Inhaler for electronically monitoring the parenteral administration of a pharmaceutical composition

Abstract

An inhaler (400) for electronically supervised parenteral administration of a dry powder pharmaceutical composition, comprising: a storage device (410) for the pharmaceutical composition in dry powder form; an administration device (411) for administering the pharmaceutical composition; a memory (404) and a processing device (402); a communication device (401); a controlled blocking device (403) for preventing the administration of the pharmaceutical composition, wherein the inhaler (400) is adapted to receive data corresponding to an administration schedule (11), determine whether there is a mobile device (300) assigned an authorization token, and control the controlled blocking device (403) to effect administration of the pharmaceutical composition only in accordance with the administration schedule (11) in the presence of a mobile device (300) assigned an authorization token (12).

Description

[0001] This application relates to an inhaler for electronically supervised parenteral administration of a pharmaceutical composition, and more particularly to an inhaler for restricting the abuse and misuse of a dry powder pharmaceutical composition containing ketamine for the treatment of depression.

[0002] Depression, especially major depressive disorder, bipolar disorder, and treatment-resistant depression (TRD), is a serious problem in modern society. Many treatment options for depression have been developed, including monotherapy or combination therapy with convenient oral administration regimens for patients. However, a relatively high percentage of patients are refractory or partially or completely treatment-resistant to existing antidepressants. In practice, the only real option in such severe cases may currently be electroconvulsive therapy.

[0003] Ketamine is a known anesthetic and analgesic used in anesthesia and the treatment of chronic pain. Ketamine is a chiral compound and can exist as a racemate and the S-enantiomer (known as esketamine) or the R-enantiomer (known as arketamine). Ketamine can form pharmaceutically acceptable salts and is commonly used as the preferred hydrochloride salt in pharmaceutical applications. The specific rotation of the enantiomers varies in ketamine and its salts. For example, while esketamine free base is dextrorotatory S-(+), esketamine hydrochloride is levorotatory S-(-).

[0004] For about a decade, the antidepressant activity of ketamine and its S-isomer (esketamine) has been explored, especially in the treatment of treatment-resistant or refractory depression (G. Serafini et al., The Role of Ketamine in Treatment-Resistant Depression: A Systematic Review., Current Neuropharmacology, 2014, 12, 444 - 461). Treatment-resistant depression is a term used in clinical psychiatry to describe cases of major depressive disorder that do not respond adequately to an appropriate course of at least two antidepressants at appropriate times and doses.

[0005] The data collected so far indicate the excellent performance of ketamine and esketamine. The onset of action is very fast (after 2 - 3 hours of administration) and the duration is relatively long - for several days after a single-dose regimen. The rapidity of clinical efficacy is surprisingly high and unexpected, as the efficacy of existing antidepressants on the market appears only after daily administration for at least two weeks, or even three to four weeks. Therefore, ketamine or esketamine can be used as a first-choice drug for patients with severe depression at increased risk of suicide who are resistant to existing oral antidepressants. The proportion of efficacy is also very high; approximately 2 / 3 of patients with treatment-resistant depression respond to ketamine treatment.

[0006] The understanding of the pharmacology of ketamine is still poor. As a dissociative anesthetic, the drug may produce dissociative and psychomimetic effects (DP). Existing data suggest that such effects are related to the systemic concentration of the drug. Dissociative and psychomimetic effects are among the most commonly observed side effects and significantly reduce patient comfort. However, there are still some patients who respond to treatment with ketamine without experiencing DP effects. Therefore, there is still a therapeutic window for the effective and safe use of ketamine in the treatment of depression without DP, although it is narrow.

[0007] Ketamine undergoes extensive first-pass metabolism in the liver. First, norketamine is produced as the initial metabolite. Then norketamine is metabolized into other metabolites. The understanding of norketamine and other metabolites is still incomplete. At the level of acting on NMDA receptors, the activity of norketamine is many times lower than that of ketamine. The activities of other metabolites are also mostly lower than that of ketamine. In addition, little is known about the toxicity of norketamine and other metabolites. Combined with the high individual differences in their concentrations depending on the hepatic enzyme status, this usually makes them unwanted compounds. There are also reports that some hydroxylated metabolites of ketamine are related to psychiatric and dissociative symptoms.

[0008] In previous studies, ketamine and esketamine were administered intravenously or intranasally in the treatment of depression. Attempts at oral administration were usually unsuccessful or only efficacy was observed after several weeks of administration.

[0009] The literature documents many examples of the pharmacokinetics of ketamine depending on the administration route.

[0010] The administration route with the lowest metabolite levels currently expected is intravenous administration. After intravenous infusion of racemic ketamine at 0.5 mg / kg for 40 minutes, the parent drug maintains its systemic concentration at about 200 ng / ml for about 40 minutes, after which the concentration rapidly decreases and its half-life is less than 2 hours. At the same time, norketamine reaches its maximum concentration at 10 - 20% of the ketamine concentration level. The percentage of the area under the curve (AUC) of norketamine to ketamine is about 20 - 40%.

[0011] Oral administration is the administration route at which the maximum concentration of metabolites is reached after administration. However, after oral administration, the drug is rapidly metabolized into norketamine. The level of norketamine is equal to 500 - 1000% of the ketamine level. The area under the curve (AUC) of norketamine is even higher, exceeding 1000%.

[0012] The bioavailability of orally administered ketamine is very low (about 16 - 20%); although intravenous administration results in a significant increase in ketamine bioavailability, it also has many drawbacks (such as long infusion times, patient discomfort, and the need for monitoring).

[0013] US2007 / 0287753A1 discloses the use of ketamine for the treatment of treatment - resistant or refractory depression. The only tested formulation is intravenous infusion, and transdermal administration is also considered. Intranasal administration is only generally described, including intranasal administration of a dry powder aerosol formulation containing subdivided powder of ketamine, a dispersant, and a filler. However, by intranasally administering ketamine to the oropharyngeal region, a large amount of ketamine will be swallowed by the patient via the oral route and can be metabolized systemically to norketamine, thereby causing unwanted side effects.

[0014] DE102007009888 discloses the use of S - ketamine in the treatment of depression at a dose of 0.3 to 1.0 mg / kg. Although all possible administration routes are generally mentioned, the only tested formulation is intravenous infusion, which is mentioned as the preferred administration route.

[0015] WO2013 / 138322 discloses the use of esketamine in the treatment of refractory or treatment - resistant depression. The efficacy test of esketamine is described in a predictive example with an esketamine intravenous infusion.

[0016] WO2014 / 143646 and WO2014 / 152196 disclose pharmaceutical compositions of esketamine in the form of an aqueous formulation of esketamine hydrochloride for the treatment of refractory or treatment - resistant depression, preferably for nasal administration.

[0017] The mucoadhesive oral form of esketamine and the pharmacokinetics of esketamine after oral, intranasal, and intravenous administration are described in WO2014 / 020155.

[0018] K. Jonkman et al., Anesthesiology 127(4), 675 - 683, 10, 2017, studied the safety and feasibility of delivering ketamine via inhalation of an aerosolized esketamine hydrochloride salt solution as a new ketamine administration route in healthy volunteers. It has been found that the bioavailability of inhaled ketamine is reduced due to dose - independent and dose - dependent impairment of pulmonary uptake. This is related to the high viscosity of esketamine; the viscosity of esketamine is three to four times higher than that of water. Therefore, administration by nebulization would be imprecise and unreliable.

[0019] Singh et al., Biological Psychiatry 80:424-413, 2016, observed a rapid and potent antidepressant effect in patients with treatment-resistant depression (TRD) following a 40-minute intravenous infusion of 0.20 mg / kg or 0.40 mg / kg esketamine. The lower dose may have better tolerability while maintaining efficacy.

[0020] The foregoing illustrates the absolute medical need and importance of developing high-dose ketamine formulations that are both highly effective and convenient for daily self-administration by patients (including self-administration in an outpatient setting) to ensure high patient compliance. Such formulations should first deliver a therapeutic dose of ketamine to the bloodstream and should be characterized by high efficacy, including rapid therapeutic effects due to precise administration and a low risk of unwanted effects such as DP. Such formulations should permit only minimal levels of systemic first-pass metabolites (such as norketamine and hydroxylated metabolites), especially ensuring an acceptable ratio of (es)ketamine to (es)norketamine, both to avoid reducing the level of ketamine actually administered and the impact of unwanted metabolites.

[0021] The goal is to achieve a similar ketamine plasma concentration and a similar antidepressant effect as that of Singh et al. with a 40-minute intravenous infusion of 0.20 mg / kg using an administration route that is more convenient for the patient and produces fewer side effects.

[0022] The above problems have been solved by the present invention, which provides a high-dose and stable dry powder ketamine pharmaceutical composition for treating depression by a pulmonary administration route in a reliable, reproducible, and convenient manner.

[0023] However, in medicine, due to a wide range of medical conditions, it is often necessary to control and / or monitor the correct intake of drugs, such as drugs and medicines commonly prescribed for conditions involving the nervous system, especially the brain, peripheral nerves, and spinal cord. Within this scope, there are drugs and medicines described and classified by the FDA (U.S. Food and Drug Administration) as neurology drugs and nervous system drugs, including drugs for pain relief purposes (such as opioids), and strict control and monitoring of their associated effects are required. Regarding drugs for pain relief purposes, such as opioids, four subcategories will be mentioned in this document: opiates, semi-synthetic opioids, synthetic opioids, and endogenous opioids.

[0024] The above-mentioned drugs and medications can be widely applied to different types of patient conditions, including but not limited to post-surgery, cancer treatment, and brain and nervous system conditions, such as: Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), carpal tunnel syndrome, Huntington's disease, dementia, memory loss, multiple sclerosis, muscular dystrophy, Parkinson's disease, Tourette syndrome, etc. All of these require careful compliance with the relevant prescriptions and their effects.

