Systems and methods for treating neurological diseases in parkinson disease subjects

Abstract

To provide systems and methods which can efficiently treat motor symptoms of PD patients while ameliorating nonmotor symptoms or which can ameliorate nonmotor symptoms without having an adverse effect on the motor symptom treatment.SOLUTION: There are provided, herein, systems and methods for treating diseases associated with Parkinson's disease (PD) patients, for example, systems and methods for treating or ameliorating motor symptoms or disorders and / or nonmotor symptoms or disorders in Parkinson's disease patients. A system includes a sleep sensing circuit and a drug dispensing mechanism. The sleep sensing circuit is used to detect a sleep pattern of a PD patient, and the drug dispensing mechanism is used to continuously deliver a therapeutically effective compound to the PD patient on the basis of, the sleep pattern.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a system and method for delivering a formulation / composition / compound (e.g., levodopa (LD) and / or carbidopa (CD), or a formulation based on a prodrug of LD and / or CD, or a formulation containing LD and / or CD, or a prodrug of LD and / or CD) for treating (e.g., improving) movement and non-motor neurological disorders (e.g., sleep disorders) in patients with Parkinson's disease (PD). The present invention also relates to a system and method for optimizing sleep, improving the quality of sleep, and ameliorating sleep disorders in PD patients.

Background Art

[0002] PD is a chronic neurodegenerative disorder characterized by the progressive loss of dopamine-producing neurons. PD results in motor symptoms including, for example, slowness of movement / bradykinesia, rigidity, tremors, muscle stiffness, dyskinesia, postural instability, etc. LD, a dopamine precursor, is currently considered the most efficient and highest level of therapy for treating patients with PD. NeuroDerm Limited (a company based in Israel) has developed patented technology for a liquid formulation to continuously deliver LD / CD subcutaneously to PD patients by using a small, portable pump device.

[0003] Parkinson's disease (PD) patients also experience non-motor symptoms. While motor complications in PD patients result in physical disability, non-motor complications are equally, if not more, important to some PD patients. Non-motor symptoms include, for example, affective disorders (e.g., depression, anxiety, irritability); cognitive changes (e.g., difficulty concentrating on attention and planning, speech and memory impairment, difficulty thinking, dementia); delusions and illusions, constipation and early satiety, distress, fatigue, visual disturbances, excessive sweating (especially of the hands and feet, even with little or no movement); urinary urgency (frequent and incontinence); loss of smell; autonomic dysfunction; and various types of sleep disorders, including, for example, insomnia, excessive daytime sleepiness (EDS), rapid eye movement disorder (RBD), vivid dreams, talking and moving in sleep, restless legs syndrome (RLS), periodic limb movement disorder (PLMD), sleep latency, insufficient total sleep time, impaired sleep efficiency, difficulty falling asleep, difficulty maintaining sleep, sleep fragmentation, and changes in the sleep cycle associated with daytime sleepiness and nocturnal psychosis. PD patients who experience nocturnal sleep disturbances, or those with no sleep disturbances, tend to have sudden, unintentional sleep attacks (narcolepsy) during the day. Some examples of sleep disturbances that are significant non-motor symptoms in PD patients include insomnia, sleep fragmentation, rapid eye movement sleep behavior disorder (RBD), and excessive daytime sleepiness (EDS). [Overview of the project] [Problems that the invention aims to solve]

[0004] Several scientific publications suggest that, at least in some PD patients, some of the non-motor symptoms (e.g., sleep disturbances) described above may be side effects or worsened by long-term use of levodopa. It would be beneficial to have systems and methods that can effectively treat motor symptoms in PD patients, or improve non-motor symptoms without adversely affecting the treatment of motor symptoms, while improving (e.g., alleviating or minimizing) non-motor symptoms (e.g., sleep disturbances). [Means for solving the problem]

[0005] Systems and methods are provided for treating diseases related to PD patients, for example, systems and methods for treating or improving motor symptoms and / or non-motor symptoms or disorders in PD patients. The systems generally include a sleep sensing circuit and a drug delivery device (e.g., a pump). The sleep sensing circuit can be used to detect the sleep patterns of PD patients, and the drug delivery device can be used to continuously deliver therapeutically effective compounds (e.g., drugs) to PD patients based on the sleep patterns. The operating parameters of the drug delivery device (e.g., drug delivery flow rate and drug delivery time) can be pre-programmed, for example, before bedtime and / or adjusted in real time, for example, during sleep, based on the detected sleep patterns (or based on past sleep patterns) to treat diseases related to PD patients, for example, to optimize sleep, improve sleep quality, and improve non-motor disorders in PD patients being treated.

[0006] One example of a method for operating a therapeutic drug delivery system to treat a disease related to PD patients includes the steps of: the therapeutic drug delivery system characterizing the chronological sleep pattern (CSP) of a PD patient or receiving sleep data including the chronological sleep pattern of a PD patient; determining values ​​for one or more operating parameters of the therapeutic drug delivery system based on the CSP; and / or receiving values ​​for one or more operating parameters of the therapeutic drug delivery system from an external source, e.g., a remote computer. The method also includes the steps of operating the therapeutic drug delivery system according to the values ​​of the received or determined operating parameters in order to deliver a therapeutic drug composition (or compound) to a PD patient by a drug delivery pattern (DDP) that is favorable for treating the disease (a particular DDP may be used to treat a particular disease in a particular PD patient). A similar method may be used by the therapeutic drug delivery system to deliver compounds for treating neurological disorders in patients with PD.

[0007] An example of a DDS for treating diseases related to patients with PD (DDS100 in Figure 1, DDS202 in Figure 2, DDS1200 in Figure 12) includes a Sleep Data Acquisition Unit (SDCU). The SDCU generally generates, collects (e.g., receives), and / or stores sleep data related to PD patients (e.g., real-time sleep data and / or historical sleep data) and / or sleep data related to other PD patients (real-time sleep data and / or historical sleep data). The SDCU can be configured such that it can be selected from at least one of the following: (i) a first configuration in which the SDCU is a sleep monitoring system (SMS) (120, 280) or includes a sleep monitoring system; and (ii) a second configuration in which the SDCU is a user interface (160, 240) or includes a user interface (160, 240) for manually uploading sleep data and / or communication interface (180) to remotely receive sleep data and / or values ​​of operational parameters in order to operate a drug distribution mechanism.

[0008] The sleep monitoring system (SMS) includes n sensors (n=1, 2, 3, ...) configured to individually or collectively generate signals related to the sleep state and / or motor activity of PD patients. The SMS also includes sensor interfaces (132, 260) connected to the n sensors to convert the sensor signals into sleep data.

[0009] The DDS also includes drug delivery units (140, 230). The drug delivery unit includes drug reservoirs (142, 232) for containing therapeutic drug compositions and distribution mechanisms (144, 234) for distributing the therapeutic drug compositions from the drug reservoirs to PD patients.

[0010] The system also includes controllers (150, 210, 1212) for controlling the operation of the distribution mechanism. These controllers may, among others, be configured to (i) receive and / or determine values ​​obtained from sleep data for one or more drug delivery operation parameters of the distribution mechanism, and (ii) operate the dissolution mechanism for delivering the therapeutic drug composition to the PD patient according to the received and / or determined values ​​for one or more operation parameters. The controllers may further be configured to detect a temporal sleep pattern (CSP) in sleep data relevant to the PD patient and to deliver the therapeutic drug composition to the patient using a drug delivery pattern (DDP) that corresponds to, is adjusted for, conforms to, or originates from that CSP. The values ​​of the operation parameters used by the controllers to operate the distribution mechanism can define the DDP. For example, the controllers may adjust the values ​​of the operation parameters to deliver (distribute) the drug according to a therapeutically preferred DDP.

[0011] Treatment conditions can be selected from a group consisting of Parkinsonian symptoms, motor complications, motor symptoms, non-motor symptoms, and sleep disorders. Values ​​determined for operational parameters and values ​​received for operational parameters can be optimized in terms of sleep optimization, improvement of sleep quality, improvement of sleep disorders, improvement of Parkinsonian symptoms including tremors, shaking, bradykinesia, muscle rigidity, postural instability, difficulty walking / stepping, and dystonia; sleep duration, time interval from bedtime to sleep onset, number of awakenings during sleep, speed of body movement during sleep, time from awakening to getting up, duration of on and off periods of Parkinsonian symptoms during wakefulness, duration of wakefulness during sleep, number of body rotations during sleep, average speed of body rotations during sleep, average duration of body rotations, degree of body rotation, or any combination thereof. [Brief explanation of the drawing]

[0012] There is no intention to limit the types of embodiments, and various embodiments are shown in the accompanying drawings. For the sake of simplification and clarity of illustration, it should be understood that the elements shown in the following drawings are not necessarily in proportion to their actual size. Reference numerals are repeated in the drawings to indicate corresponding or similar elements.

[0013] [Figure 1] Figure 1 shows a first configuration of a drug delivery system for treating the disease in PD patients according to one embodiment.

[0014] [Figure 2] Figure 2 shows a second configuration of a drug delivery system for treating the disease in PD patients according to another embodiment.

[0015] [Figure 3] Figure 3 shows an example of a hypnogram including an example of a sleep pattern over time (CSP).

[0016] [Figure 4] Figure 4 schematically shows a drug delivery control scheme for treating the disease in PD patients according to one embodiment.

[0017] [Figure 5] Figure 5 schematically illustrates a drug delivery control scheme for treating the disease in PD patients according to another embodiment.

[0018] [Figure 6] Figure 6 schematically illustrates a drug delivery control scheme for treating the disease in PD patients according to yet another embodiment.

[0019] [Figure 7] Figure 7 shows how to operate a drug delivery system for treating the disease in PD patients according to one embodiment.

[0020] [Figure 8]FIG. 8 shows a method of operating a therapeutic pharmaceutical delivery device for treating the disease of a PD patient according to one embodiment.

[0021] [Figure 9] FIG. 9 shows a method of operating a therapeutic pharmaceutical delivery device for treating the disease of a PD patient according to another embodiment.

[0022] [Figure 10] FIG. 10 shows a method of operating a therapeutic pharmaceutical delivery device for treating the disease of a PD patient according to yet another embodiment.

[0023] [Figure 11] FIG. 11 shows a method of operating a therapeutic pharmaceutical delivery device for treating the disease of a PD patient according to yet another embodiment.

[0024] [Figure 12] FIG. 12 shows a third configuration of a pharmaceutical delivery system for treating the disease of a PD patient according to yet another embodiment.

[0025] [Figure 13] FIG. 13 shows a method of controlling a pharmaceutical delivery control scheme in real time according to one embodiment.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The following description provides various details of the specific embodiments. However, the following description is not intended to limit the scope of the present invention, but to explain various principles of the present invention and typical methods of implementing it.

[0027] The terms “treat,” “treatment,” “treating,” “improving,” and “ameliorating” are used in this specification to refer to obtaining a desirable pharmacological and / or physiological effect. The effect relates to a therapeutic effect in terms of partially or completely curing the disease and / or any undesirable actions or symptoms that are considered to be caused by the disease. The term “treatment” as used in the following specification includes the treatment of diseases in mammals, particularly humans. Treatment includes (a) suppressing the disease, i.e., preventing an increase in the severity and extent of the disease; (b) alleviating the disease, i.e., achieving partial or complete improvement or amelioration of the disease; and (c) preventing relapse of the disease, i.e., successfully treating the symptoms of the disease or treating the disease to prevent it from returning to a progressive state. The “disease” being treated in PD patients is, for example, the motor and / or non-motor symptoms of PD experienced by PD patients. Treating non-motor symptoms in PD patients includes, for example, optimizing sleep, improving sleep quality, and / or alleviating any sleep disorders.

[0028] "Preventing" includes slowing the onset of disease symptoms, complications, biochemical signs of the condition, disorder, disease, or the progression of disease in a patient who suffers from or is susceptible to the condition, disorder, disease, or disorder but does not experience or show any clinical or subclinical symptoms of the condition, disorder, disease, or disorder. "Preventing" also includes preventively treating clinical symptoms, complications, biochemical signs of the condition, disorder, disease, or patient to prevent the onset of disease or symptoms in that condition, disorder, disease, or patient.

[0029] As used in this specification, the terms “pharmaceutical composition” and “pharmaceutical preparation” refer to a composition or preparation comprising a pharmaceutically acceptable salt of levodopa disclosed herein, formulated with at least one biologically active compound, such as levodopa or a prodrug of levodopa, such as a conjugated levodopa amino acid, or one or more pharmaceutically acceptable excipients. The terms “preparation” and “composition” are substitutable unless explicitly stated otherwise or understood differently by those skilled in the art. As used in this specification, the term “pharmaceutically acceptable salt” refers to a salt of an acid or base that forms a conjugate used in the compositions disclosed herein.

[0030] 'Individual', 'patient', or 'subject' includes and is replaceable with animals, including mammals, mice, rats, other rodents, rabbits, dogs, cattle, pigs, cattle, sheep, horses, non-human primates, and humans. In some embodiments, the mammal treated by the method of the present invention is a human suffering from a neurodegenerative disease such as Parkinson's disease.

