by a mean intracellular dexmedetomidine flow rate of hr.

[0106] In some embodiments, the method includes determining the percutaneous dexmedetomidine flow rate. Any convenient protocol can be used, such as that employed with human cadaver skin having an epidermal layer (stratum corneum and epidermis) in Franz cells having donor and recipient sides clamped together and a recipient solution containing phosphate buffer. The amount of permeated dexmedetomidine can also be characterized by liquid chromatography. The percutaneous dexmedetomidine flow rate can be determined at any time during the method of the invention. In some embodiments, the percutaneous dexmedetomidine flow rate can be monitored throughout the entire time the percutaneous dexmedetomidine composition is in contact with a permeation barrier (e.g., human cadaver skin), such as through real-time data acquisition. In other cases, the percutaneous dexmedetomidine flow rate is monitored by acquiring data at regular intervals, such as every 0.25 hours, every 0.5 hours, every 1 hour, every 2 hours, every 4 hours, every 12 hours, every 24 hours, including every 72 hours, or some other regular or irregular interval. In other cases, transdermal dexmedetomidine flow rate is monitored by collecting data according to a specific schedule. For example, the transdermal dexmedetomidine flow rate may be determined at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 76 hours, 80 hours, 84 hours, 96 hours, 120 hours, and including 168 hours after the application of the transdermal delivery device.

[0107] The transcutaneous dexmedetomidine flow rate can be determined once or multiple times in any given measurement cycle, such as two or more times, three or more times, including five or more times in each measurement cycle. In some cases, the upper limit for the number of times the transcutaneous dexmedetomidine flow rate is 10 times or less, such as seven times or less, five times or less, three times or less and including two times or less. In some embodiments, the range of the number of times the transcutaneous dexmedetomidine flow rate is such as two to ten times, three to nine times, four to eight times and including five to seven times.

[0108] In some embodiments, while maintaining contact between the dexmedetomidine transdermal delivery device and the subject, the average cumulative amount of permeated dexmedetomidine increases at a substantially linear rate over a period of time (e.g., 2 days or longer, such as 3 days or longer). "Substantially linear" means that the cumulative amount of dexmedetomidine released from the transdermal composition increases at a substantially constant rate (i.e., defined by zero-order kinetics). Therefore, while maintaining contact between the transdermal composition and the subject, the rate of change of the cumulative permeated dexmedetomidine increases or decreases by 10% or less at any given time, such as 8% or less, such as 7% or less, such as 6% or less, such as 5% or less, such as 3% or less, such as 2.5% or less, such as 2% or less, and includes an increase or decrease of 1% or less at any time while maintaining contact between the dexmedetomidine transdermal delivery device and the subject.

[0109] As described above, aspects of the present invention include managing pain in a subject by applying a percutaneous delivery device containing a dexmedetomidine composition and maintaining the dexmedetomidine delivery device in contact with the subject for a period of time sufficient to deliver an effective amount of dexmedetomidine to the subject for pain relief. In some embodiments, the method for managing pain may include maintaining the percutaneous dexmedetomidine delivery device in contact with the subject in a manner sufficient to deliver a predetermined amount of dexmedetomidine to the subject. In a protocol that includes the delivery of a predetermined amount of dexmedetomidine to a subject, the amount of dexmedetomidine in the transdermal composition of interest may range from 0.001 mg to 50 mg, such as 0.005 to 40 mg, such as 0.01 mg to 30 mg, such as 0.05 to 20 mg, such as 0.1 mg to 15 mg, such as 0.5 mg to 12.5 mg and including 0.5 mg to 10 mg, such as 0.5 mg to 2 mg or 0.7 mg to 1.5 mg, 2 to 10 mg, including 4 to 9 mg, such as 6 to 8 mg.

[0110] In some embodiments, the predetermined amount of dexmedetomidine delivered to the subject may be a certain percentage of the total amount of dexmedetomidine present in the percutaneous composition of the dexmedetomidine delivery device. For example, the predetermined amount of dexmedetomidine delivered to the subject may be 1% or more of the total amount of dexmedetomidine present in the percutaneous composition, such as 2% or more, such as 5% or more, such as 10% or more, such as 25% or more, and including 50% or more of the total amount of dexmedetomidine present in the percutaneous composition. In other words, methods for managing pain may include maintaining the percutaneous composition of dexmedetomidine in contact with the subject in a manner sufficient to deliver 5% or more of the dexmedetomidine in the percutaneous composition to the subject over a single dose interval. In these embodiments, the percentage of dexmedetomidine utilized during the time the percutaneous delivery device is maintained in contact with the subject is 5% or more. Therefore, 95% or less of the original amount of dexmedetomidine remains in the percutaneous composition of dexmedetomidine after the dose interval. As described in more detail below, the percutaneous delivery device of the present invention is capable of having a high utilization percentage. In other words, after a given dosing interval, the percutaneous delivery device of the present invention is capable of delivering dexmedetomidine to the subject, thereby leaving very little residual dexmedetomidine in the percutaneous delivery device. The utilization percentage during the dosing interval can be 5% or greater, such as 10% or greater, such as 25% or greater, such as 40% or greater, such as 45% or greater, and includes 50% or more of dexmedetomidine during the dosing interval. For the utilization percentage, in some cases, the upper limit during the dosing interval is 90% or less, such as 50% or less, such as 25% or less, and includes 5% or less during the dosing interval.

[0111] For example, in the case where the dexmedetomidine transdermal composition of the present invention contains 1 mg of dexmedetomidine, the method for managing pain may include maintaining the transdermal delivery device in contact with the subject in a manner sufficient to deliver 0.05 mg or more, such as 0.1 mg or more, such as 0.25 mg or more, such as 0.4 mg or more, such as 0.45 mg or more of dexmedetomidine in the transdermal composition over a period of time (e.g., 2 to 3 days or longer), and includes maintaining the transdermal delivery device in contact with the subject in a manner sufficient to deliver 0.5 mg or more of dexmedetomidine in the transdermal composition. Thus, after 2 to 3 days or longer, 0.95 mg or less of dexmedetomidine remains in the transdermal composition, such as 0.9 mg or less, such as 0.75 mg or less, such as 0.6 mg or less, and including 0.5 mg or less of dexmedetomidine remaining in the transdermal composition after the said dose interval.

[0112] As described above, the method according to certain embodiments includes applying one or more percutaneous delivery devices of the present invention having a dexmedetomidine composition to a subject who is not experiencing pain and maintaining the percutaneous delivery device in contact with the subject in a manner sufficient to deliver an amount of dexmedetomidine that effectively prevents the subject from experiencing pain. In embodiments, the percutaneous delivery device is applied to the subject's skin surface before the subject experiences (or is expected to experience) pain (e.g., in response to a pain-inducing event, such as a surgical procedure), such as 1 hour or more before experiencing (or expecting to experience) pain, such as 2 hours or more, such as 3 hours or more, such as 4 hours or more, such as 6 hours or more, such as 8 hours or more, such as 12 hours or more, such as 16 hours or more, such as 20 hours or more, and including 24 hours or more before the pain-inducing event.

[0113] In some embodiments, applying a dexmedetomidine-containing percutaneous delivery device according to an embodiment of the invention before the subject experiences pain is sufficient to reduce the amount of pain experienced by the subject by 5% or more, such as 10% or more, such as 15% or more, such as 25% or more, such as 50% or more, such as 75% or more, such as 90% or more, such as 95% or more, and including 99% or more, compared to a subject who has not received the dexmedetomidine-containing percutaneous delivery device of the invention. In some cases, the method includes applying the dexmedetomidine-containing percutaneous delivery device to a subject who has not experienced pain and maintaining contact between the percutaneous delivery device and the subject in a manner sufficient to completely eliminate any pain experienced by the subject in response to a pain-inducing event (i.e., reducing the amount of pain by 100%). For example, when a percutaneous delivery device is applied before the start of surgery, such as 1 hour or more before the start of surgery, such as 2 hours or more before the start of surgery, such as 3 hours or more before the start of surgery, such as 4 hours or more before the start of surgery, such as 6 hours or more before the start of surgery, such as 8 hours or more before the start of surgery, such as 12 hours or more before the start of surgery, such as 16 hours or more before the start of surgery, such as 20 hours or more before the start of surgery and including 24 hours or more before the start of surgery, the subject may experience a reduced amount of pain in response to the surgical procedure.

[0114] As described in more detail below, in some embodiments, the percutaneous delivery device may include a monolayer matrix dexmedetomidine composition, the percutaneous delivery device being configured to deliver a non-sedated amount of dexmedetomidine to a subject. Thus, the method according to certain examples includes applying the percutaneous delivery device having a monolayer matrix dexmedetomidine composition to a subject and maintaining the monolayer dexmedetomidine composition in contact with the subject for a period of time sufficient to deliver an effective amount of dexmedetomidine to the subject.

[0115] In some embodiments, each of the methods of the invention described in more detail below may further include a step of removing contact between one or more percutaneous delivery devices and the subject at the end of a dosing interval. For example, contact between the percutaneous delivery device and the subject may be removed after maintaining contact for 0.5 hours or longer, such as 1 hour or longer, such as 2 hours or longer, such as 4 hours or longer, such as 8 hours or longer, such as 12 hours or longer, such as 24 hours or longer, such as 36 hours or longer, such as 48 hours or longer, such as 60 hours or longer, such as 72 hours or longer, such as 96 hours or longer, such as 120 hours or longer, including 144 hours or longer and including 168 hours or longer. In some cases, the maximum amount of time that the percutaneous delivery device can remain in contact with the subject before removal is 168 hours or less, such as 144 hours or less, such as 120 hours or less, such as 96 hours or less, such as 84 hours or less, such as 78 hours or less, such as 72 hours or less.

[0116] "Removing" the percutaneous delivery device from contact with the subject means that the percutaneous delivery device is no longer in contact with the subject. In other words, when the percutaneous delivery device is removed, it no longer comes into contact with the skin or mucous membrane surface at the application site.

[0117] As described above, a dose interval is a single administration that applies one or more (e.g., two) percutaneous delivery devices and maintains contact between the percutaneous delivery devices and the subject, the single administration beginning with the application of one or more percutaneous dexmedetomidine compositions to the skin or mucous membrane of the subject and ending with the removal of contact between the one or more percutaneous delivery devices and the subject. As summarized above, in some embodiments, the protocol includes a single dose interval. Alternatively, in some embodiments, the protocol may include multiple dose intervals. "Multiple dose intervals" means applying more than one percutaneous delivery device sequentially and maintaining contact with the subject. Thus, contact between the percutaneous delivery device and the subject is removed and a new percutaneous delivery device is reapplied to the subject. In the practice of the methods of the present invention, the administration protocol may include two or more dose intervals, such as three or more dose intervals, such as four or more dose intervals, such as five or more dose intervals, including ten or more dose intervals.

[0118] In some embodiments, the method further includes hydrating the subject. The term “hydration” is used herein in its conventional sense to provide hydration to a subject, such as by administering a hydration fluid composition (e.g., an aqueous fluid) to the subject. The hydration fluid composition may be administered to the subject by any suitable protocol, including but not limited to oral or intravenous administration. In some embodiments, a certain amount of fluid is administered intravenously to the subject. The hydration fluid administered to the subject may be any suitable composition that provides the subject with an increased hydration effect (as determined by a qualified healthcare professional), including but not limited to saline solutions, electrolyte supplements, buffer solutions, nutrient solutions, etc. In some cases, hydration fluids such as balanced salt / electrolyte solutions, including isotonic, hypertonic, and hypotonic electrolyte solutions, are administered intravenously. Exemplary hydration fluids according to certain embodiments may be lactated Ringer's solution, physiological saline, D5 lactated Ringer's dextran solution, D5 physiological saline dextran solution, D5,45 physiological saline dextran solution, D5,25 physiological saline dextran solution, 7.5% physiological saline solution, D5 anhydrous dextran solution, 6% hydroxyethyl starting solution, and other types of hydration fluids.

[0119] During the method of the present invention, the subject may be hydrated at any convenient time. A certain amount of the hydration fluid composition may be applied to the subject before, during, or after the surgical procedure, or any combination thereof. In some embodiments, the hydration fluid composition is applied in combination with the application of a percutaneous delivery device to the subject, and this continues as long as the percutaneous delivery device remains in contact with the subject. In some cases, the application of the hydration fluid composition prior to the application of the percutaneous delivery device to the subject is sustained for a period of time, such as 1 minute or longer, 2 minutes or longer, 5 minutes or longer, 10 minutes or longer, 15 minutes or longer, 30 minutes or longer, 1 hour or longer, 2 hours or longer, 3 hours or longer, 6 hours or longer, and includes 12 hours or longer prior to the application of the percutaneous delivery device to the subject. In some embodiments, the hydration fluid composition is continued to be applied to the subject while maintaining contact between the percutaneous delivery device and the subject. Hydration may continue after the percutaneous delivery device is removed from the subject, such as for 1 minute or longer, such as for 2 minutes or longer, such as for 5 minutes or longer, such as for 10 minutes or longer, such as for 15 minutes or longer, such as for 30 minutes or longer, such as for 1 hour or longer, such as for 2 hours or longer, such as for 3 hours or longer, such as for 6 hours or longer, and including for 12 hours or longer after the percutaneous delivery device is removed from the subject.

[0120] In other cases, the hydrated fluid composition is applied at a time prior to the commencement of the surgical procedure on the subject, such as 1 minute or longer before the commencement of the surgical procedure, such as 2 minutes or longer before the commencement of the surgical procedure, such as 5 minutes or longer before the commencement of the surgical procedure, such as 10 minutes or longer before the commencement of the surgical procedure, such as 15 minutes or longer before the commencement of the surgical procedure, such as 30 minutes or longer before the commencement of the surgical procedure, such as 1 hour or longer before the commencement of the surgical procedure, such as 2 hours or longer before the commencement of the surgical procedure, such as 3 hours or longer before the commencement of the surgical procedure, such as 6 hours or longer before the commencement of the surgical procedure, and including 12 hours or longer before the commencement of the surgical procedure on the subject. In some embodiments, the hydrated fluid composition is continued to be applied to the subject while maintaining contact between the percutaneous delivery device and the subject and during the surgical procedure. Hydration may continue after the completion of the surgical procedure on the subject, such as for 1 minute or longer, such as for 2 minutes or longer, such as for 5 minutes or longer, such as for 10 minutes or longer, such as for 15 minutes or longer, such as for 30 minutes or longer, such as for 1 hour or longer, such as for 2 hours or longer, such as for 3 hours or longer, such as for 6 hours or longer, and including for 12 hours or longer after the completion of the surgical procedure on the subject.

[0121] In some embodiments, the method includes administering an hydrated fluid composition to a subject at a first rate for a first predetermined time period; and administering the hydrated fluid composition to a subject at a second rate for a second predetermined time period.

[0122] In one example, the method includes orally administering a hydration fluid composition to a subject at a first rate for a first predetermined time period; and orally administering the hydration fluid composition to the subject at a second rate for a second predetermined time period. For example, the method may include orally administering the hydration fluid composition to the subject at a rate of 450 mL / h to 550 mL / h for two hours; and, after the initial two hours, orally administering the hydration fluid composition to the subject at a rate of 100 mL / h to 150 mL / h for 12 hours. In some cases, the method for hydrating a subject includes orally administering the hydration fluid composition to the subject at a rate of 500 mL / h for two hours; and, after the initial two hours, orally administering the hydration fluid composition to the subject at a rate of 125 mL / h for 12 hours.

[0123] In another example, the method includes administering a hydration fluid composition intravenously to a subject at a first infusion rate for a first predetermined time period; and administering the hydration fluid composition intravenously to a subject at a second infusion rate for a second predetermined time period. For example, the method may include administering the hydration fluid composition intravenously to a subject at a rate of 450 mL / h to 550 mL / h for two hours; and, after the initial two hours, administering the hydration fluid composition intravenously to a subject at a rate of 100 mL / h to 150 mL / h for 12 hours. In some cases, the method for hydrating a subject includes administering the hydration fluid composition intravenously to a subject at a rate of 500 mL / h for two hours; and, after the initial two hours, administering the hydration fluid composition intravenously to a subject at a rate of 125 mL / h for 12 hours.

[0124] In some embodiments, the dexmedetomidine percutaneous delivery device can be administered before, simultaneously with, or after other therapeutic agents used to treat or manage pain. If provided concurrently with another therapeutic agent, the dexmedetomidine of the present invention can be administered via the percutaneous delivery device in the same or different compositions. Therefore, the dexmedetomidine delivery device of interest and other therapeutic agents can be administered to a subject via concurrent therapy. "Concurrent therapy" means administration to a subject to induce a therapeutic effect of the combination of substances in the subject undergoing the therapy. For example, concurrent therapy can be achieved by administering dexmedetomidine via the percutaneous delivery device of the present invention and by administering a pharmaceutical composition having at least one other agent, such as pain treatment compositions, including but not limited to anesthetics, including intravenous agents, such as non-opioid intravenous general anesthetics (such as, but not limited to, propofol, etomidate, ketamine, barbiturates (e.g., sodium pentobarbital, mesobarbital, thiopental), benzodiazepines (e.g., diazepam, lorazepam, and midazolam), opioid intravenous general anesthetics (such as, but not limited to, alfentanil, fentanyl, remifentanil, sufentanil, buprenorphine, butorphanol, diacetylmorphine, hydromorphone, levonorgestrel, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine), and inhaled general anesthetics (e.g., desflurane, enflurane). The following drugs are permitted in combination according to a specific dosing regimen: halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, and xenon; local anesthetics (such as, but not limited to, procaine, amesocaine, lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, and dibutylcaine); NSAIDs and COX2 inhibitors (aspirin, ibuprofen, naproxen, celecoxib, acetaminophen); opioids such as codeine, oxycodone, morphine, methadone, buprenorphine, and fentanyl; antidepressants; anticonvulsants; dexmedetomidine; cannabinoids; N-methyl-D-aspartate; neuromodulators, etc., which together constitute a therapeutically effective dose according to a specific dosing regimen. The individual drug combinations may be administered simultaneously or at different times (i.e., sequentially, in any order, on the same day or on different days), provided that the combination of these substances induces a therapeutic effect in the subject undergoing the therapy.

