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    • 专利摘要:
    Drug delivery devices are described that include a microphone and processing circuitry that can detect operating events, such as peak inspiratory flow (PIF) and Breath Actuated Mechanism (BAM) in dry powder inhalers. This information can be used to improve clinical trials by providing information about the way in which the inhalers under test are being used.
    公开号:EP3679972A1
    申请号:EP20157352.4
    申请日:2013-11-05
    公开日:2020-07-15
    发明作者:Mark Parry-Billings；Mario Scuri；Maria Chiara TAVERNA
    申请人:Chiesi Farmaceutici SpA；
    IPC主号:A61M15-00
    专利说明:
    [0001] The present invention relates to a drug delivery device, parts thereof and methods.
    [0002] In particular, the invention relates to a drug delivery system comprising a dry powder inhaler (DPI), a microphone mounted on the external surface of the body of said inhaler, and a processing circuitry for use for the treatment of patients affected by respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD). BACKGROUND OF THE INVENTION
    [0003] Drugs such as beta2-adrenergic agonists, steroids and anticholinergics are widely administered by inhalation for the treatment of respiratory diseases.
    [0004] Presently, the most widely used systems for inhalation therapy are the pressurised metered dose inhalers (MDIs) which use a propellant to expel droplets containing the pharmaceutical product to the respiratory tract.
    [0005] Dry powder inhalers (DPIs) constitute a valid alternative to MDIs for the administration of drugs to airways. The main advantages of DPIs are summarized below:i) being breath-actuated delivery systems, they do not require co-ordination of actuation since release of the drug is dependent on the patient own inhalation; ii) they do not contain propellants acting as environmental hazards.
    [0006] For example, the Applicant has disclosed in EP 1386630 a pocket size, breath actuated, medium resistance DPI, having a body with a mouthpiece and provided with a deagglomerator system for deagglomerating the powdered drug, characterized by a vortex chamber having an opening for the supply of the powdered medicament, two air inlets for directing air tangentially into the vortex chamber, and an outlet for outputting air with the deagglomerated powdered medicament, the outlet being spaced from the air inlets in an axial direction of the deagglomerator arrangement, wherein an outer wall of each air inlet is connected to the other air inlet by an arched wall portion of the vortex chamber.
    [0007] However since DPIs rely on the force of the patient to break-up the powder into particles that are small enough to reach the lungs, insufficient patient inhalation flow rates may lead to reduced dose delivery and incomplete deaggregation of the powder, leading to unsatisfactory device performance.
    [0008] Said deagglomerator system has also been termed as cyclone.
    [0009] It is therefore of paramount importance to understand the relationship between the inspiratory flow generated by the patient inside the device and its association with different degrees of functional limitation, and the corresponding efficiency with which the drug is dispersed and eventually inhaled into the airways.
    [0010] In particular, it would be highly advantageous to provide tools for an accurate assessment of the inspiratory flow generated by the patients through the device of EP 1386630 and to investigate whether this manoeuvre results in the activation of the breath actuated mechanism (BAM) and, hence, the delivery of the intended dose in patients with respiratory diseases.
    [0011] However, the deagglomerator system of the inhaler of EP 1386630 , when the inspired air passes through, does not generate detectable vortex frequencies.
    [0012] WO 2011/135353 discloses a technology to measure/monitor key performance characteristics during the inspiratory manoeuvre of formulations through the air path of inhaler, such as such as dry powder inhalers, metered dose inhalers, nasal inhalers and nebulisers.
    [0013] However, it is silent about the application to DPI's provided with a deagglomerator system for deagglomerating the powdered drug arranged as disclosed in EP 1386630 .
    [0014] The Applicant found that the technology disclosed in WO 2011/135353 can be applied to said inhaler and can be successfully used for monitoring/assessing its key performances in patients with respiratory diseases. SUMMARY OF THE INVENTION
    [0015] The invention is directed to a dry powder inhaler constituted of a body (1) and a cover (2), said body comprising a container (7) for storing a powdered medicament, a metering member (15) having a dosing recess (18), the metering member (15) being moveable between a filling position, in which the dosing recess (18) is in alignment with an opening of the container (7) so as to be filled with a dose of the powdered medicament, and an inhalation position, in which the dosing recess (18) is in alignment with an inhalation channel (27), a mouthpiece (3) being in communication with the inhalation channel (27) for enabling inhalation of the dose of the powdered drug contained in the dosing recess (18) of the metering member (15) when the metering member (15) is in the inhalation position, a protective member (19) provided between the metering member (15) and the inhalation channel (27), being moveable between a closed position, in which the protective member (19) at least covers the dosing recess (18) of the metering member (15) when the metering member (15) is in the inhalation position, thereby preventing the powdered medicament contained in the dosing recess (18) from entering into the inhalation channel (27) and an open position, in which the protective member (19) does not cover the dosing recess (18), thereby exposing the dosing recess (18) to the inhalation channel (27) so as to enable inhalation of the dose of the powdered medicament contained in the dosing recess (18), a breath actuated mechanism (BAM) coupled to the protective member (19) such that, if the protective member (19) is in the closed position, the BAM (21, 23) causes the protective member (19) to move into the open position if an inhalation suction force being effected by a patient exceeds a predetermined value, an inhalation cannel (27) provided with a deagglomerator arrangement (16) for deagglomerating a powdered medicament, comprising a vortex chamber (73) having an opening for the supply of the powdered medicament, two air inlets (75) for directing air tangentially into the vortex chamber (73), and an outlet (74) for outputting air with the deagglomerated powdered medicament, the outlet (74) being spaced from the air inlets (75) in an axial direction of the deagglomerator arrangement (16), wherein an outer wall of each air inlet (75) is connected to the other air inlet (75) by an arched wall portion (79) of the vortex chamber (73), each arched wall portion (79) being positioned non-concentric to a horizontal circle (77) defining a diameter (d) of the vortex chamber (73) of 6 mm ≤ d ≤ 10 mm; in combination with a microphone integrated with a preamplifier mounted on the external surface of the body of said inhaler, and processing circuitry operable to process the acoustic signal obtained from said microphone to determine the operating conditions of the dry powder inhaler,for use for the treatment of patients affected by a respiratory disease.
