Dofetilide formulations

Abstract

The present invention relates to novel dofetilide-containing pharmaceutical formulations, particularly those that contain sodium chloride, sodium acetate, and acetic acid. The present invention further relates to dilutions of these formulations in normal saline or dextrose solutions. The present invention also provides a method of manufacturing the pharmaceutical formulations and uses of the pharmaceutical formulations and dilutions as a medicine.

Description

DOFETILIDE FORMULATIONSFIELD OF THE INVENTIONThe present invention relates to novel formulations of dofetilide and their manufacturing and use.BACKGROUND OF THE INVENTION

[0001] Dofetilide (P-((p-methanesulfonamidophenethyl)methylamino)methanesulfono-p- phenetidide) is an anti-arrhythmic of the Vaughn Williams Class III. Dofetilide is commercially available as an oral capsule, with tradename Tykosin® by Pfizer, for the maintenance of sinus rhythm in individuals prone to the formation of atrial fibrillation and flutter, and for the chemical cardioversion to sinus rhythm from atrial fibrillation and flutter. However, patients under nothing by mouth (NPO), or having emesis, severe gastrointestinal (GI) absorption problems, are intubated, or who have problems swallowing, cannot take dofetilide orally. To avoid these complications, and to enhance the patient compliance it would be advantageous to develop a dofetilide parenteral dosage form. Currently there is no commercially approved sterile solution for infusion for Dofetilide.

[0002] As discussed in US Patent No. 11,364,213, dofetilide is currently being investigated for use intraveneously. However, US Patent No. 11 ,364,213 compositions either use excipients that have unfavourable toxicity profile or have an acidic pH (lower to 5).

[0003] Atrial fibrillation, long considered the most common condition leasing to an irregular heartbeat, is a growing and serious global health problem. Hence, there is a need for additional treatment option.

[0004] Thus, it would be beneficial to discover formulations of dofetilide that would allow for intravenous administration. For intravenous administration it can be beneficial to have storage stable, ready-to-dilute or ready-to-use dofetilide formulations. In addition, it could be advantageous to have dofetilide formulations ready-to-dilute or ready-to-use for one-day loading and methods of one-day dofetilide loading.SUMMARY OF THE INVENTION

[0005] Accordingly, in an aspect, the present invention describes novel pharmaceutical compositions, comprising: a therapeutically effective amount of dofetilide and a pharmaceutically acceptable carrier.

[0006] In another aspect, the formulations described herein are suitable for intravenous administration.

[0007] These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors’ discovery of dofetilide formulations.

[0008] In a first aspect, the invention provides a dofetilide pharmaceutical composition comprising: a. 10-1000 pg / mL dofetilide; b. 4-8 mg / mL sodium chloride; c. 0.1 -0.5 mg / mL acetic acid; d. 2-6 mg / mL sodium acetate; and e. water; wherein: the pH of the composition is 4-7; and, the composition is provided for intravenous administration.

[0009] In a preferred embodiment, the amount of dofetilide in the composition is 10-500 pg / mL, preferably 10-100 pg / mL, more preferably 40-60 pg / mL, most preferred 50 pg / mL.

[0010] In a preferred embociment, the amount of sodium chloride in the composition is 5-8 mg / mL, preferably 6-7 mg / mL, more preferably 6.3-6.7 mg / mL, most preferred 6.5 mg / mL.

[0011] In a preferred embodiment, the amount of acetic acid in the composition is 0.2-0.4 mg / mL, preferably 0.25-0.35 mg / mL, more preferably 0.3-0.35 mg / mL, most preferred 0.31 mg / mL.

[0012] In a preferred embodiment, the amount of sodium acetate in the composition is 3-5 mg / mL, preferably 3.5-4.5 mg / mL, more preferably 3.5-4.0 mg / mL, most preferred 3.7 mg / mL.

[0013] In another preferred embodiment, the pH of the composition is 5-6, preferably the pH is 5.2-5.8, more preferably the pH is 5.4-5.6

[0014] In another preferred embodiment, the composition has an osmolality of 285-320 mOsmol / 1 as determined by point depression according to USP 788, preferably 290-315 mOsmol / 1, more preferably 295-310 mOsmol / 1, even more preferably 300-305 mOsmol / 1 as determined by point depression according to USP 788.