[0125] Depending on the second therapeutic agent administered and the indicated symptoms, co-administration with dexmedetomidine can reduce the required dosage of the second therapeutic agent. For example, co-administration with dexmedetomidine can reduce the amount of opioids or other analgesics required for the effective treatment or management of pain such as postoperative pain, chemotherapy-induced pain, or radiation-induced pain. Co-administration with dexmedetomidine can reduce the required dosage of the second therapeutic agent by 10% or more, such as 25% or more, such as 35% or more, and includes reducing the required dosage of the second therapeutic agent by 50% or more.

[0126] In some embodiments, the method includes co-administering one or more opioids to a subject. The term "opioid" is used herein in its conventional sense to refer to a naturally occurring or synthetic chemical substance that exerts a pharmacological effect through interaction at opioid receptors (i.e., μ, κ, and δ opioid receptors). In some embodiments, the opioid is a biosynthetic benzylisoquinoline alkaloid and may be an opioid receptor agonist, antagonist, or inverse agonist. The opioid may be administered to the subject at any time during the method of the invention, such as before or after applying the dexmedetomidine percutaneous delivery device to the subject's skin surface. The opioid may be delivered to the subject using any convenient method, including but not limited to oral, intravenous, injectable, percutaneous, or other delivery methods. In some embodiments, the method includes intravenous administration of the opioid. In some embodiments, the opioid is administered perioperatively.

[0127] The types of opioids commonly administered to the subjects in these implementation methods may vary, including but not limited to codeine, morphine, papaverine, pseudomorphine, thebaine, 14-hydroxymorphine, 2,4-dinitrophenylmorphine, 6-methyldihydromorphine, 6-methylenedihydrodeoxymorphine, 6-acetyldihydromorphine, azidomorphine, chlorenaltrexate, chloroxymorphamine, desomorphine (dihydrodeoxymorphine), dihydromorphine, ethyldihydromorphine, hydromorphol, methyldesomorphine, N-phenethylnormorphine, RAM-378, 6-nicotinyldihydromorphine, acetylpropionylmorphine, diacetyldihydromorphine (dihydroheroin, acetylmorphol), dibutyrylmorphine, dibenzoylmorphine, diformylmorphine, dipropionylmorphine, and heroin. (diacetylmorphine), nicomorphine, 6-monoacetylcodeine, benzylmorphine, codeine methyl bromide, dihydrodeoxycodeine, dimethylmorphine (6-O-methylcodeine), ethyl dihydromorphine, methyl dihydromorphine (dihydroisocodeine), ethylmorphine (dionine), heterocodeine, isocodeine, pholcodine, morpholinoethylmorphine, myrophine, nalodeine (N-Allyl-norcodeine), trans-isocodeine, 14-cinnamoyloxycodeinone, 14-ethoxymetopon, 14-methoxymetopon, 14-phenylpropoxymetopon, 7-spironinylhydroxymorphone, 8,14-dihydroxydihydromorphone, acetylcodone, acetylmorphone, α-hydrocodone, bromoisopropyldihydromorphone, codeine, codorphone, codol, codoxime, IBNtxA, acetyldihydrocodeinone, dihydrocodeinone enol acetate, hydrocodone, hydromorphone, hydroxycodeinone Due to, methyldihydromorphone, morphine alcohol, morphine ketone, morphine phenol, N-phenylethyl-14-ethoxymetodone, oxycodone, oxymorphol, oxymorphone, pentamoxetine, semorphone, α-chlorocodeine, β-chlorocodeine, α-chloromorphine, bromocodeine, bromomorphine, chlorodihydrocodeine, chloromorphine, codeine, 14-hydroxydihydrocodeine, acetyldihydrocodeine, dihydrocodeine, dihydrodeoxycodeine, dihydroisocodeine, nicotinic acid codeine, nicotinic acid dihydrocodeine1-Nitrocodeine, N-Oxycodeine, N-Oxymorphine, Oxymorphazone, 1-Bromocodeine, 1-Chlorocodeine, 1-Iodomorphine, N-Oxycodeine, 7,8-Oxyheroin, 6-Glucoside Morphine, 6-Monoacetylmorphine, N-Oxymorphine, Naltrexol, Norcodeine, Normorphine, 4-Chlorophenylpyridomorphinan, Cyclorphan, Dextrallorphan, Levargorphan, Levophenacylmorphan, Levomethorphan, Norlevorphanol, N-Methylmorphinan, Oxilorphan Phenomorphan, methorphan, morphanol, Ro4-1539, stephodeline, Xorphanol, 1-nitroaknadinine, episinomenine, dihydronorsalutaridine, nalbuphine, morphanine, butorphanol, cephakicine, cephasamine, cyprodime, drotebanol, fenfangjine G, nalbuphine, sinococuline, sinomenine, tannagine, 5,9 α-Diethyl-2-hydroxybenzomorphine (5,9-DEHB), 8-carboxyamide cyclozocine (8-CAC), alarzocine, anazocine, brumazocine, butinazocine, carbazocine, cogazocine, cyclazocine, dezocine, eptazocine, etazocine, ethylketocyclazocine, fedotozine, fluorophen, gemazocine, ibazocine, ketazocine, metazocine, moxazocinePentazocine, phenazocine, quadazocine, thiazocine, tonazocine, volazocine, zenazocine, 4-fluoropermetadine, allylnorpethidine, anileridine, benzethidine, carperidine, difenoxetine, diphenoxylate, etoxeridine, methylphenidate, furethidine, hydroxypethidine, bemidone, morphopeptide Morpheridine, meperidine-N-oxide, oxpheneridine, carbamethidine, pethidine, meperidine, norpethidine, pethidinicacid, pheneridine, phenoperidine, piminodine, properidine, ipropethidine, sameridine, allylprodine, (α / β)-meprodine, desmethylprodine (MPPP), PEPAP, (α / β)-Prosidin, Prosidol, Trimeperidine, Promedol, Acetoxyketobemidone, Droxypropine, Ketobemidone, Methylketobemidone, Propylketobemidone, Alvimopan, Loperamide, Picenadol, Dextromethadone, Dipipanone, Isomethadone, Levoisomethadone, Levomethadone, Methadone, Normethadone, NorpipanonePhenadoxone (heptazone), pipedone (6-piperidine-4,4-biphenyl-5-methyl-hexanone-3 hydrochloride), alphaacetylmethadol, and dimepheptanol. Racemethadol, levacetylmethadol, noracetylmethadol, desmethylmoramide, dextromoramide, levomoramide, moramide intermediate, racemoramide, diethylthiambutene, dimethylthiambutene, ethylmethylthiambutene, piperidylthiambutene, pyrrolidinylthiambutene, thiambutene, tipepidine, dextropropoxyphene, propoxyphene, dimenoxadol, dioxaphetyl (butyrate), levopropoxyphene, norpropoxyphene, diampromide, phenampromide, propiram, IC-26, isoaminile, lefetamine, R-4066, 3-allylfentanyl, 3-methylfentanyl, 3-methylthiofentanyl, 4-phenylfentanyl, alfentanil α-Methylacetylfentanyl, α-methylfentanyl, α-methylthiofentanyl, benzylfentanyl, β-hydroxyfentanyl, β-hydroxythiofentanyl, β-methylfentanyl, bifentanyl, carfentanyl, fentanyl, lofentanyl, mifentanyl, ocfentanyl, ohmefentanyl, parafluorofentanyl, phenaridineRemifentanil, sufentanil, thenylfentanyl, thiofentanyl, trefentanil, 7-PET, acetorphine, alletorphine (N-Allyl-Noretorphine), BU-48, Dexmedetomidine, Cyprenorphine, Dihydroetorphine, Etorphine, Homprenorphine, 18,19-Dehydromedetomidine, Cyclopropylmethylnoretorphine, Nepenthone, Nordexmedetomidine, Thevinone, Thienorphine, Ethoheptazine, Meptazinol, Metheptazine, Methoheptazine, Proheptazine azine), bezitramide, piritramide, clonitazene, etonitazene, nitazene, 18-methoxycoronaridine, 7-acetoxymitragynine, 7-hydroxymitragynine, akuammidine, akuammine, eseroline, hodgkinsine, mitragynine, pericine, pseudoakuammigine, BW373U86, DPI-221, DPI-287, DPI-3290, SNC-80, dynorphin A A) Dynorphin; B) β-Endorphin, α-Endorphin, γ-Endorphin, α-Neo-Endorphin, β-Neo-Endorphin, DADLE, DAMGO, Dermenkephalin, Met-enkephalin, Leucine-enkephalin, AdrenorphinAmidorphin, casomorphin, DALDA (Tyr-D-Arg-Phe-Lys-NH2), deltorphin, dermorphin, DPDPE, endomorphin, gliadorphin, morphiceptin, nociception, octreotide, opiorphin, rubiscolin, TRIMU 5. 3-(3-Methoxyphenyl)-3-ethoxycarbonyltropane, AD-1211, AH-7921, azaprocin, BDPC, bisnortilidine, BRL-52537, bromadoline, C-8813, ciramadol, doxpicomine, enadoline, faxeladol, GR-89696, herkinorin, ICI-199,441, ICI-204,448, J-113,397, JTC-801, ketamine, KNT-42, LPK-26, methopholine, MT-45, desmethylclozapine, NNC 63-0532, nortilidine, desmethyltramadol, phenadone, phencyclidine, prodilidine, profadol, Ro64-6198, salvinorin A, SB-612,111, SC-17599, RWJ-394,674, TAN-67, Tapentadol, Oxycodone, Tifluadom, Tilidine, Tramadol, Trimebutine, U-50,488, U-69,593, Viminol, 1-(4-nitrophenylethyl)piperidinyl-2-(4-chlorophenyl)sulfonamide (W-18), 5'-guanidinolaltrindole, β-funaltrexamine, 6β-naltrexol, Alvimopanbinaltorphimine, chlornaltrexamine, clocinnamox, cyclazocine, cyprodime, diacetylnalorphine, difenamizole, diprenorphine, fedotozine, JDTic, levallorphan, methocinnamox, methylnaltrexone, nalfurafine, nalmefene, nalmexone, naloxazone, naloxonazine, naloxone, naloxone benzoylhydrazone Benzoylhydrazone), nalorphine, naltrexone, naltriben, naltrindole, norbinaltorphimine, oxilorphan, S-allyl-3-hydroxy-17-thioniamorphinan, alimadol, anilopam HCl, asimadoline, FE 200665, fedotozine, MCOPPB, nalfurafine, nalorphine, nalorphinedinicotinate, SoRI-9409, and other opioids.

[0128] In some embodiments, when co-administered with opioids, the dexmedetomidine percutaneous delivery device applied as described herein can reduce the amount of opioid required for effective treatment or management of pain (e.g., postoperative pain). In some cases, applying the dexmedetomidine percutaneous delivery device according to the methods described above reduces the amount of co-administered opioid required for pain management by 1% or more by weight, such as 2% or more by weight, such as 3% or more by weight, such as 5% or more by weight, such as 10% or more by weight, such as 15% or more by weight, such as 25% or more by weight, and includes reducing the amount of co-administered opioid required for pain management by 50% or more by weight. In other words, the amount of opioids required to manage pain is reduced by 1% or more by weight, such as 2% or more by weight, such as 3% or more by weight, such as 5% or more by weight, such as 10% or more by weight, such as 15% or more by weight, such as 25% or more by weight, and includes a reduction of 50% or more by weight compared to the amount of opioids required to manage pain alone.

[0129] In some implementations, the opioid is administered before the percutaneous delivery device is applied to the subject, such as 1 minute or more before the percutaneous delivery device is applied to the subject, such as 2 minutes or more before the percutaneous delivery device is applied to the subject, such as 5 minutes or more before the percutaneous delivery device is applied to the subject, such as 10 minutes or more before the percutaneous delivery device is applied to the subject, such as 15 minutes or more before the percutaneous delivery device is applied to the subject, such as 30 minutes or more before the percutaneous delivery device is applied to the subject, such as 1 hour or more before the percutaneous delivery device is applied to the subject, such as 2 hours or more before the percutaneous delivery device is applied to the subject, such as 3 hours or more before the percutaneous delivery device is applied to the subject, such as 6 hours or more before the percutaneous delivery device is applied to the subject, and including 12 hours or more before the percutaneous delivery device is applied to the subject. In other embodiments, the opioid is administered to the subject after the percutaneous delivery device has been applied to the subject, such as 1 minute or longer, such as 2 minutes or longer, such as 5 minutes or longer, such as 10 minutes or longer, such as 15 minutes or longer, such as 30 minutes or longer, such as 1 hour or longer, such as 2 hours or longer, such as 3 hours or longer, such as 6 hours or longer, and including 12 hours or longer after the percutaneous delivery device has been applied to the subject.

[0130] In other embodiments, the opioid is administered before the start of the surgical procedure on the subject, such as 1 minute or longer before the start of the surgical procedure, such as 2 minutes or longer before the start of the surgical procedure, such as 5 minutes or longer before the start of the surgical procedure, such as 10 minutes or longer before the start of the surgical procedure, such as 15 minutes or longer before the start of the surgical procedure, such as 30 minutes or longer before the start of the surgical procedure, such as 1 hour or longer before the start of the surgical procedure, such as 2 hours or longer before the start of the surgical procedure, such as 3 hours or longer before the start of the surgical procedure, such as 6 hours or longer before the start of the surgical procedure, and including 12 hours or longer before the start of the surgical procedure on the subject. In other embodiments, the opioid is administered after the start of the surgical procedure on the subject, such as 1 minute or longer after the start of the surgical procedure on the subject, such as 2 minutes or longer after the start of the surgical procedure, such as 5 minutes or longer after the start of the surgical procedure, such as 10 minutes or longer after the start of the surgical procedure, such as 15 minutes or longer after the start of the surgical procedure, such as 30 minutes or longer after the start of the surgical procedure, such as 1 hour or longer after the start of the surgical procedure, such as 2 hours or longer after the start of the surgical procedure, such as 3 hours or longer after the start of the surgical procedure, such as 6 hours or longer after the start of the surgical procedure on the subject.

[0131] In some embodiments, the method includes replacing the administration of one or more doses of opioids (e.g., opioid agonists) in an opioid pain management regimen with a percutaneous delivery device containing dexmedetomidine as described herein. The term "opioid pain management regimen" refers to a pain management regimen involving the administration of a predetermined dose of opioids to manage a subject's pain (e.g., by a healthcare professional in a healthcare facility, under the supervision of a healthcare professional, or at the subject's home under the guidance / prescription of a healthcare professional). For example, an opioid pain management regimen of interest may include a pain management regimen employing multiple predetermined doses of opioids to manage, reduce, or eliminate pain in the following situations: acute pain, chronic pain, neuropathic pain, cancer-related pain, postoperative pain, moderate to severe pain, labor pain, perioperative pain, and other types of pain known to be managed by opioids. In some implementations, the opioid pain management regimen, which is an alternative to or supplement to opioid-based treatment by applying a transdermal delivery device containing dexmedetomidine as described herein, is for moderate to severe pain that typically requires opioids and for which alternative pain relief regimens have proven inadequate.

[0132] Methods according to these embodiments include managing pain by applying a percutaneous delivery device containing dexmedetomidine as described herein in place of one or more predetermined opioid administrations, such as two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, fifteen or more, twenty-five or more, fifty or more, seven or more, seven or more, and including one hundred or more predetermined opioid administrations. Therefore, applying and maintaining a percutaneous delivery device containing dexmedetomidine as described herein may be sufficient to reduce the number of opioid administrations predetermined in an opioid pain management program by 5% or more, such as 10% or more, such as 15% or more, such as 20% or more, such as 25% or more, such as 50% or more, such as 75% or more, such as 90% or more, such as 95% or more, and including reducing the number of opioid administrations predetermined in an opioid pain management program by 99% or more.

[0133] In some embodiments, the method of the present invention is adapted to completely replace the opioid in an opioid pain management regimen with a dexmedetomidine-containing transdermal delivery device as described herein (i.e., 100% of the administered opioid dose). In some embodiments, the method includes applying and maintaining one or more of the present invention's transdermal delivery devices containing dexmedetomidine and the administration of opioids in an opioid pain management regimen, as described above. In some cases, when the dexmedetomidine transdermal delivery device comes into contact with the subject, a reduced dose of opioid may be administered to the subject in the opioid pain management regimen, such as a reduction of 5% or more, such as 10% or more, such as 15% or more, such as 20% or more, such as 25% or more, such as 50% or more, and including 75% or more, in each time period of the opioid pain management regimen. In some cases, one or more predetermined doses of opioid administration are eliminated (i.e., skipped), such as every other predetermined dose, every two predetermined doses, every three predetermined doses, every four predetermined doses, or some other interval. In some cases, applying one or more of the dexmedetomidine transdermal delivery devices of the present invention is sufficient to eliminate the administration of consecutive predetermined doses of opioids in an opioid pain management regimen, such as two or more consecutive predetermined doses, three or more consecutive predetermined doses, and including four or more consecutive predetermined doses of opioids in an opioid pain management regimen.