[0031] As used in this specification, the term “about” shall be interpreted to include a range of ±10% of the stated numerical value unless otherwise explicitly stated or understood differently by a person skilled in the art. It should also be noted that even without the use of the term “about,” the stated numerical value may include a range of ±10% of that numerical value. This includes numerical values ​​in examples that vary depending on the equipment and machinery used, such as the purity of the compound. As used in this specification, the term “liquid” shall refer to any type of fluid, including gels, aqueous compositions, non-aqueous compositions, etc., unless otherwise explicitly stated or understood differently by a person skilled in the art.

[0032] As used in this description, the terms 'continuous' and 'substantially continuous' refer to the period during which a therapeutic drug (composition or compound) is administered for the entire duration, along with any one or more intermittent periods that are effective with respect to the treatment, unless otherwise explicitly stated or understood differently by those skilled in the art. Examples of intermittent periods include periods shorter than approximately 24 hours, 12 hours, 5 hours, 3 hours, 1 hour, 30 minutes, 15 minutes, 5 minutes, or 1 minute. Periods during which the composition is administered include periods of at least approximately 6 hours, 8 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 3 days, 7 days, 2 weeks, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, etc.

[0033] As described in detail in this specification, PD patients suffer from various types of non-motor symptoms of sleep disorders. In some cases, such non-motor symptoms (e.g., sleep disorders) are caused by the repeated or continuous use of levodopa administered to treat PD motor symptoms. This application proposes a drug delivery system and a drug delivery method for improving non-motor symptoms in PD patients, including, but not limited to, PD patients to whom levodopa is continuously delivered to treat their motor symptoms.

[0034] Some aspects of this application include distinguishing between expressionless sleep stages (e.g., REM sleep stages), their contribution to the patient's overall sleep quality being so small that it is virtually nonexistent, promoting sleep stages (e.g., sleep stages 3 and 4), and the completeness or absence of sleep that directly relates to sleep quality. That is, the less interference there is with promoting sleep stages, the better the sleep quality. In general, the drug delivery systems described in this specification can selectively and beneficially deliver therapeutic drugs (e.g., levodopa) to patients as an effect on the patient's actual sleep stages or sleep stages expected to be present in the patient. For example, levodopa can be delivered to PD patients by the drug delivery system at relatively high flow rates during sleep stages, even though its contribution to overall sleep quality is so small that it is virtually nonexistent. Whenever the drug delivery system determines from the PD patient's sleep pattern (e.g., in real time) or based on the PD patient's sleep pattern (e.g., in real time) that the PD patient is experiencing or is expected to experience a sleep stage augmentation (e.g., sleep stage 3), the drug delivery system may reduce or initiate a reduction in the flow rate of the drug delivered to the PD patient (which is beneficial from the standpoint of treating non-motor symptoms). Delivering levodopa to PD patients at relatively high flow rates is beneficial from the standpoint of treating motor symptoms, while delivering levodopa to PD patients at relatively low flow rates is beneficial from the standpoint of treating non-motor symptoms.

[0035] A drug delivery system can control the flow rate of drugs by adjusting the values ​​of operating parameters that control the operation of the drug distribution mechanism of the drug delivery system. The drug delivery system can adjust the values ​​of the operating parameters of the drug distribution mechanism, for example, by receiving the latest values ​​for the operating parameters from a remote system, or by receiving those values ​​locally (for example, via a local user interface). Alternatively, or in addition to the above, the drug delivery system can also adjust the numerical values ​​of the operating parameters after determining the values ​​from sleep data related to PD patients.

[0036] Figure 1 shows a first configuration of a therapeutic drug delivery system (100) for treating diseases related to PD patients, for example, according to an embodiment, in order to optimize sleep, improve sleep quality, and / or improve sleep disorders in PD patients. In this configuration, the therapeutic drug delivery system 100 includes two separate subsystems, namely (1) a drug delivery device (DDD) 110 and (2) a sleep monitoring system (SMS) 120. The two subsystems (110, 120) can communicate with each other (e.g., exchange data and commands) via a suitable communication channel 130, utilizing the same communication protocol. The communication channel 130 can implement a computer communication cable (e.g., coaxial cable, Ethernet cable, USB cable, etc.) and can also communicate wirelessly by using a known communication protocol (Bluetooth®, WiFi, GSM (2nd generation mobile communication system)).

[0037] The DDD110 may include a controllable drug delivery unit (DDU) 140, a controller 150 for controlling the operation of the DDU 140 (152), a user interface (UI) 160, a data storage unit (DSU) 170, a communication interface 180, and a battery 190 (rechargeable or finite) for powering the DDD110. The communication interface 180 may be configured to communicate with, for example, an SMS 120 (shown in Figure 1), or, in various embodiments, with any data storage medium (e.g., a cloud, memory, server, or computer hosted by a third-party tracker such as Fitbit, Whoop Band, or Apple Watch). The DDD110 is designed to be wearable or attachable to a PD patient 112. The DDU 140 may include a therapeutic drug reservoir 142 for storing therapeutic drugs therein, and a controllable distribution mechanism 144 (mechanically or electrically, or both mechanically and electrically) designed to discharge therapeutic drugs from the therapeutic drug reservoir 142 in a controlled manner (146) for delivery of the discharged therapeutic drugs to a patient 112, for example, via an infusion catheter 148.

[0038] The controller 150 can be configured to receive sleep data via the communication interface 180 or the user interface 160 and to use that sleep data to calculate the values ​​of one or more operational parameters, and the controller 150 can be used to operate the distribution mechanism 144. The controller 150 can also be configured to receive (rather than calculate) the values ​​of operational parameters via the communication interface 180 or the user interface 160.

[0039] The user interface (UI) 160 allows users of the DDD 110 (e.g., physicians, PD patients, or caregivers assisting PD patients) to manually save various types of data (e.g., sleep data corresponding to sleep events that form sleep patterns) within the DSU 170. The user interface (UI) 160 also allows users of the DDD 110 to set therapeutically valid values ​​for one or more drug delivery operation parameters (sometimes abbreviated as “operation parameters” in this specification) to the controller 150. The values ​​set by the user for the operation parameters can also be saved in the DSU 170. The controller 150 can implement or use the parameter values ​​to control the operation of the drug distribution mechanism 144 according to these values.

[0040] The values ​​that a user can set for the operating parameters of the controller 150 can be selected to optimize the sleep of PD patients who are generally suffering from or suspected to be suffering from PD, improve the quality of their sleep, and / or improve non-motor symptoms, by applying them (for example, by the controller 150) to the drug distribution mechanism 144. Examples of operating parameters that the controller 150 can use to activate the drug distribution mechanism 144 include drug flow rate, drug delivery timing (including drug delivery start time and / or drug delivery stop time), increasing drug flow rate per unit time, decreasing drug flow rate per unit time, or any combination thereof. Depending on the type of non-motor symptom to be improved, different or additional operating parameters can be used, and all relevant operating parameters can be used individually or collectively (i.e., together with other operating parameters) to improve one or more non-motor symptoms experienced by the PD patient.

[0041] The user interface (UI) 160 may further output useful feedback signals (visual, auditory, and / or tactile) for the user regarding stored data and / or values ​​set by the user for operation parameters and / or the resulting instantaneous (current) drug delivery flow rate and / or drug delivery timing that the controller 150 is currently performing or scheduled to perform.

[0042] In general, pharmaceuticals can be delivered to patients using any known technology. In some embodiments, the therapeutic drug reservoir 142 may include a plunger head connected to a plunger rod and driveable by the plunger rod. The distribution mechanism 144 may include, for example, a drive unit which may include an electric motor and a gear unit actuated by the electric motor. The gear unit may engage with the plunger rod of the drug reservoir and be configured to move the plunger rod, and therefore the plunger head, linearly. Using values ​​set by the user for operating parameters and stored in the DSU 170, the controller 150 may control the electric motor so that it operates the gear unit to move the plunger head at a desired (e.g., therapeutically effective) speed (which may be fixed or variable) from, for example, a clinically desired drug delivery start time to a clinically desired drug delivery stop time. Similar control principles are applicable, and this specification is intended for applications of other drug delivery mechanisms.

[0043] As described herein (for example above), a user of the DDD110 can use the UI160 to set therapeutically valid values ​​for the operating parameters of the controller 150, so that the controller 150 can control the operation of the distribution mechanism 144 according to those values. Alternatively, the controller 150 can use the communication interface 180 to receive sleep data based on signals transmitted from one or more sleep sensors, or sleep data obtained from such signals. The sleep monitoring sensors can be worn by the treated PD patient, or otherwise connected to the treated PD patient, or otherwise (e.g., remotely by an optical system) to monitor the sleep of the treated PD patient. The controller 150 can use an algorithm to analyze the sleep data received via the communication interface 180 and detect or identify one or more sleep events (e.g., REM sleep, sleep stages 1, 2, 3, etc.) in the received sleep data that may collectively form a temporal sleep pattern (CSP) of the relevant (treated) PD patient. The controller 150 can determine (e.g., calculate) values ​​for the operating parameters from or based on the CSP. Sleep data that the controller 150 can receive via the communication interface 180, and the values ​​of parameters determined (e.g., calculated) by the controller 150, can also be stored in the DSU 170.

[0044] According to the first scenario, the controller 150 can only use the values ​​set for the operation parameters by the user of DDD110. According to the second scenario, the controller 150 can only use the values ​​set for the operation parameters by the controller 150 itself. According to the third scenario, the controller 150 can, in some cases, use the values ​​set for the operation parameters by the user of DDD110, but in other cases, the controller 150 can use the values ​​set for the operation parameters by the controller 150 itself. In the third scenario, the controller 150 can, for example, initially use the values ​​set by the controller 150 for the operation parameters, but if the user desires, the parameter values ​​set by the controller 150 can be overwritten (replaced) by the values ​​set for the operation parameters by the user. In some embodiments, the values ​​set (e.g., programmed) for the operation parameters by the user are overwritten by the values ​​set by the controller. Such overwriting may occur intermittently, such as occasionally or for a limited period of time.

[0045] The sleep monitoring system (SMS) 120 may include a controller 122, a user interface (UI) 124, a data storage unit (DSU) 126, a communication interface 128, and a sensor interface 132. The communication interfaces 128 and 180 are configured (electrically and in software) to communicate with each other via a communication channel 130.

[0046] The sensor interface 132 can be connected by wire or wirelessly to n sleep sensors (shown in Figure 1 as Sensor-1, Sensor-2, ..., Sensor-n). Some of the n sensors are generally any sensors capable of collecting patient data, such as electrodes, neural activity sensors, EEG sensors, ECG sensors, EMG sensors, polysomnography (PSG) sensors, sleep sensors, sleep state sensors, local electric field potential sensors, accelerometers, watches configured to detect movement during sleep, optical sensors, cameras, etc. Alternative or additional sensors can be connected to the sensor interface 132. Some of the n sensors, or some of the n sensors, may be physiological sensors configured to measure one or more physiological parameters or physiological characteristics of a PD patient. The sensors can provide physiological data (e.g., physiological data indicating sleep disorders or sleep states) before, during, and / or after the application of a therapeutic drug delivery pattern (DDP) to a PD patient. Some sensors can be used to sense the spatial movement of a PD patient. DDP refers to the flow rate of medication delivered to PD patients during treatment, as well as the timing and duration of each medication flow rate.

[0047] A sleep sensor, or several sleep sensors, can be worn by the user (or otherwise connectable to the user), or otherwise configured to monitor the user's (e.g., a PD patient) sleep. The sleep sensor can generate electrical signals that represent or indicate the sleep stage the user may currently be in, or the user's current sleep state. The sensor interface 132 can receive electrical signals generated by n sensors, convert those signals into sleep data, and store the resulting sleep data in the DSU 126. The controller 122 can receive a “request” for sleep data (e.g., sleep data stored in the DSU 126) from the DDD 110 via the communication channel 130. The controller 122 can respond to the request by transferring the requested sleep data to the DDD 110 (via the communication channel 130) for further processing by the controller 150. The user interface 124 can be used by the user, for example, to select (or deselect) the sensors from which sleep data is collected (e.g., to be stored in the DSU 126), and / or to manipulate the sleep data stored in the DSU 126.

[0048] Figure 2 shows a second configuration of DDD(200) for treating disorders associated with Parkinson's disease (PD), for example, according to other embodiments, for optimizing sleep, improving sleep quality, and / or improving sleep disorders in PD patients. DDD200 may include a controller 210 for controlling the operation of DDU230 (220), a user interface (UI) 240, a data storage unit (DSU) 250, a sensor interface 260, and a battery 270 (e.g., rechargeable or finite) for powering DDD200. DDD200 is designed to be wearable by or attachable to a PD patient 212. DDU230 may include a therapeutic drug reservoir 232 for storing therapeutic drugs therein, and a controllable dispensing mechanism 234. The distribution mechanism 234 is designed to discharge the therapeutic drug from the drug reservoir 232 in a controlled manner (236) so as to deliver the discharged therapeutic drug to the patient 212, for example, via an infusion set (e.g., a catheter) 238 (mechanically or electrically, or both mechanically and electrically).