[0015] It is beneficial to have dofetilide formulations for intravenous administration with osmolality and pH near physiological blood / plasma levels.

[0016] In another preferred embodiment, the composition is a solution.

[0017] In a preferred embodiment, the composition has a storage stability of at least 6 months, preferably at least 12 months, more preferably at least 18 months, most preferably at least 24 months, as measured at 40°C and 75% Relative Humidity.

[0018] In a preferred embodiment, the composition has a storage stability of at least 6 months, preferably at least 12 months, more preferably at least 18 months, most preferably at least 24 months, as measured at 25°C and60% Relative Humidity.

[0019] In a preferred embodiment, the composition has less than 1.00% w / w dofetilide related compound A (USP). More preferably the composition has less than 0.9% w / w, even more preferably less than 0.7% w / w, most preferably less than 0.5% w / w dofetilide related compound A (USP).

[0020] In a most preferred embodiment, the composition consists of: a) 50 pg / mL dofetilide; b) 6.5 mg / mL sodium chloride; c) 0.31 mg / mL acetic acid; d) 3.7 mg / mL sodium acetate; and, e) water; wherein: the pH of the composition is 5.4-5.6 and, the composition is provided for intravenous administration.

[0021] In a further aspect, the invention provides a dofetilide pharmaceutical composition according to an embodiment of the invention for use as a medicine, particularly as a medicine for intravenous administration in a patient in need thereof. Preferably, the dofetilide pharmaceutical composition is for use in the maintenance of sinus rhythm in individuals prone to the formation of atrial fibrillation and flutter, or for use in the chemical cardioversion to sinus rhythm from atrial fibrillation and flutter. Preferably, the dofetilide pharmaceutical composition is for use wherein the patient cannot take oral tablets.

[0022] In a preferred embodiment, the intravenous administration is preceded by diluting in saline 0.09% or dextrose 5% a composition according to an embodiment of the invention.

[0023] In a further aspect, the invention provides a container comprising a composition according to an embodiment of the invention; wherein the container is amber colored glass.

[0024] In a further aspect, the invention provides a method of manufacturing a composition according to an embodiment of the invention, comprising the step of providing dofetilide with a particle side D(90) of less than 10 microns. Preferably dofetilide is poymorph Pl 62 dofetilide. Preferably the composition is aseptically filtrated.DETAILED DESCRIPTION OF THE INVENTION

[0025] All references cited herein are hereby incorporated in their entirety by reference.

[0026] Thus, in an aspect, the present invention relates to novel dofetilide formulations.

[0027] In another aspect, the present invention relates to a novel pharmaceutical composition, comprising: a. 10-1000 pg / mL dofetilide; b. 4-8 mg / mL sodium chloride; c. 0.1 -0.5 mg / mL acetic acid; d. 2-6 mg / mL sodium acetate; and e. water; wherein: the pH of the composition is between 4-7; and, the composition is provided for intravenous administration.

[0028] Between refers to values that are inclusive of the endpoints (e.g., between 4-7 include both 4 and 7 in the recited range).

[0029] Provided for intravenous administration means that the composition needs to fulfill some specific physiological conditions to ensure safety, compatibility, and efficacy when administered intravenously such as having pH and osmolality values similar to the physiological blood / plasma levels. In addition, the composition is sterile.

[0030] The inventors have surprisingly found that a composition according to an embodiment of the invention is advantageous as it provides a dofetilide composition with longterm stability, and provided for intravenous administration. The latter means that the pH andpreferably also osmolality values are close to the physiological blood / plasma levels (e.g., typically 275-295 mOsm / kg). In addition, the composition is sterile.

[0031] Furthermore, a composition according to an embodiment of the invention complies with IIG limits, which facilitates regulatory approval. IIG = Inactive Ingredient Database (FDA). The IIG specifies the maximum amount of inactive ingredient for a route of administration / dosage form.