[0134] In some embodiments, the method includes applying one or more of the dexmedetomidine percutaneous delivery devices of the present invention to manage obstetric pain associated with childbirth (e.g., labor and delivery). In these embodiments, the percutaneous delivery device may be applied to the subject after the onset of labor (e.g., after the onset of the first labor contractions) or before the onset of labor, and then maintained on the subject throughout labor and delivery, as well as for a period of time postpartum. For example, dexmedetomidine may be applied via the percutaneous delivery device for 30 minutes or more, 1 hour or more, 2 hours or more, 5 hours or more, 8 hours or more, 9 hours or more, 10 hours or more, 11 hours or more, 12 hours or more, 15 hours or more, 18 hours or more, 24 hours or more, such as 1 day or more, before the onset of labor, and maintained on the subject throughout labor and delivery. In some cases, the percutaneous delivery device is applied at any time from 0.50 to 30 hours before the onset of labor, such as 1 to 24 hours before surgery. The composition of the present invention is then maintained on the subject for a period of time postpartum, wherein this postpartum maintenance period can vary and is, in some cases, 1 hour or longer, such as 2 hours or longer, such as 4 hours or longer, such as 8 hours or longer, such as 12 hours or longer, such as 24 hours or longer, such as 48 hours or longer, such as 72 hours or longer, such as 96 hours or longer, such as 120 hours or longer, such as 144 hours or longer, and including 168 hours or longer. For the above ranges, in some cases, the upper limit of the time period is 168 hours or less, such as 144 hours or less, such as 120 hours or less, such as 96 hours or less, such as 72 hours or less, such as 48 hours or less, and including 24 hours or less. In some embodiments, the extended percutaneous delivery range is, for example, 0.5 hours to 168 hours, 1 hour to 144 hours, 1.5 hours to 120 hours, 2 hours to 96 hours, 2.5 hours to 72 hours, or 3 hours to 72 hours. In some embodiments, the delivery and labor protocol is a multi-day percutaneous dexmedetomidine delivery protocol spanning a period before and after the delivery and labor procedure, wherein in some cases, this protocol ranges from 2 days to 30 days, for example, 2 days to 15 days, 2 days to 7 days, 2 days to 4 days, and includes 2 days to 4 days, such as 3 days.

[0135] In some implementations, the percutaneous delivery device is applied and maintained in contact with the subject for a total duration of 72 hours. In one example, the percutaneous delivery device is applied 4 hours before the onset of labor, maintained in contact with the subject during labor, and removed after a total duration of 72 hours. In another example, the percutaneous delivery device is applied 6 hours before the onset of labor, maintained in contact with the subject during labor, and removed after a total duration of 72 hours. In yet another example, the percutaneous delivery device is applied 12 hours before the onset of labor, maintained in contact with the subject during labor, and removed after a total duration of 72 hours. In yet another example, the percutaneous delivery device is applied 24 hours before the onset of labor, maintained in contact with the subject during labor, and removed after a total duration of 72 hours. In yet another example, the percutaneous delivery device is applied 24 hours before the onset of labor, maintained in contact with the subject during labor, and removed after a total duration of 84 hours. In yet another instance, a percutaneous delivery device was applied 24 hours before the onset of labor, maintained in contact with the subject during labor, and removed after a total duration of 96 hours.

[0136] In other embodiments, one or more percutaneous delivery devices of the present invention are applied to the subject for a predetermined period of time (e.g., 4 hours, 6 hours, 12 hours, 18 hours, 24 hours, etc.) before the onset of labor, and contact with the subject is maintained for 72 hours or more post-procedure. Thus, the total duration of contact between the percutaneous delivery device and the subject can be 76 hours or more, such as 80 hours or more, such as 84 hours or more, such as 90 hours or more, and includes 96 hours or more. In one example, the percutaneous delivery device is applied 4 hours before the onset of labor, maintained in contact with the subject during labor, and maintained in contact with the subject for 72 hours or more post-procedure. In another example, the percutaneous delivery device is applied 6 hours before the onset of labor, maintained in contact with the subject during labor, and maintained in contact with the subject for 72 hours or more post-procedure. In yet another example, the percutaneous delivery device is applied 12 hours before the onset of labor, maintained in contact with the subject during labor, and maintained in contact with the subject for 72 hours or more post-procedure. In yet another instance, a percutaneous delivery device was applied 18 hours before the onset of labor, with contact maintained with the subject during labor and for 72 hours or more post-operatively. In yet another instance, a percutaneous delivery device was applied 24 hours before the onset of labor, with contact maintained with the subject during labor and for 72 hours or more post-operatively. In yet another instance, a percutaneous delivery device was applied 24 hours before the onset of labor, with contact maintained with the subject during labor and for 84 hours or more post-operatively. In yet another instance, a percutaneous delivery device was applied 24 hours before the onset of labor, with contact maintained with the subject during labor and for 96 hours or more post-operatively.

[0137] Dexmedetomidine percutaneous delivery device containing a dexmedetomidine composition for managing surgical pain in subjects.

[0138] The invention also includes, in accordance with the methods of practicing the invention, a percutaneous delivery device for delivering an effective amount (e.g., a sedative or non-sedative amount) of dexmedetomidine to a subject. Percutaneous delivery devices of interest comprise a composition having dexmedetomidine and a pressure-sensitive adhesive. Dexmedetomidine is the S-enantiomer of dexmedetomidine described by the following formula:

[0139]

[0140] According to embodiments of the present invention, dexmedetomidine may be in the form of a free base, salt, solvate, hydrate, or complex. For example, dexmedetomidine may be in the form of pharmaceutically acceptable salts, including but not limited to mesylate, maleate, fumarate, tartrate, hydrochloride, hydrobromide, ethanesulfonate, p-toluenesulfonate, benzoate, acetate, phosphate, and sulfate. According to some embodiments, dexmedetomidine may be a free base. In other cases, dexmedetomidine may form a complex.

[0141] Depending on the application site, the type of pain being managed, and the subject's physiological function (e.g., weight), the amount of dexmedetomidine in the composition of interest can vary. In some cases, the amount of dexmedetomidine ranges from 0.001 mg to 50 mg, such as 0.005 mg to 40 mg, such as 0.01 mg to 30 mg, such as 0.05 mg to 20 mg, and includes 0.1 mg to 10 mg. In some embodiments, the amount of dexmedetomidine in the transdermal composition ranges from 0.1% to 20% w / w, such as 0.5% to 18% w / w, such as 1% to 15% w / w, such as 2% to 12.5% ​​w / w, and includes 3% to 10% w / w. In other embodiments, the amount of dexmedetomidine in the transdermal composition of the present invention is 10% by weight or less of the total weight of the transdermal composition, such as 9% by weight or less, such as 8% by weight or less, such as 7% by weight or less, such as 6% by weight or less, such as 5% by weight or less, and includes 3% by weight or less of the total weight of the transdermal composition. In some embodiments, the dexmedetomidine composition contains an amount of dexmedetomidine below the saturation point. In other embodiments, the dexmedetomidine composition contains a saturated amount of dexmedetomidine. In still other embodiments, the dexmedetomidine composition contains a supersaturated amount of dexmedetomidine.

[0142] In some embodiments of the invention, the dexmedetomidine composition described herein is formulated to deliver a non-sedating amount of dexmedetomidine. As described above, non-sedating means that the dexmedetomidine composition is formulated to deliver an amount of dexmedetomidine to the subject that does not cause complete sedation. In other words, the subject remains conscious and responsive throughout the entire period of transdermal administration of the dexmedetomidine composition of interest. In some cases, the subject remains cooperative, oriented, and euthanized during the administration of the transdermal dexmedetomidine composition. In other cases, the subject remains alert and responsive to instructions (e.g., verbal or written instructions) during the administration of the transdermal dexmedetomidine composition. In still other cases, the subject is alert, cooperative, oriented, and euthanized and responsive to instructions (e.g., verbal or written instructions) during the administration of the transdermal dexmedetomidine composition.

[0143] As described in more detail below, in some embodiments, the dexmedetomidine transdermal composition of interest is formulated such that, during transdermal administration, the subject can be evaluated according to the Wilson Sedation Rating Scale and assigned a Wilson score of 3 or less, such as a Wilson score of 2 or less, including cases where the subject is assigned a Wilson score of 1. In some cases, during administration of the dexmedetomidine transdermal composition, the subject shows a quick response to tapping between the eyebrows or a loud auditory stimulus. In other cases, during administration of the dexmedetomidine transdermal composition, the subject responds to verbal commands. In still other cases, during administration of the dexmedetomidine transdermal composition, the subject is cooperative, oriented, and calm. In still other cases, during administration of the dexmedetomidine transdermal composition, the subject is anxious, agitated, or restless.

[0144] In embodiments of the present invention, the transdermal dexmedetomidine composition further comprises a pressure-sensitive adhesive. The pressure-sensitive adhesive may include, but is not limited to, poly-isobutene adhesives, poly-isobutylene adhesives, poly-isobutene / polyisobutylene adhesive mixtures, carboxylated polymers, acrylic or acrylate copolymers, such as carboxylated acrylate copolymers.

[0145] In the case where the pressure-sensitive adhesive contains polybutene, the polybutene can be saturated polybutene. Alternatively, the polybutene can be unsaturated polybutene. Furthermore, the polybutene can be a mixture or combination of saturated and unsaturated polybutene. In some embodiments, the pressure-sensitive adhesive may comprise or be substantially the same as the following compositions: 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, Panalane® H-300E, and combinations thereof. In some embodiments, the polybutene pressure-sensitive adhesive is Indopol. ®H-1900. In other embodiments, the polybutene pressure-sensitive adhesive is Panalane® H-300E.

[0146] Acrylic copolymers of interest include copolymers of various monomers, such as “soft” monomers, “hard” monomers, or “functional” monomers. Acrylic copolymers can be composed of copolymers including dimers (i.e., made from two monomers), trimers (i.e., made from three monomers), or tetramers (i.e., made from four monomers), or copolymers having more than one number of monomers. Acrylic copolymers can be crosslinked or non-crosslinked. The polymers can be crosslinked by known methods to provide the desired polymer. The monomers that produce acrylate copolymers may contain at least two or more exemplary components selected from the group consisting of acrylic acid, alkyl acrylates, methacrylates, copolymerizable second monomers, or monomers having functional groups. Monomers (“soft” monomers and “hard” monomers) can 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, dodecane acrylate, dodecane methacrylate, tridecane acrylate, tridecane methacrylate, acrylonitrile, methoxyethyl acrylate, methoxyethyl methacrylate, etc. Further examples of acrylic adhesive monomers are described in Satas, "Acrylic Adhesives," Handbook of Pressure-Sensitive Adhesive Technology, 2nd edition, pp. 396-456 (edited by D. Satas), Van Nostrand Reinhold, New York (1989), the disclosure of which is incorporated herein by reference. In some embodiments, the pressure-sensitive adhesive is an acrylate-vinyl acetate copolymer. In some embodiments, the pressure-sensitive adhesive may comprise or be substantially the same as the following compositions: 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, and Duro-Tak® 87-2074, and combinations thereof.As used in this context, the term "substantially identical" refers to compositions of acrylate-vinyl acetate copolymers in organic solvent solutions. In some embodiments, the acrylic pressure-sensitive adhesive is Duro-Tak. ® 87-2054.

[0147] For example, an acrylate copolymer of interest can be formed from a monomer having the following formula:

[0148]

[0149] Wherein R is hydrogen, a straight-chain alkyl group, a branched alkyl group, or an alkyl group substituted therewith. In some embodiments, the pressure-sensitive adhesive is an acrylate adhesive that is a non-functionalized acrylate, a hydroxyl-functionalized acrylate, or an acid-functionalized acrylate. For example, the acrylate adhesive may be an acrylic adhesive having one or more –OH functional groups. In cases where the acrylic adhesive has one or more –OH functional groups, in some cases, the pressure-sensitive adhesive may be a composition or a composition substantially the same as the following: Duro-Tak® 87-4287, Duro-Tak® 87-2287, Duro-Tak® 87-2510, and Duro-Tak® 87-2516, and combinations thereof. The acrylate adhesive may also be an acrylic adhesive having one or more –COOH functional groups. In cases where the acrylic adhesive has one or more –COOH functional groups, the pressure-sensitive adhesive may, in some instances, be a composition or a composition substantially the same as the following: Duro-Tak® 87-387, Duro-Tak® 87-2979, and Duro-Tak® 87-2353, and combinations thereof. Furthermore, the acrylic adhesive may be a non-functionalized acrylic adhesive. In cases where the acrylic adhesive is non-functionalized, the pressure-sensitive adhesive may, in some instances, be a composition or a composition substantially the same as the following: Duro-Tak® 87-9301.

[0150] The amount of pressure-sensitive adhesive in the transdermal dexmedetomidine composition of interest can vary, ranging from 0.1 mg to 2000 mg, such as 0.5 mg to 1500 mg, such as 1 to 1000 mg, such as 10 to 750 mg, and including 10 mg to 500 mg. Therefore, the amount of pressure-sensitive adhesive in the transdermal composition ranges from 1% to 99% w / w, such as 5% to 95% w / w, such as 10% to 95% w / w, such as 15% to 90% w / w, and including 20% ​​to 85% w / w. In other embodiments, the amount of pressure-sensitive adhesive in the transdermal composition of the present invention is 70% by weight or more of the total weight of the transdermal composition, such as 75% by weight or more, such as 80% by weight or more, such as 85% by weight or more, such as 90% by weight or more, such as 95% by weight or more, and including 97% by weight or more of the total weight of the transdermal composition.

[0151] The weight ratio of pressure-sensitive adhesive to dexmedetomidine in the compositions of the present invention can be within the ranges of 1:2 to 1:2.5; 1:2.5 to 1:3; 1:3 to 1:3.5; 1:3.5 to 1:4; 1:4 to 1:4.5; 1:4.5 to 1:5; 1:5 to 1:10; 1:10 to 1:25; 1:25 to 1:50; 1:50 to 1:75; and 1:75 to 1:99 or the range thereof. For example, the weight ratio of pressure-sensitive adhesive to dexmedetomidine in the compositions of the present invention can be within the ranges of 1:1 to 1:5; 1:5 to 1:10; 1:10 to 1:15; 1:15 to 1:25; 1:25 to 1:50; 1:50 to 1:75 or 1:75 to 1:99. Alternatively, the weight ratio of dexmedetomidine to pressure-sensitive adhesive in the compositions of the present invention is within the range of 2:1 to 2.5:1; 2.5:1 to 3:1; 3:1 to 3.5:1; 3.5:1 to 4:1; 4:1 to 4.5:1; 4.5:1 to 5:1; 5:1 to 10:1; 10:1 to 25:1; 25:1 to 50:1; 50:1 to 75:1; and 75:1 to 99:1. For example, the ratio of dexmedetomidine to pressure-sensitive adhesive in the compositions of the present invention may be within the range of 1:1 to 5:1; 5:1 to 10:1; 10:1 to 15:1; 15:1 to 25:1; 25:1 to 50:1; 50:1 to 75:1; or 75:1 to 99:1.

[0152] In some embodiments, the transdermal dexmedetomidine composition 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 may include, but is not limited to, polyethyleneimine, amine-terminated polyethylene oxide, amine-terminated polyethylene oxide / polypropylene oxide, polymers of dimethylaminoethyl methacrylate, and copolymers of dimethylaminoethyl methacrylate and vinylpyrrolidone. In some embodiments, the crosslinked polymer is crosslinked polyvinylpyrrolidone, such as PVP-CLM.

[0153] Depending on the adhesive used, the matrix may contain other additives. For example, materials that inhibit drug crystallization, such as PVP-CLM, PVP K17, PVP K30, and PVP K90, have hygroscopic properties that improve wear duration and enhance the physical properties of the adhesive, such as cold flow, tackiness, and adhesive strength.

[0154] The amount of crosslinked polymer in the dexmedetomidine composition of interest can vary, ranging from 0.1 mg to 500 mg, such as 0.5 mg to 400 mg, such as 1 to 300 mg, such as 10 to 200 mg, and including 10 mg to 100 mg. Therefore, the amount of crosslinked polymer in the transdermal composition ranges from 2% to 30% w / w, such as 4% to 30% w / w, such as 5% to 25% w / w, such as 6% to 22.5% w / w, and including 10% to 20% w / w. In other embodiments, the amount of crosslinked polymer in the transdermal composition of the present invention is 8% by weight or more of the total weight of the transdermal composition, such as 10% by weight or more, such as 12% by weight or more, such as 15% by weight or more, such as 20% by weight or more, such as 25% by weight or more, and includes 30% by weight or more of crosslinked polymer in the total weight of the transdermal composition.

[0155] In some embodiments, the transdermal dexmedetomidine composition of the present invention further comprises a dexmedetomidine solubilizer. "Solubilizer" means a compound or composition that increases the solubility of dexmedetomidine in the composition of the present invention, for example, to prevent any unwanted crystallization of dexmedetomidine in the composition. The dexmedetomidine solubilizer may be incorporated into the dexmedetomidine composition in amounts ranging from 0.01% to 20% (w / w), such as 0.05% to 15% (w / w), such as 0.1% to 10% (w / w), such as 0.5% to 8% (w / w), and including 1% to 5% (w / w).

