Devices, kits, and methods for delivering medication via the lungs

Abstract

Disclosed herein are devices, kits, and methods of use thereof for administering a medication by depositing aerosol particles to the lungs. In some embodiments, the device of the present disclosure comprises a timer that controls an indicator to the user of when to inhale and exhale, and aerosolizes a pharmaceutical composition and / or provides aerosol particles to user only when providing indication to the user to inhale.

Description

DEVICES, KITS, AND METHODS FOR DELIVERING MEDICATION VIA THELUNGSCROSS REFERENCE

[0001] This application claims benefit of U.S. Provisional Application No. 63 / 632,437, filed April 10, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Cardiac arrhythmia (also dysrhythmia) is a term for any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heartbeat may be too fast or too slow and may be regular or irregular.

[0003] Atrial arrhythmia therapy is a field with a high level of unmet clinical need. Many drugs used today have been on the market since the early 1980s and 1990s and are mostly inadequate due to either lack of efficacy or a side-effect profile that is often cardiac related, that necessitates extensive monitoring of the patient.

[0004] What is needed for fast and safe cardioversion (resolution of arrhythmia) is therapy that:(a) minimizes risk of acceleration of ventricular rate before cardioversion;(b) slows atrio-ventricular (AV) conduction so that there is ventricular rate control and cardioversion at the same time;(c) causes minimal to no effect in prolonging the QRS interval above the upper range of normal value (about 120 milliseconds) and should have a low risk of torsade de pointes;(d) causes minimal to no negative inotropic effect; it should have only mild negative chronotropic effect, without the risk of severe bradycardia when the patient reverts to sinus rhythm;(e) causes minimal to no hypotension; and(f) causes no adverse event other than one that is mild, is transient (i.e. lasting no more than several minutes), does not require treatment with oral medication or DC cardioversion, and has no sequelae.

[0005] None of the current approved drug products exhibit these characteristics. High oral and intravenous (IV) doses required to compensate for absorption, metabolism, and dilution result in blood high blood concentrations for an extended period of time that can cause the dangerous adverse cardiac events like pro-arrhythmias, QT prolongation, and torsade de pointes. FELDMAN et al., “Analysis of Coronary Response to Various Doses of IntracoronaryNitroglycerin,” Circulation, 66:321-327 (1982); and BARBATO et al., “Adrenergic Receptors in Human Atherosclerotic Coronary Arteries,” Circulation, 111 :288-294 (2005). Comorbid conditions also limit use of ideal drugs in some patients, for example the case with intravenous adenosine. GAGLIONE et al., “Is There Coronary Vasoconstriction after Intracoronary Beta- adrenergic Blockade in Patients with Coronary Artery Disease,” J Am Coll Cardiol, 10:299-310 (1987). Drugs like verapamil and diltiazem injections are second line of therapy requiring close monitoring of patients. NOGUCHI et al., “Effects of Intracoronary Propranolol on Coronary Blood Flow and Regional Myocardial Function in Dogs,” Eur J Pharmacol., 144(2):201 - 10 (1987); and ZALEWSKI et al., “Myocardial Protection during Transient Coronary Artery Occlusion in Man: Beneficial Effects of Regional Beta-adrenergic Blockade,” Circulation, 73:734-73 (1986).

[0006] Paroxysmal atrial fibrillation (PAF) is a subset of the overall atrial fibrillation (AF) population and is estimated to be 25-30% of the overall AF population. Estimates by the CDC of the number of patients affected by AF in the United States range from about 2.7 million to 6.1 million. The population of PAF patients is estimated to be 900,000 to 1.5 million worldwide.

[0007] Paroxysmal supraventricular tachycardia (PSVT) is a type of arrhythmia that affects about 500,000 to 600,000 patients in the United States.

[0008] Ablation techniques, e.g., RF ablation, are often used to treat arrhythmias. But ablation is expensive with the cost typically ranging from about $25,000 to $36,000 per procedure. Despite the high expense, ablation may not completely correct the arrhythmia. Often, multiple ablation procedures are required to achieve a satisfactory therapeutic result.

[0009] Oral medications, e.g., pills, tend to require high doses and long time for onset of action. The oral dose for heart medications generally tends to be well over 1 mg. High doses increase the likelihood of side effects and drug-drug interactions as these patients typically take multiple medications. The time for onset for oral cardiovascular medications tends to be around 60 minutes. Oral anti arrhythmic medications have been predominantly developed for prevention whereas acute treatment is given intravenously.

[0010] Intravenous injection usually requires a hospital setting for administering a medicine and typically involves a visit to the emergency room (ER). These overheads result in this therapy being expensive compared to therapies where the patients can self-administer their medicines. Intravenous injection requires a dose that is higher than what is actually needed in the heart to compensate for dilution and metabolism. Drug injected by IV passes through the right side of the heart and then the lungs before reaching the left side of the heart. (See FIG. 1) The drug remains in the blood stream at a high concentration bathing all the organs and tissues with thisdrug in a high concentration, until the drug gets excreted through the kidneys or through other metabolic routes (e.g., hepatic). As a result, IV drugs may cause unwanted side effects. Drugs administered via the IV route are significantly diluted in the venous blood volume and lungs before reaching the cardiac circulation.

[0011] Injecting a drug to the heart directly is usually a last-resort taken by a cardiologist as a life saving measure in an emergency. The doses of the drugs injected directly into the heart in this manner are usually less than their IV and / or oral doses.

[0012] In some cases, an unplanned surgery is necessary to save the patient's life. Of course, unplanned surgeries are expensive and risky to the patient.

[0013] Cardiac arrhythmias are associated with disabling symptoms like tightness around the chest, palpitations, feeling tired, shortness of breath, and sometimes chest pain.

[0014] In view of the above, arrhythmias frequently result in emergency room (ER) visits, where intravenous drugs are administered, sometimes necessitating an extended length of stay (several hours) in the emergency room and in some cases also leading to admission to the hospital. Pipeline Insights: Antiarrhythmics, Datamonitor (June 2006); and TWISS et al., “Efficacy of Calcium Channel Blockers as Maintenance Therapy for Asthma,” British J of Clinical Pharmacology, 53(3): 243-249 (2002).

[0015] In light of the current complexity and cost of treatment, improved devices, methods, and compositions for treating heart conditions is needed. InCarda has described improved compositions and methods for treating heart conditions via administration of aerosolized medications by inhalation (U.S. patent Nos. US 11547663 B2, US 11020384 B2, US 11007185 B2, US 10744087 B2, US 10668015 B2, US 10660578 B2, US 10441537 B2, US 10045939 B2, US 10010294 B2, US 8974828 B2).

[0016] In light of the challenges of the existing art, it is evident that there remains a need for improved aerosolization devices and methods for treating heart conditions that are inexpensive enough to be disposable, and thus facilitate use in the hospital setting.SUMMARY

[0017] The present disclosure provides devices and methods for treating certain heart conditions. Other features and advantages of the present disclosure will be set forth in the description of invention that follows, and in part will be apparent from the description or may be learned by practice of the invention.

[0018] In some embodiments, the present disclosure provides a device for administering aerosol particles to a subject, the device comprising:(a) an aerosolization unit configured to aerosolize a pharmaceutical composition to generate the aerosol particles;(b) an indicator; and(c) a timer, wherein the timer is:(i) set with a designated inhalation time value and a designated exhalation time value;(ii) configured to cause the indicator to indicate, via a perceptible signal, occurrence of a designated inhalation period, and following the designated inhalation period, indicate, via the perceptible signal, occurrence of a designated exhalation period, wherein each designated inhalation period lasts for an interval of time equal to the designated inhalation time value, and each designated exhalation period lasts for an interval of time equal to the designated exhalation time value;(iii) configured to cause the aerosolization unit to activate at the beginning of each designated inhalation period and remain activated for an active period, wherein each active period independently lasts for an interval of time that is no longer than the designated inhalation time value; and cause the aerosolization unit to deactivate at the end of each active period, wherein during each active period, the aerosolization unit aerosolizes the pharmaceutical composition and delivers the aerosol to the subject through a mouthpiece of the aerosolization unit, wherein the designated inhalation period and the designated exhalation period are set to occur consecutively and alternate over a course of deposition of the aerosol particles.

[0019] In some embodiments, the timer is a microcontroller. In some embodiments, the timer is electronically coupled to a relay that interrupts supply of power to a source of aerosol generation in the aerosolization unit.

[0020] In some embodiments, the source of aerosol generation is a vibrating mesh of a vibrating mesh nebulizer.

[0021] In some embodiments, the perceptible signal is audible, tactile, or visual. In some embodiments, the indicator is a light. In some embodiments, the indicator is a video screen and the perceptible signal is a graphic displayed on the video screen.

[0022] In some embodiments, during the designated inhalation period, the perceptible signal is a rising bar, and during the designated exhalation period, the perceptible signal is a falling bar. In some embodiments, the designated inhalation time value is from about 1 second to about 6 seconds and the designated exhalation time value is from about 1 second to about 8 seconds. In some embodiments, the designated inhalation time value is about 4 seconds and the designatedexhalation time value is about 4.25 seconds.

[0023] In some embodiments, each designated exhalation period comprises a rest period that occurs during the terminal portion of one or more designated exhalation periods, wherein the timer is configured to cause the indicator to indicate to the subject to neither inhale nor exhale during each rest period. In some embodiments, each rest period is from about 0.1 seconds to about 0.5 seconds in duration.

[0024] In some embodiments, the aerosolization unit comprises a vibrating mesh nebulizer. In some embodiments, the device comprises:(a) a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the first apertures each having an exit opening with a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size;(b) a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm; wherein at least some of the plurality of first apertures are within the diameters of the liquid supply cavities defined by the second apertures, and wherein the first material and the second material form a mesh for use in the vibrating mesh nebulizer.

[0025] In some embodiments, the aerosolization unit is a single-use aerosolization unit.

[0026] In some embodiments, each active period is set to last for an interval of time that is equal to the designated inhalation time value.

[0027] In some embodiments, at least one active period is set to last for an interval of time that is equal to a fraction of the designated inhalation time value. In some embodiments, each active period is set to last no longer than a fraction of the designated inhalation time value. In some embodiments, the timer is configured to cause the duration of an active period to be longer than a duration of a preceding active period.

[0028] In some embodiments, for each active period within an initial set of active periods of a dosing session, the timer is configured to increase the duration of the active period relative to the duration of the immediately preceding active period. In some embodiments, the initial set of active periods consists of the first three, first four, first five, first six, first seven, first eight, first nine, or first ten active periods of the dosing session. In some embodiments, the timer is configured to cause each active period subsequent to the initial set of active periods to beconstant in duration. In some embodiments, the timer is configured to cause each active period subsequent to the initial set of active periods to last for a duration that is equal to the duration of the last active period of the initial set of active periods.

[0029] In some embodiments, the timer is configured to increase the duration of the active period from an initial value to a terminal value over the initial set of active periods, wherein the initial value is from about 0.5 seconds to about two seconds, and the terminal value is from about 2.5 seconds to about four seconds. In some embodiments, the timer is configured to increase the duration of the active period from an initial value to a terminal value over the initial set of active periods, wherein the initial value is about one second, and the terminal value is about three seconds. In some embodiments, the initial set of active periods comprises a first active period, a second active period, a third active period, and a fourth active period, wherein the first active period is about one second, the second active period is about 1.5 seconds, the third active period is about two seconds, the fourth active period is about 2.5 seconds, and each active period subsequent to the fourth active period is about three seconds.

[0030] In some embodiments, causing the aerosolization unit to activate comprises causing the aerosolization unit to begin aerosolizing the pharmaceutical composition. In some embodiments, causing the aerosolization unit to activate comprises causing aerosol to be supplied to a mouthpiece of the aerosolization unit. In some embodiments, causing the aerosolization unit to activate comprises causing a valve to open, thereby allowing passage of aerosol particles from a source of aerosol generation in the aerosolization unit (e.g., a vibrating mesh of a vibrating mesh nebulizer) to a mouthpiece of the aerosolization unit. In some embodiments, causing the aerosolization unit to activate comprises causing a relay to supply power from a power source to the source of aerosol generation (e.g., a vibrating mesh of a vibrating mesh nebulizer). In some embodiments, the aerosolization unit comprises a vibrating mesh nebulizer, wherein the vibrating mesh nebulizer comprises a vibrating mesh, wherein causing the aerosolization unit to activate comprises causing the vibrating mesh to vibrate.

[0031] In some embodiments, the present disclosure provides a kit comprising a device provided herein and a topical anesthetic.

[0032] In some embodiments, the present disclosure provides a kit for treating atrial arrhythmia comprising a device provided herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises an effective amount of flecainide or a pharmaceutically- acceptable salt thereof.

[0033] In some embodiments, the pharmaceutical composition is provided in unit dose form. In some embodiments, the unit dose comprises about 10 mg to about 200 mg flecainide acetate. Insome embodiments, flecainide acetate is provided as an aqueous formulation at a concentration ranging from 45 to 90 mg / mL. In some embodiments, the course of deposition of aerosol particles is sufficient to exhaust the aqueous formulation.

[0034] In some embodiments, the present disclosure provides a method of administering an aerosol to a subject, the method comprising: aerosolizing a pharmaceutical composition via a nebulizer to generate the aerosol over a course of a plurality of cycles, each cycle consisting of: a designated inhalation period, wherein each designated inhalation period lasts for an interval of time equal to a designated inhalation time value, wherein the aerosolizing occurs only during an active period that begins at the start of each designated inhalation period and lasts for an interval of time that is no more than the designated inhalation time value; and a designated exhalation period, wherein each designated exhalation period lasts for an interval of time equal to a designated exhalation time value; providing indication to the subject of occurrence of each designated inhalation period or each designated exhalation period via a perceptible signal; and instructing the subject to conduct, in synchrony with the perceptible signal, (i) a single inhalation during each designated inhalation period, and (ii) a single exhalation during each designated exhalation period.

[0035] In some embodiments, each designated exhalation period comprises a rest period that occurs during the terminal portion of each designated exhalation period, wherein during each rest period, the subject neither inhales nor exhales. In some embodiments, each rest period is from about 0.1 seconds to about 1 second in duration. In some embodiments, each rest period is about 0.25 seconds in duration.

[0036] In some embodiments, the method further comprises instructing the subject to continue inhaling the aerosol in synchrony with the perceptible signal until a unit dose of the pharmaceutical composition is depleted.

[0037] In some embodiments, the pharmaceutical composition comprises an anti arrhythmic agent and the subject suffers from cardiac arrythmia.

[0038] In some embodiments, the method further comprises, after a first unit dose of the pharmaceutical composition has been administered, administering a second unit dose of the pharmaceutical composition upon determining that the subject still suffers from the cardiac arrythmia. In some embodiments, the second unit dose is equal to the first unit dose. In some embodiments, the second unit dose is one-half of the first unit dose. In some embodiments, thesecond unit dose is administered about 10 minutes to about 1 hour after administration of the first unit dose is completed.

[0039] In some embodiments, the method further comprises instructing the subject to pause inhalation of the aerosol after about one half of the unit dose has been administered, and resume inhalation of the remaining half of the unit dose after a 30 second to three minute break.

[0040] In some embodiments, the method further comprises instructing the subject to:(i) inhale the aerosol in synchrony with the perceptible signal for a first duration that is from about 3 minutes to about 4 minutes;(ii) after said first duration, pause inhalation for a second duration that is from about 30 seconds to about 90 seconds; and(iii) after said second duration, resume inhalation in synchrony with the perceptible signal for a third duration that is from about 3 minutes to about 4 minutes.

[0041] In some embodiments, the present disclosure provides a method of administering an aerosol to a subject, the method comprising: aerosolizing a pharmaceutical composition via a nebulizer to generate the aerosol over a course of a plurality of cycles, each cycle consisting of: a designated inhalation period, wherein each designated inhalation period lasts for an interval of time equal to a designated inhalation time value, wherein the aerosolizing occurs only during an active period that begins at the start of each designated inhalation period and lasts for an interval of time that is no more than the designated inhalation time value; and a designated exhalation period, wherein each designated exhalation period lasts for an interval of time equal to a designated exhalation time value; providing indication to the subject of occurrence of each designated inhalation period or each designated exhalation period via a perceptible signal.

[0042] In some embodiments, the subject conducts, in synchrony with the perceptible signal, a single inhalation of the aerosol during each designated inhalation period, and a single exhalation during each designated exhalation period.

[0043] In some embodiments, each designated exhalation period comprises a rest period that occurs during the terminal portion of each designated exhalation period, wherein during each rest period, the subject neither inhales nor exhales. In some embodiments, each rest period is from about 0.1 seconds to about 1 second in duration.

[0044] In some embodiments, the subject continues inhaling the aerosol in synchrony with the perceptible signal until a unit dose of the pharmaceutical composition is depleted.

[0045] In some embodiments, the pharmaceutical composition comprises an anti arrhythmic agent and the subject suffers from cardiac arrythmia.

[0046] In some embodiments, the method further comprises, after a first unit dose of the pharmaceutical composition has been administered, administering a second unit dose of the pharmaceutical composition upon determining that the subject still suffers from the cardiac arrythmia. In some embodiments, the second unit dose is equal to the first unit dose. In some embodiments, the second unit dose is one-half of the first unit dose. In some embodiments, the second unit dose is administered about 10 minutes to about 1 hour after administration of the first unit dose is completed. In some embodiments, the subject pauses inhalation of the aerosol after about one half of the unit dose has been administered, and resumes inhalation of the remaining half of the unit dose after a 30 second to three minute break.

[0047] In some embodiments, the subject:(i) inhales the aerosol in synchrony with the perceptible for a first duration that is from about 3 minutes to about 4 minutes;(ii) after said first duration, pauses inhalation for a second duration that is from about 30 seconds to about 90 seconds; and(iii) after said second duration, resumes inhalation in synchrony with the perceptible signal for a third duration that is from about 3 minutes to about 4 minutes.

[0048] In some embodiments, the nebulizer is a vibrating mesh nebulizer. In some embodiments, the nebulizer is single-use.

[0049] In some embodiments, the perceptible signal is audible, tactile, or visual. In some embodiments, the perceptible signal is provided by an indicator. In some embodiments, the indicator is a light. In some embodiments, the indicator is a video screen and the perceptible signal is a graphic displayed on the video screen.

[0050] In some embodiments, each active period lasts for an interval of time that is equal to the designated inhalation time value. In some embodiments, at least one active period lasts for an interval of time that is equal to a fraction of the designated inhalation time value.

[0051] In some embodiments, the method further comprises increasing the duration of an active period relative to a duration of a preceding active period in the plurality of cycles. In some embodiments, the method further comprises increasing the duration of an active period relative to that of the immediately preceding active period for each successive active period within an initial set of active periods of a dosing session. In some embodiments, the initial set of active periods consists of the first three, first four, first five, first six, first seven, first eight, first nine, or first ten active periods of the dosing session.

[0052] In some embodiments, the timer is configured to cause each active period subsequent to the initial set of active periods to be constant in duration. In some embodiments, each active period subsequent to the initial set of active periods lasts for a duration that is equal to the duration of the last active period of the initial set of active periods. In some embodiments, over the initial set of active periods, the timer increases the duration of the active period from an initial value to a terminal value, wherein the initial value is from about 0.5 seconds to about two seconds, and the terminal value is from about 2.5 seconds to about four seconds.

[0053] In some embodiments, over the initial set of active periods, the timer increases the duration of the active period from an initial value to a terminal value, wherein the initial value is about one second, and the terminal value is about 3 seconds. In some embodiments, the initial set of active periods comprises a first active period, a second active period, a third active period, a fourth active period, and a fifth active period, wherein the first active period is about one second, the second active period is about 1.5 seconds, the third active period is about two seconds, the fourth active period is about 2.5 seconds, and the fifth active period is about three seconds. In some embodiments, each active period subsequent to the fifth active period lasts for an interval of time equal to the fifth active period.

[0054] In some embodiments, the providing indication further comprises modulating the perceptible signal over time according to a waveform, wherein each period of the waveform has a duration equal to the sum of the designated inhalation time value and the designated exhalation time value. In some embodiments, the modulating comprises modulating the frequency or intensity of an audible tone. In some embodiments, the modulating comprises modulating a dimension of a two-dimensional graphic displayed on a video screen.

[0055] In some embodiments, the designated inhalation time value is from about 1 second to about 6 seconds and the designated exhalation time value is from about 1 second to about 8 seconds. In some embodiments, the designated inhalation time value is 2 seconds and the designated exhalation time value is 3 seconds. In some embodiments, the designated inhalation time value is 4.25 seconds and the designated exhalation time value is 4 seconds. In some embodiments, the designated inhalation time value is 3 seconds and the designated exhalation time value is 4 seconds.

[0056] In some embodiments, the plurality of cycles is sufficient to exhaust the pharmaceutical composition. In some embodiments, the device produces aerosol at a designated liquid output rate.

[0057] In some embodiments, the designated liquid output rate is adjusted to at least 0.3 mL / min and particle mass median aerodynamic diameter is less than 4 pm with a geometric standarddeviation less than 1.8.

[0058] In some embodiments, the pharmaceutical composition comprises an anti arrhythmic medication. In some embodiments, the pharmaceutical composition comprises amiodarone, digitoxin, digoxin, dofetilide, dronedarone, flecainide, fluindione, phenindione, procainamide, quinidine, sotalol, or warfarin, or pharmaceutically-acceptable salts thereof. In some embodiments, the medication is delivered to the heart via the lungs.

[0059] In some embodiments, the subject suffers from cardiac arrhythmia, and wherein the aerosol particles comprise a therapeutically-effective amount of an anti arrhythmic agent. In some embodiments, the pharmaceutical composition is in unit-dose form, wherein the unit dose comprises a therapeutically-effective amount of a class 1c antiarrhythmic drug. In some embodiments, the 1c antiarrhythmic drug is flecainide or a pharmaceutically-acceptable salt thereof. In some embodiments, the 1c antiarrhythmic drug is flecainide acetate. In some embodiments, the therapeutically effective amount is from about 10 mg to about 200 mg.

[0060] In some embodiments, the pharmaceutical composition is an aqueous formulation comprising from about 45 to about 90 mg / mL flecainide acetate. In some embodiments, the pharmaceutical composition is an aqueous formulation comprising about 75 mg / mL flecainide acetate.

[0061] In some embodiments, a target serum concentration of flecainide of at least 200 ng / mL is achieved in the subject. In some embodiments, a target serum concentration of flecainide of at least 300 ng / mL is achieved in the subject. In some embodiments, a target serum concentration of flecainide of at least 400 ng / mL is achieved in the subject. In some embodiments, a target serum concentration of flecainide of at least 500 ng / mL is achieved in the subject.

[0062] In some embodiments, the subject is administered the aerosol in a medically supervised setting. In some embodiments, the subject self-administers the medication.

[0063] In some embodiments, the administration minimizes sustained cough or throat irritation that normally results from deposition of the medication into the oropharyngeal region.INCORPORATION BY REFERENCE

[0064] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0065] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will beobtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0066] FIG. 1 is a diagram that illustrates the passage of intravenous drugs through the heart and lungs before reaching coronary arteries, hence coronary circulation.

[0067] FIG. 2A is a diagram that illustrates the passage of an inhaled drug of the present disclosure from the lungs directly to the left atrium, left ventricle, and then into the coronary arteries.

[0068] FIG. 2B is a diagram that illustrates the passage of an inhaled drug of the present disclosure from the pulmonary vein to the left atrium.

[0069] FIG. 3 is a chart illustrating that molecules with high Log-P values and those that have high lipid solubility are likely to exhibit faster absorption through the lung.

[0070] FIG. 4A & FIG. 4B are diagrams that illustrate the effects of continuous flow aerosol delivery (FIG. 4A) vs. directed breathing (FIG. 4B).

[0071] FIG. 5A & FIG. 5B are charts illustrating the breathing patterns of subjects during resting tidal breathing.

[0072] FIG. 6A & FIG. 5B are charts illustrating the breathing patterns of subjects during directed breathing.

[0073] FIG. 7 is a schematic illustrating an experimental setup for monitoring drug delivery with a breathing simulator.

[0074] FIG. 8 shows the percentage of drug mass according to particle size produced from a jet nebulizer and a vibrating mesh nebulizer (VMN) equipped with a photo-defined aperture plate (PDAP).

[0075] FIG. 9A illustrates an exemplary device configuration of the invention. FIG. 9B is a simplified schematic of the exemplary device.

[0076] FIG. 10 is a graphic illustrating an example profile governing the rates of rising and falling of a bar in a video graphic display used for directing the inhalation / exhalation cycles of a patient.

[0077] FIG. 11A is a diagram illustrating the time course of Designated Exhalation Periods (DEP), Designated Inhalation Periods (DIP), and active periods during the initial cycles of a dosing session in Cohort A of the study described in EXAMPLE 7.

[0078] FIG. 11B is a diagram illustrating the time course of DEPs, DIPs, and active periods during the initial cycles of a dosing session in Cohort B of the study described in EXAMPLE 7.

[0079] FIG. 11C is a diagram illustrating the time course of DEPs, DIPs, and active periodsduring the initial cycles of a dosing session in Cohorts C and D of the study described in EXAMPLE 7

[0080] FIG. 11D is a diagram illustrating the time course of DEPs, DIPs, and active periods during the initial cycles of a dosing session in Cohort E of the study described in EXAMPLE 7.

[0081] FIG. 12A is a chart illustrating the time course of administration of an initial first dose and a booster dose in Cohort E of the study described in EXAMPLE 7.

[0082] FIG. 12B is a chart illustrating the time course of administration of an initial first dose and a booster dose in Cohort F of the study described in EXAMPLE 7.

[0083] FIG. 13A is a dot chart depicting the Cmax values observed in subjects in Cohorts B, C, and D of the study described in EXAMPLE 7. FIG. 13B depicts mean Cmax and 95% confidence interval associated with the data depicted in FIG. 13A.

[0084] FIG. 14 and FIG. 15 are charts depicting mean flecainide blood concentration from 0 to 130 minutes in Cohort E and Cohort F subjects, respectively, of the study described in EXAMPLE 7. The shaded area surrounding the line represents 95% CI.DETAILED DESCRIPTION

[0085] There is an unmet clinical need for an inexpensive, reliable, disposable nebulization device that is simple to use and integrates with a component of breathing control. There are several devices on the market that are disposable and relatively inexpensive, but these devices operate continuously, generating aerosol that accumulates in the device’s reservoir while the patient is exhaling, causing a large bolus of aerosol to be taken in at the beginning of the subsequent inhalation. This excess drug can lead to deposition in the throat, causing throat irritation and coughing, and inconsistent delivery to the lungs.

[0086] The present disclosure contemplates a means for minimizing these inefficiencies by use of directed breathing. In some embodiments, a timing device controls both an indicator to the patient and production of aerosol by a nebulizer. The timer can be set to turn on both the indicator and nebulizer aerosol production, then turn both off, cycling through on and off cycles. For directed breathing, the patient can be instructed to conduct a single inhalation throughout the period the indicator is on, coinciding with aerosol production, and conduct a single exhalation throughout the period the indicator is off, during which time the nebulizer does not produce aerosol. In one non-limiting example, the indicator is a graphic of a rising and falling bar displayed on a video screen, and the patient inhales when the bar rises, and exhales when the bar falls. In another non-limiting example, the indicator is a light, and the patient inhales when thelight is on, and exhales when the light is out. This process for training a patient to breathe synchronously with aerosol production can result in several advantages. Less drug is lost as fugitive aerosol because aerosol is only generated during inhalation. Because a large bolus of drug is not introduced at the beginning of inhalation, much less drug is deposited in the throat, alleviating throat irritation and cough, and increasing patient acceptance and tolerability of treatment, improving patient compliance. More consistent drug delivery to the lungs improves clinical outcomes. In some embodiments, the controller and indicator are integrated with a nebulizer equipped with a single-use AEROGEN® Ultra chamber, providing a device that incorporates directed breathing, while still being inexpensive and having disposable parts that interface with the patient.

[0087] It is to be understood that unless otherwise indicated the present invention is not limited to specific formulation components, drug delivery systems, manufacturing techniques, administration steps, or the like, as such may vary. In this regard, unless otherwise stated, a reference to a compound or component includes the compound or component by itself, as well as the compound or component in combination with other compounds or components, such as mixtures of compounds.

[0088] Before further discussion, a definition of the following terms will aid in the understanding of the present invention.

[0089] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an anti arrhythmic pharmaceutical agent” includes not only a single active agent but also a combination or mixture of two or more different active agents.

[0090] Reference herein to “one embodiment,” “one version,” or “one aspect” shall include one or more such embodiments, versions, or aspects, unless otherwise clear from the context.

[0091] The term “about” in relation to a reference numerical value can include a range of values plus or minus 10% from that value. For example, the amount “about 10” includes amounts from 9 to 11, including the reference numbers of 9, 10, and 11. The term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.

[0092] As used herein, “atrial arrhythmia” can mean an arrhythmia that affects at least one atrium and does not include bradycardia. For instance, atrial arrhythmia may originate in and affect at least one atrium.

[0093] As used herein, “effective amount” can refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts.

[0094] As used herein, “geometric standard deviation” or GSD is a measure of the shape of the distribution of a plurality of particles in size by diameter. A smaller GSD is indicative of a distribution of particle sizes that is narrower, with a greater proportion of the particles represented within that narrower distribution.

[0095] As used herein, “pm” or “p” refers to a micrometer or micron in diameter.

[0096] As used herein, “mL” refers to a milliliter in volume.

[0097] As used herein, “mass median aerodynamic diameter” or “MMAD” can refer to the median aerodynamic size of a plurality of particles or particles, typically in a polydisperse population. The “aerodynamic diameter” can be the diameter of a unit density sphere having the same settling velocity, generally in air, as a powder and is therefore a useful way to characterize an aerosolized powder or other dispersed particle or particle formulation in terms of its settling behavior. The aerodynamic diameter encompasses particle or particle shape, density, and physical size of the particle or particle. As used herein, MMAD refers to the median of the aerodynamic particle or particle size distribution of aerosolized particles determined by cascade impaction, unless the context indicates otherwise.

[0098] As used herein, the phrase “minimum effective amount” can mean the minimum amount of a pharmaceutical agent necessary to achieve an effective amount.

[0099] As used herein, the term “patient” may be used as an alternative with the terms “user,” “subject,” or “individual.”

[0100] As used herein, a “fraction” of a value shall be understood to refer to any part of said value that is less than the whole of said value.

[0101] By a “pharmaceutically acceptable” component is meant a component that is not biologically or otherwise undesirable, e.g., the component may be incorporated into a pharmaceutical formulation of the invention and administered to a patient as described herein without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained. When the term “pharmaceutically acceptable” is used to refer to an excipient, it is generally implied that the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0102] As used herein, the term “pharmaceutically acceptable salt” is intended to mean those salts that retain one or more of the biological activities and properties of the free acids and bases and that are not biologically or otherwise undesirable. Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites,bi sulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenyipropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthal ene-2-sulfonates, and mandelates.

[0103] As used herein, the term “salt” is intended to include, but not be limited to, pharmaceutically acceptable salts.