[0025] The list of FDA-approved drugs for neurology and the nervous system includes various types of such drugs, which should be prescribed to patients by their doctors as these drugs are considered "prescription drugs" or "prescription potent drugs", and they include:

[0026] Opioid drugs, as opioid painkillers, such as methadone, morphine, oxycodone (OxyContin), fentanyl, sufentanil, levorphanol, oxymorphone, hydromorphone, meperidine (Demerol), and tramadol, and any of their chemical variants or combinations;

[0027] Drugs that can be used together with opioid painkillers. These drugs are usually prescribed for their pain-relieving properties in treating the symptoms of patients, or they are specifically prescribed for certain types of pain. These drugs include but are not limited to: bisphosphonates (such as dexamethasone and prednisone), anti-inflammatory drugs and corticosteroids, local anesthetics (such as lidocaine and capsaicin to relieve pain in the skin and surrounding tissues), anticonvulsants, antidepressants, and other drugs designed to have similar effects. The above-mentioned drugs are administered to patients in various ways according to the specific conditions of each patient and are usually administered orally. Although in some cases, such as when a patient may have difficulty swallowing capsules or has related problems, these types of drugs may be ingested in several other ways, including in cases where faster pain relief is needed.

[0028] Generally, these drugs have the following common intake methods: Oral: such as pills, capsules, tablets, liquids, and drugs that dissolve on or under the tongue, as well as drugs that are absorbed into the body through the mouth and respiratory system via an aerosol; Using a skin patch: The patch contains drugs that are absorbed into the body through the skin; Using a rectal suppository: such as pills or capsules, which are placed in the rectum and absorbed into the body; Using a needle: such as an injection, or injecting into a vein (IV - intravenous). Patients who ingest drugs via IV may be able to use a patient-controlled analgesia (PCA) pump, which allows the patient to control the pain medication in some limited ways.

[0029] Due to the specificity of these types of drugs, patients have potential problems and risks related to situations of misuse, including non-compliance with the prescribed medical prescriptions, and may occur through the following main failure modes:

[0030] 1) The patient lacks self-control over the frequency and / or quantity of intake of a specific medicine or pharmaproduct containing an opioid to be administered according to a medical prescription - classified as misuse of a pharmaceutical composition;

[0031] 2) The patient deliberately misintakes a specific medicine or pharmaproduct containing an opioid, exceeding the medically prescribed quantity and / or frequency - classified as misuse of a pharmaceutical composition;

[0032] 3) Unintentional intake or intentional conscious intake by an individual who is not the intended patient and user of a specific medicine or pharmaproduct according to a medical prescription.

[0033] Therefore, unsupervised or self-administration of a pharmaceutical composition is limited to pharmaceutical compositions with limited effects, and even in cases of abuse or violation of the administration plan or protocol, their effects are to some extent predictable and have a limited risk of health damage. This problem has been solved in various different ways in the prior art to establish controlled conditions for the administration of drugs or pharmaceutical compositions.

[0034] In publication EP1973593, a drug storage and dispensing device for dispensing a drug dosage form to a patient is disclosed. The dispensing device has a programmable lock-out feature for locking the dispensing device and is capable of detecting the identity of the user. The invention also provides a method of treating a subject by administering a drug dosage form to the subject using the dispensing device of the invention.

[0035] In US2017 / 242976, a dispenser is disclosed, comprising: a) a re-closable opening on or for placement on and / or around an opening of a container, the container having a cavity for receiving at least one unit of a product to be dispensed; b) a controller adapted to control the opening of the re-closable opening; c) a receiver adapted to receive a user authentication signal; d) a power source for powering the controller and the receiver; and wherein the dispenser allows the re-closable opening to be opened only when the receiver receives a user authentication signal. The publication also discloses a dispensing system, a dispensing method, and a kit comprising such a dispenser. The invention is particularly suitable for dispensing medicines only to the intended recipients and also ensuring compliance with the administration protocol.

[0036] US2010 / 100237 discloses a dispenser having means for dispensing a desired number of pills from a large number of pills contained in the dispenser. The dispenser includes a storage compartment having a large number of pills and an outlet that empties into a counting compartment. The counting compartment contains a first conveyor belt and a second conveyor belt that move at a first speed and a second speed, respectively; wherein the second speed is greater than the first speed so that the pills can be separated; and the second conveyor belt discharges the pills into a dispensing compartment. Sensors are strategically placed along the conveyor belts to count the pills discharged into the dispensing compartment. A pill recovery system and means are provided within the dispenser having means for recovering the pills remaining on the conveyor belts upon completion of a dispensing cycle and returning the recovered pills to the storage compartment for use in future dispensing cycles. A docking station having a receptacle for receiving the dispenser is provided. The docking station has a communication port capable of two-way communication with a personal computer. The dispenser has a variety of safety features including locking mechanisms at the inlet and outlet; and an internal circuit responsive to a "disable" electronic signal from an internal clock of the dispenser and a remote server in communication link with the dispenser.

[0037] US2013 / 226339 discloses systems and methods for detecting possible misuse of medications by a user. The system includes a computer communicatively coupled to a dispensing device. The computer receives the user's pattern of use of the medication as indicated by the dispensing device and test results related to the user's actual consumption of the medication. Based on the pattern of use, the computer calculates an estimated result of a test corresponding to at least one predetermined test. Based on a comparison between the estimated result and the test result, it is determined whether the user may have misused the medication.

[0038] US2014 / 297028 discloses a battery-powered rechargeable handheld device that dispenses medicated film strips in a controlled manner. The device is password protected, dose-limiting, communicates wirelessly with a server host so that doctors and pharmacists can monitor the device, and can remotely destroy the medication in the event that the device is lost, stolen, or tampered with. The device is trackable via GPS location. Software can track the device as well as the doctor's workload to ensure regulatory compliance. The device is an automated device that uses sophisticated electronics to eliminate the human factor and force the patient to follow a programmed protocol. The device also simplifies the process of monitoring and tracking doctors. The problem of accidental child access is eliminated. The problems of drug abuse and diversion are effectively controlled and limited. In practice, there is little for humans to interpret or variability.

[0039] WO2019 / 038580 discloses a drug dispenser for delivering drugs to a user, the drug dispenser comprising one or more internal reservoirs for storing one or more drugs; a dispensing unit configured to access the one or more internal reservoirs and dispense drugs based on a predefined dispensing scheme; a control unit comprising a user identification unit adapted to collect user authentication data; and a communication module configured to send to / receive from a remote server the user authentication data and delivery control data associated with the predefined dispensing scheme; wherein the control unit is configured to enable / disable the dispensing unit based on the user authentication data and the delivery control data. A drug refilling device for use with the drug dispenser when authenticating and confirming its user's medical condition is also disclosed.

[0040] As pointed out above, the administration of a pharmaceutical composition without the direct control of an authorized entity responsible for controlling the administration process is part of a therapy that only relies on the patient's sense of responsibility for his / her health. The unsupervised administration of pharmaceutical compositions is also a major factor leading to the misuse or abuse of pharmaceutical compositions. Since pharmaceutical compositions are usually administered by patients outside of the scheduled plan and not in accordance with the assigned scheme, this is also the main reason why the applied therapy is ineffective.

[0041] The present invention provides an inhaler for electronically supervised parenteral administration of a dry powder pharmaceutical composition as described in this specification.

[0042] The system according to the present invention provides a secure way to control the administration schedule, which eliminates the problems existing in the prior art. The use of an authorization token eliminates the need for time control and the involvement of calculating personal authentication methods. It eliminates the need for storing personal biometric data, memorizing passwords, and complex authorization procedures.

[0043] The present invention provides an inhaler having a dry powder pharmaceutical composition, the dry powder pharmaceutical composition comprising ketamine or a pharmaceutically acceptable salt thereof as a drug for use in a method of treating depression by pulmonary administration.

[0044] In another aspect, the present invention provides an inhaler having ketamine or a pharmaceutically acceptable salt thereof for use in a method of treating depression, wherein ketamine or a pharmaceutically acceptable salt thereof is administered via the pulmonary route in the form of a dry powder pharmaceutical formulation.

[0045] The inhaler according to the present invention provides a secure way to control the administration schedule, which eliminates the problems existing in the prior art. The use of an authorization token eliminates the need for time control and the involvement of calculating personal authentication methods. It eliminates the need to store personal biometric data, memorize passwords, and complex authorization procedures.

[0046] Providing secure authorization for using a personal device takes advantage of the new behavioral patterns observed when a mobile phone is a device that is always with a person.

[0047] Another advantage of the system according to the present invention is to provide a system that provides high-quality monitoring data for doctors. Doctors refer to the administration process that excludes the assumption in the prior art that the dispensed drug is equal to the correct administration of the drug.

[0048] Referring to the figures in the accompanying drawings, the following detailed description of the preferred embodiments presented in a non-limiting example manner will make other advantages, features, and ways of implementing the present invention obvious. In the accompanying drawings:

[0049] Figure 1 The NGI deposition data of the composition of Example 1 is shown;

[0050] Figure 2 The NGI deposition data of the composition of Example 2 is shown;

[0051] Figure 3 The NGI deposition data of the composition of Example 3 is shown;

[0052] Figure 4 The NGI deposition data of the composition of Example 4 is shown;

[0053] Figure 5 The NGI deposition data of the composition of Example 5 is shown;

[0054] Figure 6 The NGI deposition data of the composition of Example 6 is shown;

[0055] Figure 7 The relationship between the plasma concentration of esketamine and time after multiple single doses of the dry powder composition of Example 2 is shown;

[0056] Figure 8 The relationship between the plasma concentration of esketamine and time after a single dose sequence of the dry powder composition of Example 2 is shown; and

[0057] Figure 9 The side effect distribution (Part A) after administration of the dry powder composition of Example 2 is shown.

[0058] Figure 10Shows the side effect distribution (Part B) after administration of the dry powder composition of Example 2.

