Inhaler System

Abstract

A pharmaceutical composition is provided comprising an oral corticosteroid for use in post-exacerbation treatment of a respiratory disease in a subject, the post-exacerbation treatment comprising an initial dose of said oral corticosteroid, which continues until satisfaction of an inhalation parameter criterion with one or more post-exacerbation inhalations by the subject using at least one inhaler and / or satisfaction of a rescue inhaler use criterion for post-exacerbation use of a rescue inhaler configured to deliver rescue medication to the subject, at which time a dose of the oral corticosteroid is altered from the initial dose. Additionally, systems and methods are provided for determining whether an inhalation parameter criterion has been met and for comparing a post-exacerbation value of the inhalation parameter to a baseline value of the inhalation parameter.

Description

[Technical field]

[0001] The present disclosure relates to treatment methods, systems, and related methods for guiding the continued or reduced use of oral corticosteroids or other medications, such as biologics, for post-exacerbation treatment in subjects suffering from respiratory diseases, such as asthma and / or COPD. [Background technology]

[0002] Many respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are lifelong conditions that involve treatment with long-term administration of medications to manage the patient's symptoms and reduce the risk of irreversible changes. There is currently no cure for diseases such as asthma and COPD. Treatment comes in two forms. The first is the maintenance aspect, which is treatment aimed at reducing inflammation in the airways and therefore controlling symptoms in the future. Maintenance therapy is usually provided with inhaled corticosteroids alone or in combination with long-acting bronchodilators and / or muscarinic antagonists. The second is the rescue aspect, where the patient is given fast-acting bronchodilators to relieve acute attacks such as wheezing, coughing, chest tightness, and shortness of breath.

[0003] Patients suffering from respiratory diseases such as asthma or COPD may experience occasional flare-ups of their respiratory disease, or exacerbations, in which symptoms suddenly worsen. In the worst cases, exacerbations can become life-threatening.

[0004] Following clinical diagnosis of a patient's respiratory exacerbation, the patient may be treated with oral corticosteroids. Such administration of oral corticosteroids may also be combined with controlled-flow oxygen, which requires hospitalization.

[0005] Post-exacerbation treatment with the administration of oral corticosteroids can improve patient outcomes and potentially shorten hospital stays. However, the administration of oral corticosteroids is not without problems. In particular, such use of oral corticosteroids is associated with a variety of adverse drug reactions (ADRs). DISCLOSURE OF THEINVENTION

[0006] [overview] Accordingly, the present disclosure provides a pharmaceutical composition comprising an oral corticosteroid for use in post-exacerbation treatment of a respiratory disease in a subject, the post-exacerbation treatment comprising an initial dose of an oral corticosteroid.

[0007] The present disclosure also provides systems and methods for guiding continued or reduced use of oral corticosteroids.

[0008] Further provided is a method of post-exacerbation treatment of a respiratory disease in a subject, comprising treating the subject with an initial dose of an oral corticosteroid.

[0009] Post-exacerbation treatment continues until the subject meets the inhalation parameter criteria with one or more post-exacerbation inhalations using at least one inhaler and / or the rescue inhaler use criteria for post-exacerbation use of a rescue inhaler configured to deliver rescue medication to the subject, at which point a dose of oral corticosteroid is changed from the initial dose.

[0010] Despite the improved patient outcomes associated with the administration of oral corticosteroids, various adverse drug reactions (ADRs) are associated with such use of oral corticosteroids that must be considered, particularly in determining the duration of treatment and how to discontinue treatment. Longer durations of oral corticosteroids tend to necessitate a gradual tapering at the end of treatment, known as weaning, rather than an abrupt cessation.

[0011] It is advisable to monitor the subject's, i.e., patient's, respiratory disease so that the initial dose of oral corticosteroid can be adjusted accordingly. Such monitoring can be used, for example, to justify a reduction in the dose relative to the initial dose if an improvement in the patient's condition is observed. With chronic oral corticosteroid use, such monitoring can allow for a planned reduction in the oral corticosteroid dose.

[0012] Such monitoring is usually difficult, especially after patients have been discharged from the hospital. Forced expiratory volume in 1 second (FEV1) can be used. However, such expiratory flow tests impose a burden on the patient in the form of additional / different maneuvers. This burden may lead to a reduction in data collection to justify an adjustment of the initial dose of oral corticosteroids. Thus, patients may be maintained on the initial dose of oral corticosteroids for longer than necessary or desirable, especially in terms of the risk of ADRs.

[0013] Post-exacerbation treatment according to the present disclosure continues until the subject has met the inhalation parameter criteria with one or more post-exacerbation inhalations using at least one inhaler, and / or the rescue inhaler use criteria for post-exacerbation use of a rescue inhaler configured to deliver rescue medication to the subject. Post-exacerbation inhalations can be administered by the patient regardless of the purpose of respiratory disease monitoring. Thus, monitoring can be performed in a manner that minimizes patient burden, thereby increasing the likelihood of obtaining the data necessary to justify an adjustment of an initial dose of oral corticosteroid in a timely manner.

[0014] The invention will now be described in more detail with reference to the accompanying drawings, which are not intended to be limiting. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 is a block diagram of a system according to an embodiment. [Diagram 2] FIG. 2 shows a system according to another embodiment. [Figure 3A] FIG. 3A is a flow chart of a method according to an embodiment. [Figure 3B] FIG. 3B is a flowchart of a method according to another embodiment. [Figure 3C] FIG. 3C is a flowchart of a method according to yet another embodiment. [Figure 3D] FIG. 3D is a flowchart of a method according to a further embodiment. [Figure 4] FIG. 4 is a front perspective view of the inhaler. [Diagram 5] FIG. 5 is a cross-sectional internal perspective view of the inhaler shown in FIG. [Figure 6] FIG. 6 is an exemplary exploded perspective view of the inhaler shown in FIG. [Figure 7] FIG. 7 is an exploded perspective view of the top cap and electronics module of the inhaler shown in FIG. [Figure 8] FIG. 8 is a graph of airflow versus pressure through the exemplary inhaler shown in FIG.

[0016] [Detailed Description] It should be understood that the detailed description and specific examples, while indicating exemplary embodiments of the devices, systems and methods, are for purposes of illustration only and are not intended to limit the scope of the invention. These and other features, aspects, and advantages of the devices, systems and methods of the present invention will become better understood from the following description, the appended claims, and the accompanying drawings. It should be understood that the drawings are only schematic and are not drawn to scale. It should also be understood that the same reference numerals are used throughout the figures to represent the same or similar parts.

[0017] Asthma and COPD are chronic inflammatory diseases of the airways. Both are characterized by variable and recurrent symptoms of airflow obstruction and bronchospasm. Symptoms include episodes of wheezing, coughing, chest tightness, and shortness of breath.

[0018] Symptoms are managed by avoiding triggers and by the use of medications, particularly inhaled medications, including inhaled corticosteroids (ICS) and bronchodilators.

[0019] Inhaled corticosteroids (ICS) are steroid hormones used for the long-term control of respiratory diseases. They work by reducing inflammation in the airways. Examples include budesonide, beclomethasone (dipropionate), fluticasone (propionate or furoate), mometasone (furoate), ciclesonide, and dexamethasone (sodium). Parentheses indicate preferred salt or ester formation. Among others are budesonide, beclomethasone, and fluticasone, especially budesonide, beclomethasone dipropionate, fluticasone propionate, and fluticasone furoate.

[0020] Different classes of bronchodilators target different receptors in the airways. Two commonly used classes are the β2-agonists and the anticholinergics.

[0021] Beta2-adrenergic agonists (or "beta2-agonists") act on beta2-adrenergic receptors inducing smooth muscle relaxation and dilating the bronchial passages. They tend to be classified by their duration of action. Examples of long-acting beta2-agonists (LABAs) include formoterol (fumaric acid), salmeterol (xinafoic acid), indacaterol (maleic acid), bambuterol (hydrochloric acid), clenbuterol (hydrochloric acid), olodaterol (hydrochloric acid), carmoterol (hydrochloric acid), tulobuterol (hydrochloric acid) and vilanterol (triphenylacetate). Examples of short-acting beta2-agonists (SABAs) include albuterol (sulfate) and terbutaline (sulfate). Mention may be made, inter alia, of formoterol, salmeterol, indacaterol, vilanterol, and in particular formoterol fumarate, salmeterol xinafoate, indacaterol maleate, vilanterol triphenylacetate.

[0022] Typically, short-acting bronchodilators provide rapid relief from acute bronchoconstriction (and are often referred to as "rescue" or "reliever" drugs), while long-acting bronchodilators help control and prevent symptoms for longer periods of time. However, some fast-acting long-acting bronchodilators may be used as rescue drugs, such as formoterol (fumarate). Thus, rescue drugs provide relief from acute bronchoconstriction. Rescue drugs are taken pro re nata. Rescue drugs may also be in the form of combination products, such as ICS-formoterol (fumarate), typically budesonide-formoterol (fumarate). Thus, rescue drugs are preferably SABAs or fast-acting LABAs, more preferably albuterol (sulfate) or formoterol (fumarate), most preferably albuterol (sulfate).

[0023] Albuterol (also known as salbutamol), typically administered as the sulfate salt, is a preferred rescue medication of the present disclosure.

[0024] Anticholinergics (or "antimuscarinics") block the neurotransmitter acetylcholine by selectively blocking the receptors on nerve cells. When applied locally, anticholinergics act primarily on the M3 muscarinic receptors present in the airways, resulting in smooth muscle relaxation and thus bronchodilatory effects. Examples of long-acting muscarinic antagonists (LAMAs) include tiotropium (bromide), oxitropium (bromide), aclidinium (bromide), ipratropium (bromide), glycopyrronium (bromide), oxybutynin (hydrochloric acid or hydrobromide), tolterodine (tartrate), trospium (chloride), solifenacin (succinic acid), fesoterodine (fumaric acid), and darifenacin (hydrobromide). Mention may be made, inter alia, of tiotropium, aclidinium, umeclidinium and glycopyrronium, in particular tiotropium bromide, aclidinium bromide, umeclidinium bromide and glycopyrronium bromide.

[0025] Many approaches have been taken in preparing and formulating these medications for delivery by inhalation, such as via dry powder inhalers (DPIs), pressurized metered dose inhalers (pMDIs) or nebulizers.