    [0016] The invention is directed to a powdered medicament consisting of a formulation comprising coarse carrier particles of a physiologically acceptable excipient and micronised particles of one or more active ingredients selected from the group consisting of short-acting and long-acting beta2-agonists, anticholinergics, corticosteroids and phosphodiesterase-inhibitors which is used for the treatment of patients affected by a respiratory disease in a method comprising the administration of said medicament by means of a dry powder inhaler according to the invention.The active ingredient may be a combination of a long-acting beta2-agonist and a corticosteroid; in particular, the long-acting beta2-agonist may be formoterol fumarate dihydrate and the corticosteroid may be beclometasone dipropionate.The patients may be affected by a respiratory disease selected from various forms of asthma or chronic obstructive pulmonary disease (COPD); in particular the disease is moderate- to -severe persistent asthma or severe COPD. Furthermore, the patients may be children younger than 12 years.
    [0017] Further, the invention is directed to the use of the aforementioned inhaler in combination with a microphone integrated with a preamplifier mounted on the external surface of the body of said inhaler, and processing circuitry operable to process the acoustic signal obtained from said microphone to determine the operating conditions of the dry powder inhaler in the manufacture of a device useful for the treatment of patients affected by a respiratory disease.The invention accordingly provides the following embodiments: 1. A dry powder inhaler constituted of a body (1) and a cover (2), said body comprising a container (7) for storing a powdered medicament, a metering member (15) having a dosing recess (18), the metering member (15) being moveable between a filling position, in which the dosing recess (18) is in alignment with an opening of the container (7) so as to be filled with a dose of the powdered medicament, and an inhalation position, in which the dosing recess (18) is in alignment with an inhalation channel (27), a mouthpiece (3) being in communication with the inhalation channel (27) for enabling inhalation of the dose of the powdered medicament contained in the dosing recess (18) of the metering member (15) when the metering member (15) is in the inhalation position, a protective member (19) provided between the metering member (15) and the inhalation channel (27), being moveable between a closed position, in which the protective member (19) at least covers the dosing recess (18) of the metering member (15) when the metering member (15) is in the inhalation position, thereby preventing the powdered medicament contained in the dosing recess (18) from entering into the inhalation channel (27) and an open position, in which the protective member (19) does not cover the dosing recess (18), thereby exposing the dosing recess (18) to the inhalation channel (27) so as to enable inhalation of the dose of the powdered medicament contained in the dosing recess (18), a breath actuated mechanism (BAM) coupled to the protective member (19) such that, if the protective member (19) is in the closed position, the BAM (21, 23) causes the protective member (19) to move into the open position if an inhalation suction force being effected by a patient exceeds a predetermined value, an inhalation channel (27) provided with a deagglomerator arrangement (16) for deagglomerating a powdered medicament, comprising a vortex chamber (73) having an opening for the supply of the powdered medicament, two air inlets (75) for directing air tangentially into the vortex chamber (73), and an outlet (74) for outputting air with the deagglomerated powdered medicament, the outlet (74) being spaced from the air inlets (75) in an axial direction of the deagglomerator arrangement (16), wherein an outer wall of each air inlet (75) is connected to the other air inlet (75) by an arched wall portion (79) of the vortex chamber (73), each arched wall portion (79) being positioned non-concentric to a horizontal circle (77) defining a diameter (d) of the vortex chamber (73) of 6 mm ≤ d ≤ 10 mm; in combination with a microphone integrated with a preamplifier mounted on the external surface of the body of said inhaler, and processing circuitry operable to process the acoustic signal obtained from said microphone to determine the operating conditions of the dry powder inhalerfor use for the treatment of patients affected by a respiratory disease. 2. The dry powder inhaler according to embodiment 1, wherein the cover (2) being rotatably coupled to the body (1) so that the cover (2) is moveable between a closed position, in which it covers the mouthpiece (3), and an open position, in which it exposes the mouthpiece (3). 3. The dry powder inhaler according to embodiment 2, wherein the body (1) comprises a window (4) for displaying a number of doses of the powdered medicament left in the container (7) or having been inhaled, the number of doses of the powdered medicament being counted by a dose counting unit (24-26). 4. The dry powder inhaler according to any one of the preceding embodiments, wherein the body (1) comprises an opening (5) for displaying a mark (38) showing if the dose of the powdered medicament contained in the dosing recess (18) of the metering member (15) is ready for inhalation, or has already been inhaled. 