PRIORITY CLAIM

This application claims the benefit of U.S. Provisional Patent Application Ser. No. 61/353,927 filed on Jun. 11, 2010, the entire disclosure of which is hereby incorporated by reference.

I. FIELD OF THE INVENTION

The invention encompasses ready to use liquid formulations including amiodarone or a salt thereof and a substituted cyclodextrin. The invention also encompasses methods of making the liquid formulations to provide acceptable concentrations of amiodarone suitable for parenteral administration while avoiding the formation of gel or particulates. The liquid formulations of the invention are formulations, for example, included in an intravenous bag or bottle.

II. BACKGROUND OF THE INVENTION

Amiodarone is approved for the treatment of life-threatening ventricular tachyarrhythmias. Amiodarone is also useful in treating less severe ventricular arrhythmias and many supraventricular arrhythmias including atrial fibrillation and reentrant tachyarrhythmias involving accessory pathways. Because amiodarone exhibits marked inter-individual variations, close monitoring of the individual is essential to adjust the amount of the drug delivered. The most important treatment-emergent adverse effects are hypotension, asystole/cardiac arrest/electromechanical dissociation (â€œEMDâ€ ), cardiogenic shock, congestive heart failure, bradycardia, liver function abnormalities, ventricular tachycardia, and atrio-ventricular block (See, e.g., Wyeth-Ayerst product insert for CORDARONEÂ® Intravenous).

The solubility of amiodarone hydrochloride in water is low, but reportedly highly temperature dependent. The solubility ranges from 0.3 to 0.5 mg/ml at 20Â° C. to about 7 mg/ml at 50Â° C. At about 60Â° C., the solubility increases to greater than 100 mg/ml. At concentrations of about 50 mg/mL, amiodarone reportedly forms colloidal structures about 100 nm in diameter and micelles containing approximately 150 monomeric units and having a molecular weight in excess of 100,000 (Ravin et al., J. Pharm. Sci. (1975), 64 (11), 1830-1833).

Due to its low intrinsic water solubility, amiodarone is difficult to formulate in a water-based parenteral formulation that is sufficiently concentrated and stable and present in a medium having a physiologically acceptable pH. The water solubility can be increased by adjusting the pH of the solution to a value below its pKa, where the amiodarone takes on a positive ionic charge. Bonati et al. (J. Pharm. Sci. (1984), 73 (6), 829-831) report a pKa of 6.56. Even at low pH values, the solubility is insufficient to provide a ready to use formulation in the concentration range of 1-2 mg/mL.

Co-solvents and or surfactants can also be used to solubilize amiodarone in water. Ravin et al. (J. Pharm. Sci. (1969), 58 (10), 1242-45) report that cetyldimethyl-benzylammonium chloride, sodium lauryl sulfate and TweenÂ® 80 increased the solubility of amiodarone at surfactant concentrations up to about 0.02% wt. Higher concentrations of sodium lauryl sulfate led to the formation of a colloidal suspension.

The currently marketed formulation (CORDARONEÂ® Intravenous; CORDARONE I.V.Â®) of amiodarone contains 50 mg/ml amiodarone hydrochloride (â€œHClâ€ ), 20.2 mg/mL benzyl alcohol and 100 mg/mL polysorbate 80 (TWEENÂ® 80; a nonionic surfactant, emulsifier, dispersant and/or stabilizer) in water. The CORDARONE I.V.Â® formulation is packaged in single use containers.

Polysorbate 80 and benzyl alcohol, however, are known to cause unwanted side effects. For example, polysorbate 80, either alone or in combination with benzyl alcohol, reportedly acts as a potent cardiac depressant and causes hypotension and cancer. Moreover, parenteral administration of benzyl alcohol has reportedly been associated with hemolysis, death and a number of other side effects.

A number of patents and scientific publications disclose parenteral preparations of amiodarone that reportedly have reduced side effects as compared to the currently marketed formulation. U.S. Pat. No. 5,234,949 to Ehrenpreis et al. discloses a parenteral solution of amiodarone (25-75 mg/ml) in a surfactant-free acetate buffer solution having a pH below 4. Ehrenpreis et al. disclose that the concentration and choice of the buffering agent are critical for physical stability in order to reduce precipitation or gel formation. Solutions containing amiodarone at concentrations of 15-50 mg/ml in an acetate buffer with a pH of between 3.2 and 3.8 cannot be diluted in glucose-saline water beyond 1 mg/ml without forming very opalescent or even milky solutions. Preparation of the 15-50 mg/mL formulations is reported to include a step whereby the solutions are heated to 60Â° C.-75Â° C. The preparations can be sterilized by filtration and sealed in sterile glass ampoules.

U.S. Pat. No. 6,143,778 to Gautier et al. discloses a parenteral formulation containing amiodarone, a buffer solution and a non-ionic hydrophilic surfactant. The hydrophilic surfactant is required in order avoid the above-mentioned problem associated with dilution of a buffered solution containing amiodarone hydrochloride. Solutions containing 1.5-8.0% wt. amiodarone were reportedly prepared in the presence of surfactant. Solutions containing 30-50 mg amiodarone/mL of solution at pH 2.4-3.8 were reportedly prepared in the presence of buffers such as acetate (0.1-0.3 M), phosphate (0.1-0.15 M), or glycine (0.2 M), where the ionic strength was maintained between 0.08-0.3 M. At higher ionic strengths, cloudy solutions were reported. Citrate reportedly was not suitable at any concentration. Suitable surfactants reportedly included nonionic hydrophilic compounds with HLB values in the range of 13-29, and present in concentrations of about 0.5-2.0%. Some stated examples were PluronicsÂ®, CremophorsÂ®, TweensÂ® and SolutolsÂ®. The formulation reportedly could be diluted to concentrations both approximating (about 0.5-0.8 mg/mL) and below (0.1-0.15 mg/mL) the critical concentration zone where turbidity is normally observed with dilution of aqueous amiodarone solutions prepared by heating.