[0026] GINA ( G lobal In initiative for AAccording to the STHMA guidelines, a stepwise approach to the treatment of asthma can be taken. In step 1, representing mild asthma, the patient is given a SABA, such as albuterol sulfate, as needed. The patient may also be given low-dose ICS-formoterol as needed, or low-dose ICS whenever a SABA is taken. In step 2, regular low-dose ICS is given in parallel with the SABA, or low-dose ICS-formoterol is given as needed. In step 3, a LABA is added. In step 4, the dose is increased, and in step 5, further add-on treatments, such as anticholinergics or low-dose oral corticosteroids, are included. Each step can therefore be considered a treatment regimen, and each of the regimens may be configured according to the degree of acute severity of the respiratory disease.

[0027] COPD is the leading cause of death worldwide. It is a heterogeneous long-term disease that includes chronic bronchitis, emphysema, and also involves the small airways. The pathological changes that occur in patients with COPD are predominantly localized in the airways, lung parenchyma, and pulmonary vasculature. Phenotypically, these changes reduce the healthy ability of the lungs to absorb and release gas.

[0028] Bronchitis is characterized by long-term inflammation of the bronchi. Common symptoms include wheezing, shortness of breath, coughing and expectoration of sputum, all of which are very uncomfortable and detrimental to the patient's quality of life. Emphysema is also associated with long-term bronchial inflammation, the inflammatory response of which leads to the breakdown of lung tissue and progressive narrowing of the airways. Over time, the lung tissue loses its natural elasticity and expands. In this way, the efficiency with which gases are exchanged decreases and respiratory air is often trapped within the lungs. This results in localized hypoxia, decreasing the volume of oxygen being delivered into the patient's bloodstream with each inhalation. Thus, the patient experiences shortness of breath and difficulty in breathing.

[0029] Patients living with COPD will routinely experience some, if not all, of these symptoms. Their severity will depend on a range of factors, but will most commonly correlate with disease progression. Regardless of their severity, these symptoms indicate stable COPD, a condition that is maintained and managed through the administration of a variety of medications. Treatments vary but often include inhaled bronchodilators, anticholinergics, long- and short-acting beta2-agonists, and corticosteroids. Medications are often administered as monotherapy or in combination therapy.

[0030] Patients should follow the GOLD guidelines ( G lobal Initiative for Chronic O bstructive L Ung D Patients are classified according to the severity of their COPD using categories defined by the National Institutes of Health (NIH). The categories are labeled A-D, and the recommended first choice of treatment varies by category. Patient group A is recommended a short-acting muscarinic antagonist (SAMA) or a short-acting beta2-agonist (SABA) as needed. Patient group B is recommended a long-acting muscarinic antagonist (LAMA) or a long-acting beta2-agonist (LABA). Patient group C is recommended an inhaled corticosteroid (ICS) + LABA or LAMA. Patient group D is recommended an ICS + LABA and / or LAMA.

[0031] Patients suffering from respiratory diseases such as asthma or COPD suffer from periodic exacerbations beyond the baseline day-to-day fluctuations of their condition. An exacerbation is an acute worsening of respiratory symptoms that requires additional therapy, i.e. beyond maintenance therapy.

[0032] In asthma, add-on therapy for moderate exacerbations is repeated administration of SABAs, oral corticosteroids and / or controlled-flow oxygen (the latter requiring hospitalization). Severe exacerbations add anticholinergics (typically ipratropium bromide), nebulized SABAs or IV magnesium sulfate.

[0033] In COPD, add-on therapy for moderate exacerbations is repeated administration of SABAs, oral corticosteroids, and / or antibiotics. Severe exacerbations require the addition of controlled-flow oxygen and / or respiratory support (both of which require hospitalization).

[0034] Exacerbations within the meaning of this disclosure include both moderate and severe exacerbations.

[0035] A pharmaceutical composition is provided comprising an oral corticosteroid for use in post-exacerbation treatment of a respiratory disease in a subject, the post-exacerbation treatment comprising an initial dose of an oral corticosteroid. By "oral corticosteroid" is meant a corticosteroid that is administered orally (and swallowed).

[0036] Further provided is a method of post-exacerbation treatment of a respiratory disease in a subject, the method comprising treating the subject with an initial dose of an oral corticosteroid.

[0037] The initial dose of oral corticosteroid can be an initial daily (per day) dose of oral corticosteroid. The initial daily dose can be administered at any suitable time, such as in the morning.

[0038] The pharmaceutical composition may be in tablet form, delayed release tablet form, or liquid form.

[0039] As an example of a liquid form, the oral corticosteroid is dissolved or dispersed in an oral solution. Such oral solution can have any suitable concentration of oral corticosteroid, for example, from 1 mg / mL to 20 mg / mL, preferably from 5 mg / mL to 15 mg / mL.

[0040] The pharmaceutical composition can include any suitable oral corticosteroid, such as prednisone, prednisolone (sodium), dexamethasone (sodium), among others. Prednisone and prednisolone (sodium) are included. Prednisolone is the active metabolite of prednisone.

[0041] In some embodiments, an initial dose of prednisone or prednisolone ranges from 5 to 60 mg per day for adults 18 years of age or older.

[0042] Preferably, an initial dose of prednisone or prednisolone ranges from 25 to 60 mg per day for adults 18 years of age or older.

[0043] More preferably, an initial dose of prednisone or prednisolone ranges from 30 to 50 mg daily for adults 18 years of age or older.

[0044] Most preferably, an initial dose of prednisone or prednisolone ranges from 40 to 50 mg daily for adults 18 years of age or older.

[0045] In some embodiments, the initial dose of prednisone or prednisolone ranges from 40 to 50 mg per day for children aged 12 to 17 years.

[0046] In some embodiments, the initial dose of prednisone or prednisolone ranges from 1 to 2 mg / kg per day for children 1 month to 11 years of age.

[0047] Post-exacerbation treatment is continued until the subject meets the inhalation parameter criterion (or, in some non-limiting examples, multiple inhalation parameter criteria) on one or more post-exacerbation inhalations using at least one inhaler, at which point the oral corticosteroid dose is changed from the initial dose.

[0048] Alternatively or additionally, post-exacerbation treatment is continued until satisfaction of a rescue inhaler use criterion (or, in some non-limiting examples, multiple rescue inhaler use criteria) for post-exacerbation use of a rescue inhaler configured to deliver rescue medication to the subject.

[0049] Post-exacerbation treatment comprising the administration of oral corticosteroids may improve patient outcomes and shorten hospital stays. However, the administration of oral corticosteroids is not without problems. In particular, such use of oral corticosteroids is associated with a variety of adverse drug reactions (ADRs).

[0050] ADRs are considered, among other things, to determine the duration of treatment and how treatment should be discontinued. Longer durations of oral corticosteroids tend to necessitate tapering the dose toward the end of treatment, known as weaning, rather than stopping it abruptly. However, this is sometimes done with little or no empirical data to support the reduction.

[0051] It is advisable to monitor the patient's respiratory disease so that the initial dose of oral corticosteroid can be adjusted accordingly. Such monitoring can be used, for example, to justify a dose reduction from the initial dose if the patient's condition is observed to be improving. With chronic oral corticosteroid use, such monitoring can guide planned reductions or increases in the oral corticosteroid dose.

[0052] Post-exacerbation treatment according to the present disclosure continues until the subject has met the inhalation parameter criteria with one or more post-exacerbation inhalations using at least one inhaler and / or until the rescue inhaler use criteria for post-exacerbation use of a rescue inhaler configured to deliver rescue medication to the subject have been met. Post-exacerbation inhalations may be administered by the patient regardless of the purpose of respiratory disease monitoring. Thus, monitoring may be performed in a manner that minimizes patient burden, thereby increasing the likelihood of obtaining the data necessary to justify an adjustment of an initial dose of oral corticosteroid in a timely manner.

[0053] In certain embodiments, the oral corticosteroid dose is reduced relative to the initial dose after satisfaction of the inhalation parameter criteria and / or rescue inhaler use criteria. Satisfaction of either or both of these criteria may thus indicate that the patient has recovered to an extent that a reduction in the oral corticosteroid dose is justified. Thus, satisfaction of either or both of these criteria may help balance the patient's risk associated with respiratory disease and the risk posed by ADRs associated with oral corticosteroids.

[0054] In some embodiments, the oral corticosteroid dose is reduced to zero after the inhalation parameter criteria and / or rescue inhaler use criteria are met. In this case, withdrawal from oral corticosteroid may not be justified because the oral corticosteroid has been administered to the patient for a short period of time, such as less than two weeks, e.g., daily. Nonetheless, the inhalation parameter criteria and / or rescue inhaler use criteria provide an indication of when administration of oral corticosteroid can be safely discontinued.

[0055] In an alternative embodiment, the initial dose is first reduced to a subsequent dose based on satisfaction of an inhalation parameter criterion and / or a rescue inhaler use criterion, and then the subsequent dose is reduced to an additional subsequent dose less than the initial dose based on satisfaction of additional inhalation parameter criterion and / or additional rescue inhaler use criterion.

[0056] In this way, a patient can be gradually weaned off oral corticosteroids based on monitoring of the patient's condition via inhalation administered using an inhaler.

[0057] Such parameterized and / or rescue inhaler guided weaning is particularly useful when oral corticosteroids have been administered to a patient for a relatively long period of time, such as for two weeks or more, e.g., daily, which may be the case due to concerns regarding, for example, the severity of the respiratory disease and / or adrenal insufficiency.

[0058] Alternatively or additionally, the inhalation parameter criteria and / or rescue inhaler use criteria may provide a method to justify increasing the oral corticosteroid dose relative to an initial dose. For example, the oral corticosteroid dose may be increased from an initial dose if the inhalation parameter criteria and / or rescue inhaler use criteria are not met within a predetermined period of time, such as within 1-3 weeks.

[0059] Each of the at least one inhaler may comprise a sensor system configured to measure a post-exacerbation value of an inhalation parameter.

[0060] The rescue inhaler may include a usage determination system configured to determine post-exacerbation usage of the rescue inhaler.

[0061] More generally, satisfaction of inhalation parameter criteria and / or rescue inhaler use criteria may be established empirically and / or based on an individual's baseline values ​​prior to a previous exacerbation, as described in more detail herein.

[0062] In at least some embodiments, the at least one inhaler comprises a maintenance inhaler configured to deliver a maintenance medication to the subject during one or more post-exacerbation inhalations.

[0063] Thus, patients can begin or resume maintenance therapy simultaneously with post-exacerbation treatment with oral corticosteroids. Because patients routinely inhale for administration of the maintenance medication, monitoring of the patient's condition does not require the patient to perform additional measurements, such as spirometry measurements to determine expiratory flow parameters. This reduces the burden on the patient, as previously mentioned.

[0064] In non-limiting examples, the maintenance medication is selected from budesonide, beclomethasone (dipropionate), fluticasone (propionate or furoate), and salmeterol (xinafoate) in combination with fluticasone (propionate or furoate).