[0032] Additional examples of the concentration of dofetilide include: (a) 10, 20, 30,40, 50, 60, 70, 80 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, and 500 pg / mL, (b) 10-500 pg / mL, (c) 10-100 pg / mL, (d) 20-80 pg / mL, (e) 30-70 pg / mL, (f) 40-60 pg / mL, and (g) 50 pg / mL.

[0033] In a preferred embodiment, the amount of dofetilide in the composition is 10-500 pg / mL, preferably 10-100 pg / mL, more preferably 40-60 pg / mL, most preferred 50 pg / mL.

[0034] Additional examples of the concentration of sodium chloride include: (a) 4, 4.1,4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4,6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8 mg / mL; (b) 5-8 mg / mL; (c) 6-7 mg / mL, (d) 6.3-6.7 mg / mL; and (e) 6.5 mg / mL.

[0035] In a preferred embodiment, the amount of sodium chloride in the composition is 5-8 mg / mL, preferably 6-7 mg / mL, more preferably 6.3 to 6.7 mg / mL, most preferred 6.5 mg / mL.

[0036] Additional examples of the concentration of acetic acid include: (a) 0.1, 0.11,0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, and 0.5 mg / mL; (b) 0.2-0.4 mg / mL; (c) 0.25-0.35 mg / mL; (d) 0.3-0.35 mg / mL; and, (e) 0.31 mg / mL.

[0037] In a preferred embodiment, the amount of acetic acid in the composition is 0.2-0.4 mg / mL, preferably 0.25-0.35 mg / mL, more preferably 0.3-0.35 mg / mL, most preferred 0.31 mg / mL.

[0038] Additional examples of the concentration of sodium acetate include: (a) 2, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4,4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, and 6 mg / mL; (b) 3-5 mg / mL; (c) 3.5-4.5 mg / mL; (d) 3.5-4 mg / mL; and, (e) 3.7 mg / mL.

[0039] In a preferred embodiment, the amount of sodium acetate in the composition is3-5 mg / mL, preferably 3.5-4.5 mg / mL, more preferably 3.5-4.0 mg / mL, most preferred 3.7 mg / mL.

[0040] Examples of the pH of the intravenous formulation include (a) 4, 4.1, 4.2, 4.3,4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7; (b) 5-6; (c) 5.2-5.8, (d) 5.4-5.6; and, (e) 5.5.

[0041] In a preferred embodiment, the pH of the composition is 5-6, preferably the pH is 5.2-5.8, more preferably the pH is 5.4-5.6.

[0042] In another aspect, the present invention relates to a composition comprising l. lxlO'9to 0.0003M of hydrochloric acid (HC1). Preferably, the composition comprises l. lxlO'9to 0.00029M of HC1, more preferably l. lxlO'9to 0.00028M of HC1, even more preferably 1.1x10"9to 0.00027M, most preferred 1.1x10-9 to 0.00026M of HC1, even most preferred l. lxlO'9to 0.00025M of HCl.

[0043] In another aspect, the present invention relates to a novel pharmaceutical composition, comprising: a. 10-500 pg / mL dofetilide; b. 5-8 mg / mL sodium chloride; c. 0.2-0.4 mg / mL acetic acid; d. 3-5 mg / mL sodium acetate; and e. water; wherein: the pH of the composition is between5-6; and, the composition is suitable for intravenous administration.

[0044] In another aspect, the present invention relates to a novel pharmaceutical composition, comprising: a. 10-100 pg / mL dofetilide; b. 6-7 mg / mL sodium chloride; c. 0.25-0.35 mg / mL acetic acid; d. 3.5-4.5 mg / mL sodium acetate; and e. water; wherein: the pH of the composition is between5.2-5.8; and,the composition is suitable for intravenous administration.

[0045] In another aspect, the present invention relates to a novel pharmaceutical composition, comprising: a. 40-60 pg / mL dofetilide; b. 6.3-6.7 mg / mL sodium chloride; c. 0.3-0.35 mg / mL acetic acid; d. 3.5-4 mg / mL sodium acetate; and e. water; wherein: the pH of the composition is between 5.4-5.6; and, the composition is suitable for intravenous administration.