[0156] Exemplary solubilizers include, but are not limited to: acids, including linoleic acid, oleic acid, linolenic acid, stearic acid, isostearic acid, levulinic acid, palmitic acid, caprylic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid (i.e., 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 solubilizers of interest may include, but are not limited to: fatty alcohols, such as saturated or unsaturated higher alcohols having 12 to 22 carbon atoms (e.g., oleyl alcohol or lauryl alcohol); fatty acid esters, such as isopropyl myristate, diisopropyl adipate, lauryl lactate, propyl lauryl acid, ethyl oleate, and isopropyl palmitate; alkanolamines, such as triethanolamine, triethanolamine hydrochloride, and diisopropanolamine; and polyol alkyl ethers, such as alkyl ethers of polyols, such as glycerol, ethylene glycol. Propylene glycol, 1,3-butanediol, diglyceride, polyglycerol, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, polypropylene glycol monolaurate, sorbitol, sorbitol, isosorbide, methyl glucoside, oligosaccharides, and reduced oligosaccharides, wherein the number of carbon atoms in the alkyl portion of the polyol alkyl ether is preferably 6 to 20; polyoxyethylene alkyl ethers, such as polyoxyethylene alkyl ethers (wherein the number of carbon atoms in the alkyl portion is 6 to 20, and polyoxyethylene... The number of repeating units in the olefin chain (e.g., –O–CH2CH2–) is 1 to 9, such as, but not limited to, polyoxyethylene lauryl ether, polyoxyethylene cetyl 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 can 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, octadecanoic 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. Other types of solubilizers may include 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, the solubility absorption enhancer is levulinic acid, lauryl lactate, or propylene glycol monolaurate.

[0157] The formulation of the transdermal dexmedetomidine composition of the present invention can be varied. For example, the compositions of the present invention can be in the form of a liquid solution or suspension, syrup, gel, foam, or any combination thereof for application via a transdermal delivery device.

[0158] In some embodiments, the transdermal delivery device is configured to comprise a monolayer matrix of dexmedetomidine composition. "Monolayer" means that the transdermal delivery device comprises only a single layer of the dexmedetomidine composition disposed on the substrate surface of the transdermal delivery device and does not include separate, distinct layers of pressure-sensitive adhesive, transdermal dexmedetomidine composition, or (if present) any solubilizer. Similarly, the monolayer transdermal delivery device of the present invention does not further comprise a separate dexmedetomidine reservoir (i.e., an active agent reservoir) separate from the pressure-sensitive adhesive. Therefore, the monolayer transdermal delivery device of the present invention may comprise in a single matrix each of the components of the transdermal dexmedetomidine composition necessary for practicing the method of the present invention, as described in more detail below. For example, in some embodiments, the monolayer transdermal delivery device of interest comprises a monolayer matrix of dexmedetomidine and a pressure-sensitive adhesive configured to deliver an unsedated amount of dexmedetomidine to a subject. In another embodiment, the monolayer transdermal delivery device of interest comprises a monolayer matrix of dexmedetomidine, a pressure-sensitive adhesive, and a solubilizer configured to deliver an unsedated amount of dexmedetomidine to a subject. In another embodiment, the monolayer percutaneous delivery device of interest comprises a monolayer matrix of dexmedetomidine, a pressure-sensitive adhesive, and a fatty acid ester configured to deliver a non-sedated dose of dexmedetomidine to a subject. In some embodiments, the monolayer percutaneous delivery device of interest comprises a monolayer matrix containing only dexmedetomidine and a pressure-sensitive adhesive. The thickness of the monolayer matrix of interest can vary depending on the length of the dose interval and the desired target dose, and in some cases, the thickness ranges from 10 to 260 micrometers, such as 15 to 250 micrometers, such as 25 to 225 micrometers, such as 50 to 200 micrometers, such as 75 to 175 micrometers, and includes 20 to 130 micrometers, such as 35 to 110 micrometers.

[0159] The size of the percutaneous delivery device of the present invention can be varied, and in some cases, the size is set to cover the entire application site on the subject. Therefore, the percutaneous delivery device can have a length ranging from 1 to 100 cm, such as 1 to 60 cm, and a width ranging from 1 to 100 cm, such as 1 to 60 cm. Thus, the area of ​​the percutaneous delivery device can range from 4 cm². 2 Up to 10,000 cm 2 Such as 5 cm 2 Up to 1000 cm 2 Such as 10 cm 2 Up to 100 cm 2 Such as 15 cm 2 Up to 50 cm2 And including 20cm 2 Up to 40 cm 2 In some embodiments, the size of the transdermal delivery device is set to have 30 cm. 2 The area. In some cases, the transdermal delivery device is insoluble in water. Insoluble in water means that the transdermal delivery device can be immersed in water for a period of time of one day or longer, such as one week or longer, including one month or longer, and exhibits very little dissolution (if any), for example, no observable dissolution.

[0160] In some embodiments, the transdermal delivery device described above further includes a cover backing layer. The cover backing can be flexible, such as allowing it to make close contact with the desired application site on the subject. The cover backing can be made of a material that does not absorb dexmedetomidine and does not allow dexmedetomidine to leach from the matrix. Cover backing layers of interest may include, but are not limited to, nonwoven fabrics, woven fabrics, films (including sheets), porous materials, foams, paper, composite materials obtained by laminating films onto nonwoven or woven fabrics, and combinations thereof.

[0161] Nonwoven fabrics may include polyolefin resins, such as polyethylene and polypropylene; polyester resins, such as 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. Fabrics may include cotton, rayon, polyacrylic resin, polyester resin, polyvinyl alcohol, and combinations thereof. Films may include polyolefin resins, such as polyethylene and polypropylene; polyacrylic resins, such as polymethyl methacrylate and polyethyl methacrylate; polyester resins, such as polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate; and furthermore, cellophane, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyvinyl chloride, polystyrene, polyurethane, polyacrylonitrile, fluoropolymers, styrene-isoprene-styrene copolymer, styrene-butadiene rubber, polybutadiene, ethylene-vinyl acetate copolymer, polyamide, and polysulfone; and combinations thereof. Paper may include impregnated paper, coated paper, wood-free paper, kraft paper, Japanese paper, cellophane, synthetic paper, and combinations thereof.

[0162] Depending on the dosing interval and the required target dose, the size of the cover backing can vary, and in some cases the size is set to cover the entire application site on the subject. Therefore, the backing layer can have a length ranging from 2 to 100 cm, such as 4 to 60 cm, and a width ranging from 2 to 100 cm, such as 4 to 60 cm. In some cases, the cover backing layer may be insoluble in water. Insoluble in water means that the backing layer can be immersed in water for a period of one day or longer, such as one week or longer, including one month or longer, and exhibits very little dissolution (if any), for example, no observable dissolution.

[0163] The percutaneous delivery device having the dexmedetomidine composition according to an embodiment of the invention causes no skin irritation at the application site in the subject. Skin irritation, in its general sense herein, refers to adverse effects, discoloration, or damage to the skin, such as redness, pain, swelling, or dryness. Therefore, in the practice of using the percutaneous delivery device of the invention, the quality of the skin remains normal and the percutaneous delivery is consistent throughout the dosing interval.

[0164] In some implementations, skin irritation is evaluated to determine the quality and color of the skin at the application site and to determine whether any damage, pain, swelling, or dryness is due to maintaining contact between the transdermal composition and the subject. Skin irritation can be evaluated using any convenient method, such as the Draize rating, as disclosed in Draize, JH, Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, pp. 46-49, The Association of Food and Drug Officials of the United States: Austin, Texas, the disclosure of which is incorporated herein by reference. Specifically, erythema or edema can be evaluated for the skin at the transdermal application site. For example, the grades of erythema and edema can be assigned based on visual observation or palpation.

[0165] Erythema: 0 = No visible redness; 1 = Very slight redness (only perceptible); 2 = Slight but distinct redness; 3 = Moderate redness; 4 = Severe erythema (deep red discoloration of the skin).

[0166] 5 = Eschar formation

[0167] Edema: 0 = No visible reaction or swelling; 1 = Very slight edema (swelling that can only be felt); 2 = Mild edema (the corners of the area are clearly defined due to swelling); 3 = Moderate edema (swelling up to 1 mm); 4 = Severe edema (swelling exceeding 1 mm).

[0168] The application site can be evaluated for skin irritation at any time during the method of the present invention. In some cases, the skin is evaluated for irritation by observing or palpating the skin at regular intervals, such as every 0.25 hours, every 0.5 hours, every 1 hour, every 2 hours, every 4 hours, every 12 hours, every 24 hours, including every 72 hours, or some other interval, while maintaining contact between the percutaneous delivery device and the subject. For example, the application site can be evaluated for skin irritation while maintaining contact between the percutaneous delivery device and the subject, such as 15 minutes after application of the percutaneous delivery device to the subject, 30 minutes after application of the percutaneous delivery device, 1 hour after application of the percutaneous delivery device, 2 hours after application of the percutaneous delivery device, 4 hours after application of the percutaneous delivery device, 8 hours after application of the percutaneous delivery device, 12 hours after application of the percutaneous delivery device, 24 hours after application of the percutaneous delivery device, 48 hours after application of the percutaneous delivery device, 72 hours after application of the percutaneous delivery device, 76 hours after application of the percutaneous delivery device, 80 hours after application of the percutaneous delivery device, 84 hours after application of the percutaneous delivery device, 96 hours after application of the percutaneous delivery device, 120 hours after application of the percutaneous delivery device, and 168 hours after application of the percutaneous delivery device.

[0169] In other embodiments, the percutaneous application site is evaluated for skin irritation after the percutaneous delivery device has been removed from contact with the subject. For example, the evaluation may be performed 30 minutes after removal of the percutaneous delivery device, such as 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, or even 72 hours after removal of the percutaneous delivery device.

[0170] In some implementations, skin irritation is evaluated at the percutaneous application site before the percutaneous delivery device is applied to the subject, such as to record skin color and texture prior to the start of the dosing interval. For example, the evaluation may be performed 5 minutes, such as 10 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, or up to 480 minutes before the application of the percutaneous delivery device. In cases where the method includes multiple sequential dosing intervals, skin irritation may be evaluated at the application site after each percutaneous delivery device is removed and before the application of a subsequent percutaneous delivery device. For example, when the first percutaneous delivery device is removed, the evaluation may be performed 2 hours, 24 hours, and 48 hours after removal and before the application of a second percutaneous delivery device. Subsequent percutaneous delivery devices may be applied immediately after skin irritation evaluation to the previously applied site, or at predetermined times after skin irritation evaluation, such as 4 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, or 168 hours after skin irritation evaluation.

[0171] The application site may be evaluated for skin irritation once or multiple times before, during, or after a dose interval, such as two or more times, three or more times, including five or more times before, during, or after a dose interval. The upper limit for the number of times the application site may be evaluated for skin irritation before, during, or after a dose interval is, in some cases, 10 times or fewer, such as seven times or fewer, five times or fewer, three times or fewer, and including two times or fewer. In some embodiments, the range of the number of times the application site may be evaluated for skin irritation before, during, or after a dose interval is such as two to ten times, three to nine times, four to eight times, and including five to seven times. In some embodiments, skin irritation may be monitored (e.g., via video monitoring) throughout the entire time the percutaneous delivery device remains in contact with the subject.

[0172] Other aspects of the methods of the present invention include methods for increasing a pain threshold. As used herein, "increasing a pain threshold" means reducing, attenuating, and / or minimizing pain associated with surgery, incision, trauma, or wound (including reducing, attenuating, and / or minimizing the subjective perception of pain). In yet another aspect, the methods of the present invention provide enhanced surgical recovery, as well as enhanced wound, trauma, and / or incision recovery.

[0173] In some embodiments, the method of the present invention includes a diagnostic step. An individual may be diagnosed as needing the method of the present invention using any convenient means. Additionally, an individual may be known to need the method of the present invention prior to practicing it, for example, they have symptoms of a target disease or have been identified as being at risk of having symptoms of a target disease. The diagnosis or assessment of pain is well-established in the art. Assessments may be performed based on objective measurements, such as observing behavior such as responses to stimuli, facial expressions, etc. Assessments may also be based on subjective measurements, such as patient characterization of pain using various pain scales. See, for example, Katz et al., Surg. CHn. North Am. (1999) 79 (2):231-52; Caraceni et al. J. Pain Symptom Manage (2002) 23(3):239-55.

[0174] Pain relief can also be characterized by the time course of relief. Therefore, in some embodiments, pain relief is observed subjectively or objectively after 1, 2, or several hours (and in some embodiments, it peaks at approximately 12-18 hours). In other embodiments, pain relief is observed subjectively or objectively 24, 36, 48, 60, 72, or more hours after surgery (or wound- or trauma-related activity).

[0175] utility

[0176] The dexmedetomidine percutaneous delivery device and method of the present invention can be used in a variety of applications, including the prevention or treatment of surgical pain. Therefore, the dexmedetomidine percutaneous delivery device and method of the present invention can be used to treat surgical pain in a subject, delay the development of surgical pain in a subject, and / or prevent surgical pain in a subject, said subject including all mammals, including humans and non-humans, including carnivores (e.g., dogs and cats), rodents (e.g., mice, guinea pigs, and rats), lagomorphs (e.g., rabbits), and primates (e.g., humans, chimpanzees, and monkeys). In some embodiments, the subject, such as a patient, is a human. Furthermore, the dexmedetomidine percutaneous delivery device and method of the present invention can be used in individuals with tissue incision wounds, whether internal or external cuts, punctures, or tears. Such incision wounds may occur accidentally due to traumatic wounds or intentionally due to surgery.

[0177] In some embodiments, the methods and percutaneous delivery devices of the present invention, as described above, can be used to treat surgical pain caused by surgical procedures (e.g., those involving incisions in the patient). Surgical pain can be perioperative pain and / or postoperative pain. Surgical procedures that can be used with the percutaneous delivery devices and methods are variable, and may be bone model surgeries or soft tissue surgeries, including but not limited to: median sternotomy, laparoscopy, mastectomy, arthroplasty, osteotomy, cancer surgery, knee surgery, shoulder surgery, and other types of surgeries. In embodiments, the surgery is bunion removal, total knee arthroplasty, hernia repair, open cholecystectomy, total hip replacement, or arthroscopic surgery of the patient's shoulder and knee. In some embodiments, the surgical procedure is a dental procedure, such as surgical extraction of a molar (e.g., the first, second, or third adult molar).

[0178] In some cases, the methods and percutaneous delivery devices of the present invention can be used to treat surgical pain associated with bunion excision. A bunion, or hallux valgus, is an inflammation or thickening of the joint capsule of the big toe. This inflammation leads to joint damage and deformity due to abnormal bone growth. The big toe is forced to grow towards the other toes, causing the head of the first metatarsal bone to protrude and rub against the side of the shoe; the underlying tissue becomes inflamed and forms a painful growth. As this bone growth progresses, a bunion forms when the big toe is forced to grow at an increasingly larger angle towards the other toes. Bunions can also develop in the fifth metatarsal bone, in which case it is called a little toe cyst or tailor's bunion. Bunions often develop due to wearing narrow, high shoes with pointed toes, which puts enormous pressure on the forefoot and causes the foot and toes to be supported at an unnatural angle. Joint damage can also cause bunions to develop over time. Genetics plays a role in 10% to 15% of all bunion problems; a hereditary deformity, hallux valgus, causes the bones and joints of the big toe to shift inward and grow, allowing a second toe to cross over it. Flat feet, gout, and arthritis increase the risk of bunions. Bunion surgery, commonly known as bunion excision, is almost always performed as an outpatient procedure. The surgery itself varies depending on the type and severity of the deformity. While the procedures differ, recovery is the same for everyone. Depending on the area of ​​bone being cut and the type of cut performed, some bunion excision procedures are called Akin, Austin Akin, Keller, Silver, SilverAkin, and Kalish. Once the patient is in the operating room and after anesthesia begins, a tourniquet is applied to the thigh or ankle, depending on the type of anesthesia. The tourniquet is used to prevent bleeding during the procedure. After the tourniquet is applied, the foot and lower leg are aseptically cleaned to help prevent infection. The surgeon then makes an incision at the top of the big toe to access the joint capsule.

[0179] Once the bone is exposed, the surgeon cuts it to correct the deformity. This is called an "osteotomy." As defined in this article, an osteotomy is a surgical procedure in which bone is cut to shorten, lengthen, or alter its alignment. For example, it is used to straighten bone that has healed twistedly after a fracture. Bone, as defined in this article, is connective tissue composed of osteoblasts that form bone, quiescent osteocytes, and osteoclasts that break down bone, embedded in a mineralized matrix filled with spaces and channels. In the case of hallux valgus, a small piece of bone is removed and the bone is realigned to correct the deformity. Tendon and other soft tissue correction may also be necessary to ensure complete correction.

[0180] Depending on the type of bunion excision, fixation may be required. Fixation can be internal, percutaneous, or external, such as a cast or splint, surgical shoe, adhesive form, or dressing. In bunion excision, fixation is usually internal. This is typically done with screws or sutures. Once the bones are realigned, the wound is rinsed with warm, sterile saline solution and then sutured and dressed. Recovery varies depending on the extent of the surgical procedure and each individual's healing rate.