[0059] Figure 11 Is a schematic diagram of a first embodiment of a system for electronically supervising parenteral administration of a pharmaceutical composition by an inhaler according to the present invention;

[0060] Figure 12 Is a schematic diagram of a control signal generated by a console for controlling an inhaler according to the present invention;

[0061] Figure 13 Is a schematic diagram of an inhaler according to the present invention;

[0062] Figure 14 Is a schematic diagram of an inhaler with a measuring unit according to the present invention;

[0063] Figure 15 Is a schematic diagram of a sorting matrix for use in a system for electronically supervising parenteral administration of a pharmaceutical composition by an inhaler according to the present invention;

[0064] Figure 16 Is a schematic diagram of a process for assigning values of quality metrics to measured physical properties using a sorting matrix in a system for electronically supervising parenteral administration of a pharmaceutical composition by an inhaler according to the present invention;

[0065] Figure 17 Is a schematic diagram of a second embodiment of a system for electronically supervising parenteral administration of a pharmaceutical composition by an inhaler according to the present invention;

[0066] Figure 18 Is a schematic diagram of another embodiment of an inhaler according to the present invention.

[0067] In one embodiment of the present invention, there is an inhaler with a dry powder pharmaceutical composition, the dry powder pharmaceutical composition containing ketamine or a pharmaceutically acceptable salt thereof as a medicament for use in a method of treating depression by pulmonary administration (i.e., administration via the pulmonary route).

[0068] The inhaler may contain ketamine or a pharmaceutically acceptable salt thereof for use in a method of treating depression, wherein the ketamine or a pharmaceutically acceptable salt thereof is administered via the pulmonary route in the form of a dry powder pharmaceutical formulation.

[0069] Preferably, in the uses according to the present invention, esketamine, in particular esketamine hydrochloride, is self-administered by the patient by inhalation of a dry powder esketamine composition or formulation in an administration sequence consisting of a plurality of single doses (inhalation events), such as at least 3 single doses, each inhalation event consisting of a plurality of puffs, such as 1, 2, 3 or 4 puffs, preferably 3 or 4 puffs, and the sequences are separated from each other by an intermission period (rest period) without any inhalation. Preferably, such a sequence lasts at least 30 minutes, for example 30 minutes, and includes 3 administration sequences, and the intermission periods between them are preferably equal, i.e., an intermission (rest) period of 15 minutes.

[0070] Preferably, in the uses according to the present invention, esketamine, especially esketamine hydrochloride, is self-administered by the patient by inhalation of a dry powder esketamine composition or formulation in a 30-minute sequence consisting of 3 single doses (inhalation events), each inhalation event consisting of 3 or 4 puffs, where each puff corresponds to a nominal dose of 4 mg of esketamine in the dry powder composition or formulation. Such compositions or formulations are described in Example 2 below. An intermission period without any inhalation is provided between each of the inhalation events (single doses), and preferably there are two equal intermissions lasting approximately 15 minutes, i.e., the first single dose is administered at time 0, the second single dose is administered after approximately 15 minutes, and the third single dose is administered at 30 minutes. As is known from prior art intravenous infusion tests, such a sequence allows for obtaining a plasma concentration profile that provides a plasma concentration infusion at levels with antidepressant effects.

[0071] According to the present invention, the term "ketamine" includes racemic ketamine and its enantiomers esketamine and arketamine, both as the free base and its pharmaceutically acceptable salts.

[0072] In a preferred embodiment, the ketamine is esketamine.

[0073] In another embodiment, the ketamine is racemic ketamine.

[0074] A preferred pharmaceutically acceptable salt of ketamine is the hydrochloride.

[0075] In a most preferred embodiment, the composition of the present invention comprises esketamine hydrochloride.

[0076] In another embodiment, the composition of the present invention comprises racemic ketamine hydrochloride.

[0077] Preferably, in the use according to the present invention, ketamine, especially esketamine (such as esketamine hydrochloride), is self-administered by the patient by inhalation of a dry powder ketamine composition or formulation in an administration sequence consisting of a plurality of single doses (inhalation events), such as at least 3 single doses, each single dose or inhalation event consisting of multiple inhalations, such as 1, 2, 3 or 4 inhalations, preferably in 3 or 4 inhalations, and the sequences are separated from each other by an intermission period (rest period) without any inhalation. Preferably, such a sequence lasts at least 30 minutes, for example 30 minutes, and includes 3 use sequences, and the intermission periods between them are preferably equal, i.e., an intermission (rest) period of 15 minutes.

[0078] Preferably, in the use according to the present invention, esketamine, such as esketamine hydrochloride, is self-administered by the patient by inhalation of a dry powder esketamine composition or formulation in a 30-minute sequence consisting of 3 single doses (inhalation events), each inhalation event consisting of 3 or 4 inhalations, where each inhalation corresponds to a nominal dose of 4 mg of esketamine in the dry powder composition or formulation. Such compositions or formulations are described in Example 2 below. An intermission period without any inhalation is provided between each of the inhalation events (single doses), and preferably there are two equal intermissions lasting approximately 15 minutes, i.e., the first single dose is administered at time 0, the second single dose is administered after approximately 15 minutes, and the third single dose is administered at 30 minutes. As is known from prior art intravenous infusion tests, such a sequence allows obtaining a plasma concentration profile that provides a plasma concentration infusion at an antidepressant-effective level.

[0079] As used herein, the term "drug" may be used interchangeably with the term "medicine". It should be understood that for the purposes of the present invention, "drug" and "medicine" have substantially the same meaning.

[0080] The term "treatment-resistant or refractory depression" (TRD) is well known in the art and means that a patient's depression is unresponsive to at least two previous attempts at adequate antidepressant treatment with known antidepressant therapies. The term is generally described, for example, in US8,785,500 and US2015 / 0056308.

[0081] The term "bipolar disorder" is well known in the art and means a disorder that results in periods of depression and abnormal periods of elevated mood.

[0082] The term "major depressive disorder" is well known in the art and means a disorder characterized by a low mood that is present for at least two weeks in most cases.

[0083] In one aspect, the composition of the present invention contains 2 mg to 100 mg of ketamine, calculated as the free base per nominal unit dose.

[0084] In a particular embodiment, the composition of the present invention comprises 2 mg to 60 mg of ketamine, especially 2 mg to 40 mg of ketamine, such as 3 mg to 15 mg of ketamine, calculated as the free base per nominal unit dose.

[0085] In another embodiment, the composition of the present invention further comprises one or more additives selected from a carbohydrate filler in an amount of 30 to 95% by weight and a stabilizer in an amount of 0.2 - 3% by weight, based on the total weight of the composition.

[0086] The composition comprises ketamine, especially esketamine hydrochloride, having a median particle size d50 of 1 - 10 μm, such as 1 - 8 μm, especially 3 μm, d10 of 0.2 - 5 μm, and d90 of 3 - 35 μm.

[0087] The median particle size d50 is a parameter obtained by laser diffraction technique with dry dispersion using a Sympatec HELOS laser diffractometer attached with an ASPIROS feeder. For measurement, the raw material ketamine, especially esketamine hydrochloride, is dispersed at a total amount of 30 mg per sample under a pressure of 3.0 bar.

[0088] The composition is a dry powder formulation for administration using a dry powder inhaler. Conventional and typical dry powder inhalers can be used for this purpose.

[0089] The term "dry powder" is known to those skilled in the art and should be understood in the conventional manner in the art as a solid mixture of particles that fluidizes upon inhalation by the patient after actuation of the inhaler device.

[0090] According to the present invention, the term "nominal unit dose" refers to the dose of ketamine present (loaded) in the composition designated for a single administration. The nominal unit dose can be the measured dose of the dry powder prepared for administration to the patient contained in a single unit (such as a single compartment in a capsule or blister), or the dose withdrawn from a multi - dose dry powder reservoir for delivery.

[0091] The term "emitted dose" refers to the proportion of the nominal unit dose that exits / leaves the device after being inhaled by the patient.

[0092] The dry powder pharmaceutical composition or formulation used according to the present invention may comprise other pharmaceutical excipients, namely one or more additives selected from a carbohydrate filler (carrier) in an amount of 30 to 95% by weight and a stabilizer in an amount of 0.2 - 3% by weight, based on the total weight of the composition.

[0093] Suitable carbohydrate fillers (carriers) can be lactose, D-mannitol, glucose monohydrate, trehalose (especially trehalose dihydrate), erythritol, dextrose, maltose, sorbitol or xylitol. Particularly convenient fillers are ground lactoses having a suitable particle size, such as lactose monohydrate or anhydrous lactose, especially lactose monohydrate. A suitable particle size is defined as having a d50 of 30 - 200 μm (Sympatec HELOS) as the main coarse fraction (especially 80 μm). Examples of suitable commercial grades of lactose monohydrate are Lactohale 200 (LH200), Lactohale 100 (LH100) and Lactohale 200LP. Various types of inhalers may require appropriate selection of the lactose grade most suitable for their performance. This selection is within the ordinary skill of the person skilled in the art.

[0094] Typical amounts of the filler in the compositions of the present invention are 30 - 95% by weight, especially 30 - 80% by weight, based on the total weight of the composition.

[0095] The pharmaceutical excipients / additives also include stabilizers (also known as force control agents - FCA), i.e., substances that reduce the adhesion and cohesion forces. Suitable stabilizers are, for example, magnesium stearate, lecithin and amino acids such as leucine. Particularly preferred stabilizer is magnesium stearate.

[0096] The stabilizer "interferes" with the weak binding forces between small particles, thus helping to keep the particles separated, reducing the self-adhesion of small particles and the adhesion to other particles in the formulation (if such other particles are present), reducing the adhesion to the inner surface of the inhaler, and improving the rheological properties of the powder - powder flowability.

[0097] The amount of the stabilizer in the compositions of the present invention is 0.2 - 3% by weight, especially 0.8% by weight, based on the total weight of the composition.

[0098] The compositions or formulations used according to the present invention are prepared by blending a filler / carrier of suitable particle size with a stabilizer in a high-shear mixer, then adding ketamine of suitable particle size (especially esketamine hydrochloride), and blending again in a high-shear mixer.

[0099] Alternatively, ketamine of suitable particle size, especially esketamine hydrochloride, is co-processed (blended) with the stabilizer in a high-shear mixer, and then the filler / carrier is added and mixed again in a high-shear mixer.