[0046] In another aspect, the present invention relates to a novel pharmaceutical composition, comprising: a. 50 pg / mL dofetilide; b. 6.5 mg / mL sodium chloride; c. 0.31 mg / mL acetic acid; d. 3.7 mg / mL sodium acetate; and e. water; wherein: the pH of the composition is 5.5; and, the composition is suitable for intravenous administration.

[0047] In another aspect, the present invention relates to a novel pharmaceutical composition, consisting essentially of: a. 50 pg / mL dofetilide; b. 6.5 mg / mL sodium chloride; c. 0.31 mg / mL acetic acid; d. 3.7 mg / mL sodium acetate; and e. water; wherein:less than 1.00% w / w dofetilide related compound A (USP) is present; the pH of the composition is between5.4-5.6 and is optionally obtained by the addition of NaOH or HC1; and, the composition is suitable for intravenous administration.

[0048] In another aspect, the present invention relates to a novel pharmaceutical composition, consists of: a. 50 pg / mL dofetilide; b. 6.5 mg / mL sodium chloride; c. 0.31 mg / mL acetic acid; d. 3.7 mg / mL sodium acetate; and e. water; wherein: less than 1.00% w / w dofetilide related compound A (USP) is present; the pH of the composition is between 5.4-5.6 and is optionally obtained by the addition of NaOH or HC1; and, the composition is suitable for intravenous administration.

[0049] In another aspect, the present invention relates to compositions which are substantially free of surfactants (e.g., to solubilize dofetilide). By “free of surfactant” as used herein is meant, below a detection limit of 0.03 microgram / mL.

[0050] In another aspect, the present invention relates to compositions which are substantially free of oils (e.g., to emulsify dofetilide). By “free of oil” as used herein is meant, below a detection limit of 0.03 microgram / mL.

[0051] In another aspect, the present invention relates to compositions that are solutions.

[0052] In another aspect, the present invention relates to compositions that are substantially free of suspended materials. This means solution clarity.

[0053] In another aspect, the present invention relates to compositions that are suitable for IV administration.

[0054] In another aspect, the present invention relates to compositions having an osmolality of between 285-320 mOsmol / L as determined by point depression according to USP788. Additional examples of osmolality include (a) 285, 290, 295, 300, 305, 310, 315, and 320, (b) 290-315, (c) 295-310, and (d) 300-305 mOsmol / L.

[0055] In a preferred embodiment, the composition has an osmolality of 285-320 mOsmol / 1 as determined by point depression according to USP 788, preferably 290-315 mOsmol / 1, more preferably 295-310 mOsmol / 1, even more preferably 300-305 mOsmol / 1 as determined by point depression according to USP 788.

[0056] In another aspect, the present invention relates to compositions having a dofetilide related compound A below 1% w / w (USP). Preferably the composition has less than 0.9% w / w, more preferably less than 0.7% w / w, even more preferably less than 0.5% w / w dofetilide related compound A (USP). Dofetilide related compound A is known as (N-[4-(2-{2-[4- Methanesulfonamido)phenoxy] ethylamino} ethyl)phenyl]methanesulfonamide (CAS number 176447-94-2; United States Pharmacopeia).

[0057] In a preferred embodiment, the composition has a storage stability of at least 6 months, preferably at least 12 months, more preferably at least 18 months, most preferably at least 24 months, as measured at 40°C and 75% Relative Humidity.

[0058] In a preferred embodiment, the composition has a storage stability of at least 6 months, preferably at least 12 months, more preferably at least 18 months, most preferably at least 24 months, as measured at 25°C and60% Relative Humidity.

[0059] In another aspect, the present invention relates to a method of manufacturing compositions according to the invention, comprising the step of using dofetilide active ingredient with particle size D(90) of 10 microns. Additional examples include particles sizes less than 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, and 2 microns.

[0060] In another aspect, the present invention relates to a method of manufacturing dofetilide compsitions according to the invention, comprising dofetilide in polymorph Pl 62 form. The polymorph P162 form is discussed in EP1027329 and US36124363.

[0061] In another aspect, the present invention relates to a method of manufacturing dofetilide composition according to the invention, comprising aseptic filtration of the composition.

[0062] In another aspect, the present invention provides a method of treatment of a patient in need of dofetilide therapy, comprising the step of providing a composition described herein; diluting the composition in normal saline 0.09% or dextrose 5% prior to intravenous administration to said patient.