Ravin et al. (J. Pharm. Sci. (1975), 64 (11), 1830-1833) disclose that chloride ion suppresses the solubility of amiodarone and that sodium citrate and tartrate, in very low concentrations ranging from 0.002-0.008 M and at pH values of 4.3-5.4, increase the solubility of amiodarone to 4.8 and 6 mg/mL, respectively. At higher concentrations, however, the solubility was suppressed. Under the conditions tested, acetate in any concentration decreased the solubility of amiodarone at pH 4-4.7. The ability to prepare more concentrated solutions of amiodarone was demonstrated to be temperature dependent. At 25Â° C., 40Â° C., and about 60Â° C., amiodarone concentrations of 0.35 mg/mL, 0.95 mg/mL and >13 mg/mL, respectively, could be achieved. The solution heated to 60Â° C. could be cooled to 25Â° C. without precipitation; however, it could not be diluted below the critical micellar concentration (â€œCMCâ€ ) without precipitation. The reported CMC value was approximately 0.5 mg/mL.

Contrary to the findings of Ravin et al., Benedini, et al. (J. Colloid Interface Sci. (2010), 342 (2), 407-414) report a CMC of 1.69 mg/mL occurring at a Krafft point of Ëœ70Â° C. and a pKa value for amiodarone of 7.95 in aqueous solution. They also describe a complicated phase diagram where the CMC value changes with temperature (increasing with temperatures below the Krafft point) and where at room temperature, a coacervate exists at amiodarone concentrations from the CMC down to about 0.8 mg/mL, and a gel forms in solutions diluted below this concentration.

Mosher et al. (U.S. Pat. No. 6,869,939) disclose aqueous formulations of amiodarone containing a sulfoalkyl ether cyclodextrin (â€œSAE-CDâ€ ). Formulations having a molar ratio of SAE-CD to amiodarone greater than or equal to 1.1:1 are reported to be dilutable in water without significant precipitation of amiodarone, i.e. if precipitation occurs it is less than or equal to about 3% wt. Adjusting the pH of the formulation reportedly can enhance the chemical stability in terms of precipitate or gel forming. Exemplified formulations are prepared as 50 mg/mL or greater concentrates of amiodarone which are prepared in cyclodextrin solutions at temperatures of 55Â° C. or 75Â° C. Dilution of a 50 mg/mL amiodarone formulation to Ëœ0.6-8.3 mg/mL with a dextrose solution is reported at room temperature. Formulations containing 50 or 0.5 mg/mL amiodarone were reportedly prepared in cyclodextrin solutions at room temperature and subsequently dried to prepare powders. The aqueous solubility of amiodarone in the presence of other derivatized cyclodextrins including 2-hydroxypropyl beta cyclodextrin is reported.

Cyclodextrins and their derivatives are widely used in liquid formulations to enhance the aqueous solubility of hydrophobic compounds. 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 Î±-, Î²-, and Î³-cyclodextrin respectively. Each cyclodextrin subunit has secondary hydroxyl groups at the 2 and 3-positions and a primary hydroxyl group at the 6-position. The cyclodextrins may be pictured as hollow truncated cones with hydrophilic exterior surfaces and hydrophobic interior cavities. In aqueous solutions, these hydrophobic cavities provide a haven for hydrophobic organic compounds, which can fit all, or part of their structure into these cavities. This process, known as inclusion complexation, may result in increased apparent aqueous solubility and stability for the complexed drug. The complex is stabilized by hydrophobic interactions and does not involve the formation of any covalent bonds.

Chemical modification of the parent cyclodextrins (usually at the hydroxyl moieties) has resulted in substituted cyclodextrins with sometimes improved safety while retaining or improving the complexation ability of the cyclodextrin. Of the numerous substituted cyclodextrins prepared to date, two have been included in commercial injectable pharmaceutical formulations; the 2-hydroxypropyl derivatives (â€œHP-Î²-CDâ€ or â€œHPCDâ€ ), neutral molecules being commercially developed by Janssen and others, and the sulfoalkyl ether derivatives (â€œSAE-Î²-CDâ€ or â€œSAE-CDâ€ ), being developed by CyDex and others.

The SAE-CDs are a class of negatively charged cyclodextrins, which vary in the nature of the alkyl spacer, the salt form, the degree of substitution and the starting parent cyclodextrin. The presence of the negative charge allows for ionic interactions with drugs in solution as well as complexation.

Amiodarone is currently marketed and sold in vials, ampoules and syringes as a concentrate of 50 mg/mL amiodarone hydrochloride. The formulation is typically diluted with dextrose to a concentration of 0.5 to 2 mg/mL prior to administration. Since injectable forms of amiodarone are often used in emergency conditions (e.g. cardiac arrest), having a solution, premixed at the required dosing concentration, ready for administration is critical. The extra time required for preparation of a dilution can delay therapy and potentially have serious and negative consequences for the patient.

Several patents disclose amiodarone formulations that are reported to be ready to use. U.S. Pat. No. 7,067,143 to Doty et al report formulations at pH 2.9-3.2 containing 0.2 to 6 mg/mL amiodarone and a non-ionic surfactant in a polymeric container. Preparation of the formulation is exemplified with the steps of dissolving the surfactant, TweenÂ® 80, in 40% of the final volume of water, heating the solution to 55Â° C., adding and dissolving the amiodarone, cooling the solution to 30Â° C., adding and dissolving dextrose, diluting to 90% of final volume, adjusting the pH to 3, then diluting to the final volume. The formulations can be sterilized and filled into plastic or other acceptable containers. When stored in plastic containers at 25Â° C., the formulations showed a loss of 1.6% amiodarone due to adsorption to the container and degradation of about 1% at 1 month, 1.5% at 4 months and 2.6% at 11 months.

U.S. Pat. No. 6,479,541 to Kipp et al report ready to use, surfactant free formulations of amiodarone containing a lactate and/or methanesulfonate buffer. Preparation of the formulation is described as including steps of dissolving amiodarone and a lactate and/or methanesulfonate buffer in 45-60Â° C. water, adjusting the pH to 3-4.5 and diluting the solution to a final volume. The formulations are chemically stable when refrigerated or frozen.

The inventors have identified improved ready to administer formulations containing amiodarone that are premixed at the concentrations recommended in the United States Food and Drug Administration (â€œFDAâ€ ) approved commercial labeling and typically used in clinical therapy, remain chemically and physically stable under a variety of storage conditions in both glass and plastic containers, and reduce the severity or occurrence of side effects, such as hypotension, bradycardia, hemolysis, and phlebitis, which are associated with the presently marketed formulations of amiodarone. Additionally, the inventors have identified a process for making the formulations that avoids the formation of gels and particulates, minimizes foaming, and that eliminates the need for a surfactant or organic solvent and therefore avoids side effects associated therewith. None of the art discloses or suggests the invention as claimed herein.

