Amlodipine formulations
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).
1. An oral liquid formulation, consisting essentially of:
(i) amlodipine benzoate in an amount corresponding to 1.0 mg/ml amlodipine freebase;
(ii) 0.2 mg/ml to 10 mg/ml of sodium benzoate;
(iii) a suspension aid that is selected from silicon dioxide, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidone, xanthan gum, or a combination thereof;
(iv) 0.05 mg/ml to 1.0 mg/ml of an antifoaming agent, wherein the antifoaming agent is simethicone;
(v) a non-ionic surfactant that is present at about 0.1 mg/ml to about 3.0 mg/ml in the oral liquid formulation, wherein the non-ionic surfactant is polysorbate 80;
(vi) optionally one or more selected from a flavoring agent, a sweetener, and a preservative; and
(vii) water;
wherein the formulation has a pH between 4 and 6,
wherein the formulation is stable at 5±5° C. for a storage period of 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 comprises a flavoring agent and a sweetener.
7. The formulation of claim 1 , wherein the formulation is in the form of a suspension.
8. The formulation of claim 1 , wherein the pH is adjusted to between 4 and 6 with a solution comprising citric acid.
9. The formulation of claim 1 , wherein the amlodipine benzoate functions as a buffer.
10. The formulation of claim 1 , wherein the suspension aid is present in the formulation at 5.0 mg/ml to 15.0 mg/ml.
11. The formulation of claim 1 , wherein the suspension aid is present in the formulation at 3.0 mg/ml to 10.0 mg/ml.
12. 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.
13. The formulation of claim 1 , wherein the suspension aid comprises silicon dioxide and hydroxypropyl methylcellulose.
14. The formulation of claim 1 , wherein the suspension aid comprises microcrystalline cellulose and carboxymethyl cellulose sodium.
15. The formulation of claim 1 , wherein the antifoaming agent is present in the oral liquid formulation at 0.05 mg/ml to about 0.3 mg/ml.
16. The formulation of claim 1 , wherein the formulation comprises about 0.5 mg/ml, about 1.0 mg/ml, or about 2.0 mg/ml of polysorbate 80.
17. The formulation of claim 1 , wherein the formulation is stable at 5±5° C. for at least 24 months.
18. An oral liquid formulation, consisting essentially of:
(i) amlodipine naphthalene sulfonate in an amount corresponding to 1.0 mg/ml amlodipine freebase;
(ii) 0.5 mg/ml to 2.5 mg/ml of sodium naphthalene-2-sulfonate;
(iii) a suspension aid that is selected from silicon dioxide, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidone, xanthan gum, or a combination thereof;
(iv) 0.05 mg/ml to 1.0 mg/ml of an antifoaming agent, wherein the antifoaming agent is simethicone;
(v) optionally a non-ionic surfactant that is present at about 0.1 mg/ml to about 3.0 mg/ml in the oral liquid formulation, wherein the non-ionic surfactant is polysorbate 80;
(vi) optionally one or more selected from a flavoring agent, a sweetener, and a preservative; and
(vii) water;
wherein the formulation has a pH between 4 and 6 wherein the amlodipine naphthalene sulfonate is formed in situ,
wherein the formulation is stable at 25±5° C. for a storage period of 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.
19. The formulation of claim 18 , 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.
20. The formulation of claim 18 , wherein the amlodipine naphthalene sulfonate is formed by the reaction of amlodipine besylate with a molar excess of sodium naphthalene-2-sulfonate.
21. The formulation of claim 18 , wherein the pH is adjusted to between 4 and 6 with a solution comprising citric acid.
22. The formulation of claim 18 , wherein the amlodipine naphthalene sulfonate functions as a buffer.
23. The formulation of claim 18 , 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.
24. The formulation of claim 18 , wherein the suspension aid is present in the formulation at 20% w/w to 50% w/w of the solids in the suspension.
25. The formulation of claim 18 , wherein the suspension aid comprises (i) silicon dioxide and hydroxypropyl methylcellulose or (ii) microcrystalline cellulose and carboxymethyl cellulose sodium.