ANTIARRHYTHMIC FORMULATION

CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/146,155, filed February 5, 2021, 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 heart beat 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, which necessitates extensive monitoring of the patient.

[0004] Cardiac arrhythmias are associated with disabling symptoms like tightness around the chest, palpitations, feeling tired, shortness of breath, and sometimes chest pain. Arrhythmias frequently result in emergency room (ER) visits where intravenous drugs are administered, sometimes necessitating an extended stay in the hospital and in some cases also leading to unplanned invasive procedures.

[0005] There remains a need for improved compositions and methods for treating heart conditions. Accordingly, there also remains a need for methods of making these compositions.

SUMMARY

[0006] In certain aspects, the present disclosure provides pharmaceutical compositions, comprising a therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof, and cyclodextrin, wherein said therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof and said cyclodextrin have a weight ratio from about 5 :95 to about 95:5, and wherein said pharmaceutical composition is in a form of an inhalable dry powder.

[0007] In some embodiments, said cyclodextrin is selected from the group consisting of a- cyclodextrin, P-cyclodextrin, y-cyclodextrin, hydroxypropyl-P-cyclodextrin, hydroxyethyl-P- cyclodextrin, hydroxypropyl-y-cyclodextrin, hydroxyethyl-y-cyclodextrin, dihydroxypropyl-P- cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-P-cyclodextrin, diglucosyl-P-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-P-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-P- cyclodextrin, maltotriosyl-y-cyclodextrin dimaltosyl-P-cyclodextrin, succinyl-P-cyclodextrin, 6A- amino-6A-deoxy-N-(3-hydroxypropyl)-P-cyclodextrin, sulfobutylether-P-cyclodextrin, sulfobutylether-y-cyclodextrin, sulfoalkylether-P-cyclodextrin, and sulfoalkylether-y- cyclodextrin. In some embodiments, said cyclodextrin comprises hydroxypropyl-P-cyclodextrin.

[0008] In certain aspects, the present disclosure provides pharmaceutical compositions, comprising a therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof, and_hydroxypropyl-P-cyclodextrin, wherein said pharmaceutical composition is in a form of an inhalable dry powder.

[0009] In some embodiments, said therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof and said cyclodextrin have a weight ratio from about 5 :95 to about 95:5. In some embodiments, said therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof and said cyclodextrin have a weight ratio from about 10:90 to about 90: 10, from about 15:85 to about 85: 15, from about 20:80 to about 80:20, from about 25:75 to about 75:25, from about 30:70 to about 70:30, from about 35:65 to about 65:35, from about 40:60 to about 60:40, or from about 45:55 to about 55:45. In some embodiments, said therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof and said cyclodextrin have a weight ratio of about 50:50. In some embodiments, said therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof and said cyclodextrin have a weight ratio of about 23 :77.

[0010] In some embodiments, said pharmaceutical composition further comprises a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutically acceptable excipient or carrier comprises lactose, mannitol, sorbitol, erythritol, raffinose, sucrose, xylitol, trehalose, dextrose, a cyclodextrin, maltitol, maltose, glucose, hydroxyapatite, or any combination thereof. In some embodiments, the pharmaceutically acceptable excipient or carrier comprises porous particles, a crystallization inhibitor, a biodegradable polymer, ammonium bicarbonate, an amino acid, or any combination thereof. In some embodiments, the crystallization inhibitor comprises polymers, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polysaccharide, hydroxypropyl methylcellulose (HPMC or Hypromellose), hydroxy ethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl-P-cyclodextrin (HP- P-CD), sulfobutylether-P-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMC- AS-HF), polyethylene glycol (PEG), or any combination thereof. In some embodiments, the pharmaceutically acceptable excipient or carrier comprises L-leucine or L-isoleucine.

[0011] In some embodiments, reconstitution of said pharmaceutical composition at a concentration of 9 mg/mL in water to 10 mg/mL affords a solution with a pH of about 5.0 to about 8.0. In some embodiments, reconstitution of said pharmaceutical composition at a concentration of 9 mg/mL in water to 10 mg/mL affords a solution with a pH of about 5.5 to about 7.0. In some embodiments, reconstitution of said pharmaceutical composition at a concentration of 9 mg/mL in water to 10 mg/mL affords a solution with a pH of about 6.7.

[0012] In some embodiments, said therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof comprises flecainide acetate. In some embodiments, said pharmaceutical composition further comprises an acid. In some embodiments, said acid comprises acetic acid, aconitic acid, adipic acid, alginic acid, benzoic acid, caprylic acid, citric acid, cholic acid, formic acid, lactic acid, linoleic acid, malic acid, maleic acid, propionic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid, glutamic acid, hydrochloric acid, phosphoric acid, ascorbic acid, erythorbic acid, sorbic acid, thiodipropionic acid, or any combination thereof. In some embodiments, said acid comprises acetic acid.

[0013] In some embodiments, said dry inhalable powder is formulated for administration via oral inhalation. In some embodiments, said dry powder has a mass median aerodynamic diameter of about 0.3 pm to about 20 pm. In some embodiments, said dry powder has a mass median aerodynamic diameter of about 4.0 pm. In some embodiments, said dry powder has a mass median aerodynamic diameter of about 5.0 pm. In some embodiments, said dry powder has a mass median aerodynamic diameter of about 6.0 pm. In some embodiments, said pharmaceutical composition has a glass transition temperature of about 15 °C to about 70 °C. In some embodiments, said pharmaceutical composition has a glass transition temperature of about 45.0 °C. In some embodiments, said pharmaceutical composition has a glass transition temperature of about 65.0 °C. In some embodiments, said glass transition temperature is measured by Differential Scanning Calorimetry (DSC).

[0014] In some embodiments, said pharmaceutical composition described herein is in the form of a unit dose, comprising about 50 mg to about 350 mg of said flecainide or said pharmaceutically acceptable salt thereof. In some embodiments, said unit dose comprises from about 100 mg to about 150 mg of said flecainide or said pharmaceutically acceptable salt thereof.

[0015] In certain aspects, the present disclosure provides kits, comprising a pharmaceutical composition described herein or a unit dose described herein and instructions for use of said pharmaceutical composition for treatment of a heart condition.

[0016] In some embodiments, said kit further comprising a container that contains said pharmaceutical composition. In some embodiments, wherein said container is selected from the group consisting of a capsule, blister pack, blister strip, reservoir, and cartridge.

[0017] In certain aspects, the present disclosure provides kits, comprising a pharmaceutical composition that comprises a therapeutically effective amount of flecainide or pharmaceutically acceptable salt thereof, and a cyclodextrin, a receptacle containing said pharmaceutical composition, instructions for use of a dry powder inhaler for inhalation of a dose of said pharmaceutical composition in aerosol to a subject, wherein said pharmaceutical composition is in the form of an inhalable dry powder, and wherein said therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof and said cyclodextrin have a weight ratio from about 5:95 to about 95:5.

[0018] In some embodiments, wherein said kit comprises a unit dose of said pharmaceutical composition, and wherein said unit dose comprises from about 50 mg to about 350 mg of said flecainide or said pharmaceutical acceptable salt thereof.

[0019] In certain aspects, the present disclosure provides systems, comprising a pharmaceutical composition described herein and a dry powder inhaler.

[0020] In some embodiments, said system further comprising instructions for use of said dry powder inhaler and said pharmaceutical composition for treatment of a heart condition. In some embodiments, said heart condition comprises atrial arrhythmia. In some embodiments, said instructions contain instructions for use of said dry powder inhaler to deliver said pharmaceutical composition in a unit dose that comprises from about 50 mg to about 350 mg of flecainide or said pharmaceutically acceptable salt thereof.

[0021] In certain aspects, the present disclosure provides systems, comprising a pharmaceutical composition that comprises a therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof, and a cyclodextrin, a dry powder inhaler configured to deliver said pharmaceutical composition as an inhalable dry powder, instructions for use of said dry powder inhaler to deliver said pharmaceutical composition in a unit dose that comprises about 50 mg to about 350 mg amount of flecainide or said pharmaceutically acceptable salt thereof, wherein said pharmaceutical composition is in the form of an inhalable dry powder that has said therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof and said cyclodextrin have a weight ratio from about 5:95 to about 95:5.

[0022] In certain aspects, the present disclosure provides methods of treating a subject suffering from a heart condition, comprising administering to said subject via inhalation a pharmaceutical composition in the form of an inhalable dry powder, wherein said pharmaceutical composition comprises a therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof, and a cyclodextrin, wherein said therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof and said cyclodextrin have a weight ratio from about 5 :95 to about 95:5.

[0023] In some embodiments, said cyclodextrin is selected from the group consisting of: a- cyclodextrin, P-cyclodextrin, y-cyclodextrin, hydroxypropyl-P-cyclodextrin, hydroxyethyl-P- cyclodextrin, hydroxypropyl-y-cyclodextrin, hydroxyethyl-y-cyclodextrin, dihydroxypropyl-P- cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-P-cyclodextrin, diglucosyl-P-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-P-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-P- cyclodextrin, maltotriosyl-y-cyclodextrin dimaltosyl-P-cyclodextrin, succinyl-P-cyclodextrin, 6A- amino-6A-deoxy-N-(3-hydroxypropyl)-P-cyclodextrin, sulfobutylether-P-cyclodextrin, sulfobutylether-y-cyclodextrin, sulfoalkylether-P-cyclodextrin, and sulfoalkylether-y- cyclodextrin. In some embodiments, said cyclodextrin comprises hydroxypropyl-P-cyclodextrin. In some embodiments, said therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof comprises from about 50 mg to about 350 mg of flecainide or said pharmaceutically acceptable salt thereof. In some embodiments, said administration of said pharmaceutical composition is performed in up to six inhalation sessions. In some embodiments, said administration of said pharmaceutical composition is performed in one or two inhalation sessions. In some embodiments, said administration is performed via a dry powder inhaler. In some embodiments, said heart condition comprises atrial arrhythmia. In some embodiments, said atrial arrhythmia comprises tachycardia. In some embodiments, comprising acute treatment after detection of said atrial arrhythmia. In some embodiments, said heart condition comprises atrial fibrillation. In some embodiments, said atrial fibrillation is recurrent atrial fibrillation. In some embodiments, said atrial fibrillation is paroxysmal atrial fibrillation.

[0024] In certain aspects, the present disclosure provides methods, comprising converting a solution containing flecainide to an inhalable dry powder, thereby producing a pharmaceutical composition described herein.

[0025] In some embodiments, said converting said solution containing flecainide to said inhalable dry powder comprises using spray drying, freeze drying, spray-freeze drying, emulsion spray drying, or an aerosol flow reactor method. In some embodiments, said spray drying comprises spray drying at a solution flow rate of about 1.0 g/min to about 15.0 g/min, an atomization pressure of about 10 psi to about 100 psi, an inlet temperature of about 100 °C to about 200 °C, or an outlet temperature of about 40 °C to about 70 °C. In some embodiments, said spray drying comprises spray drying a solution flow rate of about 1.0 g/min to about 15.0 g/min, an atomization pressure of about 10 psi to about 100 psi, an inlet temperature of about 100 °C to about 200 °C, and an outlet temperature of about 40 °C to about 70 °C. In some embodiments, said solution containing flecainide further comprises a cyclodextrin. In some embodiments, said cyclodextrin comprises hydroxypropyl-P-cyclodextrin. In some embodiments, said solution containing flecainide further comprises an acid. In some embodiments, said acid comprises acetic acid, aconitic acid, adipic acid, alginic acid, benzoic acid, caprylic acid, citric acid, cholic acid, formic acid, lactic acid (e.g., D-(-)-lactic acid or L-(+)-lactic acid), linoleic acid, malic acid, maleic acid, propionic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid, glutamic acid, hydrochloric acid, phosphoric acid, ascorbic acid, erythorbic acid, sorbic acid, thiodipropionic acid, or any combination thereof. In some embodiments, said acid comprises acetic acid. In some embodiments, said solution containing flecainide is prepared by dissolving flecainide or a pharmaceutically acceptable salt thereof, cyclodextrin, and pH buffer agents in water, thereby providing said solution containing flecainide. In some embodiments, said cyclodextrin is selected from the group consisting of: a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, hydroxypropyl-P- cyclodextrin, hydroxyethyl-P-cyclodextrin, hydroxypropyl-y-cyclodextrin, hydroxyethyl-y- cyclodextrin, dihydroxypropyl-P-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-P-cyclodextrin, diglucosyl-P-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-P-cyclodextrin, maltosyl-y- cyclodextrin, maltotriosyl-P-cyclodextrin, maltotriosyl-y-cyclodextrin dimaltosyl-P-cyclodextrin, succinyl-P-cyclodextrin, 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-P-cyclodextrin, sulfobutylether-P-cyclodextrin, sulfobutylether-y-cyclodextrin, sulfoalkylether-P-cyclodextrin, and sulfoalkylether-y-cyclodextrin. In some embodiments, said cyclodextrin comprises hydroxypropyl-P-cyclodextrin. In some embodiments, said converting said solution containing flecainide further comprises heating said solution containing flecainide. In some embodiments, comprising heating said solution containing flecainide to about 40 °C. In some embodiments, said solution containing flecainide is cooled to 25 °C prior to spray drying. In some embodiments, said flecainide solution is diluted with water prior to spray drying. In some embodiments, pH of said solution containing flecainide is adjusted to about 6.0 using said a pH buffer agent prior to spay drying. In some embodiments, said pH buffer agent comprises sodium hydroxide. In some embodiments, reconstitution of said inhalable dry powder pharmaceutical composition at a concentration of 9 mg/mL to 10 mg/mL in water affords a solution with a pH of about 5.0 to about 8.0. In some embodiments, reconstitution of said inhalable dry powder pharmaceutical composition at a concentration of 9 mg/mL to 10 mg/mL in water affords a solution with a pH of about 5.5 to about 7.0. In some embodiments, reconstitution of said inhalable dry powder pharmaceutical composition at a concentration of 9 mg/mL to 10 mg/mL in water affords a solution with a pH of about 6.7. In some embodiments, the inhalable dry powder pharmaceutical composition has a mass median aerodynamic diameter of about 0.3 pm to about 20 pm. In some embodiments, said pharmaceutical composition has a glass transition temperature of about 15 °C to about 70 °C. In some embodiments, said flecainide or said pharmaceutically acceptable salt thereof comprises flecainide acetate. In some embodiments, said method further comprising packaging said pharmaceutical composition in unit dose form. In some embodiments, said unit dose form further comprises a container selected from the group consisting of: a capsule, blister pack, blister strip, reservoir, and cartridge. INCORPORATION BY REFERENCE

[0026] 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

[0027] 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 be obtained 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:

[0028] FIG. 1 illustrates the particle size distribution of flecainide acetate powder.

[0029] FIG. 2 illustrates X-ray powder diffraction (XRPD) data obtained from pure flecainide acetate drug and processed neat flecainide acetate.

[0030] FIG. 3 illustrates XRPD data obtained from 20% w/w flecainide acetate, 48% w/w flecainide acetate, and 70% w/w flecainide acetate with leucine.

[0031] FIG. 4 illustrates XRPD data obtained from neat flecainide acetate and non-powder forming formulations.

[0032] FIG. 5 illustrates the particle size distribution flecainide acetate spray dried powders (Batch J - Batch N).

[0033] FIG. 6 illustrates non-reversing heat flow signals observed via differential scanning calorimetry (DSC) analysis of flecainide acetate spray dried powders (Batch J - Batch N).

[0034] FIG. 7 illustrates reversing heat flow signals observed via DSC analysis of flecainide acetate spray dried powders (Batch J - Batch N).

[0035] FIG. 8 illustrates XRPD diffractograms of flecainide acetate spray dried powders (Batch J - Batch N).

[0036] FIG. 9 illustrates the dynamic vapor sorption (DVS) isotherm profile of a 23/77 (w/w) flecainide acetate/HP-P-CD spray dried formulation prepared from a nebulization solution preparation (Batch J).

[0037] FIG. 10 illustrates the DVS isotherm profile of a 23/77 (w/w) flecainide acetate/HP-P-CD spray dried formulation prepared from a nebulization solution preparation at lower feed rate (Batch K).

[0038] FIG. 11 illustrates the DVS isotherm profile of a 23/77 (w/w) flecainide acetate/HP-P-CD spray dried formulation (Batch M, direct solution preparation).

[0039] FIG. 12 illustrates DVS isotherms of flecainide acetate spray dried powder Batches J, K, and M. [0040] FIG. 13 illustrates a DVS mass change profile of flecainide acetate spray dried powder Batch J.

[0041] FIG. 14 illustrates a DVS mass change profile for flecainide acetate spray dried powder Batch K.

[0042] FIG. 15 illustrates a DVS mass change profile for flecainide acetate spray dried powder Batch M.

[0043] FIG. 16 illustrates particle size distributions of flecainide acetate spray powders stored at 40 °C / 75% RH in a closed container for 1 month.

[0044] FIG. 17 illustrates reversing heat flow signals observed via DSC analysis of flecainide acetate spray dried powders stored in closed containers for 1 -month (Batches J, K, and M).

[0045] FIG. 18 illustrates non-reversing heat flow signals observed via DSC analysis of flecainide acetate spray dried powders stored in closed containers for 1 month (Batches J, K, and M).

[0046] FIG. 19 illustrates reversing heat flow signals observed via DSC analysis of flecainide acetate spray dried powders stored in open containers for 1 month.

[0047] FIG. 20 illustrates non-reversing heat flow signals observed via DSC analysis of flecainide acetate spray dried powders stored in closed containers for 1 month.

[0048] FIG. 21 illustrates an overlay of XRPD diffractograms of flecainide acetate spray dried powder Batches J-M after storage for 1 month.

[0049] FIG. 22 illustrates total and reversing heat flow signals observed via DSC analysis of flecainide acetate spray dried powder Batch J.

[0050] FIG. 23 illustrates total and reversing heat flow signals observed via DSC analysis of flecainide acetate spray dried powder Batch K.

[0051] FIG. 24 illustrates total and reversing heat flow signals observed via DSC analysis of analysis of flecainide acetate spray dried powder Batch L.

[0052] FIG. 25 illustrates total and reversing heat flow signals observed via DSC analysis of analysis of flecainide acetate spray dried powder Batch M.