5. The dry powder inhaler, according to any one of the preceding embodiments, wherein the processing circuitry is operable to: i) track the acoustic signal received from the microphone during an inhalation; ii) convert the acoustic signal into a flow inhalation profile using stored first calibration data; iii) process the signal obtained from the microphone to detect the firing of the BAM and hence, the timing of the delivery of the powdered medicament during the inhalation; iv) and compare the detected timing of said delivery relative to said flow inhalation profile with stored second calibration data to determine if the delivery of the medicament meets a desired delivery condition. 6. The dry powder inhaler according to embodiment 5, wherein the operating conditions of said inhaler comprise the inspiratory flow rate by time, the flow at and time to BAM, the peak inspiratory flow (PIF) and time to PIF, the initial acceleration and the total inhaled air volume. 7. The dry powder inhaler according to any one of the preceding embodiments, wherein the processing circuitry is mounted within the body of said inhaler. DEFINITIONS
    [0018] As used herein, the term "dry powder inhaler (DPI)" refers to a device that delivers medication to the lungs in the form of a dry powder DPIs can be divided into two basic types: i) single dose inhalers, for the administration of pre-subdivided single doses of the active compound; ii) multidose dry powder inhalers (MDPIs), either with pre-subdivided single doses or pre-loaded with quantities of active ingredient sufficient for multiple doses; each dose is created by a metering unit within the inhaler.
    [0019] On the basis of the required inspiratory flow rates (1/min) which in turn are strictly depending on their design and mechanical features, DPI's are also divided in: i) low-resistance devices (> 90 l/min); ii) medium-resistance devices (about 60-90 1/min); iii) medium-high resistance devices (about 50-60 1/min); iv) high-resistance devices (less than 30 l/min).
    [0020] The reported classification is generated with respect to the flow rates required to produce a pressure drop of 4 KPa (KiloPascal) in accordance to the European Pharmacopoeia (Eur Ph).
    [0021] The terms "body" and "casing" are used as synonymous.
    [0022] The term "inspiratory flow rate by time" refers to the profile of the rate of the inspiratory flow of air, measured in volume per unit time, along the time.
    [0023] The expression "the flow at and time to BAM" refers to the air flow measured at the firing (opening) of the breath actuation mechanism (BAM) and delivery of the medicament from the device and the time at which the BAM opens.
    [0024] The terms "peak inspiratory flow (PIF) and time to PIF" refer to the maximum flow during inspiration of the patient through the device, and the time at which PIF occurs.
    [0025] The term initial acceleration refers to the rate at which the inspiratory flow changes starting from time 0 to the BAM firing (opening).
    [0026] The term "MicroElectrical-Mechanical System (MEMS) microphone" refers to a microphone chip or silicon microphone. The pressure-sensitive diaphragm is etched directly into a silicon chip by MEMS techniques, and is usually accompanied with integrated preamplifier. Most MEMS microphones are variants of the condenser microphone design. Often MEMS microphones have built in analog-to-digital converter (ADC) circuits on the same CMOS chip making the chip a digital microphone and so more readily integrated with modern digital products. Major manufacturers producing MEMS silicon microphones are Wolfson Microelectronics, Analog Devices, and Akustica Infineon, Knowles Electronics, Memstech, NXP Semiconductors, Sonion MEMS, AAC Acoustic Technologies, and Omron. FIGURE
    [0027] Figure - Main parameters defining the flow profile within the device of EP 1386630 in controlled and poorly controlled or uncontrolled asthmatic patients. From the top to the bottom: flow at BAM firing, peak inspiratory flow (PIF) and initial acceleration. DETAILED DISCLOSURE OF THE INVENTION
    [0028] The invention relates to the use of a dry powder inhaler in combination with a microphone integrated with a preamplifier mounted on the external surface of the body of said inhaler, and processing circuitry operable to process the acoustic signal obtained from said microphone to determine the operating conditions of the dry powder inhaler for the treatment of patients affected by a respiratory disease.
    [0029] Preferably, the microphone is a MicroElectrical-Mechanical System (MEMS) microphone and it is mounted on the bottom of the body of the inhaler.
    [0030] The characteristics of the inhaler are reported in EP 1386630 which is incorporated herein by reference.
    [0031] Advantageously, the cover (2) of the device is rotatably coupled to the body (casing) (1) so that the cover (2) is moveable between a closed position, in which it covers the mouthpiece (3), and an open position, in which it exposes the mouthpiece (3).
    [0032] Preferably, the body (1) comprises a window (4) for displaying a number of doses of the powdered medicament left in the container (7) or having been inhaled, the number of doses of the powdered medicament being counted by a dose counting unit (24-26).