III. SUMMARY OF THE INVENTION

The invention encompasses aqueous parenteral formulations including amiodarone or a salt thereof and a substituted cyclodextrin. The liquid formulations are isoosmotic, clear, sterile, and chemically and physically stable under a variety of storage conditions. The liquid formulations do not require a surfactant or organic solvent. The formulation includes a substituted cyclodextrin such as a sulfoalkyl ether cyclodextrin (â€œSAE-CDâ€ ), a hydroxyalkyl ether cyclodextrin (â€œHAE-CDâ€ ), a sulfoalkyl ether-alkyl ether cyclodextrin (â€œSAE-AE-CDâ€ ) or a sulfoalkyl ether-hydroxyalkyl ether cyclodextrin (â€œSAE-HAE-CDâ€ ) which provides significant advantages over other formulations of amiodarone. In certain embodiments, the liquid formulations of the invention are formulations included, for example, in an IV-bag, or bottle and are ready to use, requiring no further dilution or admixture.

In one embodiment, the invention encompasses a ready to use injectable intravenous bag formulation comprising a bag comprised of polyvinyl chloride, polyolefin, polypropylene, polyethylene, polyvinylidene chloride, nylon or combinations thereof comprising:

i. an aqueous solution containing a sulfobutylether beta-cyclodextrin and amiodarone or a pharmaceutically acceptable salt thereof wherein,
- 1. the sulfobutylether beta-cyclodextrin:amiodarone mole ratio is greater than 2.7:1 and less than or equal to 7: 1; and
- 2. the amiodarone concentration ranges from about 0.7 mM to about 7 mM.

The invention encompasses liquid formulations including amiodarone or a salt thereof complexed with a SAE-CD, a HAE-CD, a SAE-AE-CD, or a SAE-HAE-CD which are useful as an antiarrhythmic agent indicated for example, for the treatment and prophylaxis of frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients refractory to other therapy. The liquid formulations of the invention are used to suppress cardiac arrhythmias and/or life threatening arrhythmias. An arrhythmia can be suppressed in a patient by administering a therapeutically effective initial dose of a formulation of the invention including the amiodarone or salt thereof followed by a maintenance dose over a period of time sufficient to suppress the arrhythmia. In general, the initial loading dose of the amiodarone or salt thereof is accomplished by a first rapid infusion or injection of a therapeutically effective dose followed by a slow infusion or injection of a therapeutically effective dose depending on the needs of the individual patient. In certain embodiments, maintenance of an antiarrhythmic action with the formulations of the invention including amiodarone or salt thereof is typically accomplished by administering to a patient by injection or infusion of a lower amount of a therapeutically effective dose of the formulation of the invention including amiodarone or salt thereof over a period of time depending upon the individual needs of the patient.

The invention also encompasses methods of preparing ready to use aqueous parenteral formulations including amiodarone or a salt thereof and a substituted cyclodextrin. The methods substantially reduce or eliminate the formation of a gel in the solution. The methods provide a ready to use formulation with reduced potential for forming a foam when agitated or during manufacture and which can meet the United States Pharmacopeial requirements for particulate matter in injections upon-storage in pharmaceutically acceptable containers. The formulations are stable when stored under a variety of temperature conditions.

In one embodiment the invention encompasses a method for making a ready to use injectable pharmaceutical composition comprising the steps of:

- a. preparing an aqueous solution containing a sulfobutylether beta-cyclodextrin and amiodarone or a pharmaceutically acceptable salt thereof, wherein:
  - i. the sulfobutylether beta-cyclodextrin:amiodarone mole ratio is greater than 2.7:1 and less than or equal to 7:1, and
  - ii. the amiodarone is dissolved while maintaining a solution temperature ranging from about 15Â° C. to about 65Â° C. and a pH less than or equal to the pKa of amiodarone to give a clear solution absent of gel,
- b. adding water as needed to provide a final solution with an amiodarone concentration ranging from about 0.7 mM to about 7 mM;
- c. sterile filtering the final solution to substantially reduce microbial contamination; and
- d. aseptically filling the final solution into a pharmaceutically acceptable container.

In another embodiment the invention encompasses a method for making a ready to use injectable pharmaceutical composition free of visible particulates comprising the steps of:

- a. preparing an aqueous solution comprising a sulfobutylether-beta-cyclodextrin and amiodarone or a pharmaceutically acceptable salt thereof, wherein:
  - i. the sulfobutylether-beta-cyclodextrin:amiodarone mole ratio ranges from about 1.1:1 to less than or equal to about 7:1,
  - ii. the amiodarone is dissolved while maintaining a solution temperature ranging from about 15Â° C. to less than about 40Â° C. and a pH less than or equal to the pKa of amiodarone to give a clear solution absent of gel,
- b. optionally adding additional cyclodextrin as needed to provide a sulfobutylether-beta-cyclodextrin:amiodarone mole ratio ranging from greater than 2.7:1 to about 7:1; and
- c. adding additional water as needed to provide a final solution with an amiodarone concentration ranging from about 0.73 mM to about 7.3 mM.

In another embodiment the invention encompasses a method for making a ready to use injectable pharmaceutical composition free of visible particulates comprising the steps of:

- a. preparing an aqueous solution containing a sulfobutylether beta-cyclodextrin and amiodarone or a pharmaceutically acceptable salt thereof, wherein:
  - i. the sulfobutylether-beta-cyclodextrin:amiodarone mole ratio ranges from about 1.5:1 to about 7:1,
  - ii. the amiodarone is dissolved while maintaining a solution temperature ranging from about 15Â° C. to about 65Â° C. and a pH less than or equal to the pKa of amiodarone to give a clear solution absent of gel,
- b. optionally adding additional sulfobutylether beta-cyclodextrin as necessary to provide a cyclodextrin:amiodarone mole ratio of greater than about 2.7:1 to about 7:1 in the final solution, and
- c. adding additional water as needed to provide a final solution with an amiodarone concentration ranging from about 0.73 mM to about 7.3 mM.