[0053] FIG. 26 illustrates total and reversing heat flow signals observed via DSC analysis of analysis of flecainide acetate spray dried powder Batch N.

[0054] FIG. 27 shows aerodynamic particle size distribution for T=0M (0 month) powders tested in RS01 medium flow resistance (0.10R) and 50 mg capsule powder mass. Mean of three replicates with standard deviation.

[0055] FIG. 28 shows aerodynamic particle size distribution for T=0M powders tested in RS01 high flow resistance (0.16R) and 50 mg capsule powder mass. Mean of three replicates with standard deviation. [0056] FIG. 29 shows aerodynamic particle size distribution for T=1M (1 month) powders tested in RS01 medium flow resistance (0.10R) and 50 mg capsule powder fill mass. Mean of three replicates with standard deviation.

[0057] FIG. 30 shows aerosol clearance volume by laser photometry for powder batch Lot B (T=0M) using two different flow resistance inhaler devices and tested at 2 kPa (n=3); 0.10R (Left) and 0.16R (Right).

[0058] FIG. 31 shows aerosol clearance volume by laser photometry for powder batch Lot D (T=0M) using two different flow resistance inhaler devices and tested at 2 kPa (n=3); 0.10R (Left) and 0.16R (Right).

[0059] FIG. 32 shows aerosol clearance volume by laser photometry for powder batch Lot B (T=0M) using two different flow resistance inhaler devices and tested at 4 kPa (n=3); 0.10R (Left) and 0.16R (Right).

[0060] FIG. 33 shows aerosol clearance volume by laser photometry for powder lot Lot D (T=0M) using two different flow resistance inhaler devices and tested at 4 kPa (n=3); 0.1 OR (Left) and 0.16R (Right).

[0061] FIG. 34 is an APSD cumulative plot for T=0M two powder batches (Lot B & Lot D) and evaluated in two flow resistance devices (0.10 and 0.16R) at 4 kPa pressure drop. Mean of 3 replicates and standard deviation.

[0062] FIG. 35 is an APSD cumulative plot for T=0M and T=1M for powder lots (Lot A, Lot B, & Lot D) tested with medium flow resistance device (0.10R) at 4 kPa pressure drop. Mean of 3 replicates and standard deviation.

[0063] FIG. 36 is a drug mass distribution plot comparing T=0M and T=1M for powder batch (Lot A) tested with medium flow resistance device (0.1 OR) at 4 kPa pressure drop. Mean of 3 replicates with standard deviation.

[0064] FIG. 37 is a drug mass distribution plot comparing T=0M and T=1M for powder batch (Lot B) tested with medium flow resistance device (0.10R) at 4 kPa pressure drop. Mean of 3 replicates with standard deviation.

[0065] FIG. 38 is a drug mass distribution plot comparing T=0M and T=1M for powder batch (Lot D) tested with medium flow resistance device (0.1 OR) at 4 kPa pressure drop. Mean of 3 replicates with standard deviation.

DETAILED DESCRIPTION

[0066] In some aspects, the present disclosure relates to a novel inhalable dry powder formulation comprising a therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof and a cyclodextrin for treatment of a heart condition (e.g., cardiac arrhythmic) in a subject in need thereof. In some aspects, provided herein are methods of treatment comprising administering a novel formulation comprising a therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof and a cyclodextrin for treatment of a heart condition (e.g., cardiac arrhythmic) in a subject in need thereof. In some embodiments, the pharmaceutical composition is inhalable when delivered via a dry powder inhaler for the treatment of a heart condition e.g., atrial fibrillation (AF)) in a subject in need thereof.

PMARMACEUTICAL COMPOSITION

[0067] In some embodiments, the pharmaceutical composition and the method of treatment provided herein are advantageous in offering a fast, efficient, and safe therapeutic solution to heart conditions, such as cardiac arrhythmia, including atrial arrhythmia. In some embodiments, the present disclosure relates to inhalational administration of a pharmaceutical composition in the form of an inhalable dry powder that comprises flecainide or pharmaceutically acceptable salt thereof and a cyclodextrin or pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the pharmaceutical composition or formulation provided herein enables delivery of a greater quantity of pharmaceutically active ingredient, e.g., flecainide, to the subject. In some embodiments, the subject pharmaceutical composition or formulation has an increased weight ratio of flecainide or pharmaceutically acceptable salt thereof to cyclodextrin as compared to a corresponding flecainide formulation (e.g., flecainide to cyclodextrin weight ratio of 50/50 compared to a weight ratio of 20/80). In some cases, the increased weight ratio of flecainide or pharmaceutically acceptable salt thereof increases the amount of flecainide administered via inhalation. In some embodiments, the increased flecainide weight ratio to cyclodextrin shortens the inhalation duration as a given dose can be delivered at a higher speed as compared to a corresponding formulation with a lower weight of flecainide to cyclodextrin. Shortening the period of time required for a subject to completely inhale a target dose can improve subject compliance, which can further increase the delivery efficiency of the drug. In some embodiments, the pharmaceutical composition or formulation provided herein reduces adverse cough of the subject while inhaling, has improved organoleptic properties, and improves overall patient experience of inhalation. In some embodiments, the improved overall inhalation experience results in better compliance with the full inhalation program. In some embodiments, more effective drug delivery is achieved when the subject has better inhalation compliance, and thus more drug is delivered.

[0069] In one aspect of the present disclosure, provided herein is a unit dose of a pharmaceutical composition provided herein. In some embodiments, the unit dose comprises about 50 mg to about 350 mg of the salt of flecainide. In another aspect, provided herein are kits comprising the pharmaceutical composition or the unit dose provided herein and instructions for use of the pharmaceutical composition for treatment of a heart condition (e.g., cardiac arrhythmia, e.g., atrial arrhythmia).

FLECAINIDE

[0070] In some aspects of the present disclosure, the pharmaceutical composition comprises a anti arrhythmic pharmaceutical agent. In some embodiments, the anti arrhythmic pharmaceutical agent is flecainide or therapeutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of flecainide is flecainide acetate. In some embodiments, the anti arrhythmic pharmaceutical agent is a flecainide derivative (e.g., QX-FL, NU-FL) or pharmaceutically acceptable salt thereof. Flecainide is N-(piperidin-2-ylmethyl)-2,5-bis(2,2,2- trifluoroethoxy)benzamide, which has the structure:

CYCLODEXTRIN

[0071] In some aspects of the present disclosure, a cyclodextrin is used as a solubility enhancer of a flecainide salt. Cyclodextrins are cyclic carbohydrates derived from starch. The unmodified cyclodextrins differ by the number of glucopyranose units joined together in the cylindrical structure. The parent cyclodextrins contain 6, 7, or 8 glucopyranose units and are referred to as a- , P-, and y-cyclodextrin respectively. Each cyclodextrin subunit can have secondary hydroxyl groups at the 2 and 3 positions and a primary hydroxyl group at the 6-position. The cyclodextrins can be pictured as hollow truncated cones with hydrophilic exterior surfaces and hydrophobic interior cavities. In aqueous solutions, these hydrophobic cavities can sequester hydrophobic organic compounds that can fit all or part of their structure into these cavities. This process, known as inclusion complexation, can result in increased apparent aqueous solubility and stability for the complexed drug.

[0072] Non-limiting examples of a cyclodextrin suitable for inclusion in a pharmaceutical composition provided herein can include a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, derivatized a-cyclodextrins, derivatized P-cyclodextrins, and derivatized y-cyclodextrins. Nonlimiting examples of a cyclodextrin that can be used in the subject pharmaceutical composition include a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, hydroxypropyl-P-cyclodextrin, hydroxyethyl-P-cyclodextrin, hydroxypropyl -y-cyclodextrin, hydroxyethyl-y-cyclodextrin, dihydroxypropyl-P-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-P-cyclodextrin, diglucosyl-P- cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-P-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-P-cyclodextrin, maltotriosyl-y-cyclodextrin dimaltosyl-P-cyclodextrin, succinyl-P- cyclodextrin, 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-P-cyclodextrin, sulfobutylether-P- cyclodextrin, sulfobutylether-y-cyclodextrin, sulfoalkylether-P-cyclodextrin, and sulfoalkylether- y-cyclodextrin. In some embodiments, the pharmaceutical composition comprises hydroxypropyl- P-cyclodextrin (HPpCD). In some embodiments, the pharmaceutical composition comprises more than one species of cyclodextrin, such as, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more different species of cyclodextrin. In some embodiments, the pharmaceutical composition comprises HPpCD and one or more other cyclodextrins, such as, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more other different species of cyclodextrin. In some cases, the cyclodextrin is selected from the group consisting of: a- cyclodextrin, P-cyclodextrin, y-cyclodextrin, derivatized a-cyclodextrins, derivatized P- cyclodextrins, and derivatized y-cyclodextrins. In some cases, the cyclodextrin is selected from the group consisting of: a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, hydroxypropyl-P- cyclodextrin, hydroxyethyl-P-cyclodextrin, hydroxypropyl-y-cyclodextrin, hydroxyethyl-y- cyclodextrin, dihydroxypropyl-P-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-P-cyclodextrin, diglucosyl-P-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-P-cyclodextrin, maltosyl-y- cyclodextrin, maltotriosyl-P-cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-P-cyclodextrin, succinyl-P-cyclodextrin, 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-P-cyclodextrin, sulfobutylether-P-cyclodextrin, sulfobutylether-y-cyclodextrin, sulfoalkylether-P-cyclodextrin, and sulfoalkyl ether-y-cy cl odextrin .

[0073] In some embodiments, the concentration of the cyclodextrin contributes to the viscosity of the solution, which can reduce the nebulization efficiency (or rate) of the solution. For instance, in some cases, the higher the concentration of the cyclodextrin is, the higher viscosity of the solution is. In some cases, the concentration of the cyclodextrin in the pharmaceutical composition is controlled so that the viscosity of the solution is not higher than a reference value, such as about 1.0, 1.1, 1.2, 1.3 cP, 1.4 cP, 1.5 cP, 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, 2.0, 2.1 cP, 2.2 cP, 2.3 cP, 2.4 cP, 2.5 cP, 2.6 cP, 2.7 cP, 2.8 cP, 2.9 cP, 3.0 cP, 3.1 cP, 3.2 cP, 3.3 cP, 3.4 cP, 3.5 cP, 3.6 cP, 3.7 cP, 3.8 cP, 3.9 cP, 4.0 cP, 4.1 cP, 4.2 cP, 4.3 cP, 4.4 cP, 4.5 cP, 4.6 cP, 4.7 cP, 4.8 cP, 4.9 cP, 5.0 cP, 6.0 cP, 7.0 cP, 8.0 cP, 9.0 cP, 10.0 cP. In some cases, the concentration of the cyclodextrin in the pharmaceutical composition is at most about 2%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, 20.5%,

21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 31%, 32%, 33%, 34%, 35%, 38%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% (w/v) of the solution. [0074] In some embodiments, the pharmaceutical compositions described herein comprises a therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof and a cyclodextrin in weight ratio from about 5:95 to about 95:5. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 15:85 to about 95:5. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 25:75 to about 95:5. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 35:65 to about 95:5. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 45:55 to about 95:5. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 55:45 to about 95:5. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 65:35 to about 95:5. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 75:25 to about 95:5. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 85: 15 to about 95:5. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 5:95 to about 85: 15. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 5:95 to about 75:25. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 5:95 to about 65:35. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 5:95 to about 55:45. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 5:95 to about 45:55. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 5:95 to about 35:65. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 5:95 to about 25:75. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 5:95 to about 15:85. In some embodiments, flecainide or a pharmaceutically acceptable salt thereof and the cyclodextrin is in a weight ratio about 5:95, about 15:85, about 25:75, about 35:65, about 45:55, about 55:45, about 65:35, about 75:25, about 85: 15, or about 95:5.

[0075] Without wishing to be bound by a certain theory, the presence of a cyclodextrin in the pharmaceutical composition can reduce the concentration of acid that is required to achieve a desirable concentration of flecainide salt according to some aspects of the present disclosure. In some embodiments, the presence of a cyclodextrin (e.g., HPpCD) increases flecainide solubility, e.g., through inclusion complexation that “dissolves” flecainide salt (e.g., flecainide acetate) inside the cavity of the cyclodextrin. The inclusion complexation, on the other hand, can decopule the solubility of flecainide and the acidicity (the low pH) of the solution. As a result, the introduction of cyclodextrin (e.g., HPpCD) can lead to reduction in the concentration of acid necessary to maintain sufficient flecainide solubility, and can synergistically lead to increased flecainide concentration in the solution, improved organoleptic properties, increased delivery speed, and improved delivery efficiency.

ACIDS

[0076] Some aspects of the present disclosure relate to use of one or more acids in the pharmaceutical composition. In some cases, the acid enhances solubility of flecainide. In some cases, flecainide freebase has a low solubility, e.g., in water. In some cases, certain salts of flecainide have higher solubility as compared to other salts of flecainide and flecainide freebase. For instance, flecainide acetate can have a higher solubility as compared to some other flecainide salts. Without wishing to be bound to a certain theory, in some cases, the acid is provided in the pharmaceutical composition to provide the proton and anion for flecainide salt formation. In some cases, acid is provided in the pharmaceutical composition to lower pH to promote solubility of the flecainide salt. In some cases, acid is provided in the pharmaceutical composition to provide the proton and anion for flecainide salt formation and sufficiently lower pH to ensure the solubility of the flecainide salt.

[0077] In some cases, a mixture of more than one acid increases flecainide solubility as compared to a single acid. In some instances, the pharmaceutical composition comprises acetic acid as the single acid. In some instances, the pharmaceutical composition comprises citric acid as the single acid. In some cases, the pharmaceutical composition comprises a mixture of different acids. In some cases, the pharmaceutical composition comprises lactic acid. In some cases, the pharmaceutical composition comprises L-(+)-lactic acid. In some cases, the pharmaceutical composition comprises D-(-)-lactic acid. In some cases, the pharmaceutical composition comprises a mixture of D-(-)-lactic acid and L-(+)-lactic acid, i.e., the pharmaceutical composition comprises DL-lactic acid. In some cases, there are equal amounts of D-(-)-lactic acid and L-(+)-lactic acid in the pharmaceutical composition. In some cases, the pharmaceutical composition comprises ascorbic acid. Non-limiting examples of the acids that can be used in the subject pharmaceutical compositions and methods of treatment include any suitable organic or inorganic acid, such as any GRAS (Generally Recognized As Safe) listed acid, e.g., acetic acid, aconitic acid, adipic acid, alginic acid, benzoic acid, caprylic acid, citric acid, cholic acid, formic acid, lactic acid (e.g., D-(- )-lactic acid or L-(+)-lactic acid), linoleic acid, malic acid, maleic acid, propionic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid, glutamic acid, hydrochloric acid, phosphoric acid, ascorbic acid, erythorbic acid, sorbic acid, or thiodipropionic acid, or any other acid that is not listed in GRAS but is pharmaceutically acceptable in the subject pharmaceutical composition. [0078] In some cases, the pharmaceutical composition comprises a mixture of different acids, such as 2, 3, 4, 5, 6, 7, 8, 9, 10 or more different acids. In some cases, the pharmaceutical composition comprises one of the following: acetic acid and nitric acid; acetic acid and sulfuric acid; acetic acid and citric acid; acetic acid, nitric acid, and sulfuric acid; acetic acid, nitric acid, and citric acid; acetic acid, citric acid, and sulfuric acid; or acetic acid, nitric acid, citric acid, and sulfuric acid.

[0079] In some embodiments, the dry powder pharmaceutical composition is reconstituted in water. The process of reconstitution can involve dissolving the pharmaceutical composition described herein with high purity water, for instance, MilliQ water. In some embodiments, 120 mg of dry powder pharmaceutical composition described herein is dissolved in 3 mL of water. In some embodiments, the pharmaceutical composition has a reconstituted pH that is about 5.0 to about 8.0 when the pH is measured at room temperature, such as about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5,9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8.0 when the pH is measured at room temperature and at a concentration of about 9 mg/mL to about 10 mg/mL. In some cases, the pharmaceutical composition is acidic when reconstituted, e.g., having a pH at most from about at least 5.0 to about at most 8.0. In some embodiments, the pH of the pharmaceutical composition when reconstituted is at most 5.0, at most 5.1, at most 5.2, at most 5.3, at most 5.4. at most 5.5, at most 5.5, at most 5.6, at most 5.7, at most 5.8, at most 6.0, at most

6.1, at most 6.2, at most 6.3, at most 6.4, at most 6.5, at most 6.6, at most 6.7, at most 6.8, at most

6.9, at most 7.0, at most 7.1, at most 7.2, at most 7.3, at most 7.4, at most 7.5, at most 7.6, at most

7.7, at most 7.8, at most 7.9, or at most 8.0 when the pH is measured at room temperature and at a concentration of about 9 mg/mL to about 10 mg/mL. In some cases, the pharmaceutical composition has a pH that is from about 5.5 and about 6.5 when the pH is measured at room temperature, such as from about 5.6 and about 6.4, from about 5.7 and about 6.3, from about 5.8 and about 6.2, or from about 5.9 and about 6.1 when the pH is measured at room temperature and flecainide acetate at a concentration of about 9 mg/mL to about 10 mg/mL. In some instances, the pharmaceutical composition has a reconstituted pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 7.0, or 8.0 when the pH is measured at room temperature and at a concentration of about 9 mg/mL to about 10 mg/mL. In some examples, the pharmaceutical composition has a reconstituted pH of about 7.4 when the pH is measured at room temperature and at a concentration of about 9 mg/mL to about 10 mg/mL. [0080] Solutions can also comprise a buffer or a pH adjusting agent, typically a salt prepared from an organic acid or base. Representative buffers comprise organic acid salts of citric acid, lactic acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride, or phosphate buffers. Thus, the buffers can include citrates, phosphates, phthalates, and lactates. Examples of buffers include, but are not limited to, acetate, tris, or citrate. Examples of acids include, but are not limited to, carboxylic acids. Examples of salts include, but are not limited to, sodium chloride, salts of carboxylic acids, (e.g., sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride), ammonium carbonate, ammonium acetate, ammonium chloride, and the like. Examples of organic solids include, but are not limited to, camphor, and the like. The pharmaceutical composition of one or more embodiments of the present disclosure can also include a biocompatible, such as biodegradable polymer, copolymer, or blend or other combination thereof. In this respect useful polymers comprise polylactides, polylactide-glycolides, cyclodextrins, polyacrylates, methylcellulose, carboxymethylcellulose, polyvinyl alcohols, polyanhydrides, polylactams, polyvinyl pyrrolidones, polysaccharides (dextrans, starches, chitin, chitosan), hyaluronic acid, proteins, (albumin, collagen, gelatin). Those skilled in the art will appreciate that, by selecting the appropriate polymers, the delivery efficiency of the composition and/or the stability of the dispersions can be tailored to optimize the effectiveness of the anti arrhythmic pharmaceutical agent(s).