[0181] Typical postoperative care consists of rest, limb elevation, and ice application for the first 3-5 days. Depending on the procedure performed, some walking may be allowed during this period in special shoes. Check-ups and bandage changes are performed at the office. Depending on work requirements, patients typically return to work after 3-7 days. Skin usually heals within two weeks, at which point sutures are removed. Bone requires 6-8 weeks to heal. X-rays taken at regular intervals assess bone healing. Any bunion surgery results in some stiffness. Physical therapy begins in the second or third week to minimize this stiffness; home exercises are usually sufficient. Failure to perform these short chains can lead to adverse outcomes due to excessive stiffness. Swelling gradually decreases, and by two months, sufficient bone healing has occurred, allowing the wearing of normal shoes. Regular activities can usually be resumed at two or three months, depending on tolerance. Some swelling may persist for six months or longer. Recovery time varies depending on the surgery and each individual's healing rate. Several factors, such as circulation, smoking, bone quality, and overall health, can also have an impact.

[0182] As summarized above, the method and percutaneous delivery device of the present invention can be used to treat pain after bunion excision and provide patients with immediate and effective relief of moderate to severe acute pain after postoperative procedures (especially outpatient postoperative procedures), thereby delaying, reducing or completely eliminating the need for alternative pain relievers (e.g., NSAIDs, opioids, etc.).

[0183] As used in this article, "acute pain" refers to pain that comes on suddenly and usually subsides within a short period (days, hours, minutes), occurs after bodily injury, and usually disappears as the injury heals. The intensity of acute pain after bunion removal surgery can be mild to moderate, moderate to moderately severe, or moderate to severe. Pain rating scales are used in routine clinical practice to measure pain intensity. Commonly used scales include the Visual Analogue Scale (VAS), Graphical Rating Scale (GRS), Simple Descriptor Scale (SDS), Numerical Rating Scale (NRS), and Facial Rating Scale (FRS). All of these scales are recorded as valid measures of pain intensity. The three most commonly used scales in the United States are the Numerical, Word, and Facial Rating Scales. The Visual Analogue Scale (VAS) is 10 cm long. A vertical or horizontal line with a word ends at one end with an extreme value such as "no pain" and at the other end with "the most severe pain possible." Patients are asked to mark along the line to represent pain intensity. The Graphical Rating Scale (GRS) is a variation of the visual scale that adds words or numbers between extreme values. Added words may include "no pain," "mild," or "severe." The Descriptor Scale (SDS) is a list of adjectives describing different levels of pain intensity. For example, pain intensity may be described as "no pain," "mild," "moderate," or "severe." The Numerical Pain Rating Scale (NPRS) is a numerical rating from 0 to 10 or 0 to 5, or a visual scale with both words and numbers. Patients are asked to rate pain as no pain on a 0 and as most severe pain on a 10. Facial scales were developed for use in children. These scales exist in several variations but rely on a range of facial expressions to convey pain intensity.

[0184] Grouping patients' pain intensity ratings, measured using a numerical scale ranging from 0 to 10, into categories of mild, moderate, and severe pain can be used to report treatment decisions and interpret study results. In 1995, Serlin and colleagues (Pain, 1995, 277–84) developed a technique to establish cutoff points for mild, moderate, and severe pain by grading pain intensity and functional inference. Since then, numerous studies have been conducted to associate numerical scales (e.g., the NPRS) with cutoff points associated with pain intensity levels. Common severity cutoff points are (1–4) for mild pain, (5–6) for moderate pain, and (7–10) for severe pain.

[0185] As used herein, the term "patient" refers to a warm-blooded animal, such as a mammal, who is the subject of surgical trauma. It should be understood that at least dogs, cats, mice, and humans are included within the scope of the term's meaning. As used herein, the term "treatment" or its derivatives envision partial or complete suppression of acute pain when the percutaneous delivery device of the present invention is applied after an acute pain attack. In one embodiment, a method is provided for treating acute pain after postoperative procedures, particularly after osteotomies such as bunionectomy.

[0186] Reagent test kit

[0187] Kits for practicing certain methods described herein are also provided. In some embodiments, the kit includes one or more transdermal delivery devices containing a dexmedetomidine composition having a quantity of dexmedetomidine and a pressure-sensitive adhesive, as described above. In some embodiments, the kit includes an adhesive cover as described above. In a given kit comprising two or more transdermal delivery devices of the present invention, the composition may be individually packaged or contained in a common container.

[0188] In some embodiments, the kit further includes instructions for practicing the methods of the invention or means for obtaining the methods of the invention (e.g., directing the user to a website URL providing the instructions), wherein these instructions may be printed on a substrate, which may be one or more of the following: packaging inserts, packaging materials, reagent containers, etc. In the kit of the present invention, one or more components may be present in the same or different containers, if convenient or desired.

[0189] The following embodiments are provided in an illustrative rather than limiting manner. Specifically, the following embodiments are specific implementations for carrying out the invention. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention in any way. Efforts have been made to ensure accuracy for the figures used (e.g., quantities, temperatures, etc.), but some experimental error and deviation should of course be allowed.

[0190] experiment

[0191] I. Materials and Methods

[0192] Preparation of an exemplary transdermal formulation of dexmedetomidine

[0193] The formulation is prepared by mixing dexmedetomidine and a pressure-sensitive adhesive in an organic solvent (e.g., 30-60% by weight solids in ethyl acetate, isopropanol, hexane, or heptane), followed by further mixing. Once a homogeneous mixture is formed, the solution is poured onto a release liner (2-3 mils of silicone-coated polyester or fluoropolymer-coated polyester sheet) and dried at 60-80°C for 10-90 minutes. The monolayer adhesive film is then laminated onto a PET backing, cut to the desired size, and placed in bags. In some cases, crosslinked polyvinylpyrrolidone (PVP-CLM), polyvinylpyrrolidone K90 (PVPK90), levulinic acid (LA), oleic acid (OA), lauryl lactate (LL), or propylene glycol monolaurate (PGML) is added to the adhesive composition.

[0194] Transcutaneous flow rate test

[0195] Human cadaver skin was used, and the epidermis (stratum corneum and viable epidermis) was separated from the full-thickness skin, such as a skin membrane. The sample was punched to approximately 2.0 cm using an arched punch. 2 The final diameter was determined. The peeling liner was removed and the system was placed on top of the epidermis / stratum corneum with the dexmedetomidine adhesive layer facing the outer surface of the stratum corneum. Slight pressure was applied to create good contact between the adhesive layer and the stratum corneum. The donor and recipient sides of the Franz cells were clamped together and a recipient solution containing phosphate buffer (pH 6.5) and 0.01% gentamicin was added to the Franz cells. For the duration of the experiment, the cells were maintained at 32°C–35°C for the duration of the experiment. Samples of the recipient solution were obtained at regular intervals and the active agent concentration was measured by HPLC. The removed recipient solution was replaced with fresh solution to maintain the leak. The flow rate was calculated by calculating the cumulative amount of drug permeating into the receiving chamber relative to the slope of the time curve.

[0196] II. Examples

[0197] Example 1

[0198] In vitro flow rate obtained from dexmedetomidine transdermal composition formulation in PIB / PB polymer

[0199] The pressure-sensitive adhesive used in this embodiment is a polyisobutylene / polybutene (PIB / PB) adhesive. The PIB / PB adhesive is a mixture of high molecular weight PIB (5% Oppanol B100), low molecular weight PIB (25% Oppanol B12), and a polybutene tackifier (e.g., Indopol H1900 or Panalane H-300e) (20%) in an organic solvent (e.g., heptane) (50%). The combination is mixed for approximately 3 days until homogeneous. Exemplary dexmedetomidine transdermal composition formulations are shown in Tables 1 and 2.

[0200] In vitro skin flow rates were studied using transdermal delivery devices with different concentrations of dexmedetomidine as shown in Table 1, as described above. The average in vitro skin flow rate of dexmedetomidine relative to time was... Figure 1 As shown in the image. Figure 1 As described, the in vitro skin flow rate of dexmedetomidine was higher in the first few hours in the 1% formulation (formulation 1) compared to higher drug loads (formulations 2 and 3). Formulations 2 and 3 were found to contain needle-like crystals of dexmedetomidine, indicating that the flow rate distribution was constant and did not change with drug load. However, no crystals were observed in formulation 1. Formulation 1 contains saturated or supersaturated amounts of dexmedetomidine.

[0201] PIB prepared by Indopol H1900 was also used to prepare transdermal dexmedetomidine formulations, as shown in Table 2. Figure 2 The results show the in vitro permeation of dexmedetomidine from a 1% dexmedetomidine custom formulation (formulation 4) prepared with 20% PVP-CLM in a PIB / PB adhesive through skin with different skin permeability. Figure 2 (A) shows the cumulative dexmedetomidine delivery over time. In vitro penetration of dexmedetomidine varies depending on skin permeability. In vitro dexmedetomidine delivery can vary from 4 to 35 ug / cm² at 8 hr and from 15 to 67 ug / cm² at 24 hr. Figure 2 (B) shows the flow rate or derivative of the cumulative drug delivery over time. The delivery rate of dexmedetomidine from formulation 2 reaches its maximum at approximately 5–7 hr and then remains constant for at least 24 hr. In the case of highly permeable skin (skin #14), the flow rate may decrease due to consumption. Figure 2 (C) shows the percentage of drug remaining in the patch over time. (See also:) Figure 2 As described in (C), the utilization rate of dexmedetomidine obtained from formulation 4 was 20%-70% after the patch was applied for 24 hours.

[0202] Table 1

[0203]

[0204] Table 2

[0205]

[0206] Example 2

[0207] In vitro flow rates obtained from dexmedetomidine transdermal composition formulations in nonfunctionalized acrylate polymers

[0208] Dexmedetomidine in vitro flow rate was measured using a nonfunctionalized acrylate adhesive. Examples of nonfunctionalized acrylate adhesives used in experiments include the nonfunctionalized acrylate polymer Duro-Tak 87-9301. In vitro skin flow rate studies were conducted using transdermal delivery devices with different concentrations of dexmedetomidine in nonfunctionalized Duro-Tak 87-9301, as described above. The dexmedetomidine transdermal composition formulations are shown in Table 3. The average in vitro flow rate of dexmedetomidine relative to time was... Figure 3 As shown in [the image / document]. Figure 3 As described, higher dexmedetomidine loading resulted in increased in vitro skin flow.

[0209] Table 3

[0210]

[0211] Example 3

[0212] In vitro flow rates obtained from dexmedetomidine transdermal composition formulations of hydroxyl (-OH)-functionalized acrylate polymers

[0213] In vitro flow rates of dexmedetomidine were measured using hydroxyl (-OH)-functionalized acrylate adhesives. Examples of hydroxyl-functionalized acrylate adhesives used in experiments include hydroxyl-functionalized acrylate polymers such as Duro-Tak 87-4287, Duro-Tak 387 / 87-2510, Duro-Tak 387 / 87-2287, and Duro-Tak 387 / 87-2516. In vitro skin flow rate studies were conducted using transdermal delivery devices with different concentrations of dexmedetomidine and different hydroxyl-functionalized acrylate adhesives, as described above.

[0214] Tables 4 and 5 show dexmedetomidine formulations with different concentrations of dexmedetomidine in Duro-Tak 87-4287 (acrylate-vinyl acetate polymer) or Duro-Tak 387 / 87-2510 (acrylate polymer). The average in vitro flow rate of dexmedetomidine is... Figure 4 and Figure 5 As shown in the image. Figure 4 and Figure 5 As described in the study, the in vitro flow rate of dexmedetomidine increases with the dexmedetomidine loading in the formulation.

[0215] Table 4

[0216]

[0217] Table 5

[0218]

[0219] Table 6 shows dexmedetomidine transdermal composition formulations containing 1% dexmedetomidine in another vinyl acetate-containing hydroxyl-functionalized acrylate polymer, such as Duro-Tak 87-2287 (polymer without crosslinking agent) and Duro-Tak 87-2516 (polymer with crosslinking agent). The average in vitro flow rate of dexmedetomidine is... Figure 6 As shown in the image. Figure 6 As described, the in vitro flow rate obtained from Duro-Tak 387 / 87-2287 is slightly higher than that obtained from Duro-Tak 387 / 87-2516, which may be due to the higher adhesive properties of Duro-Tak 387 / 87-2287 compared to Duro-Tak 387 / 87-2516.

[0220] Table 6

[0221]

[0222] Example 4

[0223] In vitro flow rates obtained from 1% dexmedetomidine transdermal composition formulations in nonfunctionalized or hydroxyl (-OH)-functionalized acrylate polymers

[0224] Another set of examples of dexmedetomidine transdermal formulations are transdermal compositions comprising 1% w / w dexmedetomidine with a nonfunctionalized acrylate polymer (Duro-Tak 87-9301, formulation 5), a hydroxyl-functionalized acrylate polymer (Duro-Tak 387 / 87-2510, formulation 11), and a hydroxyl-functionalized acrylate polymer containing vinyl acetate (Duro-Tak 87-4287, formulation 8). In vitro flow assays were performed for 3 days and 1 day, and results were obtained at [times not specified]. Figure 7A and Figure 7B As shown in [the image / document]. Figure 7A and Figure 7B As described, dexmedetomidine in vitro flow rate is lower in non-functionalized adhesives compared to hydroxyl-functionalized adhesives with the same drug load.

[0225] Example 5

[0226] In vitro flow rates obtained from dexmedetomidine transdermal composition formulations in acid (-COOH)-functionalized or acid / hydroxyl (-COOH / OH)-functionalized acrylate polymers

[0227] The in vitro flow rate of dexmedetomidine was measured using acid (-COOH)-functionalized or acid / hydroxyl (-COOH / OH)-functionalized acrylate adhesives. An example of an acid (-COOH)-functionalized acrylate adhesive used in this study is Duro-Tak 387 / 87-2353 (an acrylate polymer without crosslinking agents). An acid / hydroxyl (-COOH / OH)-functionalized acrylate adhesive used in this study is Duro-Tak 87-2979 (an acrylate-vinyl acetate polymer with crosslinking agents).

[0228] Tables 7 and 8 show dexmedetomidine transdermal formulations of acrylate polymers with different acid (-COOH)-functionalized or acid / hydroxyl (-COOH / OH)-functionalized properties. The concentration of dexmedetomidine in the formulations was selected based on the solubility of dexmedetomidine in each adhesive. The solubility of dexmedetomidine in Duro-Tak 387 / 87-2353 was found to be approximately 10%-15%, while the solubility of dexmedetomidine in Duro-Tak 87-2979 was found to be less than 2%. The drug solubility in acid-functionalized acrylate adhesives is greater than that in non-functionalized or hydroxyl-functionalized acrylate adhesives.

[0229] In vitro skin flow rate studies were conducted as described above. The average in vitro flow rate of dexmedetomidine was... Figure 8 and Figure 9 As shown in the image.

[0230] Table 7

[0231]

[0232] Table 8

[0233]

[0234] Example 6

[0235] In vitro flow rates obtained from dexmedetomidine transdermal composition formulations containing PVP-CLM and Duro-Tak 387 / 87-2353 in PIB / PB polymers

[0236] Another example of dexmedetomidine transdermal formulations is shown in Table 9. To increase the solubility of the drug in PIB / PB (e.g., Indopol H-1900) binders, PVP-CLM and acid (-COOH) functionalized acrylate polymers (Duro-Tak 387 / 87-2353) were used. Formulations 18 to 21 were prepared using different Duro-Tak 387 / 87-2353 loadings.

[0237] As in Figure 10 As described, formulations (Formulations 19, 20, and 21) containing acid-(-COOH)-functionalized acrylate polymers (Duro-Tak 387 / 87-2353) exhibited lower initial flow rates compared to the formulation without Duro-Tak 2353 (Formulation 18). The in vitro flow rate of dexmedetomidine remained unchanged with 3% and 6% acid-functionalized binders; however, a slight decrease in in vitro flow rate was observed with 9% acid-functionalized binders.

[0238] Table 9

[0239]

[0240] Example 7

[0241] In vitro flow rates obtained from dexmedetomidine transdermal composition formulations containing PVP-CLM and levulinic acid in PIB / PB polymers

[0242] Another example of a transdermal composition formulation of dexmedetomidine is shown in Table 10. To increase the solubility of the drug in PIB / PB (e.g., Indopol H-1900) binder in the presence of 20% PVP-CLM, different concentrations of acid were used to test the increased solubility of dexmedetomidine. Formulations 22 to 25 were prepared with different levulinic acid loadings.

[0243] Table 10

[0244]

[0245] As in Figure 11As described, the in vitro flow rate of dexmedetomidine was significantly reduced in formulations containing 6.9% levulinic acid. However, at a concentration of 1.75% levulinic acid, the in vitro flow rate was comparable to that at lower concentrations of levulinic acid (i.e., 0.6% and 0.9%). The initial flow rates obtained from formulations containing levulinic acid (formulations 22, 23, 24, and 25) were lower than those obtained from a formulation without levulinic acid (formulation 18). However, after 24 hours, the flow rates obtained from formulations containing levulinic acid (formulations 22, 23, 24, and 25) appeared to be higher than those obtained from a formulation without levulinic acid (formulation 17). Dexmedetomidine crystals were observed at 1.75% and lower levulinic acid concentrations.

[0246] Example 8

[0247] In vitro flow rates obtained from dexmedetomidine transdermal composition formulations containing PVP-CLM and lactic acid lauryl ester or propylene glycol monolaurate.

[0248] Another example of a dexmedetomidine transdermal composition formulation is shown in Tables 11 and 12. Dexmedetomidine has a solubility of 5% to 10% in lauryl lactate and propylene glycol monolaurate. Each of lauryl lactate and propylene glycol monolaurate increases the solubility of dexmedetomidine in the PIB / PB adhesive in the formulation of the present invention. The in vitro flow distribution of formulations 26 to 28 is as follows: Figure 12 The in vitro flow distribution of formulations 29 to 31 is shown in the figure. Figure 13 As shown in the figure. Formulations 26 to 31 were found to contain needle-like crystals of dexmedetomidine.