[0104] As used herein, “short form-36 quality of life” can mean the Short Form 36 (SF-36) survey of patient health (updated August 2005). The SF-36 consists of eight scaled scores, which are the sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The eight sections are: (1) vitality; (2) physical functioning; (3) bodily pain; (4) general health perceptions; (5) physical role functioning; (6) emotional role functioning; (7) social role functioning; and (8) mental health. It can also refer to any Quality of Life questionnaire for AF symptoms.

[0105] As used herein, the term “solvate” is intended to include, but not be limited to, pharmaceutically acceptable solvates.

[0106] As used herein, the term “pharmaceutically acceptable solvate” is intended to mean a solvate that retains one or more of the biological activities and / or properties of the anti arrhythmic.

[0107] As used herein, “tachycardia” can mean an arrhythmia in which the heart beat is too fast, e.g., faster than normal. For instance, tachycardia may involve a resting heart rate of over 100 beats per minute, such as greater than 110, greater than 120, or greater than 130 beats minute.

[0108] As used herein, a “therapeutically effective amount” of an active agent refers to an amount that is effective to achieve a desired therapeutic result. A therapeutically effective amount of a given active agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the subject. In some cases, “inhalation” (e.g., “oral inhalation”) can refer to inhalation delivery of a therapeutically effective amount of a pharmaceutical agent contained in one unit dose receptacle, which, in some instance, can require one or more breaths, like 1, 2, 3, 4, 5, 6, 7, 8, 9, or more breaths. For example, if the effective amount is 90 mg, and each unit dose receptacle contains 30 mg, the delivery of the effective amount can require 3 inhalations. In some instances, breathingmay occur over the course of several minutes.

[0109] Unless otherwise specified, the term “therapeutically effective amount” can include a “prophylactically effective amount,” e.g., an amount of active agent that is effective to prevent the onset or recurrence of a particular condition, disease, or disorder in a susceptible individual.

[0110] As used herein, the terms “treating” and “treatment” can refer to reduction in severity and / or frequency of symptoms, elimination of symptoms and / or underlying cause, reduction in likelihood of the occurrence of symptoms and / or underlying cause, and / or remediation of damage. Thus, “treating” a subject with an active agent as provided herein includes prevention of a particular condition, disease, or disorder in a susceptible individual as well as treatment of a clinically symptomatic individual.[OHl] As used herein, the term “perceptible signal” when used to describe a signal emitted by a device of the present disclosure, includes any signal capable of being perceived by human senses, including signals that can be seen, heard, felt, or otherwise noticed by a human.

[0112] As an overview, the present invention relates to methods of treating atrial arrhythmia. The methods may comprise administering an effective amount of at least one antiarrhythmic pharmaceutical agent to a subject in need thereof, such that the at least one antiarrhythmic pharmaceutical agent first enters the heart through the pulmonary veins to the left atrium. More specifically, the present invention relates to methods of teaching a subject appropriate breathing patterns to optimize delivery of medicament; more specifically, the drug delivery device of the invention teaches the subject appropriate breathing patterns.

[0113] Inhalation is the shortest route for a drug to reach the heart, next only to intracardiac injection, as shown in FIGS. 2A and 2B. Drugs delivered by inhalation generally exhibit “pulsatile pharmacokinetics” of transient high drug concentrations, followed by dilution to sub- therapeutic levels.

[0114] The pulsatile pharmacokinetic behavior of the drugs shows that the drug is diluted within a few seconds of reaching effective concentrations in the heart and is diluted to sub -therapeutic levels in the volume of the blood. This characteristic will minimize drug-drug interactions that produce significant toxicological responses normally seen at steady state.

[0115] Inhalation results in a pulsatile pharmacokinetic profile and transient pharmacodynamic effect mimicking the effect of an IV. This method delivers high drug concentrations that are safe and effective to the heart, while the distribution to the rest of the body results in the drug being diluted to sub-therapeutic levels. This method is the shortest route of delivery to the heart next to intracardial injection. This provides the convenience of self-administration like the “pill-in-the- pockef ’ approach, but the effectiveness and fast onset of action of an IV. Although the deliveryof medications through the lung for systemic effect is not new, it was thought it wouldn't be effective to the heart, because of the fast passage of drug through it. The animal and human PK / PD data disclosed in US 10,441,537 B2, incorporated herein by reference in its entirety, show that the drug exposure is sufficient for therapeutic effect at a much lower dose compared to other routes of administration. This method ensures drug concentrations in overall plasma are much lower than what is achieved by effective doses of oral / IV, hence minimizing drug-drug interactions and side effects.

[0116] Thus, in certain embodiments, the present invention relates to achieving transient high drug concentrations in the heart that effect rate and rhythm changes in the heart within a short period of time allowing for treatment of episodic arrhythmias such as paroxysmal atrial arrhythmias.

[0117] The results of the invention are surprising and unexpected. In this regard, the antiarrhythmic pharmaceutical agents pass through the lungs quickly. For instance, verapamil and diltiazem will ionize if in salt form, so the base will pass through the lungs quickly. In some aspects, the methods of the present invention take advantage of fast onset of action, high drug bioavailability, and fast absorption through the lung. Most cardiovascular drugs are small molecules that have high lipid solubility (e.g., diltiazem, verapamil, ibutilide, propafenone) and are therefore expected to have high pulmonary bioavailability and a fast rate of absorption. This ensures that they reach the heart through the pulmonary veins. FIG. 3 shows the log-p values and lipid solubility of exemplary cardiovascular molecules along with their expected high pulmonary bioavailability.

[0118] Another reason why the results of the present invention are surprising and unexpected involves the rate at which the antiarrhythmic pharmaceutical agents pass through the heart. While a skilled artisan might expect the rate to be too fast, modeling indicates that the drug will not pass through the heart too fast. Thus, a therapeutic effect is achieved despite fast pass- through and despite only one pass-through at therapeutic levels.

[0119] Inhalation also avoids metabolism, such as hepatic metabolism. For instance, calcium channel blockers, such as diltiazem, undergo significant hepatic metabolism when taken orally. Inhalation allows rapid delivery of the parent diltiazem compound to the heart as a bolus. Surprisingly, administration by inhalation of diltiazem via the inhalation route according to the present invention converted atrial fibrillation to normal sinus rhythm and reduced heart rate. Thus, administration by inhalation of diltiazem can be useful for treating both atrial fibrillation and supraventricular tachycardia (SVT). In contrast, administration by IV of diltiazem is typically only used for converting SVT to normal sinus rhythm and in atrial fibrillation to reduceheart rate (not for converting to normal sinus rhythm).

[0120] Inhalation also avoids red blood cell metabolism. For instance, the reduced dilution and short route associated with inhalation reduces red blood cell metabolism of esmolol.

[0121] Inhalation may also avoid reduced blood pressure and fainting. For instance, IV administration of beta blockers, such as esmolol, may reduce mean arterial blood pressure (MAP). Inhalation allows rapid delivery of esmolol without reducing MAP. As a result, inhalation of beta blockers may result in an MAP of 10 mm Hg to 20 mm Hg greater than the MAP resulting from IV administration of the same beta blocker.

[0122] With inhaled cardiotherapy, the drug is directed to the heart from the lungs as a bolus. So, the heart sees a high concentration. The drug is rapidly diluted as it passes through the heart, but the exposure time is sufficient for the desired pharmacological action. Once the drug passes through the heart, the concentration of the drug in the systemic circulation (e.g., peripheral venous blood) is below the therapeutic concentration and is considered ineffective. The therapeutic index is the range of dosage of a drug or of its concentration in a bodily system that provides safe effective therapy. Anything below the minimum amount is sub -therapeutic and hence ineffective in that concentration. In view of the dilution, unwanted side effects are minimized.

[0123] Accordingly, the compositions of one or more embodiments of the present invention will be useful for delivery of medication directly to the heart via the lungs. Moreover, the doses of composition that are inhaled are typically much less than those administered by other routes and required to obtain similar effects, due to the efficient targeting of the inhaled composition to the heart.

[0124] In one or more embodiments of the invention, a pharmaceutical composition comprising anti arrhythmic pharmaceutical agent is administered to the lungs of a subject in need thereof.For example, the subject may have been diagnosed with an arrhythmia. Examples of arrhythmias include, but are not limited to, tachycardia, supraventricular tachycardia (SVT), paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), paroxysmal atrial fibrillation (PAF), persistent atrial fibrillation, permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter, and lone atrial fibrillation.

[0125] Thus, the pharmaceutical compositions of one or more embodiments of the present invention can be used to treat and / or provide prophylaxis for a broad range of subjects. A suitable subject for, receiving treatment and / or prophylaxis as described herein is any mammalian subject in need thereof, preferably such mammal is a human. Examples of subjects include, but are not limited to, pediatric subjects, adult subjects, and geriatric subjects. In someembodiments, the composition is intended only as a treatment for rapid resolution of symptoms and restoration of normal sinus rhythm, and is not taken as a preventative, e.g., when the subject is well, there is no need for drug — this can increase the benefit-risk ratio of the therapy and overall safety due to the sporadic or intermittent dosing, and the focus on reducing disabling symptoms and restoring sinus rhythm only when needed.

[0126] In yet another embodiment of the invention, the methods for administering a medication by depositing aerosol particles into the lungs of a subject may be used for delivering drugs with a narrow therapeutic index. A drug product is defined by the US Food and Drug Administration as having a narrow therapeutic index when (a) there is less than a twofold difference in median lethal dose and median effective dose values or (b) there is less than a twofold difference in the minimum toxic concentrations and minimum effective concentrations in the blood, and (c) safe and effective use of the drug requires careful titration and patient monitoring.

[0127] Examples of drugs with a narrow therapeutic index suitable for use in the present invention include, for example, amiodarone, digitoxin, digoxin, dofetilide, dronedarone, flecainide, fluindione, phenindione, procainamide, quinidine, sotalol, and warfarin. These drugs are listed by way of example, and are not intended to be limiting to the scope of the invention. Most of these drugs have oral dosage forms, which commonly show a large degree of interpatient variability, requiring them to be titrated to an effective dose, and to be used with careful patient monitoring. Intrapatient variability may also be observed, such as when taken with food or on an empty stomach.

[0128] Deep breathing, i.e., taking inhalation periods that are longer than “resting” tidal breathing, results in an increased volume of inspired air. This in turn will result in increased drug deposition in the lung when a subject is inhaling drug in the inspired air. The rate at which drug is inspired is directly related to the resulting Cmax of the drug in the body’s circulation. As will be illustrated in the examples, upon administration of an anti arrhythmic drug to subjects, the resulting Cmax of that drug is proportional to conversion of atrial fibrillation patients a normal sinus rhythm (NSR). Thus, it can be appreciated that having atrial fibrillation patients inhale more deeply when being treated with anti arrhythmic drugs using an inhalation device will result in a greater proportion of those patients achieving the desired conversion to NSR.

[0129] When a patient first seeks medical attention due to experiencing an episode of atrial fibrillation, having symptoms including tightness around the chest, palpitations, feeling tired, shortness of breath, feeling dizzy or lightheaded, and sometimes chest pain, they will typically go to a hospital emergency room. In order to administer an antiarrhythmic drug by inhalation according to the present invention, an inhalation device is required. In the hospitalsetting, it is desirable to use devices that have components that interface with the patient that are disposable and intended for a single-use, in order to reduce the chances of contamination. Moreover, desirably, such single-use devices would also be relatively inexpensive, simple to operate, and reliable.

[0130] A number of devices are available that exert some level of control over the patient’s breathing in order to guide them to breathing more deeply than tidal breathing, thereby achieving a greater and / or deeper lung deposition of administered medications. Some examples of devices that exert breathing control and / or monitor the patient to assure appropriate breathing include the Vectura Group (Chippenham, Wiltshire, United Kingdom) AKITA® vibrating mesh nebulizer (U.S. Patent Nos. US 20140116426 Al, US 8534277 B2, US 20090056708 Al, US 20100092397 Al), which monitors the breathing flow rate of the user, and releases aerosol only when breathing is appropriate, the Koninklijke Philips N.V. (Eindhoven, Netherlands) I-neb® AAD system vibrating mesh nebulizer with metering chambers and adaptive aerosol delivery software (U.S. Patent Nos. US 10342457 B2, US 11247002 B2), which adjusts aerosol emission based on the patient’s breathing pattern, or the PARI LC Plus® breath-enhanced jet nebulizer from PARI Respiratory Equipment, Inc. of Midlothian, Va. (U.S. Patent Nos. US 20230028709 Al, US 11610473 B2, US 9119930 B2), which has an integrated valve that responds to breathing, and opens only on inspiration. While all of these devices could be used for efficacious delivery of anti arrhythmic drugs, they are all relatively complex devices in order to exert breathing control, can be difficult to learn to operate correctly, and their costs preclude their use as a disposable, single-use device.

[0131] There is thus an unmet clinical need for a device having an inexpensive, reliable, disposable aerosolization unit that is simple to use and incorporates a component of breathing control.

[0132] In some embodiments, a device of the present disclosure comprises a means for (a) directing the pace of inhalation of an aerosol by a patient according to a predetermined pace, and (b) controlling the timing of aerosol production according to the predetermined pace to align with the desired pace of inhalation by the patient.

[0133] A first embodiment of the disclosure is directed to a device with an aerosolization unit that generates aerosolized particles of a desired medicament, and deposits those particles into the lungs of a subject. In some embodiments, the aerosolization unit is single use. In some embodiments, the aerosolization unit does not comprise a breath actuated nebulizer. In some embodiments, the aerosolization unit comprises an inhalation chamber and mouthpiece, a vibrating mesh nebulizer, and optionally a bacterial / viral filter. In some embodiments, the devicefurther comprises a timer that controls an indicator (e.g., visual, tactile, or audible indicator) that can be seen, felt, or heard, and monitored by the subject. The timer can be programmed with a designated inhalation period during which a subject conducts a single inhalation, and a designated exhalation period during which a subject conducts a single exhalation, which can be repeated over the course of the oral inhalation treatment time and of deposition of aerosol particles. In addition to controlling the indicator, the timer can also control the device to produce aerosol particles only during the designated inhalation period of the breathing cycle.

[0134] The indicator of the device can serve as one of any of several means that can be used to guide a subject to inhale throughout the designated inhalation period, and exhale throughout the designated exhalation period. Some means contemplated by the invention include device elements capable of emitting a perceptible signal, which can include any form of human sensory stimuli. Perceptible signals can include, for example, audible signals such as a tone, tactile signals such as vibration, or visual signals such as a light or a graphic displayed on an electronic display (e.g., video screen).

[0135] In one embodiment, the indicator is a light (a visual indicator) that turns on during the designated inhalation period and turns off during the designated exhalation period. In one embodiment, the indicator is a video graphic of a bar displayed on a screen that rises during the designated inhalation period and falls during the designated exhalation period. In some embodiments, the subject is instructed to inhale while the light is on and exhale while the light is off. In some embodiments, the subject is instructed to inhale while the bar rises and exhale while the bar falls. The breathing pattern indicated by the indicator light or electronic display can be repeated over the course of treatment. In embodiments where aerosol production substantially or completely stops during the designated exhalation period, the subject will not receive a large bolus of aerosol at the beginning of the subsequent designated inhalation period.

[0136] In another aspect, the designated inhalation periods and designated exhalation periods are programmed according to the pharmacokinetic requirements for optimal delivery of the drug being administered. In some embodiments, the designated inhalation periods are programmed in a range from about 1 second to about 6 seconds, including fractional times (seconds / milliseconds) thereof. The designated exhalation periods can be programmed in a range from about 1 second to about 8 seconds, including fractional times thereof. In some embodiments, the designated inhalation period is two seconds in duration, and the designated exhalation period is three seconds. In some embodiments, the designated inhalation period and the designated exhalation period are each independently from about three to about five seconds in duration. In some embodiments, the designated duration of the inhalation period is four seconds,and the designated duration of the designated exhalation period is four seconds. In some embodiments, the designated duration of the inhalation period is four seconds, and the designated duration of the designated exhalation period is 4.25 seconds.

[0137] In yet another aspect, the designated inhalation period and designated exhalation period are repeated over the course of deposition of aerosol particles. In some embodiments, the course of deposition lasts until a fixed dose of formulated medicament has been aerosolized. In another embodiment, the course of deposition lasts until a desired medical outcome is attained, such as, e.g., return to normal sinus rhythm with a subject experiencing atrial fibrillation. In another embodiment, the course of deposition (treatment) is for a fixed total time.

[0138] In another embodiment, the aerosolization unit of the device used for generating aerosolized particles includes a vibrating mesh nebulizer. In another embodiment, the vibrating mesh of the nebulizer device is comprised of two materials - a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the exit opening of the first apertures having a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size, and a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm. In some embodiments, at least some of the plurality of first apertures are within the diameter of the liquid supply cavity defined by one of the second apertures, and wherein the first and second materials combine to form the mesh for use in a vibrating mesh nebulizer.

[0139] Yet another embodiment is a kit comprising the device disclosed herein and a drug formulation for administration by the device. The formulation of the kit can comprise a therapeutically-effective amount of flecainide or a pharmaceutically-acceptable salt thereof for treatment of atrial arrhythmia. In some embodiments, the formulation comprises flecainide acetate. In some embodiments, the therapeutically effective amount ranges from 10 mg to 200 mg. In some embodiments, the flecainide acetate formulation for use in the kit may be an aqueous formulation in concentrations ranging from 45 to 90 mg / mL, intended for administration over multiple inhalations. In some embodiments, the flecainide acetate formulation for use in the kit may be an aqueous formulation in a concentration of 75 mg / mL, intended for administration over multiple inhalations. In yet another embodiment, the course of deposition of aerosol particles when utilizing the kit is sufficient to exhaust the aqueous formulation provided.

[0140] Another embodiment contemplates a method for administering a medication by depositing aerosol particles into the lungs of a subject. Administration can be accomplished with a device having an aerosolization unit that generates the aerosol particles at a designated liquid output rate, the device further comprising a timer that controls an indicator that can be monitored by the subject. The aerosolization unit may be optionally single-use. The timer is programmed with a designated inhalation period during which a subject is instructed to conduct a single inhalation, and a designated exhalation period during which a subject is instructed to conduct a single exhalation, which are repeated over the course of deposition of aerosol particles. In addition to controlling the indicator, the timer can also control the device to produce aerosol particles only during the designated duration of the inhalation period.

[0141] The indicator of the device is intended to be one of any of several means that can be used to guide a subject to inhale throughout the designated inhalation period, and exhale throughout the designated exhalation period. Some means contemplated by the present disclosure include an audible signal such as a tone, a tactile signal such as vibration, or a visual signal such as a light or a graphic displayed on an electronic display (e.g., video screen).

[0142] In one embodiment, the indicator is a video graphic of a bar displayed on a screen that rises during the designated inhalation period and falls during the designated exhalation period. The subject can be instructed to inhale while the bar rises and exhale while the bar falls, repeating this breathing pattern over the course of treatment. In another embodiment, the indicator is a light that turns on during the designated inhalation period and turns off during the designated exhalation period. The subject can be instructed to inhale while the light is on and exhale while the light is off, repeating this breathing pattern over the course of treatment. In this case, because aerosol particles are not generated during the designated exhalation period, the subject will not receive a large bolus of aerosol at the beginning of the subsequent designated inhalation period.

[0143] In another aspect, the designated inhalation periods and designated exhalation periods of the method for administering medication may be programmed according to the pharmacokinetic demands of the drug being delivered. It is contemplated that the designated duration of the inhalation periods may be programmed in a range from about 1 second to about 6 seconds, including fractional times (seconds / milliseconds) thereof. It is further contemplated that the designated duration of the exhalation periods may be programmed in a range from about 1 second to about 8 seconds, including fractional times thereof. In some embodiments, a designated duration of the inhalation period may be two seconds, and a designated duration of the exhalation period may be three seconds. In some embodiments, a designated duration of theinhalation period may be about four seconds, and a designated duration of the exhalation period may be about four seconds. In some embodiments, a designated duration of the inhalation period may be about four seconds, and a designated duration of the exhalation period may be about 4.25 seconds. In some embodiments, a designated duration of the inhalation period may be four seconds, and a designated duration of the exhalation period may be 4.25 seconds.

[0144] In yet another aspect, the designated inhalation period and designated exhalation period are repeated over the course of deposition of aerosol particles. In another aspect of the invention, the course of deposition is sufficient for achieving a designated target serum concentration (e.g., above 200 ng / mL). Preferably, the course of deposition is until a fixed dose of formulated medicament has been aerosolized. In some embodiments, the fixed dose is from about 40 mg to about 125 mg of flecainide acetate. In some embodiments, the fixed dose is about 105 mg of flecainide acetate. In another preferred embodiment, the course of deposition may be until a desired medical outcome is attained, such as, e.g., return to normal sinus rhythm with a subject experiencing atrial fibrillation. In yet another preferred embodiment, the course of deposition may be for a fixed total time.

[0145] In some embodiments, the aerosolization unit of the device used for generating aerosolized particles includes a vibrating mesh nebulizer. In another embodiment, the vibrating mesh of the nebulizer device is comprised of two materials - a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the exit opening of the first apertures having a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size, and a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm. At least some of the plurality of first apertures are within the diameter of the liquid supply cavity defined by one of the second apertures, and wherein the first and second materials combine to form the mesh for use in a vibrating mesh nebulizer.

[0146] In another embodiment, the liquid output rate of the device is adjusted to be at least 0.3 mL / min. At this liquid output rate, the device will preferably produce particles with a mass median aerodynamic diameter (MMAD) less than 4 pm, having a geometric standard deviation (GSD) less than 1.8.

[0147] In yet another embodiment, the methods for administering a medication by depositingaerosol particles into the lungs of a subject is used for delivering drugs with a narrow therapeutic index. Some of the drugs with a narrow therapeutic index contemplated for use in the invention include, for example, amiodarone, digitoxin, digoxin, dofetilide, dronedarone, flecainide, fluindione, phenindione, procainamide, quinidine, sotalol, and warfarin, or pharmaceutically- acceptable salts thereof, however the scope of the invention is not intended to be limited to these examples.

[0148] In yet another embodiment, the methods for administering a medication by depositing aerosol particles into the lungs of a subject is used when it is desirable or necessary to reduce interpatient and intrapatient variability in the pharmacokinetics or pharmacodynamics of the drug’s effects as compared to those properties obtained when a medication is administered in its normally accepted dosage form.

[0149] In another embodiment, the methods for administering a medication by depositing aerosol particles into the lungs of a subject is used when it is desirable to deliver the medication to the heart.

[0150] In yet another embodiment, the methods for administering a medication by depositing aerosol particles into the lungs of a subject is used for delivering drugs that are anti arrhythmic agents. Some drugs contemplated for use in the invention include Class 1 Sodium Channel Blockers, including Class la, e.g., ajmaline, disopyramide, procainamide, quinidine, Class lb, e.g., lidocaine, mexiletine, phenytoin, tocainide, Class 1c, e.g., flecainide, moricizine, propafenone, Class 2 -Adrenergic Blockers (Beta Blockers), e.g., acebutolol, atenolol, bisoprolol, carvedilol, esmolol, metoprolol, nebivolol, propranolol, timolol, Class 3 Potassium Channel Blockers, e.g., amiodarone, bretylium, dofetilide, dronedarone, ibutilide, sotalol, vernakalant, Class 4 Calcium Channel Blockers, e.g., diltiazem, etripamil, verapamil, and Class 5 Other Mechanisms, e.g., adenosine, digoxin.

[0151] In one embodiment, the class 1c anti arrhythmic drug is flecainide or a pharmaceutically- acceptable salt thereof. In another embodiment, the class 1c anti arrhythmic drug is a flecainide acetate in a total amount from 10 mg to 200 mg, which may optionally be provided as an aqueous formulation in concentrations ranging from 45 to 90 mg / mL, administered over multiple inhalations. In certain embodiments, the total time of the course of deposition of the aqueous flecainide acetate formulation is sufficient to exhaust the dosage.

[0152] In another embodiment, the dosage of flecainide acetate is sufficient to achieve a target serum concentration of flecainide of at least 200 ng / mL. In other embodiments, the dosage of flecainide acetate is sufficient to achieve a target serum concentration of flecainide of at least 300 ng / mL. In still other embodiments, the dosage of flecainide acetate is sufficient to achieve atarget serum concentration of flecainide of at least 400 ng / mL. And in still other embodiments, the dosage of flecainide acetate is sufficient to achieve a target serum concentration of flecainide of at least 500 ng / mL.

[0153] In another embodiment, a second dose of flecainide acetate is administered after determining that a subject’s cardiac arrhythmia has not resolved. In some embodiments, after a first unit dose of the pharmaceutical composition (e.g., a unit dose comprising about 40 mg to about 150 mg flecainide acetate) has been administered, administering a second unit dose of the pharmaceutical composition upon determining that the subject still suffers from the cardiac arrythmia. In some embodiments, the second unit dose is equal to the first unit dose. In some embodiments, the second dose is a fractional amount of the first unit dose. In some embodiments, the second unit dose is one-half of the first unit dose. In some embodiments, the second unit dose is administered about 10 minutes to about 1 hour after administration of the first unit dose is completed.

[0154] In another embodiment, the subject is administered a medication in a medically supervised setting. In some embodiments, the subject self-administers the drug. In some embodiments, the subject is instructed to pause inhalation of the aerosolized pharmaceutical composition after about one half of the unit dose has been administered, and resume inhalation of the remaining half of the unit dose after a break of about 30 seconds to about three minutes.

[0155] In some embodiments, the subject is instructed to:(i) inhale the aerosol in synchrony with the perceptible signal for a first duration that is from about 3 minutes to about 4 minutes;(ii) after said first duration, pause inhalation for a second duration that is from about 30 seconds to about 90 seconds; and(iii) after said second duration, resume inhalation in synchrony with the perceptible signal for a third duration that is from about 3 minutes to about 4 minutes.

[0156] In yet another embodiment, administration of a medication minimizes sustained cough or throat irritation that normally results from deposition of the medication into the oropharyngeal region, and which commonly result in poor patient compliance or medical outcomes.

[0157] In some embodiments, the present disclosure provides a method for more consistently and reliably achieving a target serum concentration upon administration of a medication. This can be accomplished by depositing aerosol particles into the lungs of a subject with a device having an aerosolization unit to generate the aerosol particles at a designated liquid output rate, the device further comprising a timer that controls an indicator that can be monitored by the subject. The timer can be programmed with a designated inhalation period and a designated exhalation period,which are repeated over the course of deposition of aerosol particles. In addition to controlling the indicator, the timer can control the device to produce aerosol particles only during the designated inhalation period.

[0158] An exemplary device equipped with a timer (e.g., “Timed Switch Module”) is provided in FIG. 9B. A timer 100 may include a microcontroller 101, which in turn is coupled to an indicator capable of emitting a signal that is perceptible by the subject. In the non-limiting example of FIG. 9B, the indicator is a video screen 102 (e.g., an OLED display). The timer may optionally further comprise a second display 103 for displaying the elapsed time in the dosing session and one or more user-operable interfaces (e.g., a tactile push button switch 104 or touchscreen) to start / stop the inhalation sequence and select the desired pattern of active periods, designated inhalation periods, and designated exhalation periods. In the non-limiting example of FIG 9B., a relay (KY-019) 106 controlled by a 5V output from the microcontroller 101 is used to interrupt the power supply from the aerosolization unit control module 107 to the PDAP vibrating mesh nebulizer 108. The aerosolization unit control module 107 and timer 100 may optionally be integrated into a single unit in which the timer controls the control module internally to that unit.

[0159] In some embodiments, aerosolization unit control module 107 and timer 100 may optionally be integrated into a single unit in which the timer controls the control module internally to that unit.

[0160] The indicator of the device is intended to be one of any of several means that can be used to guide a subject to inhale throughout the designated inhalation period, and exhale throughout the designated exhalation period. Some means contemplated by the present disclosure include an audible signal such as a tone, a tactile signal such as vibration, or a visual signal such as a light or a graphic displayed on an electronic display (e.g., video screen).

[0161] In one embodiment, the indicator is a light that turns on during the designated inhalation period and turns off during the designated exhalation period. The subject can be instructed to inhale while the light is on and exhale while the light is off, repeating this breathing pattern over the course of treatment. In another embodiment, the indicator is a video graphic of a bar displayed on a screen that rises during the designated inhalation period and falls during the designated exhalation period. The subject can be instructed to inhale while the bar rises and exhale while the bar falls, repeating this breathing pattern over the course of treatment. Because aerosol particles are not generated during the designated exhalation period, the subject will not receive a large bolus of aerosol at the beginning of the subsequent designated inhalation period.

[0162] In another aspect of the present disclosure, the designated inhalation periods anddesignated exhalation periods of the method for administering medication may be programmed according to the pharmacokinetic demands of the drug being delivered. It is contemplated that the designated inhalation periods may be programmed in a range from about 1 second to about 6 seconds, including fractional times (seconds / milliseconds) thereof. It is further contemplated that the designated exhalation periods may be programmed in a range from about 1 second to about 8 seconds, including fractional times thereof. In certain embodiments, the designated inhalation period and the designated exhalation period are each independently from about two to about five seconds. In certain embodiments, a designated inhalation period may be two seconds, and a designated exhalation period may be three seconds. In certain embodiments, a designated inhalation period may be four seconds, and a designated exhalation period may be four seconds. In certain embodiments, a designated inhalation period may be four seconds, and a designated exhalation period may be 4.25 seconds.

[0163] In yet another aspect of the methods of disclosure, the designated inhalation period and designated exhalation period are repeated over the course of deposition of aerosol particles. In another aspect of the invention, the course of deposition is sufficient for achieving a designated target serum concentration. Preferably, the course of deposition is until a fixed dose of formulated medicament has been aerosolized. In another preferred embodiment, the course of deposition may be until a desired medical outcome is attained, such as, e.g., return to normal sinus rhythm with a subject experiencing atrial fibrillation. In yet another preferred embodiment, the course of deposition may be for a fixed total time.

[0164] In a preferred embodiment of the methods of the disclosure, the aerosolization unit of the device used for generating aerosolized particles includes a vibrating mesh nebulizer. In another preferred embodiment, the vibrating mesh of the nebulizer device is comprised of two materials - a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the exit opening of the first apertures having a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size, and a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm. At least some of the plurality of first apertures are within the diameter of the liquid supply cavity defined by one of the second apertures, and wherein the first and second materials combine to form the mesh for use in a vibrating mesh nebulizer.

[0165] In another embodiment, the liquid output rate of the device is adjusted to be at least 0.3 mL / min. At this liquid output rate, the device will preferably produce particles with a mass median aerodynamic diameter (MMAD) less than 4 pm, having a geometric standard deviation (GSD) less than 1.8.

[0166] In yet another embodiment, the methods for administering a medication by depositing aerosol particles into the lungs of a subject is used for delivering drugs with a narrow therapeutic index. Some of the drugs with a narrow therapeutic index contemplated for use in the invention include, for example, amiodarone, digitoxin, digoxin, dofetilide, dronedarone, flecainide, fluindione, phenindione, procainamide, quinidine, sotalol, and warfarin, however the scope of the invention is not intended to be limited to these examples.