[0063] In another aspect, the present invention provides a dofetilide composition for use in the treatment of a dofetilide-responsive disease in a patient in need of dofetilide therapy comprising the step of diluting in saline 0.09% or dextrose 5% the composition according to an embodiment of the invention and intravenous administration of the diluted composition obtained to the patient.

[0064] In another aspect the diluted composition has an osmolality of 285-320 mOsmol / 1 as determined by point depression according to USP 788. Additional examples of osmolality include (a) 285, 290, 295, 300, 305, 310, 315, and 320, (b) 290-315, (c) 295-310, and (d) 300-305 mOsmol / L.

[0065] In a preferred embodiment, the diluted composition has an osmolality of 285-320 mOsmol / 1 as determined by point depression according to USP 788, preferably 290-315 mOsmol / 1, more preferably 295-310 mOsmol / 1, even more preferably 300-305 mOsmol / 1 as determined by point depression according to USP 788.

[0066] In a further aspect, the invention provides a dofetilide pharmaceutical composition according to an embodiment of the invention for use as a medicine, particularly as a medicine for intravenous administration. Preferably the dofetilide pharmaceutical composition is for use in the maintenance of normal sinus rhythm in a patient prone to the formation of atrial fibrillation and flutter, or for use in the chemical cardioversion to normal sinus rhythm from atrial fibrillation and flutter. Preferably the patient is a human patient. Preferably the human patient was not previously on dofetilide oral tablets.

[0067] In a preferred embodiment, the intravenous administration is preceded by diluting in saline 0.09% or dextrose 5% a composition according to an embodiment of the invention.

[0068] In a further aspect, the invention provides a diluted dofetilide composition for use in a patient in need of dofetilide therapy comprising the step of diluting in saline 0.09% or dextrose 5% acomposition according to an embodiment of the invention prior to intravenous administration of the diluted dofetilide composition to the patient.

[0069] In a further aspect, the invention provides a container comprising a composition according to an embodiment of the invention; wherein the container is an amber colored glass container. Use of amber colored glass protects the composition from UV rays below 450 nm.

[0070] In an alternative embodiment, the container is an infusion bag. Preferably the infusion bag is provided in an amber bag. The amber bag is beneficial for restricting exposure of the composition to UV light.

[0071] In a preferred embodiment the container holds a unit dose of 5 to 10 ml of a sterile composition according to an embodiment of the invention, with a dofetilide concentration of 50 microgram per ml. This is advantageous as it provides a product which is ready-to-dilute or ready-to-use. This is especially beneficial for one-day loading and methods of one-day dofetilide loading.

[0072] In a further aspect, the invention provides a method of manufacturing a composition according to an embodiment of the invention, comprising the step of providing dofetilide with a particle side D(90) of less than 10 microns. Preferably dofetilide is poymorph Pl 62 dofetilide. Preferably the composition is aseptically filtrated. Preferably the containers for receipt of the sterilized composition are pre-sterilized.

[0073] In a preferred embodiment, the composition according to an embodiment of the invention is sterile and comprises less than 25 EU / mL of bacterial endotoxin as determined by USP<85>.

[0074] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is intended to be taken individually as its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