[0249] Table 11

[0250]

[0251] Table 12

[0252]

[0253] Example 9

[0254] In vitro flow rates obtained from dexmedetomidine transdermal composition formulations containing levulinic acid, PVP K90, or Duro-Tak 387 / 87-2287 polymer (Duro-Tak 387 / 87-2353).

[0255] Another set of examples of dexmedetomidine transdermal formulations includes transdermal compositions having 1% w / w dexmedetomidine with a solubilizer used to improve the physical stability of the composition. In these formulations, levulinic acid, PVPK90, and Duro-Tak 87-2353 are used. The formulation compositions are shown in Tables 13, 14, and 15. The in vitro flow distribution of a transdermal composition having 1% dexmedetomidine with 0.3% and 0.6% levulinic acid is shown in Figure 14(A). The in vitro flow distribution of a transdermal composition having 1% dexmedetomidine with 5% and 10% PVPK90 is shown in Figure 14(B). The in vitro flow distribution of a transdermal composition having 1% dexmedetomidine with 2% or 3% Duro-Tak 387 / 87-2353 is shown in Figure 14(C). Based on the in vitro flow distribution, levulinic acid enhanced permeability after continuous application for 15 hours, PVP K90 delayed the percutaneous flow of dexmedetomidine, while Duro-Tak 2353 slightly reduced the percutaneous flow.

[0256] Table 13

[0257]

[0258] Table 14

[0259]

[0260] Table 15

[0261]

[0262] Example 10

[0263] In vitro flow rates obtained from dexmedetomidine transdermal composition formulations containing levulinic acid, oleic acid, or Duro-Tak 87-9301 polymer (Duro-Tak 387 / 87-2353).

[0264] Another set of examples of dexmedetomidine transdermal formulations includes transdermal compositions comprising 3% w / w dexmedetomidine and a nonfunctionalized acrylate polymer, Duro-Tak 87-9301, combined with 3.3% levulinic acid, 5% oleic acid, or 15% Duro-Tak 387 / 87-2353. These formulations are shown in Table 16. The in vitro flow distribution of these formulations (Formulations 38, 39, and 40) compared to 3% dexmedetomidine (Formulation 7) in an additive-free, nonfunctionalized acrylate polymer, Duro-Tak 87-9301, is shown in Table 16. Figure 15As shown in the figure. The composition containing only 3% dexmedetomidine and the nonfunctionalized acrylate polymer Duro-Tak87-9301 is supersaturated. Lipylpropionic acid and oleic acid are used as solubilizers and permeation enhancers, and increase the flow rate at the beginning of in vitro flow, but decrease over time. Similar to the 1% dexmedetomidine composition, Duro-Tak 87-2353 reduces the flow rate.

[0265] Table 16

[0266]

[0267] Example 11

[0268] In vitro permeation of dexmedetomidine obtained from 1%, 2%, 3% and 4% dexmedetomidine in a mixture of adhesives (15% of Duro-Tak 2287 and Duro-Tak 2353).

[0269] Dexmedetomidine transdermal composition formulations containing mixtures of hydroxyl-functionalized acrylate polymers (e.g., Duro-Tak 87-2287) and acid-functionalized acrylate polymers (e.g., Duro-Tak 87-2353) are summarized in Table 17. Formulations 41 to 44 were prepared with different dexmedetomidine loadings.

[0270] Table 17

[0271]

[0272] As in Figure 16 As described in the study, the in vitro flow rate of dexmedetomidine increases with the increase of the dexmedetomidine loading percentage.

[0273] Example 12

[0274] In vitro permeation of dexmedetomidine obtained from a dexmedetomidine formulation containing oleic acid.

[0275] Another example of dexmedetomidine transdermal formulations is summarized in Table 18. Oleic acid was used to increase the solubility of dexmedetomidine in hydroxyl-functionalized acrylate polymers (e.g., Duro-Tak 87-2287). Formulations 45 to 47 were prepared with different oleic acids and dexmedetomidine loadings.

[0276] Table 18

[0277]

[0278] As in Figure 17As described, dexmedetomidine in formulations containing oleic acid has a higher flow rate than dexmedetomidine compositions without oleic acid (e.g., formulation 43). Oleic acid enhances the penetration of dexmedetomidine across the skin. Increases in oleic acid from 5% to 7% (e.g., formulation 46) did not show an enhancing effect compared to formulations containing 5% oleic acid (e.g., formulation 45). This is likely a result of oleic acid's contribution to increasing the solubility of dexmedetomidine in the composition. A comparison of formulation 45 with formulation 47 shows that the in vitro flow rate increases with increasing percentage of drug loading.

[0279] Example 13

[0280] In vitro permeation of dexmedetomidine obtained from a dexmedetomidine formulation containing levulinic acid.

[0281] Dexmedetomidine transdermal formulations were also prepared using levulinic acid. The compositions are shown in Table 19.

[0282] Table 19

[0283]

[0284] As in Figure 18 As shown, the in vitro flow rate of dexmedetomidine in formulations containing levulinic acid (formulations 48 and 49) increases with the percentage of dexmedetomidine loading. Levulinic acid enhances the permeation of dexmedetomidine through the skin more than oleic acid.

[0285] The results of the percentage of dexmedetomidine in vitro permeation relative to the amount of dexmedetomidine in the patches are summarized in Table 20. Formulations 45 and 48, containing levulinic acid and oleic acid, showed significantly enhanced permeation of dexmedetomidine under in vitro conditions.

[0286] Table 20

[0287]

[0288] The solubility of dexmedetomidine in hydroxyl-functionalized acrylate polymers is less than 1%. To increase the solubility of dexmedetomidine, acid-functionalized acrylate polymers (e.g., Duro-Tak2353), oleic acid, and levulinic acid are used. The solubilities of dexmedetomidine in Duro-Tak2353, oleic acid, and levulinic acid are approximately 10%-15%, 40%, and 60%, respectively. The amount of acid added to the formulation is adjusted according to the solubility of each component in the formulation.

[0289] After preparation, the presence of crystals was examined using a microscope. The results of this microscopic examination indicated that none of the formulations (formulations 41 to 48) contained crystals.

[0290] The flow distribution of all formulations (formulations 41 to 48) shows a clear increasing trend in flow rate over time during the initial 24 hours. Figures 16 to 18 The flow rate then gradually decreases over time. Therefore, in some cases, an increase in flow rate during the initial 24 hours can be used to achieve a rapid and higher initial therapeutic concentration in vivo. Where the flow rate decreases over time, this decrease may be due to crystallization of the drug in the adhesive induced by water absorbed from the patch.

[0291] Example 14

[0292] External flow rate obtained from different backings

[0293] The pressure-sensitive adhesive used in this embodiment is a polyisobutylene / polybutene (PIB / PB) adhesive. The PIB / PB adhesive is a mixture of high molecular weight PIB (5% Oppanol B100), low molecular weight PIB (25% Oppanol B12), and a polybutene tackifier (e.g., Indopol H1900 or Panalane H-300e) (20%) in an organic solvent (e.g., heptane) (50%). The combination is mixed for approximately 3 days until homogeneous. Exemplary dexmedetomidine transdermal composition formulations are shown in Table 21. The same formulation is coated onto a release liner but laminated with three different backing materials: Backing 1 has an MVTR value of approximately 10 (g / m³). 2 / 24hr), backing 2 has approximately 50 (g / m²) 2 The MVTR value is approximately 150 g / m³ (24hr), and the backing 3 has a MVTR value of approximately 150 g / m³ (24hr). 2 MVTR value ( / 24hr).

[0294] Average in vitro dexmedetomidine flow rate over time Figure 19 As shown in [the image / document]. Figure 19 As described, the in vitro skin flow rate of dexmedetomidine was similar for backing 1 and backing 2. However, the in vitro skin flow rate of dexmedetomidine was significantly lower for backing 3.

[0295] Table 21

[0296]

[0297] Example 15

[0298] In vitro flow rates obtained from formulations containing lauryl lactate as an enhancer

[0299] Another set of examples of dexmedetomidine transdermal formulations includes

[0300] Transdermal compositions comprising 2%-4% w / w dexmedetomidine with an enhancer to improve skin permeability. In these formulations, lauryl lactate (LL) and Duro-Tak 87-2287 are used. The formulation compositions are shown in Table 22. In vitro flow distribution of the transdermal compositions. Figure 20 and Figure 21 The flow rates on two different skin samples are shown. Based on the in vitro flow rate distribution, LL demonstrates its skin permeability enhancement effect. The flow rate is also proportional to the API load.

[0301] Table 22

[0302]

[0303] Example 16

[0304] Dexmedetomidine percutaneous system for postoperative analgesia after bunion removal surgery

[0305] Randomized, double-blind, placebo-controlled, single-dose studies were conducted over a 3-day timeframe using a dexmedetomidine percutaneous system (DMTS) or matched placebo patches as described above. The DMTS provides prolonged release of dexmedetomidine over a 3-day administration period. Each DMTS has a 3 cm [diameter missing]. 2 The surface area of ​​the DMTS is [not specified] and contains 0.73 mg of dexmedetomidine. In this study, subjects received two DMTSs, totaling a dose of 1.46 mg of dexmedetomidine. The excipients in the DMTS include lauryl lactate and acrylate copolymers. The matched placebo patch is identical to the DMTS, except that it does not contain dexmedetomidine.

[0306] Subjects scheduled for surgical correction of unilateral hallux valgus (first metatarsal hallux valgus, without accompanying hammer toe) were screened up to 28 days prior to surgery. Eligible subjects were randomized 1:1 to receive either two DMTS patches or two matched placebo patches and remained in the clinical study unit from the day before surgery until three days after surgery. Surgery was performed in a hospital or outpatient surgery center. The surgical procedure (i.e., Austin bunionectomy) and intraoperative anesthesia (Mayo area (Mayoblock)) were standardized.

[0307] In this study, depending on randomization, participants received either two DMTS patches or two matched placebo patches. On Day 1, 12 ± 2 hours prior to the scheduled bunion removal surgery, the patches were applied to the hairless portion of the participant's upper arm by trained field personnel. The DMTS / matched placebo patches were applied after an overnight fast (as per the surgical center's instructions). The two DMTS / matched placebo patches were worn for three days.

[0308] Following surgery and a timely postoperative recovery period, subjects returned to the clinical study unit. During the 3-day postoperative period in the clinical study unit, recovery procedures were standardized (including the use of emergency analgesics); and the following procedures were performed: pain assessment (using the NRS), sedation level assessment, safety assessment (vital signs, including oxygen saturation [SpO2]), patch adhesion, and skin irritation. Additionally, plasma concentrations of dexmedetomidine were obtained for subgroups of subjects.

[0309] During the treatment period, subjects received either two DMTS patches (1.46 mg dose) or two matched placebo patches over three days. Subjects also received emergency analgesia as needed.

[0310] Perform the procedures and assessments described below during the treatment period; in addition to these procedures, assess adverse events, vital signs, and concomitant medications throughout the entire study period.

[0311] On day 1, subjects rated pain intensity, sedation levels were assessed by researchers / on-site staff, and the use of emergency analgesics was evaluated starting 4 hours after surgery; blood samples were collected for pharmacokinetic analysis; and adhesions were evaluated.

[0312] On days 2 and 3, subjects rated pain intensity, sedation levels were assessed by researchers / field staff, use of emergency analgesics was evaluated, blood samples were collected for pharmacokinetic analysis, and patch adhesion was evaluated.

[0313] On day 4, prior to removal of the DMTS / matched placebo patch, subjects rated pain intensity, sedation levels were assessed by investigators / field staff, use of emergency analgesics was evaluated, blood samples were collected for pharmacokinetic analysis, and patch adhesion was evaluated. The DMTS / matched placebo patch was then removed. Following patch removal, blood samples were collected for pharmacokinetic analysis; ECG telemetry monitoring was discontinued; and skin irritation at the patch application site was assessed (1 hour after patch removal; follow-up was scheduled if the skin irritation score was >0). One hour after the skin irritation assessment, any visible residue at the patch application area was removed with a damp cloth.

[0314] After completing all research procedures, the subjects were discharged from the clinic on day 4.

[0315] In the above studies, it was observed that the use of DMTS as described above effectively managed pain in patients caused by bunion excision.

[0316] Example 17

[0317] TPU-006 for postoperative pain relief after bunion removal surgery

[0318] A Phase 2 proof-of-concept (POC) study was conducted on TPU-006 (3-day dexmedetomidine percutaneous patch (formulation provided above)) to determine the effectiveness of the patch in managing postoperative pain following bunion excision. Specifically, a double-blind, placebo-controlled, single-dose study evaluated the analgesic efficacy and safety of TPU-006 after bunion excision. A total of 87 patients received the patch (active or placebo).

[0319] Preliminary results indicate that TPU-006 provides effective pain control across several parameters and did not produce any unexpected safety events in the postoperative setting. Throughout the study, treatment with TPU-006 showed statistically significant key findings compared to placebo, including lower pain scores and reduced use of opioid emergency medications. TPU-006 was well-tolerated with no unexpected serious adverse events, and minimal to no application site skin irritation or drowsiness. Patients treated with TPU-006 experienced less constipation and nausea due to reduced opioid emergency medication use.

[0320] The study demonstrates the potential of TPU-006 to improve current postoperative or chronic pain management practices. It also shows that TPU-006 offers a much-needed strategy for reducing the use of anesthetic analgesics. As this study demonstrates, ease of application (applying and removing) means that the TPU-006 patch can be used in both inpatient and outpatient settings.

[0321] Example 18

[0322] Percutaneous dexmedetomidine for postoperative pain relief after bunion removal surgery

[0323] Using the 3-day dexmedetomidine transdermal delivery device (2×3 cm) containing the dexmedetomidine composition and pressure-sensitive adhesive as described above. 2 A patch was used to investigate the effectiveness of the patch in managing postoperative pain following bursectomy. Specifically, a double-blind, placebo-controlled, single-dose study evaluated the analgesic efficacy and safety of a dexmedetomidine percutaneous delivery device after bursectomy. Patches, either dexmedetomidine patches or placebos, were applied to 87 patients. Each percutaneous delivery device was applied to the subject between 10 and 14 hours prior to undergoing Austin bursectomy under standard intraoperative anesthesia. The percutaneous delivery device showed little to no skin irritation, and subjects were well hydrated and experienced low levels of constipation and nausea.

[0324] Pain was assessed in patients immediately post-surgery up to 72 hours post-surgery using the Numerical Rating Scale for Pain Intensity (NRS) and the Total Pain Intensity Scale (NRSSPI). Pain was also assessed based on time, first use of emergency analgesics, and total use of emergency medications.

[0325] The results of this study indicate that percutaneous delivery devices with dexmedetomidine compositions provide effective pain control across several parameters and do not result in any unexpected safety events in the postoperative setting. Figure 22 The study depicted the control of pain intensity over time using a numerical rating scale compared to placebo in patients using a percutaneous delivery device containing dexmedetomidine. Figure 22 The study described patients receiving dexmedetomidine who had lower pain ratings within 72 hours post-surgery compared to those receiving placebo. In addition to lower pain ratings, a lower proportion of patients receiving patches containing the dexmedetomidine composition required emergency medication within the first six hours post-surgery. Patients receiving patches containing dexmedetomidine also required emergency medication less frequently compared to those receiving placebo. Figure 23 The timeframe for comparing patients using a percutaneous delivery device containing a composition containing dexmedetomidine and a placebo was depicted up to the first use of the emergency medication. Figure 23 As shown, patients using placebo patches required emergency medication earlier than those using patches containing dexmedetomidine. Table 23 below summarizes the use of emergency medication (oxycodone) in patients receiving placebo transdermal delivery devices and those receiving transdermal delivery devices containing dexmedetomidine. As summarized in Table 23, throughout all test time periods (0–24 hours; 0–48 hours; and 0–72 hours), fewer patients required emergency medication when receiving transdermal delivery devices containing dexmedetomidine compared to when receiving placebo patches.

[0326] Table 23

[0327]

[0328] The pharmacokinetic parameters of dexmedetomidine administration via a percutaneous delivery device were also evaluated in conjunction with the pain assessment described above. Mean plasma dexmedetomidine concentrations were highest on the first day post-surgery and lowest on the third day. Figures 24A to 24B Compare the relationship between mean plasma dexmedetomidine concentration and the estimated total pain intensity. Figure 24A Numerical pain ratings (LOCF) were depicted from patients receiving a percutaneous delivery device containing a dexmedetomidine composition and placebo (last observation carryover extrapolation; LOCF extrapolation was used to adjust for the contribution of emergency medications to the NRSPI). Figure 24B Depicts plasma concentrations of dexmedetomidine in patients receiving a percutaneous delivery device containing a dexmedetomidine composition. Figures 24A to 24B The study demonstrated that the difference in pain intensity between dexmedetomidine and placebo was constant within a 4-fold difference in mean plasma dexmedetomidine concentration. In other words, the pain-reducing effect of dexmedetomidine remained almost constant within approximately a 4-fold difference in plasma concentration.

[0329] Figure 25 The study describes the sedative effects in patients receiving a percutaneous delivery device containing dexmedetomidine compared to patients receiving a placebo patch according to the Wilson Sedation Rating Scale. Figure 25 As shown, patients receiving a percutaneous delivery device containing dexmedetomidine experienced the aforementioned pain reduction in the presence of non-sedated doses of dexmedetomidine.