[0167] In yet another embodiment, the methods for administering a medication by depositing aerosol particles into the lungs of a subject is used when it is desirable or necessary to reduce interpatient and intrapatient variability in the pharmacokinetics or pharmacodynamics of the drug’s effects as compared to those properties obtained when a medication is administered in its normally accepted dosage form.

[0168] In another embodiment, the methods for administering a medication by depositing aerosol particles into the lungs of a subject is used when it is desirable to deliver the medication to the heart.

[0169] In another aspect of the disclosure, the subject is being treated for atrial arrhythmia by delivering drugs that are antiarrhythmic agents. Some drugs contemplated for use in the invention include Class 1 Sodium Channel Blockers, including Class la, e.g., ajmaline, disopyramide, procainamide, quinidine, Class lb, e.g., lidocaine, mexiletine, phenytoin, tocainide, Class 1c, e.g., flecainide, moricizine, propafenone, Class 2 [3-Adrenergic Blockers (Beta Blockers), e.g., acebutolol, atenolol, bisoprolol, carvedilol, esmolol, metoprolol, nebivolol, propranolol, timolol, Class 3 Potassium Channel Blockers, e.g., amiodarone, bretylium, dofetilide, dronedarone, ibutilide, sotalol, vemakalant, Class 4 Calcium Channel Blockers, e.g., diltiazem, etripamil, verapamil, and Class 5 Other Mechanisms, e.g., adenosine, digoxin.

[0170] In yet another embodiment, the medication being administered is an effective amount of flecainide or a pharmaceutically-acceptable salt thereof. In another embodiment, the class 1c antiarrhythmic drug is flecainide acetate in a total amount from 10 mg to 200 mg, which may optionally be provided as an aqueous formulation in concentrations ranging from 45 to 90 mg / mL, administered over multiple inhalations. In certain embodiments, the total time of the course of deposition of the aqueous flecainide acetate formulation is sufficient to exhaust the dosage.

[0171] In yet another embodiment, the effective dosage of flecainide is that which is sufficient to achieve a target serum concentration of at least 200 ng / mL. In another embodiment of the invention, the effective dosage of flecainide is that which is sufficient to achieve a target serum concentration of at least 300 ng / mL. In another embodiment of the invention, the effective dosage of flecainide is that which is sufficient to achieve a target serum concentration of at least 400 ng / mL. In another embodiment, the effective dosage of flecainide is that which is sufficient to achieve a target serum concentration of at least 500 ng / mL.

[0172] In another embodiment, the subject is administered a drug by the methods of the invention in a medically supervised setting.

[0173] In yet another aspect of the present disclosure, the subject is able to self-administer treatment at home, after self-diagnosis without guidance of a medical professional. In this aspect, the present invention is directed to a method of self-diagnosing comprising detecting atrial arrhythmia by at least one of the symptoms of shortness of breath, heart palpitations, and above normal heart rate. The method also comprises self-administering by inhalation an effective amount of at least one anti arrhythmic pharmaceutical agent within two hours, one hour, 30 minutes or 15 minutes of the self-diagnosing. In some cases, the self-administering continues until the subject no longer detects the at least one of shortness of breath, heart palpitations, and above normal heart rate.

[0174] In yet another embodiment, throat irritation and cough can be minimized by gradually increasing the time in which drug aerosol is introduced during the inhalation phase of a breathing cycle. During an initial set of designated inhalation periods, the device can be configured to produce aerosol particles for a gradually increasing fraction of the designated inhalation period. In some embodiments, the initial set of designated inhalation periods is the first three, first four, first five, first six, first seven, first eight, first nine, or first ten designated inhalation periods of a dosing session.

[0175] For example, the device may produce aerosol particles for one quarter of the first designated inhalation period, one half of the second designated inhalation period, three quarters of the third designated inhalation period, and for the full duration of all subsequent designated inhalation periods. In another example, the device may produce aerosol particles for one quarter of the first designated inhalation period, three eighths of the second designated inhalation period, one half of the third designated inhalation period, five eighths of the fourth designated inhalation period, and three fourths of each designated inhalation period subsequent to the fourth designated inhalation period. In some embodiments, the timer causes the device to produce aerosol particles for about one second during the first designated inhalation period, for about 1.5 seconds duringthe second designated inhalation period, for about two seconds during the third designated inhalation period, for about 2.5 seconds during the fourth designated inhalation period, and for three seconds during each designated inhalation period subsequent to the fourth designated inhalation period. The gradually increasing fraction of the designated inhalation period during which aerosol particles are produced optionally occurs at the beginning of each designated inhalation period.

[0176] In yet another embodiment, throat irritation and cough can be minimized by application of a topical anesthetic to the throat of a subject prior to administering a medication by depositing aerosol particles into the lungs of a subject. The form of the topical anesthetic may be, for example, in the form of a spray, lozenge, or liquid gargle, and may be menthol, benzocaine, lidocaine, dyclonine, or other topical anesthetic.

[0177] The present disclosure concerns a device and methods of its use that provide a simplified means of teaching the user of the device how to breathe more deeply than is attained with tidal breathing, in order to maximize the rate of drug deposition into the lungs, and thereby increase the resulting Cmax. Without incorporating means for direct breath control or for monitoring the breathing pattern of the user, the device comprises a simple timing mechanism that controls an indicator on the device that turns on for a first period of time, then off for a second period of time, and cycles these on / off periods over the course of administration of a drug. The user is instructed to conduct a single inhalation throughout the first period of time, and conduct a single exhalation throughout the second period of time, and to continue breathing with this cadence while simply following the indicator.

[0178] In addition to controlling the indicator, the timing mechanism also controls generation of aerosol by the device such that aerosol generation is turned on during the first period of time (i.e., designated inhalation period), for inhalation, then turned off when the timer indicates the second period of time (i.e., designated exhalation period), for exhalation, in order to avoid a surge of medication at the beginning of the subsequent inhalation. In some embodiments, aerosol generation is turned on for an entirety of the first period of time. In some embodiments, aerosol generation is turned on for only a fraction of the first period of time, such as a fraction that can range from one eighth to seven eighths of the first period of time.

[0179] Many of the advantages of the invention are illustrated in FIG. 4. As shown in FIG. 4A, with continuous flow of medication from a nebulizer, aerosol particles are generated even while a subject is exhaling. This fraction of drug escapes the device with the exhale, condenses within the device, or accumulates as a bolus of drug taken in with the following inhalation. The excess drug generated at the beginning of a subsequent inhalation can lead to deposition in the throat,causing throat irritation and cough, and inconsistent delivery to the lungs. These inefficiencies can be mitigated by use of directed breathing. In this instance, a timing device controls both an indicator and production of aerosol by a nebulizer. The timer is set to turn on both the indicator and nebulizer aerosol production, then turn off both, cycling through on and off cycles. For directed breathing, the subject is instructed to inhale throughout the period the indicator is on, coinciding with aerosol production, and exhale throughout the period the indicator is off, during which time the nebulizer does not produce aerosol. By example, the indicator may be a graphic of a rising and falling bar displayed on a video screen, and the subject inhales when the bar rises, and exhales when the bar falls. This simple process for training a subject to breath synchronously with aerosol production results in several advantages, as illustrated in FIG. 4B. Less drug is lost as fugitive aerosol because aerosol is only generated during inhalation. Because a large bolus of drug is not introduced during the inhalation, much less drug is deposited in the throat, alleviating throat irritation and cough, and increasing patient acceptance and tolerability of treatment, improving patient compliance. The more consistent drug delivery to the lungs improves clinical outcomes.

[0180] It is thus contemplated that one embodiment of the present invention is directed to a device with an aerosolization unit that generates aerosolized particles of a desired medicament, and deposits those particles into the lungs of a subject. The aerosolization unit is optionally single-use. In some embodiments, the aerosolization unit comprises an inhalation chamber and mouthpiece, a vibrating mesh nebulizer, and optionally a bacterial / viral filter. The device further comprises a timer that controls an indicator that can be monitored by the subject. The timer is programmed with a designated inhalation period and a designated exhalation period, which are repeated over the course of deposition of aerosol particles. In addition to controlling the indicator, the timer also controls the device to produce aerosol particles only during the designated inhalation period.

[0181] The indicator of the device can be any one of several means that can be used to guide a subject to inhale during the designated inhalation period, and exhale during the designated exhalation period. Some means contemplated by the present disclosure include an audible signal such as a tone, a tactile signal such as vibration, or a visual signal such as a single light turning on during inhalation and off during exhalation or a series of lights turning on in sequence during inhalation and off during exhalation, or a graphic displayed on a display (e.g., a raster display such as an OLED pixel display). Graphics on a display may contain text with instructions on when to inhale / exhale, a sinusoidal display which during inhalation shows the upper portion of the wave filled to indicate “inhale” and during exhalation the lower portion of the wave is emptyto indicate “exhale”, an “inflating circle”, which becomes larger to indicate to the subject to inhale and smaller to indicate to the subject to exhale, or a bar that progressively increases in height or length to indicate when to inhale and progressively decreases in height or length to indicate when to exhale. Such a bar can be in any orientation, such as vertical or horizontal.

[0182] In one embodiment, the indicator is a video graphic of a bar displayed on a screen that rises during the designated inhalation period and falls during the designated exhalation period. In this instance, the subject is instructed to inhale while the bar rises and exhale while the bar falls. The breathing pattern indicated by the video graphic can be repeated over the course of treatment. Designated inhalation periods are programmed in a range from about 1 second to about 6 seconds, including fractional times (seconds / milliseconds) thereof, and designated exhalation periods can be programmed in a range from about 1 second to about 8 seconds, including fractional times thereof. The rising and falling rates of such a bar graphic may be directed by equations, and can thereby deviate from a simple linear rising and falling rate. For example, a non-linear profile can be created that introduces decreased velocity at both the end of inhalation and the end of exhalation, mimicking a natural breathing pattern. This modification may be implemented by, for example, introducing a slow change in bar height at the beginnings of inhalation and exhalation. One example of equations to visually introduce a non-linear profile by controlling the change in bar height in a video graphic is the following: For Inhalation:Heightbar = (l-(C0S(7t / 2 * (t-tinh start) / tinhalation duration)) )* heightdisplayFor exhalation:Heightbar = ((sin(7t / 2 *(1 - (t-tinh end) / texhalation duration))) )* heightdisplay whereHeightbar is the height of the bar in pixels “cos” is the cosine function“f ’ is the current time since the beginning of the current inhalation-exhalation cycle tinh start is the time when the current inhalation started tmhaiation duration and texhaiation duration are the selected inhalation period (i.e. “designated inhalation time value” or “designated inhalation period”) and exhalation time period (i.e. “designated exhalation time value” or “designated exhalation period”), respectively heightdisplay is the height of the display in pixels “sin” is the sine function tinh end is the time when the current inhalation will endcl and c2 are constants in the range of 0 to 1 that modulate the length or the pause at the beginning of inhalation and exhalation, respectively - the larger the value, the larger the pause.

[0183] FIG. 10 Shows the bar height aS a function Of time for tinhalation duration = texhalation duration = 4s, cl = c2 = 0.2, and heightdisplay = 64 for one inhalation-exhalation cycle.

[0184] In yet another aspect of the invention, the designated inhalation periods and designated exhalation periods may be programmed according to the pharmacokinetic demands of the drug being delivered. It is contemplated that the designated inhalation periods may be programmed in a range from about 1 second to about 6 seconds, including fractional times (seconds / milliseconds) thereof. It is further contemplated that the designated exhalation periods may be programmed in a range from about 1 second to about 8 seconds, including fractional times thereof. In some embodiments, designated inhalation periods may be in a range from about 2 second to about 5 seconds, including fractional times thereof. It is further contemplated that the designated exhalation periods may be programmed in a range from about 2 second to about 5 seconds, including fractional times thereof. In certain embodiments, designated inhalation periods may be in a range from about 3 seconds to about 5 seconds, including fractional times thereof, and designated exhalation periods may be programmed in a range from about 3 seconds to about 5 seconds, including fractional times thereof. In certain embodiments, designated inhalation periods may be in a range from about 3 seconds to about 4 seconds, including fractional times thereof, and designated exhalation periods may be programmed in a range from about 3 seconds to about 4 seconds, including fractional times thereof.

[0185] In some embodiments, each designated exhalation period comprises a rest period that occurs during the terminal portion of one or more designated exhalation periods, wherein during each rest period, indication is provided to the subject to neither inhale nor exhale. For example, in embodiments where the indicator is a video graphic of a bar, the bar may remain static throughout the rest period, maintaining its position as it was at the instant before the beginning of the rest period. In some embodiments, each rest period is from about 0.1 seconds to about 1 second in duration. In some embodiments, each rest period is from about 0.1 seconds to about 0.5 seconds in duration. In some embodiments, each rest period is about 0.25 seconds in duration. In some embodiments, the rest period occurs during the terminal portion of each designated exhalation period. In some embodiments, the end of each rest period and the end of each designated exhalation period coincide.

[0186] In some embodiments, each designated inhalation period comprises a hold period that occurs during the terminal portion of one or more designated inhalation periods, wherein duringeach hold period, indication is provided to the subject to neither inhale nor exhale. For example, in embodiments where the indicator is a video graphic of a bar, the bar may remain static throughout the hold period, maintaining its position as it was at the instant before the beginning of the hold period. In some embodiments, each rest period is from about 0.1 seconds to about 1 second in duration. In some embodiments, each hold period is from about 0.1 seconds to about 0.5 seconds in duration. In some embodiments, each hold period is about 0.25 seconds in duration. In some embodiments, the hold period occurs during the terminal portion of each designated inhalation period. In some embodiments, the end of each hold period and the end of each designated inhalation period coincide.

[0187] In yet another aspect of the invention, the designated inhalation period and designated exhalation period are repeated over the course of deposition of aerosol particles. Preferably, the course of deposition is until a fixed dose of formulated medicament has been aerosolized. The amount of the fixed dose will be dependent on the drug being delivered. In another preferred embodiment, the course of deposition may be until a desired medical outcome is attained, such as, e.g., return to normal sinus rhythm with a subject experiencing atrial fibrillation. In yet another preferred embodiment, the course of deposition may be for a fixed total time.

[0188] In another embodiment of the invention, the aerosolization unit of the device includes a vibrating mesh nebulizer for use in aerosolizing a liquid. In certain embodiments, the vibrating mesh of the nebulizer comprises a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the exit opening of the first apertures having a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size, and a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm. At least some of the plurality of first apertures are within the diameters of the liquid supply cavities defined by the second apertures. The first material and the second material form a mesh for use in a vibrating mesh nebulizer.

[0189] In some embodiments, the present disclosure provides a device for depositing aerosol particles into the lungs of a subject comprising:(a) an aerosolization unit for aerosolizing a pharmaceutical composition of a medication to generate the aerosol particles, and(b) a timer that is (i) configurable with a designated inhalation period and a designatedexhalation period, (ii) capable of causing the device to produce the aerosol particles only during the designated inhalation period, and (iii) capable of controlling an indicator, wherein the designated inhalation period, the designated exhalation period, or both.

[0190] In some embodiments, the indicator is audible, tactile, or visual. In some embodiments, the indicator is a light. In some embodiments, the indicator is a graphic displayed on a video screen.

[0191] In some embodiments, each designated inhalation period is from 1 second to 6 seconds and each designated exhalation period is from 1 second to 8 seconds. In some embodiments, the designated inhalation period is 4 seconds and the designated exhalation period is 4 seconds. In some embodiments, the designated inhalation period is about 4 seconds and the designated exhalation period is about 4 seconds. In some embodiments, the designated inhalation period is about 4 seconds and the designated exhalation period is about 4.25 seconds.

[0192] In some embodiments, the device comprises a vibrating mesh nebulizer. In some embodiments, the aerosolization unit is a vibrating mesh nebulizer.

[0193] In some embodiments, the vibrating mesh of the nebulizer comprises:(a) a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the first apertures each having an exit opening with a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size;(b) a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm; wherein at least some of the plurality of first apertures are within the diameters of the liquid supply cavities defined by the second apertures, and wherein the first material and the second material form a mesh of the vibrating mesh nebulizer.

[0194] In some embodiments, the present disclosure provides a kit for treating atrial arrhythmia comprising the device provided herein and a pharmaceutical composition provided herein. In some embodiments, the pharmaceutical composition comprises an effective amount of flecainide or a pharmaceutically-acceptable salt thereof.

[0195] In some embodiments, the pharmaceutical composition is provided in unit dose form. In some embodiments, the unit dose comprises at least about 10 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about175 mg, or at least about 200 mg flecainide acetate. In some embodiments, the unit dose comprises about 50 mg to about 200 mg flecainide acetate. In some embodiments, the unit dose comprises about 10 mg to about 200 mg flecainide acetate. In some embodiments, the pharmaceutical composition is an aqueous formulation comprising at least about 30 mg / mL, at least about 45 mg / mL, at least about 50 mg / mL, at least about 60 mg / mL, or at least about 70 mg / mL flecainide acetate. In some embodiments, the pharmaceutical composition is an aqueous formulation comprising from about 45 to about 90 mg / mL flecainide acetate. In some embodiments, the course of deposition of aerosol particles is sufficient to exhaust the aqueous formulation. In some embodiments, the aerosolization unit is single-use.

[0196] In some embodiments, the timer causes the device to produce aerosol particles for the entire inhalation period. In some embodiments, during an initial set of inhalation periods within the course of deposition of aerosol particles, the timer causes the device to produce aerosol particles for a gradually increasing fraction of the inhalation period. In some embodiments, the timer causes the device to produce aerosol particles for one quarter of the first inhalation period, one half of the second inhalation period, three quarters of the third inhalation period, and the full inhalation period of all subsequent inhalation periods. In some embodiments, the gradually increasing fraction of the inhalation period during which aerosol particles are produced occurs at the beginning of each inhalation period.

[0197] In some embodiments, the present disclosure provides a kit comprising a device provided herein and a topical anesthetic.

[0198] In some embodiments, the present disclosure provides a method of depositing aerosol particles into the lungs of a subject, the method comprising administering the aerosol particles to the subject with a device comprising:(a) an aerosolization unit that aerosolizes a pharmaceutical composition of a medication to generate the aerosol particles, and(b) a timer set to a designated inhalation period and a designated exhalation period, wherein the timer causes the device to produce the aerosol particles only during the designated inhalation period, and wherein the timer controls an indicator, wherein the indicator provides indication to the subject of when to inhale and exhale, wherein the device produces the aerosol particles at a designated liquid output rate, the designated inhalation and exhalation periods repeated over the course of deposition of aerosol particles.

[0199] In some embodiments, the indicator is audible, tactile, or visual. In some embodiments, the indicator is a light. In some embodiments, the indicator is a graphic displayed on a videoscreen.

[0200] In some embodiments, each designated inhalation period is from 1 second to 6 seconds and each designated exhalation period is from 1 second to 8 seconds. In some embodiments, each designated inhalation period is from about 3 seconds to about 6 seconds in duration and each designated exhalation period is from about 3 second to 6 seconds in duration.

[0201] In some embodiments, the designated inhalation period is 4 seconds and the designated exhalation period is 4 seconds. In some embodiments, the designated inhalation period is about 4 seconds and the designated exhalation period is about 4 seconds. In some embodiments, the designated inhalation period is about 4 seconds and the designated exhalation period is about 4.25 seconds.

[0202] In some embodiments, the designated inhalation period is about 4 seconds and the designated exhalation period is about 4 seconds. In some embodiments, the course of deposition is sufficient to exhaust a unit dose of a formulation of medicament used to generate the aerosol particles.

[0203] In some embodiments, the single-use aerosolization unit comprises a vibrating mesh nebulizer. In some embodiments, the vibrating mesh of the nebulizer comprises:(a) a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the first apertures each having an exit opening with a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size;(b) a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm; wherein at least some of the plurality of first apertures are within the diameters of the liquid supply cavities defined by the second apertures, and wherein the first material and the second material form a mesh of the vibrating mesh nebulizer.

[0204] In some embodiments, the designated liquid output rate is adjusted to at least 0.3 mL / min and particle mass median aerodynamic diameter is less than 4 pm with a geometric standard deviation less than 1.8.

[0205] In some embodiments, the medication has a narrow therapeutic index.

[0206] In some embodiments, the medication with a narrow therapeutic index is selected from amiodarone, digitoxin, digoxin, dofetilide, dronedarone, flecainide, fluindione, phenindione,procainamide, quinidine, sotalol, and warfarin, or pharmaceutically-acceptable salts thereof.

[0207] In some embodiments, the medication is an anti arrhythmic medication. In some embodiments, the anti arrhythmic medication is selected from amiodarone, digitoxin, digoxin, dofetilide, dronedarone, flecainide, fluindione, phenindione, procainamide, quinidine, sotalol, and warfarin, or pharmaceutically-acceptable salts thereof. In some embodiments, the medication is delivered to the heart via the lungs.

[0208] In some embodiments, the subject suffers from arrhythmia, and wherein the aerosol particles comprise a therapeutically-effective amount of an anti arrhythmic agent. In some embodiments, the subject suffers from atrial arrhythmia, and wherein the aerosol particles comprise a therapeutically-effective amount of a class 1c antiarrhythmic drug. In some embodiments, the class 1c antiarrhythmic drug comprises a therapeutically-effective amount of flecainide or a pharmaceutically-acceptable salt thereof. In some embodiments, the class 1c antiarrhythmic drug is flecainide acetate. In some embodiments, flecainide acetate is provided as an aqueous formulation in concentrations ranging from 45 to 90 mg / mL. In some embodiments, the course of deposition is sufficient to exhaust the aqueous formulation.

[0209] In some embodiments, a target serum concentration of flecainide of at least 200 ng / mL is achieved in the subject. In some embodiments, a target serum concentration of flecainide of at least 300 ng / mL is achieved in the subject. In some embodiments, a target serum concentration of flecainide of at least 400 ng / mL is achieved in the subject. In some embodiments, a target serum concentration of flecainide of at least 500 ng / mL is achieved in the subject.

[0210] In some embodiments, the subject is administered the aerosol particles in a medically supervised setting. In some embodiments, the subject self-administers the aerosol particles. In some embodiments, the administration minimizes sustained cough or throat irritation that normally results from deposition of the aerosol particles into the oropharyngeal region.

[0211] In some embodiments, the aerosolization unit is single-use.

[0212] In some embodiments, the timer causes the device to produce aerosol particles for the entire inhalation period. In some embodiments, during an initial set of inhalation periods within the course of deposition of aerosol particles, the timer causes the device to produce aerosol particles for a gradually increasing fraction of the inhalation period.

[0213] In some embodiments, the timer causes the device to produce aerosol particles for one quarter of the first inhalation period, one half of the second inhalation period, three quarters of the third inhalation period, and for the full inhalation period of all subsequent inhalation periods. In some embodiments, the gradually increasing fraction of the inhalation period during which aerosol particles are produced occurs at the beginning of each inhalation period.

[0214] In some embodiments, a topical anesthetic is applied to the throat of the subject prior to administering the aerosol particles.

[0215] In some embodiments, the present disclosure provides a method of achieving a target serum concentration of a medication in a subject, the method comprising administering the medication to the lungs of the subject with a device comprising:(a) an aerosolization unit for aerosolizing a pharmaceutical composition of the medication to generate aerosol particles, and(b) a timer set with a designated inhalation period and a designated exhalation period, wherein the timer causes the device to produce the aerosol particles only during the designated inhalation period, and wherein the timer controls an indicator, wherein the indicator provides indication to the subject of when to inhale and exhale, wherein the device produces the aerosol particles at a designated liquid output rate, the designated inhalation and exhalation periods repeated over a course of deposition of aerosol particles sufficient for achieving the target serum concentration.

[0216] In some embodiments, the indicator is audible, tactile, or visual. In some embodiments, the indicator is a light. In some embodiments, the indicator is a graphic displayed on a video screen.

[0217] In some embodiments, each designated inhalation period is from 1 second to 6 seconds and each designated exhalation period is from 1 second to 8 seconds. In some embodiments, each designated inhalation period is from about 3 seconds to about 6 seconds in duration and each designated exhalation period is from about 3 second to 6 seconds in duration. In some embodiments, the designated inhalation period is 4 seconds and the designated exhalation period is 4 seconds. In some embodiments, the designated inhalation period is about 4 seconds and the designated exhalation period is about 4 seconds. In some embodiments, the inhalation period is about 4.25 seconds and the designated exhalation period is about 4 seconds. In some embodiments, the inhalation period is about 4.25 seconds and the designated exhalation period is about 4.25 seconds. In some embodiments, the inhalation period is about 4 seconds and the designated exhalation period is about 4.25 seconds.

[0218] In some embodiments, the course of deposition is sufficient to exhaust a volume (e.g., a unit dose) of a formulation of medicament used to generate the aerosol particles.

[0219] In some embodiments, the single-use aerosolization unit comprises a vibrating mesh nebulizer. In some embodiments, the vibrating mesh of the nebulizer comprises:(a) a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generallycylindrical shapes, the first apertures each having an exit opening with a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size;(b) a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm; wherein at least some of the plurality of first apertures are within the diameters of the liquid supply cavities defined by the second apertures, and wherein the first material and the second material form a mesh of the vibrating mesh nebulizer.

[0220] In some embodiments, the designated liquid output rate is adjusted to at least 0.3 mL / min and particle mass median aerodynamic diameter is less than 4 pm with a geometric standard deviation less than 1.8.

[0221] In some embodiments, the medication has a narrow therapeutic index. In some embodiments, the medication with a narrow therapeutic index is selected from amiodarone, digitoxin, digoxin, dofetilide, dronedarone, flecainide, fluindione, phenindione, procainamide, quinidine, sotalol, and warfarin, or pharmaceutically-acceptable salts thereof. In some embodiments, the administration of the medication with a narrow therapeutic index results in reduced inter- and intra-patient variability as compared to the medication’s normally accepted dosage form.

[0222] In some embodiments, the medication is delivered to the heart via the lungs.

[0223] In some embodiments, the subject suffers from arrhythmia, and wherein the aerosol particles comprise a therapeutically-effective amount of an anti arrhythmic agent. In some embodiments, the aerosol particles comprise a therapeutically-effective amount of a class 1c antiarrhythmic drug. In some embodiments, the class 1c anti arrhythmic drug is flecainide or a pharmaceutically-acceptable salt thereof. In some embodiments, the class 1c antiarrhythmic drug is flecainide acetate. In some embodiments, flecainide acetate is provided as an aqueous formulation in concentrations ranging from 45 to 90 mg / mL.

[0224] In some embodiments, the course of deposition is sufficient to exhaust the aqueous formulation.

[0225] In some embodiments, a target serum concentration of flecainide of at least 200 ng / mL is achieved in the subject. In some embodiments, a target serum concentration of flecainide of at least 300 ng / mL is achieved in the subject. In some embodiments, a target serum concentration offlecainide of at least 400 ng / mL is achieved in the subject. In some embodiments, a target serum concentration of flecainide of at least 500 ng / mL is achieved in the subject.

[0226] In some embodiments, the subject is administered the aerosol particles in a medically supervised setting. In some embodiments, the subject self-administers the aerosol particles. In some embodiments, the aerosolization unit is single-use.

[0227] In some embodiments, the timer causes the device to produce aerosol particles for the entire inhalation period. In some embodiments, during an initial set of inhalation periods within the course of deposition of aerosol particles, the timer causes the device to produce aerosol particles for a gradually increasing fraction of the inhalation period. In some embodiments, the timer causes the device to produce aerosol particles for one quarter of the first inhalation period, one half of the second inhalation period, three quarters of the third inhalation period, and for the full inhalation period of all subsequent inhalation periods. In some embodiments, the timer causes the device to produce aerosol particles for one quarter of the first designated inhalation period, three eighths of the second designated inhalation period, one half of the third designated inhalation period, five eighths of the fourth designated inhalation period, and three fourths of each designated inhalation period subsequent to the fourth designated inhalation period. In some embodiments, the timer causes the device to produce aerosol particles for about one second during the first designated inhalation period, for about 1.5 seconds during the second designated inhalation period, for about two seconds during the third designated inhalation period, for about 2.5 seconds during the fourth designated inhalation period, and for three seconds during each designated inhalation period subsequent to the fourth designated inhalation period. In some embodiments, the gradually increasing fraction of the inhalation period during which aerosol particles are produced occurs at the beginning of each inhalation period.

[0228] In some embodiments, a topical anesthetic is applied to the throat of the subject prior to administering the aerosol particles.

[0229] In some embodiments, the present disclosure provides a device for administering aerosol particles to a subject, the device comprising:(a) an aerosolization unit suitable for aerosolizing a pharmaceutical composition to generate the aerosol particles;(b) an indicator; and(c) a timer, wherein the timer is suitable for:(i) causing the indicator to indicate occurrence of a designated inhalation period or occurrence of a designated exhalation period, wherein each designated inhalation period lasts for an interval of time equal to the designated inhalation time value,and each designated exhalation period lasts for an interval of time equal to the designated exhalation time value;(ii) causing the aerosolization unit to release the aerosol particles for an active period at the beginning of each designated inhalation period, wherein each active period independently lasts for an interval of time that is no longer than the designated inhalation time value; and at the end of each active period, causing the aerosolization unit to stop releasing the aerosol particles, wherein the designated inhalation period and the designated exhalation period occur consecutively and are repeated over a course of deposition of the aerosol particles.

[0230] In some embodiments, the present disclosure provides a device for administering aerosol particles to a subject, the device comprising:(a) an aerosolization unit suitable for aerosolizing a pharmaceutical composition to generate the aerosol particles;(b) an indicator; and(c) a timer, wherein the timer is suitable for:(i) causing the indicator to indicate occurrence of a designated inhalation period or occurrence of a designated exhalation period, wherein each designated inhalation period lasts for an interval of time equal to the designated inhalation time value, and each designated exhalation period lasts for an interval of time equal to the designated exhalation time value;(ii) causing the aerosolization unit to aerosolize the pharmaceutical composition for an active period at the beginning of each designated inhalation period, wherein each active period independently lasts for an interval of time that is no longer than the designated inhalation time value; and at the end of each active period, cause the aerosolization unit to aerosolize the pharmaceutical composition, wherein the designated inhalation period and the designated exhalation period occur consecutively and are repeated over a course of deposition of the aerosol particles.

[0231] In some embodiments, the present disclosure provides a device for administering aerosol particles to a subject, the device comprising:(a) an aerosolization unit suitable for aerosolizing a pharmaceutical composition to generate the aerosol particles;(b) an indicator; and(c) a timer, wherein the timer is configured to:(i) cause the indicator to indicate, via a perceptible signal, occurrence of a designatedinhalation period or occurrence of a designated exhalation period, wherein each designated inhalation period lasts for an interval of time equal to the designated inhalation time value, and each designated exhalation period lasts for an interval of time equal to the designated exhalation time value;(ii) cause the aerosolization unit to aerosolize the pharmaceutical composition for an active period at the beginning of each designated inhalation period, wherein each active period independently lasts for an interval of time that is no longer than the designated inhalation time value; and at the end of each active period, cause the aerosolization unit to stop aerosolizing the pharmaceutical composition, wherein the designated inhalation period and the designated exhalation period occur consecutively and are repeated over a course of deposition of the aerosol particles.