PHARMACEUTICALLY ACCEPTABALE EXCIPIENTS

[0081] In one aspect, provided herein are formulations for treatment of a heart condition, e.g., cardiac arrhythmia, e.g., atrial arrhythmia. The formulations can include the pharmaceutical compositions provided herein and a pharmaceutically acceptable carrier, excipient, diluent, or any other suitable component for the intended administration routes, such as oral or nasal inhalation. Examples of pharmaceutically acceptable excipients include, but are not limited to, lipids, metal ions, surfactants, amino acids, carbohydrates, buffers, salts, polymers, sweeteners, and the like, and combinations thereof.

[0082] Examples of carbohydrates include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. For example, monosaccharides such as dextrose (anhydrous and monohydrate), galactose, mannitol, D-mannose, sorbitol, sorbose and the like; disaccharides such as lactose, maltose, sucrose, trehalose, and the like; trisaccharides such as raffinose and the like; and other carbohydrates such as starches (hydroxy ethyl starch), and maltodextrins.

[0083] Non-limiting examples of lipids include phospholipids, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids bearing polymer chains such as polyethylene glycol, chitin, hyaluronic acid, or polyvinylpyrrolidone; lipids bearing sulfonated mono-, di-, and polysaccharides; fatty acids such as palmitic acid, stearic acid, and oleic acid; cholesterol, cholesterol esters, and cholesterol hemisuccinate.

[0084] In some cases, the phospholipid comprises a saturated phospholipid, such as one or more phosphatidylcholines. Exemplary acyl chain lengths are 16:0 and 18:0 e.g., palmitoyl and stearoyl). The phospholipid content can be determined by the active agent activity, the mode of delivery, and other factors.

[0085] Phospholipids from both natural and synthetic sources can be used in varying amounts. When phospholipids are present, the amount is typically sufficient to coat the active agent(s) with at least a single molecular layer of phospholipid. In general, the phospholipid content ranges from about 5 wt% to about 99.9 wt%, such as about 20 wt% to about 80 wt%.

[0086] Generally, compatible phospholipids can comprise those that have a gel to liquid crystal phase transition greater than about 40 °C, such as greater than about 60 °C, or greater than about 80 °C. The incorporated phospholipids can be relatively long chain (e.g., C16-C22) saturated lipids. Exemplary phospholipids useful in the present disclosure include, but are not limited to, phosphoglycerides such as dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidyl glycerols, short-chain phosphatidylcholines, hydrogenated phosphatidylcholine, E-100-3 (available from Lipoid KG, Ludwigshafen, Germany), long-chain saturated phosphatidylethanolamines, long- chain saturated phosphatidylserines, long-chain saturated phosphatidylglycerols, long-chain saturated phosphatidylinositols, phosphatidic acid, phosphatidylinositol, and sphingomyelin.

[0087] Examples of metal ions include, but are not limited to, divalent cations, including calcium, magnesium, zinc, iron, and the like. For instance, when phospholipids are used, the pharmaceutical composition can also comprise a polyvalent cation, as disclosed in WO 01/85136 and WO 01/85137, which are incorporated herein by reference in their entireties. The polyvalent cation can be present in an amount effective to increase the melting temperature (T _m ) of the phospholipid such that the pharmaceutical composition exhibits a T _m which is greater than its storage temperature (T _m ) by at least about 20 °C, such as at least about 40 °C. The molar ratio of polyvalent cation to phospholipid can be at least about 0.05: 1, such as about 0.05: 1 to about 2.0: 1 or about 0.25: 1 to about 1.0: 1. In some embodiments, the molar ratio of polyvalent cation to phospholipid is about 0.50: 1. When the polyvalent cation is calcium, it can be in the form of calcium chloride. Although metal ion (e.g., calcium) is often included with phospholipid, none is required.

[0088] The pharmaceutical composition can include one or more surfactants. For instance, one or more surfactants can be in the liquid phase with one or more being associated with solid particles or particles of the composition. By “associated with” it is meant that the pharmaceutical compositions can incorporate, adsorb, absorb, be coated with, or be formed by the surfactant. Surfactants include, but are not limited to, fluorinated and nonfluorinated compounds, such as saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants, and combinations thereof. It should be emphasized that, in addition to the aforementioned surfactants, suitable fluorinated surfactants are compatible with the teachings herein and can be used to provide the desired preparations.

[0089] Examples of nonionic detergents include, but are not limited to, sorbitan esters including sorbitan trioleate (Span™ 85), sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, and polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, glycerol esters, and sucrose esters. Other suitable nonionic detergents can be easily identified using McCutcheon’s Emulsifiers and Detergents (McPublishing Co., Glen Rock, N.J.), which is incorporated herein by reference in its entirety.

[0090] Examples of block copolymers include, but are not limited to, diblock and triblock copolymers of polyoxyethylene and poly oxypropylene, including pol oxamer 188 (Pluronic™ F- 68), poloxamer 407 (Pluronic™ F-127), and poloxamer 338. Examples of ionic surfactants include, but are not limited to, sodium sulfosuccinate, and fatty acid soaps. Examples of amino acids include, but are not limited to hydrophobic amino acids, for instance, L-leucin or L-isoleucin. Use of amino acids as pharmaceutically acceptable excipients is known in the art as disclosed in WO 95/31479, WO 96/32096, and WO 96/32149, which are incorporated herein by reference in their entireties.

[0091] The pharmaceutical composition according to one or more embodiments of the disclosure may, if desired, contain a combination of anti arrhythmic pharmaceutical agent (e.g., flecainide salt) and one or more additional active agents. Examples of additional active agents include, but are not limited to, agents that can be delivered through the lungs.

[0092] Additional active agents can comprise, for example, hypnotics and sedatives, psychic energizers, tranquilizers, respiratory drugs, anticonvulsants, muscle relaxants, antiparkinson agents (dopamine antagonists), analgesics, anti-inflammatories, antianxiety drugs (anxiolytics), appetite suppressants, antimigraine agents, muscle contractants, additional anti-infectives (antivirals, antifungals, vaccines) antiarthritics, antimalarials, antiemetics, antiepileptics, cytokines, growth factors, anti-cancer agents, antithrombotic agents, antihypertensives, cardiovascular drugs, antiarrhythmics, antioxidants, anti-asthma agents, hormonal agents including contraceptives, sympathomimetics, diuretics, lipid regulating agents, anti androgenic agents, antiparasitic, anticoagulants, neoplasties, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, antienteritis agents, vaccines, antibodies, diagnostic agents, and contrasting agents. The additional active agent, when administered by inhalation, can act locally or systemically.

[0093] The additional active agent can fall into one of a number of structural classes, including but not limited to small molecules, peptides, polypeptides, proteins, polysaccharides, steroids, proteins capable of eliciting physiological effects, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes, and the like.

[0094] Examples of additional active agents suitable for use in this disclosure include but are not limited to one or more of calcitonin, amphotericin B, erythropoietin (EPO), Factor VIII, Factor IX, ceredase, cerezyme, cyclosporin, granulocyte colony stimulating factor (GCSF), thrombopoietin (TPO), alpha- 1 proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin- 1 receptor, interleukin-2, interleukin- 1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, luteinizing hormone releasing hormone (LHRH), factor IX, insulin, pro-insulin, insulin analogues (e.g., mono-acylated insulin as described in U.S. Pat. No. 5,922,675, which is incorporated herein by reference in its entirety), amylin, C-peptide, somatostatin, somatostatin analogs including octreotide, vasopressin, follicle stimulating hormone (FSH), insulin-like growth factor (IGF), insulintropin, macrophage colony stimulating factor (M- CSF), nerve growth factor (NGF), tissue growth factors, keratinocyte growth factor (KGF), glial growth factor (GGF), tumor necrosis factor (TNF), endothelial growth factors, parathyroid hormone (PTH), glucagon-like peptide thymosin alpha 1, Ilb/IIa inhibitor, alpha- 1 antitrypsin, phosphodiesterase (PDE) compounds, VLA-4 inhibitors, bisphosponates, respiratory syncytial virus antibody, cystic fibrosis transmembrane regulator (CFFR) gene, deoxyribonuclease (DNase), bactericidal/permeability increasing protein (BPI), anti-CMV antibody, 13-cis retinoic acid, oleandomycin, troleandomycin, roxithromycin, clarithromycin, davercin, azithromycin, flurithromycin, dirithromycin, josamycin, spiromycin, midecamycin, leucomycin, miocamycin, rokitamycin, andazithromycin, and swinolide A; fluoroquinolones such as ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin, moxifloxicin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin, fleroxacin, tosufloxacin, prulifloxacin, irloxacin, pazufloxacin, clinafloxacin, and sitafloxacin, teicoplanin, rampolanin, mideplanin, colistin, daptomycin, gramicidin, colistimethate, polymixins such as polymixin B, capreomycin, bacitracin, penems; penicillins including penicllinase-sensitive agents like penicillin G, penicillin V, penicillinase-resistant agents like methicillin, oxacillin, cioxacillin, dicloxacillin, floxacillin, nafcillin; gram negative microorganism active agents like ampicillin, amoxicillin, and hetacillin, cillin, and galampicillin; antipseudomonal penicillins like carbenicillin, ticarcillin, azlocillin, mezlocillin, and piperacillin; cephalosporins like cefpodoxime, cefprozil, ceftbuten, ceftizoxime, ceftriaxone, cephalothin, cephapirin, cephalexin, cephradrine, cefoxitin, cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil, cephaloglycin, cefuroxime, ceforanide, cefotaxime, cefatrizine, cephacetrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan, cefinetazole, ceftazidime, loracarbef, and moxalactam, monobactams like aztreonam; and carbapenems such as imipenem, meropenem, pentamidine isethiouate, lidocaine, metaproterenol sulfate, beclomethasone diprepionate, triamcinolone acetamide, budesonide acetonide, fluticasone, ipratropium bromide, flunisolide, cromolyn sodium, ergotamine tartrate and where applicable, analogues, agonists, antagonists, inhibitors, and pharmaceutically acceptable salt forms of the above. In reference to peptides and proteins, the disclosure is intended to encompass synthetic, native, glycosylated, unglycosylated, pegylated forms, and biologically active fragments, derivatives, and analogs thereof.

[0095] Additional active agents for use in the disclosure can further include nucleic acids, as bare nucleic acid molecules, vectors, associated viral particles, plasmid DNA or RNA or other nucleic acid constructions of a type suitable for transfection or transformation of cells, e.g., suitable for gene therapy including antisense. Further, an active agent can comprise live attenuated or killed viruses suitable for use as vaccines. Other useful drugs include those listed within the Physician’s Desk Reference (most recent edition), which is incorporated herein by reference in its entirety.

[0096] When a combination of active agents is used, the agents can be provided in combination in a single species of pharmaceutical composition or individually in separate species of pharmaceutical compositions.

[0097] The pharmaceutical compositions of one or more embodiments of the present disclosure can lack taste. In this regard, although taste masking agents are optionally included within the composition, the compositions in some embodiments do not include a taste masking agent other than a cyclodextrin and lack taste even without a taste masking agent.

[0098] In some embodiments, the pharmaceutical composition provided herein comprises a sweetener to improve the organoleptic properties of the composition. The sweetener can be a natural sweet substance, e.g. certain sugars, or an artificial sweetener. Without wishing to be bound to a certain theory, the presence of the sweetener in the pharmaceutical composition can improve the organoleptic properties of the composition. In some cases, the presence of the sweetener in the pharmaceutical composition can improve the compliance of the subject. In some embodiments, presence of the sweetener in the pharmaceutical composition increases the delivery efficiency of the composition. In some embodiments, the presence of the sweetener in the pharmaceutical composition can enhance the therapeutic effects of the composition. [0099] Non-limiting examples of artificial sweeteners that can be used in the pharmaceutical composition include acesulfame potassium, aspartame, cyclamate, mogrosides, saccharin, stevia, sucralose, neotame, and sugar alcohols (e.g., erythritol, hydrogenated starch hydrolysates, isomalt, lactitol, maltitol, mannitol, sorbitol, and xylitol), such as those used in commercial products, like Sweet n’ low powder sweetener, Truvia powder sweetener, Equal (aspartame), Stevia powder sachet, Aspen Naturals liquid stevia, Now Better Stevia liquid sweetener, Sweet N’ Low liquid sweetener, Quick Sweet: Neotame liquid sweetener, or Splenda powder sachet, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition comprises saccharin. In some embodiments, the pharmaceutical composition comprises a salt of saccharin. In some embodiments, the pharmaceutical composition comprises saccharin sodium.

[0100] Natural sweet substances that can be used in the pharmaceutical composition include, but are not limited to, sucrose, agave, brown sugar, confectioner’s (powdered) sugar, com syrup, dextrose, fructose, fruit juice concentrate, glucose, high-fructose corn syrup, honey, invert sugar, lactose, malt sugar, maltose, maple syrup, molasses, nectars, raw sugar, and syrup. Sugars can increase the viscosity of the liquid solution, thus the concentration of any sugar added into the pharmaceutical composition, in some embodiments, is tightly controlled below a certain threshold value.

[0101] In some embodiments, pharmaceutically acceptable excipient or carrier comprises lactose, mannitol, sorbitol, erythritol, raffinose, sucrose, xylitol, trehalose, dextrose, cyclodextrins, maltitol, maltose, glucose, hydroxyapatite, or any combinations thereof.

[0102] Besides the above mentioned pharmaceutically acceptable excipients, it can be desirable to add other pharmaceutically acceptable excipients to the pharmaceutical composition to improve particle rigidity, production yield, emitted dose and deposition, shelf-life, and patient acceptance. Such optional pharmaceutically acceptable excipients include, but are not limited to: coloring agents, taste masking agents, buffers, hygroscopic agents, antioxidants, and chemical stabilizers. Further, various pharmaceutically acceptable excipients can be used to provide structure and form to the particle compositions (e.g., latex particles). In this regard, it will be appreciated that the rigidifying components can be removed using a post-production technique such as selective solvent extraction.

[0103] In some embodiments, the pharmaceutical composition comprises crystallization inhibitors. Exemplary pharmaceutically acceptable crystallization inhibitors can be, but are not limited to, polymers, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polysaccharide, hydroxypropyl methylcellulose (HPMC or Hypromellose), hydroxyethyl cellulose (ELEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl-P-cyclodextrin (HP-P-CD), sulfobutylether-P-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMC-AS- HF), or polyethylene glycol (PEG).

DRY POWDER

PARTICLES

[0104] The distribution of aerosol particle of an inhalable can be expressed in terms of either: the mass median aerodynamic diameter (MMAD) — the size at which half of the mass of the aerosol is contained in smaller droplets and half in larger droplets; volumetric mean diameter (VMD); mass median diameter (MMD); the fine particle fraction (FPF) — the percentage of particles that are <5 um in diameter. These measures have been used for comparisons of the in vitro performance of different inhaler device and drug combinations. In general, the higher the fine particle fraction, the higher the proportion of the emitted dose that is likely to deposit the lung. Generally, inhaled particles are subject to deposition by one of two mechanisms: impaction, which usually predominates for larger particles, and sedimentation, which is prevalent for smaller particles. Impaction occurs when the momentum of an inhaled particle is large enough that the particle does not follow the air stream and encounters a physiological surface. In contrast, sedimentation occurs primarily in the deep lung when very small particles which have traveled with the inhaled air stream encounter physiological surfaces as a result of random diffusion within the air stream. For pulmonary administration, the upper airways are avoided in favor of the middle and lower airways. Pulmonary drug delivery can be accomplished by inhalation of an aerosol through the mouth and throat. Particles having a mass median aerodynamic diameter (MMAD) of greater than about 5 microns generally do not reach the lung; instead, they tend to impact the back of the throat and are swallowed and possibly orally absorbed. Particles having diameters of about 1 to about 5 microns are small enough to reach the upper-to-mid-pulmonary region (conducting airways), but are too large to reach the alveoli. Smaller particles, z.e., about 0.5 to about 2 microns, are capable of reaching the alveolar region. Particles having diameters smaller than about 0.5 microns can also be deposited in the alveolar region by sedimentation, although very small particles can be exhaled. Measures of particle size can be referred to as volumetric mean diameter (VMD), mass median diameter (MMD), or MMAD. These measurements can be made by impaction (MMD and MMAD) or by laser (VMD). Inhalable dry powder particle size can be expressed in terms of the mass median aerodynamic diameter (MMAD). Large particles (e.g., MMAD-5 um) can deposit in the upper airway because they are too large to navigate the curvature of the upper airway. Small particles (e.g., MMAD-2 um) can be poorly deposited in the lower airways and thus become exhaled, providing additional opportunity for upper airway deposition. Hence, intolerability (e.g., cough and bronchospasm) can occur from upper airway deposition from both inhalation impaction of large particles and settling of small particles during repeated inhalation and expiration.

[0105] In some embodiments, described herein, the geometric particle size distribution measurement of the dry powder pharmaceutical composition is characterized through standard methods such as cascade impaction, dynamic image analysis, static image analysis, laser diffraction, dynamic light scattering, sieve analysis, microscopic imaging (/.< ., optical microscopy, electron microscopy) to obtain average particle size, MMAD, VMD, FPF, and MMD. In some embodiments, the preferable method of geometric particle size characterization is laser diffraction. In some embodiments, the MMD values are determined by laser diffraction. In some embodiments, the dry powders samples are added directly to the feeder funnel of the dry powder dispersion unit and are dispersed to primary particles via application of pressurized air (2 to 3 bar), with vacuum depression (suction) maximized for a given dispersion pressure. Dispersed particles are probed with a 632.8 nm laser beam that intersects the dispersed particles’ trajectory at right angles. Laser light scattered from the ensemble of particles is imaged onto a concentric array of photomultiplier detector elements using a reverse-Fourier lens assembly. Scattered light is acquired in time-slices of 5 ms. Particle size distributions are back-calculated from the scattered light spatial/intensity distribution using a proprietary algorithm.