[0100] The compositions are dry powder formulations for administration using a dry powder inhaler. Conventional and typical dry powder inhalers can be used for this purpose.

[0101] The formulation can be administered by three device categories: single-unit dose inhalers, where each dose (such as in a capsule) is loaded into the device before use; multi-dose reservoir inhalers, where a large quantity of dry powder with multiple doses is pre-loaded into the device; and multi-unit dose inhalers, where multiple single doses are individually sealed in separate compartments, such as in blister cavities, and are expelled each time the device is actuated. A multi-unit dose inhaler is preferred, where multiple single doses are individually sealed, such as in blisters, and are expelled each time the device is actuated.

[0102] In one embodiment of the use according to the invention as defined above, the medicament administered via the pulmonary route is a blister with multiple independent nominal unit doses that are pre-metered and individually sealed. A preferred example of such an inhaler is the Diskus-type inhaler.

[0103] In another embodiment of the use according to the invention as defined above, the medicament administered via the pulmonary route is a capsule with a single nominal unit dose.

[0104] In another embodiment of the use according to the invention as defined above, the medicament administered as a single dose via the pulmonary route is a multi-dose powder reservoir.

[0105] The composition used according to the invention provides a spray dose of at least 1.0 mg of ketamine calculated as the free base, corresponding to 1.2 mg of ketamine hydrochloride.

[0106] The composition used according to the invention provides a dose fraction that is delivered directly to the lungs locally, and this dose fraction is at least 40% of the sprayed unit dose, such as 40% to 50%, especially 40% to 60%, especially up to 85%.

[0107] The spray dose is the part that is ejected from the inhaler device and leaves the inhaler device as an aerosol and is thus available for the patient in the nominal unit dose.

[0108] Only a part of the spray dose reaches the lungs and thus reaches the patient's circulating blood as the dose delivered to the lungs (also called the fine particle dose - FPD) or the fraction delivered to the lungs (also called the fine particle fraction - FPF). Some parts reach the gastrointestinal tract via the oropharyngeal and oral routes, i.e., are swallowed, and can be used for the unwanted first-pass metabolism.

[0109] Surprisingly, it has been found that, despite the well-known problems with dry powder inhalable formulations of high-dose active substances for pulmonary administration, a uniform and stable high-dose ketamine, especially esketamine hydrochloride dry powder compositions, can be obtained when administered via the pulmonary route to provide therapeutic ketamine levels in the patient's circulating blood (i.e., at least 50 to 100 ng / ml, such as 70 to 100 ng / ml, such as 70 - 80 ng / ml, such as approximately 100 ng / ml). Therapeutic ketamine levels are related to the levels in the blood that are effective for treating depression, especially major depressive disorder (such as treatment-resistant or refractory depression), and may depend on the subject, gender, age, severity of the disease, type of inhaler, and may vary depending on whether the ketamine is racemic ketamine or an enantiomeric ketamine.

[0110] Compared to typical inhaled compositions where only 15% to 20% of the jet dose is delivered to the lungs, the fraction of the jet dose delivered to the lungs is unexpectedly high.

[0111] The fraction of the jet dose delivered directly to the lungs (also known as the fine particle fraction - FPF) can be determined using well-known conventional methods and tests. Such methods and tests include any of those described in European Pharmacopeia 9.0, Chapter 2.9.18, Preparations for inhalation; Aerodynamic assessment of fine particles for determination of Fine Particle Dose. In particular, the Next Generation Impactor (NGI) (Ph.Eur. Apparatus E) can be used to evaluate and control the Aerodynamic Particle Size Distribution (APSD). The NGI device is shown as in Figure 2 .9.18.-12 and 2.9.18.-13 of page 333 of European Pharmacopeia 9.0.

[0112] The jet dose and the fine particle dose and fraction (FPF and FPD) depend to a large extent on two factors, namely the formulation and the device. For the device, the most differentiating factor for the jet dose is the resistance. The resistance of a dry powder inhaler (DPI) is an inherent value that depends on the design of the inhalation channel, dosing cup, and inlet. In terms of the inhalation flow rate required to generate a pressure drop of 4 kPa, DPIs can be divided into four resistance groups (low, medium, medium-high, high). This value is chosen because it is the value recommended by the pharmacopeia for the in vitro characterization of the dose ejected from a DPI. Additionally, capsule-based DPIs are limited by powder retention in the capsule and the device, which results in a reduction in the jet dose.

[0113] The spray dose test is relatively simple. The device is "fired" into a sampling device capable of capturing the measured dose on a filter. The technique of multi-stage cascade impaction (in this case, the Next Generation Impactor (NGI)) is used to measure the aerodynamic particle size distribution of the inhaled product. The collected amount of the active ingredient is further determined by HPLC analysis. The inhaler is tested at a constant flow rate, and the pressure drop across the inhaler is 4.0 kPa in accordance with Ph Eur.

[0114] Effective particle capture is ensured by coating the particle collection surfaces of each of stages 1 - 7, as well as the MOC and the pre-separator base, with a coating substance. The central cup of the pre-separator is filled with sufficient diluent.

[0115] After discharging the powder into the NGI (the number of actuations of each impactor in one analysis, n = 1) by opening a two-way solenoid valve for the required time under flow control generating a 4 kPa pressure drop across the inhaler, the following operations are performed:

[0116] I. Stages 1 to 7 and MOC. Each stage is washed with an appropriate diluent (extraction of the drug substance). The NGI tray with cups loaded on a Copley Gentle Rocker is gently shaken for 10 minutes.

[0117] II. Mouthpiece adapter. The inhaled powder deposited on the adapter is rinsed into a volumetric flask with an appropriate diluent and sonicated for 10 minutes.

[0118] III. Inlet. The deposited powder from the inlet is rinsed into a volumetric flask with an appropriate diluent and sonicated for 10 minutes.

[0119] IV. Pre-separator. The deposited inhaled powder from these components is rinsed into a volumetric flask with an appropriate diluent and sonicated for 10 minutes.

[0120] Finally, the samples collected from each stage of the impactor are analyzed by filtration through high performance liquid chromatography.

[0121] The composition used according to the present invention has appropriate pharmacokinetic properties of ketamine, especially esketamine hydrochloride, which enables a ketamine plasma concentration of about 50 to 100 ng / ml to be achieved within 40 minutes after direct pulmonary administration to the lungs by inhalation. The said plasma concentration corresponds to an antidepressant effect. Maintaining this concentration over time mimics a 40-minute intravenous infusion known to be effective and well-tolerated for depression.

[0122] The present invention will now be described with reference to the accompanying examples, but is not intended to be limiting. Example

[0123] General manufacturing procedure:

[0124] Sieve all of the lactose monohydrate and magnesium stearate through a 0.25 mm sieve and mix in a high shear mixer for 3 minutes. The obtained mixture is sieved together with the active substance through a 0.5 mm sieve and mixed in a high shear mixer for 5 minutes.

[0125] To eliminate static charges, an antistatic PE bag is used during this process.

[0126] Vacuum filling process (blister):

[0127] The vacuum drum technology dosage forming process is used for blister filling. The volume of the blister cavity ranges from 15 to 45 mm3 (especially about 30 mm3). The amount of powder filled into the cavity is 10 - 30 mg (especially 23 mg).

[0128] During this process, the parameters of the vacuum drum equipment are:

[0129] Vacuum pressure: -0 - 500 mBar, especially 50 - 400 mBar

[0130] Fluidization pressure: -0.1 - -0.4 Bar

[0131] Fluidization time: 50 - 2000 ms, especially 50 - 300 ms

[0132] Filling time: 50 - 700 ms, especially 50 - 400 ms

[0133] Sealing time: 100 - 600 ms

[0134] A sealing test is performed on the blisters filled under vacuum.

[0135] Finally, the blister strip is wound into the inhaler.

[0136] Filling process (capsule):

[0137] Place the capsules to be filled in a socket with the closed end facing down. The powder is discharged from the dosator and directly enters the capsule. The powder to fill the capsules is placed in the dosator, and it can be tamped and discharged into the capsules.

[0138] During this process, the parameters of the capsule filling equipment are:

[0139] Rotational speed: 1 - 70 rpm

[0140] Tamping height: 1 - 10 mm

[0141] Doser height: 1 - 250 mm

[0142] Finally, the filled capsules are installed into the inhaler.

[0143] Ketamine dry inhalation powder for blisters and capsules

[0144] The following compositions were prepared on a scale of 0.9 kg according to the above general procedure.

[0145] Example 1

[0146] Component Dosage (mg / unit)

[0147] Es ketamine hydrochloride 3.45 (equivalent to 2.99 mg es ketamine)

[0148] Lactose monohydrate LH200 LP 19.16

[0149] Magnesium stearate 0.39

[0150] Example 2

[0151] Component Dosage (mg / unit)

[0152] Es ketamine hydrochloride 4.61 (equivalent to 4 mg es ketamine)

[0153] Lactose monohydrate LH200 LP 18.20

[0154] Magnesium stearate 0.18

[0155] Example 3

[0156] Component Dosage (mg / unit)

[0157] Es ketamine hydrochloride 5.06 (equivalent to 4.39 mg es ketamine)

[0158] Lactose monohydrate LH200 LP 17.581

[0159] Magnesium stearate 0.359

[0160] According to the requirements of Ph.Eur. 2.9.40, the compositions were found to be homogeneous. The average es ketamine hydrochloride content (n = 10) was in the range of 92.5% - 107.5% of the nominal dose.

[0161] The process was found to be scalable to a scale of 1.8 kg.

[0162] Aerodynamic particle size distribution (APSD) tests of the compositions of Examples 1, 2, and 3 of the composition according to the invention.

[0163] The compositions of Examples 1, 2 and 3 of the present invention have been tested according to the procedures of a powder inhaler using a Next Generation Impactor (NGI) (Ph.Eur. Apparatus E).