[0232] In some embodiments, the present disclosure provides a device for administering aerosol particles to a subject, the device comprising:(a) an aerosolization unit for aerosolizing a pharmaceutical composition to generate the aerosol particles;(b) an indicator;(c) a timer, wherein the timer:(i) is configured with a designated inhalation time value and a designated exhalation time value;(ii) causes the indicator to indicate, via a perceptible signal, occurrence of a designated inhalation period or occurrence of a designated exhalation period, wherein each designated inhalation period lasts for an interval of time equal to the designated inhalation time value, and each designated exhalation period lasts for an interval of time equal to the designated exhalation time value;(iii) at the beginning of each designated inhalation period, causes the aerosolization unit to start releasing aerosol of the pharmaceutical composition for an active period, wherein each active period independently lasts for an interval of time that is no longer than the designated inhalation time value; and(iv) at the end of each active period, causes the aerosolization unit to stop releasing the aerosol of the pharmaceutical composition, wherein the designated inhalation period and the designated exhalation period occur consecutively and are repeated over a course of deposition of the aerosol particles.

[0233] In some embodiments, the present disclosure provides a device for depositing aerosol particles into a patient comprising:(a) an aerosolization unit configured to aerosolize a pharmaceutical composition to generate the aerosol particles;(b) an indicator; and(c) a timer, wherein the timer is:(i) set with a designated inhalation time value and a designated exhalation time value;(ii) configured to cause the indicator to indicate, via a perceptible signal, occurrence of a designated inhalation period, and following the designated inhalation period, indicate, via a perceptible signal, occurrence of a designated exhalation period, wherein each designated inhalation period lasts for an interval of time equal to the designated inhalation time value, and each designated exhalation period lasts for an interval of time equal to the designated exhalation time value;(iii) configured to cause the aerosolization unit to switch to and remain in active mode for an active period at the beginning of each designated inhalation period, wherein each active period independently lasts for an interval of time that is no longer than the designated inhalation time value; and at the end of each active period, cause the aerosolization unit to switch to inactive mode, wherein in the active mode, the aerosolization unit aerosolizes the pharmaceutical composition and delivers the aerosol to the patient through a mouthpiece, and in the inactive mode, the aerosolization unit stops delivering the aerosol through the mouth piece, and wherein the designated inhalation period and the designated exhalation period are set to occur consecutively and alternate over a course of deposition of the aerosol particles.

[0234] In some embodiments, the present disclosure provides a device for administering aerosol particles to a subject, the device comprising:(a) an aerosolization unit configured to aerosolize a pharmaceutical composition to generate the aerosol particles;(b) an indicator; and(c) a timer, wherein the timer is:(i) set with a designated inhalation time value and a designated exhalation time value;(ii) configured to cause the indicator to indicate, via a perceptible signal, occurrence of a designated inhalation period or occurrence of a designated exhalation period, wherein each designated inhalation period lasts for an interval of time equal to the designated inhalation time value, and each designated exhalation period lasts for an interval of time equal to the designated exhalation time value;(iii) configured to cause the aerosolization unit to release aerosol of the pharmaceuticalcomposition for an active period at the beginning of each designated inhalation period, wherein each active period independently lasts for an interval of time that is no longer than the designated inhalation time value; and at the end of each active period, cause the aerosolization unit to stop releasing the aerosol of the pharmaceutical composition, wherein the designated inhalation period and the designated exhalation period occur consecutively and are repeated over a course of deposition of the aerosol particles.

[0235] In some embodiments, the present disclosure provides a device for regulating administration of aerosol particles to a subject, the device comprising:(a) a switch configured to modulate flow of the aerosol particles;(b) an indicator; and(c) a timer, wherein the timer is:(i) set with a designated inhalation time value and a designated exhalation time value;(ii) configured to cause the indicator to indicate, via a perceptible signal, occurrence of a designated inhalation period, and following the designated inhalation period, indicate, via the perceptible signal, occurrence of a designated exhalation period, wherein each designated inhalation period lasts for an interval of time equal to the designated inhalation time value, and each designated exhalation period lasts for an interval of time equal to the designated exhalation time value;(iii) configured to cause the switch to enter active mode at the beginning of each designated inhalation period and remain activated for an active period, wherein each active period independently lasts for an interval of time that is no longer than the designated inhalation time value; and cause the switch to deactivate at the end of each active period, wherein in active mode, the switch enters a configuration that is capable of allowing or causing aerosol to be delivered from a source of aerosol generation to an output of the device, wherein the designated inhalation period and the designated exhalation period are set to occur consecutively and alternate over a course of deposition of the aerosol particles.

[0236] In some embodiments, an output of the device is a mouthpiece. In some embodiments, the output of the device is an output adaptable to a mouthpiece (e.g., a tube, a port, or a port connected to a tube).

[0237] In some embodiments, the switch is a relay capable of interrupting supply of power to the source of aerosol generation. In some embodiments, causing the switch to enter active modecomprises causing the relay to permit transmission of power. In some embodiments, causing the switch to deactivate comprises causing the relay to forbid transmission of power.

[0238] In some embodiments, the switch is a valve capable of controlling passage of aerosol particles from the source of aerosol generation (e.g., a vibrating mesh of a vibrating mesh nebulizer) to the output of the device. In some embodiments, causing the switch to enter active mode comprises causing the valve to open, thereby permitting passage of aerosol particles to the output. In some embodiments, causing the switch to deactivate comprises causing the valve to close.

[0239] In some embodiments, the device further comprises the source of aerosol generation. In some embodiments, the source of aerosolization is a nebulizer. In some embodiments, the source of aerosol generation is a vibrating mesh of a vibrating mesh nebulizer.

[0240] In some embodiments, the present disclosure provides a device for administering aerosol particles to a subject, the device comprising:(a) an aerosolization unit configured to aerosolize a pharmaceutical composition to generate the aerosol particles;(b) an indicator; and(c) a timer, wherein the timer is:(i) set with a designated inhalation time value and a designated exhalation time value;(ii) configured to cause the indicator to indicate, via a perceptible signal, occurrence of a designated inhalation period, and following the designated inhalation period, indicate, via the perceptible signal, occurrence of a designated exhalation period, wherein each designated inhalation period lasts for an interval of time equal to the designated inhalation time value, and each designated exhalation period lasts for an interval of time equal to the designated exhalation time value;(iii) configured to cause the aerosolization unit to activate at the beginning of each designated inhalation period and remain activated for an active period, wherein each active period independently lasts for an interval of time that is no longer than the designated inhalation time value; and cause the aerosolization unit to deactivate at the end of each active period, wherein during each active period, the aerosolization unit aerosolizes the pharmaceutical composition and delivers the aerosol to the subject through a mouthpiece of the aerosolization unit, wherein the designated inhalation period and the designated exhalation period are set to occur consecutively and alternate over a course of deposition of the aerosol particles.

[0241] In some embodiments, the timer is a microcontroller. In some embodiments, the microcontroller comprises at least one processor and memory.

[0242] In some embodiments, the indicator is audible, tactile, or visual. In some embodiments, the indicator is a light. In some embodiments, the indicator is a video screen and the perceptible signal displayed on the video screen.

[0243] In some embodiments, the designated inhalation time value is from 1 second to 6 seconds and the designated exhalation time value is from 1 second to 8 seconds. In some embodiments, the designated inhalation time value is from about 3 seconds to about 6 seconds and each designated exhalation time value is from about 3 second to 6 seconds. In some embodiments, the designated inhalation time value is 4 seconds and the designated exhalation time value is 4 seconds. In some embodiments, the designated inhalation time value is about 4 seconds and the designated exhalation time value is about 4 seconds. In some embodiments, the inhalation time value is about 4.25 seconds and the designated exhalation time value is about 4 seconds. In some embodiments, the inhalation time value is about 4.25 seconds and the designated exhalation time value is about 4.25 seconds. In some embodiments, the inhalation time value is about 4 seconds and the designated exhalation period is about seconds.

[0244] In some embodiments, each designated exhalation period comprises a rest period that occurs during the terminal portion of one or more designated exhalation periods, wherein the timer is configured to cause the indicator to indicate to the subject to neither inhale nor exhale during each rest period. In some embodiments, each rest period is from about 0.1 seconds to about 1 second in duration. In some embodiments, each rest period is from about 0.1 seconds to about 0.5 seconds in duration. In some embodiments, each rest period is about 0.25 seconds in duration. In some embodiments, the rest period is set to occur during the terminal portion of each designated exhalation period. In some embodiments, the end of each rest period is set to coincide with the end of each designated exhalation period.

[0245] In some embodiments, each designated inhalation period comprises a hold period that occurs during the terminal portion of one or more designated inhalation periods, wherein the timer is configured to cause the indicator to indicate to the subject to neither inhale nor exhale during each hold period. In some embodiments, each hold period is from about 0.1 seconds to about 1 second in duration. In some embodiments, each hold period is from about 0.1 seconds to about 0.5 seconds in duration. In some embodiments, each hold period is about 0.25 seconds in duration. In some embodiments, the hold period is set to occur during the terminal portion of each designated inhalation period. In some embodiments, the end of each hold period is set to coincide with the end of each inhalation exhalation period.

[0246] In some embodiments, the timer causes the indicator to modulate the perceptible signal over time according to a waveform, wherein each period of the waveform has a duration equal to the sum of the designated inhalation time value and the designated exhalation time value. In some embodiments, each period of the waveform corresponds to a cycle of the perceptible signal. In some embodiments, modulating the perceptible signal comprises modulating the intensity of the perceptible signal (e.g., an audible tone or a light) according to amplitude of the waveform. In some embodiments, modulating the perceptible signal comprises modulating the frequency of the perceptible signal (e.g., an audible tone or a light) according to amplitude of the waveform. In some embodiments, the indicator is a video screen, and modulating the perceptible signal comprises modulating a dimension of a two-dimensional graphic displayed on a video screen according to amplitude of the waveform. In some embodiments, the first indication is emitted when the first derivative of the waveform is positive. In some embodiments, for the entirety of each designated inhalation period, the first derivative of the waveform is positive or zero, and, for the entirety of each designated exhalation period, the first derivative of the waveform is negative or zero. In some embodiments, for the entirety of each designated inhalation period, the first derivative of the waveform is negative or zero, and, for the entirety of each designated exhalation period, the first derivative of the waveform is positive or zero. In some embodiments, each peak of the waveform corresponds to the end of a designated inhalation period and the beginning of a designated exhalation period. In some embodiments, each trough of the waveform corresponds to the beginning of a designated inhalation period and the end of a designated exhalation period. In some embodiments, for the entirety of each rest period, the first derivative of the waveform is zero. In some embodiments, for the entirety of each hold period, the first derivative of the waveform is zero.

[0247] In some embodiments, the aerosolization unit comprises a vibrating mesh nebulizer.

[0248] In some embodiments, the device comprises:(a) a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the first apertures each having an exit opening with a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size;(b) a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm;wherein at least some of the plurality of first apertures are within the diameters of the liquid supply cavities defined by the second apertures, and wherein the first material and the second material form a mesh for use in the vibrating mesh nebulizer.

[0249] In some embodiments, the aerosolization unit is a single-use aerosolization unit.

[0250] In some embodiments, each active period lasts for an interval of time that is equal to the designated inhalation time value. In some embodiments, at least one active period lasts no longer than a fraction of the designated inhalation time value. In some embodiments, each active period lasts no longer than a fraction of the designated inhalation time value. In some embodiments, the timer causes the duration of an active period to be longer than a duration of a preceding active period. In some embodiments, for each active period within an initial set of active periods, the timer increases the duration the active period relative to the duration of the immediately preceding active period. In some embodiments, the initial set of active periods is the first three, first four, first five, first six, first seven, first eight, first nine, or first ten active periods of a dosing session. In some embodiments, the timer causes each active period subsequent to the initial set of active periods to be constant in duration. In some embodiments, the timer causes each active period subsequent to the initial set of active periods to last for a duration that is equal to the duration of the last active period of the initial set of active periods. In some embodiments, over the initial set of active periods, the timer increases the duration of the active period from an initial value to a terminal value, wherein the initial value is from about 0.5 seconds to about two seconds, and the terminal value is from about 2.5 seconds to about four seconds. In some embodiments, over the initial set of active periods, the timer increases the duration of the active period from an initial value to a terminal value. In some embodiments, the initial value is about one second, and the terminal value is about three seconds. In some embodiments, the initial value is about 0.5 seconds, and the terminal value is about three seconds.

[0251] In some embodiments, each active period is set to last for an interval of time that is equal to the designated inhalation time value. In some embodiments, at least one active period is set to last no longer than a fraction of the designated inhalation time value. In some embodiments, each active period is set to last no longer than a fraction of the designated inhalation time value. In some embodiments, the timer is configured to cause the duration of an active period to be longer than a duration of a preceding active period. In some embodiments, for each active period within an initial set of active periods, the timer is configured to increases the duration the active period relative to the duration of the immediately preceding active period. In some embodiments, the initial set of active periods is the first three, first four, first five, first six, first seven, first eight, first nine, or first ten active periods of a dosing session. In some embodiments, the timer is set tocause each active period subsequent to the initial set of active periods to be constant in duration. In some embodiments, the timer is configured to cause each active period subsequent to the initial set of active periods to last for a duration that is equal to the duration of the last active period of the initial set of active periods. In some embodiments, over the initial set of active periods, the timer is configured to increase the duration of the active period from an initial value to a terminal value, wherein the initial value is from about 0.5 seconds to about two seconds, and the terminal value is from about 2.5 seconds to about four seconds. In some embodiments, over the initial set of active periods, the timer is configured to increase the duration of the active period from an initial value to a terminal value. In some embodiments, the initial value is about one second, and the terminal value is about three seconds. In some embodiments, the initial value is about 0.5 seconds, and the terminal value is about three seconds.

[0252] In some embodiments, the initial set of designated inhalation periods comprises a first designated inhalation period, a second designated inhalation period, and a third designated inhalation period, wherein the timer causes the device to produce aerosol particles for about one quarter of the first designated inhalation period, about one half of the second designated inhalation period, about three quarters of the third inhalation period, and an entirety of each designated inhalation period subsequent to the third designated inhalation period.

[0253] In some embodiments, the initial set of designated inhalation periods comprises a first designated inhalation period, a second designated inhalation period, and a third designated inhalation period, wherein the timer is configured to cause the device to produce aerosol particles for about one quarter of the first designated inhalation period, about one half of the second designated inhalation period, about three quarters of the third inhalation period, and an entirety of each designated inhalation period subsequent to the third designated inhalation period.

[0254] In some embodiments, the initial set of designated inhalation periods comprises a first designated inhalation period, a second designated inhalation period, a third designated inhalation period, and a fourth designated inhalation period, wherein the timer causes the device to produce aerosol particles for about one quarter of the first designated inhalation period, about three eighths of the second designated inhalation period, about one half of the third inhalation period, about five eighths of the fourth designated inhalation period, and about three fourths of each designated inhalation period subsequent to the fourth designated inhalation period. In some embodiments, the timer causes the device to produce aerosol particles for about one second during the first designated inhalation period, for about 1.5 seconds during the second designated inhalation period, for about two seconds during the third designated inhalation period, for about 2.5 seconds during the fourth designated inhalation period, and for three seconds during eachdesignated inhalation period subsequent to the fourth designated inhalation period.

[0255] In some embodiments, the initial set of designated inhalation periods comprises a first designated inhalation period, a second designated inhalation period, a third designated inhalation period, and a fourth designated inhalation period, wherein the timer is configured to cause the device to produce aerosol particles for about one quarter of the first designated inhalation period, about three eighths of the second designated inhalation period, about one half of the third inhalation period, about five eighths of the fourth designated inhalation period, and about three fourths of each designated inhalation period subsequent to the fourth designated inhalation period. In some embodiments, the initial set of designated inhalation periods comprises a first designated inhalation period, a second designated inhalation period, a third designated inhalation period, and a fourth designated inhalation period, wherein the timer is configured to cause the device to produce aerosol particles for about one second during the first designated inhalation period, for about 1.5 seconds during the second designated inhalation period, for about two seconds during the third designated inhalation period, for about 2.5 seconds during the fourth designated inhalation period, and for three seconds during each designated inhalation period subsequent to the fourth designated inhalation period.

[0256] In some embodiments, the initial set of designated inhalation periods comprises a first designated inhalation period, a second designated inhalation period, a third designated inhalation period, and a fourth designated inhalation period, wherein active period is: about one second during the first designated inhalation period, about 1.5 seconds during the second designated inhalation period, about two seconds during the third designated inhalation period, about 2.5 seconds during the fourth designated inhalation period, and three seconds during each designated inhalation period subsequent to the fourth designated inhalation period.

[0257] In some embodiments, the present disclosure provides a device for administering aerosol particles to a subject, the device comprising:(a) an aerosolization unit;(b) an indicator;(c) at least one processor; and(d) memory including computer executable instructions which, when executed by the at least one processor, cause the processor to:(i) retrieve a designated inhalation time value and a designated exhalation time value from the memory;(ii) cause the indicator to emit a perceptible signal, the perceptible signal comprising a plurality of cycles formed from a cycle repeated consecutively over time, whereineach cycle comprises: a first indication that is emitted for a designated inhalation period, wherein the designated inhalation period lasts for a duration of time equal to the designated inhalation time value, and, a second indication that is emitted for a designated exhalation period, wherein the designated exhalation period occurs subsequently and consecutively to the designated inhalation period and lasts for a duration of time equal to the designated exhalation time value,(iii) cause the aerosolization unit to activate at the beginning of each designated inhalation period and remain activated for an active period, wherein each active period independently lasts for an interval of time that is no longer than the designated inhalation time value; and(iv) cause the aerosolization unit to deactivate at the end of each active period.

[0258] In some embodiments, the first indication and second indication are configured to sufficiently differ such that they are discernable from one another by the subject. In some embodiments, the perceptible signal is audible, tactile, or visual. In some embodiments, the indicator is a light. In some embodiments, the indicator is a visual indicator. In some embodiments, the indicator is a video screen. In some embodiments, the perceptible signal is a graphic displayed on the video screen. In some embodiments, the first indication is a rising bar displayed on the video screen, and the second indication is a falling bar displayed on the video screen. In some embodiments, the second indication is a rising bar displayed on the video screen, and the first indication is a falling bar displayed on the video screen.

[0259] In some embodiments, during the active period, the aerosolization unit aerosolizes the pharmaceutical composition and delivers the aerosol to the subject through a mouthpiece of the aerosolization unit. In some embodiments, causing the aerosolization unit to activate comprises causing the aerosolization unit to begin aerosolizing a pharmaceutical composition. In some embodiments, causing the aerosolization unit to deactivate comprises causing the aerosolization unit to cease aerosolizing a pharmaceutical composition.

[0260] In some embodiments, causing the aerosolization unit to activate comprises causing aerosol to be supplied to a mouthpiece of the aerosolization unit. In some embodiments, causing the aerosolization unit to deactivate comprises ceasing supply of aerosol to a mouthpiece of the aerosolization unit.

[0261] In some embodiments, causing the aerosolization unit to activate comprises causing a valve to open, wherein the value controls passage of aerosol particles from a source of aerosolgeneration (e.g., a vibrating mesh of a vibrating mesh nebulizer) to a mouthpiece of the aerosolization unit. In some embodiments, causing the aerosolization unit to deactivate comprises causing the valve to close.

[0262] In some embodiments, the timer is a microcontroller. In some embodiments, causing the aerosolization unit to activate comprises causing a relay to supply power to the source of aerosol generation (e.g., a vibrating mesh of a vibrating mesh nebulizer), thereby causing the source of aerosol generation to generate aerosol. In some embodiments, causing the aerosolization unit to deactivate comprises causing the relay cease supplying power to the source of aerosol generation. In some embodiments, the source of aerosol generation is a vibrating mesh of a vibrating mesh nebulizer. In some embodiments, the timer is electronically coupled to a relay that interrupts the supply of power to a source of aerosol generation in the aerosolization unit.

[0263] In some embodiments, the timer is a microcontroller. In some embodiments, the timer is in electronic communication with a second microcontroller, wherein the second microcontroller is electronically coupled to a relay that interrupts the supply of power to the aerosolization unit.

[0264] In some embodiments, the designated inhalation time value is from about three seconds to about 6 seconds and each designated exhalation time value is from about three seconds to six seconds. In some embodiments, the designated inhalation time value is four seconds and the designated exhalation time value is four seconds. In some embodiments, the designated inhalation time value is about four seconds and the designated exhalation time value is about 4 seconds. In some embodiments, the inhalation time value is about 4.25 seconds and the designated exhalation time value is about four seconds. In some embodiments, the inhalation time value is about 4.25 seconds and the designated exhalation time value is about 4.25 seconds. In some embodiments, the inhalation time value is about four seconds and the designated exhalation period is about 4.25 seconds.

[0265] In some embodiments, each designated exhalation period comprises a rest period that occurs during the terminal portion of one or more designated exhalation periods, wherein the processor causes the indicator to indicate to the subject to neither inhale nor exhale during each rest period. In some embodiments, each rest period is from about 0.1 seconds to about 1 second in duration. In some embodiments, each rest period is from about 0.1 seconds to about 0.5 seconds in duration. In some embodiments, each rest period is about 0.25 seconds in duration. In some embodiments, the rest period occurs during the terminal portion of each designated exhalation period. In some embodiments, the end of each rest period coincides with the end of each designated exhalation period.

[0266] In some embodiments, each designated inhalation period comprises a hold period thatoccurs during the terminal portion of one or more designated inhalation periods, wherein the processor causes the indicator to indicate to the subject to neither inhale nor exhale during each hold period. In some embodiments, each hold period is from about 0.1 seconds to about 1 second in duration. In some embodiments, each hold period is from about 0.1 seconds to about 0.5 seconds in duration. In some embodiments, each hold period is about 0.25 seconds in duration. In some embodiments, the hold period occurs during the terminal portion of each designated inhalation period. In some embodiments, the end of each hold period coincides with the end of each designated exhalation period.

[0267] In some embodiments, the processor causes the indicator to modulate the perceptible signal over time according to a waveform, wherein each period of the waveform has a duration equal to the sum of the designated inhalation time value and the designated exhalation time value. In some embodiments, each period of the waveform corresponds to a cycle of the perceptible signal. In some embodiments, modulating the perceptible signal comprises modulating the intensity of the perceptible signal (e.g., an audible tone or a light) according to amplitude of the waveform. In some embodiments, modulating the perceptible signal comprises modulating the frequency of the perceptible signal (e.g., an audible tone or a light) according to amplitude of the waveform. In some embodiments, the indicator is a video screen, and modulating the perceptible signal comprises modulating a dimension of a two-dimensional graphic displayed on a video screen according to amplitude of the waveform. In some embodiments, the first indication is emitted when the first derivative of the waveform is positive. In some embodiments, for the entirety of each designated inhalation period, the first derivative of the waveform is positive or zero, and, for the entirety of each designated exhalation period, the first derivative of the waveform is negative or zero. In some embodiments, for the entirety of each designated inhalation period, the first derivative of the waveform is negative or zero, and, for the entirety of each designated exhalation period, the first derivative of the waveform is positive or zero. In some embodiments, each peak of the waveform corresponds to the end of a designated inhalation period and the beginning of a designated exhalation period. In some embodiments, each trough of the waveform corresponds to the beginning of a designated inhalation period and the end of a designated exhalation period. In some embodiments, for the entirety of each rest period, the first derivative of the waveform is zero. In some embodiments, for the entirety of each hold period, the first derivative of the waveform is zero.

[0268] In some embodiments, the aerosolization unit comprises a vibrating mesh nebulizer.

[0269] In some embodiments, the vibrating mesh nebulizer comprises:(a) a first material having a plurality of first apertures, the first material being formed througha photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the first apertures each having an exit opening with a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size;(b) a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm; wherein at least some of the plurality of first apertures are within the diameters of the liquid supply cavities defined by the second apertures, and wherein the first material and the second material form a mesh for use in the vibrating mesh nebulizer.

[0270] In some embodiments, the aerosolization unit is a single-use aerosolization unit (e.g., a single-use nebulizer).

[0271] In some embodiments, each active period lasts for an interval of time that is equal to the designated inhalation time value. In some embodiments, at least one active period lasts no longer than a fraction of the designated inhalation time value. In some embodiments, each active period lasts no longer than a fraction of the designated inhalation time value. In some embodiments, the processor causes the duration of an active period to be longer than a duration of a preceding active period. In some embodiments, for each active period within an initial set of active periods, the timer increases the duration the active period relative to the duration of the immediately preceding active period. In some embodiments, the initial set of active periods is the first three, first four, first five, first six, first seven, first eight, first nine, or first ten active periods of a dosing session. In some embodiments, the processor causes each active period subsequent to the initial set of active periods to be constant in duration. In some embodiments, the processor causes each active period subsequent to the initial set of active periods to last for a duration that is equal to the duration of the last active period of the initial set of active periods. In some embodiments, over the initial set of active periods, the processor increases the duration of the active period from an initial value to a terminal value, wherein the initial value is from about 0.5 seconds to about two seconds, and the terminal value is from about 2.5 seconds to about four seconds. In some embodiments, over the initial set of active periods, the processor increases the duration of the active period from an initial value to a terminal value. In some embodiments, the initial value is about one second, and the terminal value is about three seconds. In some embodiments, the initial value is about 0.5 seconds, and the terminal value is about three seconds.

[0272] In some embodiments, the initial set of active periods comprises a first active period, asecond active period, a third active period, and a fourth active period, wherein the first active period is about one second, the second active period is about 1.5 seconds, the third active period is about two seconds, the fourth active period is about 2.5 seconds, and each active period subsequent to the fourth active period is about three seconds.

[0273] In some embodiments, the present disclosure provides a kit comprising a device provided herein and a topical anesthetic.

[0274] In some embodiments, the present disclosure provides a method of administering an aerosol particles to a subject, the method comprising: aerosolizing a pharmaceutical composition via a nebulizer to generate the aerosol over a course of a plurality of cycles, each cycle consisting of: a designated inhalation period, wherein each designated inhalation period lasts for an interval of time equal to a designated inhalation time value, wherein the aerosolizing occurs only during an active period that begins at the start of each designated inhalation period and lasts for an interval of time that is no more than the designated inhalation time value; and a designated exhalation period, wherein each designated exhalation period lasts for an interval of time equal to a designated exhalation time value; providing indication to the subject of occurrence of each designated inhalation period or each designated exhalation period via a perceptible signal; and instructing the subject to, in synchrony with the perceptible signal, conduct: (i) a single inhalation of the aerosol during each designated inhalation period, and (ii) a single exhalation during each designated exhalation period.

[0275] In some embodiments, each designated exhalation period comprises a rest period that occurs during the terminal portion of one or more designated exhalation periods, wherein during each rest period, indication is provided to the subject to neither inhale nor exhale. In some embodiments, each rest period is from about 0.1 seconds to about 1 second in duration. In some embodiments, each rest period is from about 0.1 seconds to about 0.5 seconds in duration. In some embodiments, each rest period is about 0.25 seconds in duration. In some embodiments, the rest period occurs during the terminal portion of each designated exhalation period.

[0276] In some embodiments, each designated exhalation period comprises a hold period that occurs during the terminal portion of one or more designated inhalation periods, wherein during each hold period, indication is provided to the subject to neither inhale nor exhale. In some embodiments, during each hold period, indication is provided to the subject to maintain their peak inspiratory volume. In some embodiments, each hold period is from about 0.1 seconds toabout 1 second in duration. In some embodiments, each hold period is from about 0.1 seconds to about 0.5 seconds in duration. In some embodiments, each hold period is about 0.25 seconds in duration. In some embodiments, the hold period occurs during the terminal portion of each designated inhalation period.

[0277] In some embodiments, the method further comprises instructing the subject to continue inhaling the aerosol in synchrony with the perceptible signal until a unit dose of the pharmaceutical composition is depleted.

[0278] In some embodiments, the pharmaceutical composition comprises an anti arrhythmic agent and the subject suffers from cardiac arrythmia. In some embodiments, the method further comprises, after a first unit dose of the pharmaceutical composition has been administered, administering a second unit dose of the pharmaceutical composition upon determining that the subject still suffers from the cardiac arrythmia. In some embodiments, the second unit dose is equal to the first unit dose. In some embodiments, the second unit dose is one-half of the first unit dose.In some embodiments, the second unit dose is administered about 10 minutes to about 1 hour after administration of the first unit dose is completed. In some embodiments, the method further comprises instructing the subject to pause inhalation of the aerosol after about one half of the unit dose has been administered, and resume inhalation of the remaining half of the unit dose after a 30 second to three minute break.

[0279] In some embodiments, the method further comprises instructing the subject to:(i) inhale the aerosol in synchrony with the perceptible signal for a first duration that is from about 3 minutes to about 4 minutes;(ii) after said first duration, pause inhalation for a second duration that is from about 30 seconds to about 90 seconds; and(iii) after said second duration, resume inhalation in synchrony with the perceptible signal for a third duration that is from about 3 minutes to about 4 minutes.

[0280] In some embodiments, the present disclosure provides a method of administering an aerosol particles to a subject, the method comprising: aerosolizing a pharmaceutical composition via a nebulizer to generate the aerosol over a course of a plurality of cycles, each cycle consisting of: a designated inhalation period, wherein each designated inhalation period lasts for an interval of time equal to a designated inhalation time value, wherein the aerosolizing occurs only during an active period that begins at the start of eachdesignated inhalation period and lasts for an interval of time that is no more than the designated inhalation time value; and a designated exhalation period, wherein each designated exhalation period lasts for an interval of time equal to a designated exhalation time value; providing indication to the subject of occurrence of each designated inhalation period or each designated exhalation period via a perceptible signal.

[0281] In some embodiments, the subject conducts, in synchrony with the perceptible signal, a single inhalation of the aerosol during each designated inhalation period, and a single exhalation during each designated exhalation period.

[0282] In some embodiments, each designated exhalation period comprises a rest period that occurs during the terminal portion of one or more designated exhalation periods, wherein during each rest period, indication is provided to the subject to neither inhale nor exhale. In some embodiments, each rest period is from about 0.1 seconds to about 1 second in duration. In some embodiments, each rest period is from about 0.1 seconds to about 0.5 seconds in duration. In some embodiments, each rest period is about 0.25 seconds in duration. In some embodiments, the rest period occurs during the terminal portion of each designated exhalation period.

[0283] In some embodiments, each designated exhalation period comprises a hold period that occurs during the terminal portion of one or more designated inhalation periods, wherein during each hold period, indication is provided to the subject to neither inhale nor exhale. In some embodiments, during each hold period, indication is provided to the subject to maintain their peak inspiratory volume. In some embodiments, each hold period is from about 0.1 seconds to about 1 second in duration. In some embodiments, each hold period is from about 0.1 seconds to about 0.5 seconds in duration. In some embodiments, each hold period is about 0.25 seconds in duration. In some embodiments, the hold period occurs during the terminal portion of each designated inhalation period.

