Claims for Patent: 6,869,939

Summary for Patent: 6,869,939

Title:	Formulations containing amiodarone and sulfoalkyl ether cyclodextrin
Abstract:	The present invention provides aqueous parenteral formulations containing an antiarrhythmic agent, such as amiodarone, and a sulfoalkyl ether cyclodextrin. The liquid formulations are clear, sterilizable, and chemically and physically stable. The liquid formulations do not require a surfactant and do not precipitate upon dilution with distilled water or other pharmaceutically acceptable liquid carrier. The sulfoalkyl ether cyclodextrin-containing formulation provides significant advantages over other cyclodextrin-containing formulations of amiodarone. The formulation can be prepared in acidic, neutral and slightly basic medium while providing acceptable concentrations of amiodarone suitable for parenteral administration. An SAE-CD-containing formulation of amiodarone can be provided in liquid form or as a reconstitutable powder. Moreover, highly concentrated solutions exceeding 200 mg of amiodarone per mL can be prepared. Solutions can be made either dilutable or non-dilutable with water at room temperature or under conditions typically encountered in the clinic.
Inventor(s):	Mosher; Gerold L. (Kansas City, MO), Johnson; Karen T. (Lawrence, KS), Gayed; Atef A. (Overland Park, KS)
Assignee:	CyDex, Inc. (Lenexa, KS)
Application Number:	10/139,620
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,869,939
Patent Claims:	1. A water dilutable clear liquid formulation comprising amiodarone and a sulfoalkyl ether cyclodextrin (SAE-CD), wherein the molar ratio of SAE-CD to amiodarone is greater than or equal to about 1.1.+-.0.01, and the liquid formulation is dilutable with water at ambient temperature without significant precipitation of amiodarone and without the need of surfactant, organic solvent, soap or detergent, and wherein the SAE-CD is a compound or mixture of compounds of the Formula 1 ##STR4## wherein: n is 5, or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are each, independently, --O-- or a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group, wherein at least one of R.sub.1 and R.sub.2 is independently a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group; and S.sub.1, S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8, and S.sub.9 are each, independently, a pharmaceutically acceptable cation. 2. The formulation of claim 1, wherein the amiodarone concentration is in the range of less than or equal to about 3 mg/ml, the SAE-CD concentration is less than or equal to about 0.9% wt., and the pH of the liquid approximates or is less than the pKa of amiodarone. 3. The formulation of claim 1, wherein the amiodarone concentration is greater than or equal to about 34 mg/mL, the SAE-CD concentration is greater than or equal to about 55 mM, and the pH of the liquid approximates or is less than the pKa of amiodarone. 4. The formulation of claim 1, wherein the compound of Formula 1 has an average degree of substitution of about 4 or 7. 5. The formulation of claim 1 further comprising a solubilizing agent, antioxidant, buffering agent, acidifying agent, complexation enhancing agent, saline, dextrose, lyophilizing aid, bulking agent, stabilizing agents, electrolyte, another therapeutic agent, alkalizing agent, antimicrobial agent, antifungal agent or a combination thereof. 6. The formulation of claim 5, wherein the buffering agent is an organic or inorganic acid, organic or inorganic base, or salt thereof. 7. The formulation of claim 6, wherein the buffering agent is selected from the group consisting of acetic acid, citric acid, phosphoric acid, boric acid, or a salt thereof. 8. The formulation of claim 5, wherein the total ionic strength of charged species in solution, excluding amiodarone and SAE-CD, is less than about 0.5 M. 9. The formulation of claim 1, wherein the formulation has a surface tension greater than about 50 dynes/cm when the concentration of amiodarone is less than or equal to about 10 mg/mL. 10. The formulation of claim 1, wherein the formulation has a tonicity between about 280 to 500 mOsm when the concentration of amiodarone is less than or equal to about 10 mg/mL. 11. A water dilutable clear liquid formulation comprising amiodarone and an SAE-CD, wherein a. the molar ratio of SAE-CD to amiodarone is greater than or equal to about 1.1.