[0164] The test results are presented in Table 1 below and in the Figure 1 (Example 1), Figure 2 (Example 2) and Figure 3 (Example 3), where the upper figure shows the APSD data for the whole NGI and the lower figure shows the APSD data for Stages 1 - 7 and the MOC. The following abbreviations have been used for the test results:

[0165] MA - Mouth adapter

[0166] T - Suction inlet

[0167] PS - Pre - separator

[0168] S1 - S7 - Stages of the NGI

[0169] MOC - Micro - orifice collector

[0170] ISM - Impactor - sized mass; mass entering the impactor excluding the non - sizing part

[0171] MMAD (μm) - Mass median aerodynamic diameter. Defined as the diameter at which 50% of the particles are larger and 50% are smaller by mass.

[0172] GSD - Geometric standard deviation. Measure of the spread of the aerodynamic particle size distribution

[0173] FPF - Fine particle fraction (%)

[0174] FPD - Fine particle dose

[0175] Table 1. NGI deposition data

[0176] Example Number 1 2 3 MA [mg] 0.043 0.194 0.074 T 0.166 0.713 0.740 PS 0.598 0.262 0.825 S1 0.063 0.157 0.179 S2 0.193 0.599 0.541 S3 0.308 0.538 0.588 S4 0.243 0.392 0.345 S5 0.112 0.201 0.179 S6 0.061 0.121 0.105 S7 0.048 0.087 0.070 MOC 0.037 0.054 0.054 ISM (mg) 1.00 1.99 1.88 Total Mass on Impactor (mg) 1.07 2.15 2.06 Total Mass on System (mg) 1.87 3.32 3.70 Mass / Actuation on Impactor (mg) 1.07 2.15 2.06 Mass / Actuation on System (mg) 1.87 3.32 3.70 FPD ≤ 5.0 mcm (mg) Esketamine 1.0 1.7 1.6 FPF ≤ 5.0 mcm (%) 49.0 51.0 44.0 MMAD (mcm) 2.6 2.9 3.0 GSD 1.8 1.8 1.8

[0177] The results obtained indicate that the product has the expected quality attributes.

[0178] The compositions of the present invention exhibit suitable uniformity and a very high level of fine particle fraction, where:

[0179] FPF > 49%, FPD 1.0 mg; and delivered dose: 2.3 mg, for Example 1

[0180] FPF > 47%, FPD: 1.7 mg; and delivered dose: 3.6 mg, for Example 2, and

[0181] FPF > 44%, FPD: 1.6 mg; and spray dose: 3.9 mg, for Example 3.

[0182] Esketamine dry powder for inhalation for capsules

[0183] Prepare the following compositions on a scale of 0.9 kg according to the above general procedure.

[0184] Example 4

[0185]

[0186] Example 5

[0187]

[0188] Example 6

[0189]

[0190] Aerodynamic particle size distribution (APSD) testing of the compositions of Examples 4, 5, and 6 of the present invention.

[0191] The compositions of Examples 4, 5, and 6 of the present invention have been tested according to the procedure of a powder inhaler using a Next Generation Impactor (NGI) (Ph.Eur. Apparatus E).

[0192] The test results are shown in Table 2 below and in the Figure 4 (Example 4), Figure 5 (Example 5), and Figure 6 (Example 6), where the upper figure shows the APSD data of the entire NGI, and the lower figure shows the APSD data of stages 1 - 7 and MOC.

[0193] Table 2. NGI deposition data

[0194]

[0195]

[0196] The results obtained indicate that the product has the expected quality attributes.

[0197] The formulations of the invention exhibit appropriate uniformity and a very high level of fine particle fraction, where:

[0198] FPF > 59%, FPD 2.4 mg; spray dose: 4.2 mg, for Example 4

[0199] FPF > 54%, FPD: 3.9 mg; spray dose: 7.1 mg, for Example 5, and

[0200] FPF > 51%, FPD: 7.9 mg; injection dose: 16.5 mg, for Example 6.

[0201] The dry powder pharmaceutical composition of the present invention provides a dose of esketamine hydrochloride for inhalation at a level of up to 97% of the maximum nominal dose, such as 85% of the maximum nominal dose, and a fine particle fraction (fraction delivered to the lungs) of at least 40% of the esketamine dose injected.

[0202] Example 7

[0203] Pharmacokinetics of esketamine dry powder inhaled by healthy volunteers

[0204] The dry powder preparation of esketamine hydrochloride of Example 2 was administered to the lungs of healthy volunteers, i.e., directly administered to the lungs using a dry powder inhaler (DPI) (by self - administration).

[0205] One puff of the dry powder preparation contains 4.6 mg of esketamine hydrochloride (corresponding to 4 mg of esketamine free base) and excipients, 18.22 mg of lactose monohydrate and 0.18 mg of magnesium stearate.

[0206] A single dose is an inhalation event consisting of 1 to 6 puffs, i.e., a nominal dose of 4 to 24 mg of esketamine free base.

[0207] In part A of this study, designed as a one - centre single - ascending dose, a single dose once daily (up to 6 consecutive puffs) was administered to 18 healthy volunteer subjects. The subjects were divided into 6 groups, and the groups received 1, 2, 3, 4, 5, or 6 puffs respectively in a single dose (inhalation event).

[0208] Blood samples were collected up to 24 hours after the start of the test to determine esketamine and esnorketamine concentrations and calculate pharmacokinetic parameters.

[0209] The purpose of this study was to determine the number of puffs required to obtain plasma concentrations similar to those sufficient to achieve an antidepressant effect (such as a 40 - minute intravenous infusion of 0.20 mg / kg). It was predicted from the literature data that this corresponded to a concentration of approximately 60 to 100 ng / ml at 40 minutes of infusion. The purpose was also to determine the number of puffs that could avoid plasma concentration spikes, which are considered an important factor causing adverse psychotomimetic and dissociative effects.

[0210] The results of part A of the test are shown in Figure 7 in Figure 7Shows the esketamine plasma concentration over time after administration of multiple single doses of the dry powder composition of Example 2. It can be seen that the number of inhalations allowing to obtain a plasma esketamine concentration sufficient to produce an antidepressant effect and without the spikes in said concentration was determined to be from 1 to 4 inhalations, corresponding to a nominal dose of esketamine free base from 4 to 16 mg.

[0211] Accordingly, a single dose (inhalation event) consisting of from 1 to 4 inhalations was selected for the next part B of the test.

[0212] In part B of the study, the composition of Example 2 was administered to 12 healthy volunteer subjects divided into 4 groups in one day in a dosing sequence consisting of three administrations of a single dose (inhalation event) within 30 minutes, with 4 different single doses (i.e., each single dose consisting of 1, 2, 3 or 4 inhalations respectively) for each group. There was an inter-inhalation event interval of 15 minutes, i.e., the first single dose was administered at 0 min, the second at 15 min, and the third at 30 min.

[0213] The aim of part B was to study the pharmacokinetic properties of esketamine in healthy subjects after different dosing schedules and to determine the schedule (part B) that would be able to reach an appropriate plasma concentration over time to mimic a 40-minute intravenous infusion.

[0214] The results of part B of the test are shown in Figure 8 in Figure 8 which shows the esketamine plasma concentration over time after administration of multiple single doses of the dry powder composition of Example 2 in a sequence of 3 administrations of a single dose within 30 minutes. Figure 8 Also shown (the area between the two thick black lines) is the simulation of the esketamine plasma concentration after a 40-minute 0.2 mg / kg i.v. infusion.

[0215] From Figure 8 it can be seen that the sequence of 3 single doses consisting of 3 or 4 inhalations allows to obtain a plasma concentration curve that well mimics the esketamine intravenous infusion at levels corresponding to an antidepressant effect.

[0216] In parts A and B of the study, side effects were monitored and evaluated by a psychiatrist. A summary of the side effects is shown in Figure 9 in which it can be seen that no serious effects were observed, all side effects were evaluated as mild, occasionally moderate. The psychotomimetic effects were transient, lasting up to 30 minutes after administration. There were no withdrawals due to side effects or toxicity.

[0217] The above shows that pulmonary administration of esketamine, i.e., direct administration to the lungs, is a promising method for the treatment of depression (especially TRD) by convenient self-administration by the patient. The plasma concentration curve is very smooth, consistent with the target curve, and safe for long-term administration.

[0218] A system for electronically supervised administration of a pharmaceutical composition according to the present invention is disclosed in a non-limiting embodiment of a dry powder inhaler used in the treatment of resistant depression.

[0219] A system for electronically supervised parenteral administration of a pharmaceutical composition according to the present invention includes a digital communication device, a control terminal for an authorized entity, and an inhaler for the administration of the pharmaceutical composition. Preferably, the inhaler can be provided with a sensor for measuring at least one physical property characterizing the administration process from an angle inside the inhaler, and the system can further include a processing station adapted to convert the measured physical values and convert them into a quality metric of the administration process.

[0220] In Figure 11 an embodiment of the system shown above, system 1 includes several nodes: a control terminal 100 for an authorized entity, a processing station 200, an inhaler 400 for administering the pharmaceutical composition, and a mobile device 300 of the patient.

[0221] The communication device is symbolically depicted by an arrow, which is an element capable of establishing a communication link between the system nodes in the communication system, preferably a secure encrypted communication link using the TLS / SSL encryption protocol.

[0222] The communication device can be any standard communication device known in the art of digital communication capable of transmitting message frames between the nodes of the system, which includes cable, wireless, terrestrial or satellite communication systems supporting the Internet communication protocol TCP / IP. The communication device also encompasses near-field communication systems such as NFC, Bluetooth, etc. These are particularly suitable for establishing a communication link between the patient's mobile device 300 and the inhaler 400.

[0223] The mobile device 300 is a mobile phone, a tablet computer, an electronic watch, or any other handheld or wearable device with or having a user interface, a memory, a processing device, and a communication device. It is necessary to provide the mobile device with unique identification data so that the device can be distinguished from other devices.

