Claims for Patent: 10,952,998

Summary for Patent: 10,952,998

Title:	Amlodipine formulations
Abstract:	Provided herein are stable amlodipine oral liquid formulations. Also provided herein are methods of using amlodipine oral liquid formulations for the treatment of certain diseases including hypertension and Coronary Artery Disease (CAD).
Inventor(s):	Brauer; Scott (Harrisonville, MO), Mosher; Gerold L. (Kansas City, MO)
Assignee:	Silvergate Pharmaceuticals, Inc. (Greenwood Village, CO)
Application Number:	16/927,678
Patent Claims:	1. An oral liquid formulation, comprising: (i) amlodipine benzoate in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) a buffer that maintains a pH value of the formulation between 4 and 6; (iii) 0.2 mg/ml to 10 mg/ml of sodium benzoate; (iv) a suspension aid that is selected from silicon dioxide, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidone, xanthan gum, or a combination thereof; (v) 0.05 mg/ml to 1.0 mg/ml of simethicone; (vi) 0.1 mg/ml to 3.0 mg/ml of polysorbate 80; and (vii) water; wherein the formulation is stable at 5.+-.5.degree. C. for at least 12 months; and wherein the stable oral liquid formulation has 95% w/w or greater of the initial amlodipine amount and 5% w/w or less total impurities or related substances at the end of the given storage period. 2. The formulation of claim 1, wherein the amlodipine benzoate is formed in situ. 3. The formulation of claim 1, wherein the amlodipine benzoate is formed by a reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate with a molar excess of sodium benzoate. 4. The formulation of claim 3, wherein the salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate is selected from amlodipine besylate, amlodipine tosylate, amlodipine mesylate, amlodipine succinate, amlodipine salicylate, amlodipine maleate, amlodipine acetate, and amlodipine hydrochloride. 5. The formulation of claim 1, wherein the amlodipine benzoate is formed by the reaction of amlodipine besylate with a molar excess of sodium benzoate. 6. The formulation of claim 1, wherein the formulation further comprises a flavoring agent. 7. The formulation of claim 1, wherein the formulation further comprises a sweetener. 8. The formulation of claim 7, wherein the sweetener is sucralose. 9. The formulation of claim 1, wherein the formulation is in the form of a suspension. 10. The formulation of claim 1, wherein the pH is between 5 and 6. 11. The formulation of claim 1, wherein the buffer comprises a citrate buffer, a phosphate buffer, an acetate buffer, or a combination thereof. 12. The formulation of claim 1, wherein the suspension aid is present in the formulation at 5.0 mg/ml to 15.0 mg/ml. 13. The formulation of claim 1, wherein the suspension aid is present in the formulation at 3.0 mg/ml to 10.0 mg/ml. 14. The formulation of claim 1, wherein the suspension aid is present in the formulation at 20% w/w to 50% w/w of the solids in the suspension. 15. The formulation of claim 1, wherein the suspension aid comprises silicon dioxide and hydroxypropyl methylcellulose. 16. The formulation of claim 1, wherein the suspension aid comprises microcrystalline cellulose and carboxymethyl cellulose sodium. 17. The formulation of claim 1, wherein the formulation comprises 0.05 mg/ml to 0.3 mg/ml of simethicone. 18. The formulation of claim 1, wherein the formulation comprises 0.5 mg/ml, 1.0 mg/ml, or 2.0 mg/ml of polysorbate 80. 19. The formulation of claim 1, wherein the formulation is stable at 5.+-.5.degree. C. for at least 24 months. 20. An oral liquid formulation, comprising: (i) amlodipine naphthalene sulfonate in an amount corresponding to 1.0 mg/ml amlodipine freebase; (ii) a buffer that maintains a pH value of the formulation between 4 and 6; (iii) 0.5 mg/ml to 2.5 mg/ml of sodium naphthalene-2-sulfonate; (iv) a suspension aid that is selected from silicon dioxide, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidone, xanthan gum, or a combination thereof; (v) 0.05 mg/ml to 1.0 mg/ml of simethicone; (vi) optionally 0.1 mg/ml to 3.0 mg/ml of polysorbate 80; and (vii) water; wherein the formulation is stable at 25.+-.5.degree. C. for at least 12 months; and wherein the stable oral liquid formulation has 95% w/w or greater of the initial amlodipine amount and 5% w/w or less total impurities or related substances at the end of the given storage period. 21. The formulation of claim 20, wherein the amlodipine naphthalene sulfonate is formed in situ. 22. The formulation of claim 20, wherein the amlodipine naphthalene sulfonate is formed by a reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine naphthalene sulfonate with a molar excess of sodium naphthalene-2-sulfonate. 23. The formulation of claim 22, wherein the salt of amlodipine that is more soluble in aqueous media than amlodipine naphthalene sulfonate is selected from amlodipine besylate, amlodipine tosylate, amlodipine mesylate, amlodipine succinate, amlodipine salicylate, amlodipine maleate, amlodipine acetate, and amlodipine hydrochloride. 24. The formulation of claim 20, wherein the amlodipine naphthalene sulfonate is formed by the reaction of amlodipine besylate with a molar excess of sodium naphthalene-2-sulfonate. 25. The formulation of claim 20, wherein the pH is between 5 and 6. 26. The formulation of claim 20, wherein the buffer comprises a citrate buffer, a phosphate buffer, an acetate buffer, or a combination thereof. 27. The formulation of claim 20, wherein the suspension aid is present in the formulation at 5.0 mg/ml to 15.0 mg/ml or 3.0 mg/ml to 10.0 mg/ml. 28. The formulation of claim 20, wherein the suspension aid is present in the formulation at 20% w/w to 50% w/w of the solids in the suspension. 29. The formulation of claim 20, wherein the suspension aid comprises silicon dioxide and hydroxypropyl methylcellulose. 30. The formulation of claim 20, wherein the suspension aid comprises microcrystalline cellulose and carboxymethyl cellulose sodium.