[0284] In some embodiments, the nebulizer is a vibrating mesh nebulizer. In some embodiments, the nebulizer is single-use. In some embodiments, the perceptible signal is audible, tactile, or visual. In some embodiments, the perceptible signal is provided by an indicator. In some embodiments, the indicator is a light. In some embodiments, the indicator is a indicator is a video screen and the perceptible signal displayed on the video screen.

[0285] In some embodiments, each active period lasts for an interval of time that is equal to the designated inhalation time value. In some embodiments, at least one active period lasts no longer than a fraction of the designated inhalation time value. In some embodiments, the method further comprises increasing the duration of an active period relative to a duration of a preceding activeperiod in the plurality of cycles.

[0286] In some embodiments, the method further comprises, for each successive cycle within an initial set of cycles, increasing the duration of an active period relative to that of the preceding cycle’s active period.

[0287] In some embodiments, the initial set of cycles comprises a first designated inhalation period, a first active period, a second designated inhalation period, a second active period, a third designated inhalation period, and a third active period, wherein the first active period lasts for about one quarter of the first designated inhalation period, the second active period lasts for about one half of the second designated inhalation period, and the third active period lasts for about three quarters of the third designated inhalation period.

[0288] In some embodiments, the initial set of cycles comprises a first a first active period, a second active period, a third active period, a fourth active period, and a fifth active period, wherein the first active period is about one second, the second active period is about 1.5 seconds, the third active period is about two seconds, the fourth active period is about 2.5 seconds, and the fifth active period is about three seconds. In some embodiments, each active period subsequent to the fifth active period lasts for an interval of time equal to the designated inhalation time value. In some embodiments, each active period subsequent to the fifth active period lasts for an interval of time equal to the duration of the fifth active period.

[0289] In some embodiments, the initial set of designated inhalation periods comprises a first designated inhalation period, a second designated inhalation period, a third designated inhalation period, and a fourth designated inhalation period, wherein the timer causes the device to produce aerosol particles for about one quarter of the first designated inhalation period, about three eighths of the second designated inhalation period, about one half of the third inhalation period, about five eighths of the fourth designated inhalation period, and about three fourths of each designated inhalation period subsequent to the fourth designated inhalation period. In some embodiments, the timer causes the device to produce aerosol particles for about one second during the first designated inhalation period, for about 1.5 seconds during the second designated inhalation period, for about two seconds during the third designated inhalation period, for about 2.5 seconds during the fourth designated inhalation period, and for three seconds during each designated inhalation period subsequent to the fourth designated inhalation period.

[0290] In some embodiments, each active period subsequent to the third active period lasts for an interval of time equal to the designated inhalation time value. In some embodiments, each active period subsequent to the third active period lasts for an interval of time equal to the duration of the third active period.

[0291] In some embodiments, the providing indication comprises varying a property of the perceptible signal (e.g., intensity, frequency, or size) over time according to a waveform, wherein each period of the waveform has a duration equal to the sum of the designated inhalation time value and the designated exhalation time value. In some embodiments, the perceptible signal is audible, wherein the pitch of the perceptible signal is varied according to amplitude of the waveform. For example, during a designated inhalation period, the pitch of the perceptible signal can increase in frequency, and during a designated exhalation period, the pitch of the perceptible signal can decrease in frequency. In some embodiments, the perceptible signal is graphic on a display, wherein the size or luminous intensity of the graphic is varied according to the waveform. In some embodiments, the graphic is a bar that increases in size during the designated inhalation period, and decreases in size during the designated exhalation period. In some embodiments, for the entirety of each designated inhalation period, the first derivative of the waveform is positive or zero, and, for the entirety of each designated exhalation period, the first derivative of the waveform is negative or zero. In some embodiments, for the entirety of each designated inhalation period, the first derivative of the waveform is negative or zero, and, for the entirety of each designated exhalation period, the first derivative of the waveform is positive or zero. In some embodiments, each peak of the waveform corresponds to the end of a designated inhalation period and the beginning of a designated exhalation period. In some embodiments, each trough of the waveform corresponds to the beginning of a designated inhalation period and the end of a designated exhalation period.

[0292] In some embodiments, the designated inhalation time value is from about one second to about 6 seconds and the designated exhalation time value is from about one second to about eight seconds. In some embodiments, the designated inhalation time value is two seconds and the designated exhalation time value is three seconds. In some embodiments, the designated inhalation time value is about four seconds and the designated exhalation time value is about four seconds. In some embodiments, the designated inhalation time value is four seconds and the designated exhalation time value is four seconds. In some embodiments, the designated inhalation time value is three seconds and the designated exhalation time value is four seconds. In some embodiments, the designated inhalation time value is about four seconds and the designated exhalation time value is about 4.25 seconds. In some embodiments, the designated inhalation time value is about 4.25 seconds and the designated exhalation time value is about four seconds. In some embodiments, the designated inhalation time value is about 4.25 seconds and the designated exhalation time value is about 4.25 seconds.

[0293] In some embodiments, the plurality of cycles is sufficient to exhaust the pharmaceuticalcomposition. In some embodiments, the device produces aerosol at a designated liquid output rate.

[0294] In some embodiments, the designated liquid output rate is adjusted to at least 0.3 mL / min and particle mass median aerodynamic diameter is less than 4 pm with a geometric standard deviation less than 1.8.

[0295] In some embodiments, the pharmaceutical composition comprises a medication with a narrow therapeutic index.

[0296] In some embodiments, the pharmaceutical composition comprises amiodarone, digitoxin, digoxin, dofetilide, dronedarone, flecainide, fluindione, phenindione, procainamide, quinidine, sotalol, or warfarin, or pharmaceutically-acceptable salts thereof.

[0297] In some embodiments, the administration of the medication with a narrow therapeutic index results in reduced inter- and intra-patient variability as compared to the medication’s normally accepted dosage form.

[0298] In some embodiments, the medication is delivered to the heart via the lungs.

[0299] In some embodiments, the subject suffers from arrhythmia, and wherein the aerosol particles comprise a therapeutically-effective amount of an anti arrhythmic agent. In some embodiments, the aerosol particles comprise a therapeutically-effective amount of a class 1c anti arrhythmic drug. In some embodiments, the class 1c anti arrhythmic drug comprises a therapeutically-effective amount of flecainide. In some embodiments, the 1c antiarrhythmic drug is flecainide acetate. In some embodiments, the therapeutically effective amount is from about 10 mg to about 200 mg.

[0300] In some embodiments, the pharmaceutical composition is an aqueous formulation comprising from about 45 to about 90 mg / mL flecainide acetate. In some embodiments, the pharmaceutical composition is an aqueous formulation comprising about 75 mg / mL flecainide acetate.

[0301] In some embodiments, a target serum concentration of flecainide of at least 200 ng / mL is achieved in the subject. In some embodiments, a target serum concentration of flecainide of at least 300 ng / mL is achieved in the subject. In some embodiments, a target serum concentration of flecainide of at least 400 ng / mL is achieved in the subject. In some embodiments, a target serum concentration of flecainide of at least 500 ng / mL is achieved in the subject.

[0302] In some embodiments, the subject is administered the aerosol in a medically supervised setting. In some embodiments, the subject self-administers the medication.

[0303] In some embodiments, the administration minimizes sustained cough or throat irritation that normally results from deposition of the medication into the oropharyngeal region.

[0304] In some embodiments, the nebulizer is single-use.

[0305] Another embodiment of the invention includes kits for treatment of atrial arrhythmia. Such kits would comprise a device as described heretofore, and a formulation for use with the device comprising an effective amount of flecainide. When using the device with the formulations of the kit, the course of deposition aerosol particles will be sufficient to exhaust the aqueous formulation.

[0306] In a preferred embodiment in which flecainide is being administered as an anti arrhythmic drug for treating atrial arrhythmia, flecainide may be administered as flecainide acetate in a total amount of from about 10 mg to about 200 mg. In some cases, the amount administered will range from about 60 mg to about 200 mg; in some cases the amount administered will range from about 100 mg to about 150 mg.

[0307] In another preferred embodiment, flecainide acetate may be provided as an aqueous formulation. Formulations of flecainide are described in U.S. Patent Nos. US-11020384-B2 and US-11007185-B2, incorporated herein by reference in their entirety. Aqueous formulations of flecainide acetate may be provided in concentrations ranging from about 35 mg / mL to about 90 mg / mL. In some cases, the concentration of flecainide acetate may range from about 45 mg / mL to about 75 mg / mL. In one embodiment, the flecainide acetate will be at a concentration of about 75 mg / mL.

[0308] By way of example, for dosage forms of flecainide acetate formulated at 75 mg / mL, administration of doses ranging from 75 to 200 mg will result in 1 mL to 2.67 mL of liquid formulation. Dosing is intended for administration over multiple inhalations. In some preferred embodiments, the time course of deposition will be until a fixed dose of formulated medicament has been aerosolized, i.e., wherein the course of deposition is sufficient to exhaust the aqueous formulation of flecainide acetate. The time for dosing is typically short. For nebulizers the dosing time usually ranges from 1 minute to 20 minutes, such as from 2 minutes to 15 minutes, or from 3 minutes to 10 minutes.

[0309] For applications using a medication other than flecainide, it will be appreciated that the amount of drug administered will depend on the individual drug and the needs of the subject, and the concentration of drug delivered will be dependent on the drug formulation. Thus, for liquid formulations, the volume of drug administered will be dependent on these factors. In some embodiments, delivery of a liquid formulation of a drug will be for a course of time sufficient to exhaust a volume (e.g., a unit dose) of a formulation of medicament used to generate the aerosol particles.

[0310] The dosage necessary and the frequency of dosing of the anti arrhythmic pharmaceuticalagent depend on the composition and concentration of the anti arrhythmic pharmaceutical agent within the formulation. In some cases, the dose is less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% of its normal intravenous dose. In some cases, the dose is about 5% to about 10%, is about 10% to about 20%, is about 20% to about 30%, is about 30% to about 40%, is about 50% to about 60%, is about 60% to about 70%, is about 70% to about 80%, is about 80% to about 90%, or is about 90% to about 95% of the intravenous dose. The pulmonary dose is similar to intracardiac doses. Inhalation avoids dilution of drug in the body as compared to intravenous or oral dosing.

[0311] For solutions, the amount of the composition in the unit dose typically ranges from about 0.5 mL to about 15 mL. The practicing dosage volumes will vary depending upon the particular pharmaceutical agent being used, and the concentration of that drug in its formulation.

[0312] In the instance when an antiarrhythmic pharmaceutical agent is delivered by a nebulizer, the amount administered will be less than or equal to an amount of the same antiarrhythmic pharmaceutical agent administered intravenously in the arm to achieve a minimum effective amount in the coronary circulation.

[0313] By way of example, flecainide may be formulated as an acetate salt and provided as an aqueous formulation. Formulations of flecainide are described in U.S. Patent Nos. US-11020384-B2 and US-11007185-B2, incorporated herein by reference in their entirety. Aqueous formulations of flecainide acetate may be provided in concentrations ranging from about 35 mg / mL to about 90 mg / mL. In the instance in which flecainide acetate is formulated at 75 mg / mL, administration of doses ranging from 75 to 200 mg will result in 1 mL to 2.67 mL of liquid formulation.

[0314] In view of the above, in one or more embodiments of the invention, a composition comprises an antiarrhythmic pharmaceutical agent. In the instance when an antiarrhythmic pharmaceutical agent in a pharmaceutically acceptable excipient is delivered by a nebulizer in aerosolized particles, the particles comprise the antiarrhythmic pharmaceutical agent in an amount less than or equal to an amount of the same antiarrhythmic pharmaceutical agent administered intravenously in the arm to achieve a minimum effective amount in the coronary circulation.

[0315] Examples of antiarrhythmic pharmaceutical agents include, but are not limited to, class la (sodium channel blockers, intermediate association / dissociation), class lb (sodium channel blockers, fast association / dissociation), class Ic (sodium channel blocker, slow association / dissociation), class II (beta blockers), class III (potassium channel blockers), class IV (calcium channel blockers), and class V (unknown mechanisms) antiarrhythmics.

[0316] Class la antiarrhythmics include, but are not limited to, quinidine, procainamide, and disopyramide, and pharmaceutically acceptable salts thereof. Class lb antiarrhythmics include, but are not limited to, lidocaine, tocainide, phenytoin, moricizine, and mexiletine, and pharmaceutically acceptable salts thereof. Class Ic antiarrhythmics include, but are not limited to, flecainide, propafenone, and moricizine, and pharmaceutically acceptable salts thereof. Class II antiarrhythmics include, but are not limited to, propranolol, acebutolol, soltalol, esmolol, timolol, metoprolol, and atenolol, and pharmaceutically acceptable salts thereof. Class III antiarrhythmics include, but are not limited to, amiodarone, sotalol, bretylium, ibutilide, E-4031 (methanesulfonamide), vemakalant, and dofetilide, and pharmaceutically acceptable salts thereof. Class IV antiarrhythmics include, but are not limited to, bepridil, nitrendipine, amlodipine, isradipine, nifedipine, nicardipine, verapamil, and diltiazem, and pharmaceutically acceptable salts thereof. Class V antiarrhythmics include, but are not limited to, digoxin and adenosine, and pharmaceutically acceptable salts thereof.

[0317] The present invention also includes derivatives of the above anti arrhythmic pharmaceutical agents such as solvates, salts, solvated salts, esters, amides, hydrazides, N-alkyls, and / or N-amino acyls. The derivatives of the anti arrhythmic pharmaceutical agents can be pharmaceutically acceptable derivatives. Examples of ester derivatives include, but are not limited to, methyl esters, choline esters, and dimethylaminopropyl esters. Examples of amide derivatives include, but are not limited to, primary, secondary, and tertiary amides. Examples of hydrazide derivatives include, but are not limited to, N-m ethylpiperazine hydrazides. Examples of N-alkyl derivatives include, but are not limited to, N',N',N'-trimethyl and N',N'- dimethylaminopropyl succininimidyl derivatives of anti arrhythmic pharmaceutical agent methyl esters. Examples of N-aminoacyl derivatives include, but are not limited to, N-omithyl-, N- diaminopropionyl-, N-lysil-, N-hexamethyllysil-, and N-piperidine-propionyl- or N',N'-methyl-l- piperazine-propionyl-antiarrhythmic pharmaceutical agent methyl esters.

[0318] The anti arrhythmic pharmaceutical agents may exist as single stereoisomers, racemates, and / or mixtures of enantiomers, and / or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present invention. These various forms of the compounds may be isolated / prepared by methods known in the art.

[0319] The pharmaceutical compositions of the invention may be administered using an aerosolization device such as a nebulizer, such as that disclosed in US 6946117 Bl, the disclosure of which is hereby incorporated in its entirety by reference, in order to provide an aerosolized medicament that may be administered to the pulmonary air passages of a subject in need thereof. Nebulizers are known in the art and could easily be employed for administration ofthe claimed formulations without undue experimentation.

[0320] Nebulizers impart energy into a liquid pharmaceutical formulation to aerosolize the liquid, and to allow delivery to the pulmonary system, e.g., the lungs, of a subject. A nebulizer comprises a liquid delivery system, such as a container having a reservoir that contains a liquid pharmaceutical formulation. The liquid pharmaceutical formulation generally comprises an active agent that is either in solution or suspended within a liquid medium.

[0321] In one type of nebulizer for use in the invention, generally referred to as a jet nebulizer, compressed gas is forced through an orifice in the container. The compressed gas forces liquid to be withdrawn through a nozzle, and the withdrawn liquid mixes with the flowing gas to form aerosol droplets. A cloud of droplets is then administered to the subject’s respiratory tract.

[0322] In another type of nebulizer the nebulizing comprises extrusion through micron or submicron-sized holes followed by Rayleigh break-up into fine droplets. Nebulizer that produce aerosols via Rayleigh sprays are typically limited to small medication doses in the sub-milligram range.

[0323] In another type of nebulizer preferred for use in the invention, generally referred to as a vibrating mesh nebulizer, energy, such as mechanical energy, vibrates a mesh. This vibration of the mesh aerosolizes the liquid pharmaceutical formulation through the mesh to create an aerosol cloud that is administered to the subject’s lungs. Vibrating mesh liquid nebulizers are advantageous over other types of aerosolization devices, such as jet nebulizers or ultrasound nebulizers, in that they are capable of delivering a fine aerosol mist comprising a droplet size and droplet size range appropriate for pulmonary delivery, and are more highly efficient and reliable. Vibrating mesh nebulizers can be advantageously small, do not require large and / or external power sources, and do not introduce extraneous gases into a subject’s pulmonary system.

[0324] In some cases, the nebulizer has a medication cup capacity of 6 mL. In some cases, the nebulizer has a residual volume of less than 0.3 mL. In some cases, the nebulizer generates an average liquid output rate of 0.3 mL / min. In some cases, the nebulizer generates an average liquid output rate of 0.4 mL / min. In some cases, the nebulizer generates an average liquid output rate of 0.5 mL / min. In some cases, the nebulizer generates an average liquid output rate of 0.6 mL / min. In some cases, the nebulizer generates an average liquid output rate of 0.7 mL / min. In some cases, the nebulizer generates an average liquid output rate of 0.8 mL / min. In some cases, the nebulizer generates an average liquid output rate of 0.9 mL / min. In some cases, the nebulizer generates an average liquid output rate of 1.0 mL / min. In some cases, the nebulizer generates an average liquid output rate of 1.1 mL / min. In some cases, the nebulizer generates an average liquid output rate of 1.2 mL / min.

[0325] In still another aspect, an aerosol comprises particles having a mass median aerodynamic diameter (MMAD) less than 10 pm. In some cases, the nebulizer generates an average particle size of 3.0 pm MMAD. In some cases, the nebulizer generates an average particle size between 3.0 pm MMAD and 4.0 pm MMAD. In some cases, the nebulizer generates an average particle size between 3.0 pm MMAD and 5.0 pm MMAD. In some cases, the nebulizer generates an average particle size between 3.0 pm MMAD and 6.0 pm MMAD.

[0326] In still another type of nebulizer, ultrasonic waves are generated to directly vibrate and aerosolize the pharmaceutical formulation.

[0327] In some cases, pulmonary administration comprises nebulizing a solution comprising the at least one anti arrhythmic pharmaceutical agent. In some cases, the aerosolization device is a nebulizer configured to administer the at least one antiarrhythmic pharmaceutical agent in a liquid pharmaceutical formulation, wherein the aerosolization occurs at room temperature. In some cases, the nebulizing comprises nebulizing with a vibrating mesh nebulizer. In preferred embodiments, the nebulizer is a hand-held inhaler, e.g., the Ultra Solo from AEROGEN® Ltd. Of Galway, Ireland.

[0328] The pharmaceutical formulation may be in a liquid form and may be aerosolized using a nebulizer as described in WO 2004 / 071368 A2, which is herein incorporated by reference in its entirety, as well as U.S. Patent Nos. US 7334580 B2 and US 8245708 B2, which are both herein incorporated by reference in their entireties. Examples of nebulizers include, but are not limited to, the Aeroneb® Ultra Solo or Aeroneb® Pro nebulizers, available from AEROGEN® Ltd. Of Galway, Ireland; the PARI eRapid® and other PARI nebulizers available from PARI Respiratory Equipment, Inc. of Midlothian, Va.; Philips’ InnoSpire Go® from Koninklijke Philips of Amsterdam, the Netherlands; the Omron NE-U100® available from Omron Healthcare, Inc. of Kyoto, Japan; and Deepro®, from Hcmed, of Taipei City, China.

[0329] Nebulizers generate a soft mist of medicament, and are capable of delivering a larger dose of medication than is possible with pressurized metered dose inhalers (pMDIs) or dry powder inhalers (DPIs) because medication can be delivered over an extended period of time under conditions of relatively normal breathing. The simpler end of the spectrum of nebulizers includes devices that operate with a continuous flow of medicament. Examples include the AEROGEN® Ultra Solo, Medline Industries’ HEART®, and Sarnova’s RES-QNEB®. While disposable and relatively inexpensive, these devices operate continuously, generating aerosol that accumulates in the device’s reservoir while the subject is exhaling, causing a large bolus of aerosol to be taken in at the beginning of the subsequent inhalation, often leading to deposition in the oropharyngeal airways and subsequent throat irritation and coughing, and decreasing thelikelihood of compliance with therapy. More complex nebulizers, such as Vectura’s AKITA®, HCMed’s AdheResp®, or the Koninklijke Philips I-neb® incorporate various means of controlling the subject’s breath or responding to the subject’s breath in order to activate the nebulizer to release aerosol at the start of inhalation or when a target inspiratory flow rate is achieved. However, these devices must actively monitor the user, making them fairly complex and expensive. In addition, these devices often cause throat irritation and cough that result from the continuous flow of medicament, either throughout the inhalation / exhalation cycles, or throughout the inhalation cycle alone. Cough sensitivity can be objectively assessed, as described for example in WALLACE et al., “A Systematic Review of Methods of Citric Acid Cough Reflex Testing,” Pulm Pharmacol & Ther, vol. 58 (2019) 101827; and MAI et al., “Methods for Assessing Cough Sensitivity,” J Thorac Dis, 12(9): 5224-5237 (2020). Devices and methods for reducing cough and throat irritation are needed in order to ensure patient compliance and successful delivery of medicament by aerosol inhalation.

[0330] The device of the present invention discloses a means for controlling the timing of aerosol production to align with the subject’s inhalation, avoiding a large bolus of aerosol at the beginning of inhalation, while still having aerosolization parts that interface with the subject that are inexpensive and disposable. Throat irritation and cough that normally result from deposition of excess medication into the oropharyngeal region is minimized.

[0331] In addition to reducing throat irritation and cough by halting aerosol production during the exhalation phase in order to prevent a large bolus of drug from being introduced at the beginning of the subsequent inhalation, throat irritation and cough can also be minimized by gradually increasing the time in which drug aerosol is introduced during the inhalation phase of a breathing cycle, thereby priming the airways to the drug with minimal irritation. During an initial set of inhalation periods, the device can be configured to produce aerosol particles for a gradually increasing fraction of the inhalation period. For example, the device may produce aerosol particles for one quarter of the first inhalation period, one half of the second inhalation period, three quarters of the third inhalation period, and for the full duration of all subsequent inhalation periods. The gradually increasing fraction of the inhalation period during which aerosol particles are produced optionally occurs at the beginning of each inhalation period, but also may easily be programmed to occur in the middle or end of each inhalation period. Priming of the airways to minimize coughing improves tolerability and results in higher compliance to completing dosing of drugs via inhalation, thereby increasing efficacy.

[0332] Throat irritation and cough can be further minimized by application of a topical anesthetic to the throat of a subject prior to administering a medication by depositing aerosol particles intothe lungs of a subject. A topical anesthetic helps to significantly reduce the cough reflex, and improves tolerability. The form of the topical anesthetic may be, for example, in the form of a spray, lozenge, or liquid gargle, and may be menthol, benzocaine, lidocaine, dyclonine, or other topical anesthetic. The various forms and types of topical anesthetic will be understood by those of ordinary skill in the art.

[0333] It has been found that a nebulizer of the vibrating mesh type, such as one that forms droplets without the use of compressed gas, such as preferably the AEROGEN® Ultra Solo, provides unexpected improvement in dosing efficiency and consistency. By generating fine droplets by using a vibrating perforated or unperforated membrane, rather than by introducing compressed air, the aerosolized pharmaceutical formulation can be introduced without substantially affecting the flow characteristics. In addition, the generated droplets when using a nebulizer of this type are introduced at a low velocity, thereby decreasing the likelihood of the droplets being driven to an undesired region.

[0334] A type of mesh preferred for use as the vibrating mesh in the invention is made with photo-defined aperture plate (PDAP) technology used in the AEROGEN® Ultra Solo vibrating mesh nebulizer, and described in U.S. Patent Nos. US 9719184 B2, US 10508353 B2, US 10662543 B2, US 11389601 B2, and U.S. Application No. US 20230080331 Al, the contents of which are incorporated herein by reference in their entirety. With this technology, a mesh (alternatively referred to as an aperture plate) for use in aerosolizing a liquid is comprised of a first material having a plurality of generally cylindrically shaped smaller apertures therein, the first material having a characteristic of being formed through a photolithography process. A second material is above the first material, the second material having a plurality of liquid supply cavities of generally cylindrically shaped larger apertures therein, above the plurality of apertures in the first material, wherein the second material has a characteristic of being formed through a photolithography process. At least some of the plurality of first apertures are within the perimeter of the liquid supply cavities defined by the second apertures. The first material and the second material together form an aperture plate, or mesh.

[0335] The apertures of the first material may have an exit opening having a diameter anywhere within a range from about 0.5 pm to about 6 pm, to produce droplets that are about 0.5 pm to about 6 m in size. In other embodiments, the aperture exit opening may have a diameter of from about 1 pm to about 4 pm, about 1 pm to about 3 pm, etc., or any range or value therebetween, to produce droplets of about a corresponding size. Generally, droplet size is approximately equal to outlet size, however exiting droplets may form and become slightly larger or smaller, depending upon the characteristics, such as the surface tension and / or rheological properties, of the liquidbeing aerosolized. Exit opening is used herein to mean the opening from which the droplet emerges, and which may also be considered as downstream, or distal, to the liquid supply. This is contrasted with the inlet opening formed in the second material, also referred to as a liquid supply opening, which is the opening in contact with, or proximal to, the supply of liquid to be aerosolized. The liquid supply opening is thus larger in diameter and / or area than the exit opening. In some embodiments, the liquid supply opening may range in size from about 20 pm to about 200 pm in diameter, including any range or value therebetween.

[0336] The photo-defined approach of the PDAP technology permits decoupling of the liquid output rate of the device from the droplet size and / or size distribution. Significantly, this allows for mesh production wherein liquid output rate and droplet size and / or geometric standard deviation (GSD) may be addressed and controlled independently of one another. Liquid output rate is desirably at least 0.3-0.4 mL / min, preferably higher than 0.5 mL / min, preferably as high as 0.6 mL / min. Droplet size (aerosol mass median aerodynamic diameter, or MMAD) is preferably between 2 and 4 microns (pm). The size distribution (GSD) of droplet sizes is preferably less than 2, more preferably less than 1.8.

[0337] Both liquid output rate and droplet size distribution using the PDAP mesh are a function of the specific formulation being aerosolized. The liquid output rate of the AEROGEN® Ultra PDAP vibrating mesh nebulizer was optimized for flecainide formulation FlecIH-103 (aqueous solution of 75 mg / mL flecainide acetate, 20% w / v hydroxypropyl-P-cyclodextrin, 5 mM acetic acid, 0.75mM saccharin sodium, titrated to pH 5.9 with NaOH) to maximize liquid output rate while still maintaining the integrity of the PDAP mesh. At an optimized liquid output rate of 0.5- 0.6 mL / min, droplet sizes of 3-3.5 pm was obtained, and a size distribution GSD of 1.6-1.7 was obtained.

[0338] Another embodiment of the invention is a method for administering a medication by depositing aerosol particles into the lungs of a subject. Administration is accomplished with a device with an aerosolization unit that generates the aerosol particles at a designated liquid output rate, the aerosolization unit comprising an inhalation chamber and mouthpiece, a vibrating mesh nebulizer, and optionally a bacterial / viral filter, and the device further comprising a timer that controls an indicator that can be monitored by the subject. The timer is programmed with a designated inhalation period and a designated exhalation period, which are repeated over the course of deposition of aerosol particles. In addition to controlling the indicator, the timer also controls the device to produce aerosol particles only during the designated inhalation time.

[0339] Yet another embodiment of the invention is a method for achieving a target serumconcentration upon administration of a medication, measured as Cmax. This is accomplished by depositing aerosol particles into the lungs of a subject with a device to generate the aerosol particles at a designated liquid output rate, the device comprising a timer that controls an indicator that can be monitored by the subject. The timer is programmed with a designated inhalation period and a designated exhalation period, which are repeated over the course of deposition of aerosol particles. In addition to controlling the indicator, the timer also controls the device to produce aerosol particles only during the designated inhalation period.

[0340] In another embodiment of the invention, the aerosolization unit of the device used in the methods of the invention comprises a vibrating mesh nebulizer for use in aerosolizing a liquid. In certain embodiments, the vibrating mesh of the nebulizer comprises a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the exit opening of the first apertures having a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size, and a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm. At least some of the plurality of first apertures are within the diameters of the liquid supply cavities defined by the second apertures. The first material and the second material form a mesh for use in a vibrating mesh nebulizer.

[0341] In another embodiment of the invention, the liquid output rate of the device is adjusted to be at least 0.3 mL / min, preferably 0.5 mL / min. At this liquid output rate, the device will preferably produce particles with a mass median aerodynamic diameter (MMAD) less than 4 pm, having a geometric standard deviation (GSD) less than 1.8.

[0342] In yet another embodiment of the invention, the methods for administering a medication by depositing aerosol particles into the lungs of a subject is used for delivering drugs with a narrow therapeutic index. Some of the drugs with a narrow therapeutic index contemplated for use in the invention include, for example, amiodarone, digitoxin, digoxin, dofetilide, dronedarone, flecainide, fluindione, phenindione, procainamide, quinidine, sotalol, and warfarin, however the scope of the invention is not intended to be limited to these examples. In yet another embodiment of the invention, administration of the medication with a narrow therapeutic index results in reduced inter- and intra-patient variability as compared to the medication’snormally accepted dosage form.

[0343] In certain embodiments, the present invention may be used for delivery of medication directly to the heart via the lungs. In another aspect of the invention, the subject is being treated for atrial arrhythmia by delivering drugs that are antiarrhythmic agents. Some drugs contemplated for use in the invention include Class 1 Sodium Channel Blockers, including Class la, e.g., ajmaline, disopyramide, procainamide, quinidine, Class lb, e.g., lidocaine, mexiletine, phenytoin, tocainide, Class 1c, e.g., flecainide, mori cizine, propafenone, Class 2 [3-Adrenergic Blockers (Beta Blockers), e.g., acebutolol, atenolol, bisoprolol, carvedilol, esmolol, metoprolol, nebivolol, propranolol, timolol, Class 3 Potassium Channel Blockers, e.g., amiodarone, bretylium, dofetilide, dronedarone, ibutilide, sotalol, vemakalant, Class 4 Calcium Channel Blockers, e.g., diltiazem, etripamil, verapamil, and Class 5 Other Mechanisms, e.g., adenosine, digoxin. In one embodiment, the class 1c antiarrhythmic drug is flecainide or a pharmaceutically-effective salt thereof. In some embodiments, the class 1c antiarrhythmic drug is flecainide acetate in a total amount from 10 mg to 200 mg. In some embodiments, flecainide acetate is provided as an aqueous formulation in concentrations ranging from 45 to 90 mg / mL, administered over multiple inhalations. In certain embodiments, the course of deposition by inhalation is sufficient to exhaust the aqueous formulation of flecainide acetate.