[0065] Alternatively or additionally, the at least one inhaler comprises a rescue inhaler configured to deliver rescue medication to the subject during one or more post-exacerbation inhalations.

[0066] The rescue inhaler included in the at least one inhaler may be the same as or different from the rescue inhaler whose post-exacerbation use by the subject is used to determine fulfillment of the rescue inhaler use criteria (in embodiments in which rescue inhaler use criteria are utilized).

[0067] Thus, patient-administered rescue inhalations can be used to monitor the patient's condition with a view to appropriately adjusting the initial dose of oral corticosteroid. Rescue inhaler usage data and / or inhalation parameter data collected during the mandatory rescue inhalation may avoid the need for additional spirometry measurements, thus reducing the burden on the patient.

[0068] Because rescue medication can be used by the subject as needed, use of rescue inhalers provides a useful indicator for tracking recovery after an exacerbation: fewer rescue inhalations, e.g., fewer rescue inhalations per day, would indicate that the subject's condition is improving.

[0069] In certain embodiments, the subject has baseline use of a rescue inhaler, and fulfillment of the rescue inhaler use criteria is determined based on a comparison of post-exacerbation use of a rescue inhaler obtained from one or more post-exacerbation inhalations to the baseline rescue inhaler use.

[0070] Baseline use of a rescue inhaler may be determined, for example, when the subject is not in an exacerbation and is not in a period of exacerbation prior to such an exacerbation, nor in a period of recovery following an exacerbation.

[0071] Baseline rescue inhaler use may be determined, for example, from rescue inhaler use during a baseline period. Such baseline period may be, for example, a period of 5 to 30 days.

[0072] The rescue inhaler use criterion may be met, for example, by the number of daily (per day, every day) post-exacerbation rescue inhaler uses being equal to or less than a predefined threshold daily number of rescue inhaler uses for a minimum period of time, e.g., a minimum number of days. For example, the predefined threshold may be defined by a baseline daily number of rescue inhaler uses, e.g., the baseline average (e.g., mean) daily number of rescue inhaler uses made by the subject.

[0073] Such a baseline daily number of rescue inhaler uses, e.g., a baseline average (e.g., mean) daily number of rescue inhaler uses, may be determined, for example, when the subject is not in an exacerbation and is not in a period of exacerbation prior to such an exacerbation or in a period of recovery after an exacerbation.

[0074] Rescue medications are as defined herein above and are typically SABAs, SAMAs, fast-acting LABAs such as formoterol (fumaric acid), combinations of SAMAs with LABAs and / or ICS, or combinations of LAMAs with LABAs and / or ICS.

[0075] Rescue medication may be in the form of a combination product, for example ICS-formoterol (fumarate), typically budesonide-formoterol (fumarate). Such an approach is commonly referred to as the "MART" ( m aintenance a n.d. r escape t It is called a herapy.

[0076] In non-limiting examples, the rescue agent is selected from albuterol (sulfate), formoterol (fumarate), a combination of budesonide and formoterol (fumarate), a combination of beclomethasone (dipropionate) and albuterol (sulfate), a combination of fluticasone (propionate or furoate) and albuterol (sulfate).

[0077] In some embodiments, determining whether the inhalation parameter criteria have been met is based on inhalation parameters relating to airflow through the inhaler during one or more post-exacerbation inhalations taken by the subject using at least one inhaler.

[0078] In some embodiments, the subject has baseline pulmonary function as indicated by a baseline value of an inhalation parameter, and satisfaction of the inhalation parameter criterion is determined based on a comparison of the post-exacerbation value of the inhalation parameter obtained from the one or more post-exacerbation inhalations to the baseline value.

[0079] The sensor system included in the at least one inhaler may be configured to measure a post-exacerbation value of an inhalation parameter.

[0080] A baseline value for an inhalation parameter may be established, for example, by measurement of a non-exacerbation value of one or more of the inhalation parameters during a period in which the patient is not experiencing an exacerbation.

[0081] The baseline value may be determined, for example, from the inhalation(s) taken by the subject during a baseline period. Such a baseline period may be, for example, from 5 to 30 days in duration.

[0082] Such non-exacerbation value(s) may also be measured, for example, by a sensor system included in at least one inhaler. Alternatively, the non-exacerbation value(s) of the inhalation parameter may be calculated from a spirometer, in other words from an expiratory flow measured when the patient is not in an exacerbation. Such a calculation may be based, for example, on an established correlation between peak expiratory flow and peak inhalation flow.

[0083] The inhalation parameter criteria may be considered more generally as requirements for airflow during one or more post-exacerbation inhalations using at least one inhaler.

[0084] The inhalation parameters may be considered as parameters relating to the airflow during inhalation by the subject using at least one inhaler. The inhalation parameters may serve as a proxy for the subject's pulmonary condition.

[0085] Any suitable inhalation parameters may be considered. In non-limiting examples, the inhalation parameters include, and in some examples consist of, one or more of the following: peak inhalation flow rate, inhalation volume, inhalation duration, and the time taken to reach peak inhalation flow rate (also referred to herein as "time to peak inhalation flow rate").

[0086] During multiple exacerbation inhalations by the patient using the inhaler(s), an increase in peak inhalation flow rate, an increase in inhaled volume, a longer duration of inhalation, and / or a decrease in the time to reach peak inhalation flow rate may indicate an improvement in the patient's pulmonary status. Conversely, in the case of peak inhalation flow rate, inhaled volume, and duration of inhalation, a stable or decreased (or increased in the case of time to reach peak inhalation flow rate) parameter may indicate a worsening of the patient's pulmonary status. Such information is therefore valuable in determining whether, when, and / or how to change the initial dose of oral corticosteroid.

[0087] More generally, a comparison of post-exacerbation values ​​with baseline values ​​allows for an assessment of improvement or worsening of the patient's condition. Such a comparison, showing a regression toward or to, or improvement over, baseline values, can be used to justify a change, particularly a reduction, in the oral corticosteroid dose relative to the initial dose.

[0088] Such a comparison may be quantified in any suitable manner. In a non-limiting example, an inhalation parameter criterion is met by the post-exacerbation value being within a predefined tolerance range relative to the baseline value.

[0089] This can be seen as an assessment of the "proximity" of post-progression values ​​to baseline levels or pre-progression / non-progression levels.

[0090] In certain non-limiting examples, the post-exacerbation value of the inhalation parameter increases toward the baseline value during the return to the baseline lung function, for example when the inhalation parameter is peak inhalation flow rate, inhalation volume, and / or inhalation duration.

[0091] In such instances where the inhalation parameter increases toward the baseline value during return to said baseline lung function, the inhalation parameter criterion may be met by the post-exacerbation value being at least 70% of the baseline value, at least 80% of the baseline value, or at least 90% of the baseline value.

[0092] In at least some embodiments, the post-exacerbation value may comprise an average of multiple post-exacerbation values ​​of the inhalation parameter obtained from multiple said post-exacerbation inhalations.

[0093] A dose of oral corticosteroid may be more reliably altered from an initial dose by basing the alteration of an inhalation parameter criterion on multiple post-exacerbation values, e.g., post-exacerbation values ​​collected over multiple days. In other words, the reliability associated with altering a dose of oral corticosteroid from an initial dose may be increased by using one or more inhalation parameter data points, particularly over multiple days after an exacerbation. An appropriate number of post-exacerbation values ​​may be used to determine an average value that takes into account the variability of such values.

[0094] Also provided is a method, e.g., a computer-implemented method, comprising receiving a baseline value of an inhalation parameter indicative of a subject's baseline lung function, and receiving a post-exacerbation value of the inhalation parameter determined from one or more post-exacerbation inhalations using at least one inhaler.

[0095] The method further comprises determining satisfaction of suitable inhalation parameter criteria for, e.g., altering, a dose of oral corticosteroid administered to the subject post-exacerbation from an initial dose based on a comparison of the post-exacerbation value and the baseline value.

[0096] Alternatively or additionally, the method comprises receiving baseline rescue inhaler use, e.g., a baseline number of rescue inhalations per day (per day, every day), and receiving post-exacerbation rescue inhaler use, e.g., a number of post-exacerbation rescue inhalations per day (per day, every day). Such methods further comprise determining fulfillment of rescue inhalation use criteria suitable for altering, e.g., altering, a dose of oral corticosteroid administered to the subject post-exacerbation from an initial dose based on a comparison of the post-exacerbation rescue inhalation use to the baseline rescue inhalation use.

[0097] The rescue inhaler use criterion may be met, for example, by the number of rescue inhaler uses after one day of exacerbation being equal to or less than a predetermined threshold daily number of rescue inhaler uses. For example, the predetermined threshold may be defined by the baseline daily number of rescue inhaler uses, for example, the baseline average (e.g., mean) daily number of rescue inhaler uses made by the subject, as described above.

[0098] Thus, the method may provide for automated determination of when inhalation parameter criteria and / or rescue inhaler use criteria have been met such that a dose of oral corticosteroid may be altered from an initial dose.

[0099] In some embodiments, the inhalation parameters comprise, or in some cases consist solely of, one or more of the peak inhalation flow rate, the inhalation volume, the inhalation duration, and the time taken to reach the peak inhalation flow rate, as described above.

[0100] Alternatively or additionally, the inhalation parameter criterion is met by the post-exacerbation value being within a predefined tolerance range defined relative to the baseline value, which can provide an assessment of the "proximity" of the post-exacerbation value relative to the baseline level or pre-exacerbation / non-exacerbation level.

[0101] In some embodiments, the post-exacerbation value of the inhalation parameter increases toward the baseline value during the return to said baseline lung function, for example when the inhalation parameter is peak inhalation flow rate, inhalation volume, and / or inhalation duration.

[0102] In such embodiments, the inhalation parameter criterion may be met by the post-exacerbation value being at least 70% of the baseline value, at least 80% of the baseline value, or at least 90% of the baseline value.

[0103] In at least some embodiments, the post-exacerbation value comprises an average of multiple post-exacerbation values ​​of the inhalation parameter obtained from multiple said post-exacerbation inhalations.

[0104] As previously mentioned, any appropriate number of post-progression values ​​can be used to determine the mean value, taking into account the variability of the post-progression values.

[0105] Further provided is a method comprising receiving baseline values ​​of inhalation parameters indicative of baseline lung function of the subject, and receiving post-exacerbation values ​​of the inhalation parameters determined from one or more post-exacerbation inhalations taken by the subject with at least one inhaler, the method further comprising controlling a user interface to communicate the baseline values, and controlling the user interface to communicate the post-exacerbation values ​​to enable comparison of the post-exacerbation values ​​to the at least one baseline value.