    [0033] More preferably, the body (1) also comprises an opening (5) for displaying a mark (38) showing if the dose of the powdered medicament contained in the dosing recess (18) of the metering member (15) is ready for inhalation, or has already been inhaled.
    [0034] In a particular embodiment of the invention, the container (7) comprises a medicament chamber (8) for storing the powdered medicament and an integral desiccant chamber (9) for storing a desiccant, the desiccant chamber (9) being separated from the medicament chamber (8) by a permeable membrane (10).
    [0035] The acoustic signals are recorded using the microphone, then analysed using a set of algorithms that are tailored by the skilled person for said particular inhaler according to WO 2011/135353 , which is incorporated herein by reference.
    [0036] In particular, the processing circuitry disclosed therein is operable to: i) track the acoustic signal received from the microphone during an inhalation; ii) convert the acoustic signal into a flow inhalation profile using stored first calibration data; iii) process the signal obtained from the microphone to detect the firing of the BAM and hence, the timing of the delivery of the powdered medicament during the inhalation; iv) and compare the detected timing of said delivery relative to said flow inhalation profile with stored second calibration data to determine if the delivery of the medicament meets a desired delivery condition.
    [0037] The technique disclosed in WO 2011/135353 is completely non-invasive, having no effect upon the airflow or the aerosolisation performance of the inhaler, and could give a positive and immediate user feedback to the user.
    [0038] Analysis of the acoustic signal produced by airflow through the DPI enables very accurate and reproducible determination of important operating conditions of the aforementioned dry powder inhaler comprising the inspiratory flow rate by time and the flow at and time to BAM, the peak inspiratory flow (PIF) and time to PIF, and total inhaled air volume.
    [0039] This enables four salient scenarios to be monitored with confidence: i) flow rate profile, ii) BAM did not fire, iv) BAM fired but nothing was delivered and v) BAM fired and medicament was delivered.
    [0040] Therefore, as a matter of fact, said technology allows to establish whether the delivery of the intended dose in patients with respiratory diseases has occurred.
    [0041] In an embodiment, the processing circuitry detecting the operating conditions of the inhaler is mounted within the body of the inhaler.
    [0042] In an alternative embodiment, the processing may be performed by a remote processing device. In such an embodiment, the inhaler would record the signals obtained from the microphone and the data stored in the inhaler would then be downloaded to a computer device to perform the processing.
    [0043] In the above embodiments, the processing electronics is able to process the signal obtained from the microphone and detect if the delivery mechanism is activated during the inhalation and, if it is, to detect if the drug is also delivered by the mechanism. The processing electronics may maintain a count of the number of times that the delivery device is activated and the drug is successfully delivered and the number of times that the delivery device is activated but no drug is delivered. This information may be useful for subsequent diagnosis by the clinician or physician. Additionally, real time feedback may also be provided to the user so that they know if the drug was actually delivered. Very often with inhaler devices, users take too much of the drug because they do not realize that the drug is dispensed during one or more of their inhalations.
    [0044] Advantageously, the powdered medicament filled in the inhaler is under the form of powder formulation comprising coarse carrier particles of a physiologically acceptable excipient, and micronised particles of one or more active ingredients currently utilised for the treatment of respiratory diseases.
    [0045] The coarse carrier particles may have a mass median diameter (MMD) higher than 90 micron, and preferably the mass diameter (MD) comprised between 50 micron and 500 micron, more preferably between 150 and 400 micron, even more preferably between 210 and 355 micron.
    [0046] The coarse carrier particles have preferably a relatively highly fissured surface, that is, on which there are clefts and valleys and other recessed regions, referred to herein collectively as fissures.
    [0047] The "relatively highly fissured" surface of the coarse carrier particles may be defined in terms of fissure index or rugosity coefficients as disclosed in WO 01/78695 and WO 01/78693 and they can be characterized according to the description therein reported.
    [0048] Preferably said powder formulation may further comprise a fraction of microparticles having a MMD lower than 35 micron composed of particles of a physiologically acceptable excipient and an additive material selected from the class of the anti-adherents such as the amino acids leucine and isoleucine or of the lubricants such as magnesium stearate; sodium stearyl fumarate stearyl alcohol, stearic acid and sucrose monopalmitate.
    [0049] More preferably said powder formulation comprises a fraction of microparticles having a MMD lower than 15 micron, preferably lower than 10 micron, composed of particles of a physiologically acceptable excipient and particles of magnesium stearate according to the teaching of EP 1274406 .
    [0050] The physiologically acceptable excipient may be constituted of any amorphous or crystalline physiologically acceptable inert material of animal or vegetal source or combination thereof. Preferred materials are crystalline sugars and for example monosaccharides such as glucose or arabinose, or disaccharides such as maltose, saccharose, dextrose or lactose. Polyalcohols such as mannitol, sorbitol, maltitol, lactitol may also be used. The most preferred material is α-lactose monohydrate.
    [0051] Examples of commercial lactose are Capsulac® and Pharmatose®. An example of commercial mannitol is Pearlitol®.