[0344] In certain embodiments, administration of an effective amount of flecainide will be sufficient to achieve a target serum concentration of at least 200 ng / mL. In other embodiments of the invention, the effective dosage of flecainide is that which is sufficient to achieve a target serum concentration of at least 300 ng / mL. In other embodiments of the invention, the effective dosage of flecainide is that which is sufficient to achieve a target serum concentration of at least 400 ng / mL. In still other embodiments of the invention, the effective dosage of flecainide is that which is sufficient to achieve a target serum concentration of at least 500 ng / mL.

[0345] In certain aspects, the present invention is directed towards administration of medication to a subject in a medically supervised setting. Treatment may be administered by, e.g., a suitable healthcare provider including a physician or a nurse practitioner.

[0346] In yet another aspect of the invention, the subject is able to self-administer treatment at home, after self-diagnosis without guidance of a medical professional. In this aspect, the present invention is directed to a method of self-diagnosing comprising detecting atrial arrhythmia by at least one of shortness of breath, heart palpitations, and above normal heart rate. The method also comprises self-administering by inhalation an effective amount of at least one antiarrhythmic pharmaceutical agent within two hours, one hour, 30 minutes or 15 minutes of the selfdiagnosing. In some cases, the self-administering continues until the subject no longer detectsthe at least one of shortness of breath, heart palpitations, and above normal heart rate.

[0347] In yet another aspect of the invention, administration of a drug by inhalation using the devices and methods of the invention results in depositing drug into the lungs, and minimizes deposit in the oropharyngeal region, minimizing sustained cough or throat irritation.

[0348] Thus, in some embodiments, the present invention involves a rapid acting inhaled product with a fast onset of action compared to oral medicine. The product is expected to be at least as fast as intravenous medicine.

[0349] The time for onset of action is typically short. For instance, the subject may have normal sinus rhythm within 20 minutes of initiating the administering, such as within 15 minutes, within 10 minutes, or within 5 minutes of initiating the administering. The rapid onset of action is advantageous because the longer a subject has had arrhythmia, the longer it typically takes to convert the subject to normal sinus rhythm.

[0350] In some embodiments, an amount of the at least one anti arrhythmic pharmaceutical agent peaks in the coronary circulation of the heart at a time ranging from 10 seconds to 30 minutes, such as 30 seconds to 20 minutes, 1 minute to 10 minutes, 2 minutes to 8 minutes, or 2.5 minutes to 5 minutes, from the administration. In certain embodiments, an electrophysiological effect is observed, via electrocardiography, at a time ranging from 10 seconds to 30 minutes, such as 30 seconds to 20 minutes, 1 minute to 10 minutes, 2 minutes to 8 minutes, or 2.5 minutes to 5 minutes, from the administration. In some embodiments, a cardiac score from a device with an arrhythmia detection algorithm shows a transition from an arrhythmic state to normal sinus rhythm in the subject at a time ranging from 10 seconds to 30 minutes, such as 30 seconds to 20 minutes, 1 minute to 10 minutes, 2 minutes to 8 minutes, or 2.5 minutes to 5 minutes, from the administration. In some embodiments, a short form-36 quality of life score of the subject improves at a time ranging from 10 seconds to 30 minutes, such as 30 seconds to 20 minutes, 1 minute to 10 minutes, 2 minutes to 8 minutes, or 2.5 minutes to 5 minutes, from the administration. In certain embodiments, the subject has normal sinus rhythm within 30 minutes, such as within 10 minutes, of initiating the administering.

[0351] In one aspect, a method of treating atrial arrhythmia comprises administering by inhalation an effective amount of at least one anti arrhythmic pharmaceutical agent to a subject in need thereof, wherein a concentration of the at least one anti arrhythmic pharmaceutical agent peaks (Cmax) in the coronary circulation of the heart at a time ranging from 10 seconds to 30 minutes from the administration.

[0352] In certain embodiments, the present invention is directed to a method of diagnosis by a health care provider followed by treatment of atrial arrhythmia.

[0353] In another aspect, a method of treating atrial arrhythmia comprises administering by inhalation an effective amount of at least one anti arrhythmic pharmaceutical agent to a subject in need thereof, wherein an electrophysiological effect is observed, via electrocardiography, at a time ranging from 10 seconds to 30 minutes from the administration.

[0354] In still another aspect, a method of treating atrial arrhythmia comprises administering by inhalation an effective amount of at least one anti arrhythmic pharmaceutical agent to a subject in need thereof, wherein a cardiac score from a monitor implementing an arrhythmia detection algorithm shows a transition from an arrhythmic state to normal sinus rhythm in the subject at a time ranging from 10 seconds to 30 minutes from the administration.

[0355] In yet another aspect, a method of treating atrial arrhythmia comprises administering by inhalation an effective amount of at least one anti arrhythmic pharmaceutical agent to a subject in need thereof, wherein a short form-36 quality of life score of the subject improves at a time ranging from 10 seconds to 30 minutes from the administration.

[0356] In certain embodiments, the present invention includes “pharmaco-rescue-therapies” to provide fast cardioversion in subjects with atrial arrhythmias like Paroxysmal Ventricular Tachycardia (PSVT), and Paroxysmal Atrial Fibrillation (PAF). The pharmaco-rescue therapies are usually intended for self-administration of the medicine by inhalation.

[0357] In yet another aspect, the present invention is directed to a method of self-diagnosing and treating atrial arrhythmia. The method comprises self-diagnosing atrial arrhythmia by detecting at least one of shortness of breath, heart palpitations, and above normal heart rate. The method also comprises self-administering by inhalation an effective amount of at least one anti arrhythmic pharmaceutical agent within two hours, one hour, 30 minutes, or 15 minutes of the selfdiagnosing. In some cases, the method comprises self-administering by inhalation an effective amount of at least one anti arrhythmic pharmaceutical agent within 15 minutes of the selfdiagnosing.

[0358] In certain embodiments, the subject can self-titrate. For example, the subject can selfadminister, e.g., by using a nebulizer, until disabling symptoms disappear. In some cases, the self-administering continues until the subject no longer feels heart palpitations, or until the subject detects the restoration of normal sinus rhythm using a portable / mobile ECG device (which can be worn by the subject, such as a watch; or otherwise carried by the subject, such as an over the skin patch or an implantable device connected to a smart phone or watch).

[0359] As described previously, inhalation results in a pulsatile pharmacokinetic profile and transient pharmacodynamic effect mimicking the effect of an IV. This method delivers high drug concentrations that are safe and effective to the heart, while the distribution to the rest of thebody results in the drug being diluted to sub-therapeutic levels.

[0360] A range given out in the present disclosure can be a range between two accurate numerical values, in some cases, a range in the present disclosure can also refer to a range between two approximate numerical values. For instance, “1-10” can refer to “from 1 to 10” in some cases, while in other case, “1-10” can refer to “from about 1 to about 10”.

[0361] In the following disclosures of pharmacokinetic and pharmacodynamic parameters, in one or more embodiments, the antiarrhythmic pharmaceutical agent is a class I, class II, class III, or class IV antiarrhythmic. In some embodiments, the antiarrhythmic pharmaceutical agent is a class Ic, antiarrhythmic. In some embodiments, the antiarrhythmic pharmaceutical agent is flecainide or a pharmaceutically acceptable salt thereof.

[0362] In some cases, the Tmax of the antiarrhythmic pharmaceutical agent administered via inhalation can be from about 0.1 minute to about 30 minutes. In some cases, the Tmax of the antiarrhythmic pharmaceutical agent administered via inhalation can be from about 0.1 to about 5 min. In some cases, the Tmaxof the antiarrhythmic pharmaceutical agent administered via inhalation can be from about 0.1 to about 3 min. In some cases, Tmaxof the antiarrhythmic pharmaceutical agent (e.g., flecainide) administered via inhalation can be from about 0.2 to about 5 min.

[0363] In some cases, the Tmaxcan be calculated as the amount of time after the initiation of the administration of the antiarrhythmic pharmaceutical agent when the maximum plasma concentration is reached. In some cases, the Tmaxcan be calculated as the amount of time after the completion of the administration of the antiarrhythmic pharmaceutical agent when the maximum plasma concentration is reached. In some cases, the Tax can be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the left ventricular chamber. In some cases, the Tmaxcan be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the pulmonary artery. In some cases, the Tmaxcan be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the vein (e.g., femoral vein). In some cases, the Tmaxcan be measured in a human PK / PD study. The term “human PK / PD study” as used herein can refer to any settings where a human subject receives administration of a single dose of the antiarrhythmic agent as provided herein and a pharmacokinetic (PK) or pharmacodynamic (PD) parameter is measured from the human subject after the administration of the antiarrhythmic agent. In some cases, a human PK / PD study as provided herein can refer to a clinical study performed in a clinic or hospital settings. In some cases, the human PK / PD study can be a single center or multi-center study. A human PK / PD study can be performed on healthy human subjects or human cardiovascularsubjects. In some cases, the subjects with cardiovascular disease experience arrhythmia as described herein. In some cases, a human PK / PD study can be a single-dose study, in other cases, a human PK / PD study can be a multi-dose (e.g. escalating doses) study.

[0364] The time for dosing is typically short. For nebulizers the dosing time usually ranges from 1 minute to 20 minutes, such as from 2 minutes to 15 minutes, or from 3 minutes to 10 minutes.

[0365] In some cases, the Cmax of the anti arrhythmic pharmaceutical agent administered via inhalation can be from about 10 ng / mL to about 5000 ng / mL. In some cases, the Cmax of the antiarrhythmic pharmaceutical agent administered via inhalation can be from about 20 ng / mL to about 500 ng / mL, such as 20-500, 30-500, 40-500, 50-500, 60-500, 70-500, 80-500, 90-500, 100- 500, 150-500, 200-500, or 250-500 ng / mL.

[0366] In some cases, the Cmax can be calculated as the maximum plasma concentration of the antiarrhythmic pharmaceutical agent observed. In some cases, the Cmax can be calculated as the peak plasma concentration that the antiarrhythmic pharmaceutical agent achieves after the drug has been administrated. In some cases, the Cmax can be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the left ventricular chamber. In some cases, the Cmax can be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the pulmonary artery. In some cases, the Cmax can be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the vein (e.g., femoral vein). In some cases, the Cmax can be measured in a human PK / PD study.

[0367] In some cases, the AUC / .Ifflof the antiarrhythmic pharmaceutical agent administered via inhalation can be from about 100 hr*ng / mL to about 10,000 hr*ng / mL. In some cases, the AUC / .aw of the antiarrhythmic pharmaceutical agent administered via inhalation can be from about 200 to about 2000 hr*ng / mL. In some cases, the AUC / .Ifflof the antiarrhythmic pharmaceutical agent administered via inhalation can be from about 500 to about 800 hr*ng / mL. In some cases, the AUC / .Ifflof the antiarrhythmic pharmaceutical agent administered via inhalation can be from about 400 to about 600 hr*ng / mL.

[0368] In some cases, the AUC / .Ifflcan be calculated as the area under the concentration-time curve up to the last measurable concentration. In some cases, the AUC / .(J.« can be calculated as the total drug exposure over time. In some cases, the AUC / .avz can be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the left ventricular chamber. In some cases, the AUC / .Ifflcan be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the pulmonary artery. In some cases, the AUC / .azz can be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the vein (e.g., femoral vein). In some cases, the AUC / .a.« can be measured in ahuman PK / PD study.

[0369] In some cases, the distribution ti / 2 of the anti arrhythmic pharmaceutical agent administered via inhalation can be from about 0.1 minute to about 15 minutes. In some cases, the distribution ti / 2 of the anti arrhythmic pharmaceutical agent administered via inhalation can be from about 3 to about 5 minutes.

[0370] In some cases, the distribution ti / 2 can be calculated as the time at which the antiarrhythmic pharmaceutical agent plasma levels decreased to half of what they were at equilibrium due to distribution to tissues throughout the body. In some cases, the distribution ti / 2 can be calculated as the time it takes for an antiarrhythmic pharmaceutical agent to lose half of its pharmacologic activity. In some cases, the distribution ti / 2 can be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the left ventricular chamber. In some cases, the distribution ti / 2 can be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the pulmonary artery. In some cases, the distribution ti / 2 can be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the vein (e.g., femoral vein). In some cases, the distribution ti / 2 can be measured in a human PK / PD study.

[0371] In some cases, the elimination ti / 2 of the antiarrhythmic pharmaceutical agent administered via inhalation can be from about 1 hour to about 25 hours. In some cases, the elimination ti / 2 of the antiarrhythmic pharmaceutical agent administered via inhalation can be from about 8.5 to about 10.5 hours.

[0372] In some cases, the elimination ti / 2 can be calculated as the time at which the antiarrhythmic pharmaceutical agent plasma levels decreased to half of what they were at equilibrium due to metabolism and elimination. In some cases, the elimination ti / 2 can be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the left ventricular chamber. In some cases, the elimination ti / 2 can be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the pulmonary artery. In some cases, the elimination ti / 2 can be calculated from plasma concentration of the antiarrhythmic pharmaceutical agent measured in the vein (e.g., femoral vein). In some cases, the elimination ti / 2 can be measured in a human PK / PD study.

[0373] In some cases, the maximum change in QRS interval duration (AQRS) following the antiarrhythmic pharmaceutical agent administered via inhalation can be from about 0.01 msec to about 100 msec. In some cases, the maximum change in QRS interval duration (AQRS) following the antiarrhythmic pharmaceutical agent administered via inhalation can be from about 1 to about 10 msec. In some cases, the maximum change in QRS interval duration (AQRS)following the anti arrhythmic pharmaceutical agent administered via inhalation can be from about 5 to about 20 msec. In some cases, the AQRS can be measured in a human PK / PD study. In the present disclosure, the term “AQRS”, if not referred to with reference to time post-administration of the antiarrhythmic agent, can be used interchangeably with the term “maximum AQRS”, e.g. meaning the maximum change in QRS following administration of the antiarrhythmic agent as provided herein.

[0374] In some cases, the time point at which the QRS interval is measured following the antiarrhythmic pharmaceutical agent administration via inhalation to determine the AQRS relative to pre-dose can be from about 0.1 minute to about 450 minutes.

[0375] The antiarrhythmic activity of a pharmaceutical agent can be correlated with QRS interval duration. In some examples, the antiarrhythmic pharmaceutical agent administered via inhalation can have higher antiarrhythmic activity as compared to the antiarrhythmic pharmaceutical agent administered by intravenous delivery (e.g., intravenous infusion). In some cases, such a higher antiarrhythmic activity is reflected by a higher ratio of maximum AQRS to Cmax. For example, given the same C max, e.g., peak plasma concentration of the antiarrhythmic pharmaceutic agent, inhalation delivery of the antiarrhythmic agent as provided herein can have a higher maximum AQRS as compared to intravenous delivery of the same agent. In some cases, the comparison may not be made between corresponding doses via the two different administration routes, for example, inhalation of a first dose of the agent can have a first Cmax (Cmaxi) and a first maximum AQRS (AQRSmaxi), and intravenous administration of a second dose of the agent can have a second Cmax (Cmax?) and a second maximum AQRS (AQRSmax?). In some cases, Cmaxi and Cmax2 can be similar. In other case, Cmaxi and Cmax2 can be dissimilar. In some examples of the present disclosure, the ratio of AQRSmaxi versus Cmaxi can be higher than AQRSmax? versus Cmax2, i.e., AQRSmaxi / Cmaxi AQRSmax2 / Cmax2. In some cases, AQRSmaxi / Cmaxi is at least 1.1 fold to at least 50 fold greater than AQRSmax2 / Cmax2. In some cases, AQRSmaxi / Cmaxi is at least 2 fold greater than AQRS max? / Cmax2 •NUMBERED EMBODIMENTS

[0376] Embodiment 1. A method of depositing aerosol particles into the lungs of a subject, the method comprising administering the aerosol particles to the subject with a device comprising:(a) an aerosolization unit that aerosolizes a pharmaceutical composition of a medication to generate the aerosol particles, and(b) a timer set with a designated inhalation period and a designated exhalation period, wherein the timer causes the device to produce the aerosol particles only during thedesignated inhalation period, and wherein the timer controls an indicator, wherein the indicator provides indication to the subject such that the subject is instructed to conduct inhalation during only the designated inhalation period and conduct exhalation during only the designated exhalation period, wherein the device produces the aerosol particles at a designated liquid output rate, and the designated inhalation and exhalation periods are repeated over the course of deposition of aerosol particles.

[0377] Embodiment 2. The method of embodiment 1, wherein the indicator is audible, tactile, or visual.

[0378] Embodiment 3. The method of embodiment 2, wherein the indicator is a light.

[0379] Embodiment 4. The method of embodiment 1 or embodiment 2, wherein the indicator is a graphic displayed on a video screen.

[0380] Embodiment 5. The method of any one of embodiments 1-4, wherein each designated inhalation period is from 1 second to 6 seconds and each designated exhalation period is from 1 second to 8 seconds.

[0381] Embodiment 6. The method of any one of embodiments 1-4, wherein the designated inhalation period is about 4 seconds and the designated exhalation period is about 4.25 seconds.

[0382] Embodiment 7. The method of any one of embodiments 1-6, wherein designated exhalation period comprises a rest period that occurs during the terminal portion of one or more designated exhalation periods, wherein during each rest period, indication is provided to the subject to neither inhale nor exhale.

[0383] Embodiment 8. The method of embodiment 7, wherein rest period is from about 0.1 seconds to about 0.5 seconds in duration.

[0384] Embodiment 9. The method of any one of embodiments 1-8, wherein the course of deposition is sufficient to exhaust a unit dose of a formulation of medicament used to generate the aerosol particles.

[0385] Embodiment 10. The method of any one of embodiments 1-9, wherein the single-use aerosolization unit comprises a vibrating mesh nebulizer.

[0386] Embodiment 11. The method of embodiment 10, wherein the vibrating mesh of the vibrating mesh nebulizer comprises:(a) a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the first apertures each having an exit opening with a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size;(b) a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm; wherein at least some of the plurality of first apertures are within the diameters of the liquid supply cavities defined by the second apertures, and wherein the first material and the second material form a mesh of the vibrating mesh nebulizer.

[0387] Embodiment 12. The method of any one of embodiments 1-11, wherein the designated liquid output rate is adjusted to at least 0.3 mL / min and particle mass median aerodynamic diameter is less than 4 pm with a geometric standard deviation less than 1.8.

[0388] Embodiment 13. The method of any one of embodiments 1-12, wherein the medication has a narrow therapeutic index.

[0389] Embodiment 14. The method of embodiment 13, wherein the medication with a narrow therapeutic index is selected from amiodarone, digitoxin, digoxin, dofetilide, dronedarone, flecainide, fluindione, phenindione, procainamide, quinidine, sotalol, and warfarin, or pharmaceutically-acceptable salts thereof.

[0390] Embodiment 15. The method of embodiment 13 or embodiment 14, wherein the administration of the medication with a narrow therapeutic index results in reduced inter- and intra-subject variability as compared to the medication’s normally accepted dosage form.

[0391] Embodiment 16. The method of any one of embodiments 1-15, wherein the medication is delivered to the heart via the lungs.

[0392] Embodiment 17. The method of any one of embodiments 1-16, wherein the subject suffers from arrhythmia, and wherein the aerosol particles comprise a therapeutically-effective amount of an anti arrhythmic agent.

[0393] Embodiment 18. The method of any one of embodiments 1-17, wherein the subject suffers from atrial arrhythmia, and wherein the aerosol particles comprise a therapeutically- effective amount of a class 1c anti arrhythmic drug.

[0394] Embodiment 19. The method of embodiment 18, wherein the class 1c anti arrhythmic drug comprises a therapeutically-effective amount of flecainide or a pharmaceutically-acceptable salt thereof.

[0395] Embodiment 20. The method of embodiment 18, wherein the class 1c anti arrhythmic drug is flecainide acetate.

[0396] Embodiment 21. The method of embodiment 20, wherein flecainide acetate is provided asan aqueous formulation in concentrations ranging from 45 to 90 mg / mL.

[0397] Embodiment 22. The method of embodiment 21, wherein the course of deposition is sufficient to exhaust the aqueous formulation.

[0398] Embodiment 23. The method of any one of embodiments 19-22, wherein a target serum concentration of flecainide of at least 200 ng / mL is achieved in the subject.

[0399] Embodiment 24. The method of any one of embodiments 19-22, wherein a target serum concentration of flecainide of at least 300 ng / mL is achieved in the subject.

[0400] Embodiment 25. The method of any one of embodiments 19-22, wherein a target serum concentration of flecainide of at least 400 ng / mL is achieved in the subject.

[0401] Embodiment 26. The method of any one of embodiments 19-22, wherein a target serum concentration of flecainide of at least 500 ng / mL is achieved in the subject.

[0402] Embodiment 27. The method of any one of embodiments 1-26, wherein the subject is administered the aerosol particles in a medically supervised setting.

[0403] Embodiment 28. The method of any one of embodiments 1-26, wherein the subject selfadministers the aerosol particles.

[0404] Embodiment 29. The method of any one of embodiments 1-28, wherein the administration minimizes sustained cough or throat irritation that normally results from deposition of the aerosol particles into the oropharyngeal region.

[0405] Embodiment 30. The method of any one of embodiments 1-29, wherein the aerosolization unit is single-use.

[0406] Embodiment 31. The method of any one of embodiments 1-30, wherein the timer causes the device to produce aerosol particles for the entire inhalation period.

[0407] Embodiment 32. The method of any one of embodiments 1-30, wherein during an initial set of inhalation periods within the course of deposition of aerosol particles, the timer causes the device to produce aerosol particles for a gradually increasing fraction of the inhalation period.

[0408] Embodiment 33. The method of embodiment 32, wherein the timer causes the device to produce aerosol particles for about one second during the first designated inhalation period, for about 1.5 seconds during the second designated inhalation period, for about two seconds during the third designated inhalation period, for about 2.5 seconds during the fourth designated inhalation period, and for 3 seconds during each designated inhalation period subsequent to the fourth designated inhalation period.

[0409] Embodiment 34. The method of embodiment 33, wherein the gradually increasing fraction of the inhalation period during which aerosol particles are produced occurs at the beginning of each inhalation period of the initial set of inhalation periods.

[0410] Embodiment 35. The method of any one of embodiments 1-34, wherein a topical anesthetic is applied to the throat of the subject prior to administering the aerosol particles.

[0411] Embodiment 36. A method of achieving a target serum concentration of a medication in a subject, the method comprising administering the medication to the lungs of the subject with a device comprising:(a) an aerosolization unit that aerosolizes a pharmaceutical composition of the medication to generate aerosol particles, and(b) a timer set with a designated inhalation period and a designated exhalation period, wherein the timer causes the device to produce the aerosol particles only during the designated inhalation period, and wherein the timer controls an indicator, wherein the indicator provides indication to the subject of when to inhale and exhale, wherein the device produces the aerosol particles at a designated liquid output rate, and the designated inhalation and exhalation periods are repeated over a course of deposition of aerosol particles sufficient for achieving the target serum concentration.

[0412] Embodiment 37. The method of embodiment 36, wherein the indicator is audible, tactile, or visual.

[0413] Embodiment 38. The method of embodiment 37, wherein the indicator is a light.

[0414] Embodiment 39. The method of embodiment 36 or embodiment 37, wherein the indicator is a graphic displayed on a video screen.

[0415] Embodiment 40. The method of any one of embodiments 36-39, wherein each designated inhalation period is from 1 second to 6 seconds and each designated exhalation period is from 1 second to 8 seconds.

[0416] Embodiment 41. The method of any one of embodiments 36-39, wherein the designated inhalation period is about 4 seconds and the designated exhalation period is about 4.25 seconds.

[0417] Embodiment 42. The method of any one of embodiments 36-41, wherein each designated exhalation period comprises a rest period that occurs during the terminal portion of one or more designated exhalation periods, wherein during each rest period, indication is provided to the subject to neither inhale nor exhale.

[0418] Embodiment 43. The method of embodiment 42, wherein each rest period is from about 0.1 seconds to about 0.5 seconds in duration.

[0419] Embodiment 44. The method of any one of embodiments 36-43, wherein the course of deposition is sufficient to exhaust a unit dose of a formulation of medicament used to generate the aerosol particles.

[0420] Embodiment 45. The method of any one of embodiments 36-44, wherein theaerosolization unit is single-use.

[0421] Embodiment 46. The method of embodiment 45, wherein the single-use aerosolization unit comprises a vibrating mesh nebulizer.

[0422] Embodiment 47. The method of any one of embodiments 36-45, wherein the aerosolization unit is a vibrating mesh nebulizer.

[0423] Embodiment 48. The method of embodiment 47, wherein the vibrating mesh of the vibrating mesh nebulizer comprises:(a) a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the first apertures each having an exit opening with a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size;(b) a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm; wherein at least some of the plurality of first apertures are within the diameters of the liquid supply cavities defined by the second apertures, and wherein the first material and the second material form a mesh of the vibrating mesh nebulizer.

[0424] Embodiment 49. The method of any one of embodiments 36-48, wherein the designated liquid output rate is adjusted to at least 0.3 mL / min and particle mass median aerodynamic diameter is less than 4 pm with a geometric standard deviation less than 1.8.

[0425] Embodiment 50. The method of embodiment 36, wherein the medication has a narrow therapeutic index.

[0426] Embodiment 51. The method of embodiment 50, wherein the medication with a narrow therapeutic index is selected from amiodarone, digitoxin, digoxin, dofetilide, dronedarone, flecainide, fluindione, phenindione, procainamide, quinidine, sotalol, and warfarin, or pharmaceutically-acceptable salts thereof.

[0427] Embodiment 52. The method of embodiment 50, wherein the administration of the medication with a narrow therapeutic index results in reduced inter- and intra-subject variability as compared to the medication’s normally accepted dosage form.

[0428] Embodiment 53. The method of any one of embodiments 36-52, wherein the medication is delivered to the heart via the lungs.

[0429] Embodiment 54. The method of any one of embodiments 36-53, wherein the subject suffers from arrhythmia, and wherein the aerosol particles comprise a therapeutically-effective amount of an anti arrhythmic agent.

[0430] Embodiment 55. The method of any one of embodiments 36-53, wherein the subject suffers from atrial arrhythmia, wherein the aerosol particles comprise a therapeutically-effective amount of a class 1c anti arrhythmic drug.

[0431] Embodiment 56. The method of embodiment 55, wherein the class 1c anti arrhythmic drug is flecainide or a pharmaceutically-acceptable salt thereof.

[0432] Embodiment 57. The method of embodiment 55, wherein the wherein the class 1c anti arrhythmic drug is flecainide acetate.

[0433] Embodiment 58. The method of embodiment 57, wherein the flecainide acetate is provided as an aqueous formulation in concentrations ranging from 45 to 90 mg / mL.

[0434] Embodiment 59. The method of embodiment 58, wherein the course of deposition is sufficient to exhaust the aqueous formulation.

[0435] Embodiment 60. The method of any one of embodiments 56-59, wherein a target serum concentration of flecainide of at least 200 ng / mL is achieved in the subject.

[0436] Embodiment 61. The method of any one of embodiments 56-59, wherein a target serum concentration of flecainide of at least 300 ng / mL is achieved in the subject.

[0437] Embodiment 62. The method of any one of embodiments 56-59, wherein a target serum concentration of flecainide of at least 400 ng / mL is achieved in the subject.

[0438] Embodiment 63. The method of any one of embodiments 56-59, wherein a target serum concentration of flecainide of at least 500 ng / mL is achieved in the subject.

[0439] Embodiment 64. The method of any one of embodiments 36-63, wherein the subject is administered the aerosol particles in a medically supervised setting.

[0440] Embodiment 65. The method of any one of embodiments 36-63, wherein the subject selfadministers the aerosol particles.

[0441] Embodiment 66. The method of any one of embodiments 36-64, wherein the aerosolization unit is single-use.

[0442] Embodiment 67. The method of any one of embodiments 36-65, wherein the timer causes the device to produce aerosol particles for the entire inhalation period.

[0443] Embodiment 68. The method of any one of embodiments 36-65, wherein during an initial set of inhalation periods within the course of deposition of aerosol particles, the timer causes the device to produce aerosol particles for a gradually increasing fraction of the inhalation period.

[0444] Embodiment 69. The method of any one of embodiments 36-66 and 68, wherein the timercauses the device to produce aerosol particles for one quarter of the first inhalation period, one half of the second inhalation period, three quarters of the third inhalation period, and for the full inhalation period of all subsequent inhalation periods.

[0445] Embodiment 70. The method of embodiment 68, wherein the gradually increasing fraction of the inhalation period during which aerosol particles are produced occurs at the beginning of each inhalation period.

[0446] Embodiment 71. The method of any one of embodiments 36-70, wherein a topical anesthetic is applied to the throat of the subject prior to administering the aerosol particles.

[0447] Embodiment 72. A device for depositing aerosol particles into the lungs of a subject comprising:(a) an aerosolization unit for aerosolizing a pharmaceutical composition of a medication to generate the aerosol particles, and(b) a timer capable of setting a designated inhalation period and a designated exhalation period, causing the device to produce the aerosol particles only during the designated inhalation period, and controlling an indicator to provide indication of the designated inhalation period, the designated exhalation period, or both.

[0448] Embodiment 73. The device of embodiment 72, wherein the indication provided by the indicator instructs a subject to conduct a single inhalation over the course of the designated inhalation period, and a single exhalation of the course of the designated exhalation period.

[0449] Embodiment 74. The device of embodiment 72 or embodiment 73, wherein the indicator is audible, tactile, or visual.

[0450] Embodiment 75. The device of any one of embodiments 72-74, wherein the indicator is a light.

[0451] Embodiment 76. The device of any one of embodiments 72-74, wherein the indicator is a graphic displayed on a video screen.

[0452] Embodiment 77. The device of any one of embodiments 72-76, wherein each designated inhalation period is from 1 second to 6 seconds and each designated exhalation period is from 1 second to 8 seconds.

[0453] Embodiment 78. The device of any one of embodiments 72-76, wherein the designated inhalation period is about 4 seconds and the designated exhalation period is about 4.25 seconds.

[0454] Embodiment 79. The device of any one of embodiments 72-78, wherein each designated exhalation period comprises a rest period that occurs during the terminal portion of one or more designated exhalation periods, wherein during each rest period, indication is provided to the subject to neither inhale nor exhale.

[0455] Embodiment 80. The device of embodiment 79, wherein each rest period is from about 0.1 seconds to about 0.5 seconds in duration.

[0456] Embodiment 81. The device any one of embodiments 72-80, comprising a vibrating mesh nebulizer.

[0457] Embodiment 82. The device of embodiment 81, wherein the vibrating mesh of the nebulizer comprises:(a) a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the first apertures each having an exit opening with a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size;(b) a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm; wherein at least some of the plurality of first apertures are within the diameters of the liquid supply cavities defined by the second apertures, and wherein the first material and the second material form a mesh of the vibrating mesh nebulizer.

[0458] Embodiment 83. The device any one of embodiments 72-82, wherein the aerosolization unit is single-use.

[0459] Embodiment 84. The device of any one of embodiments 72-83, wherein the timer causes the device to produce aerosol particles for the entire inhalation period.

[0460] Embodiment 85. The device of any one of embodiments 72-83, wherein during an initial set of inhalation periods within the course of deposition of aerosol particles, the timer causes the device to produce aerosol particles for a gradually increasing fraction of the inhalation period.