[0049] The controller 210 may be configured to receive sleep data via the sensor interface 260 or the user interface 240, or the communication interface included in the SMS 280 may be configured to communicate with any data storage medium (e.g., a cloud, memory, server, or computer hosted by a third-party tracker such as Fitbit, Whoop Band, or Apple Watch). The controller 210 may use the sleep data to determine (e.g., by calculation) the values ​​of one or more operating parameters that the controller 210 uses to operate the distribution mechanism 234. The controller 210 may also be configured to receive (rather than determine) the values ​​of operating parameters via the sensor interface 260 or the user interface 240.

[0050] DDU230 may function in the manner described herein, for example, in relation to DDU140 in Figure 1. User interface (UI)240 may function in the manner described herein, for example, in relation to UI160 in Figure 1. Data storage unit (DSU)250 may function in the manner described herein, for example, in relation to DSU170 and DSU126 in Figure 1. Sensor interface 260 may function in the manner described herein, for example, in relation to sensor interface 132 in Figure 1. Sensor interface 260 may function in the manner described herein, for example, in relation to sensor interface 132 in Figure 1.

[0051] Similar to sensor interface 132, sensor interface 260 can connect, either wired or wirelessly, to n sleep sensors (shown as sensor-1, sensor-2, ..., sensor-n in Figure 1) to monitor the sleep of a user (e.g., a PD patient). The sleep sensors can generate electrical signals that represent or indicate the user's sleep stages and / or sleep states. Sensor interface 260 can receive the electrical signals generated by the n sensors, convert these signals into sleep data, and store the resulting sleep data in DSU 250. The user of DDD200 can also use user interface 240 to select (or deselect) sensors for storing sleep data in DSU 250 and to manipulate sleep data already stored in DSU 250.

[0052] Users of the DDD200 (e.g., physicians, PD patients, or caregivers assisting PD patients) can use the UI240 to manually save various types of data (e.g., the user's sleep patterns, other health data of the user, the user's biological data, or sleep data corresponding to sleep events that form the user's physical data) to the DSU250. The user interface (UI)240 also allows users of the DDD200 to set therapeutically valid values ​​for the operating parameters of the controller 210. The values ​​set by the user for the operating parameters can also be saved to the DSU250. The controller 210 can implement or use the values ​​of its parameters to control the operation of the drug distribution mechanism 234 according to these values.

[0053] The values ​​that a user can set for the operating parameters of the controller 210 can be selected to optimize sleep and / or improve sleep quality and / or alleviate non-motor symptoms that a PD patient is suffering from or suspected to be suffering from, by applying them (by the controller 210) to the drug distribution mechanism 234. Examples of operating parameters that the controller 210 can use to activate the drug distribution mechanism 234 are described herein, for example, in relation to the controller 150.

[0054] The user interface (UI) 240 can output useful feedback signals (visual and / or auditory) to the user regarding stored data, / or values ​​set by the user for operating parameters, / or the resulting instantaneous (current) drug delivery flow rate, and / or drug delivery timings that the controller 210 is currently performing or scheduled to perform.

[0055] Generally, pharmaceuticals can be delivered to patients using any known technology. In some embodiments, the therapeutic drug reservoir 232 may include a plunger head connected to a plunger rod and driveable by the plunger rod. The distribution mechanism 234 may include, for example, a drive unit which may include an electric motor and a gear unit driven by the electric motor. The gear unit may engage with the plunger rod of the drug reservoir and be configured to move the plunger rod, and therefore the plunger head, linearly. Using values ​​set by the user as operating parameters and stored in the DSU 250, the controller 210 may control the electric motor so that it operates the gear unit to move the plunger head at a desired (e.g., therapeutically effective) speed in response to a desired drug delivery flow rate, which may be fixed or variable, according to a therapeutically effective timing, for example.

[0056] As described herein (for example above), a user of the DDD200 can use the UI240 to set therapeutically valid values ​​for the operating parameters of the controller 210 so that the controller 210 can control the operation of the distribution mechanism 234 according to those values. Alternatively, the controller 210 can use sleep data based on, derived from, or generated from signals produced by, all or some of, the sleep sensors, sensor-1, sensor-2, ..., sensor-n. The sleep sensors can be worn by the PD patient being treated, or otherwise connected to the PD patient being treated, or otherwise monitor the sleep stages or sleep states of the PD patient being treated. The controller 210 can use algorithms to analyze the sleep data and detect or identify one or more sleep events (e.g., sleep stages) in that sleep data that can collectively form a temporal sleep pattern (CSP) of the PD patient concerned. The controller 210 can determine (e.g., calculate) values ​​for the operating parameters from or based on the CSP. Sleep data and parameter values ​​determined (e.g., calculated) by the controller 210 can also be stored in the DSU 250.

[0057] In the first scenario, controller 210 can only use the values ​​of the operating parameters set by the user of DDD200. In the second scenario, controller 210 can only use the values ​​that controller 210 itself sets for the operating parameters. In the third scenario, controller 210 can sometimes use the values ​​that controller 20 has set for the operating parameters, but in other cases, controller 210 can use the values ​​that controller 20 itself has set for the operating parameters. In the third scenario, for example, controller 210 can initially use the values ​​that controller 210 has set for the operating parameters, but if the user wishes, the parameter values ​​set by controller 210 can be overwritten (replaced) by the values ​​that the user has set for the operating parameters. The user-set (e.g., programmed) values ​​for the operating parameters are intermittently overwritten by the values ​​set by the controller for a limited time or for the remainder of the sleep period.

[0058] Figure 3 schematically illustrates an example of a sleep pattern (hypnogram 300). A hypnogram represents, for example, recordings of electroencephalogram (EEG) activity during sleep, and optionally, recordings from other sleep monitoring sensors and systems during sleep. A hypnogram is a type of polysomnography, and it is a graph that represents sleep stages as a function of time, for example, sleep with rapid eye movements (REM) and sleep without rapid eye movements (NREM) that can be identified during sleep. NREM sleep can be further classified (including) into sleep stage 1, sleep stage 2, and sleep stage 3. Sleep stage 3 essentially includes a fourth sleep stage (sleep stage 4), also known as slow-wave sleep (SWS). Slow-wave sleep is the deepest sleep stage. The duration and wakefulness of each of the three NREM stages, as well as REM sleep, can be determined and displayed in the hypnogram.

[0059] Hypnogram 300 includes a time axis (horizontal axis) and a sleep stage axis (vertical axis). For example, the sleep stage axis includes five sleep stages: wakefulness stage (W), REM sleep stage (R), sleep stage 1 (1), sleep stage 2 (2), and sleep stage 3 (3). Referring to hypnogram 300, the total sleep time 310 in this example begins at time T1, which is the transition from wakefulness to sleep stage 1 (shown in 320), and ends at time T2, which is the transition from sleep stage 1 back to wakefulness (through sleep stage 2, shown in 330, etc.). The total sleep time 310 is the time between preceding and succeeding wakefulness periods.

[0060] Typically, total sleep time includes several sleep cycles. For example, Hypnogram 300 includes five sleep cycles (n=5), shown in Figure 3 as 350, 360, 370, 380, and 390. In some sleep cycles, normal transitions between different sleep stages may occur. A sleep cycle may be incomplete or defective. This means that one or more sleep stages are missing from the sleep cycle, resulting in a decrease in overall sleep quality. Another sleep deprivation problem is unintentionally waking up after skipping one or more sleep stages within a sleep cycle.

[0061] Sleep cycles 350 and 360 include all sleep stages, both during descending and ascending transitions between sleep stages. Sleep cycles 350 and 360 include sleep stage 3, which is either a deep sleep period or includes a deep sleep period. Sleep cycles that include slow-wave sleep (SWS), the deepest stage of sleep, are generally considered to contribute to high-quality sleep. Sleep cycle 370 lacks sleep stage 1 during ascending transitions between sleep stages and sleep stage 3 during descending transitions between sleep stages. Therefore, sleep cycle 370 interferes with overall sleep quality. Sleep cycle 380 lacks sleep stage 3 during both descending and ascending transitions between sleep stages. Sleep cycle 380 also includes an abnormal (unintentional) transition 382 (time T3) between sleep stage 1 and the wakefulness stage (W). Therefore, sleep cycle 380 also interferes with overall sleep quality. Sleep cycle 390 also lacks sleep stage 3 during both descending and ascending transitions between sleep stages. Therefore, sleep cycle 390 also interferes with overall sleep quality.

[0062] Figure 4 schematically illustrates a drug delivery control scheme for controlling the flow rate of therapeutic drugs delivered to PD patients to treat diseases related to PD patients. The drug delivery control scheme is determined or explicitly indicated by the values ​​set in the operating parameters used to operate drug delivery units (e.g., DDU140, DDU230). A particular drug delivery control scheme explicitly indicates a specific pattern used to deliver drugs to PD patients. Thus, drug delivery control schemes (DDCS) and DDPs are interrelated, as the values ​​set in the operating parameters indirectly indicate the drug delivery pattern (DDP). Disease treatments include, to name a few, sleep optimization, improvement of sleep quality, and / or improvement of sleep disorders. Figure 4 shows an example of a hypnogram 400 embodying an example of a sleep pattern 410 in a PD patient, and a toggle (on / off) of the therapeutic drug flow control scheme 420 as a function of the sleep pattern. Simply put, the on / off drug flow control scheme 420 involves delivering therapeutic drugs to PD patients at a high flow rate (430) when the PD patient is awake and at a low flow rate (440) when the PD patient is asleep (for example, between time T1 and wake time T2).

[0063] During the daytime, for example, to treat the motor symptoms of PD patients, PD patients can be treated by continuously delivering therapeutic drugs (typically levodopa or levodopa-carbidopa-based formulations) to the patients. To make the motor treatment effective, therapeutic drugs are often delivered to PD patients at a relatively high flow rate (e.g., flow rate level L1), which is the flow rate level shown in Figure 430. The value of L1 can be selected from a range of, for example, 0.50 ml / h to 0.80 ml / h, and for example, the value of L1 can be 0.64 ml / h. The value of L2 can be selected from a range of, for example, 0.05 ml / h to 0.10 ml / h, and for example, the value of L2 can be 0.08 ml / h.

[0064] When a PD patient falls asleep, motor symptoms are less severe compared to the daytime motor symptom manifestation when the patient is awake and requires assistance to control their involuntary movements. Furthermore, once a PD patient has fallen asleep, it is necessary to reduce the nighttime drug delivery rate to avoid overdosing on nighttime medication and maintain a low total nighttime dose. In some PD patients, a high nighttime dose of medication causes sleep disturbances. Therefore, delivering therapeutic medication at a low rate at night is beneficial, especially if a sleep monitoring system indicates that the PD patient has just fallen asleep. For some PD patients, a low drug delivery rate over the entire sleep period (e.g., period 4-10) is beneficial in terms of treatment and sleep quality, while for others, a low drug delivery rate only for specific periods within the total sleep period 4-10 is beneficial in terms of treatment and sleep quality. Other PD patients may require modifying the drug delivery rate according to a different scheme to achieve efficient treatment. In other words, drug delivery rates can be modified according to drug delivery control schemes tailored to the specific treatment needs of particular PD patients, both in terms of treating motor symptoms and non-motor symptoms (e.g., sleep disorders).

[0065] While Figures 4, 5, and 6 show two flow rates (e.g., L1 and L2), it is noted that further embodiments of the present invention may implement any number of flow rates (e.g., L1, L2, ..., Lm: m=1, 2, 3, ...) as desirable, required, or beneficial to the PD patient. For example, there may be a medium rate between L1 and L2, implemented at specific times. For example, one of the flow rates L1 and / or L2 shown in Figures 4, 5, and / or 6 may be replaced or partially replaced. There may be flow rates lower than L2 or higher than L1, implemented at appropriate times. Furthermore, there may be times when the flow rate is 0.00 ml / h, resulting in no or essentially no administration of the drug for a specific period of time, the length of which is determined by data obtained from the PD patient's health status (e.g., sleep data, exercise data, etc.) recorded by sensors, physicians, caregivers, or the PD patient themselves, as detailed herein.

[0066] It should be further noted that, as detailed herein, the various flow rates include both nocturnal and daytime flow rates. However, since daytime sleep symptoms also occur, when PD patients sleep or rest during the day, the drug delivery rate may be altered, as detailed herein.

[0067] Furthermore, all references to PD patients, such as falling asleep, may also refer to resting PD patients, i.e., those who are not very active and whose flow rate changes are appropriate, as detailed herein. Similarly, references to wakefulness, etc., include becoming more active, as their flow rate changes are appropriate, as detailed herein. In addition, references to "daytime" and "nighttime," etc., may refer to active or high-activity periods and inactive or low-activity periods, respectively.

[0068] Referring again to Figure 4, which shows an example of a drug delivery control scheme, at time T1, the PD patient falls asleep (the patient's sleep onset is sensed or detected by the sleep monitoring system). Considering the above description of the recommended drug delivery flow rate during sleep, at time T1, the drug delivery flow rate decreases from level L1 to level L2 (level "L2" is indicated by 440; L1 > L2). At time T2, the PD patient wakes up (as indicated by the sleep monitoring system), and considering the above description, with respect to the recommended drug delivery flow rate during the waking period, at time T2, a high drug delivery flow rate is resumed by increasing the drug delivery flow rate from flow level L2 back to flow level L1.