[0075] Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.FURTHER EMBODIMENTS1. A dofetilide pharmaceutical composition, comprising: a) 10-1000 pg / mL dofetilide; b) 4-8 mg / mL sodium chloride; c) 0.1 -0.5 mg / mL acetic acid; d) 2-6 mg / mL sodium acetate; and e) water; wherein: the pH of the composition is between 4-7; and, the composition is suitable for intravenous administration.2. The composition of embodiment 1, wherein the composition, comprises: a) 10-500 pg / mL dofetilide; b) 5-8 mg / mL sodium chloride; c) 0.2-0.4 mg / mL acetic acid; d) 3-5 mg / mL sodium acetate; and e) water; wherein: the pH of the composition is between 5-6; and, the composition is suitable for intravenous administration.3. The composition of embodiment 1, wherein the composition, comprises: a) 10-100 pg / mL dofetilide; b) 6-7 mg / mL sodium chloride; c) 0.25-0.35 mg / mL acetic acid; d) 3.5-4.5 mg / mL sodium acetate; and e) water; wherein: the pH of the composition is between 5.2-5.8; and, the composition is suitable for intravenous administration.The composition of embodiment 1, wherein the composition, comprises: a) 40-60 pg / mL dofetilide; b) 6.3-6.7 mg / mL sodium chloride; c) 0.3-0.35 mg / mL acetic acid; d) 3.5-4 mg / mL sodium acetate; and e) water; wherein: the pH of the composition is between 5.4-5.6; and, the composition is suitable for intravenous administration. The composition of embodiment 1, wherein the composition, comprises: a) 50 pg / mL dofetilide; b) 6.5 mg / mL sodium chloride; c) 0.31 mg / mL acetic acid; d) 3.7 mg / mL sodium acetate; and e) water; wherein: the pH of the composition is between 5.4-5.6; and, the composition is suitable for intravenous administration. The composition of one of embodiments 1-4, wherein the concentration of dofetilide is 50 pg / mL. The composition of one of embodiments 1-5, wherein the composition has an osmolality of 285-320 mOsmol / 1 as determined by point depression according to USP 788. The composition of one of embodiments 1-6, wherein the composition is a solution. The composition of one of embodiments 1-7, wherein the composition has a storage stability of at least 6 months as measured at 40°C and 75% Relative Humidity.The composition of embodiment 5, wherein the composition consists essentially of: a) 50 pg / mL dofetilide; b) 6.5 mg / mL sodium chloride; c) 0.31 mg / mL acetic acid; d) 3.7 mg / mL sodium acetate; and, e) water; wherein: less than 1.00% w / w dofetilide related compound A (USP) is present; the pH of the composition is between 5.4-5.6 and is optionally obtained by the addition of NaOH or HC1; and, the composition is suitable for intravenous administration. The composition of embodiment 5, wherein the composition consists of: a) 50 pg / mL dofetilide; b) 6.5 mg / mL sodium chloride; c) 0.31 mg / mL acetic acid; d) 3.7 mg / mL sodium acetate; and, e) water; wherein: less than 1.00% w / w dofetilide related compound A (USP) is present; the pH of the composition is between 5.4-5.6 and is optionally obtained by the addition of NaOH or HC1; and, the composition is suitable for intravenous administration. A method of manufacturing a composition according to embodiment 1, comprising the steps of providing dofetilide with a particle size D(90) less than 10 microns. The method of embodiment 12, wherein dofetilide is polymorph Pl 62 dofetilide. The method of embodiment 12, wherein the composition is aseptically filtrated. A container comprising a composition according to embodiment 1, wherein the container is amber colored glass. A method of treatment of a patient in need of dofetilide therapy, comprising the step of providing a composition of embodiment 1 ; diluting the composition in normal saline 0.09% or dextrose 5% prior to intravenous administration to the patient.EXAMPLES

[0076] Examples 1 and 2 as exemplified in the table below are manufactured at 2 different locations using different manufacturing processes. In example 1 the API is added first in the water and then rest of the excipients / buffers were mixed, while in Example 2 the API is added after the addition of buffers. API=dofetilide.

[0077] Molecular weight for reference: a. Acetic acid: 60.05 b. Hydrochloric acid: 36.5 c. Sodium acetate anhydrous: 82.03 d. Sodium Chloride: 58.44

[0078] Examples 1 and 2*q.s =quantum santis, as much as needed

[0079] Example 1: Dofetilide 50 pg / ml solution for injection in 0.05M acetate buffer pH 5.5