[0106] Thus, in one embodiment, an optimum particle size is used e.g., MMAD=2-5 um) in order to maximize deposition at a mid-lung and to minimize intolerability associated with upper airway deposition. Moreover, generation of a defined particle size with limited geometric standard deviation (GSD) can optimize deposition and tolerability. Narrow GSD limits the number of particles outside the desired MMAD size range. In one embodiment, an aerosol containing one or more compounds disclosed herein is provided having a MMAD from about 2 microns to about 5 microns with a GSD of less than or equal to about 2.5. In another embodiment, an aerosol having an MMAD from about 2.8 microns to about 4.3 microns with a GSD less than or equal to 2 is provided. In another embodiment, an aerosol having an MMAD from about 2.5 microns to about 4.5 microns with a GSD less than or equal to 1.8 is provided.

DRY POWDER INHALER

[0107] Dry powders can use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substance effectively. Dry powder inhaler devices can use a variety of dosage containers (e.g., capsule, blister pack, blister strip, reservoir, cartridge).

[0108] A desired particle size and distribution can be obtained by choosing an appropriate device. For dry powders, the moisture content is typically less than about 15 wt %, such as less than about 10 wt %, less than about 5 wt %, less than about 2 wt %, less than about 1 wt %, or less than about 0.5 wt %. Such powders are described in WO95/24183, WO 96/32149, WO 99/16419, WO 99/16420, and WO 99/16422, which are incorporated herein by reference in their entireties.

[0109] Efficient drug delivery to the lungs through dry powder inhalers (DPIs) is dependent on several factors including inhaler device, formulation, and inhalation maneuver. Preparing ideal DPI formulations requires control overall formulation characteristics at particulate and bulk level to ensure the drug delivery to lower airway regions. In DPI formulations, it is customary to blend micronized drug particles (less than 5 micron in size) with larger carrier particles to address flowability and dose variability issues. The typical concentration of drug in drug-carrier DPI formulations is low (e.g., 1 drug.: 67.5 carrier), but can vary depending on the aerosol dispersion properties of the formulation. Therefore, during drug-carrier mixing, drug particles will preferably adhere to the active binding sites (more adhesive areas) on the carrier surface and expected to separate from carrier surface upon inhalation. Drug re-dispersion is considered most important for getting drug particles into deep lung airway regions. Usually, only small amounts of drug reaches the lower airway regions due to strong drug-carrier adhesion. Indeed, drug re-dispersion is a function of balance between cohesive forces (between the drug particles) and the adhesive forces (between drug and carrier particles). In order to aerosolize drug particles, patient inspiratory force should overcome drug-carrier adhesive forces which are dependent on physicochemical properties of both drug particles and carrier particles. Consequently, it can be desirable to control the characteristics of carrier particles in terms of size, morphology, crystal form, surface energy. It has been reported that the differences in carrier particle size is likely to have significant impact on DPI aerosolization performance. The presence of fine particles on carrier surface can decrease the drugcarrier contact area and consequently drug-carrier adhesion forces leading to improved DPI performance. Better aerosolization performance was observed when the carrier tap density was higher, whereas no correlation was found between carrier flowability and DPI performance. Carriers with reduced dispersive surface energy produced higher fine particle fraction (FPF) of the drug upon aerosolization. Carrier particles with higher elongation ratio or increased surface roughness showed favorable inhalation properties.

PREPARATIONS

[0110] In some aspects, the present disclosure provides a method of preparing an inhalable dry powder pharmaceutical composition that comprises an anti arrhythmic pharmaceutical agent and cyclodextrin.

[oni] In some embodiments, flecainide or pharmaceutically acceptable salt is dissolved in water thereby resulting in a flecainide solution. In some embodiments, the flecainide solution further comprises an acid. In some embodiments, the acid is glacial acetic acid. In some embodiments, the flecainide solution or flecainide solution with acid further comprises cyclodextrin. In some embodiments, the cyclodextrin is hydroxypropyl-P-cyclodextrin. In some embodiments, the flecainide/cyclodextrin solution or flecainide/cyclodextrin/acid solution is heated to 40 °C. The steps above are not limited to any specific order. In some embodiments, the heated flecainide/cyclodextrin solution or flecainide/cyclodextrin/acid solution is further cooled to 25 °C. In some embodiments, the flecainide/cyclodextrin solution or flecainide/cyclodextrin/acid solution is not heated. In some embodiments, the pH of the flecainide/cyclodextrin solution or flecainide/cyclodextrin/acid solution is adjusted using a pH adjusting agent, thereby resulting in the pharmaceutical composition solution. In some embodiments, the pH adjusting agent is acetic acid. In some embodiments, the pH adjusting agent is sodium hydroxide. In some embodiments, the pH adjusting agent is both acetic acid and sodium hydroxide. In some embodiments, the pH is adjusted to about 5.8 to about 6.0. In some embodiments, the pharmaceutical composition solution is spray-dried, thereby resulting in the inhalable dry powder pharmaceutical composition. In some embodiments, the pharmaceutical composition is diluted using water. In some embodiments, the pharmaceutical composition is diluted with water to form a 24.5 wt/wt% solution before the manufacturing process for inhalable dry powder pharmaceutical composition. In some embodiments, the pharmaceutical composition is diluted with water to form a 4 wt/wt% solution before the manufacturing process for inhalable dry powder pharmaceutical composition. In some embodiments, the pharmaceutical composition described herein is formulated into a dry powder form through methods such as, but not limited to, microfabrication, rapid expansion templating, supercritical fluid, lithography, antisolvent particle formation (e.g., liquid antisolvent, vapor antisolvent), spray drying, spray-freeze drying, jet milling, bead milling, ball milling, pearl milling, or high-pressure homogenization.

[0112] For dry powders, the composition can be formed by spray drying, spray-freeze-drying, aerosol flow reactor method, lyophilization, milling (e.g., wet milling, dry milling), and the like. In methods involving rapid freezing of the pharmaceutical composition liquid during the process of spray can lead to sublimation of frozen water and leading to the dry powder particles. In methods involving flow reactors, the aerosolized formulation create nucleation points for growth and the particle size can be tuned based on carrier gas and flow rate. In aerosol flow reactor method of manufacturing, the process involves first dissolving the drug material (e.g., flecainide or a pharmaceuticaly acceptable salt thereof) into a suitable solvent to produce a solution, which is then followed by atomising the solution as fine droplets into carrier gas. A heated laminar flow reactor tube can be used to evaporate the solvent, and solid drug nanoparticles (e.g., dry powder particles) are formed as a result. In some embodiments, the method of producing the dry powder pharmaceutical composition disclosed herein is spray drying. [0113] In spray drying, the manufacturing process can have a variety of parameters adjusted. In some embodiments, the solution flow rate is about 4.0 g/min to about 10.0 g/min. In some embodiments, the nozzle is 2-fluid (Sprays System 1650LC/64AC), airless atomization, pressure, rotary/disk, or ultrasonic. In some embodiments, the atomization pressure is about 20 psi to about 100 psi. In some embodiments, the atomization G/L ratio is about 4.8 to about 4.9. In some embodiments, the inlet temperature is about 80 °C to about 200 °C. In some embodiments, the outlet temperature is about 35 °C to about 150 °C. In some embodiments, the calculated relative humidity is about 5.2% to about 12.2%. In some embodiments, the in-going batch size is about 9.6 g to about 24 g. In some embodiments, the solids load are about 1% to about 10% of the entire load of material. In some embodiments, the feed temperature of the spray drying process is about 15 °C to about 75 °C.

[0114] In spray drying, the preparation to be spray dried or feed stock can be any solution, coarse suspension, slurry, or colloidal dispersion that can be atomized using the selected spray drying apparatus. In the case of insoluble agents, the feedstock can comprise a suspension as described above. Alternatively, a dilute solution and/or one or more solvents can be utilized in the feedstock. In one or more embodiments, the feed stock comprises a colloidal system such as an emulsion, reverse emulsion, microemulsion, multiple emulsion, particle dispersion, or slurry, n one version, the antiarrhythmic pharmaceutical agent and the matrix material are added to an aqueous feedstock to form a feedstock solution, suspension, or emulsion. The feedstock is then spray dried to produce dried particles comprising the matrix material and the antiarrhythmic pharmaceutical agent. Suitable spray-drying processes are known in the art, for example as disclosed in WO 99/16419 and U.S. Pat. Nos. 6,077.543; 6,051.256; 6,001,336; 5,985,248; and 5,976,574, which are incorporated herein by reference in their entireties. Whatever components are selected, the first step in particle production typically comprises feedstock preparation. If a phospholipids-based particle is intended to act as a carrier for the antiarrhythmic pharmaceutical agent, the selected active agent(s) can be introduced into a liquid, such as water, to produce a concentrated suspension. The concentration of antiarrhythmic pharmaceutical agent and optional active agents typically depends on the amount of agent required in the final powder and the performance of the delivery device employed (e.g., the fine particle dose for a dry powder inhaler (DPI)). Any additional active agent(s) can be incorporated in a single feedstock preparation and spray dried to provide a single pharmaceutical composition species comprising a plurality of active agents. Conversely, individual active agents could be added to separate stocks and spray dried separately to provide a plurality of pharmaceutical composition species with different compositions. These individual species could be added to the suspension medium or dry powder dispensing compartment in any desired proportion and placed in the aerosol delivery system. [0115] In one version, the pharmaceutical composition comprises anti arrhythmic pharmaceutical agent incorporated into a phospholipid matrix. The pharmaceutical composition can comprise phospholipid matrices that incorporate the active agent and that are in the form of particles that are hollow and/or porous microstructures, as described in the aforementioned WO 99/16419, WO 99/16420, WO 99/16422, WO01/85136, and WO 01/85137, which are incorporated herein by reference in their entireties. The hollow and/or porous microstructures are useful in delivering the anti arrhythmic pharmaceutical agent to the lungs because the density, size, and aerodynamic qualities of the hollow and/or porous microstructures facilitate transport into the deep lungs during inhalation. In addition, the phospholipid-based hollow and/or porous microstructures reduce the attraction forces between particles, making the pharmaceutical composition easier to deagglomerate during aerosolization and improving the flow properties of the pharmaceutical composition making it easier to process. In one version, the pharmaceutical composition is composed of hollow and/or porous microstructures having a bulk density less than about 1.0 g/cm, less than about 0.5 g/cm, less than about 0.3 g/cm, less than about 0.2 g/cm, or less than about 0.1 g/cm. Moreover, the elimination of carrier particles will potentially reduce throat deposition and any gag effect or coughing, since large carrier particles, e.g., lactose particles, will impact the throat and upper air ways due to their size. In some aspects, the present disclosure involves high rugosity particles. For instance, the particles can have a rugosity of greater than 2. Such as greater than 3, or greater than 4, and the rugosity can range from 2 to 15, such as 3 to 10. In one version, the pharmaceutical composition is in dry powder form and is contained within a unit dose receptacle which can be inserted into or near the aerosolization apparatus to aerosolize the unit dose of the pharmaceutical composition. This version is useful in that the dry powder form can be stably stored in its unit dose receptacle for a long period of time. In some examples, pharmaceutical compositions of one or more embodiments of the present disclosure can be stable for at least 2 years. In some versions, no refrigeration is required to obtain stability. In other versions, reduced temperatures, e.g., at 2-8 °C., can be used to prolong stable storage. It will be appreciated that the pharmaceutical compositions disclosed herein can comprise a structural matrix that exhibits, defines or comprises voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations or holes. The absolute shape (as opposed to the morphology) of the perforated microstructure is generally not critical and any overall configuration that provides the desired characteristics is contemplated as being within the scope of the disclosure. Accordingly, Some embodiments comprise approximately spherical shapes. However, collapsed, deformed or fractured particles are also compatible. In one version, the anti arrhythmic pharmaceutical agent is incorporated in a matrix that forms a discrete particle, and the pharmaceutical composition comprises a plurality of the discrete particles. The discrete particles can be sized so that they are effectively administered and/or so that they are available where needed. For example, for an aerosolizable pharmaceutical composition, the particles are of a size that allows the particles to be aerosolized and delivered to a user's respiratory tract during the user's inhalation. The matrix material can comprise a hydrophobic or a partially hydrophobic material. For example, the matrix material can comprise a lipid, such as a phospholipid, and/or a hydrophobic amino acid, such as leucine (e.g., L-leucine), isoleucine (e.g., L-isoleucine), or tri -leucine. Examples of phospholipid matrices are described in WO 99/16419, WO 99/16420, WO 99/16422, WO 01/85136, and WO 01/85137 and in U.S. Pat. Nos. 5,874,064; 5,855,913: 5,985,309; 6,503,480; and 7,473,433, and in U.S. Published App. No. 2004.0156792, all of which are incorporated herein by reference in their entireties. Examples of hydrophobic amino acid matrices are described in U.S. Pat. Nos. 6,372, 258; 6,358,530; and 7,473.433, which are incorporated herein by reference in their entireties. When phospholipids are utilized as the matrix material, the pharmaceutical composition can also comprise a polyvalent cation, as disclosed in WO 01/85136 and WO 01/85137, which are incorporated herein by reference in their entireties. According to another embodiment, release kinetics of the composition containing anti arrhythmic pharmaceutical agent(s) is controlled. According to one or more embodiments, the compositions of the present disclosure provide immediate release of the anti arrhythmic pharmaceutical agent(s). Alternatively, the compositions of other embodiments of the present disclosure can be provided as non-homogeneous mixtures of active agent incorporated into a matrix material and unincorporated active agent in order to provide desirable release rates of anti arrhythmic pharmaceutical agent. According to this embodiment, anti arrhythmic pharmaceutical agents can be formulated using the emulsion-based manufacturing process (i.e. emulsion spray drying).

[0116] In one or more embodiments of the present disclosure, a formulation described herein can have utility in immediate release applications when administered to the respiratory tract. Rapid release is facilitated by: (a) the high specific surface area of the low density porous powders; (b) the small size of the drug crystals that are incorporated therein, and; (c) the low surface energy of the particles. Alternatively, it can be desirable to engineer the particle matrix so that extended release of the active agent(s) is effected. This can be particularly desirable when the active agent(s) is rapidly cleared from the lungs or when sustained release is desired. For example, the nature of the phase behavior of phospholipid molecules is influenced by the nature of their chemical structure and/or preparation methods in spray drying feedstock and drying conditions and other composition components utilized. In the case of spray-drying of active agent(s) solubilized within a small unilamellar vesicle (SUV) or multilamellar vesicle (MLV), the active agent(s) are encapsulated within multiple bilayers and are released over an extended time. In contrast, spraydrying of a feedstock comprised of emulsion droplets and dispersed or dissolved active agent(s) in accordance with the teachings herein leads to a phospholipid matrix with less long-range order, thereby facilitating rapid release. While not being bound to any particular theory, it is believed that this is due in part to the fact that the active agent(s) are never formally encapsulated in the phospholipid, and the fact that the phospholipid is initially present on the surface of the emulsion droplets as a monolayer (not a bilayer as in the case of liposomes). The spray-dried particles prepared by the emulsion-based manufacturing process of one or more embodiments of the present disclosure often have a high degree of disorder. Also, the spray-dried particles typically have low surface energies, where values as low as 20 mN/m have been observed for spray-dried DSPC particles (determined by inverse gas chromatography). Small angle X-ray scattering (SAXS) studies conducted with spray-dried phospholipid particles have also shown a high degree of disorder for the lipid, with scattering peaks smeared out, and length scales extending in some instances only beyond a few nearest neighbors. It should be noted that a matrix having a high gel to liquid crystal phase transition temperature is not sufficient in itself to achieve sustained release of the active agent(s). Having sufficient order for the bilayer structures is also important for achieving sustained release. To facilitate rapid release, an emulsion-system of high porosity (high surface area), and minimal interaction between the drug substance and phospholipid can be used. The pharmaceutical composition formation process can also include the additions of other composition components (e.g., small polymers such as Pluronic F-68; carbohydrates, salts, hydrotropes) to break the bilayer structure are also contemplated. To achieve a sustained release, incorporation of the phospholipid in bilayer form can be used, especially if the active agents encapsulated therein. In this case increasing the temperature of the phospholipid can provide benefit via incorporation of divalent counterions or cholesterol. As well, increasing the interaction between the phospholipid and drug substance via the formation of ion-pairs (negatively charged active steaylamine, positively charged active phosphatidylglycerol) would tend to decrease the dissolution rate. If the active agent is amphiphilic, surfactant/surfactant interactions can also slow active dissolution. The addition of divalent counterions e.g., calcium or magnesium ions) to long- chain saturated phosphatidylcholines results in an interaction between the negatively charged phosphate portion of the zwitterionic headgroup and the positively charged metal ion. This results in a displacement of water of hydration and a condensation of the packing of the phospholipid lipid headgroup and acyl chains. Further, this results in an increase in the T _m of the phospholipid. The decrease in headgroup hydration can have profound effects on the spreading properties of spray-dried phospholipid particles on contact with water. A fully hydrated phosphatidylcholine molecule will diffuse very slowly to a dispersed crystal via molecular diffusion through the water phase. The process is exceedingly slow because the solubility of the phospholipid in water is very low (about 10 mol/L for DPPC). Prior art attempts to overcome this phenomenon include homogenizing the crystals in the presence of the phospholipid. In this case, the high degree of shear and radius of curvature of the homogenized crystals facilitates coating of the phospholipid on the crystals. In contrast, “dry” phospholipid powders according to one or more embodiments of this disclosure can spread rapidly when contacted with an aqueous phase, thereby coating dispersed crystals without the need to apply high energies. For example, upon reconstitution, the surface tension of spray-dried DSPC/Ca mixtures at the air/water interface decreases to equilibrium values (about 20 mN/m) as fast as a measurement can be taken. In contrast, liposomes of DSPC decrease the surface tension (about 50 mN/m) very little over a period of hours, and it is likely that this reduction is due to the presence of hydrolysis degradation products such as free fatty acids in the phospholipid. Single-tailed fatty acids can diffuse much more rapidly to the air/water interface than can the hydrophobic parent compound. Hence, the addition of calcium ions to phosphatidylcholines can facilitate the rapid encapsulation of crystalline drugs more rapidly and with lower applied energy. In another version, the pharmaceutical composition comprises low density particles achieved by co-spray-drying with a perfluorocarbon-in-water emulsion. Examples of perfluorocarbons include, but are not limited to, perfluorohexane, perfluorooctyl bromide, perfluorooctyl ethane, perfluorodecalin, perfluorooctyl ethane. In accordance with the teachings herein the particles can be provided in a “dry” state.