[0069] Figure 5 schematically illustrates a control scheme for controlling the flow rate of therapeutic drugs delivered to Parkinson's disease (PD) patients to treat disorders related to PD, such as optimizing sleep, improving sleep quality, and / or improving sleep disorders through another example of the control scheme. In this example, the drug delivery flow control scheme targets REM sleep events identified by (e.g., matching or originating from) a sleep pattern. Another reason the drug delivery flow control scheme targets REM sleep events is to prevent interruption of sleep stage 3 (the deepest sleep stage). Interruption of sleep stage 3 reduces sleep quality, which is usually undesirable. In short, the drug delivery flow control scheme 520 shows that, in the example of Figure 5, therapeutic drugs are delivered to PD patients at relatively high flow rates during specific sleep events, which are REM sleep events R1, R2, ... R5.

[0070] Figure 5 shows an example of a hypnogram 500 embodying an example of a sleep pattern 510 in a PD patient, and an example of a therapeutic drug flow control scheme as a function of the sleep pattern 510 (Graph 520). For example, the sleep pattern 510 begins at time T1 and ends at time T8, and includes five REM sleep periods: REM sleep period R1 beginning at time T2, REM sleep period R2 beginning at time T3, REM sleep period R3 beginning at time T4, period R4 beginning at time T5, and REM sleep period R5 beginning at time T6. Each REM sleep period represents or is related to a different sleep cycle.

[0071] As described in detail herein, the drug delivery flow rate is relatively high during the day (when the PD patient is awake), i.e., level L1 (shown at 530 in Figure 5, L1 > L2), in order to efficiently treat motor symptoms. In this example (for example, based on sleep history data related to a particular PD patient), we assume that the PD patient's sleep onset time is typically at or near time T1. At time T0, preceding time T1, the PD patient is still awake, but nevertheless (i.e., according to the example drug delivery flow rate control scheme in Figure 5), the drug delivery flow rate changes from a high drug delivery flow rate level L1 (shown at 530) to a low drug delivery flow rate level L2 (shown at 540) as preparation for entering a sleep mode in which a lower total drug intake is beneficial in terms of overall sleep quality. The time difference 550(Td) preceding the sleep onset time T1 (i.e., time difference Td = T1 - T0) is determined, for example, based on the severity of the motor symptoms and / or non-motor symptoms (e.g., sleep disturbances) that the PD patient is experiencing. For example, the more severe the motor symptoms of a Parkinson's disease (PD) patient, the smaller the Td value can be, allowing for a higher flow rate of therapeutic medication (useful for treating motor symptoms) to be maintained for as long as possible, bringing the PD patient closer to or into sleep mode. Conversely, if the motor symptoms experienced by the PD patient are moderate, the time lag (Td) may be relatively long, and thus reducing the overall expected medication intake during sleep can, on the one hand, help avoid or suppress non-motor symptoms (e.g., sleep disturbances), while on the other hand, it remains effective in managing the motor symptoms of the PD patient.

[0072] Sleep research suggests that sleep stage 3 is the deepest period of sleep, and that a decline in sleep quality and / or sleep volume correlates with sleep disturbances occurring during sleep stage 3. Generally, the greater the interruption to sleep stage 3, the greater the decline in overall sleep quality. Sleep research also suggests that excessive delivery of medications (e.g., levodopa) during sleep disrupts sleep stage 3. Therefore, it is generally beneficial to reduce medication delivery rates during sleep and deep sleep stages (sleep stage 3 or sleep stage 4), especially to optimize sleep quality.

[0073] Since REM sleep stages have less impact on sleep quality than sleep stage 3, drug delivery rates during REM sleep stages R1, R2, ..., R5 can be relatively high (e.g., level L1 in Figure 5) without significantly impairing sleep quality. Therefore, drug delivery rates are maintained at a low level (L2, 540) from time T0 to T2 (time when the first REM sleep (R1) event begins), and then changed to a high level (L1) for a period d1 corresponding to (e.g., at least partially overlapping or coinciding with) the REM sleep event R1 at time T2 (time when the first REM sleep (R1) event begins). When the REM sleep event R1 ends (or immediately before or after the end of the REM sleep event R1), drug delivery rates are reduced to a low level L2 until time T3. The drug delivery flow rate is restarted at time T3 (the time when the second REM sleep (R2) event begins) at a high level (L1) for a period d2 corresponding to (e.g., at least partially overlapping with or coinciding with) the REM sleep event R2. The same drug delivery flow rate process applies to each subsequent REM sleep event, such as R3, R4, and R5. Thus, Figure 5 illustrates pulsating drug flow rate control.

[0074] The drug delivery flow rate level in each REM sleep event changes as shown in Figure 5. In other words, in all REM sleep events, the drug flow rate can be increased from a low level L2 to a high level (e.g., level L1), but in other scenarios, the drug flow rate can be increased to other high flow rate levels, some of which may be lower or higher than level L1. For example, the drug delivery flow rate value in REM sleep event R1 may be L1-delta_1, the drug delivery flow rate value in REM sleep event R2 may be L1+delta_2, and the drug delivery flow rate value in REM sleep event R3 may be L1-delta_3, etc. (delta_1, delta_2, delta_3, etc. are, for example, percentages of the underlying flow rate level L1, for example, approximately 5%, 3%, and 2% of flow rate level L1, respectively).

[0075] The drug delivery flow rate level between REM sleep events changes as shown in Figure 5. For example, after each REM sleep event, the drug delivery rate can be reduced from a high level L1 to a low level (e.g., level L2), but in other scenarios, the drug delivery rate can be reduced to other low levels, some of which may be lower than or higher than low level L2. For example, the drug delivery flow rate value for the period following REM sleep event R1 (i.e., the time between REM sleep event R1 and REM sleep event R2) can be L2-delta_1. The drug delivery flow rate value for the period following REM sleep event R2 (i.e., the time between REM sleep event R2 and REM sleep event R3) can be L2+delta_2. The drug delivery flow rate value for the period following REM sleep event R3 (i.e., the time between REM sleep event R3 and REM sleep event R4) can be L2-delta_3. (delta_1, delta_2, delta_3, etc. are, for example, percentages of the underlying flow rate level L2 (e.g., approximately 6%, 4%, and 1% of flow rate level L2, respectively). In some scenarios, they can be modified according to a combined scheme of drug delivery flows. That is, both the underlying levels L1 and L2 can be modified using the modifier delta_i (i=1, 2, 3, ...).

[0076] Figure 6 schematically illustrates a drug delivery control scheme for controlling the flow rate of therapeutic drugs delivered to PD patients in order to treat diseases related to PD patients, e.g., sleep optimization, improvement of sleep quality, and / or improvement of sleep disorders according to another embodiment. Briefly, drug delivery control scheme 650 shows that, before the PD patient enters sleep mode (e.g., anticipated), the drug delivery flow rate is gradually reduced between time T0 and time T1 (e.g., from a relatively high daytime drug delivery flow rate). Next, the low drug delivery flow rate is maintained during sleep (between time T1 and time T2), and finally, in anticipation of the PD patient waking up, the drug delivery flow rate is gradually increased between time T2 and time T3 (e.g., back to a daytime drug delivery flow rate).

[0077] Figure 6 shows a hypnogram 600 embodying a sleep pattern 610 of a PD patient, and a therapeutic drug flow control graph 650 as a function of the sleep pattern. In this example, the drug delivery flow control scheme is based on a predetermined number n (depending on, based on, or derived from) sleep cycles of the patient's sleep pattern. For example, sleep pattern 610 begins at time T1 (sleep onset) and ends at time T3 (wake-up), and includes five REM sleep events: REM sleep event R1, REM sleep event R2, REM sleep event R3, REM sleep event R4, and REM sleep event R5. Each REM sleep event is associated with (and thus can be represented by) a different sleep cycle. For example, three sleep cycles are shown as 620, 630, and 640.

[0078] In this example, the PD patient remains awake until time T0. During this time, the drug delivery flow rate is at a high level (L2; indicated at 652) to improve the patient's motor symptoms. At time T0, preceding the sleep onset time T1, the PD patient is still awake, but according to the example drug delivery flow rate control scheme in Figure 6, the drug delivery flow rate is gradually reduced from a high drug delivery flow rate level L1 to a low drug delivery flow rate level L2 (e.g., linear, monotonic, stepwise, etc., as indicated at 654) at a decreasing angle 660, as (anticipated) preparation for reducing the drug dosage and entering sleep mode. This is beneficial in terms of overall sleep quality. The time difference Td preceding the sleep onset time T1 (time 654, i.e., Td = T1 - T0) and the decreasing angle 660 of the decreasing flow rate between T0 and T1 can be determined, for example, based on the severity of motor and / or non-motor symptoms (e.g., sleep disturbances) experienced by the PD patient.

[0079] According to the drug delivery flow rate control scheme in Figure 6, the drug delivery flow rate can be maintained at a low level, e.g., flow rate level L2 (indicated as 670), for n consecutive sleep cycles. As an example, Figure 6 shows three (n=3) consecutive sleep cycles (sleep cycles 620, 630, and 640), during which the drug delivery flow rate is maintained at a low level L2. Maintaining a low drug delivery flow rate (L2) for three consecutive sleep cycles is beneficial because one or more of sleep cycles 620, 630, and 640 include sleep stage 3 (the deepest sleep stage), and maintaining a low drug flow rate in sleep stage 3 prevents the deep sleep stage from being interrupted, increasing the patient's chances of achieving normal (uninterrupted) or near-normal sleep.

[0080] Time T2 roughly indicates the completion of three sleep cycles 620, 630, and 640. In this example (for example, based on past sleep data), assuming that the sleep pattern of the PD patient involved totals, for example, five sleep cycles (two additional sleep cycles are shown as R4 and R5 in Figure 6), it can be determined (for example, by DDD100 in Figure 1 or DDD200 in Figure 2) that the PD patient is about to wake up after the completion of three sleep cycles 620, 630, and 640 (60% of the total number of sleep cycles). Thus, at time T2, the drug delivery flow rate increases gradually (e.g., linear, monotonic, stepwise, etc.) at an increasing angle of, for example, 680, until the drug delivery flow rate reaches a high flow rate level L1 at time T3, which is the time when the PD patient is fully awake or is expected to be awake. The time immediately following n sleep cycles, i.e., the time between time T2 and T3, can be considered the pre-wake period. Gradually increasing the drug delivery rate between time T2 and time T3 (for example, while the PD patient is still asleep in the pre-awakening period) gradually increases the drug level as preparation for the PD patient to wake up. Such preparation helps the PD patient get out of bed, get dressed, and generally do what he or she would normally do after waking up.

[0081] Figure 7 illustrates, according to an embodiment, how to operate a therapeutic drug delivery system for treating disorders related to Parkinson's disease (PD) patients, for example, to optimize sleep, improve sleep quality, and / or alleviate sleep disorders. Figure 7 is described in relation to Figure 1.

[0082] In step 710, the therapeutic drug delivery system 100, in some embodiments, characterizes the time-series sleep pattern (CSP) of a PD patient, or receives sleep data including the time-series sleep pattern of a PD patient, and based on the CSP, sets one or more operating parameters of the therapeutic drug delivery system to values ​​that are beneficial in terms of sleep optimization, improvement of general sleep quality and / or improvement of sleep dysfunction. Alternatively (for example, in other embodiments), the therapeutic drug delivery system 100 may receive values ​​for one or more operating parameters of the therapeutic drug delivery system from an external system.

[0083] In step 720, the therapeutic drug delivery system 100 can deliver therapeutic drugs to the PD patient according to values ​​set in the operating parameters of the therapeutic drug delivery system, or values ​​received for those operating parameters. The values ​​set in the operating parameters of the therapeutic drug delivery system 100, or values ​​received for those operating parameters, are used throughout the sleep period, or they can be adjusted from time to time or in real time (by using newly received values ​​or newly set operating parameter values). The adjustment can be performed in real time, from time to time, for example at pre-specified time intervals, or automatically, for example, by the system or based on input from the system, if certain objective or subjective indicators or parameters suggest that the adjustment is beneficial. Alternatively, the adjustment can be performed, for example, manually, by the PD patient, physician, or caregiver.

[0084] In step 730, the therapeutic drug delivery system 100 may check whether a new value has been received or needs to be determined for the operating parameter. If no such value has been received or does not need to be determined (indicated as "No" in step 730), the therapeutic drug delivery system 100 may continue to use the last received or last determined value. However, if the therapeutic drug delivery system 100 receives a new value for the operating parameter or needs to recalculate that value (indicated as "Yes" in step 730), the therapeutic drug delivery system 100 delivers the therapeutic drug to the PD patient according to the new value set for the operating parameter of the therapeutic drug delivery system 100 or the new value received for the operating parameter.

[0085] Figure 8 illustrates, according to another embodiment, how to operate a therapeutic drug delivery device for treating diseases related to PD patients, for example, sleep optimization, improvement of sleep quality, and / or improvement of sleep disorders. Figure 8 is described in relation to Figure 2.