[0080] A 400 mL batch size was made as follows: a. Step-1 : In a suitable stainless steel / glass container a mixing speed speed is set to create a slight vortex in WFI with overhead mixer or suitable mixing apparatus. b. Step-2: Take a sample for dissolved oxygen determination. c. Step-3: While continuing to mix, add 20 mg of dofetilide to the stirring water and allow mixing for a minimum of 60 minutes. Record the amount added and record the addition and mixing time. d. Step-4: While continuing to mix, add 2.60 g of Sodium Chloride to the stirring water and allow mixing for a minimum of 5 minutes. e. Step-5: While continuing to mix, add 1.48 g of Sodium Acetate anhydrous to the stirring water and allow mixing for a minimum of 5 minutes. f. Step-6: While continuing to mix, add 124 mg (0.188mL) of Glacial Acetic Acid to the stirring water and allow mixing for a minimum 5 minutes. g. Step-7: Weigh bulk container after addition of all excipients, transfer remaining water (to a total of 400 mL of solution) to bulk container. h. Step-8: Mix for a minimum of 10 minutes. i. Step-9: Measure the pH of the solution and record the value. j. Step- 10: Verify that the pH value is between 5.4 and 5.6. k. Step-11 : If the pH is less than 5.4, use 50% sodium hydroxide solution to adjust the pH, using a pipette and pipette tip to adjust the pH between 5.4 and 5.6. l. Step-12: If the pH is greater than 5.6, take IN hydrochloric acid using a sterile 5- mL syringe with needle to adjust the pH between 5.4 and 5.6. m. Step-13: Filter the solution using a suitable syringe filter (0.22pm). Take a sample for analysis of the specific gravity. n. Step-14: Filter the solution again using a syringe filter prior to filling, fill the vials, and stopper them. Crimp the vials.

[0081] Example 2: Dofetilide 50 pg / ml solution for injection in 0.05M acetate buffer pH 5.5

[0082] A 400 mL batch size was made as follows: a. Step-1 : In a suitable stainless-steel glass container a mixing speed speed is set so as to create a slight vortex in WFI with overhead mixer or suitable mixing apparatus. b. Step-2: Take a sample for dissolved oxygen. c. Step-3: While continuing to mix, add 2.60 g of Sodium Chloride to the stirring water and allow mixing for a minimum of 5 minutes. d. Step-4: While continuing to mix, add 1.48 g of Sodium Acetate to the stirring water and allow mixing for a minimum of 5 minutes. e. Step-5: While continuing to mix, add 124 (0.188mL) mg of Glacial Acetic Acid to the stirring water and allow mixing for a minimum 5 minutes. Check the pH. f. Step-6: While continuing to mix, add 20 mg of dofetilide to the stirring water and allow mixing for 60 minutes or till clear solution is obtained. Record the amount added and record addition and mixing time. g. Step-7: Weigh bulk container after addition of all excipients, transfer remaining water (400 mL total solution) to bulk container. h. Step-8: Mix for a minimum of 10 minutes. i. Step-9: Measure the pH of the solution and record the value. j. Step- 10: Verify that the pH value is between 5.4 and 5.6. k. Step-11 : If the pH is less than 5.4, use 50% sodium hydroxide solution to adjust the pH, using a pipette and pipette tip to adjust the pH between 5.4 and 5.6. l. Step-12: If the pH is greater than 5.6, take IN hydrochloric acid using a sterile 5-mL. syringe with needle to adjust the pH between 5.4 and 5.6. m. Step-13: Filter the solution using suitable syringe filter (0.22pm). Take sample for specific gravity. n. Step-14: Filter the solution again using syringe filter prior to filling, fill the vials, and stopper them. Crimp the vials.

[0083] Example 3

[0084] Primary packing materials for both formulation

[0085] Stability DesignOrientation of sample: @ Inverted, $ Upright, W= Weeks. Placebo to be kept for stability.Note: Samples only at accelerated stability conditions were analysed

[0086] Stability Results

[0087] Formulation Example 1

[0088] In this formulation, Example 1 , the samples were withdrawn at different time points as per stability protocol and tested at 2 weeks to 24 weeks as indicated in first column. The second column indicates the accelerated stability condition of 40°C / 75% RH from where samples were taken out during stability studies. The third column indicates the assay of the samples. The fourth column indicates dofetilide known impurity A. The fifth column indicates single unknown maximum impurity. The sixth column indicates total impurities observed in the sample. The seventh column indicates osmolality of the solution. The final eight column indicates pH of the formulation observed during the stability studies

[0089] Table 1. Stability results summary - Formulation 1 (Clear vials)

[0090] Table 2. Stability results summary - Formulation 1 (Amber vials)

[0091] N / D - Not detected (below quantifiable limit: 0.05%)

[0092] RCA - Dofetilide Related Compound A (USP)

[0093] Formulation Example 2

[0094] Table 3. Stability results summary - Formulation 2 (Clear vials)

[0095] Table 4. Stability results summary - Formulation 2 (Amber vials)N / D - Not detected (below quantifiable limit: 0.05%)RCA - Dofetilide Related Compound A (USP)

[0096] Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein.