    [0052] In a preferred embodiment, the fraction of microparticles is composed of 98% by weight of α-lactose monohydrate and 2% by weight of magnesium stearate and the ratio between the fraction of microparticles and the fraction of coarse particles made of α-lactose monohydrate particles is 10:90% by weight, respectively.
    [0053] The amount of magnesium stearate in the final formulation is advantageously comprised between 0.02% and 1.0% by weight, preferably between 0.05 and 0.5% by weight, more preferably between 0.1 and 0.4% by weight on the total weight of the formulation.
    [0054] The active ingredient may be practically any pharmaceutically active compound which can be administered by inhalation as dry powder for the treatment of respiratory diseases.
    [0055] As an example, they may be chosen from short-acting and long-acting beta2-agonists such as terbutalin, reproterol, salbutamol, salmeterol, formoterol, milveterol, indacaterol, olodaterol, fenoterol, clenbuterol, bambuterol, broxaterol, epinephrine, isoprenaline or hexoprenaline or salts and/or solvate forms thereof; short-acting and long-acting anticholinergics such as tiotropium, ipratropium, oxitropium, oxybutynin, aclidinium, trospium, or other compounds known with the codes GSK 573719 and GSK 1160274, in form of salts and/or solvate forms thereof; bifunctional Muscarinic Antagonist-beta2 Agonist (MABA) such as GSK 961081; corticosteroids such as butixocart, rofleponide, flunisolide, budesonide, ciclesonide, mometasone and its ester, i.e. furoate, fluticasone and its ester, i.e. propionate and furoate, beclomethasone and its ester, i.e. propionate, loteprednol or triamcinolone acetonide and solvate forms thereof; phosphodiesterase-inhibitors such as filaminast, piclamilast or roflumilast.
    [0056] Formulations comprising a beta2-agonist and/or an anti-cholinergic or a corticosteroid for inhalation, alone or in any combination thereof, constitute particular embodiments of the invention.
    [0057] An even more preferred embodiment of the invention concerns formulations comprising formoterol fumarate dihydrate and beclometasone dipropionate.
    [0058] Patients who may benefit of the combined use of the invention are those, of any sex and/or age, affected by mild, moderate or severe, acute or chronic, controlled or uncontrolled, symptoms of an inflammatory or obstructive respiratory disease such as asthma and chronic obstructive pulmonary disease (COPD).
    [0059] The patient who may preferably benefit of the combined use of the invention are those affected by moderate to severe persistent asthma, as defined in the Global INitiative for Asthma (GINA) guidelines, or affected by severe COPD as defined is the Global initiative for chronic Obstructive Pulmonary Disease (GOLD) guidelines.
    [0060] In fact, said patients would have a more compromised lung function, with more limited inspiratory flow, and hence they might incur in a higher risk that the delivery of the medicament does not meet the desired delivery condition.
    [0061] Another sub-population of patients that may preferably benefit of the combined use of the invention is the pediatric one, i.e. children younger than 12 years, that would have an inherent limited inspiratory flow.
    [0062] The invention is better illustrated by the following example. EXAMPLE
    [0063] The primary objective of this study is to assess the inspiratory flow profile through the device disclosed in EP 1386630 in adult asthmatics with varying degrees of disease control. 1. STUDY DESIGN
    [0064] This study is a phase IIa, single-centre, open-label, single-arm study, to evaluate the inspiration profile through the device disclosed in EP 1386630 (hereinafter the Device) in adult asthmatic patients with varying degrees of disease control.
    [0065] If the subjects meet the inclusion/exclusion criteria, they will be instructed to use the Device. The patients will subsequently inhale through the Device and the inspiration profile will be measured. 2. SUBJECT SELECTION CRITERIA 2.1 Subject Recruitment
    [0066] A total of 40 asthmatic adults (≥18 years), 20 with controlled stable disease and 20 with partly controlled or uncontrolled disease according to GINA guidelines (2011), will be enrolled.
    [0067] 44 patients will be screened in order to have 40 patients completed (assuming a screening failure rate of 10%). 2.2 Inclusion Criteria
    [0068] Patients will be enrolled at clinic if all the following criteria are satisfied: 1. Written informed consent obtained from the patient or the legal representatives. 2. Inpatients and outpatients of both sexes, aged ≥18 years. 3. Clinical diagnosis of controlled, partly controlled or uncontrolled asthma according to GINA guidelines (2011). 4. A cooperative attitude and ability to use DPIs and to be trained in the proper use of the Device as confirmed by the activation of the training device BAM 2.3 Exclusion Criteria
    [0069] Patients will not be enrolled if one or more of the following criteria are present: 1. Pregnant women confirmed by a positive urinary β-HCG laboratory test (> 5 IU/ml) or nursing (lactating) women (if applicable) 2. Significant seasonal variation in asthma or asthma occurring only during episodic exposure to an allergen or a chemical sensitizer 3. History of near fatal asthma (e.g. brittle asthma, hospitalisation for asthma exacerbation in Intensive Care Unit) 4. Diagnosis of restrictive lung disease 5. Allergy to any component of the placebo treatment 6. Inability to comply with study procedures or treatment 7. Significant unstable medical history of and/or treatments for cardiac, renal, neurological, hepatic, endocrine diseases, or any laboratory abnormality indicative of a significant underlying condition, that may interfere with patient's safety, compliance, or study evaluations, according to the investigator's opinion. 2.4 Subject Withdrawals
    [0070] Patients have the right to withdraw from the study at any time for any reason, including personal reasons. The investigator also has the right to withdraw patients from the study in the event of: Non-compliance with the protocol and/or lack of willingness or commitment to co-operate in all phases of the study Protocol deviations Adverse event which is considered intolerable by the patient or the investigator Development of an exclusion criterion. 3. DOSAGE AND ADMINISTRATION 3.1 Dosage
    [0071] At the study visit all patients will receive 2 inhalations of Placebo filled in the Device 3.2 Administration
    [0072] The administration of the device containing placebo will take place in the morning at clinic visit under medical supervision.