[0086] In step 810, the therapeutic DDD200 may receive either sleep data characterizing the PD patient's time-series sleep pattern (CSP), or sleep data containing the PD patient's time-series sleep pattern, or values ​​of one or more operating parameters of the therapeutic DDD200. These are beneficial in terms of optimizing sleep, improving sleep quality, or improving sleep dysfunction. If the therapeutic DDD200 receives sleep data, the therapeutic DDD200 (e.g., controller 210) may calculate one or more operating parameters of the therapeutic drug delivery system based on the CSP and set them to beneficial values, for example, in terms of optimizing sleep, improving sleep quality, and / or improving sleep dysfunction.

[0087] In step 820, the therapeutic DDD200 can deliver therapeutic drugs from the drug reservoir 232 to the PD patient (for example, by the controller 210 which controls the operation of the distribution mechanism 234) according to values ​​set by the controller 210 or received by the controller 210 for the operating parameters of the therapeutic drug delivery system.

[0088] The control loop 830 represents various options for adjusting (e.g., by the controller 210) the values ​​of operational parameters that the controller 210 can use to control the drug delivery unit (DDU) 230 to deliver therapeutic drugs to PD patients. For example, the values ​​of operational parameters can be manually adjusted (e.g., pre-programmed) at any time (e.g., before bedtime, when the patient is awake in the middle of the night) by the PD patient, caregiver, and / or physician (e.g., via the user interface 240). Alternatively, the values ​​of operational parameters can be automatically adjusted in real time (e.g., by the controller 210) based on real-time sleep data that the controller 210 can receive (and use to calculate or determine new values ​​for the operational parameters), or based on new operational parameter values ​​that the controller 210 can receive.

[0089] Figure 9 illustrates, according to yet another embodiment, a method for operating a therapeutic drug delivery device for treating disorders related to Parkinson's disease (PD) patients, for example, for sleep optimization, improvement of sleep quality, and / or improvement of sleep disorders. Figure 9 is described in relation to Figures 2 and 5.

[0090] As described in Figure 5 (for example), the drug delivery flow rate during REM sleep events can be increased because interruptions during REM sleep events, as explained in Figure 5, usually have little to no significant impact on sleep quality. Therefore, the drug delivery control scheme in Figure 9 is based on the detection of REM sleep events within the sleep patterns of PD patients, and the values ​​of the relevant operational parameters are set to values ​​corresponding to the high drug flow rates during each detected REM sleep event.

[0091] In step 910, the therapeutic DDD200 may receive either sleep data characterizing the PD patient's time-series sleep pattern (CSP), or sleep data including the PD patient's time-series sleep pattern, or values ​​of one or more operating parameters of the therapeutic DDD200, which are beneficial in terms of optimizing sleep, improving sleep quality, or improving sleep dysfunction. If the therapeutic DDD200 receives sleep data, the therapeutic DDD200 (e.g., controller 210) may calculate one or more operating parameters of the therapeutic drug delivery system based on the CSP and set them to beneficial values ​​in terms of optimizing sleep, improving sleep quality, and / or improving sleep dysfunction.

[0092] In step 920, the therapeutic DDD200 can deliver therapeutic drugs from the drug reservoir 232 to the PD patient (for example, by the controller 210 which controls the operation of the distribution mechanism 234) according to values ​​set by the controller 210 for operating parameters for controlling the drug delivery flow rate or values ​​received by the controller 210.

[0093] In step 930, the controller 210 checks whether a new REM sleep event or an additional REM sleep event has started (for example, based on real-time sleep data that the controller 210 can receive). If the controller 210 determines in step 930 that a new or additional REM sleep event has started (indicated as "Yes" in step 930), the controller 210 may in step 940 set the operating parameters to values ​​suitable for controlling the drug delivery unit (DDU) 230 to deliver therapeutic drugs to the PD patient at a high flow rate. The controller 210 can maintain drug delivery at a high flow rate as long as the current REM sleep event is active (this condition is checked in step 930). However, if the controller 210 determines in step 930 that the current REM sleep event has ended (a state indicated as "No" in step 930), the controller 210 may reuse the values ​​of the operating parameters last received or determined by the controller 210 in step 910, and use them in step 920 to deliver therapeutic drugs from the drug reservoir 232 to the PD patient at drug delivery rates corresponding to these values.

[0094] The controller 210 can access step 930 again to check if there are any additional REM sleep events and manage each such REM sleep event in the manner described above. That is, it can set the values ​​of the operating parameters of the therapeutic drug delivery system to deliver the therapeutic drug at a high flow rate during and throughout the REM sleep events. The controller 210 can terminate the drug delivery process when the PD patient wakes up.

[0095] Figure 10 illustrates, according to yet another embodiment, how to operate a therapeutic drug delivery device for treating disorders related to Parkinson's disease (PD) patients in order to optimize sleep, improve sleep quality, and / or alleviate sleep disorders. Figure 10 is described in relation to Figures 2 and 6.

[0096] As described with respect to (for example) Figure 6, it is beneficial for the drug delivery rate to be low during the first n consecutive sleep cycles in a sleep pattern (e.g., sleep cycles 620, 630, and 640 in Figure 6, i.e., n=3 in Figure 6) out of the total number of sleep cycles greater than n. This is because the lower drug dosage during that period contributes to sleep quality or promotes sleep. For example, n sleep cycles could be 50% of the total number of nighttime sleep cycles, or 70% of the total number of nighttime sleep cycles, or another percentage of the total number of sleep cycles in the relevant sleep pattern. During the sleep cycles following n consecutive sleep cycles, it is beneficial to gradually increase the drug delivery rate (e.g., linearly, monotonically, stepwise) as shown in Figure 690, in order to prepare the PD patient to wake up in the morning.

[0097] In step 1010, the therapeutic DDD200 may receive either sleep data characterizing the chronological sleep pattern (CSP) of a PD patient, or sleep data containing the chronological sleep pattern of a PD patient, or values ​​of one or more operating parameters of the therapeutic DDD200. These values ​​are beneficial in terms of optimizing sleep, improving sleep quality, or improving sleep dysfunction. If the therapeutic DDD200 receives sleep data, the controller 210 may use the CSP to calculate drug delivery values ​​that are beneficial, for example, in terms of optimizing sleep, improving sleep quality, and / or improving sleep dysfunction, and set one or more operating parameters of the DDD200 for these values.

[0098] In step 1020, the therapeutic DDD 200 can deliver therapeutic drugs from the drug reservoir 232 to the PD patient (for example, by the controller 210 controlling the operation of the distribution mechanism 234) according to values ​​set by the controller 210 or received by the controller 210 for operating parameters to control the drug delivery flow rate. Referring to Figure 6, a drug delivery flow rate control scheme that the controller 210 can implement in this stage is to reduce the drug delivery flow rate (indicated as 654 in Figure 6) linearly or gradually (in this example) during the pre-sleeping period, which is a short period preceding sleep onset. In the example in Figure 6, this is the time between time T0 and sleep onset time T1.

[0099] In step 1030, the controller 210 may check the number of consecutive sleep cycles that have elapsed since the time of sleep onset, e.g., time of sleep onset T1 (see Figure 6), based on (for example, past sleep data and / or real-time sleep data that the controller 210 can receive). If the controller 210 determines in step 1030 that the number of sleep cycles that have elapsed since the time of sleep onset (e.g., time of sleep onset T1) is n (indicated as "Yes" in step 1030), the controller 210 may in step 1040 set the operating parameters to values ​​suitable for controlling the drug delivery unit (DDU) 230, for example, anticipating that the PD patient will wake up at time T3 in Figure 6, and deliver the therapeutic drug to the PD patient in a gradually increasing flow rate (indicated as angle 680 at 690 in Figure 6). Next, in step 1020, the controller 210 delivers the therapeutic drug to the PD patient according to the value set for the operating parameter in step 1040. That is, the controller 210 begins delivering the drug to the PD patient so that the flow rate gradually increases. However, if the controller 210 determines in step 1030 that the number of consecutive sleep cycles is still less than n (this state is indicated as "No" in step 1030), the controller 210 can access step 1010 again and maintain the drug delivery flow rate at a low level (e.g., as shown as 670 in Figure 6) to avoid interrupting the patient's sleep. The controller 210 can wait until n consecutive sleep cycles have elapsed before beginning to gradually increase the drug delivery flow rate (e.g., linear, stepwise, etc.) toward the awakening of the PD patient.

[0100] Figure 11 illustrates, according to an embodiment, how to operate a therapeutic drug delivery device for treating disorders related to Parkinson's disease (PD) patients, for example, to optimize sleep, improve sleep quality, and / or alleviate sleep disorders. Figure 11 is described in relation to Figure 2. As described herein, it is beneficial to deliver drugs to PD patients at a low flow rate during sleep stage 3 (the deepest sleep stage of the sleep cycle) to avoid sleep disturbances during this critical sleep stage 3.

[0101] In step 1110, the DDD200 can receive either sleep data characterizing the PD patient's time-series sleep pattern (CSP), or sleep data containing the PD patient's time-series sleep pattern, or values ​​of one or more operating parameters of the DDD200 (e.g., via the user interface 240). This is beneficial in terms of optimizing sleep, improving sleep quality, and / or improving sleep disorders. If the DDD200 receives sleep data, the controller 210 can use the CSP to calculate one or more operating parameters of the DDD200 and set them to values ​​that can, for example, optimize the PD patient's sleep, improve sleep quality, and / or improve sleep disorders. In step 1120, the DDD200 can deliver therapeutic drugs from the drug reservoir 232 to the PD patient (e.g., by the controller 210 controlling the operation of the distribution mechanism 234) according to the values ​​that the controller 210 sets for the operating parameters to control the drug delivery flow rate, or the values ​​received for those operating parameters.

[0102] In step 1130, the controller 210 analyzes sleep data received in real time (e.g., via the sensor interface 260) or via the user interface 240 to determine whether the PD patient is currently in sleep stage 3 (deep sleep stage). If the controller 210 determines in step 1130 that the PD patient is currently in sleep stage 3 (indicated as "Yes" in step 1130), the controller 210 may in step 1140 set the operating parameters to values ​​suitable for controlling the drug delivery unit (DDU) 230 to deliver therapeutic drugs to the PD patient at a low flow rate. Then, in step 1120, the controller 210 delivers therapeutic drugs to the PD patient according to the values ​​set for the operating parameters in step 1140. However, if the controller 210 determines in step 1130 that the sleep stage in which the PD patient is currently in is not sleep stage 3 (a state indicated as "No" in step 1130), the controller 210 returns to step 1110 to determine the following values ​​for the operational parameters that can be used (in step 1120) to deliver therapeutic medication to the PD patient during other sleep stages (i.e., non-sleep stage 3).

[0103] Figure 12 shows a third configuration of a therapeutic drug delivery system (DDS) 1200 for treating disorders related to patients with Parkinson's disease (PD), for example, for sleep optimization, improvement of sleep quality and / or improvement of sleep disorders, according to yet another embodiment. The DDS 1200 includes the DDD 1210 and an operating parameter calculation system (OPCS).

[0104] In Figures 1 and 2, drug delivery systems 100 and 200 are local systems. That is, all parts of system 100 (e.g., the system's drug delivery devices and sleep monitoring system) are typically located in the same physical location within the PD patient's residence. Similarly, all parts of system 200 are typically located in the same physical location within the PD patient's residence. In contrast, DDS1200 proposes a means by which the calculation of drug delivery operation parameter values ​​can be performed anywhere. That is, even if appropriate sleep data is generated (e.g., by SMS or other physiological trackers worn by the PD patient, e.g., Fitbit, Whoop Band, Apple Watch, etc.), it is provided locally (e.g., within the PD patient's residence) and / or remotely (e.g., by a remote system or on a remote system), or in another way within the PD patient's residence (via a user interface). Examples of communication systems and methods that facilitate such network-based drug delivery schemes are described below.

[0105] The DDD1210 includes a controller 1212, a sleep monitoring system (SMS) 1214 for receiving sleep signals from one or more sleep sensors and optionally generating sleep data from those sleep signals for the controller 1212. The DDD1210 also includes a drug delivery unit (DDU) 1216 for delivering therapeutic drugs to PD patients 1218. The sleep monitoring system (SMS) 1214 may generally function in the same or similar manner as the SMS 120 (Figure 1) and / or the SMS 280 (Figure 2). The controller 1212 may control the DDU 1216 in the same or similar manner as the controller 150 controls the DDU 140 (Figure 1) and the controller 210 controls the DDU 230 (Figure 2).

[0106] The Operation Parameter Calculation System (OPCS) 1220 includes, for example, a communication interface (not shown in Figure 12) for receiving sleep data from the remote controller 1212 and exchanging commands and other types of data with the controller 1212 via the communication network 1230. The Operation Parameter Calculation System 1220 also includes an Operation Parameter Calculator (OPC) 1222 for calculating values ​​of the operation parameters of the controller 1212 based on the sleep data that the controller 1212 can transfer to the OPCS 1220 via the communication network 1230. The OPCS 1220 also includes a controller (not shown in Figure 12) for operating the OPC 1222 and controlling, for example, inbound and outbound data transfers via the communication network 1230. Inbound data includes, for example, a message notifying OPCS1220 that DDD1210 is ON and operational, sleep data originating from SMS1214, and requests for values ​​of DDD1210's operational parameters (e.g., for DDU1216). Outbound data includes, for example, a message from OPCS1220 acknowledging that DDD1210 is ON. Outbound data also includes values ​​of operational parameters requested by DDD1210.