[0117] That is, in one or more embodiments, the particles will possess a moisture content that allows the powder to remain chemically and physically stable during storage at ambient or reduced temperature and remain dispersible. In this regard, there is little or no change in primary particle size, content, purity, and aerodynamic particle size distribution. As such, the moisture content of the particles is typically less than about 10 wt %, such as less than about 6 wt %, less than about 3 wt %, or less than about 1 wt %. The moisture content is, at least in part, dictated by the composition and is controlled by the process conditions employed, e.g., inlet temperature, feed concentration, pump rate, and blowing agent type, concentration and post drying. Reduction inbound water leads to significant improvements in the dispersibility and flowability of phospholipid-based powders, leading to the potential for highly efficient delivery of powdered lung surfactants or particle composition comprising active agent dispersed in the phospholipid. The improved dispersibility allows simple passive DPI devices to be used to effectively deliver these powders. Yet another version of the pharmaceutical composition includes particle compositions that can comprise, or can be partially or completely coated with, charged species that prolong residence time at the point of contact or enhance penetration through mucosae. For example, anionic charges are known to favor mucoadhesion while cationic charges can be used to associate the formed particle with negatively charged bioactive agents such as genetic material. The charges can be imparted through the association or incorporation of polyanionic or polycationic materials such as polyacrylic acids, polylysine, polylactic acid, and chitosan.

[0118] In some versions, the pharmaceutical composition comprises particles having a mass median diameter less than about 20 um, such as less than about 10 um, less than about 7 um, or less than about 5um. The particles can have a mass median aerodynamic diameter ranging from about 1 um to about 6 um, Such as about 1 ,5um to about 5um, or about 2 um to about 4 um. If the particles are too large, a larger percentage of the particles can not reach the lungs. If the particles are too small, a larger percentage of the particles can be exhaled.

[0119] In some embodiments, the dry powder pharmaceutical composition is stable for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years when stored in an open container at 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% relative humidity at a temperature of from about 0°C to about 50 °C, about 10 °C to about 40 °C, about 20 °C to about 40 °C, about 30 °C to about 40 °C, or about 20 °C to about 30 °C. In some embodiments, the dry powder pharmaceutical composition is stable for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years when stored in a closed container at 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% relative humidity at a temperature of from about 0 °C to about 50 °C, about 10 °C to about 40 °C, about 20 °C to about 40 °C, about 30 °C to about 40 °C, or about 20 °C to about 30 °C. Stability can be determined by potency of the dry powder pharmaceutical composition described herein. In some embodiments, the dry powder pharmaceutical described herein has an at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% potency after storage. In some embodiments, the dry powder pharmaceutical described herein has at least 90 % to about 100% potency after storage. Stability can be determined by the moisture content or water content by weight. In some embodiments, the water content of the dry powder pharmaceutical composition after storage is less than 15 wt %, less than 10 wt%, less than 5 wt %, or less than 1 wt % when storage in an open container. In some embodiments, the water content of the dry powder pharmaceutical composition after storage is less than 15 wt %, less than 10 wt%, less than 5 wt %, or less than 1 wt % when storage in an closed container.

METHODS OF TREATMENT

CARDIAC CONDITIONS

[0120] The methods, compositions, and kits provided herein can include administration of the pharmaceutical composition via inhalation, e.g., oral or nasal inhalation. Examples of cardiac arrhythmias the methods, compositions, and kits provided herein can treat 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. In some cases, the methods, compositions, and kits provided herein find use in treating a subject suffering from atrial arrhythmia, e.g., atrial fibrillation.

[0121] Thus, the pharmaceutical compositions according to some examples of the present disclosure can be used to treat and/or provide prophylaxis for a broad range of patients. A suitable patient for, receiving treatment and/or prophylaxis as described herein is any mammalian patient in need thereof, preferably such mammal is a human. Examples of subjects include, but are not limited to, pediatric patients, adult patients, and geriatric patients. In some cases, 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 patient 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.

[0122] Pharmaceutical compositions disclosed herein can be more effective in subjects that include or lack certain physiological or demographic factors, such as, for example, age at clinical presentation, certain hemodynamic criteria, electrophysiological features, and prior treatments. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure suffers from an atrial fibrillation with an onset that occurred within 48 hours prior to the treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure suffers from an atrial fibrillation with an onset that occurred from 1 hour to 48 hours prior to the treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure suffers from recurrent atrial fibrillation. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has undergone cardiac ablation no less than 3 months prior to the treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has an ongoing prescription for an oral anti arrhythmic medication for atrial fibrillation. In some embodiments, the oral anti arrhythmic medication is flecainide, or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, a subject treated with a pharmaceutical composition of the disclosure is over 17 years in age. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure is no more than 85 years in age. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure is from 18 years old to 85 years old. [0124] In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has a systolic blood pressure that is below 180 mmHg, below 175 mmHg, below 170 mmHg, below 165 mmHg, below 160 mmHg, below 155 mmHg, or below 150 mmHg at the time of the treating. In some cases, when referring to a physiological measurement of the subject, for instance, blood pressure, e.g., systolic blood pressure or diastolic blood pressure, or heart rate, e.g., ventricular rate, the term “at the time of treating” means the measurement is taken from 1 min to 6 hr prior to the treating, for instance, when measured 1 min to 10 min, 1 min to 30 min, 1 min to 60 min, 1 min to 90 min, 1 min to 2 hr, 1 min to 3 hr, 1 min to 4 hr, 1 min to 5 hr, 10 min to 30 min, 10 min to 60 min, 30 min to 60 min, 30 min to 90 min, 30 min to 2 hr, 1 hr to 2 hr, or 2 hr to 3 hr prior to the treating. In some cases, the physiological measurement, for instance, the measurement of the systolic blood pressure or the ventricular rate of the subject provides a basis for an informed decision as to whether or not the subject is to be treated with the subject pharmaceutical composition and method. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has a systolic blood pressure that is greater than 70 mmHg, greater than 75 mmHg, greater than 80 mmHg, greater than 85 mmHg, greater than 90 mmHg, greater than 95 mmHg, greater than 100 mmHg, greater than 105 mmHg, greater than 110 mmHg, greater than 115 mmHg, or greater than 120 mmHg at the time of the treating.

[0125] In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has a systolic blood pressure that is from about 60 mmHg to about 180 mmHg, from about 65 mmHg to about 180 mmHg, from about 70 mmHg to about 180 mmHg, from about 75 mmHg to about 180 mmHg, from about 80 mmHg to about 180 mmHg, from about 85 mmHg to about 180 mmHg, from about 90 mmHg to about 180 mmHg, from about 95 mmHg to about 180 mmHg, from about 100 mmHg to about 180 mmHg, from about 105 mmHg to about 180 mmHg, from about 110 mmHg to about 180 mmHg, from about 115 mmHg to about 180 mmHg, from about 120 mmHg to about 180 mmHg, from about 70 mmHg to about 175 mmHg, from about 70 mmHg to about 170 mmHg, from about 70 mmHg to about 165 mmHg, from about 70 mmHg to about 160 mmHg, from about 70 mmHg to about 155 mmHg, from about 70 mmHg to about 150 mmHg, from about 80 mmHg to about 165 mmHg, from about 90 mmHg to about 165 mmHg, from about 100 mmHg to about 165 mmHg, from about 70 mmHg to about 160 mmHg, from about 70 mmHg to about 160 mmHg, from about 75 mmHg to about 160 mmHg, from about 80 mmHg to about 160 mmHg, from about 85 mmHg to about 160 mmHg, from about 90 mmHg to about 160 mmHg, from about 95 mmHg to about 160 mmHg, from about 100 mmHg to about 160 mmHg, from about 70 mmHg to about 155 mmHg, from about 75 mmHg to about 155 mmHg, or from about 80 mmHg to about 155 mmHg at the time of treating.

[0126] In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has a ventricular rate that is at least about 50 BPM, at least about 55 BPM, at least about 60 BPM, at least about 65 BPM, at least about 70 BPM, at least about 75 BPM, at least about 80 BPM, at least about 85 BPM, at least about 90 BPM, at least about 95 BPM, or at least about 100 BPM at the time of treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has a ventricular rate that is no greater than about 200 BPM, no greater than about 190 BPM, no greater than about 180 BPM, no greater than about 175 BPM, no greater than about 170 BPM, no greater than about 165 BPM, no greater than about 160 BPM, no greater than about 155 BPM, no greater than about 150 BPM, no greater than about 145 BPM, or no greater than about 140 BPM at the time of treating.

[0127] In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has a ventricular rate that is from about 50 BPM to about 200 BPM, 50 BPM to about 180 BPM, from about 55 BPM to about 180 BPM, from about 60 BPM to about 180 BPM, from about 65 BPM to about 180 BPM, from about 70 BPM to about 180 BPM, from about 75 BPM to about 180 BPM, from about 80 BPM to about 180 BPM, about 85 BPM to about 180 BPM, about 95 BPM to about 180 BPM, about 100 BPM to about 180 BPM, from about 50 BPM to about 175 BPM, from about 50 BPM to about 170 BPM, from about 50 BPM to about 165 BPM, from about 50 BPM to about 160 BPM, from about 50 BPM to about 155 BPM, from about 70 BPM to about 175 BPM, about 70 BPM to about 170 BPM, about 70 BPM to about 165 BPM, about 70 BPM to about 160 BPM, about 70 BPM to about 155 BPM, about 75 BPM to about 180 BPM, about 75 BPM to about 175 BPM, about 75 BPM to about 170 BPM, about 75 BPM to about 165 BPM, about 75 BPM to about 160 BPM, about 75 BPM to about 155 BPM, about 80 BPM to about 175 BPM, about 80 BPM to about 170 BPM, about 80 BPM to about 165 BPM, about 80 BPM to about 160 BPM, about 80 BPM to about 155 BPM, about 80 BPM to about 150BPM, about 80 BPM to about 145 BPM, about 85 BPM to about 155 BPM, about 90 BPM to about 155 BPM, about 95 BPM to about 155 BPM, or about 100 BPM to about 155 BPM at the time of treating.

[0128] In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has not been treated with anti arrhythmic drugs or electrical cardioversion since onset of an episode of atrial arrhythmia for which the pharmaceutical composition is being administered. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit acute decompensated heart failure at the time of treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not have heart failure with reduced ejection fraction or a history thereof. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not have myocardial ischemia or a history thereof. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not have myocardial infarction or a history thereof. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has not exhibited myocardial infarction (MI) within 3 months prior to administration of the pharmaceutical composition. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit uncorrected severe aortic or mitral stenosis at the time of treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit hypertrophic cardiomyopathy with outflow tract obstruction at the time of treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not have persistent atrial fibrillation or a history thereof. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit atrial flutter at the time of treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has not exhibited an episode of atrial flutter within 6 months prior to the treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit abnormal left ventricular ejection fraction at the time of treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit heart failure that is class 2 or greater as according to New York Heart Association Functional Classification at the time of treating.

[0129] In some embodiments, a subject treated with a pharmaceutical composition of the disclosure is hemodynamically stable, has a systolic blood pressure that is greater than about 90 mmHg, has ventricular rate from about 70 BPM to about 170 BPM at the time of treating, and does not have a condition or a history of a condition that is: myocardial infarction, myocardial ischemia, atrial stenosis, hypertrophic cardiomyopathy, and heart failure with reduced ejection fraction.

[0130] In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not have Long QT syndrome, Conduction disease (e.g., second- or third- degree heart block, bundle branch block), Sick sinus syndrome, Brugada Syndrome, Torsades de pointed (TdP), or a histories thereof. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit at the time of treating an ECG-related feature that is: a QTc interval greater than 480 msec (estimated by the Fridericia's formula); a QRS duration greater than 105 ms; monomorphic or polymorphic ventricular tachycardias that are either sustained or not sustained; and excessive premature ventricular contractions greater than 20 multifocal PVC’s per hour (ventricular extrasystoles); or a predominantly paced heart rhythm.

[0131] In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit severe renal impairment, wherein a eGFR of the subject is less than 30 mL/min/1.73 m2 at the time of treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure is not on dialysis at the time of treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit abnormal liver function at the time of treating. In some embodiments, the abnormal liver function is hepatic disease or biochemical evidence of significant liver derangement. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit uncorrected hypokalemia at the time of treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit a serum potassium less than 3.6 mEq/L at the time of treating.

[0132] In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit an established pulmonary disease in need of inhalation medication at the time of treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not have a hypersensitivity to flecainide acetate or any of its active metabolites, or a history thereof. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure is not concomitantly administered a systemic drug that is an inhibitor of CYP 2D6. In some embodiments, the inhibitor of CYP 2D6 is an antidepressant, a neuroleptic, or an antihistamine. In some embodiments, the inhibitor of CYP 2D6 is propranolol or ritonavir. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure is not concomitantly administered a systemic drug that is a CYP 2D6 inducer. In some embodiments, the CYP 2D6 inducer is phenytoin, phenobarbital, or carbamazepine.

[0133] In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has not been treated with a Class I or a Class II anti arrhythmic drug within a week prior to administration of the pharmaceutical composition. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure with an ongoing episode of atrial fibrillation has not been treated with a Class I or a Class III anti arrhythmic drug since onset of the ongoing episode. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure is administered no more than 320 mg flecainide or a pharmaceutically acceptable salt thereof per day from any source. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure with an ongoing episode of atrial fibrillation has not been treated with electrical cardioversion since onset of the ongoing episode. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has not been treated with amiodarone within 12 weeks prior to administration of the pharmaceutical composition. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has not been considered high risk for stroke based on screening coagulation panel. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit a CHA2DS2-VASc score greater than 2.

[0134] In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit a congenital heart disease at the time of treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit a history of refractory atrial fibrillation that has been pharmacologically or electrically cardioverted. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit atrial fibrillation that is secondary to electrolyte imbalance, thyroid disease, or a non- cardiovascular cause at the time of treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit syncope at the time of treating.

[0135] In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit any serious or life threatening medical condition other than cardiac arrhythmia at the time of treating. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit an acute pathogenic infection at the time of treating. [0136] In some embodiments, a subject treated with a pharmaceutical composition of the disclosure has not exhibited a drug or alcohol dependence within 12 months prior to administration of the pharmaceutical composition. In some embodiments, a subject treated with a pharmaceutical composition of the disclosure does not exhibit a body mass index greater than 40 Kg/m ² at the time of treating.

[0137] The therapy provided herein can comprise or be suitable for inhalation, e.g., oral or nasal inhalation. In some cases, during administration via oral inhalation, the pharmaceutical agent is inhaled by the patient through the mouth and absorbed by the lungs. In some cases, during administration via nasal inhalation, the pharmaceutical agent is inhaled by the patient through the nose and absorbed by the nasal mucous and/or the lungs.

[0138] The inhalation route can avoid first-pass hepatic metabolism, hence dosing variability can be eliminated. Unlike the case for oral tablets or pills, the patient’s metabolic rates can not matter as the administration is independent of the metabolic paths experienced when a drug is administered via oral route through gastrointestinal tract, e.g., as tablets, pills, solution, or suspension. A fast onset of action, a potential improvement in efficacy, and/or a reduction in dose can be achieved with the fast absorption of drugs from the nasal mucosa and/or lungs.

[0139] The fast absorption rate of drugs through the lungs can be achieved because of the large surface area available in the lungs for aerosols small enough to penetrate central and peripheral lung regions. Consequently, the rate and extent of absorption of drugs delivered via inhalation can yield plasma concentrations vs. time profiles that are comparable with the IV route of administration.

[0140] In some cases, the therapy provided herein is provided to a subject for more than once on an as-needed basis. For instance, the present disclosure can involve a follow-up inhalation if no cardioversion occurs after an initial inhalation. In some instances, if no cardioversion occurs within 30 minutes of the initial inhalation, the follow-up dosage is higher or the same as the initial dosage. [0141] The time for onset of action can be short. For instance, the patient can 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. In some cases, the rapid onset of action is advantageous because the longer a patient remains in arrhythmia (i.e. atrial fibrillation), the more difficult it will be to restore normal sinus rhythm.

[0142] In some embodiments, the method of the present disclosure allows the patient to avoid other therapies, such as ablation and/or electrical cardioversion. In other embodiments, the method of the present disclosure is used in combination with other therapies, such as before or after electrical cardioversion and/or ablation therapy.

DOSAGE

[0143] The pharmaceutical composition can be administered to the patient on an as-needed basis. [0144] In some embodiments, the unit dosage is about 50 mg to about 350 mg of the anti arrhythmic pharmaceutical agent. In some embodiments, the unit dosage is about 50 mg to about 350 mg of the anti arrhythmic pharmaceutical agent wherein the anti arrhythmic pharmaceutical agent is flecainide or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dosage is about 100 mg to about 350 mg of the anti arrhythmic pharmaceutical agent. In some embodiments, the unit dosage is about 150 mg to about 350 mg of the anti arrhythmic pharmaceutical agent. In some embodiments, the unit dosage is about 200 mg to about 350 mg of the anti arrhythmic pharmaceutical agent. In some embodiments, the unit dosage is about 250 mg to about 350 mg of the anti arrhythmic pharmaceutical agent. In some embodiments, the unit dosage is about 300 mg to about 350 mg of the anti arrhythmic pharmaceutical agent. In some embodiments, the unit dosage is about 50 mg to about 300 mg of the anti arrhythmic pharmaceutical agent. In some embodiments, the unit dosage is about 50 mg to about 250 mg of the anti arrhythmic pharmaceutical agent. In some embodiments, the unit dosage is about 50 mg to about 200 mg of the anti arrhythmic pharmaceutical agent. In some embodiments, the unit dosage is about 50 mg to about 150 mg of the anti arrhythmic pharmaceutical agent. In some embodiments, the unit dosage is about 50 mg to about 100 mg of the anti arrhythmic pharmaceutical agent. In some embodiments, the unit dosage is about 100 mg to about 300 mg of the anti arrhythmic pharmaceutical agent. In some embodiments, the unit dosage is about 150 mg to about 250 mg of the anti arrhythmic pharmaceutical agent. In some embodiments, the unit dosage is about 100 mg to about 150 mg of the anti arrhythmic pharmaceutical agent. In some embodiments, the unit dosage is about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, or about 350 mg of the antiarrhythmic pharmaceutical agent.