    [0073] The training with an empty Device will be performed by a physician during the visit at clinic. 4. STUDY PLAN 4.1 Study Schedule
    [0074] The study plan foresees one visit at clinic. Visit 1
    [0075] Written informed consent will be obtained from the patient or the legal representatives.The patient's eligibility for entry into the study will be assessed according to the inclusion and exclusion criteria.A pregnancy test (urinary β-HCG) will be done in females of child-bearing potential.Medical history will be recorded and a full physical examination will be performed.Vital signs will be measured, after 10 minutes of rest, in sitting position: heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure.A spirometry assessment will be performed.The patient will be successfully trained in the proper use of the Device as confirmed by the activation of the training device BAMThe Device containing placebo will be dispensed to the patient. The use of the device is taken on site under the investigator's supervision, verifying the appropriate inhalation.Recording of inhalation profile through acoustic monitoring will be performed during two consecutive manoeuvres (inhalations), separated by a maximum of 3 minutes. If a manoeuvre will be judged as unacceptable by the investigator, additional manoeuvres and inhalation profile recordings may be performed. The reason for performing any additional manoeuvre should be recorded by the investigator. Unless a valid justification will be provided, the first two manoeuvres following investigator's instructions will be considered in the analysis. Generally, a poor manoeuvre by the patient will not be considered as a valid reason for performing additional recordings of inhalation profile. Additional manoeuvres in case of technical issues (for example a disconnection of the audio jack during the inhalation) are acceptable.Device usability evaluation assessed by the Investigator by means of a questionnaire.
    [0076] Any adverse events occurring since the signature of the informed consent will be recorded 4.2 Investigations 4.2.1 Spirometry at clinic
    [0077] A computer-operated pneumotachographic spirometer will be used for all respiratory function measurements at the clinic visit. Lung function measurements and daily calibration of the spirometer will be done according to the recommendation of the Official Statement of the European Respiratory Society and American Thoracic Society (Miller MR, et al. Standardisation of spirometry Eur Respir J 2005; 26: 319-38).
    [0078] Lung function measurements will be done with patients either standing or sitting (for each patient, this should be consistent throughout the study) with the nose clipped after at least 10 minutes rest. Calibration of the spirometer must be performed by the same investigator at each visit prior to spirometry manoeuvres and the reports must be kept with the source study documents.
    [0079] The lung function measurement will start in the morning at 8:00-11:00 a.m., approximately at the same time of the day for each patient.
    [0080] The following parameters will be assessed at each visit: Forced Expiratory Volume in the 1st second (FEV1, L and % predicted) Forced Vital Capacity (FVC, L and % predicted) Peak Expiratory Flow (PEF, L/min and % predicted) Peak Inspiratory Flow (PIF, L/min).
    [0081] Spirometry will be performed at clinic visit to evaluate asthma control as per GINA 2011 guidelines and shown in Table. Table-Assessment of current clinical controlCharacteristics Controlled (All of the following) Partly Controlled (Any measure present) Uncontrolled Daytime symptoms None (twice or less/week) More than twice/week Three or more features of partly controlled asthma Limitation of activities None Any Nocturnal symptoms/awakening None Any Need for reliever/rescue treatment None (twice or less/week) More than twice/week Lung Function (PEF or FEV1) Normal <80% predicted or personal best (if known)
    [0082] Predicted values will be calculated according to the formulas reported by Quanjer et al. (Quanjer PH, et al. Spirometric reference values for white European children and adolescents: Polgar revisited Pediatr Pulmonol 1995; 19: 135-42; Quanjer PH. Lung volumes and forced ventilatory flows Eur Respir J 1993; 6 suppl 16: 5-40).