[0107] An example of how to operate the DDS1200 is described below. The controller 1212 receives real-time sleep data from the SMS1214 or from the (local) user interface (UI) (UIs not shown in Figure 12 may function in the same or similar way as UI160 and / or UI240). Using the communication network 1230, the controller 1212 notifies the OPCS1220 that the DDD1210 is on and operational. The controller 1212 can also notify the OPCS1220 of its intention to transfer sleep data to the OPCS1220. The controller 1212 can then send the sleep data to the OPCS1220 for processing, such as calculating or determining the values ​​of the operational parameters for operating the DDU1216. The controller 1212 can send the sleep data to the OPCS1220 along with a request to the OPCS1220 to return the values ​​of the operational parameters that the controller 1212 can use to control the operation of the DDU1216.

[0108] OPCS1220 can receive notifications and requests from the controller (controller 1212) via the communication network 1230 and can receive sleep data via the communication network 1230. The operational parameter calculator (OPC) 1222 can calculate or determine the values ​​of operational parameters based on the sleep data. The OPCS1220 can then return the requested values ​​of the operational parameters to the controller 1212 via the communication network 1230. Upon receiving the requested values ​​for the drug delivery operational parameters, the controller 1212 can activate the DDU 1216 to deliver the therapeutic drug to the PD patient 1218 using the values ​​of these operational parameters.

[0109] The Operational Parameter Calculator (OPC) 1222 can calculate, or otherwise determine, values ​​for the operational parameters of the controller 1212 based, for example, on sleep data, but also based on a predetermined drug delivery flow control scheme (e.g., custom-made) suitable for a specific PD patient. For example, sleep data can provide information on the timing (e.g., onset time and duration) of various sleep events (e.g., onset time and duration of sleep stage 1 events, onset time and duration of REM sleep events, etc.), while the drug delivery flow control scheme can specify a desired drug flow rate for each of the various sleep events, which may be low or high, constant (for a certain period) or gradually changing (sometimes increasing and / or decreasing at other times).

[0110] Figures 4 through 11 (in all cases) described herein illustrate examples of drug delivery flow control schemes that OPCS1220 can use to calculate or otherwise determine the values ​​of operational parameters (other drug delivery flow control schemes useful for treating the target disease of a particular PD patient can be used in a similar manner). A patient-specific drug delivery flow control scheme for implementation by DDD1210 can be uploaded locally to OPCS1220, for example, by using a user interface (which is not shown in Figure 12). Alternatively, the scheme can be transferred to OPCS1220 from, for example, a sleep lab (or physician) 1240 via a communication network 1230. OPCS1220 can use the uploaded or transferred drug delivery flow control scheme against sleep data (for example, by comparison) to calculate or otherwise determine the appropriate values ​​of operational parameters for each sleep event. In some embodiments, the drug delivery flow control scheme is sent directly from the sleep lab (or physician) 1240 to the controller 1212 (not the OPCS 1220) to determine the values ​​of the operational parameters, for example, by using the drug delivery flow control scheme on sleep data (e.g., by comparison).

[0111] The communication network 1230 may be, for example, a wired network and / or a wireless communication network, or may include them. Examples of communication networks include the Internet, Wi-Fi networks, Bluetooth® networks, wireless LANs (local area networks), wireless WANs (wide area networks), wireless MANs (metropolitan area networks), and digital cellular networks (e.g., GSM). The operation parameter calculation system (OPCS) 1220 and the sleep lab 1240 may be, for example, wireless mobile devices, mobile phones (e.g., smartphones), personal digital assistants (PDAs), desktop computers, laptop computers, or include them, respectively. These include appropriate applications and execute appropriate algorithms.

[0112] According to some embodiments, the drug delivery control scheme is predetermined to treat (target) a specific disease in a particular PD patient and does not change throughout the sleep process. Coordinating the drug delivery pattern (DDP) with sleep events relevant to the PD patient, as described herein (e.g., shown in Figures 4, 5, and 6), is beneficial for treating the disease. Therefore, if the coordination between the DDP and sleep events is impaired at some point during treatment (e.g., during sleep), the treatment may not be optimal, even if it is performed. In other embodiments, the drug delivery control scheme (DDCS) is initially applied based on sleep data collected or generated in real time, and later modified in real time during the day or, for example, at night. If real-time sleep data indicates or shows an inconsistency between the currently used drug delivery pattern (DDP) and real-time sleep events, the DDCS may be modified in real time based on the real-time sleep data (i.e., the values ​​of the relevant operating parameters are adjusted) so that the DDP is readjusted to the actual sleep events and the general actual sleep pattern.

[0113] Sleep Lab 1240 includes, but is not limited to, personal computers, multiprocessor systems, microprocessor-based or programmable consumer electronics, network PCs, minicomputers, mainframe computers, handheld devices, tablets, iPads®, mobile phones, and smartphones such as iPhones and Android® phones. These can establish connections with DDD1210 and OPCS1220, for example, via network 1230 (and / or other communication networks), and can generally establish connections with any server and / or cloud-based application.

[0114] Figure 13 illustrates how, according to an embodiment, the drug delivery control scheme (DDCS) is adjusted in real time to readjust the drug delivery pattern (DDP) to the sleep event at that time. In step 1310, the controller (e.g., controllers 150, 210, or 1212) can clearly define the initial drug delivery control scheme (and thus the initial drug delivery pattern) by setting initial values ​​to the operating parameters of the drug delivery units (e.g., drug delivery units 140, 230, or 1216). The initial drug delivery control scheme (DDCS) can be configured to target a specific disease in a particular PD patient. For example, an initial DDCS that the controller can use may resemble DDCS520 (Figure 5).

[0115] In step 1320, the controller can apply the initial DDCS, and simultaneously, the sleep monitoring system (SMS) (e.g., SMS120, 280, or 1214) can monitor the sleep of the PD patient while the medication is being delivered to the PD patient by using the initial DDCS. The SMS generates sleep data corresponding to the monitored sleep, and the controller processes (e.g., analyzes, interprets) the sleep data to detect various sleep events in the sleep data, such as sleep stage 1 events, sleep stage 2 events, REM sleep events, and deep sleep events.

[0116] In step 1330, the controller can determine whether the initial DDCS is consistent with the detected sleep events, for example, by analyzing the initial DDCS for the detected sleep events. Referring again to Figure 5, it shows the DDCS 520 consistent with the various sleep stages of the sleep pattern 510. For example, each time a REM sleep event is detected, the drug flow level is high during the duration of the REM sleep event (e.g., L1 in Figure 5), and the drug flow level is low between REM sleep events (e.g., L2). Since sleep patterns can vary from PD patient to patient and from night to night, the drug flow, drug timing, and / or drug duration need to be adjusted to readjust the DDCS to the actual sleep pattern. Regardless of the drug delivery control scheme used by the controller, the controller rechecks the consistency between the selected DDCS and the sleep pattern, and if a mismatch is detected, the controller adjusts the operating parameters to readjust the DDCS to the sleep pattern.

[0117] Returning to step 1330, if the controller determines that the drug delivery control scheme (DDCS) is consistent with the actual sleep pattern (indicated as "Yes" in step 1330), this means that drug delivery will proceed as planned. The initial DDCS remains unchanged, and the patient's sleep continues to be monitored (step 1320). However, if the DDCS is not consistent with the actual sleep pattern, for example, if the controller detects a mismatch between the DDCS and the sleep pattern (indicated as "No" in step 1330), the controller may modify the DDCS by adjusting the values ​​of the operating parameters of the drug delivery unit (DDU) to more appropriate values. Then, or simultaneously, by continuing to monitor the patient's sleep structure (in step 1320), the controller may determine whether the DDCS requires further adjustments during the remainder of the sleep period.

[0118] The articles “a” and “an” are used herein, depending on the context, to refer to one or more (e.g., at least one) grammatical objects of the article. For example, depending on the context, “element” may mean one element or more elements. The term “includes” is used herein to mean the phrase “includes but not limited to” and is used interchangeably. The terms “or” and “and” are used herein to mean the terms “and / or” and are used interchangeably unless the context clearly indicates otherwise. The term “such as” is used herein to mean the phrase “e.g., but not limited to” and is used interchangeably.

[0119] Having described embodiments of the present invention in this manner, it will be apparent to those skilled in the art that modifications of the disclosed embodiments fall within the scope of the invention. Accordingly, alternative embodiments include functionally equivalent subjects / articles. Features of specific embodiments are used in conjunction with other embodiments shown herein. The disclosures of this application relate to various types of motor symptoms / disorders, non-motor symptoms / disorders, pumps, syringes, therapeutic drugs, infusion tubes / sets / lines, therapeutic drug dispensing devices, etc. (e.g., performed by, used with, or for). Accordingly, the following claims are not limited by the disclosures herein.