In another embodiment the invention encompasses a method for making a ready to use injectable pharmaceutical composition free of visible particulates comprising the steps of:

- a. preparing a concentrated aqueous solution containing sulfobutylether beta-cyclodextrin and amiodarone or a pharmaceutically acceptable salt thereof, wherein:
  - i. the volume of the solution represents from about 1% to less than about 17% of the volume of the final solution,
  - ii. the sulfobutylether-beta-cyclodextrin:amiodarone mole ratio ranges from about 1.1:1 to about 7:1,
  - iii. the amiodarone is dissolved while maintaining a solution temperature of about 15Â° C. to about 65Â° C. and a pH less than or equal to the pKa of amiodarone to give a solution absent of gel,
- b. optionally adding additional sulfobutylether beta-cyclodextrin as necessary to provide a final solution with a cyclodextrin:amiodarone mole ratio of greater than about 2.7:1 to about 7:1, and
- c. adding additional water, as necessary, to provide a final solution with an amiodarone concentration ranging from about 0.73 mM to about 7.3 mM.

In another embodiment the invention encompasses a method for making a ready to use injectable pharmaceutical composition free of visible particulates comprising the steps of:

- a. preparing a first aqueous solution containing sulfobutylether beta-cyclodextrin, amiodarone or a pharmaceutically acceptable salt thereof, and optionally containing one or more components selected from pH adjusting agents, buffering agents, tonicity modifying agents and antioxidants, wherein:
  - i. the volume of the first aqueous solution represents from about 1% to less than about 17% of the volume of the final solution,
  - ii. the sulfobutylether-beta-cyclodextrin:amiodarone mole ratio ranges from about 1.1:1 to about 7:1,
  - iii. the amiodarone is dissolved while maintaining a solution temperature of about 15Â° C. to about 65Â° C. and a pH less than or equal to the pKa of amiodarone to give a clear solution absent of gel,
- b. preparing a second aqueous solution containing one or more components selected from pH adjusting agents, buffering agents, tonicity modifying agents, antioxidants, and additional sulfobutylether beta-cyclodextrin,
- c. combining the two solutions and mixing the resulting solution to give a clear solution absent of gel, and
- d. optionally adding additional water and sulfobutylether beta-cyclodextrin as necessary to provide a final solution with an amiodarone concentration of about 0.73 mM to about 7.3 mM and a cyclodextrin:amiodarone mole ratio ranging from greater than about 2.7:1 to about 7:1.

In another embodiment the invention encompasses a method for making a ready to use pharmaceutical composition free of visible particulates comprising the steps of:

- a. adding a volume of water for injection equivalent to 20% to 30% of the final solution volume to a suitable container and adjusting the temperature to 20Â° C.-30Â° C.,
- b. adding and dissolving sulfobutyl ether-7-beta-cyclodextrin, citric acid and sodium citrate such that the solution pH is in the range of about 3 to about 4,
- c. adding and dissolving amiodarone hydrochloride in an amount sufficient to provide a cyclodextrin:amiodarone mole ratio in the final solution ranging from about 3.1:1 to 3.2:1 to give a clear solution absent of gel,
- d. adding additional water for injection to bring the solution volume to 70%-80% of the final solution volume, and dissolving sufficient dextrose to provide a final solution osmolality of about 255 mOsm/kg to about 345 mOsm/kg,
- e. adjusting the pH to 3.55-3.65 with hydrochloric acid or sodium hydroxide,
- f. adding additional water for injection to bring the solution to a final solution volume wherein the amiodarone concentration ranges from about 2 mM to 3 mM and the citrate concentration ranges from about 2 mM to 3 mM,
- g. sterile filtering the solution to substantially reduce microbial contamination, and
- h. aseptically filling the solution into a pharmaceutically acceptable container.

IV. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the solubility of amiodarone hydrochloride in saline solutions containing 5 mM citrate buffer at pH 3.6 and sulfobutylether Î²-cyclodextrin, (â–¡ 9 mg/mL sodium chloride; â™¦ 7 mg/mL sodium chloride).

FIG. 2 illustrates the solubility of amiodarone hydrochloride in water in the presence of increasing amounts of sodium chloride.

FIG. 3 illustrates the solubility of amiodarone in the presence of 8.1 mg/mL sulfobutylether beta cyclodextrin and increasing amounts of a citrate buffer at a pH of about 3.5.

FIG. 4 illustrates the solubility of amiodarone hydrochloride in a 5% dextrose solution containing 0.9 mM citrate buffer at pH 3.8 and sulfobutylether Î²-cyclodextrin.

FIG. 5 illustrates the solubility of amiodarone hydrochloride in water adjusted to pH 4.5 and containing 2-hydroxypropyl Î²-cyclodextrin having different degrees of substitution, (â–ª HP-7 Î²-cyclodextrin; â–¡ HP-4 Î²-cyclodextrin).

V. DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified, all percentages and amounts expressed herein and elsewhere in the specification should be understood to refer to percent by weight. The concentration is denoted in mg/mL. Also, the term â€œabout,â€ when used in reference to a range of values, should be understood to refer to either value in the range, or to both values in the range.

As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range.

All documents, for example, scientific publications, patents, patent applications and patent publications, recited herein are hereby incorporated by reference in their entirety to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference in its entirety. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.

Definitions

As used herein, the term â€œalkalizing agentâ€ is intended to mean a compound used to provide an alkaline medium. Such compounds include, by way of example and without limitation, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, diethanolamine, organic amine base, alkaline amino acids and trolamine and others known to those of ordinary skill in the art.

As used herein, the term â€œacidifying agentâ€ is intended to mean a compound used to provide an acidic medium. Such compounds include, by way of example and without limitation, acetic acid, acidic amino acids, citric acid, fumaric acid and other alpha hydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid and others known to those of ordinary skill in the art.

The terms â€œalkyleneâ€ and â€œalkyl,â€ as used herein (e.g., in the â€”Oâ€”(C₂-C₆-alkylene) SO₃^âˆ’ group or in the alkylamines), include linear, cyclic, and branched, saturated and unsaturated (i.e., containing one double bond) divalent alkylene groups and monovalent alkyl groups, respectively. The term â€œalkanolâ€ in this text likewise includes linear, cyclic and branched, saturated and unsaturated alkyl components of the alkanol groups, in which the hydroxyl groups may be situated at any position on the alkyl moiety. The term â€œcycloalkanolâ€ includes unsubstituted or substituted (e.g., by methyl or ethyl) cyclic alcohols.

As used herein, the term â€œantioxidantâ€ is intended to mean an agent that inhibits oxidation and thus is used to prevent the deterioration of preparations by the oxidative process. Such compounds include, by way of example and without limitation, acetone, potassium metabisulfite, potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid, butylated hydroxyanisole, butylated hydroxytoluene, hypophophorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid and sodium metabisulfite and others known to those of ordinary skill in the art.