    [0083] For FEV1, FVC, PEF and PIF the highest value from three technically satisfactory attempts will be considered (irrespective of the curve they come from). The chosen value should not exceed the next one by more than 200 ml (FEV1). If the difference is larger, up to 8 measurements will be made and the largest value be reported. 4.2.2 Measurement of Inspiratory Flow Profile by Acoustic Monitoring
    [0084] Assessment of inspiratory profile through the Device will be performed according to a technology disclosed in WO 2011/135353 , that monitors and measures key performance characteristics of an inhaler (pMDI, DPI or nebuliser) providing valuable feedback to the user, clinician or healthcare provider thereby promoting correct usage. Said technology is based on the use of an acoustic analysis to accurately measure the key performance characteristics during the inspiratory manoeuvre such as flow at and time to BAM firing, flow at and time to powder ejection, PIF and time to PIF, initial acceleration, total inhaled volume and inhalation time.
    [0085] All the parameters will be automatically calculated by the software. 4.2.3 Vital signs
    [0086] Systolic and diastolic blood pressure (SBP, DBP) and heart rate (HR) will be measured at pre-dose after 10 min rest in sitting position. 5. ASSESSMENTS
    [0087] Variables measured by acoustic monitoring technology through the Device during the inspiratory manoeuvre: ∘ inspiratory flow rate by time; ∘ flow at and time to BAM firing; ∘ peak inspiratory flow (PIF) and time to PIF; ∘ initial acceleration (rate of change of flow at inhalation start); ∘ total inhaled volume and inhalation time; ∘ flow at and time to powder ejection (if feasible). Pulmonary function by spirometry: FEV1, FEV1 percent of predicted normal value, FVC, FVC percent of predicted normal value, PEF, PEF percent of predicted normal value and PIF.Device usability by means of a physician-assessed questionnaire.6. SAFETY ASSESSMENTS
    [0088] Adverse events.7. RESULTS AND DISCUSSION
    [0089] During inhalation manoeuvres, it is important that patients generate a turbulent energy inside the device in order to promote the de-aggregation of the powder and an effective release and delivery of the dose. This turbulent energy is the result of the inspiratory flow generated by the patient and the internal resistance of the device and correspond to an overall pressure drop of 4 kPa. Therefore the inspiratory flows of asthmatic patients is a critical factor in determining the de-aggregation and, hence, the correct delivery of the drug. Different asthmatic patients may be generating different inhalation flows depending on their pulmonary function status. However, it has been known that inhalation flows alone does not provide complete and accurate information about the de-aggregation event, but that the initial acceleration is another critical factor in determining the sequence of events leading to an effective powder release and delivery to the airways. In our study, therefore we studied the complete inhalation profile through a multi-dose reservoir type BAM activated device in asthmatic patients with different degrees of flow limitations. We studied 40 asthmatic subjects, 20 with controlled and 20 with poorly controlled or uncontrolled asthma as per GINA guidelines of 2011.
    [0090] The results of our study are illustrated in Figure and describe the main parameters defining the flow profile within the device of EP 1386630 in controlled and poorly controlled or uncontrolled asthmatic patients. In particular the mean (± SD) flow at BAM firing was 35.39 (± 9.49) and 34.51 (± 8.63) l/min for the first inhalation in controlled (C) and poorly controlled or uncontrolled patients (PC/U) respectively whereas it was 34.57 (± 9.17) and 36.16 (± 8.99) l/min for the second inhalation in C and PC/U respectively. The mean (± SD) peak inspiratory flow (PIF) generated inside the device was 70.46 (± 28.23) and 58.82 (± 20.13) l/min for the first inhalation in C and PC/U patients respectively, whereas for the second inhalation it was 72.10 (± 25.62) and 63.04 (± 16.83) l/min in C and PC/U patients respectively. The mean (± SD) initial acceleration was 128.15 (±80.82) and 123.52 (± 50.62) L/min/sec for the first inhalation in C and PC/U patients respectively, whereas for the second inhalation it was 146.58 (± 51.92) and 134.40 (± 46.70) L/min/sec in C and PC/U patients respectively.
    [0091] Collectively, these data showed the complete inhalation profile through the device disclosed in EP 1386630 . The results of this study suggest that the inhalation flow triggering the activation of the BAM falls within the range defining a high resistance device and that this value is fairly consistent regardless of the type of patient and its functional limitations. There seems to be a lower inhalation flows for PC/U asthmatics compared to C asthmatics (although the sample size is not large enough to reach statistical significance) which, however, appears not to occur at low flow rate and consistently in controlled and poorly controlled or uncontrolled asthmatic patients.