[0330] Example 19

[0331] Pharmacokinetic and pharmacodynamic evaluation of a transdermal delivery device containing dexmedetomidine in human subjects.

[0332] method

[0333] Part 1 was an open-label, single-dose escalation study, and Part 2 was a randomized crossover study comparing the intravenous dose (1 μg / kg) of PRECEDEEX™ dexmedetomidine intravenous infusion administered over 10 minutes with the intravenous dose of DMTS (dexmedetomidine transdermal delivery device) at or below the maximum tolerated dose (MTD).

[0334] Part 1 of the study was designed to evaluate the escalating doses of the DMTS until the MTD was determined. Three subjects were recruited for each dose group. Dosing may be repeated if deemed appropriate. After the MTD was reached, an additional group with a BMI ≥ 18 kg / m² was recruited. 2 And < 22 kg / m 2 Subjects were assigned to the study. Each subject received DMTS administration for 3 days, followed by a 3-day washout period (starting when the patch was removed). In the first dose group (Group 1), subjects received 2 DMTS. If the 2 DMTS in Group 1 were not tolerated, the dose was reduced to 1 DMTS in Group 2. If the 1 DMTS in Group 2 was not tolerated, the study was discontinued. Conversely, if the 2 DMTS in Group 1 were tolerated, the dose was increased by 1 DMTS in the next group, and subjects in Group 2 each received 3 DMTS. For each subsequent group, the dose was increased by 1 DMTS as long as the dose in the previous group was tolerated. In this manner, the dose was increased up to a maximum of 8 DMTS. If at any time the dose was not tolerated, the dose escalation was stopped, and the tolerated dose in the previous group was considered the MTD. DMTS dose escalation only occurred after the safety monitoring committee observed 72-hour safety data from the immediately preceding group and found the dose to be tolerated. Additional subjects may be recruited to obtain additional safety data and make decisions regarding dose escalation if deemed appropriate.

[0335] In Part 2 of the study, 12 participants with a BMI of 22 to 29 kg / m2 (inclusive) were recruited and randomized to one of the following treatment sequences:

[0336] • Sequence A: PRECEEDEX™ dexmedetomidine intravenous infusion, 2 DMTS (6 cm2)

[0337] • Sequence B: 2 DMTS (6 cm2), PRECEEDEX™ dexmedetomidine intravenous infusion

[0338] All 12 participants received two intravenous (IV) doses of DMTS and PRECEDEEX™ dexmedetomidine; the two doses were separated by a 3-day washout period. The washout period was based on the plasma half-life (T½) of dexmedetomidine following DMTS administration, as determined in Study TPU-DMT-01-1501, and adverse events (AEs) observed during the 72-hour period following DMTS discontinuation. Parts were screened up to 28 days prior to study drug administration for Parts 1 and 2 of the study. Eligible participants were placed in a clinic during the study for blood collection to determine plasma dexmedetomidine concentrations. Assessments of sedation levels, safety, and patch adhesion were also performed throughout the study.

[0339] Each DMTS has 3 cm 2 The study included a surface area containing 0.73 mg of dexmedetomidine. In Part 1, subjects received two DMTS in Groups 1 and 2, one DMTS in Groups 3 and 4, two DMTS in Group 5, three DMTS in Group 6, four DMTS in Group 7, and three DMTS in Group 8. In Part 2, subjects received two DMTS. In both parts of the study, each DMTS was applied to the non-haired portion of the upper arm on Day 1 and remained in place for three days.

[0340] Plasma concentrations of dexmedetomidine at each time point were summarized using the arithmetic mean, standard deviation (SD), median, range, 95% confidence interval, geometric mean, and coefficient of variation (%CV) for the group in Part 1 and for the group in Part 2.

[0341] Pharmacokinetic and pharmacodynamic results

[0342] In Part 1 of the study, the geometric mean C was found in 8 groups. 最大 The range was 58.5 to 274 pg / mL, and the geometric mean AUC was... 0-无穷大 The range was 3353 to 11085 pg×h / mL, with these values ​​generally increasing with dose. Median T最大 The value ranges from 14 to 30 hours, and the median T 1 / 2 The range was 7.9 to 16.4 hours. In part 2 of the study, in the case of DMTS treatment, the geometric mean C was at its maximum of 115.1 pg / mL, and the geometric mean AUC was... 0-无穷大 It is 6130 pg×h / mL, median T 最大 It is 24.0 hours, and the median T1 / 2 is 12.1 hours.

[0343] In contrast, in the case of PRECEEDEX™ dexmedetomidine intravenous infusion therapy, the geometric mean C 最大 It is 993.3 pg / mL, with a geometric mean AUC. 0-无穷大 It is 1478 pg×h / mL, median T 最大 It is 0.17 hours, and the median T 1 / 2 It was 2.0 hours. The mean (SD) clearance of dexmedetomidine (determined after treatment with PRECEDEEX™ dexmedetomidine intravenous infusion) was 54.6 (9.46) L / h. DMTS (6 cm 2 The geometric mean bioavailability was determined to be 330.8 μg, with a corresponding dose rate of 4.6 μg / h.

[0344] In Part 1, sedation levels at most time points were consistent with the Wilson sedation score of 1 (fully awake and oriented) in all groups. Scores of 2 (drowsy) or 3 (eyes closed but responsive to command) were observed at occasional time points in all groups. At no time point did any subject in any group achieve a sedation score of 4 (eyes closed but responsive to mild physical stimulation) or 5 (eyes closed but not responsive to mild physical stimulation).

[0345] In Part 2, in DMTS (6 cm) 2 During treatment, the majority of the 11 subjects had a Wilson sedation score of 1 at all time points; at any time point, no more than two subjects had a score of 2 or 3, and no subject had a score of 4 or 5 at any time point. In the case of PRECEDEEX™ dexmedetomidine intravenous infusion, most subjects had a Wilson sedation score of 2 at the end of the infusion, followed by a score of 2 or 3 at 1 hour post-infusion, and a score of 2 at 2 hours post-infusion. After the 2-hour time point, most subjects had a score of 1, except at the 4-hour time point, when most subjects had a score of 2 or 3.

[0346] Exemplary non-limiting aspects of this disclosure

[0347] The various aspects of the subject matter of the invention described above (including embodiments) may be advantageous individually or in combination with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of this disclosure numbered 1-171 are provided below. It will be apparent to those skilled in the art upon reading this disclosure that each individually numbered aspect may be used or combined with any preceding or following individually numbered aspect. This is intended to support combinations of all such aspects and is not limited to combinations of the aspects explicitly provided below.

[0348] 1. A method for managing pain in a subject, the method comprising: applying a percutaneous delivery device to the surface of the subject's skin in a manner sufficient to manage the subject's pain, the percutaneous delivery device comprising: a dexmedetomidine composition comprising dexmedetomidine and a pressure-sensitive adhesive; and a backing layer.

[0349] 2. The method according to Clause 1, wherein the pain is selected from the group consisting of: surgical pain, perioperative pain, postoperative pain, cancer pain, acute pain, chronic pain, nociceptive pain, somatic pain, visceral pain, neuropathic pain, labor pain, or any combination thereof.

[0350] 3. The method according to Clause 2, wherein the pain is surgical pain.

[0351] 4. The method according to Clause 3, wherein the surgical pain is caused by a surgical procedure selected from the group consisting of: median sternotomy, laparoscopy, mastectomy, arthroplasty, osteotomy, cancer surgery, knee surgery, and shoulder surgery.

[0352] 5. The method described in Clause 3, wherein the surgical pain is caused by dental surgery.

[0353] 6. The method described in Clause 5, wherein the dental procedure is the surgical extraction of one or more molars.

[0354] 7. The method described in Clause 3, wherein the surgical procedure is osteotomy.

[0355] 8. The method described in Clause 7, wherein the osteotomy is a bunion excision.

[0356] 9. The method according to any one of clauses 3-8, wherein the transdermal delivery device is applied to the skin surface prior to the onset of pain.

[0357] 10. The method according to any one of clauses 3 to 9, wherein the method comprises applying the device to the subject during the perioperative period.

[0358] 11. The method according to Clause 9 or 10, wherein the percutaneous delivery device is applied to the skin surface of the subject at a time of 12 to 24 hours prior to the surgical procedure.

[0359] 12. The method according to any one of Clauses 1-11, wherein the method comprises delivering a non-fully sedative dose of dexmedetomidine to the subject.

[0360] 13. The method according to Clause 12, wherein the method comprises delivering to the subject a non-fully sedative dose of dexmedetomidine for one day or longer.

[0361] 14. The method according to Clause 13, wherein the method comprises delivering a non-fully sedative dose of dexmedetomidine to the subject for 3 days or longer.

[0362] 15. The method according to any one of Clauses 10 to 14, wherein the method comprises delivering a non-fully sedative dose of dexmedetomidine to the subject in a manner sufficient to maintain a Wilson sedation score of no more than 4 in the subject.

[0363] 16. The method according to Clause 15, wherein the method comprises delivering a non-sedating dose of dexmedetomidine to the subject in a manner sufficient to maintain a Wilson sedation score of no more than 3 in the subject.

[0364] 17. The method according to any one of Clauses 1-16, wherein the subject is alert and responsive to verbal instructions.

[0365] 18. The method according to any one of Clauses 1-17, wherein the method comprises delivering dexmedetomidine to the subject using the transdermal delivery device at a rate ranging from about 5 μg / day to about 500 μg / day.

[0366] 19. The method according to any one of Clauses 1-17, wherein the method comprises delivering dexmedetomidine to the subject using the transdermal delivery device at a rate ranging from 1 mcg / h to 10 mcg / h.

[0367] 20. The method according to any one of clauses 1-19, wherein the method comprises delivering dexmedetomidine to the subject in a manner sufficient to maintain an average plasma concentration of about 0.01 ng / mL to about 0.4 ng / mL of dexmedetomidine in the subject.

[0368] 21. The method according to any one of clauses 1-20, wherein the method further comprises co-administering to the subject a compound selected from the group consisting of: analgesics, anesthetics, antidepressants, anticonvulsants, cannabinoids, N-methyl-D-aspartic acid, and neuromodulators and combinations thereof.

[0369] 22. The method according to Clause 21, wherein the method further comprises co-administering an anesthetic to the subject.

[0370] 23. The method according to Clause 22, wherein the anesthetic is a general anesthetic.

[0371] 24. The method according to Clause 21, wherein the general anesthetic is a non-opioid intravenous general anesthetic.

[0372] 25. The method according to any one of clauses 21-24, wherein the method is sufficient to reduce the amount of the co-administered compound by 10% or more.

[0373] 26. The method according to any one of Clauses 1-24, wherein the method comprises co-administering an opioid to the subject.

[0374] 27. The method according to Clause 26, wherein the amount of opioid required to manage the subject's pain is reduced by 50% or more.

[0375] 28. The method according to any one of Clauses 1-20, wherein the method is sufficient to replace part or all of the planned administration of one or more opioids in an opioid pain management regimen.

[0376] 29. The method according to any one of Clauses 1-28, wherein the pressure-sensitive adhesive is an acrylate pressure-sensitive adhesive having side hydroxyl functional groups.

[0377] 30. The method according to Clause 29, wherein the dexmedetomidine composition further comprises a penetration enhancer.

[0378] 31. The method according to Clause 30, wherein the penetration enhancer is lauryl lactate.

[0379] 32. The method according to any one of Clauses 1-31, wherein the percutaneous delivery device comprises a monolayer matrix containing the dexmedetomidine composition, the monolayer matrix being formulated to deliver a non-sedated amount of dexmedetomidine to the subject.

[0380] 33. The method according to any one of Clauses 1-31, wherein the percutaneous delivery device is configured to deliver 20% or more of dexmedetomidine in the dexmedetomidine composition.

[0381] 34. The method according to any one of clauses 1-33, wherein the amount of dexmedetomidine in the composition is 1%-5% w / w.

[0382] 35. The method according to any one of clauses 1-33, wherein the amount of dexmedetomidine in the composition is 3% w / w.

[0383] 36. The method according to any one of Clauses 1-35, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorbed amount of dexmedetomidine of 150 mcg to 600 mcg over 72 hours.

[0384] 37. The method according to Clause 36, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine of 175 mcg to 575 mcg over 72 hours.

[0385] 38. The method according to Clause 36, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorbed amount of dexmedetomidine of 192.7 mcg to 551.7 mcg over 72 hours.

[0386] 39. The method according to Clause 36, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine of 224 mcg to 437 mcg over 72 hours.

[0387] 40. The method according to Clause 36, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine of 278 mcg to 384 mcg over 72 hours.

[0388] 41. The method according to Clause 36, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine of 304 mcg to 357 mcg over 72 hours.

[0389] 42. The method according to Clause 36, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine of 320 mcg to 341 mcg over 72 hours.

[0390] 43. The method according to any one of clauses 1-35, wherein the method comprises maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of 1 mcg / h to 10 mcg / h over 72 hours.

[0391] 44. The method according to Clause 43, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 2 mcg / h to 8 mcg / h over 72 hours.

[0392] 45. The method according to Clause 43, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 2.7 mcg / h to 7.7 mcg / h over 72 hours.

[0393] 46. ​​The method according to Clause 43, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 3.1 mcg / h to 6.1 mcg / h over 72 hours.

[0394] 47. The method according to Clause 43, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 3.9 mcg / h to 5.3 mcg / h over 72 hours.

[0395] 48. The method according to Clause 43, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 4.2 mcg / h to 5.0 mcg / h over 72 hours.

[0396] 49. The method according to Clause 43, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 4.4 mcg / h to 4.7 mcg / h over 72 hours.

[0397] 50. The method according to any one of clauses 1-35, wherein the method comprises maintaining the percutaneous delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 50 pg / mL to 250 pg / mL over 72 hours.

[0398] 51. The method according to Clause 50, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 70 pg / mL to 225 pg / mL over 72 hours.

[0399] 52. The method according to Clause 50, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 70.1 pg / mL to 205 pg / mL over 72 hours.

[0400] 53. The method according to Clause 50, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 77 pg / mL to 153 pg / mL over 72 hours.

[0401] 54. The method according to Clause 50, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 96 pg / mL to 134 pg / mL over 72 hours.

[0402] 55. The method according to Clause 50, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 106 pg / mL to 125 pg / mL over 72 hours.

[0403] 56. The method according to Clause 50, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 111 pg / mL to 119 pg / mL over 72 hours.

[0404] 57. The method according to any one of clauses 1-35, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in such a manner that it provides an average area under a plasma dexmedetomidine concentration curve of 3,000 hx pg / mL to 10,000 hx pg / mL over 72 hours.

[0405] 58. The method according to Clause 57, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 3,500 h x pg / mL to 9,000 h x pg / mL over 72 hours.

[0406] 59. The method according to Clause 57, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 3517 h x pg / mL to 8954 h x pg / mL over 72 hours.

[0407] 60. The method according to Clause 57, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 4548 h x pg / mL to 7712 h x pg / mL over 72 hours.

[0408] 61. The method according to Clause 57, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 5339 h x pg / mL to 6921 h x pg / mL over 72 hours.

[0409] 62. The method according to Clause 57, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 5735 h x pg / mL to 6525 h x pg / mL over 72 hours.

[0410] 63. The method according to Clause 57, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 5972 h x pg / mL to 6288 h x pg / mL over 72 hours.

[0411] 64. The method according to any one of clauses 35-63, wherein the transdermal delivery device has an area of ​​about 6 cm. 2 Surface area.

[0412] 65. The method according to any one of clauses 1-35, wherein the method comprises maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average absorbed amount of dexmedetomidine of 100 mcg to 400 mcg over 72 hours.

[0413] 66. The method according to Clause 65, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine from 125 mcg to 375 mcg over 72 hours.

[0414] 67. The method according to Clause 65, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorbed amount of dexmedetomidine of 128.5 mcg to 367.8 mcg over 72 hours.

[0415] 68. The method according to Clause 65, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine from 150 mcg to 292 mcg over 72 hours.

[0416] 69. The method according to Clause 65, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine of 185 mcg to 256 mcg over 72 hours.

[0417] 70. The method according to Clause 65, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine of 203 mcg to 238 mcg over 72 hours.

[0418] 71. The method according to Clause 65, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorbed amount of dexmedetomidine of 213 mcg to 228 mcg over 72 hours.

[0419] 72. The method according to any one of clauses 1-35, wherein the method comprises maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of 0.5 mcg / h to 6 mcg / h over 72 hours.

[0420] 73. The method according to Clause 72, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 1 mcg / h to 5.5 mcg / h over 72 hours.

[0421] 74. The method according to Clause 72, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 1.8 mcg / h to 5.1 mcg / h over 72 hours.

[0422] 75. The method according to Clause 72, wherein the method comprises maintaining the transdermal composition delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of 2.1 mcg / h to 4.1 mcg / h over 72 hours.

[0423] 76. The method according to Clause 72, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 2.6 mcg / h to 3.6 mcg / h over 72 hours.

[0424] 77. The method according to Clause 72, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 2.8 mcg / h to 3.3 mcg / h over 72 hours.

[0425] 78. The method according to Clause 72, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 3.0 mcg / h to 3.2 mcg / h over 72 hours.

[0426] 79. The method according to any one of Clauses 1-35, wherein the method comprises maintaining the percutaneous delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 25 pg / mL to 150 pg / mL over 72 hours.

[0427] 80. The method according to Clause 79, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 40 pg / mL to 140 pg / mL over 72 hours.