[0120] Various aspects and embodiments of the disclosure of this application will be further understood by referring to the following numbered clauses. 1. A method for operating a therapeutic drug delivery system for treating a disease related to Parkinson's disease (PD) in a patient who requires treatment for said disease, the method comprising: A therapeutic drug delivery system characterizes the temporal sleep patterns (CSPs) of PD patients, or receives sleep data including the temporal sleep patterns of PD patients, and determines values ​​for one or more operating parameters of the therapeutic drug delivery system based on the CSPs, and / or Receiving the above values ​​for one or more operating parameters of a therapeutic drug delivery system, and To deliver a therapeutic drug composition to a PD patient by operating a therapeutic drug delivery system according to the values ​​of the received operating parameters or according to the values ​​of the determined operating parameters. 2. The method according to Clause 1, wherein the disease related to PD is selected from the group consisting of Parkinsonian symptoms, motor complications, motor symptoms, non-motor symptoms, and sleep disorders. 3. The method according to Clause 1 or 2, wherein the values ​​determined for the operational parameters and the values ​​received for the operational parameters are optimized in terms of sleep optimization, improvement of sleep quality, improvement of sleep disorders, and improvement of Parkinsonian symptoms including tremors, shaking, slowing of movement (bradykinesia), muscle rigidity, postural instability, difficulty walking / stepping and dystonia; duration of sleep, time interval from bedtime to falling asleep, number of awakenings during sleep, rate of body movement during sleep, time interval from wakefulness to getting up, duration of "on" and "off" periods of Parkinsonian symptoms during wakefulness, duration of wakefulness during sleep, number of body rotations during sleep, average rate of body rotations during sleep, average time of body rotations, degree of body rotations, or any combination thereof. 4. The method according to any one of the preceding clauses, wherein the time-series sleep pattern (CSP) includes at least one of the following sleep events: sleep stage 1, sleep stage 2, sleep stage 3, rapid eye movement (REM) sleep, deep sleep stage, sleep cycle, wake time, sleep onset time and bedtime of a PD patient, and the first operating parameter is the flow rate of the therapeutic drug composition, and the second operating parameter is the drug delivery timing relative to the therapeutic drug flow rate. 5. The method according to any one of the preceding clauses, wherein operating a therapeutic drug delivery system includes delivering a therapeutic drug composition at a flow rate corresponding to delivering a low drug dose, a gradually decreasing drug dose, a high drug dose, a gradually increasing drug dose, a pulsating drug dose, or a continuous drug dose. 6. The method described in any one of the preceding clauses, wherein the values ​​received and determined for the operating parameters of the therapeutic drug delivery system clearly indicate a drug delivery pattern (DDP). 7. The method described in Clause 6, wherein the DDP corresponds to, conforms to, or originates from a temporal sleep pattern (CSP). 8. The method according to any one of the preceding clauses, wherein the sleep data includes data relating to the habitual bedtime, habitual sleep onset time, and habitual wake-up time of a PD patient, and the value of the operating parameter is determined based on one or more of the habitual bedtime, habitual sleep onset time, and / or habitual wake-up time. 9. The method of any one of the preceding clauses, wherein the sleep data includes past sleep data, the past sleep data includes at least past sleep onset data and past wake-up data, the value of the operating parameter is determined based on the past sleep data, and the past sleep data includes sleep data related to the PD patient and / or sleep data related to other PD patients. 10. The method described in any one of the preceding clauses, wherein the value of an operating parameter is user-set, pre-programmed, or determined based on the output signals of one or more sensors. 11. The method described in any one of the preceding clauses, wherein the disorder being treated is a sleep disorder, and the sleep disorder is selected from the group consisting of rapid eye movement sleep behavior disorder (RBD), REM sleep without atony (RWA), acting out dream content (DEB), nocturnal awakenings, insomnia (insomnia), difficulty falling asleep, daytime sleep, number of nighttime awakenings, sleep fragmentation, early morning dystonia, akinesia, nocturnal atony, sleep onset, sleep maintenance, sudden daytime sleep-attack episodes (narcolepsy), excessive daytime sleepiness (EDS), hallucinations, sleep-movement disorders, difficulty falling asleep, NREM stage III, REM sleep, sleep latency, awakenings after falling asleep, circadian rhythm disorders (circadian rhythm disorders, abnormal sleep-wake cycles), slow-wave sleep (SWS), and periodic leg movements during sleep (PLMS). 12. Generating sleep data by using a sleep monitoring system (SMS), a wearable sleep sensor, and / or an electronic patient sleep diary, as described in any one of the preceding clauses. 13. The method according to any one of the clauses 6 to 12, including generating sleep data and / or setting values ​​for operational parameters in real time, in accordance with the drug delivery pattern (DDP) applicable to PD patients. 14. The method according to any one of the preceding clauses, wherein the therapeutic drug composition comprises a compound for treating or improving a disease related to PD. 15. The method according to Clause 14, wherein the compound is selected from the group consisting of levodopa, levodopa salts, levodopa prodrugs, dopa decarboxylase inhibitors (DDIs), DDI salts, DDI prodrugs, catechol-O-methyltransferase (COMT) inhibitors, COMT inhibitor salts, COMT inhibitor prodrugs, and any combination thereof. 16. The method according to Clause 15, wherein the DDI, DDI salt, or DDI prodrug is selected from the group consisting of carbidopa, benzacerazide, difluoromethyldopa, α-methyldopa, their salts, their prodrugs, and any combination thereof. 17. The method according to Clause 15 or 16, wherein the dosage of each DDI is selected independently of other DDIs or active ingredients in the therapeutic drug. 18. The method according to any one of the clauses 15 to 17, wherein the DDI is selected from the group consisting of carbidopa, carbidopa salts, carbidopa prodrugs, and any combination thereof. 19. The method according to Clause 14, wherein the therapeutic drug composition comprises at least one of levodopa, levodopa salt, levodopa prodrug, or any combination thereof. 20. The method according to clause 15, wherein the COMT inhibitor is selected from the group consisting of entacapone, tolcapone, and any combination thereof. 21. The method according to Clause 20, wherein the dosage of each COMT inhibitor is selected independently of other COMT inhibitors or active ingredients in the therapeutic drug. 22. The method according to any one of the claims 14 to 21, wherein the therapeutic drug composition comprises levodopa and carbidopa. 23. The method according to any one of the claims 14 to 22, wherein the therapeutic drug composition comprises levodopa, carbidopa, and arginine. 24. The method according to any one of the claims 14 to 23, wherein the therapeutic drug composition comprises about 4 w / v% to about 8 w / v% levodopa, about 0.5 w / v% to about 1.0 w / v% carbidopa, and about 12 w / v% to about 17 w / v% arginine. 25. The method according to any one of the claims 14 to 21, wherein the therapeutic drug composition comprises a levodopa prodrug. 26. The method according to Clause 25, wherein the levodopa prodrug is a levodopa-tyrosine conjugate. 27. The method according to any one of the claims 24 to 26, wherein the therapeutic drug composition further comprises carbidopa. 28. The method according to any one of the claims 24 to 27, wherein the therapeutic drug composition further comprises arginine. 29. The method according to any one of the claims 24 to 28, wherein the therapeutic drug composition comprises about 20 (w / v%) to about 50 (w / v%) of levodopa-tyrosine conjugate and about 0.5 (w / v%) to about 1.5 (w / v%) of carbidopa. 30. The method according to any one of the claims 14 to 29, wherein the therapeutic drug composition comprises levodopa, carbidopa, and entacapone. 31. The method according to clause 30, wherein the therapeutic drug composition further comprises arginine. 32. The method according to any one of the claims 14 to 29, wherein the therapeutic drug composition comprises a levodopa prodrug, carbidopa, and entacapone. 33. The method according to Clause 32, wherein the therapeutic drug composition further comprises arginine. 34. The method according to Clause 32, wherein the levodopa prodrug is a levodopa-tyrosine conjugate. 35. The method according to any one of the claims 24 to 34, wherein the therapeutic drug composition is substantially liquid at room temperature. 36. The method according to Clause 4, further comprising identifying REM sleep events in a temporal sleep pattern (CSP) and adjusting the values ​​of operational parameters to deliver a therapeutic drug at a high flow rate during REM sleep events. 37. The method according to Clause 4, further comprising identifying sleep cycles in a time-series sleep pattern (CSP) and adjusting the values ​​of operational parameters to deliver a therapeutic drug at a high flow rate after n sleep cycles (n=1, 2, ...) have been achieved. 38. The method according to Clause 4, comprising adjusting the values ​​of operating parameters to deliver a therapeutic drug at a low flow rate during deep sleep stages. 39. The method according to Clause 7, wherein the values ​​of the operational parameters are adjusted in real time to readjust the drug delivery pattern (DDP) to sleep events included in the time-series sleep pattern (CSP). 40. The method described in any one of the preceding clauses, wherein the values ​​of the operational parameters are adjusted using machine learning. 41. A method for treating a patient suffering from Parkinson's disease (PD) by a therapeutic drug delivery system, A therapeutic drug delivery system characterizes the time-series sleep patterns (CSPs) of PD patients, or receives sleep data including the time-series sleep patterns of PD patients, and / or determines values ​​for one or more operating parameters of the therapeutic drug delivery system based on the time-series sleep patterns. Receiving values ​​for one or more operating parameters of a therapeutic drug delivery system, and To deliver therapeutic compounds to PD patients by operating the therapeutic drug delivery system according to the values ​​of the received operating parameters and / or the determined values ​​of the operating parameters. A method that includes this. 42. The method according to Clause 41, wherein the compound is selected from the group consisting of levodopa, levodopa salts, levodopa prodrugs, dopa decarboxylase inhibitors (DDIs), DDI salts, DDI prodrugs, catechol-O-methyltransferase (COMT) inhibitors, COMT inhibitor salts, COMT inhibitor prodrugs, and any combination thereof. 43. The method according to Clause 42, wherein the DDI, DDI salt, or DDI prodrug is selected from the group consisting of carbidopa, benzacerazide, difluoromethyldopa, α-methyldopa, their salts, their prodrugs, and any combination thereof. 44. The method according to Clause 42 or 43, wherein the dosage of each DDI is selected independently of other DDIs or active ingredients in the therapeutic drug. 45. The method according to any one of the clauses 42 to 44, wherein the DDI is selected from the group consisting of carbidopa, carbidopa salts, carbidopa prodrugs, and any combination thereof. 46. ​​The method according to clause 41, wherein the compound is selected from the group consisting of levodopa, levodopa salts, levodopa prodrugs, or any combination thereof. 47. The method according to clause 42, wherein the COMT inhibitor is selected from entacapone, tolcapone, and any combination thereof. 48. The method according to Clause 47, wherein the dosage of each COMT inhibitor is selected independently of other COMT inhibitors or active ingredients in the compound. 49. A drug delivery system for treating diseases related to patients with Parkinson's disease (PD) (Figure 1, 100; Figure 2, 200; Figure 12, 1200), A sleep data acquisition unit (SDCU) for collecting and / or storing sleep data related to PD patients and / or sleep data related to other PD patients, A drug delivery unit (140, 230) includes a drug reservoir (142, 232) for containing a therapeutic drug composition and a distribution mechanism (144, 234) for distributing the therapeutic drug composition from the drug reservoir to the patient, (i) receiving and / or determining values ​​obtained from sleep data for one or more drug delivery operation parameters of the distribution mechanism, and (ii) Controllers (150, 210) configured to operate the distribution mechanism to deliver a therapeutic drug composition to a PD patient according to a value received or determined for one or more operating parameters. A pharmaceutical delivery system including... 50. The system described in Clause 49, wherein the disease to be treated is selected from the group consisting of Parkinsonian symptoms, motor complications, motor symptoms, non-motor symptoms, and sleep disorders. 51. The system described in Clause 49 or 50, in which the values ​​determined for the operational parameters and the values ​​received for the operational parameters are optimized in terms of sleep optimization, improvement of sleep quality, improvement of sleep disorders, and improvement of Parkinsonian symptoms including tremors, shaking, slowing of movement (bradykinesia), muscle rigidity, postural instability, difficulty walking / stepping and dystonia; duration of sleep, time interval from bedtime to sleep onset, number of awakenings during sleep, rate of body movement during sleep, time interval from wakefulness to getting up, duration of Parkinson's "on" and "off" periods during wakefulness, duration of wakefulness during sleep, number of body rotations during sleep, average rate of body rotations during sleep, average duration of body rotations, degree of body rotation, or any combination thereof. 52. A system in which a sleep data acquisition unit (SDCU) is configured by a configuration selected from at least one of the following configurations: I. Whether the SDCU is a sleep monitoring system (SMS) (120, 280) or a first configuration including a sleep monitoring system (SMS), the SMS is: a. A set of n sensors (n=1, 2, 3, ...) configured to generate signals that are individually or collectively related to the sleep state and / or activity level of PD patients, The system has sensor interfaces (132, 260) connected to the n sensors in order to receive signals generated by bn sensors and convert the above signals into sleep data, and II. A second configuration in which the SDCU has a user interface (160, 240) for manually uploading sleep data and / or a communication interface (180) for remotely uploading sleep data. A system as described in clause 49, which has the following characteristics. 53. The controller, (i) Detect the patient's temporal sleep pattern (CSP) from sleep data, and (ii) Delivering the therapeutic drug composition to the patient in a drug delivery pattern that corresponds to, conforms to, or originates from CSP. The system described in Clause 49 is configured as follows. 54. The system according to Clause 52, wherein at least one of the n sensors is wearable by the user or can be attached to the patient. 55. The system according to Clause 52, wherein n sensors are selected from the group consisting of electrodes, neural activity sensors, EEG sensors, ECG sensors, EMG sensors, polysomnography (PSG) sensors, sleep sensors, sleep state sensors, local electric field potential sensors, accelerometers, watches configured to detect movement during sleep, optical sensors, cameras, and any combination thereof. 56. The system described in Clause 52, wherein the drug delivery system (200) includes a sensor interface (260). 57. The system according to Clause 52, wherein one or more operating parameters of the distribution mechanism are user-configurable or pre-programmable by a user interface (160, 240). 58. The system according to Clause 49, wherein the distribution mechanism is configured to deliver a therapeutic drug composition to a PD patient by using an intestinal, subcutaneous, intravenous (IV), cutaneous, or cerebrospinal fluid (CSF) pump. 59. The system described in Clause 53, in which the chronological sleep pattern (CSP) includes one or more of the following sleep events: sleep stage 1, sleep stage 2, sleep stage 3, rapid eye movement (REM) sleep, deep sleep stage, sleep cycle, wake time, sleep onset time, and bedtime for PD patients. 60. The system according to Clause 49, wherein the operating parameters include a first operating parameter which is the flow rate of the therapeutic drug composition or is related to the flow rate of the therapeutic drug composition, and a second operating parameter which is the drug delivery timing of the therapeutic drug composition or is related to the drug delivery timing. 61. The system described in Clause 52, wherein the sleep data acquisition unit (SDCU) is configured to collect data selected from the group consisting of upper limb (hand) movement, lower limb (leg) movement, head movement, hip movement, heart rate, respiratory rate, electromyography (EMG) signal, electrocardiogram (ECG) signal, electroencephalogram (EEG) signal, electrical potential signal, blood oxygen saturation level, skin conductivity, and chest movement via n sensors. 62. The system according to Clause 59, wherein the controller is configured to adjust the values ​​of operating parameters to deliver a therapeutic drug composition at a high flow rate during a REM sleep event. 63. The system according to Clause 59, wherein the controller is configured to adjust the values ​​of operating parameters to deliver a therapeutic drug composition at a low flow rate during a deep sleep event. 64. The system according to Clause 59, wherein the controller is configured to identify sleep cycles in sleep data or sleep patterns over time (CSP) and adjust the values ​​of operating parameters to deliver a therapeutic drug composition at a high flow rate after n sleep cycles have been achieved. 65. The system according to Clause 49, wherein the controller is configured to deliver a therapeutic drug composition at a flow rate corresponding to an item selected from the group consisting of delivering a low drug dose, delivering a gradually decreasing drug dose, delivering a high drug dose, delivering a gradually increasing drug dose, delivering a pulsating drug dose, and delivering a continuous drug dose. 66. The controller is configured to adjust the values ​​of operational parameters in real time to (re)adjust the drug delivery pattern (DDP) to sleep events included in the time-series sleep pattern (CSP), as described in Clause 49. 67. The system described in Clause 49, in which the controller is configured to adjust the values ​​of the operational parameters by using machine learning. 68. Sleep disorders are selected from the group consisting of rapid eye movement sleep behavior disorder (RBD), REM sleep without atony (RWA), acting out dream content (DEB), nocturnal awakenings, insomnia, difficulty falling asleep, daytime sleep, number of nighttime awakenings, sleep fragmentation, early morning dystonia, akinesia, nocturnal atony, sleep onset, sleep maintenance, sudden daytime sleep-attack episodes (narcolepsy), excessive daytime sleepiness (EDS), hallucinations, sleep-movement disorders, difficulty falling asleep, NREM stage III, REM sleep, sleep latency, awakenings after falling asleep, circadian rhythm disorders (circadian rhythm disorders, abnormal sleep-wake cycles), slow-wave sleep (SWS), and periodic leg movements during sleep (PLMS), as described in Clause 50. 69. The system according to Clause 50, wherein the therapeutic drug composition comprises a compound for treating or improving a disease related to PD patients. 70. The system according to Clause 69, wherein the compound is selected from the group consisting of levodopa, levodopa salts, levodopa prodrugs, dopa decarboxylase inhibitors (DDIs), DDI salts, DDI prodrugs, catechol-O-methyltransferase (COMT) inhibitors, COMT inhibitor salts, COMT inhibitor prodrugs, and any combination thereof. 71. The system according to Clause 70, wherein the DDI, DDI salt, or DDI prodrug is selected from the group consisting of carbidopa, benzacerazide, difluoromethyldopa, α-methyldopa, their salts, their prodrugs, and any combination thereof. 72. The system according to Clause 70 or 71, wherein the dosage of each DDI is selected independently of other DDIs or active ingredients in the therapeutic drug composition. 73. A system according to any one of clauses 70 to 72, wherein the DDI is selected from the group consisting of carbidopa, carbidopa salts, carbidopa prodrugs, and any combination thereof. 74. The system according to Clause 69, wherein the compound is selected from the group consisting of levodopa, levodopa salts, levodopa prodrugs, or any combination thereof. 75. The system according to Clause 70, wherein the COMT inhibitor is selected from the group consisting of entacapone, tolcapone, and any combination thereof. 76. The system according to Clause 75, wherein the dosage of each COMT inhibitor is selected independently of other COMT inhibitors or active ingredients in the therapeutic drug composition. 77. A system according to any one of the clauses 69 to 76, wherein the therapeutic drug composition comprises levodopa and carbidopa. 78. A system according to any one of the clauses 69 to 77, wherein the therapeutic drug composition comprises levodopa, carbidopa, and arginine. 79. The system according to any one of the clauses 69 to 78, wherein the therapeutic drug composition comprises about 4 (w / v%) to about 8 (w / v%) of levodopa, about 0.5 (w / v%) to about 1.0 (w / v%) of carbidopa, and about 12 (w / v%) to about 17 (w / v%) of arginine. 80. A system according to any one of the clauses 69 to 76, wherein the therapeutic drug composition comprises a levodopa prodrug. 81. The system according to Clause 80, wherein the levodopa prodrug is a levodopa-tyrosine conjugate. 82. A system according to any one of the clauses 79 to 81, wherein the therapeutic drug product further comprises carbidopa. 83. The system according to any one of the clauses 79 to 82, wherein the therapeutic drug composition further comprises arginine. 84. The system according to any one of the clauses 79 to 83, wherein the therapeutic drug composition comprises about 20 (w / v) to about 50 (w / v) levodopa tyrosine conjugate and about 0.5 (w / v) to about 1.5 (w / v) carbidopa. 85. A system according to any one of the clauses 69 to 84, wherein the therapeutic drug composition comprises levodopa, carbidopa, and entacapone. 86. The system according to Clause 85, wherein the therapeutic drug composition further comprises arginine. 87. A system according to any one of the clauses 69 to 84, wherein the therapeutic drug composition comprises a levodopa prodrug, carbidopa, and entacapone. 88. The system according to Clause 87, wherein the therapeutic drug composition further comprises arginine. 89. The system described in Clause 87, wherein the levodopa prodrug is a levodopa tyrosine conjugate. 90. The system according to any one of the clauses 69 to 89, wherein the therapeutic drug composition is substantially liquid at room temperature.

