Amlodipine formulations
Provided herein are stable amlodipine liquid formulations. Also provided herein are methods of using amlodipine liquid formulations for the treatment of certain diseases including hypertension and Coronary Artery Disease (CAD).
1. A suspension comprising particles comprising amlodipine benzoate and having a particle size D10 value of between 1 μm and 10 μm as measured by a light scattering particle size analyzer, wherein the suspension is made by mixing amlodipine besylate and a sodium benzoate in an aqueous mixture between 1 minute and 1 hour, thereby forming the suspension comprising particles comprising amlodipine benzoate.
2. The suspension of claim 1 , wherein the concentration of amlodipine besylate is between 12 mg/ml and 20 mg/ml.
3. The suspension of claim 1 , wherein the final concentration of amlodipine benzoate in the suspension is equivalent to 1.0 mg/ml of amlodipine free base.
4. The suspension of claim 1 , wherein the mixing comprises ultrasonic agitation.
5. The suspension of claim 4 , wherein the ultrasonic agitation has a frequency of between 20 kHz and 100 kHz.
6. The suspension of claim 1 , wherein the mixing occurs by a mixing device, wherein the mixing device is a homogenizer or a blender.
7. The suspension of claim 1 , wherein the duration of the mixing is between 1 minute and 30 minutes.
8. The suspension of claim 1 , wherein, after the mixing of the aqueous mixture, at least one of the following is added into the suspension: a buffer, a preservative, a sweetening agent, a suspension agent, an antifoaming agent, and a flavoring agent.
9. The suspension of claim 8 , wherein the suspension agent is selected from the group consisting of silicon dioxide, hydroxypropyl methylcellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, xanthan gum, magnesium aluminum silicate, crosslinked polyacrylic acid polymers, and any combination thereof.
10. The suspension of claim 8 , wherein the suspension agent is a combination of silicon dioxide and hydroxypropyl methylcellulose.
11. The suspension of claim 8 , wherein the amount of preservative is from 0.1 mg/ml to 5.0 mg/ml.
12. The suspension of claim 8 , wherein the buffer is a citrate buffer.
13. The suspension of claim 12 , wherein the citrate buffer concentration is 3 mM.
14. The suspension of claim 8 , wherein the antifoaming agent is simethicone.
15. The suspension of claim 1 , wherein the suspension is stable at 25±5° C. for at least 6 months.
16. The suspension of claim 1 , wherein the suspension is stable at 5±5° C. for at least 6 months.
17. The suspension of claim 1 , wherein the sodium benzoate is present in the aqueous mixture at a concentration of from 40 mg/ml to 70 mg/ml.
18. The suspension of claim 1 , wherein the suspension is stable at 5±5° C. for at least 12 months.
19. The suspension of claim 8 , wherein the amount of antifoaming agent is from 0.1 mg/ml to 1.0 mg/ml.
20. The suspension of claim 1 , wherein the suspension comprises:
(i) amlodipine benzoate in an amount corresponding to 1.0 mg/ml of amlodipine free base;
(ii) 1 mM to 5 mM of citrate buffer;
(iii) 0.1 mg/ml to 5.0 mg/ml of sodium benzoate;
(iv) 0.1 mg/ml to 1.0 mg/ml of silicon dioxide;
(v) 3 mg/ml to 10 mg/ml of hydroxypropyl methylcellulose;
(vi) 0.1 mg/ml to 1.0 mg/ml of simethicone;
(vii) 0.1 mg/ml to 2 mg/ml of the surfactant; and
(viii) water.