[0428] 81. The method according to Clause 79, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 47 pg / mL to 137 pg / mL over 72 hours.

[0429] 82. The method according to Clause 79, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 51 pg / mL to 102 pg / mL over 72 hours.

[0430] 83. The method according to Clause 79, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 64 pg / mL to 90 pg / mL over 72 hours.

[0431] 84. The method according to Clause 79, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 70 pg / mL to 83 pg / mL over 72 hours.

[0432] 85. The method according to Clause 79, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 74 pg / mL to 79 pg / mL over 72 hours.

[0433] 86. The method according to any one of clauses 1-35, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in such a manner that it provides an average area under a plasma dexmedetomidine concentration curve of 2000 hx pg / mL to 7500 hx pg / mL over 72 hours.

[0434] 87. The method according to Clause 86, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 2250 h x pg / mL to 6000 h x pg / mL over 72 hours.

[0435] 88. The method according to Clause 86, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 2345 h x pg / mL to 5969 h x pg / mL over 72 hours.

[0436] 89. The method according to Clause 86, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 3032 h x pg / mL to 5141 h x pg / mL over 72 hours.

[0437] 90. The method according to Clause 86, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 3559 h x pg / mL to 4614 h x pg / mL over 72 hours.

[0438] 91. The method according to Clause 86, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 3823 h x pg / mL to 4350 h x pg / mL over 72 hours.

[0439] 92. The method according to Clause 86, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 3981 h x pg / mL to 4192 h x pg / mL over 72 hours.

[0440] 93. The method according to any one of clauses 65-92, wherein the transdermal delivery device has an area of ​​about 4 cm. 2 Surface area.

[0441] 94. The method according to any one of Clauses 1-35, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine of 50 mcg to 200 mcg over 72 hours.

[0442] 95. The method according to Clause 94, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine of 60 mcg to 190 mcg over 72 hours.

[0443] 96. The method according to Clause 94, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine of 64 mcg to 184 mcg over 72 hours.

[0444] 97. The method according to Clause 94, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine of 75 mcg to 146 mcg over 72 hours.

[0445] 98. The method according to Clause 94, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine of 93 mcg to 128 mcg over 72 hours.

[0446] 99. The method according to Clause 94, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine of 101 mcg to 119 mcg over 72 hours.

[0447] 100. The method according to Clause 94, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average absorption of dexmedetomidine of 107 mcg to 114 mcg over 72 hours.

[0448] 101. The method according to any one of Clauses 1-35, wherein the method comprises maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of 0.1 mcg / h to 5 mcg / h over 72 hours.

[0449] 102. The method according to Clause 101, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 0.5 mcg / h to 3 mcg / h over 72 hours.

[0450] 103. The method according to Clause 101, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 0.9 mcg / h to 2.6 mcg / h over 72 hours.

[0451] 104. The method according to Clause 101, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 1.0 mcg / h to 2.0 mcg / h over 72 hours.

[0452] 105. The method according to Clause 101, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 1.3 mcg / h to 1.8 mcg / h over 72 hours.

[0453] 106. The method according to Clause 101, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 1.4 mcg / h to 1.7 mcg / h over 72 hours.

[0454] 107. The method according to Clause 101, wherein the method comprises maintaining the transdermal delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average dexmedetomidine absorption of 1.5 mcg / h to 1.6 mcg / h over 72 hours.

[0455] 108. The method according to any one of Clauses 1-35, wherein the method comprises maintaining the percutaneous delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 10 pg / mL to 80 pg / mL over 72 hours.

[0456] 109. The method according to Clause 108, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 20 pg / mL to 70 pg / mL over 72 hours.

[0457] 110. The method according to Clause 108, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 23.4 pg / mL to 68.3 pg / mL over 72 hours.

[0458] 111. The method according to Clause 108, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 26 pg / mL to 51 pg / mL over 72 hours.

[0459] 112. The method according to Clause 108, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 32 pg / mL to 45 pg / mL over 72 hours.

[0460] 113. The method according to Clause 108, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 35 pg / mL to 42 pg / mL over 72 hours.

[0461] 114. The method according to Clause 108, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 37 pg / mL to 40 pg / mL over 72 hours.

[0462] 115. The method according to any one of clauses 1-35, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in such a manner that it provides an average area under a plasma dexmedetomidine concentration curve of 1000 hx pg / mL to 3500 hx pg / mL over 72 hours.

[0463] 116. The method according to Clause 115, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 1100 hx pg / mL to 3000 hx pg / mL over 72 hours.

[0464] 117. The method according to Clause 115, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in such a manner that it provides an average area under a plasma dexmedetomidine concentration curve of 1172 hx pg / mL to 2985 hx pg / mL over 72 hours.

[0465] 118. The method according to Clause 115, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in such a manner that it provides an average area under a plasma dexmedetomidine concentration curve of 1516 hx pg / mL to 2571 hx pg / mL over 72 hours.

[0466] 119. The method according to Clause 115, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 1780 hx pg / mL to 2307 hx pg / mL over 72 hours.

[0467] 120. The method according to Clause 115, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 1912 hx pg / mL to 2175 hx pg / mL over 72 hours.

[0468] 121. The method according to Clause 115, wherein the method comprises maintaining the percutaneous delivery device in contact with the subject’s skin surface in a manner sufficient to provide an average area under a plasma dexmedetomidine concentration curve of 1991 hx pg / mL to 2096 hx pg / mL over 72 hours.

[0469] 122. The method according to any one of clauses 94-121, wherein the transdermal delivery device has about 2 cm 2 Surface area.

[0470] 123. The method according to any one of clauses 1-122, wherein the method further comprises administering a certain amount of hydrating fluid to the subject.

[0471] 124. The method according to Clause 123, wherein the hydration fluid is administered intravenously to the subject.

[0472] 125. The method according to Clause 123, wherein the hydration fluid is administered orally to the subject.

[0473] 126. The method according to any one of clauses 123-125, wherein the hydration fluid is applied to the subject during the perioperative period.

[0474] 127. The method according to any one of clauses 123-125, wherein the hydration fluid is administered together with the application of the transdermal delivery device to the subject.

[0475] 128. The method according to any one of clauses 123-125, wherein the hydration fluid is applied at a predetermined time prior to the application of the transdermal delivery device to the subject.

[0476] 129. The method according to any one of clauses 123-128, wherein the method comprises:

[0477] The hydration fluid is administered intravenously to the subject at a first infusion rate for a first predetermined time period; and

[0478] The hydration fluid was administered intravenously to the subject at a second infusion rate for a second predetermined time period.

[0479] 130. The method according to Clause 129, wherein the method comprises:

[0480] The hydration fluid was administered intravenously to the subject at a rate of 450 mL / h to 550 mL / h for two hours; and

[0481] After the initial two hours, the hydration fluid was administered intravenously to the subject at a rate of 100 mL / h to 150 mL / h for 12 hours.

[0482] 131. The method according to Clause 130, wherein the method comprises:

[0483] The hydration fluid was administered intravenously to the subject at a rate of 500 mL / h for two hours; and

[0484] After the initial two hours, the hydration fluid was administered intravenously to the subject at a rate of 125 mL / h for 12 hours.

[0485] 132. The method according to Clause 125, wherein the method comprises:

[0486] The hydration fluid was orally administered to the subject at a first infusion rate for a first predetermined time period; and

[0487] The hydration fluid was administered orally to the subject at a second infusion rate for a second predetermined time period.

[0488] 133. The method according to Clause 132, wherein the method comprises:

[0489] The hydration fluid was orally administered to the subject at a rate of 450 mL / h to 550 mL / h over two hours; and

[0490] Two hours after the initial administration, the hydrated fluid was orally administered to the subject at a rate of 100 mL / h to 150 mL / h for 12 hours.

[0491] 134. The method according to Clause 130, wherein the method comprises:

[0492] The hydrated fluid was orally administered to the subject at a rate of 500 mL / h over two hours; and

[0493] Two hours after the initial administration, the hydration fluid was orally administered to the subject at a rate of 125 mL / h for 12 hours.

[0494] 135. The method according to any one of clauses 1-134, wherein the method further comprises co-administering an opioid to the subject.

[0495] 136. The method according to Clause 135, wherein the opioid is administered orally to the subject.

[0496] 137. The method according to Clause 135, wherein the opioid is administered intravenously to the subject.

[0497] 138. The method according to any one of clauses 135-137, wherein the opioid is oxycodone.

[0498] 139. The method according to any one of clauses 135-138, wherein the opioid is administered to the subject after the transdermal delivery device is applied to the subject.

[0499] 140. The method according to any one of clauses 135-138, wherein the opioid is administered to the subject perioperatively together with the transdermal delivery device.

[0500] 141. The method according to any one of clauses 1 to 140, wherein the percutaneous delivery device is applied to the skin surface of the subject prior to the onset of pain.

[0501] 142. The method according to Clause 141, wherein the percutaneous delivery device is applied to the skin surface of the subject one hour or more before the onset of pain.

[0502] 143. The method according to Clause 141, wherein the percutaneous delivery device is applied to the subject’s skin surface 12 hours or more before the onset of pain.

[0503] 144. The method according to any one of clauses 1-35, wherein the transdermal delivery device has a 1 cm 2 Up to 10cm 2 Surface area.

[0504] 145. The method according to any one of clauses 1-35, wherein the transdermal delivery device has a 2 cm 2 Up to 6cm2 Surface area.

[0505] 146. The method according to any one of clauses 1-145, wherein the pressure-sensitive adhesive comprises a vinyl polymer.

[0506] 147. The method according to Clause 146, wherein the vinyl polymer is selected from the group consisting of: polyethylene, polypropylene, polyisobutylene, polybutene, polystyrene, polyvinyl chloride, polyvinyl acetate, polyvinyl alcohol, and organosiloxanes.

[0507] 148. The method according to Clause 146, wherein the pressure-sensitive adhesive comprises polyisobutylene or polybutene or a combination thereof.

[0508] 149. The method according to Clause 148, wherein the pressure-sensitive adhesive comprises polyisobutylene or polybutene.

[0509] 150. The method according to Clause 148, wherein the pressure-sensitive adhesive comprises unsaturated polybutene.

[0510] 151. The method according to any one of clauses 1-145, wherein the pressure-sensitive adhesive comprises an acrylic polymer, an acrylate copolymer, an acrylate-vinyl acetate copolymer, or a polyacrylonitrile.

[0511] 152. The method according to any one of clauses 1-145, wherein the pressure-sensitive adhesive comprises a nonfunctionalized polymer.

[0512] 153. The method according to Clause 152, wherein the pressure-sensitive adhesive comprises a nonfunctionalized acrylate polymer.

[0513] 154. The method according to any one of clauses 1-145, wherein the pressure-sensitive adhesive comprises a carboxylic acid or hydroxyl-functionalized polymer.

[0514] 155. The method according to Clause 154, wherein the pressure-sensitive adhesive comprises a carboxylic acid-functionalized polymer.

[0515] 156. The method according to Clause 155, wherein the pressure-sensitive adhesive comprises a carboxylic acid-functionalized acrylate polymer.

[0516] 157. The method according to Clause 154, wherein the pressure-sensitive adhesive comprises a hydroxyl-functionalized polymer.

[0517] 158. The method according to Clause 157, wherein the pressure-sensitive adhesive comprises a hydroxyl-functionalized acrylate polymer.

[0518] 159. The method according to any one of clauses 1-145, wherein the pressure-sensitive adhesive comprises a mixture of a hydroxyl-functionalized polymer and a carboxylic acid-functionalized polymer.

[0519] 160. The method according to Clause 159, wherein the pressure-sensitive adhesive comprises a mixture of a hydroxyl-functionalized acrylate polymer and a carboxylic acid-functionalized acrylate polymer.

[0520] 161. The method according to any one of Clauses 1-145, wherein the pressure-sensitive adhesive is substantially the same as or selected from the group consisting of: Duro-Tak® 87-9301, Duro-Tak® 87-2353, Duro-Tak® 87-2510, Duro-Tak® 87-2516, and Duro-Tak® 87-4287, Duro-Tak® 87-2052, Duro-Tak® 87-2194, Duro-Tak® 87-2677, Duro-Tak® 87-201A, Duro-Tak® 87-2979, and Duro-Tak® 87-2074.

[0521] 162. The method according to any one of clauses 1-161, wherein the pressure-sensitive adhesive comprises crosslinked polyvinylpyrrolidone or crosslinked polyacrylic acid or a combination thereof.

[0522] 163. The method according to any one of clauses 1-162, wherein the method comprises delivering a sedative dose of dexmedetomidine to the subject.

[0523] 164. The method according to any one of clauses 135-138, wherein the opioid is administered to the subject prior to the application of the transdermal delivery device to the subject.

[0524] 165. The method according to any one of clauses 135-138, wherein the opioid is administered to the subject simultaneously with the application of the transdermal delivery device to the subject.

[0525] 166. A kit for managing pain in a subject, the kit comprising:

[0526] (a) One or more transdermal delivery devices, wherein each transdermal delivery device comprises:

[0527] Dexmedetomidine composition comprising:

[0528] Dexmedetomidine; and

[0529] Pressure-sensitive adhesives; and

[0530] Backing layer; and

[0531] (b) Instructions for use of the two or more percutaneous delivery devices in a method for managing pain in a subject in accordance with any one of Clauses 1 to 165.

[0532] 167. The kit according to Clause 166 further includes an hydration fluid composition.

[0533] 168. The kit according to Clause 166, wherein the hydration fluid is an oral hydration fluid.

[0534] 169. The kit according to Clause 166, wherein the hydration fluid composition is an intravenous hydration fluid composition.

[0535] 170. The kit according to any one of clauses 167-169, wherein the hydration fluid composition comprises physiological saline.

[0536] 171. The kit according to any one of clauses 167-169, wherein the hydration fluid composition comprises dextrose.

[0537] 172. The kit according to any one of clauses 166-171, further comprising instructions for hydrating the subject.

[0538] 173. The kit according to any one of clauses 166-172, further comprising one or more opioids for co-administration to the subject.

[0539] 174. The kit according to Clause 173, wherein the opioid is oxycodone.

[0540] Although the invention has been described in considerable detail by way of description and examples for purposes of clarity, it will be readily apparent to those skilled in the art that certain changes and modifications may be made to it without departing from the spirit or scope of the appended claims, based on the teachings of the invention.

[0541] Therefore, the foregoing has merely illustrated the principles of the invention. It should be understood that those skilled in the art will be able to design various arrangements that, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all embodiments and conditional language described herein are primarily intended to aid the reader in understanding the principles of the invention and the ideas provided by the inventors to promote the field, and should be construed as not constituting a limitation on such specifically described embodiments and conditions. Moreover, all statements herein describing the principles, aspects, and embodiments of the invention, as well as specific embodiments thereof, are intended to cover their structural and functional equivalents. Furthermore, it is intended that such equivalents include currently known equivalents and those developed in the future, i.e., any element developed to perform the same function, regardless of its structure. Therefore, the scope of the invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the invention are embodied in the appended claims.

Claims

1. A method for managing pain in a subject, the method comprising: A percutaneous delivery device is applied to the skin surface of a subject, the percutaneous delivery device comprising: A dexmedetomidine composition comprising dexmedetomidine and a pressure-sensitive adhesive; and Backing layer, It is performed in a manner sufficient to manage the pain of the subject.

2. The method of claim 1, wherein the pain is selected from the group consisting of: surgical pain, perioperative pain, postoperative pain, cancer pain, acute pain, chronic pain, nociceptive pain, somatic pain, visceral pain, neuropathic pain, labor pain, or any combination thereof.

3. The method of claim 2, wherein the surgical pain is caused by a bone model surgical procedure or a soft tissue model surgical procedure.

4. The method of claim 3, wherein the surgical pain is caused by a surgical procedure selected from the group consisting of: median sternotomy, laparoscopy, mastectomy, arthroplasty, osteotomy, cancer surgery, knee surgery, and shoulder surgery.

5. The method of claim 3, wherein the surgical procedure is osteotomy.

6. The method of claim 5, wherein the osteotomy is a bunion excision.

7. The method according to any one of claims 2-6, wherein the percutaneous delivery device is applied to the skin surface of the subject 12 to 24 hours prior to the surgical procedure.

8. The method of claim 1, wherein the method comprises maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average absorption of dexmedetomidine of 150 mcg to 600 mcg over 72 hours.

9. The method of claim 1, wherein the method comprises maintaining the transdermal delivery device in contact with the skin surface of the subject in a manner sufficient to provide an average dexmedetomidine absorption of 1 mcg / h to 10 mcg / h over 72 hours.

10. The method of claim 1, wherein the method comprises maintaining the transdermal composition in contact with the skin surface of the subject in a manner sufficient to provide an average maximum dexmedetomidine plasma concentration of 50 pg / mL to 250 pg / mL over 72 hours.

11. The method of claim 1, wherein the method comprises maintaining the percutaneous delivery device in contact with the skin surface of the subject in such a manner that it provides an average area under a plasma dexmedetomidine concentration curve of 3000 h x pg / mL to 10000 h x pg / mL over 72 hours.

12. The method of claim 1, wherein the method further comprises administering a certain amount of hydrating fluid to the subject.

13. The method of claim 12, wherein the method comprises: The hydration fluid is administered to the subject at a first infusion rate for a first predetermined time period; as well as The hydration fluid was administered to the subject at a second infusion rate for a second predetermined time period.

14. The method of claim 1, wherein the method further comprises co-administering an opioid to the subject.

15. The method of claim 14, wherein the opioid is oxycodone.

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