As used herein, the term â€œbuffering agentâ€ is intended to mean a compound used to resist change in pH upon storage, dilution or addition of acid or alkali. Such compounds include, by way of example and without limitation, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, citric acid, maleic acid, monobasic sodium phosphate, dibasic sodium phosphate, lactic acid, tartaric acid, glycine, potassium metaphosphate, potassium phosphate, sodium acetate, sodium bicarbonate, sodium tartrate and sodium citrate anhydrous and dihydrate and others known to those of ordinary skill in the art.

As used herein, the term â€œgelâ€ is intended to mean a colloidal dispersion of particles that forms a solid or semisolid. For example, gels are visible area(s) or region(s) of a solution that appear as an undissolved semisolid mass. Additional non-limiting information on gels can be found in the following references: Remington, The Science and Practice of Pharmacy, 21^stEdition, and The United States Pharmacopoeia 30, 2007, Chapter <1151>.

By â€œcomplexedâ€ is meant â€œbeing part of a clathrate or inclusion complex withâ€ , i.e., a complexed therapeutic agent is part of a clathrate or inclusion complex with a substituted cyclodextrin. By â€œmajor portionâ€ is meant at least about 50% by weight of the therapeutic compound. The actual percent of drug that is complexed will vary according to the complexation equilibrium constant characterizing the complexation of a specific cyclodextrin derivative to a specific drug and to the concentrations of the cyclodextrin derivative and drug available for complexation. The complexation constant can be determined experimentally by conducting phase solubility studies (Higuchi, T. and Connors, K. A. in â€œAdvances in Analytical Chemistry and Instrumentation Vol. 4â€ Reilly, Charles N. Ed., John Wiley & Sons., 1965, pp. 117-212) where the solubility of a drug is determined in the presence of increasing amounts of a cyclodextrin or substituted cyclodextrin.

Phase solubility studies can also generate information as to the required amounts of a cyclodextrin needed to solubilize a drug under different conditions such as temperature, cyclodextrin type, or solution composition. For example, FIG. 1 depicts a phase solubility curve for SBE7-Î²-CD and amiodarone at pH 3.6 in a solution containing a 5 mM citrate buffer and sodium chloride at 7 or 9 mg/mL and at about 25Â° C. The figure shows that as the sodium chloride is increased from 7 to 9 mg/mL, the complexation decreases and more cyclodextrin is required to reach the same concentration of amiodarone. A solution containing 1.8 mg/mL amiodarone hydrochloride in 9 mg/mL sodium chloride should require about 10 mg/mL SBE7-Î²-CD to provide complete solubilization of the amiodarone.

The presence of sodium chloride can affect the solubility of amiodarone in the absence of a cyclodextrin as depicted in FIG. 2. At pH values below the pKa of amiodarone, a positive charge is present on the amiodarone molecule. This promotes increased water solubilization. However, as the ionic strength is increased, such as occurs with the addition of sodium chloride, this solubilization is suppressed. In addition, if a hydrochloride salt form of amiodarone is being evaluated, a common ion effect can be observed with the added chloride suppressing solubilization.

FIG. 3 illustrates a similar effect with added buffer species. The negatively charged sulfoalky ether cyclodextrin solubilizes amiodarone both by complexation and by ionic interactions. Increasing the amount of ionic buffer present in the solution decreases the solubilization of amiodarone in the water and also decreases the solubilization by the negatively charged cyclodextrin.

At pH values where amiodarone is positively charged, it is expected that substituted cyclodextrins containing negatively charged functional groups will solubilize amiodarone to a greater extent than neutral cyclodextrins, and the solubilization will vary with the number of charged substituents. The presence of other components in the formulation, especially charged ionic components will have an effect on the solubilization by either charged or neutral substituted cyclodextrins.

A 5% dextrose solution provides a comparable tonicity to 9 mg/mL saline solution, but without the ionic charges that are present with the sodium chloride. FIG. 4 depicts a room temperature phase solubility curve for SBE7-Î²-CD and amiodarone in a solution containing dextrose 5% and 0.9 mM citrate buffer at pH 3.8. A solution containing 1.8 mg/mL amiodarone hydrochloride in 5% dextrose solution should require about 6 mg/mL SBE7-Î²-CD. Amiodarone shows greater solubilization by SBE7-Î²-CD in the presence of dextrose than in the presence of sodium chloride.

Other substituted cyclodextrins also form complexes with amiodarone. The phase solubility of amiodarone hydrochloride in water at pH 4.5 in the presence of 2-hydroxypropyl Î²-cyclodextrin having an average of about 7 or 4 hydroxypropyl substituents (actual DS of 7.6 and 4.3 with molecular weights 1576 and 1384 g/m respectively) on the cyclodextrin ring is shown in FIG. 5. These HAE-CDs both solubilize amiodarone, the SBE7-Î²-CD solubilizing slightly more drug than the SBE4-Î²-CD derivative. A 1.8 mg/mL amiodarone hydrochloride solution requires about 9 mg/mL SBE4-Î²-CD for solubilization in the absence of other components such as tonicity modifying agents or buffering agents.

A â€œcomplexation-enhancing agentâ€ can be added to the aqueous liquid formulation of the invention. A complexation-enhancing agent is a compound, or compounds, that enhance(s) the complexation of amiodarone with the SAE-CD, HAE-CD, SAE-AE-CD or SAE-HAE-CD. When the complexation-enhancing agent is present, the required ratio of substituted-CD to amiodarone may need to be changed such that less cyclodextrin is required. Suitable complexation enhancing agents include one or more pharmacologically inert water soluble polymers, hydroxy acids, and other organic compounds typically used in liquid formulations to enhance the complexation of a particular agent with cyclodextrins. Suitable water soluble polymers include water soluble natural polymers, water soluble semisynthetic polymers (such as the water soluble derivatives of cellulose) and water soluble synthetic polymers. The natural polymers include polysaccharides such as inulin, pectins, algin derivatives and agar, and polypeptides such as casein and gelatin. The semi-synthetic polymers include cellulose derivatives such as methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, their mixed ethers such as hydroxypropyl methylcellulose and other mixed ethers such as hydroxyethyl ethylcellulose, hydroxypropyl ethylcellulose, hydroxypropyl methylcellulose phthalate and carboxymethylcellulose and its salts, especially sodium carboxymethylcellulose. The synthetic polymers include polyoxyethylene derivatives (polyethylene glycols) and polyvinyl derivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrene sulfonate) and various copolymers of acrylic acid (e.g. carbomer). Suitable hydroxy acids include by way of example, and without limitation, citric acid, malic acid, lactic acid, and tartaric acid and others known to those of ordinary skill in the art.