+-.0.01; b. the liquid formulation is dilutable with water at ambient temperature without significant precipitation of amiodarone and without the need of surfactant, organic solvent, soap or detergent; c. the amiodarone concentration is in the range of less than or equal to about 3 mg/ml; d. the SAE-CD concentration is less than or equal to about 4.5 mM; e. the pH of the liquid approximates or is less than the pKa of amiodarone; and f. the sulfoalkyl ether cyclodextrin is a compound or mixture of compounds of the Formula 1 ##STR5## wherein: n is 5, or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are each, independently, --O-- or a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group, wherein at least one of R.sub.1 and R.sub.2 is independently a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group; and S.sub.1, S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8, and S.sub.9 are each, independently, a pharmaceutically acceptable cation. 12. The formulation of claim 11, wherein the compound of Formula 1 has an average degree of substitution of about 4 or 7. 13. The formulation of claim 11, wherein the total ionic strength of charged species in solution, excluding amiodarone and SAE-CD, is less than about 0.5 M. 14. The formulation of claim 11, wherein the formulation has a surface tension greater than about 50 dynes/cm and a tonicity between about 280 to 500 mOsm. 15. A water dilutable clear liquid formulation comprising water, amiodarone and an SAE-CD, wherein a. the molar ratio of SAE-CD to amiodarone is greater than or equal to about 1.1.+-.0.01; b. the liquid formulation is dilutable with water at ambient temperature without significant precipitation of amiodarone and without the need of surfactant, organic solvent, soap or detergent; c. the amiodarone concentration is greater than or equal to about 50 mM; d. the SAE-CD concentration is greater than or equal to about 55 mM; e. the pH of the liquid medium approximates or is less than the pKa of amiodarone; and f. the sulfoalkyl ether cyclodextrin is a compound or mixture of compounds of the Formula 1 ##STR6## wherein: n is 5, or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are each, independently, --O-- or a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group, wherein at least one of R.sub.1 and R.sub.2 is independently a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group; and S.sub.1, S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8, and S.sub.9 are each, independently, a pharmaceutically acceptable cation. 16. The formulation of claim 15, wherein the compound of Formula 1 has an average degree of substitution of about 4 or 7. 17. A clear liquid formulation comprising amiodarone, SAE-CD and an aqueous liquid carrier, wherein the molar ratio of SAE-CD to amiodarone is less than or equal to about 1.09.+-.0.01 and greater than or equal to about 0.3; the pH of the liquid formulation approximates or is less than the pKa of amiodarone; the liquid formulation has been exposed to a temperature of greater than or equal to about 45.degree. C. thereby rendering the liquid formulation clear; and wherein the SAE-CD is a compound or mixture of compounds of the Formula 1 ##STR7## wherein: n is 4, 5, or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are each, independently, --O-- or a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group, wherein at least one of R.sub.1 and R.sub.2 is independently a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group; and S.sub.1, S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8, and S.sub.9 are each, independently, a pharmaceutically acceptable cation. 18. The formulation of claim 17, wherein the liquid formulation is dilutable with a heated pharmaceutically acceptable aqueous liquid carrier, an aqueous liquid comprising SAE-CD or an aqueous liquid comprising a solubilizing agent, soap, detergent, surfactant, or complexation enhancing agent to form a clear diluted liquid formulation. 19. A clear water dilutable concentrated liquid formulation comprising SBE7-.beta.-CD and amiodarone, wherein the amiodarone is present in an amount of greater than about 2 mg/mL, and the SBE7-.beta.-CD to amiodarone ratio is greater than or equal to about 1.1.+-.0.01, wherein the liquid formulation can be diluted with water at about 20.degree. C. to 30.degree. C. to form a clear diluted liquid formulation. 20. A clear ready-to-inject sterile liquid formulation comprising SBE7-.beta.-CD and amiodarone, wherein the SBE7-.beta.-CD is present in an amount of at least about 0.3% wt. and the amiodarone is present in amount of 1-2 mg/mL. 21. A clear water dilutable concentrated aqueous liquid formulation comprising a pharmaceutically acceptable aqueous liquid, SAE-CD and amiodarone, wherein the amiodarone is present in an amount of greater than about 2 mg/mL; the SAE-CD to amiodarone ratio is greater than or equal to about 1.1.+-.0.01; the SAE-CD is a compound or mixture of compounds of the Formula 1 ##STR8## wherein: n is 5, or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are each, independently, --O-- or a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group, wherein at least one of R.sub.1 and R.sub.2 is independently a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group; and S.sub.1, S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8, and S.sub.9 are each, independently, a pharmaceutically acceptable cation; and the liquid formulation can be diluted with water at about 20.degree. C. to 30.degree. C. to form a clear diluted liquid formulation. 