[0224] In a first embodiment of the present invention, the control terminal 100 is a computer terminal that is provided with a user interface that allows authorized entities to interact with the control terminal 100. The authorized entity can be a physician who has selected a specific treatment for a patient to be implemented using the inhaler 400, which is part of the system 1 according to the present invention. However, the authorized entity can also be one or more institutions within the local healthcare system. For example, the authorized entity can include a physician who selects a treatment for a patient by issuing a regular prescription, a pharmacist working in a pharmacy who will dispense the inhaler to the patient, or a pharmaceutical company that manufactures the inhaler loaded with the pharmaceutical composition. A common feature of the authorized entity is that at least one person within the entity has the authorization to grant a therapy for a specific identified patient to use the pharmaceutical composition distributed within the inhaler 400, and there is at least one terminal that will generate a control signal 5 having an administration plan 11 and an authorization token 12 for distribution to the patient's mobile device 300. Preferably, the authorized entity can be a person, such as a prescribing physician. However, the functionally distributed authorized entity described above is equally feasible.

[0225] Figure 12 The control signal 5 is shown, which is generated when an administration plan 11 is selected for a patient. The control signal 5 includes unique identification data 10 of the control signal, the administration plan 11, an authorization token 12 for distribution to the patient's mobile device, and a security block 13. By generating data corresponding to the administration plan 11 and the authorization token 12 for the mobile device 300, the system 1 is simplified because the authorized entity only needs to communicate with the mobile device 300. The authorized entity does not need to additionally communicate directly with the medical device 400. By providing data corresponding to the administration plan 11 and the authorization token 12 in the same signal, the system 1 is simplified because only one signal 5 is required.

[0226] The identification data 10 can be an ID code or a signal ID header of the control signal 5, including a timestamp, a serial number of the control signal, a prescription number, etc. The main function of the identification block 10 is to uniquely identify the event that generates the control signal 5.

[0227] The administration plan 11 is a part of the control signal 5 that identifies the pharmaceutical composition and administration parameters prescribed for the patient. The administration plan 11 can be only an identifier for an approved standard therapy or a data set indicating the pharmaceutical composition, administration regimen, dose, etc., or it can be a data set that identifies the pharmaceutical composition while personalizing the administration plan according to the patient's treatment needs. Preferably, the control terminal 100 is provided with a cross-checking function that cross-checks the personalized parameters of the administration plan with an approved range.

[0228] The authorization token 12 is part of the control signal, which is unique to the control signal and represents the patient's consent to use the prescribed pharmaceutical composition. This may be a serial number or hash that is unique for the approval granted. The authorization token may be a purely electronic code or may have a physical form of a sticker or label with a mark readable by a mobile device (such as a 3D code, 2D code, QR code, NFC tag). Thus, the authorization token 12 can be provided separately from the control signal 5.

[0229] The security block 13 includes data that allows verification of the integrity of the control signal 5 and allows identification of the authorized entity that issued the control signal 5. This can be a block including a digital certificate of the authorized entity that generated the control signal 5, and a hash block generated for the control signal 5 using the digital certificate. The security block can implement any feasible integrity control system.

[0230] Preferably, the control signal 5 is encrypted, and the communication device implements a secure communication channel, for example, using known protocols and encryption schemes.

[0231] The control signal 5 can be a single data packet / message or a collection of independent packets or messages linked in a way that provides its integrity and functionality, as described above. For example, the administration plan 11 can be one of many different standard administration plans stored in the memory of the inhaler 400 along with their identifiers, and the control signal 5 generated by the physician only includes an identifier pointing to the administration plan to be applied. Alternatively, the control signal 5 is generated by the pharmacist based on a prescription issued by the physician and includes an identifier of the administration plan and an authorization token issued by the pharmaceutical company responsible for manufacturing the pharmaceutical composition inside the inhaler.

[0232] When the physician grants the patient treatment with a pharmaceutical composition via an inhaler according to the present invention, an administration plan is selected. Thus, the first element of the control signal 5 is created. At this time, the physician can issue a prescription for the inhaler 400 to be picked up at the pharmacy, or alternatively, the inhaler 400 can also be provided to the patient. At the moment when the inhaler 400 is provided to the patient, the authorization token 12 is assigned to the patient's mobile device 300. Alternatively, when the prescription for the inhaler 400 is issued by the physician, the authorization token 12 is assigned to the patient's mobile device 300.

[0233] Allocating the authorization token 12 to the mobile device 300 includes the step of transmitting the authorization token 12 to the memory of the mobile device 300. This transmission can take various forms, such as scanning a QR code with the authorization token generated by the pharmaceutical company by the camera of the mobile device, which is further decoded by the software of the mobile device 300 and stored in the memory of the mobile device 300. In addition, allocating the authorization token 12 to the mobile device 300 includes the step of transmitting the authorization token 12 together with the identification data of the mobile device 300 to an authorized entity that issues the control signal 5.

[0234] To perform the allocation step, the patient's mobile device 300 needs to be provided with a software application that allows the authorization token 12 to be transmitted to the memory of the mobile device and further transmits the authorization token 12 and the identification data of the mobile device 300 to the processing station 200 of the authorized entity responsible for generating the control signal 5. The processing station 200 uses the identification data of the mobile device to link the mobile device 300 with the authorization token 12 to allocate the authorization token 12 to the mobile device 300. The processing station 200 generates a confirmation of allocating the authorization token 12 to the mobile device 300 and sends the confirmation back to the mobile device 300. The mobile device 300 is also adapted to receive the confirmation of allocating the authorization token 12 to the mobile device 300 from the processing station 200.

[0235] As Figure 13 shown above, the inhaler 400 according to the present invention includes a communication unit 401, a processing unit 402 including a clock, a controlled blocking unit 403, a storage unit 404, a drug composition reservoir 410, and a drug composition administration unit 411. As Figure 14 shown above, the inhaler 400 is preferably provided with a measurement unit 405, and the measurement unit 405 is provided with a sensor adapted to measure the physical properties of the drug composition administration process. The sensor unit 405 may include a microphone, and the measured physical property may be the amplitude of the sound wave. The microphone may be placed inside the mixing chamber where the dry powder drug composition is mixed with air during inhalation.

[0236] The inhaler 400 is a device pre-loaded with a drug composition and adapted to administer the drug composition in a predetermined dose. Preferably, the inhaler 400 is a sealed inhaler. This means that it does not allow refilling or opening or modifying the contents of the storage unit 410 for the drug composition. Alternatively, the inhaler 400 is adapted to allow the contents of the storage unit 410 to be replaced in a controlled manner.

[0237] A patient who receives the inhaler 400 and has the authorization token 12 assigned to the patient's mobile device 300 registers the authorization token 12 assigned to the mobile device 300 in the inhaler 400. Registering the authorization token 12 assigned to the mobile device 300 means transmitting the authorization token 12 assigned to the patient's mobile device 300 to the memory of the inhaler 400. Alternatively, the inhaler 400 registers the confirmation that the authorization token 12 has been assigned to the patient's mobile device 300. This can be done by a communication device that establishes a communication channel between the inhaler 400 and the mobile device 300. Preferably, the communication channel is a near-field or short-range communication channel, or the communication channel is capable of performing distance measurement between the mobile device 300 and the inhaler 400.

[0238] In response to registering the authorization token 12 assigned to the mobile device 300 in the inhaler 400, the inhaler 400 processes the administration plan 11. Processing the administration plan means that the inhaler 400 makes the administration plan 11 an active administration plan and allows a dose of the pharmaceutical composition to be administered within the time window indicated by the administration plan 11. To comply with the administration plan, the inhaler 400 is provided with a controlled blocking device 403 that effectively blocks the transfer of a dose of the pharmaceutical composition from the reservoir 410 to the administration unit 411 and, upon receiving a control signal from the processing unit 402, allows the transfer of a dose of the pharmaceutical composition from the reservoir 410 to the administration unit 411.

[0239] The blocking device 403 includes, for example, a valve, a pin, a bolt, a relay, a wedge, a normally closed switch, or any form of actuator that blocks the transfer of a dose of the pharmaceutical composition from the reservoir 410 to the administration unit 411 in the blocking position and can be positioned in the open position to allow the administration of the pharmaceutical composition in response to a control signal from the control unit 402. The blocking device 403 is normally closed (normally closed type) and only opens according to the active administration plan 12. The controlled blocking device 403 can include a drive unit and an active actuating element that blocks the transfer of a dose of the dry powder pharmaceutical composition from the reservoir 410 to the administration unit 411. The actuating element can block the transfer of a dose of the pharmaceutical composition from the reservoir 410 to the administration unit 411 in the blocking state and allows the administration of the pharmaceutical composition in the open position in response to a control signal from the control unit 402. Upon receiving a control signal from the processing unit 402, the actuating element can move to the open state and allow the administration of the pharmaceutical composition.

[0240] In addition, the inhaler 400 is adapted in such a way that the controlled blocking device 403 enables the administration of the pharmaceutical composition stored in the reservoir 410 only in compliance with the administration schedule 11 and in the presence of the patient's mobile device 300 to which the authorization token 12 is assigned. The presence of the patient's mobile device 300 is understood to mean that the mobile device 300 is located near the inhaler 400, i.e., the distance between the two devices is less than 10 m, preferably less than 5 m, and most preferably less than 2 m. By providing the authorization token 12 to the mobile device 300 and requiring the presence of the mobile device 300, the system 1 is safer than a system that requires the patient to authenticate himself directly on the medical device 400. This is because the pharmaceutical composition can be administered only when the mobile device 300 is present, rather than simply requiring the presence of the medical device 400. Thus, for example, even if an unauthorized person has the medical device 400 and the patient's password, the system 1 is secure.

[0241] Accordingly, the inhaler 400 is adapted to cross-check the presence of the mobile device 300 near the inhaler 400. This can be achieved by a variety of methods, such as using a near-field communication device. In such a scenario, the lack of a communication connection between the inhaler 400 and the mobile device 300 is understood to be outside the range of the positions of both, and thus the distance between the two devices is greater than expected.