[0461] Embodiment 86. The device of any one of embodiments 72-83 and 85, wherein the timer causes the device to produce aerosol particles for one quarter of the first designated inhalation period, three eighths of the second designated inhalation period, one half of the third designated inhalation period, five eighths of the fourth designated inhalation period, and three fourths of each designated inhalation period subsequent to the fourth designated inhalation period.

[0462] Embodiment 87. The device of any one of embodiments 72-83, 85, and 86, wherein the timer causes the device to produce aerosol particles for about one second during the first designated inhalation period, for about 1.5 seconds during the second designated inhalation period, for about two seconds during the third designated inhalation period, for about 2.5 secondsduring the fourth designated inhalation period, and for three seconds during each designated inhalation period subsequent to the fourth designated inhalation period.

[0463] Embodiment 88. The device of embodiment 85, wherein the gradually increasing fraction of the inhalation period during which aerosol particles are produced occurs at the beginning of each inhalation period.

[0464] Embodiment 89. A kit comprising the device of any one of embodiments 72-88 and a topical anesthetic.

[0465] Embodiment 90. A kit for treating atrial arrhythmia comprising the device of any one of embodiments 72-88 and a pharmaceutical composition comprising an effective amount of flecainide or a pharmaceutically-acceptable salt thereof.

[0466] Embodiment 91. The kit of embodiment 90, wherein the pharmaceutical composition comprises about 10 mg to about 200 mg flecainide acetate.

[0467] Embodiment 92. The kit of embodiment 91, wherein flecainide acetate is provided as an aqueous formulation at a concentration ranging from 45 to 90 mg / mL.

[0468] Embodiment 93. The kit of any one of embodiments 90-82, wherein the course of deposition of aerosol particles is sufficient to exhaust the aqueous formulation.

[0469] Embodiment 94. A device for administering aerosol particles to a subject, the device comprising:(a) an aerosolization unit configured to aerosolize a pharmaceutical composition to generate the aerosol particles;(b) an indicator; and(c) a timer, wherein the timer is:(i) set with a designated inhalation time value and a designated exhalation time value;(ii) configured to cause the indicator to indicate, via a perceptible signal, occurrence of a designated inhalation period, and following the designated inhalation period, indicate, via the perceptible signal, occurrence of a designated exhalation period, wherein each designated inhalation period lasts for an interval of time equal to the designated inhalation time value, and each designated exhalation period lasts for an interval of time equal to the designated exhalation time value;(iii) configured to cause the aerosolization unit to activate at the beginning of each designated inhalation period and remain activated for an active period, wherein each active period independently lasts for an interval of time that is no longer than the designated inhalation time value; and cause the aerosolization unit to deactivate at the end of each active period,wherein during each active period, the aerosolization unit aerosolizes the pharmaceutical composition and delivers the aerosol to the subject through a mouthpiece of the aerosolization unit, wherein the designated inhalation period and the designated exhalation period are set to occur consecutively and alternate over a course of deposition of the aerosol particles.

[0470] Embodiment 95. The device of embodiment 94, wherein the timer is a microcontroller.

[0471] Embodiment 96. The device of embodiment 94 or embodiment 95, wherein the timer is electronically coupled to a relay that interrupts supply of power to a source of aerosol generation in the aerosolization unit.

[0472] Embodiment 97. The device of embodiment 96, wherein the source of aerosol generation is a vibrating mesh of a vibrating mesh nebulizer.

[0473] Embodiment 98. The device of any one of embodiments 94-97, wherein the perceptible signal is audible, tactile, or visual.

[0474] Embodiment 99. The device of any one of embodiments 94-98, wherein the indicator is a light.

[0475] Embodiment 100. The device of any one of embodiments 94-98, wherein the indicator is a video screen and the perceptible signal is a graphic displayed on the video screen.

[0476] Embodiment 101. The device of any one of embodiments 94-100, wherein, during the designated inhalation period, the perceptible signal is a rising bar, and during the designated exhalation period, the perceptible signal is a falling bar.

[0477] Embodiment 102. The device of any one of embodiments 94-101, wherein the designated inhalation time value is from about 1 second to about 6 seconds and the designated exhalation time value is from about 1 second to about 8 seconds.

[0478] Embodiment 103. The device of any one of embodiments 94-101, wherein the designated inhalation time value is about 4 seconds and the designated exhalation time value is about 4.25 seconds.

[0479] Embodiment 104. The device of any one of embodiments 94-103, wherein each designated exhalation period comprises a rest period that occurs during the terminal portion of one or more designated exhalation periods, wherein the timer is configured to cause the indicator to indicate to the subject to neither inhale nor exhale during each rest period.

[0480] Embodiment 105. The device of embodiment 104, wherein each rest period is from about 0.1 seconds to about 0.5 seconds in duration.

[0481] Embodiment 106. The device of any one of embodiments 94-105, wherein theaerosolization unit comprises a vibrating mesh nebulizer.

[0482] Embodiment 107. The device of embodiment 106, comprising:(a) a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the first apertures each having an exit opening with a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size;(b) a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, the second material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm; wherein at least some of the plurality of first apertures are within the diameters of the liquid supply cavities defined by the second apertures, and wherein the first material and the second material form a mesh of the vibrating mesh nebulizer.

[0483] Embodiment 108. The device of any one of embodiments 94-107, wherein the aerosolization unit is a single-use aerosolization unit.

[0484] Embodiment 109. The device of any one of embodiments 94-108, wherein each active period is set to last for an interval of time that is equal to the designated inhalation time value.

[0485] Embodiment 110. The device of any one of embodiments 94-108, wherein at least one active period is set to last for an interval of time that is equal to a fraction of the designated inhalation time value.

[0486] Embodiment 111. The device of embodiment 110, wherein each active period is set to last no longer than a fraction of the designated inhalation time value.

[0487] Embodiment 112. The device of any one of embodiments 94-108, 110, and 111, wherein the timer is configured to cause the duration of an active period to be longer than a duration of a preceding active period.

[0488] Embodiment 113. The device of any one of embodiments 94-108 and 110-112, wherein, for each active period within an initial set of active periods of a dosing session, the timer is configured to increase the duration of the active period relative to the duration of the immediately preceding active period.

[0489] Embodiment 114. The device of embodiment 113, wherein the initial set of active periods consists of the first three, first four, first five, first six, first seven, first eight, first nine, or first ten active periods of the dosing session.

[0490] Embodiment 115. The device of embodiment 113 or embodiment 114, wherein the timer is configured to cause each active period subsequent to the initial set of active periods to be constant in duration.

[0491] Embodiment 116. The device of any one of embodiments 113-115, wherein the timer is configured to cause each active period subsequent to the initial set of active periods to last for a duration that is equal to the duration of the last active period of the initial set of active periods.

[0492] Embodiment 117. The device of any one of embodiments 113-116, wherein the timer is configured to increase the duration of the active period from an initial value to a terminal value over the initial set of active periods, wherein the initial value is from about 0.5 seconds to about two seconds, and the terminal value is from about 2.5 seconds to about four seconds.

[0493] Embodiment 118. The device of any one of embodiments 113-117, wherein the timer is configured to increase the duration of the active period from an initial value to a terminal value over the initial set of active periods, wherein the initial value is about one second, and the terminal value is about three seconds.

[0494] Embodiment 119. The device of any one of embodiments 113-118, wherein the initial set of active periods comprises a first active period, a second active period, a third active period, and a fourth active period, wherein the first active period is about one second, the second active period is about 1.5 seconds, the third active period is about two seconds, the fourth active period is about 2.5 seconds, and each active period subsequent to the fourth active period is about three seconds.

[0495] Embodiment 120. The device of any one of embodiments 94-119, wherein causing the aerosolization unit to activate comprises causing the aerosolization unit to begin aerosolizing the pharmaceutical composition.

[0496] Embodiment 121. The device of any one of embodiments 94-120, wherein causing the aerosolization unit to activate comprises causing aerosol to be supplied to a mouthpiece of the aerosolization unit.

[0497] Embodiment 122. The device of any one of embodiments 94-121, wherein causing the aerosolization unit to activate comprises causing a valve to open, thereby allowing passage of aerosol particles from a source of aerosol generation in the aerosolization unit (e.g., a vibrating mesh of a vibrating mesh nebulizer) to a mouthpiece of the aerosolization unit.

[0498] Embodiment 123. The device of any one of embodiments 94-122, wherein causing the aerosolization unit to activate comprises causing a relay to supply power from a power source to the source of aerosol generation (e.g., a vibrating mesh of a vibrating mesh nebulizer).

[0499] Embodiment 124. The device of any one of embodiments 94-123, wherein theaerosolization unit comprises a vibrating mesh nebulizer, wherein the vibrating mesh nebulizer comprises a vibrating mesh, wherein causing the aerosolization unit to activate comprises causing the vibrating mesh to vibrate.

[0500] Embodiment 125. A kit comprising the device of any one of embodiments 94-124 and a topical anesthetic.

[0501] Embodiment 126. A kit for treating atrial arrhythmia comprising the device of any one of embodiments 94-124 and the pharmaceutical composition, wherein the pharmaceutical composition comprises an effective amount of flecainide or a pharmaceutically-acceptable salt thereof.

[0502] Embodiment 127. The kit of embodiment 126, wherein the pharmaceutical composition is provided in unit dose form.

[0503] Embodiment 128. The kit of embodiment 127, wherein the unit dose comprises about 10 mg to about 200 mg flecainide acetate.

[0504] Embodiment 129. The kit of embodiment 128, wherein flecainide acetate is provided as an aqueous formulation at a concentration ranging from 45 to 90 mg / mL.

[0505] Embodiment 130. The kit of any one of embodiments 125-129, wherein the course of deposition of aerosol particles is sufficient to exhaust the aqueous formulation.

[0506] Embodiment 131. A method of administering an aerosol to a subject, the method comprising: aerosolizing a pharmaceutical composition via a nebulizer to generate the aerosol over a course of a plurality of cycles, each cycle consisting of: a designated inhalation period, wherein each designated inhalation period lasts for an interval of time equal to a designated inhalation time value, wherein the aerosolizing occurs only during an active period that begins at the start of each designated inhalation period and lasts for an interval of time that is no more than the designated inhalation time value; and a designated exhalation period, wherein each designated exhalation period lasts for an interval of time equal to a designated exhalation time value; providing indication to the subject of occurrence of each designated inhalation period or each designated exhalation period via a perceptible signal; and instructing the subject to conduct, in synchrony with the perceptible signal, (i) a single inhalation during each designated inhalation period, and (ii) a single exhalation during each designated exhalation period.

[0507] Embodiment 132. A method of administering an aerosol to a subject, the methodcomprising: aerosolizing a pharmaceutical composition via a nebulizer to generate the aerosol over a course of a plurality of cycles, each cycle consisting of: a designated inhalation period, wherein each designated inhalation period lasts for an interval of time equal to a designated inhalation time value, wherein the aerosolizing occurs only during an active period that begins at the start of each designated inhalation period and lasts for an interval of time that is no more than the designated inhalation time value; and a designated exhalation period, wherein each designated exhalation period lasts for an interval of time equal to a designated exhalation time value; providing indication to the subject of occurrence of each designated inhalation period or each designated exhalation period via a perceptible signal, wherein the subject conducts, in synchrony with the perceptible signal, a single inhalation of the aerosol during each designated inhalation period, and a single exhalation during each designated exhalation period.

[0508] Embodiment 133. The method of embodiment 131 or embodiment 132, wherein each designated exhalation period comprises a rest period that occurs during the terminal portion of each designated exhalation period, wherein during each rest period, the subject neither inhales nor exhales.

[0509] Embodiment 134. The method of embodiment 133, wherein each rest period is from about 0.1 seconds to about 1 second in duration.

[0510] Embodiment 135. The method of any one of embodiments 131-134, further comprising instructing the subject to continue inhaling the aerosol in synchrony with the perceptible signal until a unit dose of the pharmaceutical composition is depleted.

[0511] Embodiment 136. The method of any one of embodiments 131-135, wherein the pharmaceutical composition comprises an anti arrhythmic agent and the subject suffers from cardiac arrythmia.

[0512] Embodiment 137. The method of embodiment 136, further comprising, after a first unit dose of the pharmaceutical composition has been administered, administering a second unit dose of the pharmaceutical composition upon determining that the subject still suffers from the cardiac arrythmia.

[0513] Embodiment 138. The method of embodiment 137, wherein the second unit dose is equal to the first unit dose.

[0514] Embodiment 139. The method of embodiment 137, wherein the second unit dose is one-half of the first unit dose.

[0515] Embodiment 140. The method of any one of embodiments 137-139, wherein the second unit dose is administered about 10 minutes to about 1 hour after administration of the first unit dose is completed.

[0516] Embodiment 141. The method of any one of embodiments 137-140, further comprising instructing the subject to pause inhalation of the aerosol after about one half of the unit dose has been administered, and resume inhalation of the remaining half of the unit dose after a 30 second to three minute break.

[0517] Embodiment 142. The method of any one of embodiments 131-141, further comprising instructing the subject to:(i) inhale the aerosol in synchrony with the perceptible signal for a first duration that is from about 3 minutes to about 4 minutes;(ii) after said first duration, pause inhalation for a second duration that is from about 30 seconds to about 90 seconds; and(iii) after said second duration, resume inhalation in synchrony with the perceptible signal for a third duration that is from about 3 minutes to about 4 minutes.

[0518] Embodiment 143. The method of any one of embodiments 131-142, wherein the nebulizer is a vibrating mesh nebulizer.

[0519] Embodiment 144. The method of any one of embodiments 131-143, wherein the nebulizer is single-use.

[0520] Embodiment 145. The method of any one of embodiments 131-144, wherein the perceptible signal is audible, tactile, or visual.

[0521] Embodiment 146. The method of any one of embodiments 131-145, wherein the perceptible signal is provided by an indicator.

[0522] Embodiment 147. The method of embodiment 146, wherein the indicator is a light.

[0523] Embodiment 148. The method of embodiment 146, wherein the indicator is a video screen and the perceptible signal is a graphic displayed on the video screen.

[0524] Embodiment 149. The method of any one of embodiments 131-148, wherein each active period lasts for an interval of time that is equal to the designated inhalation time value.

[0525] Embodiment 150. The method of any one of embodiments 131-148, wherein at least one active period lasts for an interval of time that is equal to a fraction of the designated inhalation time value.

[0526] Embodiment 151. The method of any one of embodiments 131-148 and 150, further comprising increasing the duration of an active period relative to a duration of a preceding activeperiod in the plurality of cycles.

[0527] Embodiment 152. The method of any one of embodiments 131-148, 150, and 151, further comprising, for each successive active period within an initial set of active periods of a dosing session, increasing the duration of an active period relative to that of the immediately preceding active period.

[0528] Embodiment 153. The method of embodiment 152, wherein an initial set of active periods consists of the first three, first four, first five, first six, first seven, first eight, first nine, or first ten active periods of the dosing session.

[0529] Embodiment 154. The method of embodiment 152 and embodiment 153, wherein the timer is configured to cause each active period subsequent to the initial set of active periods to be constant in duration.

[0530] Embodiment 155. The method of any one of embodiments 152-154, wherein each active period subsequent to the initial set of active periods lasts for a duration that is equal to the duration of the last active period of the initial set of active periods.

[0531] Embodiment 156. The method of any one of embodiments 152-155, wherein, over the initial set of active periods, the timer increases the duration of the active period from an initial value to a terminal value, wherein the initial value is from about 0.5 seconds to about two seconds, and the terminal value is from about 2.5 seconds to about four seconds.

[0532] Embodiment 157. The method of any one of embodiments 152-156, wherein, over the initial set of active periods, the timer increases the duration of the active period from an initial value to a terminal value, wherein the initial value is about one second, and the terminal value is about 3 seconds.

[0533] Embodiment 158. The method of any one of embodiments 152-157, wherein the initial set of active periods comprise a first active period, a second active period, a third active period, a fourth active period, and a fifth active period, wherein the first active period is about one second, the second active period is about 1.5 seconds, the third active period is about two seconds, the fourth active period is about 2.5 seconds, and the fifth active period is about three seconds.

[0534] Embodiment 159. The method of any one of embodiments 152-158, wherein each active period subsequent to the fifth active period lasts for an interval of time equal to the fifth active period.

[0535] Embodiment 160. The method of any one of embodiments 152-159, wherein the providing indication further comprises modulating the perceptible signal over time according to a waveform, wherein each period of the waveform has a duration equal to the sum of the designated inhalation time value and the designated exhalation time value.

[0536] Embodiment 161. The method of embodiment 160, wherein the modulating comprises modulating the frequency or intensity of an audible tone.

[0537] Embodiment 162. The method of embodiment 160, wherein the modulating comprises modulating a dimension of a two-dimensional graphic displayed on a video screen.

[0538] Embodiment 163. The method of any one of embodiments 131-162, wherein the designated inhalation time value is from about 1 second to about 6 seconds and the designated exhalation time value is from about 1 second to about 8 seconds.

[0539] Embodiment 164. The method of any one of embodiments 131-163, wherein the designated inhalation time value is 2 seconds and the designated exhalation time value is 3 seconds.

[0540] Embodiment 165. The method of any one of embodiments 131-163, wherein the designated inhalation time value is 4 seconds and the designated exhalation time value is 4 seconds.

[0541] Embodiment 166. The method of any one of embodiments 131-163, wherein the designated inhalation time value is 4.25 seconds and the designated exhalation time value is 4 seconds.

[0542] Embodiment 167. The method of any one of embodiments 131-163, wherein the designated inhalation time value is 3 seconds and the designated exhalation time value is 4 seconds.

[0543] Embodiment 168. The method of any one of embodiments 131-167, wherein the plurality of cycles is sufficient to exhaust the pharmaceutical composition.

[0544] Embodiment 169. The method of any one of embodiments 131-167, wherein the device produces aerosol at a designated liquid output rate.

[0545] Embodiment 170. The method of embodiment 169, wherein the designated liquid output rate is adjusted to at least 0.3 mL / min and particle mass median aerodynamic diameter is less than 4 pm with a geometric standard deviation less than 1.8.

[0546] Embodiment 171. The method of any one of embodiments 131-170, wherein the pharmaceutical composition comprises an antiarrhythmic medication.

[0547] Embodiment 172. The method of any one of embodiments 131-171, wherein the pharmaceutical composition comprises amiodarone, digitoxin, digoxin, dofetilide, dronedarone, flecainide, fluindione, phenindione, procainamide, quinidine, sotalol, or warfarin, or pharmaceutically-acceptable salts thereof.

[0548] Embodiment 173. The method of any one of embodiments 131-172, wherein the medication is delivered to the heart via the lungs.

[0549] Embodiment 174. The method of any one of embodiments 131-173, wherein the subject suffers from cardiac arrhythmia.

[0550] Embodiment 175. The method of any one of embodiments 131-174, wherein the pharmaceutical composition is in unit-dose form, wherein the unit dose comprises a therapeutically-effective amount of a class 1c anti arrhythmic drug.

[0551] Embodiment 176. The method of embodiment 175, wherein the 1c antiarrhythmic drug is flecainide or a pharmaceutically-acceptable salt thereof.

[0552] Embodiment 177. The method of embodiment 175 or embodiment 176, wherein the class 1c antiarrhythmic drug is flecainide acetate.

[0553] Embodiment 178. The method of any one of embodiments 175-177, wherein the therapeutically effective amount is from about 10 mg to about 200 mg.

[0554] Embodiment 179. The method of any one of embodiments 131-178, wherein the pharmaceutical composition is an aqueous formulation comprising from about 45 to about 90 mg / mL flecainide acetate.

[0555] Embodiment 180. The method of any one of embodiments 131-178, wherein the pharmaceutical composition is an aqueous formulation comprising about 75 mg / mL flecainide acetate.

[0556] Embodiment 181. The method of any one of embodiments 131-180, wherein a target serum concentration of flecainide of at least 200 ng / mL is achieved in the subject.

[0557] Embodiment 182. The method of any one of embodiments 131-180, wherein a target serum concentration of flecainide of at least 300 ng / mL is achieved in the subject.

[0558] Embodiment 183. The method of any one of embodiments 131-180, wherein a target serum concentration of flecainide of at least 400 ng / mL is achieved in the subject.

[0559] Embodiment 184. The method of any one of embodiments 131-180, wherein a target serum concentration of flecainide of at least 500 ng / mL is achieved in the subject.

[0560] Embodiment 185. The method of any one of embodiments 131-184, wherein the subject is administered the aerosol in a medically supervised setting.

[0561] Embodiment 186. The method of any one of embodiments 131-184, wherein the subject self-administers the medication.

[0562] Embodiment 187. The method of any one of embodiments 131-186, wherein the administration minimizes sustained cough or throat irritation that normally results from deposition of the medication into the oropharyngeal region.EXAMPLES

[0563] The following examples are provided to further illustrate some embodiments of the present disclosure, but are not intended to limit the scope of the disclosure; it will be understood by their exemplary nature that other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.EXAMPLE 1: Effect of Directed Breathing on Inspiratory Volumes

[0564] This example describes the effect of directed breathing on inhalation volumes over the course of time, as compared to normal tidal breathing. In order to measure inspiration and expiration flows and volumes, a breathing measurement device was assembled comprising a breathing mouthpiece connected to a HEPA filter, connected to a TSI-5300-2 gas mass flow meter, in turn connected to a second HEPA filter, then an exhaust port. For some of the experiments, an indicator light was employed which turned on for a designated time, then off for a designated time, the on / off cycles repeated over a two minute course of time.

[0565] For a first round of measurements of normal tidal breathing, volunteers were seated comfortably with an erect posture, and instructed to “just breathe” through the breathing measurement device. The timing and volume of each inhalation was recorded by the TSI-5300-2 flow meter over a two minute time period. FIGS. 5A and 5B show the flow rate of breathed air in liters / minute over the two minute time course, the inhalation and exhalation sequences overlaid, and the inhalation volume by inhalation number for two of the volunteers. The average inspiratory volume for tidal breathing was 0.6 L per breath for one volunteer, and 0.5 L per breath for a second volunteer.

[0566] For a second experiment, volunteers were again seated comfortably with an erect posture. However when breathing through the breathing measurement device, they were directed to adapt their breathing to an indicator light which turned on when the volunteers were to inhale, and turned off when they were to exhale (“directed breathing”). The inhalation period was set for two seconds, and exhalation period set for three seconds. As with the tidal breathing experiment, the timing and volume of each inhalation was recorded with the TSI-5300-2 flow meter over a two minute time period. FIGS. 6A and 6B show the flow rate of breathed air in liters / minute over the two minute time course, the inhalation and exhalation sequences overlaid, and the inhalation volume by inhalation number for two of the volunteers. The average inspiratory volume for directed breathing was 1.3 L per breath for one volunteer, and 1.0 L per breath for a second volunteer.

[0567] When individuals were guided into breathing more slowly, they compensated for the lowered frequency of breaths by breathing more deeply. Moreover, it was demonstrated thatindividuals can easily alter their breathing patterns in response to a simple external indicator, and they do not have to rely on complex flow rate monitors to provide feedback or to have a device actively alter their breathing pattern.EXAMPLE 2. Effect of Depth of Breathing on Drug Delivery

[0568] In order to test the effect of depth of breathing on the amount of drug delivered, a breathing simulator was used with the AEROGEN® Ultra nebulizer. The configuration of the testing setup is shown in FIG. 7. The nebulizer is shown on the left; the breathing simulator is shown on the right. In between these is a set of PARI filters to collect the delivered dose (“DD Collection Filters”).

[0569] The total delivered dose (TDD) was compared with the breathing simulator operating in three tidal breathing volumes - 750 mL, 500 mL, and 400 mL. The AEROGEN® Ultra nebulizer, containing a PDAP vibrating mesh, was set to operate in a mode of 2 seconds on, 3 seconds off. An aqueous solution containing flecainide acetate at 75 mg / mL was used, dispensing 2.7 mL (202.5 mg total) into the nebulizer cup for each test. Samples containing nebulized drug in the filter assembly were collected in two nebulization cycles: 0-5 minutes, and 5 minutes to the end of nebulization. Filters were changed between each cycle. A mass balance experiment showed that an average of 97% of total drug was recovered, distributed between the DD collection filters (PARI filters) and different parts of the nebulizer.

[0570] The results of testing are shown in TABLE 1. These results demonstrate an increase in total delivered dose to the filter assembly with increasing tidal breathing volume administered by the breathing simulator. The TDD of 15 replicates at 750 mL ranged from 101.6 mg to 158.2 mg. It is expected that guiding patients to breathe more deeply will also result in an increase in the amount of drug delivered, and that the increased drug will be delivered to the lung, rather than to the throat.TABLE 1Tidal Breathing Total Delivered Fraction of TotalParameters Dose750 Average 127.3 mg 62.9% SD 16.1 mg 8.0%.......5 QAverage 11 T m g 56.3 %400 Average 108.1 mg 53.4%.EXAMPLE 3. Performance of the PDAP Vibrating Mesh Nebulizer vs. a Jet Nebulizer

[0571] In order to assess the performance of a vibrating mesh nebulizer and understand where particles generated by the devices can be expected to be deposited in the respiratory tract, a measurement of aerosol particle size distributions was made. A vibrating mesh nebulizer (AEROGEN® Ultra Solo) was assembled with a vibrating mesh termed a photo-defined aperture plate (PDAP), which was manufactured by a photolithography process that generates highly reproducible apertures that can be made to range from 0.5 - 6 pm in diameter, which in turn are capable of generating droplet sizes of the same diameters. A jet nebulizer (AEROECLIPSE®, Trudell Medical International) was chosen as a comparator to the vibrating mesh nebulizer.

[0572] The material aerosolized was FlecIH-103, which is an aqueous solution of 75 mg / mL flecainide acetate with 20% w / v hydroxypropyl-P-cyclodextrin, 5 mM acetic acid, and 0.75 mM Na saccharin, titrated to pH 5.9 with NaOH. To generate data for the vibrating mesh nebulizer and the jet nebulizer, three duplicate devices were used, with two repeated runs for each individual device, yielding six runs in total for each value reported. Aerosol was generated by the vibrating mesh nebulizer and the jet nebulizer, and captured on a Next Generation Pharmaceutical Impactor (NGI) apparatus. The NGI apparatus separates particles into stages according to cut-off sizes, and allows measurement of the fraction of the total particles generated contained within each stage.

[0573] Results from these experiments are presented in TABLE 2 and FIG. 8. TABLE 2 includes mass median aerodynamic diameter (MMAD), which is an expression of the median particle diameter, geometric standard deviation (GSD) of the distribution of particle sizes, which is an expression of the spread of the distribution of particle sizes (with a smaller number meaning a narrower distribution), and fine particle fraction (FPF), or percentage of total particles that are below a specified cut-off size. The upper limit of the range at which particles will be deposited in the lung is about 5 pm, thus this value is one for which FPF is reported.TABLE 2: Aerosol Particle Size Distribution (NGI)Nebulizer MMAD GSD FPF <3.3 pm FPF <5.0 pmJet (Trudell 4.1 pm 2.1 38.1% 60.3%AEROECLIPSE®)Vibrating mesh (Aerogen® 3.5 pm 1.6 46.4% 77.1%Ultra-Solo-PDAP)Abbreviations: NGI = Next Generation Pharmaceutical ImpactorMMAD = Mass Median Aerodynamic DiameterGSD = Geometric Standard DeviationFPF = Fine Particle Fraction

[0574] As shown in TABLE 2, the vibrating mesh nebulizer resulted in smaller median aerosol particle sizes, as compared to the jet nebulizer, a narrower (smaller) GSD, and a largerpercentage of fine particles within the total mass.

[0575] The percentages of drug mass according to particle size produced from the vibrating mesh nebulizer and the jet nebulizer are shown in FIG. 8. A greater proportion of small diameter particles was obtained from the vibrating mesh nebulizer vs. the jet nebulizer, as can be seen by the relative areas under the curves to the left of the vertical dotted line placed at 5 pm on the X- axis. (This is also reported in TABLE 2, in which the fine particle fraction (FPF) below 5 pm is 77.1% for the vibrating mesh nebulizer, but only 60.3% for the jet nebulizer.)

[0576] Above a particle size of about 5 pm, particles tend to be deposited in the oropharyngeal region, including the throat, rather than being carried into the lungs. Medicament deposited in the throat tends to lead to throat irritation and coughing, reducing patient compliance and the effectiveness of the treatment. The hatched area of the graph shows the increase in drug mass above 5 pm generated by the jet nebulizer compared to the vibrating mesh nebulizer, and thus the increased drug mass expected to be deposited in the throat by the jet nebulizer.

[0577] These results show quantitatively that the aerosol produced by the vibrating mesh nebulizer is superior in terms of expected drug deposition to the lung, with minimization of deposition to the throat.EXAMPLE 4. Effect of Directed Breathing on Throat Irritation and Cough

[0578] The effects of continuous operation of a nebulizer with that of operation of a nebulizer only during inhalation was assessed. In “Continuous Mode,” a vibrating mesh nebulizer (AEROGEN® Ultra-Solo) equipped with a photo-defined aperture plate (PDAP) produced aerosol continuously during the experiment. In “Directed Breathing Mode,” the vibrating mesh nebulizer was equipped with a timing device that controls both an indicator light and production of aerosol. The timer was set to turn on both the indicator light and nebulizer aerosol production, then turn both off, cycling through on and off cycles. For directed breathing, the patient was instructed to conduct a single inhalation throughout the period the indicator light was on, coinciding with aerosol production, and conduct a single exhalation throughout the period the indicator is off, during which time the nebulizer does not produce aerosol.

[0579] In order to demonstrate the effect of directed breathing on throat irritation and cough as compared to breathing from a nebulizer operating in continuous mode, a comparison was made with healthy volunteers. Two formulations of different pHs were tested - FlecIH-103, pH 5.9 and FLE-004, pH 5.2. The results are presented in TABLE 3.TABLE 3: Throat Irritation and Cough Analysis.Volunteer Inhalation (n=3) Throat Irritation* Cough*Continuous Mode1 - Overwhelming Yes No- Difficult to inhale2 - Overwhelming Lingers post- No- Difficult to inhale inhalation3 - Overwhelming Yes Yes- Difficult to inhaleDirected Breathing Mode _1 - Very easy to inhale None None- No adverse reactions2 - Very easy to inhale None None- No adverse reactions3 - Very easy to inhale Very minimal** None- No adverse reactions*FLE-004 formulation exhibited low tolerability in >90% of subjects **Observed only with FLE-004 formulation (pH 5.2)

[0580] All three volunteers consistently reported that it was difficult to inhale from the device operating in continuous mode, and that it was overwhelming to try to breathe normally. By contrast, all three volunteers found inhalation to be very easy with the device operating in directed breathing mode, and had no adverse reactions while breathing. Throat irritation occurred with all three volunteers during the trials operating in continuous mode, while only one of the three volunteers had very minimal throat irritation when using the device operating in directed breathing mode. One of three volunteers experienced cough from the device operating in continuous mode, but none of the volunteers experienced cough in directed breathing mode.