The liquid formulation of the invention will comprise an effective amount of amiodarone or a salt thereof The term â€œeffective amountâ€ refers a therapeutically effective amount is contemplated. A therapeutically effective amount is an amount or quantity of amiodarone or a salt thereof that is sufficient to elicit the required or desired therapeutic response or an amount that is sufficient to elicit an appreciable biological response when administered to a subject.

As used herein and unless otherwise indicated, the term â€œformulations of the inventionâ€ means a liquid formulation for parenteral administration especially for intravenous administration which includes amiodarone or a salt thereof, a substituted cyclodextrin such as a SAE-CD, a HAE-CD, a SAE-AE-CD or a SAE-HAE-CD and one or more carriers. Illustrative formulations encompassed by the term â€œformulations of the inventionâ€ are described herein.

As used herein, the term â€œinjectable pharmaceutical compositionâ€ refers to a composition suitable for administration to a patient or subject that is essentially free of visible particulates, for example, a composition meeting the requirements of United States Pharmacopeia 33, Chapter <1>Injections.

As used herein the term â€œnon-covalent ionic bondâ€ refers to a bond formed between an anionic species and a cationic species. The bond is non-covalent such that the two species together form a salt or ion pair. The SAE-CD, SAE-AE-CD or SAE-HAE-CD provides the anionic species of the ion pair and the amiodarone provides the cationic species of the ion pair. Since the SAE-CD, SAE-AE-CD and SAE-HAE-CD are multi-valent, they can form an ion pair with one or more cationic amiodarone species.

As used herein, the term â€œpatientâ€ or â€œsubjectâ€ refers to warm blooded animals such as mammals, for example, cats, dogs, mice, guinea pigs, horses, bovine cows, sheep, and humans.

As used herein, the phrase â€œpharmaceutically acceptableâ€ is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, a â€œpharmaceutically acceptable liquid carrierâ€ is any aqueous medium used in the pharmaceutical sciences for dilution or dissolution of parenteral formulations. In a specific embodiment, the term â€œpharmaceutically acceptableâ€ means generally accepted by or approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term â€œcarrierâ€ refers to a diluent, adjuvant, excipient, or vehicle with which a formulation of the invention is administered. Such pharmaceutical carriers can be liquids, such as water, saline, aqueous solutions and the like. When administered to a patient, the formulations of the invention and pharmaceutically acceptable vehicles are preferably sterile. Water is a preferred vehicle when the compound of the invention is administered intravenously. Saline solutions and aqueous dextrose solutions can also be employed as liquid vehicles, particularly for injectable solutions. The present compositions, if desired, can also contain minor amounts of wetting agents, or pH buffering agents.

As used herein, the term â€œpharmaceutically acceptable containerâ€ is intended to mean a container closure system that: protects the drug product, for example, from factors that can cause degradation of the dosage form over its shelf-life; is compatible with the drug product, for example, the packaging components will not interact sufficiently to cause unacceptable changes in the quality of either the drug or the packaging component, such as absorption or adsorption of the drug substance, degradation of the drug substance that is induced by extractables/leachables from the container, precipitation, and changes in pH; and is safe, for example, a container that does not leach harmful or undesirable amounts of substances to which a patient will be exposed when being treated with the product, or in the case of injectable formulations, the container will protect the formulation from the introduction of microbes and not contain pyrogens. Containers useful for injectable formulations are often sterilized prior to and/or after being filled with the formulation. Pharmaceutically acceptable containers include, but are not limited to, intravenous bags, bottles, vials and syringes. Suitable pharmaceutically acceptable containers include an evacuated container, a syringe, bag, pouch, ampoule, vial, bottle, or any pharmaceutically acceptable device known to those skilled in the art for the delivery of liquid formulations. Preferred containers are plastic or polymeric containers constructed from plastics such as polyamide, ethylene vinyl acetate, polyolefin, polypropylene, polyethylene, polyvinylidene chloride, nylon, and/or polyvinylchloride or combinations thereof and marketed under trade names such as GALAXYÂ®, INTRAVIAÂ®, AVIVAÂ®, and VIAFLEXÂ®. These containers are disclosed in U.S. Pat. No. 4,686,125, No. 4,692,361, No. 4,779,997, No. 5,849,843, No. 5,998,019, and No. 6,168,862. These containers can be comprised of a single type of plastic or polymer, a blend of plastics and or polymers, or a laminate of one or more different types of plastics and or polymers. It is contemplated, however, that most plastic containers will produce comparable results.

As used herein the term â€œpH adjusting agentâ€ is an agent to increase or decrease the desired pH of the formulation when admixed into the formulation. The pH of the liquid formulation will generally range from about pH 3.0 to about pH 7.0; however, liquid formulations having higher or lower pH values can also be prepared. It is contemplated that amiodarone chemical and physical stability can be increased by optimizing the pH as well as the mole ratio of substituted cyclodextrin to amiodarone. Preferably the pH of the formulation ranges from pH 3 to about pH 4, and most preferably the pH of the formulation is 3.6. The pH of the composition may be adjusted using an appropriate pH adjusting agent, such as a suitable acid, base, amine, or any combination thereof. Preferably, a pH adjusting agent used in the formulation include hydrochloric acid, sodium hydroxide, amines, ammonium hydroxide, nitric acid, phosphoric acid, sulfuric acid, citric acid, organic acids, and/or salts thereof, and any combination thereof.

As used herein the term substituted cyclodextrin refers to an alpha, beta or gamma cyclodextrin having one or more of the hydroxyl groups in its structure replaced with a different chemical substituent attached through an ether linkage. The substituted cyclodextrin can contain a single type of chemical substituent or more than one type within the same cyclodextrin molecule. For example, a cyclodextrin can have one hydroxyl substituted with a sulfoalkyl substituent and another hydroxyl substituted with a hydroxyalkyl substituent. Substituted cyclodextrin compounds include, by way of example and without limitation, sulfoalkyl ether cyclodextrins, hydroxyalkyl ether cyclodextrins, sulfoalkyl ether-hydroxyalkyl ether cyclodextrins, sulfoalkylether-alkyl ether cyclodextrins and others known to those of ordinary skill in the art.