22. A clear ready-to-inject sterile aqueous liquid formulation comprising pharmaceutically acceptable aqueous liquid, SAE-CD and amiodarone, wherein the SAE-CD is present in an amount of at least about 0.3% wt.; amiodarone is present in an amount of about 0.482 to 100.8 mg/ml; the SAE-CD is a compound or mixture of compounds of the Formula 1 ##STR9## wherein: n is 4, 5, or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are each, independently, --O-- or a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group, wherein at least one of R.sub.1 and R.sub.2 is independently a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group; and S.sub.1, S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8, and S.sub.9 are each, independently, a pharmaceutically acceptable cation. 23. A clear ready-to-inject sterile aqueous liquid comprising pharmaceutically acceptable aqueous liquid, SAE-CD and amiodarone, wherein SAE-CD is present in an amount of less than or equal to about 0.055 M; amiodarone is present in an amount of less than or equal to about 0.05 M; the molar ratio of SAE-CD amiodarone is less than or equal to about 1.09.+-.0.01 and greater than or equal to about 0.3; and SAE-CD is a compound or mixture of compounds of the Formula 1 ##STR10## wherein: n is 4, 5, or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are each, independently, --O-- or a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group, wherein at least one of R.sub.1 and R.sub.2 is independently a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group; and S.sub.1, S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8, and S.sub.9 are each, independently, a pharmaceutically acceptable cation. 24. The liquid formulation of claim 23, wherein the liquid formulation has been prepared by heating the pharmaceutically acceptable aqueous liquid and/or the liquid formulation at a temperature of at least about 30.degree. C. 25. The liquid formulation of claim 23, wherein the liquid formulation has been prepared by heating the pharmaceutically acceptable aqueous liquid and/or the liquid formulation at a temperature of at least about 30.degree. C. 26. The liquid formulation of claim 15, wherein the liquid formulation has been prepared by heating the pharmaceutically acceptable aqueous liquid and/or the liquid formulation at a temperature of at least about 30.degree. C. 27. A water dilutable clear aqueous liquid formulation comprising water, amiodarone and an SAE-CD, wherein a. the molar ratio of SAE-CD to amiodarone is greater than or equal to about 1.1.+-.0.01; b. the liquid formulation is dilutable with water at ambient temperature without significant precipitation of amiodarone and without the need of surfactant, organic solvent, soap or detergent; c. the amiodarone concentration is less than or equal to about 50 mM; d. the pH of the liquid medium approximates or is less than the pKa of amiodarone; and e. the sulfoalkyl ether cyclodextrin is a compound or mixture of compounds of the Formula 1 ##STR11## wherein: n is 4, 5, or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are each, independently, --O-- or a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group, wherein at least one of R.sub.1 and R.sub.2 is independently a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group; and S.sub.1, S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8, and S.sub.9 are each, independently, a pharmaceutically acceptable cation. 28. The formulation of claim 27, wherein the SAE-CD concentration is less than or equal to about 55 mM. 29. A method of preparing a clear liquid formulation comprising the steps of: a. providing amiodarone, SAE-CD and a pharmaceutically acceptable aqueous liquid carrier to form a mixture, wherein the molar ratio of SAE-CD to amiodarone is less than about 1.09.+-.0.1 and greater than or equal to about 0.3; and b. heating the liquid carrier and/or liquid formulation at a temperature of at least about 45.degree. C. thereby forming the clear liquid formulation; wherein SAE-CD is a compound or mixture of compounds of the Formula 1 ##STR12## wherein: n is 4, 5, or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are each, independently, --O-- or a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group, wherein at least one of R.sub.1 and R.sub.2 is independently a --O--(C.sub.2 -C.sub.6 alkylene)-SO.sub.3.sup.- group; and S.sub.1, S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8, and S.sub.9 are each, independently, a pharmaceutically acceptable cation.