[0145] The dosage necessary and the frequency of dosing of the antiarrhythmic pharmaceutical agent depend on the composition and weight ratio of the antiarrhythmic pharmaceutical agent to cyclodextin within the composition. 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.

[0146] The pharmaceutical composition of one or more embodiments of the present disclosure can have improved emitted dose efficiency. The emitted dose (ED) of the particles of the present disclosure can be greater than about 30%, such as greater than about 40%, greater than about 50%, greater than about 60%, or greater than about 70%. The dose of the antiarrhythmic agent, e.g., flecainide salt, e.g., flecainide acetate, can be administered during a single inhalation or can be administered during several inhalation sessions. The fluctuations of antiarrhythmic pharmaceutical agent concentration can be reduced by administering the pharmaceutical composition more often or can be increased by administering the pharmaceutical composition less often. Therefore, the pharmaceutical composition provided herein can be administered from about four times daily to about once a month, such as about once daily to about once every two weeks, about once every two days to about once a week, and about once per week.

[0147] In one embodiment, the pharmaceutical compostion of the disclosure is administered via oral inhalation. In some embodiments, “inhalation session” refers to a period starting from when the patient begins inhalation of the pharmaceutical composition and ending when the patient ceases inhalation of the pharmaceutical composition. In some cases, the antiarrhythmic pharmaceutical agent is delivered over two or more inhalation sessions. In some cases, time between the two or more inhalation sessions is from about 0.1 to 10 minutes. The antiarrhythmic pharmaceutical agent is administered in the described dose in less than 60 minutes, less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, in less than 3 minutes, in less than 2 minutes, or in less than 1 minute. In some cases, delivery of the required dose of antiarrhythmic pharmaceutical agent is completed with 1, 2, 3, 4, 5, or 6 inhalation sessions. In some cases, each inhalation session is performed for about 0.5, 1, 1.2, 1.5, 1.8, 2, 2.2, 2.5, 2.8, 3, 3.2, 3.5, 3.8, 4, 4.2, 4.5, 4.8, or 5 minutes. In some cases, each inhalation session is performed for longer than 5 minutes. In some cases, each inhalation session is performed for up to 4.5 minutes. In some cases, each inhalation session comprises at least 60 inhalation breaths, 50 inhalation breaths, 40 inhalation breaths, 30 inhalation breaths, 20 inhalation breaths, 10 inhalation breaths, 8 inhalation breaths, 6 inhalation breaths, 4 inhalation breaths, 3 inhalation breaths, 2 inhalation breaths or 1 inhalation breath. In some cases, each inhalation session comprises no more than 100 inhalation breaths, 90 inhalation breaths, 80 inhalation breaths, 70 inhalation breaths, 60 inhalation breaths, 50 inhalation breaths, 40 inhalation breaths, 30 inhalation breaths, or 20 inhalation breaths. In some cases, inhalation session of the anti arrhythmic pharmaceutical agent is performed with deep lung breath that lasts for longer than 1 second, 2 seconds, 3 seconds, or 4 seconds. In some cases, inhalation session of the anti arrhythmic pharmaceutical agent is performed with deep lung breath that lasts for about 1 second, 2 seconds, 3 seconds, or 4 seconds.

[0148] In some embodiments, the subject inhales an aerosolized pharmaceutical composition of the disclosure via tidal breathing. As used herein, “tidal breathing” can refer to inhalation and exhalation during restful breathing. For example, tidal breathing can include inhaling the arosolized pharmaceutical composition while breathing at a rate of 10 to 14 breaths a minute.

[0149] In some embodiments, during inhalational delivery of the anti arrhythmic pharmaceutical agent, the subject takes, or is instructed to take, a break between two inhalation sessions. In such embodiments, the break between two inhalation session lasts for about 0.1 to 10 minutes, such as, 0.2 to 5, 1 to 5, 1.5 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 1.5, 1 to 2, 1 to 2.5, 1 to 3, 1 to 3.5 , 1 to 4, 1.5 to 2, 1.5 to 2.5, or 1.5 to 3 minutes. In some cases, the subject takes, or is instructed to take, a break for about 1 minute between two inhalation sessions. In some cases, the inhalation pattern for delivery of a single dose goes as follows: a first inhalation session for about 4 to 4.5 minutes, a break for about 1 minute, and a second inhalation session for about 4 to 4.5 minutes; a first inhalation session for about 4 to 4.5 minutes, a break for about 30 seconds, and a second inhalation session for about 4 to 4.5 minutes; a first inhalation session for about 4 to 4.5 minutes, a first break for about 1 minute, and a second inhalation session for about 4 to 4.5 minutes; a second break for about 1 minutes, and a third inhalation session for about 4 to 4.5 minutes; or a first inhalation session for about 4 to 4.5 minutes, a first break for about 30 seconds, and a second inhalation session for about 4 to 4.5 minutes; a second break for about 30 seconds, and a third inhalation session for about 4 to 4.5 minutes.

[0150] In one version, the antiarrhythmic can be administered daily. In this case, the daily dosage of the flecainide acetate ranges from about 0.1 mg to about 600 mg, such as about 0.5 mg to about 500 mg, about 1 mg to about 400 mg, about 2 mg to about 300 mg, and about 3 mg to about 200 mg.

[0151] In some cases, the therapy provided herein is provided to a subject for more than once on an as-needed basis. For instance, the present disclosure can involve a follow-up inhalation if no cardioversion occurs after an initial inhalation. In some instances, if no cardioversion occurs within 30 minutes of the initial inhalation, the follow-up dosage is higher or the same as the initial dosage. [0152] The dosing can be guided by how the patient feels. Additionally or alternatively, dosing can be guided by using a portable/mobile ECG device. For instance, the dosing can be guided by using a Holter monitor.

[0153] In another version, the pharmaceutical composition is administered prophylactically to a subject who is likely to develop an arrhythmia. For example, a patient who has a history of arrhythmias can be prophylactically treated with a pharmaceutical composition comprising anti arrhythmic pharmaceutical agent to reduce the likelihood of developing an arrhythmia.

[0154] The pharmaceutical composition can be administered to a patient in any regimen which is effective to prevent an arrhythmia. Illustrative prophylactic regimes include administering an anti arrhythmic pharmaceutical agent as described herein 1 to 21 times per week.

[0155] In some cases, patient receiving administration of pharmaceutical composition according to the method described herein needs to meet one or more of the following ECG criteria: P waves not seen on the ECG; fibrillatory waves are coarse; there are varying RR intervals; there are irregular-irregular QRS complexes; or there is an elevated ventricular rate. In some cases, method of treatment disclosed herein comprises confirming a patient in atrial fibrillation episode via ECG. In some cases, the method comprises confirming a patient having the following ECG features before administering the pharmaceutical composition as described herein: P waves not seen on the ECG; fibrillatory waves are coarse; there are varying RR intervals; there are irregular-irregular QRS complexes; and there is an elevated ventricular rate. In some cases, a patient receiving administration of pharmaceutical composition according to the method described herein has a medical history that is current within predetermined time period and qualifies the patient to receive flecainide safely. In some cases, the patient’s current AF episode has had a duration of less than 48 hours. In some cases, total flecainide exposure the patient receives within past 24 hour period does not exceed 320 mg.

[0156] The amount of the flecainide salt that is delivered to the subject (e.g., approximately the amount of the flecainide salt exiting a mouthpiece when being inhaled by the subject) for the treatment of arrhythmia, e.g., atrial arrhythmia, e.g., atrial fibrillation, can be from about 50 mg to about 300 mg, such as 50 mg to 60 mg, 50 mg to 70 mg, 50 mg to 80 mg, 50 mg to 90 mg, 50 mg to 100 mg, 50 mg to 110 mg, 50 mg to 120 mg, 50 mg to 130 mg, 50 mg to 140 mg, 50 mg to 150 mg, 50 mg to 160 mg, 50 mg to 170 mg, 50 mg to 180 mg, 50 mg to 190 mg, 50 mg to 200 mg, 50 mg to 210 mg, 50 mg to 220 mg, 50 mg to 230 mg, 50 mg to 240 mg, 50 mg to 250 mg, 50 mg to 260 mg, 50 mg to 270 mg, 50 mg to 280 mg, 50 mg to 290 mg, 70 mg to 80 mg, 70 mg to 90 mg, 70 mg to 100 mg, 70 mg to 110 mg, 70 mg to 120 mg, 70 mg to 130 mg, 70 mg to 140 mg, 70 mg to 170 mg, 70 mg to 160 mg, 70 mg to 170 mg, 70 mg to 180 mg, 70 mg to 190 mg, 70 mg to 200 mg, 70 mg to 210 mg, 70 mg to 220 mg, 70 mg to 230 mg, 70 mg to 240 mg, 70 mg to 270 mg, 70 mg to 260 mg, 70 mg to 270 mg, 70 mg to 280 mg, 70 mg to 290 mg, 70 mg to 300 mg, 80 mg to 90 mg, 80 mg to 100 mg, 80 mg to 110 mg, 80 mg to 120 mg, 80 mg to 130 mg, 80 mg to 140 mg, 80 mg to 150 mg, 80 mg to 160 mg, 80 mg to 170 mg, 80 mg to 180 mg, 80 mg to 190 mg, 80 mg to 200 mg, 80 mg to 210 mg, 80 mg to 220 mg, 80 mg to 230 mg, 80 mg to 240 mg, 80 mg to 250 mg, 80 mg to 260 mg, 80 mg to 270 mg, 80 mg to 280 mg, 80 mg to 290 mg, 80 mg to 300 mg, 100 mg to 110 mg, 100 mg to 120 mg, 100 mg to 130 mg, 100 mg to 140 mg, 100 mg to 150 mg, 100 mg to 160 mg, 100 mg to 170 mg, 100 mg to 180 mg, 100 mg to 190 mg, 100 mg to 200 mg, 100 mg to 210 mg, 100 mg to 220 mg, 100 mg to 230 mg, 100 mg to 240 mg, 100 mg to 250 mg, 100 mg to 260 mg, 100 mg to 270 mg, 100 mg to 280 mg, 100 mg to 290 mg, 100 mg to 300 mg, 120 mg to 140 mg, 120 mg to 150 mg, 120 mg to 160 mg, 120 mg to 170 mg, 120 mg to 180 mg, 120 mg to 190 mg, 120 mg to 200 mg, 120 mg to 210 mg, 120 mg to 220 mg, 120 mg to 230 mg, 120 mg to 240 mg, 120 mg to 250 mg, 120 mg to 260 mg, 120 mg to 270 mg, 120 mg to 280 mg, 120 mg to 290 mg, 120 mg to 300 mg, 150 mg to 160 mg, 150 mg to 170 mg, 150 mg to 180 mg, 150 mg to 190 mg, 150 mg to 200 mg, 150 mg to 210 mg, 150 mg to 220 mg, 150 mg to 230 mg, 150 mg to 240 mg, 150 mg to 250 mg, 150 mg to 260 mg, 150 mg to 270 mg, 150 mg to 280 mg, 150 mg to 290 mg, 150 mg to 300 mg, 180 mg to 200 mg, 180 mg to 210 mg, 180 mg to 220 mg, 180 mg to 230 mg, 180 mg to 240 mg, 180 mg to 250 mg, 180 mg to 260 mg, 180 mg to 270 mg, 180 mg to 280 mg, 180 mg to 290 mg, 180 mg to 300 mg, 200 mg to 220 mg, 200 mg to 230 mg, 200 mg to 240 mg, 200 mg to 250 mg, 200 mg to 260 mg, 200 mg to 270 mg, 200 mg to 280 mg, 200 mg to 290 mg, 200 mg to 300 mg, 220 mg to 240 mg, 220 mg to 250 mg, 220 mg to 260 mg, 220 mg to 270 mg, 220 mg to 280 mg, 220 mg to 290 mg, 220 mg to 300 mg, 250 mg to 260 mg, 250 mg to 270 mg, 250 mg to 280 mg, 250 mg to 290 mg, 250 mg to 300 mg, 280 mg to 260 mg, 280 mg to 270 mg, 280 mg to 280 mg, 280 mg to 290 mg, or 280 mg to 300 mg.

[0157] In one version, the amount of the flecainide salt that is delivered to the subject (e.g., approximately the amount of the flecainide salt exiting the aerosolization device when being inhaled by the subject) for the treatment of arrhythmia, e.g., atrial arrhythmia, e.g., atrial fibrillation, is at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 110 mg, at least about 120 mg, at least about 130 mg, at least about 140 mg, at least about 150 mg, at least about 160 mg, at least about 170 mg, at least about 180 mg, at least about 190 mg, at least about 200 mg, at least about 210 mg, at least about 220 mg, at least about 230 mg, at least about 240 mg, at least about 250 mg, at least about 260 mg, at least about 270 mg, at least about 280 mg, or at least about 290 mg. [0158] In one version, the amount of the flecainide salt that is delivered to the subject (e.g., approximately the amount of the flecainide salt exiting a mouthpiece when being inhaled by the subject) for the treatment of arrhythmia, e.g., atrial arrhythmia, e.g., atrial fibrillation, is at most about 100 mg, at most about 110 mg, at most about 120 mg, at most about 130 mg, at most about 140 mg, at most about 150 mg, at most about 160 mg, at most about 170 mg, at most about 180 mg, at most about 190 mg, at most about 200 mg, at most about 210 mg, at most about 220 mg, at most about 230 mg, at most about 240 mg, at most about 250 mg, at most about 260 mg, at most about 270 mg, at most about 280 mg, or at most about 290 mg.

[0159] In some cases, the amount of the flecainide salt that is delivered to the subject (e.g., approximately the amount of the flecainide salt exiting a mouthpiece when being inhaled by the subject) for the treatment of arrhythmia, e.g., atrial arrhythmia, e.g., atrial fibrillation, is about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, or about 290 mg.

[0160] This method of treatment 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 selfadministration like the “pill-in-the-pockef ’ approach, but the effectiveness and fast onset of action of an IV. Although the delivery of 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.

[0161] In one or more embodiments, the anti arrhythmic pharmaceutical agent is a class I, class II, class III, or class IV anti arrhythmic. In some embodiments, the anti arrhythmic pharmaceutical agent is a class Ic, anti arrhythmic. In other embodiments, the anti arrhythmic pharmaceutical agent is flecainide or a pharmaceutically acceptable salt thereof.

[0162] In some cases, the compositions and methods provided herein confer a reduced negative inotropic burden to the subject receiving inhalational delivery of the anti arrhythmic pharmaceutical agent, e.g., flecainide, as compared to receiving delivery of a corresponding dose of the same agent via a different route (e.g., oral or intravenous delivery). Certain antiarrhythmic drugs can have negative inotropic effect, which can limit their use for acute cardioversion of new- onset paroxysmal atrial fibrillation (AF). For instance, intravenous delivery of flecainide can exert negative inotropic burden to the subject’s heart, which can be measured by left ventricular (LV) contractility. In some embodiments, the negative inotropic burden of inhalational delivery of a therapeutically effective dose of anti arrhythmic pharmaceutical agent according to the methods described herein is lower than that of a corresponding therapeutically effective dose of the same agent delivered via a different route (e.g., oral or intravenous delivery).

KITSAND SYSTEMS

[0163] In one aspect, also provided herein are kits for treatment of heart conditions via inhalation. The kits can include one or more pharmaceutical agents, for instance, a salt of flecainide, or some additional active agent(s) as described herein. In some cases, the kits include container for the pharmaceutical agents or compositions. In some cases, unit doses of the pharmaceutical agents as discussed above are provided in the kits. In some cases, the kits also include containers/receptacles for containing the pharmaceutical agents.

[0164] The pharmaceutical composition according to one or more embodiments of the disclosure may, if desired, contain a combination of anti arrhythmic pharmaceutical agent (e.g., flecainide salt) and one or more additional active agents.

[0165] In some cases, all the starting materials are sterilized by established technologies that meet the standards for medical use. Typically, manufacturing equipment is sterilized before use. In some embodiments, the inhalable dry powder pharmaceutical composition described herein can be added into a suitable container, z.e., capsule, blister pack, blister strip, reservoir, and cartridge. Some or all of other additional pharmaceutically acceptable carrier or excipient, solubilizer, or other additional ingredients of the pharmaceutical composition (e.g., cyclodextrin, e.g., HPpCD; e.g., acids, e.g., acetic acid, hydrochloric acid, nitric acid, or citric acid; e.g., saccharin, e.g., saccharin sodium) can added into a suitable container.

[0166] In some cases, the kits include separate containers/receptacles for containing the pharmaceutical composition as described herein. In some other cases, the kits include a single container for containing the pharmaceutical composition. The kits can further include instructions for methods of using the kit. The instructions can be presented in the form of a data sheet, a manual, on a piece of paper, printed on one or more containers or devices of the kit. Alternatively, the instructions can be provided in electronic form, for instance, available in a disc or online with a weblink available from the kit. The instructions for use of the kit can comprise instructions for use of the pharmaceutical composition and the aerosolization device (e.g., a dry powder inhaler) to treat any applicable indication, e.g., a heart condition, e.g., cardiac arrhythmia, e.g., atrial arrhythmia. The instructions for use of the kit can comprise instructions for use of the pharmaceutical composition and the aerosolization device (e.g., a dry powder inhaler ) to treat atrial fibrillation. In some cases, the kits include a nose clip. A nose clip can be used to hinder passage of air through a nose of a subject during inhalation and increase the proportion of a total inhaled volume that is the aerosol issued by the a dry powder inhaler .

[0167] Unit doses of the pharmaceutical compositions can be placed in a container. Examples of containers include, but are not limited to, capsule, blister pack, blister strip, reservoir, cartridge, or container closure systems made of metal, polymer (e.g., plastic, elastomer), glass, or the like.

[0168] The container can be inserted into an aerosolization device. The container can be of a suitable shape, size, and material to contain the pharmaceutical composition and to provide the pharmaceutical composition in a usable condition. For example, the capsule or blister can comprise a wall which comprises a material that does not adversely react with the pharmaceutical composition. In addition, the wall can comprise a material that allows the capsule to be opened to allow the pharmaceutical composition to be aerosolized. In one version, the wall comprises one or more of gelatin, hydroxypropyl methylcellulose (HPMC), polyethyleneglycol-compounded HPMC, hydroxyproplycellulose, agar, aluminum foil, or the like.