The number of hydroxyls that have been replaced in a cyclodextrin is represented by a number referred to as the degree of substitution (â€œDSâ€ ). It should be noted that preparation of substituted cyclodextrins occurs in a controlled, although not exact manner. For this reason, the degree of substitution is actually a number representing the average number of substituent groups per cyclodextrin (for example, SBE7-Î²-CD, has an average of 7 sulfobutyl ether substitutions per beta (Î²) cyclodextrin and SBE4-Î²-CD has an average of 4 hydroxypropyl substitutions). In addition, the regiochemistry of substitution of the hydroxyl groups of the cyclodextrin is variable with regard to the substitution of specific hydroxyl groups of the hexose ring. For this reason, substitution of different hydroxyl groups is likely to occur during manufacture of the substituted cyclodextrin, and a particular substituted cyclodextrin will possess a preferential, although not exclusive or specific, substitution pattern.

As used herein the term â€œsulfoalkyl ether cyclodextrinâ€ (â€œSAE-CDâ€ ) refers to compounds encompassed by the formula 1:

[Image Omitted]

wherein n is 4, 5 or 6; R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉are each, independently, â€”Oâ€” or a â€”Oâ€”(C₂-C₆alkylene)â€”SO₃^âˆ’ group, wherein at least one of R₁and R₂is independently a â€”Oâ€”(C₂-C₆alkylene)â€”SO₃^âˆ’ group, preferably a â€”Oâ€”(CH₂)_mSO₃âˆ’ group, wherein m is 2 to 6, preferably 2 to 4, (e.g. â€”OCH₂CH₂CH₂SO₃^âˆ’ or â€”OCH₂CH₂CH₂CH₂SO₃); and S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈and S₉are each, independently, a pharmaceutically acceptable cation which includes, for example, H⁺, alkali metals (e.g., Li⁺, Na⁺, K⁺), alkaline earth metals (e.g., Ca⁺², Mg⁺²), ammonium ions and amine cations such as the cations of (C₁-C₆)-alkylamines, piperidine, pyrazine, (C₁-C₆)-alkanolamine and (C₄-C₈)-cycloalkanolamine. In certain illustrative embodiments, n is 5; R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉are each â€”Oâ€” or â€”Oâ€”((CH₂)₄)â€”SO₃^âˆ’; at least one of R₁and R₂is independently a â€”Oâ€”((CH₂)₄)â€”SO₃^âˆ’ group; and S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈, and S₉are each H or Na³⁰. In certain embodiments, the SAE-CD is represented by formula 2:

[Image Omitted]

wherein R=H_21-nor (CH₂CH₂CH₂CH₂SO₂ONa)_nand where n=6.0-7.1. In certain illustrative embodiments, the sulfoalkyl ether cyclodextrin (â€œSAE-CDâ€ ) is sulfobutylether 7-beta-cyclodextrin.

As used herein the â€œhydroxyalkyl ether cyclodextrinâ€ (â€œHAE-CDâ€ ) refers to compounds encompassed by the formula 3:

[Image Omitted]

wherein n is 4, 5 or 6; R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈and R₉are each, independently, â€”H or a â€”(C₂-C₆alkylene) group further substituted with at least one (â€”OH), wherein at least one of R₁and R₂is independently a â€”(C₂-C₆alkylene) group further substituted with at least one (â€”OH). In certain illustrative embodiments, n is 5; R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉are each â€”H or â€”CH₂CH(OH)CH₃; and at least one of R₁and R₂is independently a â€”CH₂CH(OH)CH₃group. In certain embodiments, the HAE-CD is represented by formula 4:

[Image Omitted]

wherein R=H_21-nor (CH₂CHOHCH₃)_nand where n=4 or 6. In certain illustrative embodiments, the hydroxyalkyl ether cyclodextrin (â€œHAE-CDâ€ ) is 2-hydroxypropyl 4-beta-cyclodextrin.

As used herein, the term â€œtonicity modifying agentâ€ is intended to mean a compound or compounds that can be used to adjust the tonicity of the liquid formulation. Suitable tonicity modifying agents include glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol, trehalose and others known to those of ordinary skill in the art. In one embodiment, the tonicity of the liquid formulation approximates the tonicity of blood or plasma. An isotonic or isoosmotic solution is one where the tonicity approximates the tonicity of blood or plasma.

As used herein, the term â€œvisible particulatesâ€ is intended to mean particulate matter that is visible to the eye of a person trained in making such observations without the use of magnification. In some procedures for visual examination for particulates, the bag or container is swirled or gently mixed prior to examination. Solutions with a sufficiently low surface tension may foam during this step making the observation difficult or prone to false positive results. Such solutions can also foam during manufacture or handling prior to the visual examination and residual foam may be present during the examination, causing the same difficulties in observation and false results.

General Description

The invention generally encompasses a ready to use injectable intravenous bag formulation comprising:

a. a bag comprising of polyvinyl chloride, polyolefin, polypropylene, polyethylene, polyvinylidene chloride, nylon, or combinations thereof comprising:

- i. an aqueous solution containing a sulfobutylether beta-cyclodextrin and amiodarone or a pharmaceutically acceptable salt thereof wherein,
  - 1. the cyclodextrin:amiodarone mole ratio is greater than 2.7:1 and less than or equal to 7:1; and
  - 2. the amiodarone concentration ranges from about 0.7 mM to about 7 mM.

In certain embodiments, the solution is sterile.

In certain embodiments, the bag is comprised of ethylene vinyl acetate, polyolefin, polypropylene, polyethylene, nylon, and/or polyvinylchloride or combinations thereof.

In certain embodiments, the intravenous bag comprises polyvinyl chloride.

In certain embodiments, the intravenous bag comprises polyolefin.

In certain embodiments, the intravenous bag comprises ethylene vinyl acetate.

In certain embodiments, the intravenous bag comprises polypropylene.

In certain embodiments, the intravenous bag comprises polyethylene.

In certain embodiments, the intravenous bag comprises polypropylene.

In certain embodiments, the intravenous bag comprises a combination of one or more of ethylene vinyl acetate, polyolefin, polypropylene, polyethylene, nylon, and/or polyvinylchloride.

In certain embodiments, the intravenous bag formulation further comprises one or more components selected from pH adjusting agents, buffering agents, antioxidants, and tonicity modifying agents.