    权利要求:
    Claims (12)
    [0001] A pharmaceutical formulation comprising formoterol fumarate dihydrate and beclometasone dipropionate for use for the treatment of a respiratory disease selected from the group of moderate to severe persistent asthma or severe chronic obstructive pulmonary disease (COPD), wherein said formulation is administered by a dry powder inhaler constituted of a body (1) and a cover (2), said body comprising
    - a container (7) for storing a powdered medicament,
    - a metering member (15) having a dosing recess (18), the metering member (15) being moveable between a filling position, in which the dosing recess (18) is in alignment with an opening of the container (7) so as to be filled with a dose of the powdered medicament, and an inhalation position, in which the dosing recess (18) is in alignment with an inhalation channel (27),
    - a mouthpiece (3) being in communication with the inhalation channel (27) for enabling inhalation of the dose of the powdered medicament contained in the dosing recess (18) of the metering member (15) when the metering member (15) is in the inhalation position,
    - a protective member (19) provided between the metering member (15) and the inhalation channel (27), being moveable between a closed position, in which the protective member (19) at least covers the dosing recess (18) of the metering member (15) when the metering member (15) is in the inhalation position, thereby preventing the powdered medicament contained in the dosing recess (18) from entering into the inhalation channel (27) and an open position, in which the protective member (19) does not cover the dosing recess (18), thereby exposing the dosing recess (18) to the inhalation channel (27) so as to enable inhalation of the dose of the powdered medicament contained in the dosing recess (18),
    - a breath actuated mechanism (BAM) coupled to the protective member (19) such that, if the protective member (19) is in the closed position, the BAM (21, 23) causes the protective member (19) to move into the open position if an inhalation suction force being effected by a patient exceeds a predetermined value,
    - an inhalation cannel (27) provided with a deagglomerator arrangement (16) for deagglomerating a powdered medicament, comprising a vortex chamber (73) having an opening for the supply of the powdered medicament, two air inlets (75) for directing air tangentially into the vortex chamber (73), and an outlet (74) for outputting air with the deagglomerated powdered medicament, the outlet (74) being spaced from the air inlets (75) in an axial direction of the deagglomerator arrangement (16), wherein an outer wall of each air inlet (75) is connected to the other air inlet (75) by an arched wall portion (79) of the vortex chamber (73), each arched wall portion (79) being positioned non-concentric to a horizontal circle (77) defining a diameter (d) of the vortex chamber (73) of 6 mm ≤ d ≤ 10 mm;in combination with a microphone integrated with a preamplifier mounted on the external surface of the body of said inhaler, and processing circuitry operable to process the acoustic signal obtained from said microphone to determine the operating conditions of the dry powder inhaler.
    [0002] The formulation for use according to claim 1, wherein the patients are affected by moderate to severe persistent asthma.
    [0003] The formulation for use according to claim 2, wherein the patient is a child younger than 12 years old.
    [0004] The formulation for use according to any one of claims 1 to 3, wherein the dry inhaler has a cover (2) being rotatably coupled to the body (1) so that the cover (2) is moveable between a closed position, in which it covers the mouthpiece (3), and an open position, in which it exposes the mouthpiece (3).
    [0005] The formulation for use according to claim 4, wherein the inhaler has a body (1) comprising a window (4) for displaying a number of doses of the powdered medicament left in the container (7) or having been inhaled, the number of doses of the powdered medicament being counted by a dose counting unit (24-26).
    [0006] The formulation for use according to any one of the preceding claims, wherein the body (1) of the inhaler comprises an opening (5) for displaying a mark (38) showing if the dose of the powdered medicament contained in the dosing recess (18) of the metering member (15) is ready for inhalation, or has already been inhaled.
    [0007] The formulation for use according to any one of the preceding claims, wherein the processing circuitry is operable to: i) track the acoustic signal received from the microphone during an inhalation; ii) convert the acoustic signal into a flow inhalation profile using stored first calibration data; iii) process the signal obtained from the microphone to detect the firing of the BAM and hence, the timing of the delivery of the powdered medicament during the inhalation; iv) and compare the detected timing of said delivery relative to said flow inhalation profile with stored second calibration data to determine if the delivery of the medicament meets a desired delivery condition.
    [0008] The formulation for use according to claim 7, wherein the operating conditions of the inhaler comprise the inspiratory flow rate by time, the flow at and time to BAM, the peak inspiratory flow (PIF) and time to PIF, the initial acceleration and the total inhaled air volume.
    [0009] The formulation for use according to any one of the preceding claims, wherein the processing circuitry is mounted within the body of the inhaler.
    [0010] The formulation for use according to any one of the preceding claims further comprising short-acting and long-acting beta2-agonists; short-acting or long-acting anticholinergics; bifunctional Muscarinic Antagonist-beta2 Agonists (MABA); corticosteroids selected from the group of butixocart, rofleponide, flunisolide, budesonide, ciclesonide, mometasone and its esters, , fluticasone and its esters, loteprednol and triamcinolone acetonide and solvate forms thereof; phosphodiesterase-inhibitors.
    [0011] Formulations for use according to claim 10 comprising a beta2-agonist and/or an anti-cholinergic agent.
    [0012] Formulations for use according to any one of the preceding claims comprising an anti-cholinergic agent.
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    同族专利:
    公开号 | 公开日
    AR093382A1|2015-06-03|
    CA2890419A1|2014-05-15|
    IN2015DN03811A|2015-10-02|
    BR112015009149A2|2017-07-04|
    KR20150083849A|2015-07-20|
    CN111214738A|2020-06-02|
    HK1208830A1|2016-03-18|
    WO2014072268A1|2014-05-15|
    RU2015116757A|2016-12-27|
    KR102239756B1|2021-04-14|
    CA2890419C|2021-01-12|
    EP2916897A1|2015-09-16|
    CN104780963A|2015-07-15|
    RU2648849C2|2018-03-28|
    US20140158126A1|2014-06-12|
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