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 median diameter D50 value of between about 5 μm and about 40 μm as measured by a light scattering particle size analyzer, and the said suspension is made by a process comprising:
(i) providing an aqueous mixture comprising amlodipine besylate;
(ii) adding sodium benzoate to the aqueous mixture to form a first mixture; and
(iii) subjecting the first mixture to ultrasonic agitation at a frequency of between about 20 kHz and about 100 kHz, thereby forming a second mixture comprising amlodipine benzoate.
2. The suspension made by the process of claim 1 , wherein the said particles have the D50 value of between about 10 μm and about 20 μm.
3. The suspension made by the process of claim 1 , wherein the said particles have a D90 value of between about 20 μm and about 60 μm, and wherein the D90 value refers to a particle diameter, wherein 10% of the volume of the sampled particles have a diameter larger than, and 90% of the volume of the sampled particles have a diameter smaller than said D90 value.
4. The suspension made by the process of claim 1 , wherein the aqueous mixture of step (i) further comprises polysorbate 80 acting as a first surfactant.
5. The suspension made by the process of claim 1 , wherein the concentration of amlodipine besylate is between about 12 mg/ml and about 20 mg/ml in the aqueous mixture of step (i).
6. The suspension made by the process of claim 1 , wherein the concentration of sodium benzoate is between about 40 mg/ml and about 70 mg/ml in the first mixture of step (ii).
7. The suspension made by the process of claim 1 , wherein the duration of the ultrasonic agitation in step (iii) is between about 1 minute and 1 hour.
8. The suspension made by the process of claim 1 , wherein the duration of the ultrasonic agitation in step (iii) is between about 5 minutes and 30 minutes.
9. The suspension made by the process of claim 1 , wherein the aqueous mixture of step (i) does not comprise any solvent other than water.
10. The suspension made by the process of claim 4 , wherein the process further comprises adding a second surfactant into the second mixture of step (iii).
11. The suspension made by the process of claim 10 , wherein the combined amount of the surfactants is about 0.1 mg/ml to about 2 mg/ml.
12. The suspension made by the process of claim 1 , wherein the process further comprises adding the second mixture comprising amlodipine benzoate to a third mixture comprising at least one component selected from a buffer, a preservative, a sweetening agent, a suspension agent, an antifoaming agent, water, and a flavoring agent.
13. The suspension made by the process of claim 12 , wherein the amount of preservative is about 0.1 mg/ml to about 5.0 mg/ml.
14. The suspension made by the process of claim 12 , wherein the buffer comprises a citrate buffer.
15. The suspension made by the process of claim 14 , wherein the citrate buffer concentration is about 3 mM.
16. The suspension made by the process of claim 12 , wherein the suspension agent comprises at least one component selected from silicon dioxide, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, xanthan gum, magnesium aluminum silicate, crosslinked polyacrylic acid polymers and combinations thereof.
17. The suspension made by the process of claim 12 , wherein the suspension agent is a combination of silicon dioxide and hydroxypropyl methylcellulose.
18. The suspension made by the process of claim 12 , wherein the antifoaming agent is simethicone.
19. The suspension made by the process of claim 1 , wherein a final concentration of amlodipine benzoate in the suspension is equivalent to about 0.8 mg/ml to about 1.2 mg/ml of amlodipine free base.