In certain embodiments, the aqueous solution contains about 0.9 mM to about 5 mM citrate buffering agent.

In certain embodiments, the cyclodextrin:amiodarone mole ratio ranges from about 2.9:1 to about 5:1.

In certain embodiments, the final solution sulfobutylether beta-cyclodextrin concentration ranges from about 13 mg/mL to about 40 mg/mL, and the amiodarone concentration ranges from about 2.2 mM to about 2.7 mM.

In certain embodiments, the final solution sulfobutylether beta-cyclodextrin concentration ranges from about 6 mM to about 18 mM, and the amiodarone concentration ranges from about 2.2 mM to about 2.7 mM.

In certain embodiments, the surface tension of the final solution ranges from about 59 dynes/cm to about 75 dynes/cm.

In certain embodiments, the aqueous solution has a pH of about 3.6, and comprises about 3 mM citrate buffer, about 2.2 mM amiodarone, about 6.9 mM sulfobutylether-7-beta-cyclodextrin and sufficient dextrose to provide a final solution osmolality of about 255 mOsm/kg to about 345 mOsm/kg.

In certain embodiments, the aqueous solution has a pH of about 3.6 and comprises about 3 mM citrate buffer, about 2.6 mM amiodarone, about 8.3 mM sulfobutylether-7-beta-cyclodextrin and sufficient dextrose to provide a final solution osmolality of about 255 mOsm/kg to about 345 mOsm/kg.

In certain embodiments, the final solution has a pH of about 3.6 and comprises about 3 mM citrate buffer, about 2.2 mM amiodarone, about 6.9 mM sulfobutylether-7-beta-cyclodextrin and sufficient sodium chloride to provide a final solution osmolality of about 255 mOsm/kg to about 345 mOsm/kg.

In certain embodiments, the final solution has a pH of about 3.6 and comprises about 3 mM citrate buffer, about 2.6 mM amiodarone, about 8.3 mM sulfobutylether-7-beta-cyclodextrin and sufficient sodium chloride to provide a final solution osmolality of about 255 mOsm/kg to about 345 mOsm/kg.

In certain embodiments, there is formation of no more than about 0.1% (w/w) total impurities in the solution in the container, when stored at room temperature for 6 months.

In certain embodiments, there is no more than about 1% absorptive loss of amiodarone from the solution in the container, when stored at room temperature for 6 months.

In another embodiment, the invention generally encompasses a method for making a ready to use injectable pharmaceutical composition comprising the steps of:

a. preparing an aqueous solution containing a sulfobutylether beta-cyclodextrin and amiodarone or a pharmaceutically acceptable salt thereof wherein,

- i. the cyclodextrin:amiodarone mole ratio is greater than 2.7:1 and less than or equal to 7:1, and
- ii. the amiodarone is dissolved while maintaining a solution temperature of about 15Â° C. to about 65Â° C. and a pH less than or equal to the pKa of amiodarone, to give a clear solution absent of gel,

b. adding water as needed to provide a final solution with an amiodarone concentration of about 0.7 to 7 mM;

c. sterile filtering the final solution to substantially reduce microbial contamination; and

d. aseptically filling the final solution into a pharmaceutically acceptable container.

In certain embodiments, the method further comprises adding one or more components selected from pH adjusting agents, buffering agents, antioxidants and tonicity modifying agents to the solution.

In certain embodiments, the final solution contains about 0.9 mM to about 5 mM citrate buffering agent.

In certain embodiments, the cyclodextrin:amiodarone mole ratio ranges from about 2.9:1 to about 5:1.

In certain embodiments, the pH during amiodarone dissolution ranges from about 3 to about 4.5.

In certain embodiments, the final solution sulfobutylether beta-cyclodextrin concentration ranges from about 13 mg/mL to about 40 mg/mL and the amiodarone concentration ranges from about 2.2 to 2.7 mM.

In certain embodiments, the surface tension of the final solution ranges from about 59 dynes/cm to about 75 dynes/cm.

In certain embodiments, the final solution has a pH of about 3 to about 4.

In certain embodiments, the final solution has a pH of about 3.6, and contains about 3 mM citrate buffer, about 2.2 mM amiodarone, about 6.9 mM sulfobutylether-7-beta-cyclodextrin and sufficient dextrose to provide a final solution osmolality of about 255 mOsm/kg to about 345 mOsm/kg.

In certain embodiments, the final solution has a pH of about 3.6 and comprises about 3 mM citrate buffer, about 2.6 mM amiodarone, about 8.3 mM sulfobutylether 7 beta-cyclodextrin and sufficient dextrose to provide a final solution osmolality of about 255 mOsm/kg to about 345 mOsm/kg.

In certain embodiments, the final solution has a pH of about 3.6 and comprises about 3 mM citrate buffer, about 2.2 mM amiodarone, about 6.9 mM sulfobutylether-7-beta-cyclodextrin and sufficient sodium chloride to provide a final solution osmolality of about 255 mOsm/kg to about 345 mOsm/kg.

In certain embodiments, the final solution has a pH of about 3.6 and comprises about 3 mM citrate buffer, about 2.6 mM amiodarone, about 8.3 mM sulfobutylether-7-beta-cyclodextrin and sufficient sodium chloride to provide a final solution osmolality of about 255 mOsm/kg to about 345 mOsm/kg.

In certain embodiments, there is no more than about 1% degradation or absorptive loss of amiodarone from the solution in the container, when stored at room temperature for 6 months.

In certain embodiments, there is formation of no more than about 0.1% (w/w) total impurities in the solution in the container, when stored at room temperature for 6 months.

Another embodiment encompasses a method for making a ready to use injectable pharmaceutical composition free of visible particulates comprising the steps of:

a. preparing an aqueous solution comprising a sulfobutylether-beta-cyclodextrin and amiodarone or a pharmaceutically acceptable salt thereof wherein,

- i. the cyclodextrin:amiodarone mole ratio ranges from about 1.1:1 to less than or equal to about 7:1,
- ii. the amiodarone is dissolved while maintaining a solution temperature of about 15Â° C. to less than about 40Â° C. and a pH less than or equal to the pKa of amiodarone, to give a clear solution absent of gel,

b. optionally adding additional cyclodextrin as needed to provide a cyclodextrin:amiodarone mole ratio of greater than 2.7:1 to about 7:1; and

c. adding additional water as necessary to provide a final solution with an amiodarone concentration of about 0.73 mM to about 7.3 mM.