[0106] Alternatively or additionally, the method comprises receiving baseline rescue inhaler use, e.g., a baseline number of daily rescue inhaler uses, and receiving post-exacerbation rescue inhaler use, e.g., a number of daily post-exacerbation rescue inhalations. The method further comprises controlling a user interface to communicate the baseline rescue inhaler use, and controlling a user interface to communicate the post-exacerbation rescue inhaler use to enable a comparison of the post-exacerbation rescue inhaler use to the baseline inhaler use.

[0107] By controlling the user interface to allow comparison of baseline values ​​to post-exacerbation values ​​and / or comparison of baseline rescue inhaler use to post-exacerbation rescue inhaler use, the method assists a user, e.g., a clinician, in the technical task of deciding whether and / or how to vary an oral corticosteroid dose from an initial dose.

[0108] Such communication may be accomplished in any suitable manner, such as, for example, a simultaneous display of baseline and post-exacerbation values, and / or a simultaneous display of baseline and post-exacerbation rescue inhaler use on a suitable display device. Such simultaneous display may take any suitable form that allows for comparison.

[0109] In particular, reference is made to graphical representations of values, which may assist a healthcare provider in determining changes in post-exacerbation values ​​and / or post-exacerbation rescue inhaler use over time, and in comparing current post-exacerbation values ​​to baseline values ​​and / or post-exacerbation rescue inhaler use to baseline rescue inhaler use. The baseline values ​​and / or baseline rescue inhaler use may be represented, for example, as lines superimposed on a graph of post-exacerbation values ​​and / or post-exacerbation rescue inhaler use (respectively) versus time.

[0110] Other methods of communicating baseline and post-exacerbation values, and / or baseline and post-exacerbation rescue inhaler use to allow comparisons between them will be apparent to those of skill in the art. For example, baseline values / baseline rescue inhaler use may be displayed on a calibrated (e.g., graph-like) dial, and changes in post-exacerbation values / post-exacerbation rescue inhaler use may be represented by movement of a needle relative to the dial.

[0111] It should be appreciated that the methods summarized above that comprise determining fulfilment of an inhalation parameter criterion and / or fulfilment of a rescue inhaler use criterion may be combined with methods that allow for comparison of baseline values ​​to post-exacerbation values ​​and / or comparison of baseline rescue inhaler use to post-exacerbation rescue inhaler use. Thus, methods that combine these functions are provided.

[0112] Regardless of whether the method comprises determining satisfaction of an inhalation parameter criterion or allowing a comparison of baseline and post-exacerbation values, the baseline values ​​can be determined from one or more inhalations using at least one inhaler when the subject is not in an exacerbation and is not in a period of exacerbation prior to such an exacerbation or in a period of recovery following an exacerbation.

[0113] Further, as noted above, whether the method comprises determining satisfaction of rescue inhaler use criteria or comprises enabling a comparison of baseline rescue inhaler use with post-exacerbation rescue inhaler use, baseline rescue inhaler use can be determined when the subject is not in an exacerbation and is not in a period of exacerbation prior to such an exacerbation or in a period of recovery following an exacerbation.

[0114] The present disclosure also provides a computer program comprising computer program code configured to, when said program is executed on one or more physical computing devices, cause said one or more physical computing devices to perform one or more of the above-mentioned methods.

[0115] Similarly, the present disclosure provides one or more non-transitory computer-readable media having a computer program stored thereon, the computer program comprising computer program code configured to cause one or more physical computing devices to perform one or more of the methods described above when the computer program is executed on one or more physical computing devices.

[0116] A system is provided, comprising at least one inhaler having a sensor system configured to determine a value of an inhalation parameter from an inhalation taken by a subject using the at least one inhaler.

[0117] The system further comprises one or more processors configured to receive baseline values ​​of inhalation parameters indicative of baseline lung function of the subject, and to receive post-exacerbation values ​​of the inhalation parameters determined from one or more post-exacerbation inhalations with the at least one inhaler, The one or more processors are further configured to determine fulfillment of inhalation parameter criteria suitable for altering, e.g., altering, a dose of oral corticosteroid administered to the subject post-exacerbation from an initial dose based on a comparison of the post-exacerbation values ​​to the baseline values.

[0118] Alternatively or additionally, a system is provided that includes a rescue by a subject for delivering rescue medication to the subject, and one or more processors that receive baseline rescue inhaler use, receive post-exacerbation rescue inhaler use, and determine fulfillment of rescue inhaler use criteria for changing a dose of oral corticosteroid administered to the subject post-exacerbation from an initial dose based on a comparison of the post-exacerbation rescue inhaler use to the baseline rescue inhaler use.

[0119] Thus, the system may provide for automated determination of when inhalation parameter criteria are met such that a dose of oral corticosteroid may be altered from an initial dose.

[0120] The system may include, for example, a user interface configured to provide an output responsive to a determination of satisfaction of the inhalation parameter criteria and / or the rescue inhaler use criteria.

[0121] Such output may take the form of, for example, a notification to the health care provider, which may include, for example, an indication as to whether, when, and / or how to change the dose of oral corticosteroid from an initial dose.

[0122] Alternatively or additionally, the system may include a medication container in communication, e.g., wireless communication, with the one or more processors. The medication container includes an oral corticosteroid, e.g., in the form of a tablet or delayed release tablet. In such non-limiting example, the medication container may be responsive to a determination that an inhalation parameter criterion and / or rescue inhaler use criterion has been met to assist the subject in altering a dose of oral corticosteroid from an initial dose.

[0123] As an alternative or in addition to the functionality of the above-mentioned systems, the present disclosure provides a system comprising at least one inhaler having a sensor system and a user interface, the sensor system configured to determine values ​​of inhalation parameters from inhalations performed by a subject using the at least one inhaler.

[0124] The system further comprises one or more processors configured to receive baseline values ​​of inhalation parameters indicative of the subject's baseline lung function and receive post-exacerbation values ​​of the inhalation parameters determined from one or more post-exacerbation inhalations taken by the subject with the at least one inhaler, The one or more processors are further configured to control a user interface to communicate the baseline values, and to control a user interface to communicate the post-exacerbation values ​​to enable a comparison of the post-exacerbation values ​​to the baseline values.

[0125] Alternatively or additionally, a system is provided, the system comprising a rescue inhaler having a usage determination system configured to determine rescue inhaler use by a subject to deliver rescue medication to the subject, and one or more processors configured to receive baseline rescue inhaler use, receive post-exacerbation rescue inhaler use, control a user interface to communicate the baseline rescue inhaler use, and control a user interface to communicate the post-exacerbation rescue inhaler use to enable a comparison of the post-exacerbation rescue inhaler use with the baseline rescue inhaler use.

[0126] By controlling the user interface to communicate baseline and post-exacerbation values ​​to enable comparison of the baseline and post-exacerbation values, and / or to communicate baseline and post-exacerbation rescue inhaler use to enable comparison of post-exacerbation rescue inhaler use to baseline rescue inhaler use, the system assists a user, e.g., a clinician, in the technical task of deciding whether and / or how to vary an oral corticosteroid dose from an initial dose.

[0127] More generally, any embodiment discussed with respect to the post-progression treatment methods and pharmaceutical compositions for the above mentioned uses may apply to the methods, computer programs, non-transitory computer readable media and systems, and any embodiment described with respect to the methods, computer programs, non-transitory computer readable media and systems may apply to the post-progression treatment methods and pharmaceutical compositions.

[0128] Although the above description has focused on post-exacerbation treatment comprising administration of oral corticosteroids, the principles are more broadly applicable. Thus, the present disclosure provides a pharmaceutical composition comprising a drug for use in post-exacerbation treatment of a respiratory disease in a subject, the post-exacerbation treatment comprising an initial dose of drug, the post-exacerbation treatment being continued until inhalation parameter criteria are met by one or more post-exacerbation inhalations taken by the subject using at least one inhaler, and / or until rescue inhaler use criteria are met for post-exacerbation use of a rescue inhaler configured to deliver rescue drug to the subject, at which point a dose of drug is altered from the initial dose.

[0129] The drug may be or comprise any drug employed to treat respiratory disorders, e.g., in post-exacerbation treatment. For example, the drug may be an ICS, a LABA, a LAMA, a SABA, a SAMA, or any combination of such drugs. Specific examples of such ICS, LABA, LAMA, SABA, and SAMA drugs are identified herein above.

[0130] The agent can be, for example, a biological agent for treating a respiratory disease in a subject, for example, for treating a post-exacerbation of a respiratory disease. The biological agent can be, or comprise, for example, one or more of omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab.

[0131] The term "biologic agent" may refer to a drug that contains one or more active substances made by or derived from a biological source.

[0132] The relatively high cost of biologic agents means that the duration of administration of a biologic agent tends to require careful consideration and justification. The systems and methods of the present disclosure may provide reliable indications to justify whether, when, and / or how to change a biologic agent from an initial dose. For example, a reduction in a dose of a biologic agent may be justified if inhalation parameter criteria and / or rescue inhaler use criteria are met.

[0133] FIG. 1 is a block diagram of a system 10 according to an embodiment. The system 10 includes a first inhaler 100 and one or more processors 14. The first inhaler 100 may be used to deliver a maintenance or rescue medication, such as a SABA, to a subject. The SABA may include, for example, albuterol. The first inhaler 100 may include a sensor system 12A and / or a usage determination system 12B.

[0134] System 10, for example, may alternatively be referred to as an "inhaler assembly."

[0135] The sensor system 12A may be configured to measure values ​​of inhalation parameters from an inhalation taken by a subject using the first inhaler. The sensor system 12A may comprise one or more sensors, such as, for example, one or more pressure sensors, temperature sensors, humidity sensors, orientation sensors, acoustic sensors, and / or optical sensors. The pressure sensor(s) may include air pressure sensors (e.g., atmospheric pressure sensors), differential pressure sensors, absolute pressure sensors, and / or the like. The sensors may employ Microelectromechanical Systems (MEMS) and / or Nanoelectromechanical Systems (NEMS) technology.

[0136] A pressure sensor may be particularly suitable for measuring the parameter, since airflow during inhalation by the subject may be monitored by measuring the associated pressure changes. As will be described in more detail with reference to Figures 4-8, the pressure sensor may, for example, be located within or in fluid communication with the flow path through which air and medicament are drawn by the subject during inhalation. Alternative methods of measuring the parameter, such as via a suitable flow sensor, will be apparent to those skilled in the art.

[0137] Alternatively or additionally, the sensor system 12A may comprise a differential pressure sensor. The differential pressure sensor may comprise, for example, a dual port type sensor for measuring the pressure difference across a section of the airway through which the subject inhales. Alternatively, a single port gauge type sensor may be used. The latter works by measuring the pressure difference in the airway during inhalation and no flow. The difference in readings corresponds to the pressure drop associated with inhalation.