Claims

CLAIMS1. A dofetilide pharmaceutical composition, comprising: a. 10-1000 pg / mL dofetilide; b. 4-8 mg / mL sodium chloride; c. 0.1 -0.5 mg / mL acetic acid; d. 2-6 mg / mL sodium acetate; and e. water; wherein: the pH of the composition is 4-7; and, the composition is providedfor intravenous administration.

2. The composition according to claim 1, wherein the amount of dofetilide is 10-500 pg / mL, preferably 10-100 pg / mL, more preferably 40-60 pg / mL, most preferred 50 pg / mL.

3. The composition according to any of the previous claims, wherein the amount of sodium chloride is 5-8 mg / mL, preferably 6-7 mg / mL, more preferably 6.3 to 6.7 mg / mL, most preferred 6.5 mg / mL.

4. The composition according to any of the previous claims, wherein the amount of acetic acid is 0.2-0.4 mg / mL, preferably 0.25-0.35 mg / mL, more preferably 0.3-0.35 mg / mL, most preferred 0.31 mg / mL.

5. The composition according to any of the previous claims, wherein the amount of sodium acetate is 3-5 mg / mL, preferably 3.5-4.5 mg / mL, more preferably 3.5-4.0 mg / mL, most preferred 3.7 mg / mL.

6. The composition according to any of the previous claims, wherein the pH is 5-6, preferably the pH is 5.2-5.8, more preferably the pH is 5.4-5.6.

7. The composition according to any of the previous claims, wherein the composition has an osmolality of 285-320 mOsmol / 1 as determined by point depression according to USP788, preferably 290-315 mOsmol / 1, more preferably 295-310 mOsmol / 1, even more preferably 300-305 mOsmol / 1 as determined by point depression according to USP 788.

8. The composition according to any of the previous claims, wherein the composition is a solution.

9. The composition according to any of the previous claims, wherein the composition has a storage stability of at least 6 months, preferably at least 12 months, more preferably at least 18 months, most preferably at least 24 months, as measured at 40°C and 75% Relative Humidity.

10. The composition according to any of the previous claims, wherein less than 1.00% w / w dofetilide related compound A (USP) is present in the composition.

11. The composition according to any of the previous claims, wherein the composition consists of: a) 50 pg / mL dofetilide; b) 6.5 mg / mL sodium chloride; c) 0.31 mg / mL acetic acid; d) 3.7 mg / mL sodium acetate; and, e) water; wherein: the pH of the composition is 5.4-5.6 and, the composition is provided for intravenous administration.

12. A dofetilide pharmaceutical composition according to any of the previous claims for use as a medicine, preferably as a medicine for intravenous administration in a patient in need thereof.

13. The dofetilide pharmaceutical composition for use according to claim 12 for use in the maintenance of normal sinus rhythm in a patient prone to the formation of atrialfibrillation or flutter, or for use in the chemical cardioversion to normal sinus rhythm from atrial fibrillation and flutter.

14. The dofetilide pharmaceutical composition for use according to claims 12 or 13, wherein the patient cannot take oral tablets.

15. The dofetilide pharmaceutical composition for use according to claims 12 to 14, wherein the dofetilide composition is diluted in saline 0.09% or dextrose 5% prior to intravenous administration to the patient.

16. A container comprising a composition according to any of the previous claims 1 to 15, wherein the container is amber colored glass.

17. A method of manufacturing a composition according to any of the previous claims 1 to 15, comprising the steps of providing dofetilide with a particle size D(90) of less than 10 microns.

18. The method according to claim 17 wherein dofetilide is polymorph Pl 62 dofetilide.

19. The method according to any of the previous claims 17 or 18, wherein the composition is aseptically filtrated.

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