[0169] In some cases, the DPI are pre-filled with doses of the pharmaceutical composition. In some embodiments, the DPI are pre-filled with a single dose. In some embodiments, the DPI are pre-filled with multiple doses. In some cases, the DPI is disposable after usage. In some cases, the DPI or aerolization device does not contain a capsule for the pharmaceutical compsotion, while the device itself has a compartment or compartments for filling and/or refilling of the pharmaceutical composition. In some cases, the DPI uses a capsule comprising the pharmaceutical composition. In some cases, the DPI or aerolization device requires inhalation of the patient to aerolize the pharmaceutical composition.

TERMINOLOGY

[0170] As used herein, “heart condition” can refer to a condition where heart has an abnormal function and/or structure, for example, heart is beating in an irregular rhythm, experiencing arrhythmia, atrial fibrillation, and/or tachycardia, there is myocardial infarction, and/or coronary heart disease. As used herein, “atrial arrhythmia” can refer to an arrhythmia that affects at least one atrium and does not include bradycardia. For instance, atrial arrhythmia can originate in and affect at least one atrium. As used herein, “tachycardia” can refer to an arrhythmia in which the heart beat is too fast. For instance, tachycardia can 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. In some cases, tachycardia can comprise sinus tachycardia, atrial fibrillation, atrial flutter, AV nodal reentrant tachycardia, accessory pathway mediated tachycardia, atrial tachycardia, multifocal atrial tachycardia, junctional tachycardia, ventricular tachycardia, supraventricular tachycardia, or any combination thereof. As used herein, the phrase “heart rhythm arrhythmia” can refer to an arrhythmia in which the heart beat is irregular. As used herein, the term “atrial fibrillation” can refer to an abnormal heart rhythm characterized by rapid and irregular beating of the atria. As used herein, the term “cardioversion” can refer to a process by which an abnormally fast heart rate (tachycardia) or other cardiac arrhythmia is converted to a normal sinus rhythm. Cardioversion can be induced by electricity, drugs, or both.

[0171] As used herein, the singular forms “a,” “an,” and “the” can include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an anti arrhythmic agent” can include not only a single active agent but also a combination or mixture of two or more different active agents.

[0172] Reference herein to “one embodiment,” “one version,” or “one aspect” can include one or more such embodiments, versions or aspects, unless otherwise clear from the context.

[0173] As used herein, the term “pharmaceutically acceptable solvate” can refer to a solvate that retains one or more of the biological activities and/or properties of the anti arrhythmic pharmaceutical agent and that is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable solvates include, but are not limited to, anti arrhythmic pharmaceutical agents in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, or combinations thereof.

[0174] As used herein, the term “salt” is equivalent to the term “pharmaceutically acceptable salt,” and can refer to 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, bi sulfates, sulfites, bi sulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, mal onates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne- 1,6- dioates, benzoates, chlorobenzoates, methylbenzoates, di nitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenyipropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthal ene-1 -sulfonates, naphthalene-2-sulfonates, and mandelates.

[0175] 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. [0176] As used herein, “atrial arrhythmia” can refer to an arrhythmia that affects at least one atrium and does not include bradycardia. For instance, atrial arrhythmia can originate in and affect at least one atrium.

[0177] As used herein, “tachycardia” can mean an arrhythmia in which the heart beat is too fast, e.g., faster than normal. For instance, tachycardia can 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.

[0178] As used herein, the phrase “heart rhythm arrhythmia” can refer to an arrhythmia in which the heart beat is irregular.

[0179] As used herein, the amount of an agent as described herein in the coronary circulation of the heart can be measured by extracting a sample from any vascular region of the coronary circulation of the heart (e.g., arteries, veins, including coronary sinus) by using a cannula. The amount of the agent in the sample can then be determined by known means, such as bioanalytical techniques that employ analytical equipment such as LC-MS/MS. Thus, the amount of the agent in the blood in the heart can be measured for any particular time.

[0180] 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 patient with an active agent as provided herein can include prevention of a particular condition, disease, or disorder in a susceptible individual as well as treatment of a clinically symptomatic individual.

[0181] As used herein, “nominal amount” can refer to the amount contained within the unit dose receptacle(s) that are administered.

[0182] As used herein, “effective amount” can refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts.

[0183] As used herein, a “therapeutically effective amount” of an active agent can refer to an amount that is effective to achieve a desired therapeutic result. A therapeutically effective amount of a given active agent can 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 patient. In some cases, “inhalation” (e.g., “oral inhalation” or “nasal inhalation”) refers 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 inhalation sessions. [0184] 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.

[0185] As used herein, the phrase “minimum effective amount” can mean the minimum amount of a pharmaceutical agent necessary to achieve an effective amount.

[0186] As used herein, “mass median diameter” or “MMD” can refer to the median diameter of a plurality of particles, typically in a polydisperse particle population, e.g., consisting of a range of particle sizes.

[0187] As used herein, “geometric diameter” can refer to the diameter of a single particle, as determined by microscopy, unless the context indicates otherwise.

[0188] 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.

[0189] By a “pharmaceutically acceptable” component is meant a component that is not biologically or otherwise undesirable, e.g., the component can be incorporated into a pharmaceutical formulation of the disclosure 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 can imply 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.

[0190] As used herein, “P wave” can represent the wave generated by the electrical depolarization of the atria (right and left) and is usually 0.08 to 0.1 seconds (80-100 ms) in duration.

[0191] As used herein, “active dry powder inhaler” refers to an inhalation device that does not rely solely on a patient’s inspiratory effort to disperse and aerosolize a pharmaceutical composition contained within the device in a reservoir or in a unit dose form and does include inhaler devices that comprise a means for providing energy to disperse and aerosolize the drug composition, Such as pressurized gas and vibrating or rotating elements.

[0192] As used herein, “room temperature” can refer to a temperature that is from 18 °C to 25 °C. EXAMPLES

[0193] 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 can alternatively be used.

Example 1: Vacuum dried de-constituted Flecainide acetate pH study

[0194] This example illustrates the change in pH of flecainide acetate when dried for certain vacuum dried formulations. In order to determine any loss of acid of vacuum dried flecainide acetate, a 10 mL solution with 20 mg/mL of flecainide acetate with varying amounts of acids were prepared as shown in Table 1. A 1 mL aliquot from each sample was dried for 12 hours in vacuum. The dried flecainide acetate test samples were then reconstituted in 1 mL water to the original concentration. The pH was measured to verify any acid loss.

Table 1. Reconstituted Flecainide Acetate pH

Example 2: Formulations of spray drying Flecainide powder study

[0195] This example demonstrates preparation of certain spray dried flecainide powders. Different pre-formulated powders were made via spray drying in order to determine the effects of several variables on the final product characteristics as shown in Table 2.

Table 2. Pre-formulation variables

[0196] Feedstock was prepared with the composition quantities and pH targets shown in Table 3 prior to spray drying.

Table 3. Pre-formulation of flecainide acetate powder

[0197] A specified quantity for each component was added to a fixed volume of deionized water (DI water) to achieve the desired formulation composition and solids percentage in solution. All components were readily soluble in water. The pH of the feedstock solution was adjusted by either adding acetic acid or citric acid for the feedstock.

Table 4. Spray drying process conditions

Example 3: Characteristics of Flecainide acetate powder formulations

[0198] This example characterizes certain test formulations of Flecainide acetate powder prepared in Example 2. In order to determine any acid loss during spray drying, the bulk powder was reconstituted in DI water at the same concentration as the original feedstock. The pH of the reconstituted solution was measured and compared to that of the original feedstock. The solubility of the dry powder during reconstitution was also observed. The pH was measured using an Orion Star Al l i from Thermo Scientific. Flecainide acetate powder density study.

[0199] Dry powder density was determined by bulk density and puck density. Bulk density was determined by adding a known mass of dry powder into a tared Eppendorf tube and filled up to 0.5 cubic centimeter. The weight of the powder was measured on Mettler Toledo, AT261 balance. Bulk powder density was calculated as the powder weight over the volume. Puck density was determined by using a capsule filler tool with a cavity volume of 832 p in ³ (0.0136 cm ³ ) with a vacuum pressure of 80 ±1 kPa and 1.5 to 1.7 L/min flow. The puck was extracted from the cavity and weighed on a Mettler Toledo AT261 balance. Puck density was calculated as the puck weight over the volume of the cavity.

Flecainide acetate powder particle size distribution study.

[0200] Dry powder particle size distribution was performed on a LS 13 320 Beckman Coulter laser diffraction. The suspension media was Paraffin. The concentration of the mixture was 5 mg of dry powder in 3 mL of Paraffin. The mixture was sonicated in water bath between 5 to 8 minutes and at a sonication power of 42 kHz (180 Watt) prior to analyzing the suspension.

Flecainide acetate powder thermal analysis study.

[0201] Thermal analysis using Differential Scanning Calorimetry (DSC) was performed on the powder samples to determine phase transition profiles of the samples. Thermal analysis was performed on a DSC TA QI 000 at a temperature change rate of 10 °C per minute and a range of - 60 °C to 200 °C.

Flecainide acetate powder crystallinity study.

[0202] Powder crystallinity using X-ray diffraction (XRPD) was performed on selected samples to determine the crystallinity of the pre-formulated Flecainide acetate powder. The analysis was performed on a X'pert Pro (PANalytical).

Table 5. Investigation of reconstituted Flecainide acetate pH precipitates upon reconstitution in DI water. For these test compositions, there was evidence of acid loss after vacuum drying over 12 hours as evident from the small amount of pH increase upon reconstitution.

Pre-formulation spray dried powder study. [0204] Table 6 shows the observations as well as powder reconstitution results for all the preformulation spray drying campaigns. Table 6 displays some test compositions or batches that were were spray dried using identical spray drying process conditions.

Table 6. Flecainide acetate pre-formulation summary

[0205] A test composition of neat flecainide acetate powder without excipients (Batch A) was coarse and appeared crystalline. Another test composition, Batch C, with similar formulation to Batch A but using only citric acid to adjust feedstock pH, did not yield any dry powder during spray drying. Two different test compositions, Batches B and D, containing >50%w/w flecainide acetate with trileucine did not yield any dry powder regardless of the amount of trileucine in the formulation or the type of acid used to adjust the feedstock pH. Powder from another two test compositions, Batches E and F, appeared visually fine. Batches E and F were prepared from a feedstock with a pH under 5, andcontained less than 50%w/w flecainide acetate with leucine.

[0206] For the powder reconstitution in DI water, powder formulations with drug loading higher than 20%w/w were not readily soluble in water, unlike the native flecainide acetate drug. All samples reconstituted back into water had pH ranging from 7.2 to 8.1, which was much higher than the respective feedstock pH for each batch shown in Table 3, indicating that regardless of the amount and type of acid added to the feedstock, there was acid lost during spray drying. This was especially apparent for Batch I, where the reconstituted solution had a pH of 7.7 despite a feedstock pH of 3.3, with 60%w/w of acetic acid. Powder batches with drug loading higher than 20%w/w were not reconstituted back into water.

[0207] Batches with flecainide acetate loading ranging from 20%w/w to 48%w/w with leucine produced the most uniform and smallest particle size distribution. Batch formulations with neat flecainide powder, 70%w/w flecainide acetate with leucine, and batches spray dried with feedstock pH of 3.5 or 6.8 yielded large particle size distribution.

Table 7. Flecainide acetate powder bulk and puck densities

[0208] Based on the bulk density results, the powder formulation with 48%w/w drug flecainide acetate (Batch F) had denser packing compared to the preparation containing 20%w/w flecainide acetate (Batch E). At 48%w/w drug loading, the puck density was about twice that of 20%w/w flecainide acetate. Based on this information, the following projected dose per capsule for 20%w/w and 48%w/w flecainide acetate drug loading values for a size 2 and 3 Capsugel HPMC capsules were calculated:

• Size 2 Capsule (0.37ml fill volume based on Capsugel) 48%w/w drug loading = 42.6 mg flecainide acetate/Capsule 20%w/w drug loading = 9.6 mg flecainide acetate/capsule

• Size 3 Capsule (0.30 ml fill volume based on Capsugel) 48%w/w drug loading = 34.6 mg flecainide acetate/Capsule 20%w/w drug loading = 7.8 mg flecainide acetate/capsule

[0209] Bulk and puck densities of powders with leucine plus 20%w/w flecainide acetate , as well as those with leucine plus 48%w/flecainide acetate were measured. The results show that the batch with 48%w/w flecainide loading with leucine had slightly higher bulk density and about twice the puck density as the batch with 20%w/w drug loading with leucine. Therefore, more mass per volume can be filled into a single capsule using the 48%w/w drug loading powder formulation compared to the 20%w/w drug loading powder formulation.

[0210] The particle size distributions shown in FIG. 1 were determined using a Beckman Coulter laser diffraction system.

Table 8. Flecainide acetate dry powder particles size distribution

[0211] Neat flecainide powder (Batch A) without excipients had an X50 of 40.8 pm. Batches E and F, containing leucine and less than 50%w/w flecainide acetate, and prepared from a feedstock with a pH of 5, resulted in the most uniform and smallest particle size distribution compared to other batches.

[0212] Batches containing less than 50% w/w flecainide acetate that were prepared from a feedstock with pH of 3.5 or 6.8 (H and I) yielded large particle size distribution. A preparation containing leucine and 70%w/w flecainide acetate exhibited a bimodal distribution in particle size, which indicates that the resulting bulk powder was a mixture of larger neat flecainide crystals and smaller particles. The particle size distributions observed for each of the preformulated bulk powders are shown in FIG. 1. Neat flecainide acetate powder without any excipients exhibited a powder morphology resembling large crystalline needles.

[0213] Batches containing leucine plus 20%w/w to 48%w/w flecainide acetate (batches E and F) contained small, uniform round particles. However, as flecainide loading increased to 70%/w/w (batch G), a mixture of small particles with larger, needle-shaped crystalline flecainide acetate was present in the powder sample, which is in line with the bimodal particle size distribution observed for this batch. Furthermore, there was observable presence of agglomerated particles observed in 70%w/w flecainide acetate powder.

Powder crystallinity study.

[0214] Selected test flecainide acetate powder samples were analyzed using XRPD as a tool to determine any changes to the native pure flecainide acetate drug after it was processed through spray drying. FIG. 2 compares the pure drug and the neat flecainide acetate (Batch A). The formulated flecainide acetate powder at various drug loading values with leucine as excipient (Batches E, F, and G) exhibited amorphous XRPD profiles. Batches C and D, which did not produce dry powder, exhibited amorphous XRPD profiles (FIG. 4) unlike the pure flecainide acetate. Powder thermal analysis for batches containing leucine in combination with 20%w/w, 48%w/w, or 70%w/w flecainide loading exhibited glass transition temperatures (Tg) ranging from 27-33 °C. Neat flecainide acetate powder exhibited a lower glass transition and melting temperature compared to that of pure flecainide acetate. Example 4: Method of manufacturing and characterization of selected flecainide acetate / HP-P-CD compositions

[0215] Spray drying feasibility was conducted on a custom laboratory scale dryer with 35 kg/hr drying gas capacity for five example compositions, Batches J-N.

[0216] Two different solution preparation methods were evaluated as part of the initial feasibility screen. In the first method (Method #1) the nebulized formulation is prepared at a higher concentration, and then diluted to the target spray solution concentration. The second method (Method #2) followed a simplified procedure where the solution was prepared at the spray solution concentration without any intermediate dilution steps. A comparison of the two methods are presented in Table 9.

Table 9. Comparison of solution preparation methods

Spray drying study.

[0217] Table 10 summarizes the manufacturing conditions for the Batches J - Batch N. Batch J - Batch L varied solution flow rate in order to evaluate the impact of relative humidity on yield. Atomization gas-to-liquid (G/L) ratio for the three batches was matched in order to target similar particle sizes. No significant difference in yield was observed between the lowest and highest humidity conditions. The lower yield on Batch J compared to Batch K and Batch L is likely due to start-up losses. Changing solution preparation method in Batch M did not negatively impact process yield. Increased active loading in Batch N resulted in a low yield (~30 %), and likely decreased the over glass transition temperature (Tg) of the formulation below the outlet temperature of the dryer, resulting in sticking and particle fusion. Table 10. Manufacturing summary in water, water content by Karl Fisher, particle size distribution by laser diffraction, particle morphology by scanning electron microscopy, thermal transitions by differential scanning calorimetry and physical state by X-ray powder diffraction. Results are summarized in Table 11.

Table 11. Summary of Analytical Results

¹ Water (MilliQ grade) had a pH value of 8.70 so “A from reference” is the difference between water only and solution containing formulation. Negative value indicates that it is acidic; positive indicates basic. ² DNT: Did Not Test as this formulation became gel like when reconstituted so it could not be measured. ³ Values reported are the onset glass transition temperatures, the mid-point temperature is reported in Table 16

Purity and potency study.

[0219] The purity and potency of the five formulations was determined using HPLC. The same lot of flecainide acetate used in manufacturing Batches J - Batch N were used for the reference material.

[0220] Purity of the samples was determined as 100 % as no additional peaks were observed on any of the five formulations. The amount of material tested was measured in terms of the formulation rather than scaled to the theoretical active amount, as the loadings are approximately 22 % and any potential impurities can be at a concentration below detection. Two replicate samples were prepared per formulation and the potency results are presented in Table 12. Batch M and Batch N were more difficult to handle relative to Batches J - Batch L. Batch M and Batch N were impacted by electrostatic cling, which can be related to the moisture content. This can also contribute to the variability in the potency results for those two samples. Overall, the potency of the formulations were close to target.

Table 12. Potency of the five-spray dried Flecainide acetate formulations

[0221] As the formulation is spray dried, acetic acid can be removed during the manufacturing process through vaporization, resulting in formation of the free base in the dry formulation. Accordingly, the pH of the reconstituted formulation in water was measured to determine the amount of acetate remaining in the formulation. Approximately 120 mg of each formulation was dissolved in 3 mL of high purity (MilliQ) water to target the same solids content of the spray solutions (4 wt %). Formulation Batch N (50 % API loading) formed a gel so it was further diluted with an additional 3 mL. The additional water still afforded a gel, and pH was not measured. The pH values of the reconstituted formulations are presented in Table 13.