[0138] Although not shown in FIG. 1, the system 10 may further include a second inhaler for delivering a medication, such as a rescue medication or a maintenance medication, to the subject. The first and second inhalers may be configured to deliver, for example, different medications from each other. The second inhaler may include a sensor system 12A and / or a usage determination system 12B that are distinct from the sensor system 12A and the usage determination system 12B of the first inhaler 100. The sensor system 12A of the second inhaler may be configured to measure a value of an inhalation parameter from an inhalation performed by the subject using the second inhaler. For example, the sensor system 12A may include an additional pressure sensor, such as an additional microelectromechanical system pressure sensor or an additional nanoelectromechanical system pressure sensor, to measure a value of the inhalation parameter.

[0139] In this manner, inhalation of medication, such as rescue and / or maintenance medication, may be used to gather information related to a subject's lung function and / or lung health.

[0140] Each inhalation may be associated with a decrease in pressure in the airflow path relative to when no inhalation is occurring. The point at which pressure is lowest may correspond to the peak inhalation flow rate. The sensor system 12A may detect this point of inhalation. The peak inhalation flow rate may vary from inhalation to inhalation and may depend on the subject's clinical condition. An increase in the peak inhalation flow rate may indicate that the patient's condition is improving after an exacerbation.

[0141] The pressure change associated with each inhalation may alternatively or additionally be used to determine the inhalation volume. This may be accomplished, for example, by first determining the flow rate over the time of the inhalation using the pressure change measured by the sensor system 12A, from which the total inhalation volume may then be derived. Inhalations with larger inhalation volumes may indicate an improvement following an exacerbation of the patient's condition.

[0142] The pressure change associated with each inhalation may alternatively or additionally be used to determine the duration of inhalation. The time may be recorded, for example, from the initial decrease in pressure measured by pressure sensor 12A, which coincides with the start of inhalation, until the pressure returns to a pressure corresponding to no inhalation occurring. As post-exacerbation treatment progresses, the subject's ability to inhale for extended periods may increase, so that longer inhalation times may indicate patient recovery.

[0143] In one embodiment, the inhalation parameters include, for example, the time to peak inhalation flow rate, as an alternative or in addition to the peak inhalation flow rate, the inhalation volume, and / or the inhalation duration. This time to peak inhalation flow rate parameter may be recorded, for example, from the first decrease in pressure measured by the sensor system 12A, which coincides with the start of inhalation, to the pressure reaching a minimum value corresponding to the peak flow rate. Patients whose condition is improving tend to have a shorter time to reach the peak inhalation flow rate. Note that this is an example of an inhalation parameter whose value increases during an exacerbation. The post-exacerbation value may then decrease back towards the baseline value. In this case, the inhalation parameter criterion may be met if the post-exacerbation value is below a predefined threshold value, which may be defined proportionally to the baseline value. For example, the inhalation parameter criterion may be met if the post-exacerbation value is less than 130%, or less than 120%, or less than 110% of the baseline value.

[0144] In a non-limiting example, the first and / or second inhalers may be configured such that, in the case of normal inhalation, the respective medicament is dispensed for about 0.5 seconds after the start of inhalation. The subject's inhalation reaching a peak inhalation flow rate only after 0.5 seconds, for example about 1.5 seconds, may partially indicate that the subject's lung condition is impaired. An improvement in the subject's condition may be observed accordingly by approaching a shorter time to peak inhalation flow rate, particularly the specified time of about 0.5 seconds.

[0145] In a non-limiting example shown in FIG. 1, the usage determination system 12B is configured to register an inhalation (or inhalations) made by a subject (e.g., each rescue inhalation by the subject if the inhaler is a rescue inhaler, and each maintenance inhalation by the subject if the inhaler is a maintenance inhaler).

[0146] In a non-limiting example, the inhaler 100 includes a medicament reservoir (not shown in FIG. 1) and a dose metering assembly (not shown in FIG. 1) configured to meter a dose of rescue medicament from the reservoir. The usage determination system 12B may be configured to register the metering of a dose by the dose metering assembly, each metering thereby being indicative of a rescue inhalation made by the subject using the first inhaler 100. The inhaler 100 may thus be configured to monitor the number of inhalations of medicament, as a dose must be metered via the dose metering assembly before being inhaled by the subject. A non-limiting example of a metering arrangement is described in more detail with reference to FIGS. 4-8.

[0147] Alternatively or additionally, the use-determining system 12B may register each inhalation in a different manner and / or based on additional or alternative feedback as would be obvious to one of skill in the art. For example, the use-determining system 12B may be configured to register an inhalation by a subject when feedback from the sensor system 12A indicates that an inhalation by a user has occurred (such as when a pressure measurement or flow rate exceeds a predetermined threshold associated with a successful inhalation). Furthermore, in some examples, the use-determining system 12B may be configured to register an inhalation when a switch on the inhaler or a user input on an external device (e.g., a touch screen on a smartphone) is manually actuated by the subject before, during, or after an inhalation.

[0148] To register each inhalation, a sensor (e.g., a pressure sensor) may be included, for example, in the use-determining system 12B. In such an example, the use-determining system 12B and the sensor system 12A may employ respective sensors (e.g., pressure sensors) or may employ a common sensor (e.g., a common pressure sensor) configured to serve the functions of both use detection and inhalation parameter sensing.

[0149] If a sensor is included in the usage determination system 12B, the sensor may be used, for example, to confirm or assess the extent to which a dose metered via the dose metering assembly is inhaled by the user, as described in more detail with reference to Figures 4-8.

[0150] In one embodiment, the sensor system 12A and / or the usage determination system 12B includes an acoustic sensor configured to sense noises generated when a subject inhales through the respective inhaler 100. The acoustic sensor may include, for example, a microphone.

[0151] In a non-limiting example, each inhaler may include a capsule arranged to spin when a subject inhales through the device, the spinning of the capsule generating a noise for detection by an acoustic sensor, The spinning of the capsule may thus provide a suitably decipherable noise, e.g., a rattle, to derive usage and / or inhalation parameter data.

[0152] Algorithms may be used to analyze the acoustic data to determine, for example, usage data (if an acoustic sensor is included in the usage determination system 12B) and / or values ​​for inhalation parameters related to airflow during inhalation (if an acoustic sensor is included in the sensor system 12A).

[0153] For example, algorithms such as those described in P. Colthorpe et al., "Adding Electronics to the Breezhaler: Satisfying the Needs of Patients and Regulators," Respiratory Drug Delivery 2018, 1, 71-80 may be used. Once generated sounds are detected, the algorithms may process the raw acoustic data to generate usage and / or inhalation parameter data.

[0154] The one or more processors 14 included in the system 10 may be configured in a variety of ways. As represented generally in Figure 1 by the arrow between the sensor system 12A and the processor 14, the processor 14 may receive inhalation parameter data from the sensor system 12A. Similarly, the one or more processors 14 may receive usage data from the usage determination system 12B.

[0155] The fulfillment of the rescue inhaler use criterion is based on the post-exacerbation use of rescue inhaler. Because rescue medication can be used by the subject as needed, the use of rescue inhaler can be a useful indicator for tracking recovery after an exacerbation. A reduction in post-exacerbation rescue inhalation, for example, a reduction in rescue inhalation per day (per day), as determined via the use determination system 12B, can indicate, for example, an improvement in the subject's condition.

[0156] In one embodiment, the one or more processors 14 are configured to receive baseline use of the rescue inhaler by the subject. Such baseline use may be provided to the one or more processors 14 in any suitable manner. For example, the baseline use may be derived, e.g., by the one or more processors 14, from non-exacerbation rescue inhaler use determined by the use determination system 12B, as described above.

[0157] The one or more processors 14 are also configured to receive post-exacerbation use of a rescue inhaler as determined via the use determination system 12B.

[0158] In some embodiments, the one or more processors 14 are further configured to determine fulfillment of rescue inhaler use criteria for changing the dose of oral corticosteroid administered to the subject post-exacerbation from the initial dose based on a comparison of the post-exacerbation use to the baseline use.

[0159] Alternatively or additionally, the one or more processors 14 are configured to receive baseline values ​​of inhalation parameters indicative of the subject's baseline lung function. Such baseline values ​​may be provided to the one or more processors 14 in any suitable manner. For example, the baseline values ​​may be derived, e.g., by the one or more processors 14, from one or more non-exacerbation values ​​measured by the sensor system 12A, as described above.

[0160] The one or more processors 14 are also configured to receive post-exacerbation values ​​of inhalation parameters determined from one or more post-exacerbation inhalations with the inhaler(s) 100. Such post-exacerbation values ​​may be received by the one or more processors 14 from the sensor system 12A.

[0161] In some embodiments, the one or more processors 14 are configured to determine fulfillment of an inhalation parameter criterion for altering the dose of oral corticosteroid administered to the subject post-exacerbation from the initial dose based on a comparison of the post-exacerbation value to the baseline value.

[0162] Thus, system 10 may provide for automated determination of when inhalation parameter criteria and / or rescue inhaler use criteria have been met such that a dose of oral corticosteroid may be altered from an initial dose.

[0163] 1, system 10 may include a user interface configured to provide an output responsive to a determination of satisfaction of the inhalation parameter criteria and / or rescue inhaler use criteria. Such an output may be in the form of, for example, a notification to the healthcare provider. Such a notification may include, for example, an indication as to whether, when, and / or how to modify the oral corticosteroid dose from an initial dose, as discussed above.

[0164] Alternatively or additionally, system 10 may include a medication container, such as a pillbox (not shown), in communication, e.g., wireless communication, with one or more processors 14. The medication container includes an oral corticosteroid, e.g., in the form of a tablet or delayed release tablet. In such a non-limiting example, the medication container may be responsive to a determination that an inhalation parameter criterion and / or rescue inhaler use criterion has been met to assist the subject in varying a dose of oral corticosteroid from an initial dose.

[0165] This may be accomplished in any suitable manner. The medication container may include a user interface controlled by one or more processors to provide indications regarding whether, when, and / or how the dose of oral corticosteroid should be changed from an initial dose. Alternatively or additionally, the medication container may include a lockable component configured to restrict access to at least some dosage forms of oral corticosteroid in the medication container in response to determining that the inhalation parameter criteria and / or rescue inhaler use criteria are met. This may assist the patient in changing to a different, e.g., lower, dose of oral corticosteroid from the initial dose upon satisfaction of the inhalation parameter criteria and / or rescue inhaler use criteria.