[0581] These results illustrate the potential of directed breathing to reduce throat irritation and cough in clinical applications, and the benefit of incorporating directed breathing into nebulizer devices. In particular, the devices of the present invention represent a means of integrating these advantages into a nebulizer that is still reliable and inexpensive enough to provide a disposable device.EXAMPLE 5. Clinical Performance of Flecainide Formulations Using Directed Breathing

[0582] This example describes a Phase 1 clinical study conducted with exemplary flecainide formulations as described in US 11,007,185 B2, incorporated herein. The FLE-016 study is a Phase 1 single-center study of FlecIH-103 (Flecainide Acetate Inhalation Solution) AdministeredUsing an AEROGEN® Ultra nebulizer to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Healthy Volunteers.

[0583] The primary study objectives are to evaluate the safety (pulmonary, cardiovascular [CV], and overall safety) and tolerability of FlecIH-103 (flecainide acetate inhalation solution [FlecIH]) administered using a vibrating mesh nebulizer (AEROGEN® Ultra-Solo) equipped with a photodefined aperture plate (PDAP). Secondary study objectives are to assess the pharmacokinetics (PK) of FlecIH- 103 administered using the vibrating mesh nebulizer, and to assess the pharmacodynamic (PD) effects of FlecIH-103 administered using a vibrating mesh nebulizer on vital signs and electrocardiographic (ECG) intervals.

[0584] The study population will be healthy male and female volunteers between 18 and 55 years of age (inclusive) will be enrolled. Female volunteers must not be pregnant or lactating. The study will be conducted with two cohorts: Cohort 1 with approximately 6-12 evaluable subjects, and Cohort 2 with approximately 20 evaluable subjects.

[0585] Flecainide acetate is provided in sterile aqueous formulation FlecIH-103 at 75 mg / mL, pH 5.9. FlecIH-103 will be administered via oral inhalation using the AEROGEN® Ultra-Solo vibrating mesh nebulizer comprising a PDAP nebulizer mesh. (The vibrating mesh nebulizer delivery system is described in more detail in Example 7, and shown in FIG. 9B.) Flecainide acetate inhalation solution is transferred into the reservoir of the vibrating mesh nebulizer at a volume corresponding to the required dose to the lung, in accordance with the specific instructions provided for each study protocol.

[0586] Each participant will receive a single oral inhaled dose of FlecIH-103. The dose of FlecIH-103 to be administered in Cohort 1 will be 60 mg to achieve peak plasma levels (Cmax) of flecainide not higher than 1000 ng / mL. The duration of inhalation of the dose will be approximately five minutes for participants in Cohort 1. The dose of FlecIH-103 to be administered in Cohort 2 will be determined based on the results observed in Cohort 1. The dose to be selected will be one expected to achieve peak plasma levels (Cmax) of flecainide in the range of 400-1000 ng / mL. In Cohort 2, participants will inhale the total dose in two inhalations with a one minute break (pause) between the two inhalations: Inhalation 1 will be five minutes in duration. The duration of inhalation 2 duration will depend on results of Cohort 1. The total combined duration for both inhalations will not exceed 12 minutes.Inhalation Guidelines

[0587] Participants in the study will administer study medication according the following guidelines:

[0588] The participant is seated upright in a comfortable chair or adjustable bed with table thathas adjustable height in front (e.g. overbed table on casters) where the participant can rest his / her arms (e.g. overbed table on casters) from approximately 30 minutes prior to the start of inhalation up to at least 15 minutes after the last inhalation is completed. The setting at the site allows for the participant to remain in this upright sitting position while linked to cardiac monitoring systems, while blood samples are being collected and while self-administering the inhalation solution.

[0589] The participant receives clear instructions from trained study personnel on how to selfadminister the treatment in accordance with the instructions for use. The vibrating mesh nebulizer is augmented with a timer that controls both a video graphic display that serves as an indicator, and aerosol production of the device. The timer operates inhalation / exhalation cycles set for predetermined periods. For the purposes of this study, the inhalation and exhalation periods will each be set for four seconds. The timer will cycle through the inhalation / exhalation cycles for the duration of administration of the inhalation solution. When the timer is in inhalation mode, a video graphic displays a rising bar and the device produces aerosol. When the timer is in exhalation mode, the video graphic displays a falling bar and aerosol production is paused. Participants are instructed to conduct a single inhalation throughout the period that the bar rises in the video graphic, and to conduct a single exhalation throughout the period the bar falls in the video graphic, synchronizing their inhalations with production of aerosol, and their exhalations with the period when aerosol production is paused. Such breathing pattern that follows instructions from an indicator, in this case a video graphic, is referred to as “directed breathing.”

[0590] Once the inhalation pattern is established, the participant should not remove inhaler device from the mouth for the required inhalation period. If the participant removes the nebulizer for any reason (e.g., cough, excessive saliva, etc.) for >30 seconds, then the inhalation period for that inhalation should be extended by the length of the interruption.Patient eligibility

[0591] Evaluations to be performed no more than four weeks prior to the scheduled first dose of study treatment. TABLE 4 summarizes some of the key study inclusion and exclusion criteria.TABLE 4: Patient Inclusion and Exclusion Criteria for Clinical Study2. Males or females3. 18 to 85 years of age (inclusive)4. Body mass index (BMI) >18 and <35 Kg / m2and a body weight (BW) > 60 Kg and <120 Kg5. No significant medical history condition, and in good general health6. Non-smokers or former smokers. All participants must pass a cotinine urine test to be enrolled;7. No evidence of asthma, chronic obstructive pulmonary disease (COPD) or major pulmonary airway disease8. No history of heart disease9. No cardiac issues secondary to a previous invasive cardiac procedure10. No clinically significant abnormalities detected on standard diagnostic 12-lead electrocardiogram and have no clinically significant family history of acquired or congenital cardiac arrhythmias11. No clinically significant abnormalities or left ventricular (LV) dysfunction12. Not currently participating in and have not participated in any other investigational study(ies) within 28 days or 5 half-lives of the experimental drug (whichever is longer) prior to planned study dosing13. Must meet specific cardiovascular and hemodynamic parameters in the screening visit, as follows:Heart Rate (HR) > 47 bpmPR Interval < 190 msQRS interval < 105 msQTcF (QT interval corrected < 450 ms for males using Fridericia’s formula) < 470 ms for femalesSystolic BP > 100 to < 140 mmHgDiastolic BP > 60 to < 100 mmHg14. Must meet specific pulmonary assessments related to pulmonary function testing in the screening visit, as follows:FEVi (forced expiratory volume in 1 second): FEVi > 80% of normal valuesFVC (forced vital capacity): FVC > 80% of normal valuesFEF (forced expiratory flow) 25-75%: > 70% of predictedChest X-ray normal, no clinically significant anomalyOxygen saturation > 95%Inclusion criteria for pulmonary function testing:Knudson 1976 calculations similar to NIOSH should be used - w wwLcdc . gov / ni osh / topi cs / lung spirometry / refcalculator.htmlObtain 3 acceptable tests, i.e. each test should meet the stated acceptability criteria.^vw.nationalasthma.org.au / uploads / content / 21 l-spirometer_handbook_naca.pdfStudy Design.

[0592] Participants will be monitored for cardiac and hemodynamic parameters using a standard 12-lead ECG, a continuous Holter and 5-lead ECG telemetry for 4-hour monitoring, blood pressure monitoring, pulmonary function testing, including tidal volume, auscultation, chest X-ray and oxygen saturation (SpO2). Additional evaluations will include medical / surgical history, physical examinations, vital sign measurements (blood pressure, temperature, heart rate, respiratory rate), height / weight, urinalysis and blood sample collection (hematology, coagulation, chemistry, hepatitis, HIV, drug screening), measurements of cardiac parameters (echocardiogram, 12-lead ECGs, continuous Holter and telemetry monitoring), pulmonary function (tidal volume, X-ray, lung spirometry, auscultation, oxygen saturation). Blood samples will also be collected from each participant for PK analysis.

[0593] The study comprises two cohorts with dose and dosing variations of FlecIH-103 inhalation solution administered using a hand-held nebulizer device (AEROGEN® Ultra) to healthy adult male and female volunteers as follows:• Cohort 1 : 6-12 evaluable participants will be dosed with approximately 60 mg of FlecIH- 103 by completing one 5-minute inhalation.• Cohort 2: 20 evaluable participants will be included in Cohort 2. The FlecIH-103 dose for this cohort will be determined based on the PK, PD, and safety results from Cohort 1; a total dose of 120 mg flecainide will be targeted. The durations of the two inhalations will be determined based on the PK, PD and safety results observed in Cohort 1, but the total combined duration of both inhalations will not exceed 12 minutes.

[0594] Cohort 1 will begin with 3 sentinel participants. Following dosing of the sentinel participants, the cardiac, hemodynamic, pulmonary function, safety / tolerability, and analysis of the PK data will be reviewed by the reviewed by the Safety Monitoring Group (SMG) composed of the Principal Investigator (PI), the Study Cardiologist (SC) and the Medical Monitor (MM). The decision to move forward to dosing the remaining participants in Cohort 1 will be based on the safety (including QRS from site recorded 12-lead ECGs), tolerability, ECG findings, and PK data from the first 3 participants in Cohort 1.

[0595] The number of subjects included in Cohort 1 will be determined by the results obtained but will be in the range of 6 to 12 subjects, inclusive.

[0596] After Cohort 1 is completed, all data will be reviewed by the SMG. The decision to move forward to Cohort 2 will be based on the analysis of the PK, ECG findings, safety, and tolerability data from Cohort 1.

[0597] Cohort 2 will begin with 3 sentinel participants. Following dosing of the sentinel participants, the cardiac, hemodynamic, pulmonary function, safety / tolerability, and analysis of the PK data will be reviewed by the SMG. The decision to move forward to dosing the remaining participants in Cohort 2 will be based on the data from the first 3 participants in Cohort 2.Data Collection.

[0598] Data will be collected as follows:General Safety Assessments: Evaluation of general safety in each cohort will be based on assessment of AEs, adverse drug experiences (ADEs), serious AEs (SAEs), serious ADE (SADEs), clinical laboratory tests, and vital signs.Pulmonary Safety Assessment: All participants will undergo the following tests to assess pulmonary safety.1. Lung spirometry including tidal volume2. Auscultation (heart and lung sounds, to be performed when participant is breathing in tidal volume)3. Chest X-ray4. Oxygen saturationCardiac and Hemodynamic Safety Measurements:1. Continuous real-time 5-lead ECG telemetry for surveillance of participant safety will commence at least 60 minutes pre-dose and continue for approximately 4 hours post-dose on each dosing day.2. Safety ECGs will be collected using a standard 12-lead ECG machine. The following safety ECG parameters will be reported: a. HR b. RR interval c. PR interval d. QRS duration e. QT interval and QTcF3. A continuous 12-lead Holter will be recorded starting at least 60 minutes pre-dose and continuing for approximately 4 hours post-dose on each dosing day. Triplicate 12-lead ECG recordings will be extracted from the Holter recording by the Core Laboratory. The following ECG parameters will be measured and calculated from these ECG tracings: a. HR b. RR interval c. PR interval d. QRS duration e. QT interval and QTcF f. JTc duration (QTc-QRS) g. P-wave duration and P-wave alternans4. Systemic blood pressure (BP) will be monitored throughout the study and may be obtained digitally or manually.Pharmacokinetic Measurements: Blood samples will be obtained on each dosing day for the determination of the venous plasma PK profile of flecainide.Pharmacodynamics Measurements: The following pharmacodynamic measurements will be obtained from 12-lead Holter ECG tracings:1. QRS interval2. PR interval3. QTc (and JTc)P-wave duration and P-wave alternansData analytics.

[0599] Screening, Compliance, Tolerability and Safety Data: In general, safety analyses will be performed, and the results summarized by cohort. Baseline safety assessments will be compared with measurements recorded post-baseline. Treatment-emergent AEs will be summarized using the latest version of MedDRA by System Organ Class (SOC) and preferred term (PT), classified from verbatim terms. The incidence, frequency, and severity of AEs, ADEs, SAEs, SADEs, related AEs, related SAEs, related SADEs and Suspected Unexpected Serious Adverse Reactions (SUSARS) will be summarized by dose and treatment group according to SOC and PTs. AEs and ADEs will also be summarized in listings. The duration of AEs and ADEs will be determined and included in data listings, along with the action taken and outcome. Laboratory results will be classified according to the latest version of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) and summarized by treatment group. Laboratory results not corresponding to a coded term will not be graded. The incidence of laboratory abnormalities will be summarized. Vital signs measurements will be summarized at each scheduled time point using descriptive statistics. Physical examination findings will be summarized by time point and presented in participant listings. Overall changes in cardiac (12-lead ECG and telemetry), hemodynamic (systemic blood pressure) and pulmonary function (chest X-ray, lung spirometry including tidal volume, auscultation, and oxygen saturation) parameters will be summarized. Additionally, changes from baseline and qualitative assessments will be captured. Tolerability of the inhalation dose experience will be assessed with a subject questionnaire.

[0600] Pharmacokinetics: The time-course of flecainide plasma concentrations will be modelled using non-compartmental methods. Actual time points for drug administration and PK sampling will be used in the modelling. The PK parameters Cmax, tmax, AUC0-24, AUCinf, and ti / 2for the terminal elimination phase will be estimated. Summary statistics for the PK parameters will be presented as arithmetic mean, geometric mean, median, coefficient of variation and minimum and maximum values. The geometric mean concentra...

Claims

CLAIMSWhat is claimed is:

1. A device for administering aerosol particles to a subject, the device comprising:(a) an aerosolization unit configured to aerosolize a pharmaceutical composition to generate the aerosol particles;(b) an indicator; and(c) a timer, wherein the timer is:(i) set with a designated inhalation time value and a designated exhalation time value;(ii) configured to cause the indicator to indicate, via a perceptible signal, occurrence of a designated inhalation period, and following the designated inhalation period, indicate, via the perceptible signal, occurrence of a designated exhalation period, wherein each designated inhalation period lasts for an interval of time equal to the designated inhalation time value, and each designated exhalation period lasts for an interval of time equal to the designated exhalation time value;(iii) configured to cause the aerosolization unit to activate at the beginning of each designated inhalation period and remain activated for an active period, wherein each active period independently lasts for an interval of time that is no longer than the designated inhalation time value; and cause the aerosolization unit to deactivate at the end of each active period, wherein during each active period, the aerosolization unit aerosolizes the pharmaceutical composition and delivers the aerosol to the subject through a mouthpiece of the aerosolization unit, wherein the designated inhalation period and the designated exhalation period are set to occur consecutively and alternate over a course of deposition of the aerosol particles.

2. The device of claim 1, wherein the timer is a microcontroller.

3. The device of claim 1, wherein the timer is electronically coupled to a relay that interrupts supply of power to a source of aerosol generation in the aerosolization unit.

4. The device of claim 3, wherein the source of aerosol generation is a vibrating mesh of a vibrating mesh nebulizer.

5. The device of claim 1, wherein the perceptible signal is audible, tactile, or visual.

6. The device of claim 5, wherein the indicator is a light.

7. The device of claim 5, wherein the indicator is a video screen and the perceptible signal is a graphic displayed on the video screen.

8. The device of claim 7, wherein, during the designated inhalation period, the perceptible signal is a rising bar, and during the designated exhalation period, the perceptible signal is a falling bar.

9. The device of claim 1, wherein the designated inhalation time value is from about 1 second to about 6 seconds and the designated exhalation time value is from about 1 second to about 8 seconds.

10. The device of claim 1, wherein the designated inhalation time value is about 4 seconds and the designated exhalation time value is about 4.25 seconds.

11. The device of claim 1, wherein each designated exhalation period comprises a rest period that occurs during the terminal portion of one or more designated exhalation periods, wherein the timer is configured to cause the indicator to indicate to the subject to neither inhale nor exhale during each rest period.

12. The device of claim 11, wherein each rest period is from about 0.1 seconds to about 0.5 seconds in duration.

13. The device of claim 1, wherein the aerosolization unit comprises a vibrating mesh nebulizer.

14. The device of claim 13, comprising:(a) a first material having a plurality of first apertures, the first material being formed through a photolithography process and wherein the plurality of first apertures define generally cylindrical shapes, the first apertures each having an exit opening with a diameter within a range of from 0.5 pm to 6 pm to produce droplets that are about 0.5 pm to 6 pm in size;(b) a second material above the first material, the second material having a plurality of second apertures above the plurality of first apertures in the first material, thesecond material being formed through a photolithography process and wherein the plurality of second apertures define generally cylindrical shapes defining liquid supply cavities, each liquid supply cavity having a diameter within a range of from 20 pm to 200 pm; wherein at least some of the plurality of first apertures are within the diameters of the liquid supply cavities defined by the second apertures, and wherein the first material and the second material form a mesh for use in the vibrating mesh nebulizer.

15. The device of claim 1, wherein the aerosolization unit is a single-use aerosolization unit.

16. The device of claim 1, wherein each active period is set to last for an interval of time that is equal to the designated inhalation time value.

17. The device of claim 1, wherein at least one active period is set to last for an interval of time that is equal to a fraction of the designated inhalation time value.

18. The device of claim 1, wherein each active period is set to last no longer than a fraction of the designated inhalation time value.

19. The device of claim 1, wherein the timer is configured to cause the duration of an active period to be longer than a duration of a preceding active period.

20. The device of claim 1, wherein, for each active period within an initial set of active periods of a dosing session, the timer is configured to increase the duration of the active period relative to the duration of the immediately preceding active period.

21. The device of claim 20, wherein the initial set of active periods consists of the first three, first four, first five, first six, first seven, first eight, first nine, or first ten active periods of the dosing session.

22. The device of claim 20, wherein the timer is configured to cause each active period subsequent to the initial set of active periods to be constant in duration.

23. The device of claim 20, wherein the timer is configured to cause each active period subsequent to the initial set of active periods to last for a duration that is equal to the duration of the last active period of the initial set of active periods.

24. The device of claim 20, wherein, the timer is configured to increase the duration of theactive period from an initial value to a terminal value over the initial set of active periods, wherein the initial value is from about 0.5 seconds to about two seconds, and the terminal value is from about 2.5 seconds to about four seconds.

25. The device of claim 20, wherein, the timer is configured to increase the duration of the active period from an initial value to a terminal value over the initial set of active periods, wherein the initial value is about one second, and the terminal value is about three seconds.

26. The device of claim 20, wherein the initial set of active periods comprises a first active period, a second active period, a third active period, and a fourth active period, wherein the first active period is about one second, the second active period is about 1.5 seconds, the third active period is about two seconds, the fourth active period is about 2.5 seconds, and each active period subsequent to the fourth active period is about three seconds.

27. The device of claim 1, wherein causing the aerosolization unit to activate comprises causing the aerosolization unit to begin aerosolizing the pharmaceutical composition.

28. The device of claim 1, wherein causing the aerosolization unit to activate comprises causing aerosol to be supplied to a mouthpiece of the aerosolization unit.

29. The device of claim 1, wherein causing the aerosolization unit to activate comprises causing a valve to open, thereby allowing passage of aerosol particles from a source of aerosol generation in the aerosolization unit (e.g., a vibrating mesh of a vibrating mesh nebulizer) to a mouthpiece of the aerosolization unit.

30. The device of claim 1, wherein causing the aerosolization unit to activate comprises causing a relay to supply power from a power source to the source of aerosol generation (e.g., a vibrating mesh of a vibrating mesh nebulizer).

31. The device of claim 1, wherein the aerosolization unit comprises a vibrating mesh nebulizer, wherein the vibrating mesh nebulizer comprises a vibrating mesh, wherein causing the aerosolization unit to activate comprises causing the vibrating mesh to vibrate.

32. A kit comprising the device of any one of claims 1-31 and a topical anesthetic.

33. A kit for treating atrial arrhythmia comprising the device of any one of claims 1-31 and the pharmaceutical composition, wherein the pharmaceutical composition comprises aneffective amount of flecainide or a pharmaceutically-acceptable salt thereof.

34. The kit of claim 33, wherein the pharmaceutical composition is provided in unit dose form.

35. The kit of claim 34, wherein the unit dose comprises about 10 mg to about 200 mg flecainide acetate.

36. The kit of claim 35, wherein flecainide acetate is provided as an aqueous formulation at a concentration ranging from 45 to 90 mg / mL.

37. The kit of claim 36, wherein the course of deposition of aerosol particles is sufficient to exhaust the aqueous formulation.

38. A method of administering an aerosol to a subject, the method comprising: aerosolizing a pharmaceutical composition via a nebulizer to generate the aerosol over a course of a plurality of cycles, each cycle consisting of: a designated inhalation period, wherein each designated inhalation period lasts for an interval of time equal to a designated inhalation time value, wherein the aerosolizing occurs only during an active period that begins at the start of each designated inhalation period and lasts for an interval of time that is no more than the designated inhalation time value; and a designated exhalation period, wherein each designated exhalation period lasts for an interval of time equal to a designated exhalation time value; providing indication to the subject of occurrence of each designated inhalation period or each designated exhalation period via a perceptible signal; and instructing the subject to conduct, in synchrony with the perceptible signal, (i) a single inhalation during each designated inhalation period, and (ii) a single exhalation during each designated exhalation period.

39. The method of claim 38, wherein each designated exhalation period comprises a rest period that occurs during the terminal portion of each designated exhalation period, wherein during each rest period, the subject neither inhales nor exhales.

40. The method of claim 39, wherein each rest period is from about 0.1 seconds to about 1 second in duration.

41. The method of claim 38, further comprising instructing the subject to continue inhaling the aerosol in synchrony with the perceptible signal until a unit dose of the pharmaceutical composition is depleted.

42. The method of claim 38, wherein the pharmaceutical composition comprises an anti arrhythmic agent and the subject suffers from cardiac arrythmia.

43. The method of claim 42, further comprising, after a first unit dose of the pharmaceutical composition has been administered, administering a second unit dose of the pharmaceutical composition upon determining that the subject still suffers from the cardiac arrythmia.

44. The method of claim 43, wherein the second unit dose is equal to the first unit dose.

45. The method of claim 43, wherein the second unit dose is one-half of the first unit dose.

46. The method of claim 43, wherein the second unit dose is administered about 10 minutes to about 1 hour after administration of the first unit dose is completed.

47. The method of claim 38, further comprising instructing the subject to pause inhalation of the aerosol after about one half of the unit dose has been administered, and resume inhalation of the remaining half of the unit dose after a 30 second to three minute break.

48. The method of claim 38, further comprising instructing the subject to:(i) inhale the aerosol in synchrony with the perceptible signal for a first duration that is from about 3 minutes to about 4 minutes;(ii) after said first duration, pause inhalation for a second duration that is from about 30 seconds to about 90 seconds; and(iii) after said second duration, resume inhalation in synchrony with the perceptible signal for a third duration that is from about 3 minutes to about 4 minutes.

49. A method of administering an aerosol to a subject, the method comprising: aerosolizing a pharmaceutical composition via a nebulizer to generate the aerosol over a course of a plurality of cycles, each cycle consisting of: a designated inhalation period, wherein each designated inhalation period lasts for an interval of time equal to a designated inhalation time value, wherein the aerosolizingoccurs only during an active period that begins at the start of each designated inhalation period and lasts for an interval of time that is no more than the designated inhalation time value; and a designated exhalation period, wherein each designated exhalation period lasts for an interval of time equal to a designated exhalation time value; providing indication to the subject of occurrence of each designated inhalation period or each designated exhalation period via a perceptible signal, wherein the subject conducts, in synchrony with the perceptible signal, a single inhalation of the aerosol during each designated inhalation period, and a single exhalation during each designated exhalation period.

50. The method of claim 49, wherein each designated exhalation period comprises a rest period that occurs during the terminal portion of each designated exhalation period, wherein during each rest period, the subject neither inhales nor exhales.

51. The method of claim 50, wherein each rest period is from about 0.1 seconds to about 1 second in duration.

52. The method of claim 49, wherein the subject continues inhaling the aerosol in synchrony with the perceptible signal until a unit dose of the pharmaceutical composition is depleted.

53. The method of claim 49, wherein the pharmaceutical composition comprises an anti arrhythmic agent and the subject suffers from cardiac arrythmia.

54. The method of claim 49, further comprising, after a first unit dose of the pharmaceutical composition has been administered, administering a second unit dose of the pharmaceutical composition upon determining that the subject still suffers from the cardiac arrythmia.

55. The method of claim 54, wherein the second unit dose is equal to the first unit dose.

56. The method of claim 54, wherein the second unit dose is one-half of the first unit dose.

57. The method of claim 54, wherein the second unit dose is administered about 10 minutes to about 1 hour after administration of the first unit dose is completed.

58. The method of claim 49, wherein the subject pauses inhalation of the aerosol after about one half of the unit dose has been administered, and resumes inhalation of the remaining half of the unit dose after a 30 second to three minute break.

59. The method of claim 49, wherein the subject:(i) inhales the aerosol in synchrony with the perceptible for a first duration that is from about 3 minutes to about 4 minutes;(ii) after said first duration, pauses inhalation for a second duration that is from about 30 seconds to about 90 seconds; and(iii) after said second duration, resumes inhalation in synchrony with the perceptible signal for a third duration that is from about 3 minutes to about 4 minutes.

60. The method of any one of claims 38-59, wherein the nebulizer is a vibrating mesh nebulizer.

61. The method of any one of claims 38-60, wherein the nebulizer is single-use.

62. The method of any one of claims 38-61, wherein the perceptible signal is audible, tactile, or visual.

63. The method of any one of claims 38-62, wherein the perceptible signal is provided by an indicator.

64. The method of claim 63, wherein the indicator is a light.

65. The method of claim 63, wherein the indicator is a video screen and the perceptible signal is a graphic displayed on the video screen.

66. The method of any one of claims 38-65, wherein each active period lasts for an interval of time that is equal to the designated inhalation time value.

67. The method of any one of claims 38-65, wherein at least one active period lasts for an interval of time that is equal to a fraction of the designated inhalation time value.

68. The method of any one of claims 38-65, further comprising increasing the duration of an active period relative to a duration of a preceding active period in the plurality of cycles.

69. The method of any one of claims 38-65, further comprising, for each successive active period within an initial set of active periods of a dosing session, increasing the duration of an active period relative to that of the immediately preceding active period.

70. The method of claim 69, wherein the initial set of active periods consists of the first three, first four, first five, first six, first seven, first eight, first nine, or first ten active periods of the dosing session.

71. The method of claim 69, wherein the timer is configured to cause each active period subsequent to the initial set of active periods to be constant in duration.

72. The method of claim 69, wherein each active period subsequent to the initial set of active periods lasts for a duration that is equal to the duration of the last active period of the initial set of active periods.

73. The method of claim 69, wherein, over the initial set of active periods, the timer increases the duration of the active period from an initial value to a terminal value, wherein the initial value is from about 0.5 seconds to about two seconds, and the terminal value is from about2.5 seconds to about four seconds.

74. The method of claim 69, wherein, over the initial set of active periods, the timer increases the duration of the active period from an initial value to a terminal value, wherein the initial value is about one second, and the terminal value is about 3 seconds.

75. The method of claim 69, wherein the initial set of active periods comprises a first active period, a second active period, a third active period, a fourth active period, and a fifth active period, wherein the first active period is about one second, the second active period is about1.5 seconds, the third active period is about two seconds, the fourth active period is about2.5 seconds, and the fifth active period is about three seconds.

76. The method of claim 75, wherein each active period subsequent to the fifth active period lasts for an interval of time equal to the fifth active period.

77. The method of any one of claims 38-76, wherein the providing indication further comprises modulating the perceptible signal over time according to a waveform, wherein each period of the waveform has a duration equal to the sum of the designated inhalation time value and the designated exhalation time value.

78. The method of claim 77, wherein the modulating comprises modulating the frequency or intensity of an audible tone.

79. The method of claim 77, wherein the modulating comprises modulating a dimension of a two-dimensional graphic displayed on a video screen.

80. The method of any one of claims 38-79, wherein the designated inhalation time value is from about 1 second to about 6 seconds and the designated exhalation time value is from about 1 second to about 8 seconds.

81. The method of any one of claims 38-79, wherein the designated inhalation time value is 2 seconds and the designated exhalation time value is 3 seconds.

82. The method of any one of claims 38-79, wherein the designated inhalation time value is 4.25 seconds and the designated exhalation time value is 4 seconds.

83. The method of any one of claims 38-79, wherein the designated inhalation time value is 3 seconds and the designated exhalation time value is 4 seconds.

84. The method of any one of claims 38-79, wherein the plurality of cycles is sufficient to exhaust the pharmaceutical composition.

85. The method of any one of claims 38-79, wherein the device produces aerosol at a designated liquid output rate.

86. The method of claim 85, wherein the designated liquid output rate is adjusted to at least 0.3 mL / min and particle mass median aerodynamic diameter is less than 4 pm with a geometric standard deviation less than 1.8.

87. The method of any one of claims 38-86, wherein the pharmaceutical composition comprises an anti arrhythmic medication.

88. The method of any one of claims 38-87, wherein the pharmaceutical composition comprises amiodarone, digitoxin, digoxin, dofetilide, dronedarone, flecainide, fhiindione, phenindione, procainamide, quinidine, sotalol, or warfarin, or pharmaceutically-acceptable salts thereof.

89. The method of any one of claims 38-88, wherein the medication is delivered to the heart viathe lungs.

90. The method of any one of claims 38-89, wherein the subject suffers from cardiac arrhythmia, and wherein the aerosol particles comprise a therapeutically-effective amount of an anti arrhythmic agent.

91. The method of any one of claims 38-90, wherein the pharmaceutical composition is in unitdose form, wherein the unit dose comprises a therapeutically-effective amount of a class 1c anti arrhythmic drug.

92. The method of claim 91, wherein the 1c anti arrhythmic drug is flecainide or a pharmaceutically-acceptable salt thereof.

93. The method of claim 91 or 92, wherein the 1c anti arrhythmic drug is flecainide acetate.

94. The method of claim 92 or 93, wherein the therapeutically effective amount is from about 10 mg to about 200 mg.

95. The method of any one of claims 38-94, wherein the pharmaceutical composition is an aqueous formulation comprising from about 45 to about 90 mg / mL flecainide acetate.

96. The method of any one of claims 38-95, wherein the pharmaceutical composition is an aqueous formulation comprising about 75 mg / mL flecainide acetate.

97. The method of any one of claims 92-96, wherein a target serum concentration of flecainide of at least 200 ng / mL is achieved in the subject.

98. The method of any one of claims 92-96, wherein a target serum concentration of flecainide of at least 300 ng / mL is achieved in the subject.

99. The method of any one of claims 92-96, wherein a target serum concentration of flecainide of at least 400 ng / mL is achieved in the subject.

100. The method of any one of claims 92-96, wherein a target serum concentration of flecainide of at least 500 ng / mL is achieved in the subject.

101. The method of any one of claims 38-100, wherein the subject is administered the aerosol in a medically supervised setting.

102. The method of any one of claims 38-100, wherein the subject self-administers the medication.

103. The method of any one of claims 38-102, wherein the administration minimizes sustained cough or throat irritation that normally results from deposition of the medication into the oropharyngeal region.

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