[0242] Alternatively, the inhaler 400 is provided with a rangefinder for actively or passively determining the distance between the inhaler 400 and the mobile device 300, such as a laser rangefinder, an acoustic rangefinder, a time-delay measurement system, a phase-shift rangefinder, etc.

[0243] If the distance between the mobile device 300 and the inhaler 400 is greater than a specified limit, this causes one of the conditions for administering the pharmaceutical composition to be missing, and thus the processing unit 402 does not send a control signal to the controlled blocking device 403, which does not allow the administration of the pharmaceutical composition. The pharmaceutical composition can be administered only when both conditions are met, i.e.:

[0244] a) The clock of the control unit 402 indicates that the time falls within the time window for administering a dose according to the active administration schedule 11, and

[0245] b) The patient's mobile device 300 with the assigned authorization token 12 is near the inhaler 400.

[0246] The system 1 according to the invention provides an effective way to control the abuse and misuse of the pharmaceutical composition by combining these two conditions. First, the assignment of the authorization token 12 to the patient's mobile device 300 ensures that the inhaler 400 can be activated only by an authorized person. This is due to the fact of the newly observed phenomenon of a strong emotional connection between a person and their mobile device.

[0247] As Figure 14As shown above, the inhaler 400 is preferably provided with a measuring unit 405 which is provided with sensors adapted to measure physical properties of the administration process of the pharmaceutical composition. The physical properties of the administration process of the pharmaceutical composition measured within the inhaler 400 during the administration process are air pressure, sound intensity, vibration amplitude, or any combination of said physical properties. This measurement of the internal physical process occurring inside the inhaler allows obtaining information confirming the administered dose and information regarding the quality of the administration process, i.e., whether the process is a correct process or a failed process. Information regarding the fact of the administered dose and the quality of the administration process is valuable information which can evaluate the patient's compliance with the administration plan and the patient's execution quality when the administration process requires active participation of the patient, as is the case with a dry powder inhaler when the pharmaceutical composition is excited by the air inhaled by the patient. The quality of such a process depends on the air flow generated when a dose is inhaled by the patient.

[0248] The data collected during the administration process are communicated to the processing station 200 of an authorized entity. The processing station 200 is adapted to convert the converted data representative of the measured physical properties into a quality metric of the administration process. Preferably, the quality metric is a value of an abstract index (such as 0 or 1), or a rank consisting of natural numbers between 0 and 10, or any other valued metric capable of representing the quality of the administration process. The value can be calculated according to a function based on univariate or multivariate, differential equations or systems of equations, provided by the measured values of one or more physical properties in the time domain, frequency domain or any suitable transform formed.

[0249] Preferably, the value of the quality metric is selected based on a heuristic observation allowing the assignment of the value of the quality metric to a pattern representative of the physical properties measured in the time domain or frequency domain. Preferably, during the heuristic observation, a sorting matrix 500 as shown above is generated. The sorting matrix 500 includes a set of fields which includes a pattern 420 representative of the measured values of the physical properties as described above. The fields in the sorting matrix are organized into two regions divided by a solid boundary 501, and each received pattern has an assigned quality metric of the administration process. It is not necessary to organize the fields in the sorting matrix into two separate regions with different quality values, the sorting matrix 500 can be scattered, and the fields do not need to create a continuous region with a solid boundary. The sorting matrix 500 functions as long as each field of the matrix 502 with a specific pattern has an assigned quality value. For example, the field 503 has an assigned quality value 504 of 0, and the field 505 has an assigned quality value 506 of 1. Figure 15

[0250] Figure 16 ​A process for obtaining a quality metric value from a sorting matrix 500 of a pattern 420 measured within an inhaler 400 is shown. The pattern 420 representing the measured values of the physical properties is compared with the patterns in the fields of the sorting matrix 500 to establish a measure of similarity. A measure of similarity is selected using a known method for establishing similarity, such as mean square error, least squares method, etc. The pattern in the sorting matrix 500 identified as having the best measure of similarity, for example, the pattern with the smallest mean square error, is considered the best fit, and the quality value 510 assigned to that field is returned in the result of the process. This process can be described as a best fit rule for selecting the value of the quality metric.

[0251] The processing station 200 is adapted to communicate the value 510 of the quality metric of the administration process to the control terminal 100 when the control terminal 100 is operated by a physician who grants the patient treatment with the pharmaceutical composition. The control terminal is adapted to display the received quality metric of the pharmaceutical composition administration process to the physician or an authorized entity using a user interface. This feedback loop allows for the assessment of the patient's compliance with the administration plan. Even if the administration of the pharmaceutical composition is correct, such information can also be used to modify the current administration plan of the pharmaceutical composition or switch to a different pharmaceutical composition if the current treatment lacks effectiveness.

[0252] The processing station 200 preferably returns the value 510 of the quality metric of the administration process to the patient's mobile device 300, which enhances the patient's self-control and supports the patient's motivation by presenting the patient with the quality metric. All these factors improve the patient's compliance with the administration plan and have a positive therapeutic effect.

[0253] Preferably, the processing station 200 is selected from a group of processing devices including mobile phones, personal computers, mainframe computers, cloud computing systems, or any combination of such computing devices having communication, processing, and storage capabilities suitable for processing digital signals and processing database operations and having controlled access rights. As described above, the processing station 200 performs two functions within the system according to the present invention. The processing station 200 assigns an authorization token to the patient's mobile device, and the processing station 200 further converts the measured physical properties into a quality metric representing the value of the quality of the administration process / event of the pharmaceutical composition.

[0254] A new method of treating a disease in a patient in need of treatment is obtained by having a system for electronically supervising the parenteral administration of a pharmaceutical composition in place. The method includes, in the presence of the patient's mobile device 300 assigned with an authorization token 12, parenterally self-administering, in a remotely indicated and controlled manner, the pharmaceutical composition by the patient according to a self-administration plan 11 prescribed by the attending physician, wherein the medical device operates in compliance with the self-administration plan 11 via a controlled blocking device 403, and the controlled blocking device 403 is adapted to effect the administration of the pharmaceutical composition only in compliance with the administration plan 11 in the presence of the patient's mobile device 300 assigned with the authorization token 12.

[0255] The administration process is only permitted by the controlled blocking device 403 in compliance with the administration plan and in the presence of the patient's mobile device 300 assigned with the authorization token 12. These two levels of control entrust the supervision of the administration of the pharmaceutical composition to an electronic system.

[0256] Since the administration is protected by the controlled blocking device 403 against misuse or abuse by the patient or a third party, it can be safely applied to a large number of substances that in the past required the personal supervision of qualified personnel as needed.

[0257] In a second embodiment of the present invention as shown in Figure 17 The system 1 includes a processing station adapted to transmit a control signal to an inhaler, and wherein in response to registering the authorization token with the inhaler, the inhaler receives a control signal with an administration plan from the processing station. This alternative approach may be more convenient in areas where the physician does not have a computer or where the communication network cannot provide the stability required to generate the authorization token when granting patient treatment. This scenario can also be applied when the physician needs to be freed from the administration task.

[0258] The second embodiment of the system provides the same level of security and is equally robust with respect to third-party interactions. In the second embodiment, the processing station 200 takes over the communication function from the control station 100. The communication channel between the control station 100 and the processing station 200 may have different characteristics from the communication channel established between the processing station 200 and the mobile device 300.

[0259] Figure 18Shows another embodiment of the inhaler 400 according to the present invention for use in the treatment of depression. The inhaler includes a reservoir 410 that houses a blister of a single dose of a dry powder drug composition. In this embodiment, the drug composition is esketamine in the form of a dry powder composition. The inhaler 400 also includes an administration unit 411. The administration unit 411 is provided with a mixing chamber and an air flow channel. The administration unit 411 is controlled by a loading handle 412, and pulling the handle 412 releases a dose of the dry powder drug composition into the mixing chamber of the administration unit 411. When the dose of the dry powder drug composition is in the mixing chamber, the inhaler 400 is ready for use by the patient.

[0260] Figure 18 Shows an inhaler 400 according to the present invention, which is provided with a control module that includes a communication device 401, a control device 402, a blocking device 403, a memory 404, and preferably a measuring unit 405.

[0261] Figure 18 Shows the inhaler 400 in a closed configuration suitable for storage or transportation. In this configuration, the inhaler 400 does not allow the administration of the drug composition. To open the inhaler 400 to the open configuration, the reservoir 410 and the administration unit 411 need to be rotated out of the control module. In the closed configuration, the administration unit 411 is covered by a control module that prevents access to the administration unit 411. Rotating the reservoir 410 and the administration unit 411 out of the control module exposes the administration unit 411 to the patient. In the closed configuration, the blocking device 403 does not support the rotation of the reservoir 410 and the administration unit 411. The blocking device 403 in the form of a bolt extends into a channel through which the handle 412 moves when the reservoir 410 and the administration unit 411 are rotated during the conversion of the inhaler 400 from the closed configuration to the open configuration. The blocking device 403 effectively blocks the rotation of the reservoir 410 and the administration unit 411, and in this way, the blocking device 403 does not allow the inhaler to be converted to the open configuration and thus does not allow the administration of the drug composition.

[0262] The control module of the inhaler 400 includes a communication device 401, a control device 402, a blocking device 403, a memory 404, and preferably a measuring unit 405. A power supply and a drive unit (not depicted) for actuating the blocking device are also within the control module.

[0263] The control device 402 of the inhaler 400 processes an administration plan 11 in response to an authorization token 12 registered to the patient's mobile device 300 in the inhaler 400, while the controlled blocking device 403 enables the administration of the dry powder drug composition only in accordance with the administration plan 11 in the presence of the patient's mobile device 300 assigned with the authorization token 12.

[0264] Registering the authorization token 12 assigned to the inhaler 300 means transferring the authorization token 12 assigned to the patient's mobile device 300 to the memory 404 of the inhaler 400. Alternatively, the inhaler 400 registers the confirmation that the authorization token 12 has been assigned to the patient's mobile device 300. This can be done via the communication device 401 that establishes a communication channel between the inhaler 400 and the mobile device 300. Preferably, the communication channel is a near-field or short-range communication channel, or the communication channel enables distance measurement between the mobile device 300 and the inhaler 400, such as NFC or Bluetooth.