[0166] In another embodiment, the one or more processors 14 are configured to receive baseline values ​​of inhalation parameters indicative of the subject's baseline lung function, and to receive post-exacerbation values ​​of inhalation parameters determined from one or more post-exacerbation inhalations taken by the subject using the inhaler 100. Such post-exacerbation values ​​may be received by the one or more processors 14 from the sensor system 12A, as described above. The one or more processors 14 are further configured to control a user interface, e.g., including a display device (not shown in FIG. 1 ) or in the form of a display device, to communicate the baseline values, and to control the user interface to communicate the post-exacerbation values ​​to enable comparison of the post-exacerbation values ​​to the baseline values.

[0167] Alternatively or additionally, the one or more processors 14 are also configured to receive baseline use of the rescue inhaler by the subject. The one or more processors 14 are configured to receive post-exacerbation use of the rescue inhaler. Such post-exacerbation use may be received by the one or more processors 14 from the use determination system 12B, as described above. The one or more processors 14 are further configured to control a user interface, e.g., including a display device (not shown in FIG. 1 ) or in the form of a display device, to communicate the baseline use of the rescue inhaler, and to control the user interface to communicate the post-exacerbation use of the rescue inhaler to enable a comparison of the post-exacerbation use to the baseline use.

[0168] In this manner, system 10 assists a user, such as a clinician, in the technical task of determining whether and / or how to vary a dose of oral corticosteroid from an initial dose.

[0169] More generally, the one or more processors 14 of the system 10 may be provided and implemented in any suitable manner. In a non-limiting example, the one or more processors 14 may be provided separately from the respective first and / or second inhalers, where the one or more processors 14 receive rescue inhalation count and parameter data transmitted thereto from the sensor system 12A and usage determination system 12B of the first and / or second inhalers. By processing the data in such an external processing unit, e.g., a processing unit of an external device, or a server, e.g., a remote server, battery life of the inhaler may be advantageously preserved.

[0170] In an alternative non-limiting example, the one or more processors 14 may be an integral part of the first and / or second inhaler, such as, for example, contained within a main housing or top cap (not shown in FIG. 1) of the first and / or second inhaler, such that there is no need to rely on connectivity to an external device.

[0171] It may also be envisaged that some of the functions of the one or more processors 14 may be performed by an internal processing unit included in the first and / or second inhaler, and other functions of the one or more processors 14 may be performed by an external processing unit.

[0172] More generally, system 10 may include a communication module (not shown in FIG. 1 ) configured to communicate, for example, the determined post-exacerbation rescue inhaler use and / or the determined post-exacerbation values ​​of the inhalation parameters to the subject and / or a healthcare provider (e.g., a clinician). The subject and / or clinician can then take appropriate action accordingly. For example, if a smartphone processing unit is included in the processor, communication capabilities of the smartphone, such as SMS, email, Bluetooth, etc., may be employed to communicate the determined post-exacerbation rescue inhaler use and / or the determined post-exacerbation values ​​to the healthcare provider.

[0173] 2 shows a non-limiting example of the system 10. The system 10 includes a first inhaler 100, an external device 15 (e.g., a mobile device), a public and / or private network 16 (e.g., the Internet, a cloud network, etc.), and a personal data storage device 17. The external device 15 may include, for example, a smartphone, a personal computer, a laptop, a wireless-enabled media device, a media streaming device, a tablet device, a wearable device, a Wi-Fi or wireless communication-enabled television, or any other suitable Internet protocol-enabled device. For example, the external device 15 may be configured to transmit and / or receive RF signals via a Wi-Fi communication link, a Wi-MAX communication link, a Bluetooth® or Bluetooth® Smart communication link, a Near Field Communication (NFC) link, a cellular communication link, a television white space (TVWS) communication link, or any combination thereof. The external device 15 can transfer data to the personal data storage device 17 via the public network 16 and / or the private network 16.

[0174] The first inhaler 100 may also include communications circuitry, such as a Bluetooth® radio, for transferring data to an external device 15. The data may include the above-mentioned post-exacerbation values ​​of inhalation parameter data and / or post-exacerbation rescue inhaler use data.

[0175] The first inhaler 100 may also receive data from the external device 15, such as, for example, program instructions, operating system changes, dosing information, alerts or notifications, acknowledgements, etc.

[0176] The external device 15 may include at least a portion of the one or more processors 14, thereby processing, analyzing, and / or communicating the inhalation parameter data. For example, the external device 15 may process the data to determine satisfaction of inhalation parameter criteria and / or rescue inhaler use criteria, as represented by block 18A, and provide such information to and remotely stored on the personal data storage device 17.

[0177] In some non-limiting examples, the external device 15 may also process the data to identify no inhale, low inhale, good inhale, over-inhale, and / or exhale events, as represented by block 18B. The external device 15 may also process the data to identify under-use, over-use, and optimal use events, as represented by block 18C. The external device 15 may, for example, process the data to estimate the number of doses delivered and / or remaining doses, and identify error conditions, such as an error condition associated with a timestamp error flag indicating that the subject did not inhale a dose of medication metered by the dose metering assembly. The external device 15 may include a display and software for visually presenting usage parameters through a graphical user interface.

[0178] Although illustrated as being stored in the personal data storage device 17, in some embodiments, at least some of the determinations of no inhalation events, low inhalation events, good inhalation events, and excessive inhalation events, as represented by block 18A, and / or exhalation events, as represented by block 18B, and / or under-use events, over-use events, and optimal use events, as represented by block 18C, may be stored in the external device 15.

[0179] If the above-mentioned drug container is also included in the system 10, the drug container may include additional communication circuitry, such as a Bluetooth® radio, for communicating with external devices 15, in particular one or more processors 14, as previously described.

[0180] 3A-3D show flow charts of methods 20, 30, 40, 50 according to embodiments of the present disclosure. Methods 20, 30, 40, 50 may be performed by a system such as system 10 shown in FIG. 1 and / or FIG. 2. For example, one or more of the first and / or second inhaler, external device 15, and / or personal data storage device 17 may be configured to perform all or part of methods 20, 30, 40, 50. That is, any combination of steps 22, 24, 26, and 32, 34, 36, 38, and 42, 44, 46, and 52, 54, 56, 58 may be performed by any combination of the first inhaler, second inhaler, external device 15, and / or personal data storage device 17.

[0181] Turning to Figure 3A, method 20 comprises receiving baseline values ​​of inhalation parameters indicative of baseline lung function of a subject 22, and receiving post-exacerbation values ​​of the inhalation parameters determined from one or more post-exacerbation inhalations with at least one inhaler 24. Although Figure 3A shows receiving the baseline values ​​22 occurring before receiving the post-exacerbation values ​​24, the order of these operations may be reversed.

[0182] The method 20 further comprises determining 26 satisfaction of suitable inhalation parameter criteria for, e.g., altering, a dose of oral corticosteroid administered to the subject post-exacerbation from an initial dose based on a comparison of the post-exacerbation value to the baseline value.

[0183] Thus, method 20 may provide for automated determination of when inhalation parameter criteria are met such that a dose of oral corticosteroid may be altered from an initial dose.

[0184] Turning to FIG. 3B, the method 30 comprises receiving 32 a baseline value of an inhalation parameter indicative of the subject's baseline lung function, and receiving 34 a post-exacerbation value of the inhalation parameter determined from one or more post-exacerbation inhalations taken by the subject using at least one inhaler.

[0185] The method 30 further comprises controlling a user interface to communicate 36 the baseline value, and controlling the user interface to communicate 38 the post-progression value to enable comparison of the post-progression value to at least one baseline value.

[0186] It should be noted that the order of steps 32, 34, 36, 38 depicted in FIG. 3B should not be considered limiting, and method 30 may be performed in any suitable order.

[0187] Turning to FIG. 3C, method 40 comprises receiving baseline rescue inhaler use 42, receiving post-exacerbation rescue inhaler use 44, and determining fulfillment of a rescue inhaler use criterion for changing a dose of oral corticosteroid administered to the subject post-exacerbation from an initial dose based on a comparison of the post-exacerbation rescue inhaler use to the baseline rescue inhaler use 46.

[0188] Thus, method 40 may provide for automated determination of when rescue inhaler use criteria have been met such that a dose of oral corticosteroid may be altered from an initial dose.

[0189] Although FIG. 3C shows receiving baseline rescue inhaler use 42 occurring before receiving post-exacerbation rescue inhaler use 44, the order of these operations may be reversed.

[0190] Turning to FIG. 3D, method 50 includes receiving baseline rescue inhaler use 52, receiving post-exacerbation rescue inhaler use 54, controlling a user interface to communicate the baseline rescue inhaler use 56, and controlling a user interface to communicate the post-exacerbation rescue inhaler use 58 to enable a comparison of the post-exacerbation rescue inhaler use to the baseline rescue inhaler use.

[0191] It should be noted that the order of steps 52, 54, 56, 58 depicted in FIG. 3D should not be considered limiting, and method 50 may be performed in any suitable order.

[0192] 4-8 provide non-limiting examples of inhalers that may be included in system 10. FIG.

[0193] 4 provides a front perspective view of a first inhaler 100 according to a non-limiting example embodiment. The inhaler 100 may be, for example, a breath-actuated inhaler. The inhaler 100 may include a top cap 102, a main housing 104, a mouthpiece 106, a mouthpiece cover 108, an electronics module 120, and / or a vent 126. The mouthpiece cover 108 may be hinged to the main housing 104 such that it can be opened and closed to expose the mouthpiece 106. Although hinged, the mouthpiece cover 108 may be connected to the inhalation device 100 via other types of connections. Additionally, although the electronics module 120 is illustrated as being housed within the top cap 102 on top of the main housing 104, the electronics module 120 may be integrated and / or housed within the main body 104 of the inhaler 100.

[0194] 5 is a cross-sectional interior perspective view of an exemplary inhaler 100. Inside the main housing 104, the inhaler 100 may include a medicament reservoir 110 (e.g., a hopper), a bellows 112, a bellows spring 114, a yoke (not shown), a dosing cup 116, a dosing chamber 117, a deagglomerator 121, and a flow passage 119. The medicament reservoir 110 may contain a medicament for delivery to a subject, such as a dry powder medicament. When the mouthpiece cover 108 is moved from a closed position to an open position, the bellows 112 may compress and deliver a dose of the medicament from the medicament reservoir 110 to the dosing cup 116. The subject may then inhale through the mouthpiece 106 to receive the dose of the medicament.