Claims

1. A drug delivery system (100 in FIG. 1 , 200 in FIG. 2 , 1200 in FIG. 12 ) for treating a disease associated with Parkinson's disease (PD) in a patient, comprising: a sleep data collection unit (SDCU) for collecting and / or storing sleep data related to the PD patient and / or sleep data related to other PD patients; a drug delivery unit (140, 230) including a drug reservoir (142, 232) for containing a therapeutic pharmaceutical composition and a dispensing mechanism (144, 234) for dispensing the therapeutic pharmaceutical composition from the drug reservoir to a patient; (i) receiving and / or determining values ​​derived from the sleep data for one or more drug delivery operating parameters of the dispensing mechanism; and (ii) a controller (150, 210) configured to operate the dispensing mechanism to deliver a therapeutic pharmaceutical composition to a PD patient according to received or determined values ​​for one or more operating parameters; A pharmaceutical delivery system, wherein the determined values ​​for the operating parameters and the received values ​​for the operating parameters are optimized in terms of at least one of optimizing sleep, improving sleep quality, and ameliorating sleep disorders.

2. 2. The system of claim 1, wherein the determined and received values ​​for the operating parameters are further optimized in terms of improvement of Parkinsonian symptoms including tremors, shaking, slowness of movement (bradykinesia), muscle rigidity, postural instability, difficulty walking / gait and dystonia; sleep duration, time interval between falling asleep and falling asleep, number of awakenings during sleep, speed of body movements during sleep, time interval between awakening and waking up, duration of Parkinson's "on" and "off" times during wakefulness, time awake during sleep, number of body rotations during sleep, average speed of body rotations during sleep, average time of body rotation, degree of body rotation, or any combination thereof.

3. A system in which a sleep data collection unit (SDCU) is configured according to at least one of the following configurations: I. A first configuration in which the SDCU is or includes a sleep monitoring system (SMS) (120, 280), the SMS comprising: a. n sensors (n=1, 2, 3, ...) configured to generate signals individually or collectively related to a sleep state and / or activity of a PD patient; and b. having a sensor interface (132, 260) connected to the n sensors for receiving signals generated by the n sensors and converting said signals into sleep data; and II. A second configuration in which the SDCU has a user interface (160, 240) for manually uploading the sleep data and / or a communication interface (180) for remotely uploading the sleep data. The system of claim 1 , comprising:

4. The controller (iii) detecting a chronic sleep pattern (CSP) of the patient from the sleep data; and (iV) delivering a therapeutic pharmaceutical composition to a patient in a drug delivery pattern (DDP) that corresponds to, matches, or is derived from the CSP; The system of claim 1 , configured as follows:

5. 4. The system of claim 3, wherein at least one of the n sensors is user wearable or otherwise attachable to the patient and / or the n sensors are selected from the group consisting of electrodes, neural activity sensors, EEG sensors, ECG sensors, EMG sensors, polysomnography (PSG) sensors, sleep sensors, sleep state sensors, local field potential sensors, accelerometers, wristwatches configured to detect movement during sleep, optical sensors, cameras, and any combination thereof.

6. 5. The system of claim 4, wherein the longitudinal sleep pattern (CSP) includes one or more of the following sleep events: sleep stage 1, sleep stage 2, sleep stage 3, rapid eye movement (REM) sleep, deep sleep stages, sleep cycles, wake up times, sleep onset times and bedtimes of the PD patient.

7. 2. The system of claim 1, wherein the operational parameters include a first operational parameter that is or is related to a flow rate of the therapeutic pharmaceutical composition and a second operational parameter that is or is related to a drug delivery timing of the therapeutic pharmaceutical composition.

8. 4. The system of claim 3, wherein the sleep data collection unit (SDCU) is configured to collect, via n sensors, data selected from the group consisting of: an upper limb (hand) movement representative, a lower limb (leg) movement representative, a head movement representative, a hip movement representative, a heart rate, a respiratory rate, an electromyogram (EMG) signal, an electrocardiogram (ECG) signal, an electroencephalogram (EEG) signal, an electrical potential signal, a blood oxygen saturation level, a skin conductance, and a chest movement.

9. 7. The system of claim 6, wherein the controller is configured to adjust values ​​of the operational parameters to deliver the therapeutic pharmaceutical composition at a high flow rate during REM sleep events, or the controller is configured to adjust values ​​of the operational parameters to deliver the therapeutic pharmaceutical composition at a low flow rate during deep sleep events, or the controller is configured to identify sleep cycles in the sleep data or temporal sleep patterns (CSPs) and adjust values ​​of the operational parameters to deliver the therapeutic pharmaceutical composition at a high flow rate after n sleep cycles have been achieved.

10. 10. The system of claim 1, wherein the controller is configured to deliver the therapeutic pharmaceutical composition at a flow rate corresponding to an item selected from the group consisting of delivering a low pharmaceutical dose, delivering a tapered pharmaceutical dose, delivering a high pharmaceutical dose, delivering a tapered pharmaceutical dose, delivering a pulsatile pharmaceutical dose, and delivering a continuous pharmaceutical dose.

11. 7. The system of claim 6, wherein the controller is configured to adjust values ​​of operational parameters in real time to (re)adjust the drug delivery pattern (DDP) to sleep events comprised in the chronic sleep pattern (CSP), and optionally the controller is configured to adjust values ​​of the operational parameters by using machine learning.

12. 2. The system of claim 1, wherein the sleep disorder is selected from the group consisting of Parkinson's symptoms, motor complications, motor symptoms, non-motor symptoms, and sleep disorders, and optionally the sleep disorder is selected from the group consisting of rapid eye movement sleep behavior disorder (RBD), REM sleep without atony (RWA), acting out dream content (DEB), nocturnal awakenings, insomnia (insomnia), insomnia to fall asleep, daytime sleep, nocturnal awakenings, sleep fragmentation, early morning dystonia, akinesia, nocturnal atony, sleep onset, sleep maintenance, sudden daytime sleep attack episodes (narcolepsy), excessive daytime sleepiness (EDS), hallucinations, movement disorders during sleep, difficulty falling asleep, NREM stage III, REM sleep, sleep onset latency, awakening after sleep onset, circadian rhythm disorder (circadian rhythm disorder, abnormal sleep-wake cycles), slow wave sleep (SWS), periodic leg movements during sleep (PLMS).

13. The therapeutic pharmaceutical composition comprises a compound for treating or ameliorating a disease associated with PD patients, and optionally the compound is selected from the group consisting of levodopa, a levodopa salt, a levodopa prodrug, a dopa decarboxylase inhibitor (DDI), a DDI salt, a DDI prodrug, a catechol-O-methyltransferase (COMT) inhibitor, a COMT inhibitor salt, a COMT inhibitor prodrug, and any combination thereof, and optionally the DDI, DDI salt, or DDI prodrug is selected from the group consisting of carbidopa, benzase serotonin, difluoromethyldopa, α-methyldopa, a salt thereof, a prodrug thereof, and any combination thereof; optionally, the dosage of each DDI is selected independently of other DDIs or active ingredients in the therapeutic pharmaceutical composition; optionally, the DDI is selected from the group consisting of carbidopa, a carbidopa salt, a carbidopa prodrug, and any combination thereof; optionally, the compound is selected from the group consisting of levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and optionally, the COMT inhibitor is entacapo and any combination thereof, optionally wherein the dosage of each COMT inhibitor is selected independently of other COMT inhibitors or active ingredients in the therapeutic pharmaceutical composition; optionally wherein the therapeutic pharmaceutical composition comprises levodopa and carbidopa; optionally wherein the therapeutic pharmaceutical composition comprises levodopa, carbidopa and arginine; optionally wherein the therapeutic pharmaceutical composition comprises about 4 (w / v%) to about 8 (w / v%) levodopa, about 0.5 (w / v%) to about 1.0 (w / v%) carbidopa and about 12 (w / v%) to about 17 (w / v%) arginine. (w / v%) arginine, optionally the therapeutic pharmaceutical composition comprises a levodopa prodrug, optionally the levodopa prodrug is a levodopa-tyrosine conjugate, optionally the therapeutic pharmaceutical composition further comprises carbidopa, optionally the therapeutic pharmaceutical composition further comprises arginine, optionally the therapeutic pharmaceutical composition comprises about 20 (w / v%) to about 50 (w / v%) levodopa tyrosine conjugate, and about 0.5 (w / v%) to about 1.5 (w / v%) carbidopa, optionally the therapeutic pharmaceutical composition comprises levodopa,2. The system of claim 1, wherein the therapeutic pharmaceutical composition comprises a levodopa prodrug, carbidopa, and entacapone, and optionally the therapeutic pharmaceutical composition is substantially liquid at room temperature.

14. the sleep data comprises data relating to the PD patient's habitual bedtime, habitual sleep onset time and habitual wake-up time, and the value of the operating parameter is determined based on one or more of the habitual bedtime, habitual sleep onset time and / or habitual wake-up time; and / or 2. The system of claim 1, wherein the sleep data includes past sleep data, the past sleep data including at least past sleep onset data and past wake up data, and the value of the operating parameter is determined based on the past sleep data, the past sleep data including sleep data related to the PD patient and / or sleep data related to other PD patients.

15. the controller is configured to identify REM sleep events in the chronic sleep pattern (CSP) and adjust values ​​of the operating parameters to deliver a high flow rate of the therapeutic pharmaceutical agent during the REM sleep events; and / or the controller is configured to identify sleep cycles in a chronic sleep pattern (CSP) and adjust values ​​of operational parameters to deliver the therapeutic drug at a high flow rate after n sleep cycles (n=1, 2, ...) have been achieved; and / or The system of claim 6 , wherein the controller is configured to adjust values ​​of the operational parameters to deliver the therapeutic pharmaceutical agent at a lower flow rate during deep sleep stages.

16. The SDCU and controller are configured to detect and distinguish between neutral sleep stages that do not substantially contribute to the patient's overall sleep quality and sleep promoting sleep stages that substantially contribute to the patient's overall sleep quality; and 10. The system of claim 1, wherein the controller is configured to operate the dispensing mechanism to deliver therapeutic medication to the PD patient at a high flow rate during a neutral sleep stage and at a low flow rate during a sleep-promoting sleep stage.

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