[0265] In this embodiment, the administration plan 11 is pre-stored in the memory 404 of the inhaler 400. However, it can be transmitted together with the authorization token 12 and then stored in the memory 404 of the inhaler 400.

[0266] The control device 402 provided with the administration plan 11 determines the time slot during which the inhaler 400 can be converted from the closed configuration to the open configuration. As a second-level protection against the abuse and misuse of the pharmaceutical composition (in this case esketamine), the control unit 402 checks whether the patient's mobile device 300 assigned with the authorization token 12 is present near the inhaler 400.

[0267] Therefore, the inhaler 400 cross-checks the presence of the mobile device 300 assigned with the authorization token 12 near the inhaler 400. This is done by using the short-range communication means. The lack of a communication connection between the inhaler 400 and the mobile device 300 is understood as being outside the location range of both, and thus, the distance between the two devices is greater than expected.

[0268] When both conditions are met, the control unit 402 provides a control signal to the drive unit to withdraw the blocking device 403 from the channel in which the handle 412 moves, thereby allowing the inhaler 400 to be converted from the closed configuration to the open configuration in this way.

[0269] System 1 for the electronic supervised administration of a pharmaceutical composition is in place, and a method for treating a patient suffering from depression with a treatment need can be implemented. The method includes, in the presence of the patient's mobile device 300 assigned with an authorization token 12, self-administering ketamine or a pharmaceutically acceptable salt thereof in the form of a dry powder inhalable pharmaceutical formulation via the pulmonary route by the patient in a remotely indicated and controlled manner according to an administration plan 11 prescribed by the attending physician. In the method according to the invention, the inhaler 400 operates in accordance with the administration plan 11 through a controlled blocking device 403, which is adapted to effect the administration of the pharmaceutical composition only in accordance with the administration plan 11 in the presence of the patient's mobile device 300 assigned with an authorization token 12. The inhaler 400 may comprise ketamine or a pharmaceutically acceptable salt thereof for use in the method of treating depression, wherein the ketamine or a pharmaceutically acceptable salt thereof is administered via the pulmonary route in the form of a dry powder pharmaceutical composition. The pharmaceutically acceptable salt may be a hydrochloride salt. The ketamine may be esketamine hydrochloride.

[0270] The composition may comprise micronized ketamine in an amount of 2 mg to 100 mg calculated as the free base per nominal unit dose. The composition may comprise micronized ketamine in an amount of 2 mg to 40 mg calculated as the free base per nominal unit dose. The composition may comprise 4 mg of micronized esketamine calculated as the free base per nominal unit dose. The composition may comprise one or more additives selected from a carbohydrate filler in an amount of 30 - 95% by weight and a stabilizer in an amount of 0.2 - 3% by weight relative to the total weight of the composition. The composition may comprise ketamine having a median particle size d50 of 1 - 10 µm, d10 of 0.2 - 5 µm and d90 of 3 - 35 µm, as measured by laser diffraction technology. The inhaler may be adapted to provide a spray dose of at least 1.0 mg of ketamine calculated as the free base, corresponding to 1.2 mg of ketamine hydrochloride. The share 5 of the spray dose delivered to the lungs may be at least 40%.

[0271] The composition for administration via the pulmonary route may be contained in blisters in a plurality of pre-metered and individually sealed independent nominal unit doses. The composition for administration via the pulmonary route may be contained in a capsule in a single nominal unit dose. The composition for administration via the pulmonary route may be contained in a multi-dose powder reservoir.

[0272] Administration schedule 11 may provide for self - administration by a patient of a dry - powder ketamine composition or formulation by an administration sequence consisting of multiple single - doses, such as a sequence of at least 3 single - doses, each single - dose consisting of multiple inhalations, such as 1, 2, 3 or 4 inhalations, preferably 3 or 4 inhalations, the sequences being separated from each other by an inter - mittent period without any inhalation. Administration schedule 11 may include a sequence of three single - doses of esketamine consisting of 3 or 4 inhalations within 30 minutes, the single - doses being separated by an intermittent period of 15 minutes, where each inhalation corresponds to a nominal dose of 4 mg of esketamine in the dry - powder composition or formulation.

Claims

1. An inhaler (400) for electronically supervised parenteral administration of a dry powder pharmaceutical composition, comprising: Storage device (410) for a pharmaceutical composition in dry powder form; Administration device (411) for administering the pharmaceutical composition; Memory (404) and processing device (402); Communication device (401); Controlled blocking device (403) for preventing the administration of the pharmaceutical composition, wherein the inhaler (400) is adapted to receive data corresponding to an administration schedule (11), determine whether there is a mobile device (300) assigned an authorization token, and control the controlled blocking device (403) to effect administration of the pharmaceutical composition only in accordance with the administration schedule (11) in the presence of a mobile device (300) assigned the authorization token (12); wherein the inhaler (400) is adapted to register the authorization token by transmitting a confirmation that the authorization token has been assigned to the mobile device (300) to the memory (404) of the inhaler (400).

2. The inhaler according to claim 1, wherein the inhaler (400) is further adapted to during the administration process, measure at least one physical property of the dry powder pharmaceutical composition administration process inside the inhaler (400) by means of a sensor unit (405), and transmit the measured physical property to the mobile device (300).

3. The inhaler according to claim 2, wherein the physical property of the pharmaceutical composition administration process measured inside the inhaler (400) during the administration process is air pressure, sound intensity, vibration amplitude, or any combination of these physical properties.

4. The inhaler according to any one of claims 2 or 3, wherein the sensor unit (405) comprises a microphone, and the measured physical property is the amplitude of a sound wave.

5. The inhaler according to any one of claims 2 or 3, wherein the sensor is placed inside the mixing chamber, where the dry powder pharmaceutical composition is mixed with air during inhalation.

6. The inhaler according to any one of claims 1 to 3, wherein the controlled blocking device (403) comprises a drive unit and an active actuating element, and the active actuating element blocks the dose of the dry powder pharmaceutical composition from being transferred from the storage device (410) to the administration device (411).

7. The inhaler according to any one of claims 1 to 3, wherein the actuating element blocks the dose of the pharmaceutical composition from being transferred from the storage device (410) to the administration device (411) in the blocking state, and allows the administration of the pharmaceutical composition in response to a control signal from the processing device (402) in the open position.

8. The inhaler according to any one of claims 1 to 3, wherein Upon receiving a control signal from the processing device (402), the actuating element moves to an open state and allows administration of the pharmaceutical composition.

9. The inhaler according to any one of claims 1 to 3, wherein the blocking device (403) comprises an element selected from the group consisting of: valves, pins, bolts, relays, wedges, normally closed switches.

10. The inhaler according to any one of the preceding claims 1 to 3, wherein the dry powder pharmaceutical composition comprises ketamine or a pharmaceutically acceptable salt thereof for use in a method of treating depression by direct administration to the lungs via the pulmonary route.

11. The inhaler according to any one of the preceding claims 1 to 3, comprising ketamine or a pharmaceutically acceptable salt thereof for use in a method of treating depression, wherein ketamine or a pharmaceutically acceptable salt thereof is administered via the pulmonary route in the form of a dry powder pharmaceutical composition.

12. The inhaler according to claim 10, wherein the pharmaceutically acceptable salt is hydrochloride.

13. The inhaler according to claim 10, wherein the ketamine is esketamine hydrochloride.

14. The inhaler according to claim 10, wherein the composition comprises from 2 mg to 100 mg of micronized ketamine calculated as the free base per nominal unit dose.

15. The inhaler according to claim 14, wherein the composition comprises from 2 mg to 40 mg of micronized ketamine calculated as the free base per nominal unit dose.

16. The inhaler according to claim 15, wherein the composition comprises 4 mg of micronized esketamine calculated as the free base per nominal unit dose.

17. The inhaler according to claim 10, wherein the composition comprises one or more additives selected from a carbohydrate filler in an amount of 30 to 95% by weight and a stabilizer in an amount of 0.2 to 3% by weight, based on the total weight of the composition.

18. The inhaler according to claim 10, wherein the composition comprises ketamine having a median particle size d50 of 1 - 10 µm, d10 of 0.2 - 5 µm, and d90 of 3 - 35 µm as measured by laser diffraction technique.

19. The inhaler according to claim 14, wherein the inhaler is adapted to provide a spray dose of at least 1.0 mg of ketamine calculated as the free base, corresponding to 1.2 mg of ketamine hydrochloride.

20. The inhaler according to claim 19, wherein the fraction of the spray dose delivered to the lungs is at least 40%.

21. The inhaler according to claim 10, wherein the composition for administration via the pulmonary route is contained in blisters in a plurality of pre-metered and individually sealed independent nominal unit doses.

22. The inhaler according to claim 10, wherein the composition for administration via the pulmonary route is contained in a capsule in a single nominal unit dose.

23. The inhaler according to claim 10, wherein the composition for administration via the pulmonary route is contained in a multi-dose powder reservoir.

24. The inhaler according to claim 10, wherein the administration schedule (11) provides for self-administration by the patient of a dry powder ketamine composition or formulation by inhalation in an administration sequence consisting of a plurality of single doses, each single dose consisting of a plurality of inhalations, the sequences being separated from each other by an intermission period without any inhalation.

25. The inhaler according to claim 24, wherein the administration sequence consists of at least 3 single doses.

26. The inhaler according to claim 24, wherein each single dose consists of 1, 2, 3 or 4 inhalations.

27. The inhaler according to claim 24, wherein each single dose consists of 3 or 4 inhalations.

28. The inhaler according to claim 24, wherein the administration schedule (11) comprises a sequence of three single doses of esketamine consisting of 3 or 4 inhalations each within 30 minutes, the single doses being separated by an intermission period of 15 minutes, wherein each inhalation corresponds to a nominal dose of 4 mg of esketamine in the dry powder composition or formulation.

Images