[0195] Airflow resulting from the subject's inhalation causes the deagglomerator 121 to aerosolize the dose of drug by breaking up agglomerates of drug in the dosing cup 116. The deagglomerator 121 may be configured to aerosolize the drug when the airflow through the flow passage 119 meets or exceeds a certain flow rate or is within a certain range. Once aerosolized, the dose of drug may travel from the dosing cup 116 into the dosing chamber 117, through the flow passage 119, and out of the mouthpiece 106 to the subject. If the airflow through the flow passage 119 does not meet or exceed a certain rate or is not within a certain range, the drug may remain in the dosing cup 116. If the drug in the dosing cup 116 is not aerosolized by the deagglomerator 121, another dose of drug may not be delivered from the drug reservoir 110 when the mouthpiece cover 108 is subsequently opened. Thus, a dose of medication may accumulate in the dosing cup 116 until the dose is aerosolized by the deagglomerator 121. Once the dose of medication is delivered, a dose confirmation may be stored in memory in the inhaler 100 as dose confirmation information.

[0196] When the subject inhales through the mouthpiece 106, air may enter the vent and provide an airflow for delivering medicament to the subject. The flow passage 119 may extend from the dosing chamber 117 to the end of the mouthpiece 106 and may include the dosing chamber 117 and an interior portion of the mouthpiece 106. The dosing cup 116 may be present within or adjacent to the dosing chamber 117. Additionally, the inhaler 100 may include a dose counter 111, which may be configured to be initially set to the total number of doses in the medicament reservoir 110 and to be decremented by one each time the mouthpiece cover 108 is moved from a closed position to an open position.

[0197] The top cap 102 may be attached to the main housing 104. For example, the top cap 102 may be attached to the main housing 104 via the use of one or more clips that engage recesses on the main housing 104. The top cap 102 may overlap a portion of the main housing 104 when connected, for example, such that a substantial pneumatic seal exists between the top cap 102 and the main housing 104.

[0198] 6 is an exploded perspective view of the exemplary inhaler 100 with the top cap 102 removed to expose the electronic module 120. As shown in FIG. 6, the top surface of the main housing 104 may include one or more (e.g., two) orifices 146. One of the orifices 146 may be configured to receive the slider 140. For example, when the top cap 102 is attached to the main housing 104, the slider 140 may protrude through one of the orifices 146 through the top surface of the main housing 104.

[0199] 7 is an exploded perspective view of the top cap 102 and electronic module 120 of an exemplary inhaler 100. As shown in FIG. 7, the slider 140 may define an arm 142, a stopper 144, and an end 145. The end 145 may be the bottom of the slider 140. The end 145 of the slider 140 may be configured to abut a yoke located within the main housing 104 (e.g., when the mouthpiece cover 108 is in a closed or partially open position). The end 145 may be configured to abut an upper surface of the yoke when the yoke is in any radial orientation. For example, the upper surface of the yoke may include a plurality of openings (not shown), and the end 145 of the slider 140 may be configured to abut the upper surface of the yoke, for example, regardless of whether one of the openings is aligned with the slider 140.

[0200] The top cap 102 may include a slider guide 148 configured to receive the slider spring 146 and the slider 140. The slider spring 146 may reside within the slider guide 148. The slider spring 146 may engage an inner surface of the top cap 102, and the slider spring 146 may engage (e.g., abut) a top (e.g., proximal end) of the slider 140. When the slider 140 is disposed within the slider guide 148, the slider spring 146 may be partially compressed between the top of the slider 140 and the inner surface of the top cap 102. For example, the slider spring 146 may be configured such that the end 145 of the slider 140 remains in contact with the yoke when the mouthpiece cover 108 is closed. The end 145 of the slider 140 may also remain in contact with the yoke while the mouthpiece cover 108 is opened or closed. The stopper 144 of the slider 140 can, for example, engage with a stopper of the slider guide 148 such that the slider 140 is retained within the slider guide 148 through opening and closing of the mouthpiece cover 108, or vice versa. The stopper 144 and slider guide 148 can be configured to limit the up and down (e.g., axial) movement of the slider 140. This limit can be less than the up and down movement of the yoke. Thus, when the mouthpiece cover 108 is moved to a fully open position, the yoke can continue to move up and down toward the mouthpiece 106, but the stopper 144 can stop the up and down movement of the slider 140 such that the end 145 of the slider 140 no longer contacts the yoke.

[0201] More generally, the yoke may be mechanically connected to the mouthpiece cover 108 and configured to move to compress the bellows spring 114 when the mouthpiece cover 108 is opened from the closed position, and then release the compressed bellows spring 114 when the mouthpiece cover reaches the fully open position, causing the bellows 112 to deliver a dose from the medicament reservoir 110 to the dosing cup 116. The yoke may be in contact with the slider 140 when the mouthpiece cover 108 is in the closed position. The slider 140 may be arranged to be moved by the yoke when the mouthpiece cover 108 is opened from the closed position, and to move away from the yoke when the mouthpiece cover 108 reaches the fully open position. This arrangement may be considered a non-limiting example of the dose metering assembly described above, since opening the mouthpiece cover 108 results in a dose of medicament being metered.

[0202] Movement of the slider 140 during dose metering may cause the slider 140 to engage and activate the switch 130. The switch 130 may trigger the electronic module 120 to register the dose metering. Thus, the slider 140 and the switch 130, together with the electronic module 120, may correspond to a non-limiting example of the usage determination system 12B described above. The slider 140, in this example, may be considered as a means by which the usage determination system 12B is configured to register the metering of a dose by the dose metering assembly, each metering thereby being indicative of an inhalation taken by the subject using the inhaler 100.

[0203] Actuation of switch 130 by slider 140 may also, for example, transition electronic module 120 from a first power state to a second power state and cause an inhalation by the subject through mouthpiece 106 to be sensed.

[0204] The electronic module 120 may include a printed circuit board (PCB) assembly 122, a switch 130, a power source (e.g., battery 126), and / or a power source holder 124. The PCB assembly 122 may include surface mounted components such as a sensor system 128, wireless communication circuitry 129, the switch 130, and / or one or more indicators (not shown), such as one or more light emitting diodes (LEDs). The electronic module 120 may include a controller (e.g., a processor) and / or memory. The controller and / or memory may be physically separate components from the PCB 122. Alternatively, the controller and memory may be part of another chipset mounted on the PCB 122, e.g., the wireless communication circuitry 129 may include the controller and / or memory for the electronic module 120. The controller of electronic module 120 may include a microcontroller, a programmable logic device (PLD), a microprocessor, an application specific integrated circuit (ASIC), a field programmable gate array (FPGA), or any suitable processing device or control circuitry.

[0205] The controller may access information from and store data in the memory. The memory may include any type of suitable memory, such as non-removable and / or removable memory. The non-removable memory may include random access memory (RAM), read-only memory (ROM), or any other type of memory storage device. The removable memory may include a subscriber identity module (SIM) card, a memory stick, a secure digital (SD) memory card, or the like. The memory may be internal to the controller. The controller may also access and store data from and in memory that is not physically located within the electronic module 120, such as on a server or a smartphone.

[0206] The sensor system 128 may include one or more sensors. The sensor system 128 may be an example of the sensor system 12A. The sensor system 128 may include one or more sensors of different types, such as, but not limited to, one or more pressure sensors, temperature sensors, humidity sensors, orientation sensors, acoustic sensors, and / or optical sensors. The one or more pressure sensors may include air pressure sensors (e.g., atmospheric pressure sensors), differential pressure sensors, absolute pressure sensors, and / or the like. The sensors may employ Microelectromechanical System (MEMS) and / or Nanoelectromechanical System (NEMS) technology. The sensor system 128 may be configured to provide instantaneous readings (e.g., pressure values) and / or readings (pressure values) aggregated over time to the controller of the electronic module 120. As shown in Figures 5 and 6, the sensor system 128 may be external to the flow path 119 of the inhaler 100 and ventilatedly connected to the flow path 119.

[0207] A controller of the electronic module 120 may receive signals corresponding to measurements from the sensor system 128. The controller may use the signals received from the sensor system 128 to calculate or determine one or more airflow indicators that may indicate a profile of airflow through the flow path 119 of the inhaler 100. For example, if the pressure system 128 records a pressure change of 0.3 kilopascals (kPA), the electronic module 120 may determine that the change corresponds to an airflow rate of approximately 45 liters per minute (Lpm) through the flow path 119.

[0208] Figure 8 is a graph of airflow rate versus pressure. The airflow rates and profiles shown in Figure 8 are merely examples, and the determined airflow rates may depend on the size, shape, and design of the inhalation device 100 and its components.

[0209] The one or more processors 14 may generate personalized data in real time, for example, by comparing the signals received from the sensor system 128 and / or the determined airflow indicator to one or more thresholds or ranges as part of an evaluation of how the inhaler 100 is being used and / or whether the use is likely to result in the delivery of a full dose of medication. For example, if the determined airflow indicator corresponds to an inhalation having an airflow rate below a certain threshold, the one or more processors 14 may determine that there was no inhalation or that there was an insufficient inhalation from the mouthpiece 106 of the inhaler 100. If the determined airflow indicator corresponds to an inhalation having an airflow rate above a certain threshold, the one or more processors 14 may determine that there was an excessive inhalation from the mouthpiece 106. If the determined airflow indicator corresponds to an inhalation having an airflow rate within a certain range, the one or more processors 14 may determine that the inhalation is "good" or will result in the delivery of a full dose of medication.

[0210] The pressure measurements and / or calculated airflow indicators may indicate the quality or strength of an inhalation from the inhaler 100. For example, when compared to a particular threshold or range of values, the readings and / or indicators may be used to classify an inhalation as a particular type of event, such as a good inhalation event, a low inhalation event, a no inhalation event, or an excessive inhalation event. The classification of an inhalation may be a usage parameter stored as personalized data for the subject.

[0211] A no-inhale event may be associated with a pressure measurement reading and / or airflow indicator below a particular threshold, such as an airflow rate below 30 Lpm. A no-inhale event may occur when the subject does not inhale through the mouthpiece 106 after opening the mouthpiece cover 108 and during the measurement cycle. A no-inhale event may also occur if the subject's inhalation effort is insufficient to ensure proper delivery of the medicament through the flow passage 119 (e.g., if the inhalation effort generates insufficient airflow rate to activate the deagglomerator 121, thereby aerosolizing the medicament in the dosing cup 116).

[0212] A low inhalation event may be associated with a pressure measurement and / or airflow indicator within a particular range, such as an airflow rate between 30 Lpm and 45 Lpm. A low inhalation event may occur when a subject inhales through the mouthpiece 106 after opening the mouthpiece cover 108 and the subject's inhalation effort results in at least a partial dose of the medication being delivered through the flow passage 119. That is, the inhalation need only be sufficient to activate the deagglomerator 121 such that at least a portion of the medication is aerosolized from the dosing cup 116.