Table 13. pH values of reconstituted formulations

[0222] The pH of the high purity water was significantly high (8.70) so ~4 wt% and 1 wt% reference solutions were made using the in-going flecainide lot and tested for comparison. Both solutions exhibited a lower pH (more acidic) than the water.

[0223] Formulations manufactured according to the Method #1 (Table 9) exhibited pH values that differed from water by 0.5. Formulation Batch N, prepared according toMethod #2, exhibited a larger pH difference of 1.0.

Geometric particle size distribution study.

[0224] Geometric particle size distributions were measured by laser diffraction using a Malvern Mastersizer 3000 equipped with an Aero S dispersion unit at a dispersive air pressure of 3 bar. The Mie scattering theory was applied to the diffraction pattern to obtain the particle size distribution (refractive index of the particle was set at 1.55 with the absorption set as 0.1). The particle size distribution summary is presented in Table 14 and graphically depicted in FIG. 5.

Table 14. Particle size distribution of Flecainide acetate spray dried powders

[0225] Similar particle size distributions were observed for Batch J, Batch L, and Batch M. Broader distribution and an apparent shoulder in the distribution observed in Batch N suggest particle fusion and is consistent with manufacturing observations. A larger particle size but lack of shoulder in Batch K suggests that the increase in particle size is likely due to atomization conditions at the lower end (where atomization pressure was lowered to 20 psi to maintain G/L ratio due to the solution flow rate) and not due to particle fusion.

Water content study.

[0226] Water content was evaluated by Coulometric Karl Fischer analysis and the comparison of the results against inlet temperature and calculated relative humidity is shown in Table 15.

Table 15. Process conditions and particle size

[0227] For formulations containing 23 % flecainide acetate, the calculated relative humidity correlate well with the water content, while higher flecainide acetate loading (Batch N) appears to have a lower water content with the same theoretical relative humidity. It should be noted that for formulation Batch N, a higher inlet temperature was required (170 °C vs -150 °C) to achieve the same outlet temperature (60 °C).

Particle morphology study.

[0228] The morphology for Batch J, Batch K, and Batch L show typical corrugated (collapsed sphere) particles with no signs of fusion or crystallinity. Batch M shows a similar morphology as Batch J, Batch K, and Batch L, but there are few elongated particles present. Batch N shows significantly more elongated particles which can fuse the other particles together.

Thermal transitions study.

[0229] Thermal transitions were determined using a TA Instruments Q2000 Differential Scanning Calorimeter. Samples were sealed in a Tzero hermetic pan and scans were performed in triplicate. For each analysis, the samples were heated from -30 °C to 140 °C at a scan rate of 2.5 °C per minute and a temperature modulation of ± 1.5 °C per minute. Three glass transitions were observed for four of five samples and all values are presented in Table 16. The 50/50 formulation Batch N exhibited a different heat flow versus temperature profile as compared to the other formulations (FIG. 6) and only exhibited one glass transition (FIG. 7). The thermograms for each formulation are presented in FIGS. 22-26.

Table 16. Glass transition summaries for the five spray dried formulas

[0230] Use of a spray drying outlet temperature of 60 °C could explain the reason for poor collection yield for 50/50 formulation Batch N, where a single significant glass transition was observed. This could be because there is less cyclodextrin available to increase the overall glass transition temperature.

X-ray Powder Diffraction (XRPD) study.

[0231] Physical state was measured by a Rigaku MiniFlex 600. The results are shown in FIG. 8. Batches J - N were amorphous, while Batch N exhibited additional peaks indicating that there can be some order (or partial crystallinity) present in the powder. These can result in elongated particles.

Dynamic vapor sorption (DVS) study.

[0232] Three of the five compositions were evaluated for moisture uptake as a function of environmental humidity conditions. The three samples selected each containined 23/77 Flecainide Acetate/HP-P-CD, but were prepared under different process conditions (formulations Batch J, Batch K, and Batch L). The dynamic vapor sorption (DVS) technique was employed at 25 °C to evaluate the sorption and desorption of water. Each analysis initiated at ambient conditions (40 % RH) to avoid changes to the material during the initial desorption and sorption.

[0233] Each sample exhibited a similar isotherm profile relative to others (Batch J, 7 g/min, diluted nebulization solution preparation, FIG. 9; Batch K, 4 g/min, diluted nebulization solution preparation, FIG. 10; Batch M, 7 g/min, direct solution preparation, FIG. 11) irrespective of preparation method. These results suggest that the composition contributes more significantly than differences in manufacturing process.

[0234] The isotherms can be compared directly in the overlay of FIG. 12. The difference between formulation Batch M with respect to formulations Batch J and Batch K is likely due to the sample size and experimental variation. At 90 % RH, the change in mass was 24.9 %, 25.2 %, and 26.7 % for formulations Batch J, Batch K, and Batch M, respectively, however, the 1.8 % delta for a sample size of 3.6 mg in formulation Batch M is equivalent to 0.0648 mg.

[0235] With respect to mass change as a function of time, any loss in mass at a given relative humidity can be an indication of amorphous content recrystallizing. No negative change in mass during the sorption cycle was observed for the standard spray drying condition and solution preparation (Batch J, FIG. 13), while a change was observed with a slower feed rate (4 g/min, Batch K, FIG. 14) or solution preparation (direct to concentration, Batch M, FIG. 15).

Example 5: Stability studies of exemplar compositions

[0236] Selected samples (Batch J, Batch K, and Batch M) were placed on accelerated stability (1- month) to evaluate any changes to the physicochemical properties. Environmental conditionsof 40 °C/75 % RH open and 40 °C/75 % RH closed were evaluated, where open denotes storage in a vial covered with foil punctured with pin holes, and closed denotes storage in a vial stored with desiccant in a heat sealed mylar bag.

[0237] Batch properties over time are compared to initial values in Table 17 (Batch J), Table 18 (Batch K), and Table 19 (Batch M).

Table 17. Accelerated stability results summary table for Batch J

Table 18. Accelerated stability results summary table for Batch K

Table 19. Accelerated stability results summary table for Batch M

Purity and potency study.

[0238] The purity and potency of the Batches J - Batch M were determined using the HPLC. The same lot of flecainide acetate used in manufacturing Batches J - Batch N was used for the reference material. Purity of the samples was determined to be 100 %, as no additional peaks were observed in any of the samples above LOQ. The amount of material tested was adjusted for the 23 % loading to achieve a nominal concentration of 1.5 mgA/mL. The results are summarized in Table 20.

Table 20. Summary of potency on stability samples

Water content and residual solvent

[0239] Water content was evaluated by coulometric Karl Fischer analysis after 1-month of storage. There was insignificant change in water content of the closed condition the compositions tested, but those stored under open conditions appeared to have taken up a large amount of water (Table 21). This may be attributable to a physical form change (recrystallization of the formulation) or it can be an effect from exposure at 75 % RH (~12 % water content, FIG. 12) and the absence of an opportunity to re-equilibrate back to room condition when the sample was hermetically sealed in the sample vial for analysis.

Table 21. Summary of potency on stability samples

[0240] Residual solvent was not measured in the initial sample because the spray solution was just water. However, residual solvent was evaluated on the 1-month stability samples to determine if any volatile material was present. A small amount of an unknown solvent was detected that was not part of the standard suite solvents assayed by gas chromatography (MeOH, EtOH, acetone, IP A, ACN, DCM, EtOAc, THF, and heptane).

Table 22. Residual solvent summary for stability samples in wt%

*One value reported; other value below LOQ

[0241] Overall, the values were consistent and did not significantly vary with process condition or stability storage condition (between 0.04 and 0.07 wt%). Any variance could potentially be due to loss of acetate or a residual solvent used as part of the synthesis. pH of Reconstituted Formulations.

[0242] Reconstitution of spray dried formulations stored in the closed condition for one month at 40 °C/ 75 % RH was undertaken at a concentration of approximately 40 mg/mL (not normalized to active loading), and the solutions were then measured for pH (Table 23). The pH of the high purity water was measured as reference.

Table 23. pH values of reconstituted formulations - initial vs. 1-month samples did not impact the overall pH values of the reconstituted samples.

Geometric Particle Size Distribution Study

[0244] Geometric particle size distributions were measured by laser diffraction using a Malvern Mastersizer 3000 equipped with an Aero S dispersion unit at a dispersive air pressure of 3 bar, utilizing the same process parameters as time initial (Mie scattering theory, refractive index of the particle was set at 1.55 with the absorption set as 0.1). The particle size distribution summary is presented in Table 24 and the distribution is depicted in FIG. 16. Batch K D(v 0.9) was smaller (5.3 pm) than that observed in the initial data set (5.4 pm, see Table 14). This difference is within experimental error.

Table 24. Particle size distributions of Flecainide acetate spray dried powders after 1-month accelerated stability, closed condition

Particle Morphology.

[0245] Filaments were observed in each of the one month closed condition Batch samples. Thermal Transitions.

[0246] Thermal transitions were evaluated by modulated differential scanning calorimetry using hermetically sealed sample pans. Three broad glass transition temperatures were observed at varying temperatures (Table 25). The first glass transition temperature was lower in the open samples, likely due to the uptake of water on stability (>10 wt %). Thermograms are shown for closed, reversing (FIG. 17); closed, non-reversing (FIG. 18); open, reversing (FIG. 19); open, non-reversing (FIG. 20).

Table 25. Summary of 1-month stability thermal transitions

X-Ray Powder Diffraction (XRPD) study

[0247] The physical state of the the batch samples at 1 month were evaluated by Rigaku Miniflex 600. The diffractogram overlay is shown in FIG. 21. Batch J, Batch K, and Batch M in the closed condition did not show any signs of crystallization by XPRD. However, peaks are present in samples stored under open conditions, indicating a signification amount of crystallization. Several peaks do not comport with flecainide acetate, and may be attributable to flecainide free base.

Example 6: Aerosolization studies of exemplary compositions

[0248] This example summarizes aerosol performance of three exmemplary flecainide dry powder compositions. Specifically, the three engineered powders of spray dried flecainide acetate were characterized for aerosol performance by measuring the aerosol powder release kinetics from inhaler/capsule by laser photometry and aerodynamic particle size by Next Generation Impactor (NGI). Three spray dried flecainide acetate lots and two bulk powder storage stability conditions were evaluated; T=0M (starting time point; ambient conditions) and T=1M (1 month; 40°C/75% RH). Powders were puck filled in hypromellose size 3 capsules at a target powder mass of 50 mg and tested in the Plastiape RS01 family of Dry Powder Inhalers, medium (0.10R) and high (0.16R) flow resistance models.

[0249] Through these experiments, it was found that: (a) Aerosol performance for T=0M bulk powders was comparable when tested in RS01 medium and high flow resistance devices at a 4 kPa pressure drop; (b) T=0M and T=1M bulk powders gave similar aerosol performance when evaluated with a RS01 medium flow resistance device at a 4 kPa pressure drop; and (c) Faster aerosol (T=0M) powder emptying from inhaler/capsule for RS01 medium than high flow resistance devices with emptying volumes of <1.2 L and <2.1 L, respectively. Aerosol powder emptying characteristics were consistent for all three powder lots.

[0250] Table 26 and Table 27 show the test outline of the aerosol testing performed for T=0M and T=1M spray dried flecainide acetate powders, respectively, in this study.

Table 26. In vitro aerosol performance for T=0M powders and two flow resistance inhaler devices (0.10R and 0.16R). Three replicate runs performed for each laser photometry (2 kPa and 4 kPa) and NGI (only at 4 kPa) testing.

Table 27. In vitro aerosol performance for T=1M powders and RS01 medium flow resistance device (0.10R). Three replicate runs performed for NGI testing at 4 kPa.

[0251] Capsule Filling And Polishing

[0252] Table 28 summarizes capsule filling parameters used for manufacturing the capsules in this study. Empty hypromellose size 3 capsules were preconditioned overnight at 10 to 15%RH before filling. Mean fill mass for each powder batch is summarized below. Filled capsules were pouched and stored inside a vacuum box maintained at <30% RH (ambient temperature). Capsules were used within 14 days after manufacturing.

Table 28. Capsule filling parameters and estimated bulk powder density.

¹ Lot A, n = 16; Lot B, n = 25; Lot D, n = 25

[0253] Capsule Emptying Study by Laser Photometry

[0254] Table 29 and Table 30 summarize the capsule emptying study results for RS01 medium and high flow resistance devices, respectively, and a 50 mg powder mass per capsule. Two pressure drops where evaluated for each inhaler and powder lot. For the medium resistance device, aerosol powder clearance volume was <1.2 liters for 2 and 4 kPa inspiratory efforts, suggesting an adult with tidal volume >1.5L can empty the 50 mg capsule in a single inhalation breath. However, longer emptying volumes were observed for the high flow resistance inhaler, suggesting a second inhalation may be required.

Table 29. Laser photometry summary results for 0.10R devices. Mean of three replicates with standard deviation in parenthesis.

Table 30. Laser photometry summary results for 0.16R devices. Mean of three replicates with standard deviation in parenthesis.

[0255] Potency Determination of Bulk Powder by RP-HPLC

[0256] Potency determination by RP-HPLC for each spray dried flecainide acetate bulk powder determined drug content (flecainide acetate) to be approximately 21% (Table 31).

Table 31. Potency of bulk spray dried flecainide acetate powders (T=0M). Single replicate.

[0257] APSD Analysis for T=0M Powders (Lot A, Lot B, and Lot D) with Medium Flow Resistance RS01 DPI (0.1 OR)

[0258] Table 32 and FIG. 27 present the aerosolized particle agglomerates tested with RS01 medium flow resistance device at 4 kPa (corresponding to 64 L/min) for T=0M powders. Aerosol performance data show powders Lot A and Lot D were comparable, and resulted in a finer aerosol quality than powder Lot B. Of note, this corresponds with the fact that powders Lot A and Lot D were manufactured under similar spray dried parameters and conditions, differing only by solution feedstock preparation. While the solution feedstock preparation procedure was similar between Lot B and Lot A, the spray drying parameters and conditions differed. Lot A corresponds to Batch J in Example 4, Lot B corresponds to Batch K, and Lot C to Batch M. These results also correspond with primary particle size measured by the client by laser diffraction which saw smaller particle sizes for Lot A (1.9 pm) and Lot D (1.7 pm) compared to Lot B (2.4 pm).

Table 32. Aerodynamic particle size by NGI for T=0M powders tested in the RS01 medium flow resistance (0.10R) device with a 50 mg capsule powder mass. Mean of three replicates with standard deviation in parenthesis.

¹ NGI total recovery normalized to actual capsule powder fill mass.

[0259] APSD Analysis for T=0M Powders (Lot B and Lot D) with High Flow Resistance RS01 DPI (0.16R)

[0260] Table 33 and FIG. 28 summarize the aPSD results and particle size distribution plot, respectively, for the RS01 high flow resistance device tested at 4 kPa (corresponding to 40 L/min) with the Lot B and Lot D T=0M powders. Mean MMAD was 3.9 pm and 3.2 pm for Lot B and Lot D powders, respectively, which is comparable in performance to the corresponding result for each powder with the RS01 medium flow resistance device (Table 32).

Table 33. Aerodynamic particle size by NGI for T=0M powders tested in the RS01 high flow resistance (0.16R) device with a 50 mg capsule powder mass. Mean of three replicates with standard deviation in parenthesis.

¹ NGI total recovery normalized to actual capsule powder fill mass.

[0261] APSD Analysis for T=1 Month At 40°C/75% Relative Humidity Powders (Lot A, Lot B, and Lot D) with Medium Flow Resistance RS01 DPI

[0262] For the T=1M storage timepoint, powders were stored at the Client’s powder manufacturing facility at 40°C/75% RH in glass vials and protected from moisture using over- pouching. After the 1 -month stability pull, powders were shipped for aerosol analysis. Each powder lot was filled into size 3 capsules using similar capsule filling conditions and parameters, and capsule polishing to the T=0M powders. The same RS01 medium flow resistance device at 4 kPa pressure was used to evaluate the aerosol performance for the T=1M powders. Summary aerosol data and particle size distribution plot comparing the aerosol performance for all 3 powder lots are presented in Table 34 and FIG. 29, respectively. Aerosol performance results for the T=1M powders were comparable to T=0M powders for all three lots, indicating no physical impact to powder properties after 1 -month storage at 40°C/75% RH.

Table 34. Aerodynamic particle size by NGI for T=1M powders tested in RS01 medium flow resistance (0.10R) and 50 mg capsule powder fill mass. Mean of three replicates with standard deviation in parenthesis.

¹ NGI total recovery normalized to actual capsule fill mass.

[0263] Performance of RS01 Medium Versus High Flow Resistance Devices

[0264] Aerosol powder release kinetics from the inhaler/capsule by laser photometry show faster capsule emptying for RS01 medium than high flow resistance device for all 3 powder lots and at both 2 and 4 kPa tested pressure drops. Therefore, patients that are able to generate inhaled volume of >1.5 L can receive the dose from a 50 mg capsule powder mass in a single inhalation maneuver

(FIGS. 30-33)

[0265] APSD Performance Comparing Two Flow Resistance Inhaler Devices (0.10R and 0.16R) with two different lots of T=0M powders

[0266] Aerosol performance for RS01 medium and high flow resistance devices tested at 4 kPa pressure drop were comparable (Table 35 and FIG. 34).

Table 35. NGI summary for T=0M powders tested in RS01 medium and high flow resistance devices (0.10R and 0.16R) at 4 kPa and 50 mg capsule powder fill mass. Mean of three replicates with standard deviation in parenthesis.

[0267] APSD Performance Comparing Two Stability Time Points, T=0M and T=1M (40°C/75%RH), with RS01 Medium Flow Resistance Inhaler Device

[0268] Aerosol quality for T=0M and T=1M (40°C/75% RH) powders tested with the RS01 medium flow resistance device was comparable, see Table 36 and FIGS. 35-38).

Table 36. NGI summary for T=0M and T=1M powders tested in RS01 medium flow resistance (0.10R) at 4 kPa and 50 mg capsule powder fill mass. Mean of three replicates with standard deviation in parenthesis.

[0269] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the present disclosure may be employed in practicing the present disclosure. It is intended that the following claims define the scope of the present disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.