[0213] A successful inhalation event may be associated with a pressure measurement and / or airflow indicator that exceeds a low inhalation event, such as an airflow rate between 45 Lpm and 200 Lpm. A successful inhalation event may occur when a subject inhales through the mouthpiece 106 after opening the mouthpiece cover 108 and the subject's inhalation effort is sufficient to ensure proper delivery of the medication through the flow passage 119 (e.g., when the inhalation effort generates sufficient airflow to activate the deagglomerator 121 and aerosolize a dose of the medication in the dosing cup 116).

[0214] An over-inhalation event may be associated with a pressure measurement and / or airflow indicator that exceeds a good inhalation event, such as an airflow rate of more than 200 Lpm. An over-inhalation event may occur when a subject's inhalation effort exceeds normal operating parameters of the inhaler 100. An over-inhalation event may also occur if a subject's inhalation effort is within normal ranges but the device 100 is not properly positioned or held during use. For example, if the air vent is blocked or obstructed (e.g., by a finger or thumb) while the subject is inhaling through the mouthpiece 106, the calculated airflow rate may exceed 200 Lpm.

[0215] Any suitable threshold or range may be used to classify a particular event. Some or all of the events may be used. For example, a no inhale event may be associated with an airflow rate of less than 45 Lpm, and a good inhale event may be associated with an airflow rate between 45 Lpm and 200 Lpm. Thus, a low inhale event may not be used at all.

[0216] The pressure measurements and / or the calculated airflow indicator may also indicate a direction of flow through the flow passage 119 of the inhaler 100. For example, if the pressure measurements reflect a negative change in pressure, the reading may indicate air flowing out of the mouthpiece 106 via the flow passage 119. If the pressure measurements reflect a positive change in pressure, the reading may indicate air flowing into the mouthpiece 106 via the flow passage 119. Thus, the pressure measurements and / or airflow indicator may be used to determine if the subject is exhaling into the mouthpiece 106, which may indicate that the subject is not using the device 100 properly.

[0217] The personalized data (e.g., pressure indicators, airflow indicators, lung function indicators, dosing confirmation information, etc.) collected from or calculated based on the use of the inhaler 100 may be computed and / or evaluated (e.g., partially or wholly) via an external device. More specifically, the wireless communication circuitry 129 in the electronic module 120 may include a transmitter and / or a receiver (e.g., a transceiver) as well as additional circuitry. For example, the wireless communication circuitry 129 may include a Bluetooth chipset (e.g., a Bluetooth Low Energy chipset), a ZigBee chipset, a Thread chipset, etc. Thus, the electronic module 120 may wirelessly provide personalized data such as pressure measurements, airflow indicators, lung function measurements, dosing confirmation information, and / or other aspects related to the use of the inhaler 100 to an external device such as a smartphone. The personalized data may be provided to the external device in real time to enable the determination of the above mentioned possibilities based on personalized data about the user of the inhaler, such as time of use, real-time data from the inhaler 100 indicating how the inhalation device 100 is being used, and real-time data regarding the subject's lung function and / or medical treatment. The external device may include software for processing the received information and providing compliance and adherence feedback to the user of the inhaler 100 via a graphical user interface (GUI).

[0218] The airflow index may include personalized data collected in real time from the inhaler 100, such as one or more of the average inhalation / exhalation flow rate, the peak inhalation / exhalation flow rate (e.g., maximum inspiration received), the inhalation / exhalation volume, the time to peak inhalation / exhalation, and / or the duration of inhalation / exhalation. The airflow index may also indicate the direction of flow through the flow passage 119. That is, a negative change in pressure may correspond to inhalation from the mouthpiece 106, and a positive change in pressure may correspond to exhalation into the mouthpiece 106. When calculating the airflow index, the electronic module 120 may be configured to remove or minimize any distortions caused by environmental conditions. For example, the electronic module 120 may re-zero to account for changes in atmospheric pressure before or after calculating the airflow index. One or more pressure measurements and / or airflow index may be time-stamped and stored in the memory of the electronic module 120.

[0219] In addition to the airflow index, the inhaler 100 or another computing device may use the airflow index to generate additional personalized data. For example, the controller of the electronic module 120 of the inhaler 100 may convert the airflow index into other indices indicative of the subject's lung function and / or lung health as understood by a physician, such as a peak inspiratory flow index, a peak expiratory flow index, and / or a forced expiratory volume in one second (FEV1). The electronic module 120 of the inhaler may use a mathematical model, such as a regression model, to determine a measure of the subject's lung function and / or lung health. The mathematical model may identify a correlation between the total volume of inhalation and FEV1. The mathematical model may identify a correlation between the peak inspiratory flow and FEV1. The mathematical model may identify a correlation between the total volume of inhalation and peak expiratory flow. The mathematical model may identify a correlation between the peak inspiratory flow and peak expiratory flow.

[0220] The battery 126 may provide power to the components of the PCB 122. The battery 126 may be any suitable power source for providing power to the electronic module 120, such as, for example, a coin cell battery. The battery 126 may be rechargeable or non-rechargeable. The battery 126 may be housed by a battery holder 124. The battery holder 124 may be secured to the PCB 122 such that the battery 126 remains in continuous contact with the PCB 122 and / or is in electrical communication with the components of the PCB 122. The battery 126 may have a particular battery capacity that may affect the lifespan of the battery 126. As described further below, the distribution of power from the battery 126 to one or more components of the PCB 122 may be managed to ensure that the battery 126 is able to power the electronic module 120 for the useful lifespan of the inhaler 100 and / or the medication contained therein.

[0221] In the connected state, the communication circuitry and memory may be powered on and the electronic module 120 may be "paired" with an external device such as a smartphone. The controller may retrieve data from the memory and wirelessly transmit the data to the external device. The controller may retrieve and transmit data currently stored in the memory. The controller may also retrieve and transmit a portion of the data currently stored in the memory. For example, the controller may determine which portions have already been transmitted to the external device and then transmit the portions that have not been transmitted previously. Alternatively, the external device may request specific data from the controller, such as any data collected by the electronic module 120 after a specific time or since the last transmission to the external device. The controller may retrieve specific data from the memory, if any, and transmit the specific data to the external device.

[0222] The data stored in the memory of the electronic module 120 (e.g., the signal generated by the switch 130, the pressure measurement readings obtained by the sensor system 128, and / or the airflow indicators calculated by the controller of the PCB 122) may be transmitted to an external device, which may process and analyze the data to determine usage parameters associated with the inhaler 100. Additionally, a mobile application resident on the mobile device may generate feedback for the user based on the data received from the electronic module 120. For example, the mobile application may generate daily, weekly, or monthly reports, provide confirmation of error events or notifications, provide educational feedback to the subject, and / or the like.

[0223] Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the techniques of the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite articles "a" or "an" do not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be interpreted as limiting the scope.

Claims

1. 1. A pharmaceutical composition comprising an oral corticosteroid for use in post-exacerbation treatment of a respiratory disease in a subject, the post-exacerbation treatment comprising an initial dose of the oral corticosteroid, the post-exacerbation treatment continuing until satisfaction of an inhalation parameter criterion with one or more post-exacerbation inhalations by the subject using at least one inhaler and / or satisfaction of a rescue inhaler use criterion for post-exacerbation use of a rescue inhaler configured to deliver rescue medication to the subject, at which time a dose of the oral corticosteroid is changed from the initial dose.

2. the at least one inhaler comprises a maintenance inhaler configured to deliver a maintenance medicament to the subject during the one or more post-exacerbation inhalations. A pharmaceutical composition for the use described in claim 1.

3. the at least one inhaler comprises a rescue inhaler configured to deliver rescue medication to the subject during the one or more post-exacerbation inhalations. A pharmaceutical composition for the use described in claim 1.

4. the dose of the oral corticosteroid is reduced relative to the initial dose after the inhalation parameter criterion is met and / or the rescue inhaler use criterion is met; A pharmaceutical composition for the use described in claim 1.

5. the dose of the oral corticosteroid is reduced to zero after the inhalation parameter criteria and / or the rescue inhaler use criteria are met; A pharmaceutical composition for the use described in claim 1.

6. the subject has baseline rescue inhaler use, and fulfillment of the rescue inhaler use criteria is determined based on a comparison of post-exacerbation rescue inhaler use to the baseline rescue inhaler use. A pharmaceutical composition for the use described in claim 1.

7. the subject has a baseline pulmonary function as indicated by a baseline value of an inhalation parameter; Satisfaction of the inhalation parameter criterion is determined based on a comparison of post-exacerbation values ​​of the inhalation parameter obtained from the one or more post-exacerbation inhalations to the baseline value. A pharmaceutical composition for the use described in claim 1.

8. The inhalation parameter criterion is met by the post-exacerbation value being within a predefined tolerance range defined relative to the baseline value. A pharmaceutical composition for the use described in claim 7.

9. The inhalation parameters include at least one of a peak inhalation flow rate, an inhalation volume, and an inhalation duration. A pharmaceutical composition for the use according to claim 7 or claim 8.

10. The inhalation parameters include time to reach peak inhalation flow rate. A pharmaceutical composition for the use according to claim 7 or claim 8.

11. The post-exacerbation value of the inhalation parameter increases toward the baseline value during the return to the baseline lung function, and the inhalation parameter criterion is met by the post-exacerbation value being at least 70% of the baseline value. A pharmaceutical composition for the use according to claim 7 or claim 8.

12. The pharmaceutical composition comprises: in one of the following forms: tablet, delayed release tablet, and liquid; A pharmaceutical composition for the use according to any one of claims 1 to 8.

13. receiving a baseline value of an inhalation parameter indicative of baseline pulmonary function of the subject; receiving post-exacerbation values ​​of the inhalation parameters determined from one or more post-exacerbation inhalations using at least one inhaler; and determining fulfillment of an inhalation parameter criterion for altering an initial dose of oral corticosteroid administered to the subject after an exacerbation based on a comparison of the post-exacerbation value to the baseline value.

14. receiving baseline rescue inhaler use; receiving post-exacerbation rescue inhaler use; and determining fulfillment of a rescue inhaler usage criterion for changing an oral corticosteroid dose administered to the subject post-exacerbation from an initial dose based on a comparison of the post-exacerbation rescue inhaler usage to the baseline rescue inhaler usage.

15. The baseline value is determined from one or more inhalations using the at least one inhaler when the subject is not experiencing an exacerbation. The method of claim 13.

16. The baseline rescue inhaler use is determined when the subject is not in an exacerbation. The method of claim 14.

17. One or more non-transitory computer-readable media, The computer readable medium having a computer program stored thereon, the computer program comprising computer program code configured to, when executed on one or more physical computing devices, cause the one or more physical computing devices to perform the method of any one of claims 13 to 16.

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