IP Library › Granted Patent US 12,336,984
Granted Patent B2
US 12,336,984 · App. 18/794,128 · Granted Jun 24, 2025

Amlodipine formulations

Inventors: Scott Brauer (Harrisonville, MO); Gerold L. Mosher (Kansas City, MO)
Assignee: AZURITY PHARMACEUTICALS, INC.
A61K31/4422A61K9/08A61K47/02A61K47/12A61K47/26A61K47/34A61K47/38
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Quick Facts
Patent No.
US 12,336,984
App. No.
18/794,128
Granted
Jun 24, 2025
Kind
B2
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).

Claims (48)

1. A method of treating Coronary Artery Disease (CAD) in a subject comprising administering to the subject an oral liquid formulation, wherein the oral liquid formulation comprises:

(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 comprising 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;

(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;

(vi) optionally one or more selected from a buffer, a flavoring agent, a sweetener, and a preservative; and

(vii) water;

wherein the oral liquid 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 method of claim 1 , wherein the CAD is angiographically documented coronary artery disease.

3. The method of claim 2 , wherein the angiographically documented coronary artery disease is in patients without heart failure or an ejection fraction <40%.

4. The method of claim 1 , wherein the formulation is further administered in combination with an additional anti-anginal agent.

5. The method of claim 1 , wherein the CAD is chronic stable angina.

6. The method of claim 1 , wherein the CAD is vasospastic angina.

7. The method of claim 1 , wherein the amlodipine benzoate is formed in situ.

8. The method of claim 1 , wherein the amlodipine benzoate is formed by the reaction of amlodipine besylate with a molar excess of sodium benzoate.

9. The method of claim 1 , wherein the oral liquid formulation comprises a flavoring agent and a sweetener.

10. The method of claim 1 , wherein the oral liquid formulation is in the form of a suspension.

11. The method of claim 1 , wherein the pH is between 4 and 6.

12. The method of claim 1 , wherein the suspension aid is present in the oral liquid formulation at 5.0 mg/ml to 15.0 mg/ml.

13. The method of claim 1 , wherein the suspension aid is present in the oral liquid formulation at 3.0 mg/ml to 10.0 mg/ml.

14. The method of claim 1 , wherein the suspension aid comprises silicon dioxide, hydroxypropyl methylcellulose, microcrystalline cellulose, carboxymethyl cellulose sodium, or any combination thereof.

15. The method of claim 1 , wherein the antifoaming agent is simethicone and is present in the oral liquid formulation at about 0.05 mg/ml to about 0.3 mg/ml.

16. The method of claim 1 , wherein the non-ionic surfactant is a block copolymers of polyethylene glycol and polypropylene glycol, a polyethylene glycol octylphenyl ether, polyethylene glycol alkyl ether, or any combination thereof.

17. A method of treating hypertension in a subject comprising administering to the subject an oral liquid formulation, wherein the oral liquid formulation comprises:

(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 comprising 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;

(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;

(vi) optionally one or more selected from a buffer, a flavoring agent, a sweetener, and a preservative; and

(vii) water;

wherein the oral liquid 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.

18. The method of claim 17 , wherein the hypertension is primary or secondary hypertension.

19. The method of claim 17 , wherein the subject has blood pressure values greater than or equal to 140/90 mm Hg.

20. The method of claim 17 , wherein the oral liquid formulation is further administered in combination with an agent selected from the group consisting of diuretics, beta blockers, alpha blockers, mixed alpha and beta blockers, calcium channel blockers, angiotensin II receptor antagonists, Angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists, and alpha-2 agonists.

21. The method of claim 17 , wherein the amlodipine benzoate is formed in situ.

22. The method of claim 17 , wherein the amlodipine benzoate is formed by the reaction of amlodipine besylate with a molar excess of sodium benzoate.

23. The method of claim 17 , wherein the oral liquid formulation comprises a flavoring agent and a sweetener.

24. The method of claim 17 , wherein the oral liquid formulation is in the form of a suspension.

25. The method of claim 17 , wherein the pH is between 4 and 6.

26. The method of claim 17 , wherein the suspension aid is present in the oral liquid formulation at 5.0 mg/ml to 15.0 mg/ml.

27. The method of claim 17 , wherein the suspension aid is present in the oral liquid formulation at 3.0 mg/ml to 10.0 mg/ml.

28. The method of claim 17 , wherein the suspension aid comprises silicon dioxide, hydroxypropyl methylcellulose, microcrystalline cellulose, carboxymethyl cellulose sodium, or any combination thereof.

29. The method of claim 17 , wherein the antifoaming agent is simethicone and is present in the oral liquid formulation at about 0.05 mg/ml to about 0.3 mg/ml.

30. The method of claim 17 , wherein the non-ionic surfactant is a block copolymers of polyethylene glycol and polypropylene glycol, a polyethylene glycol octylphenyl ether, polyethylene glycol alkyl ether, or any combination thereof.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 28, 2025
From: BRAUER, SCOTT; MOSHER, GEROLD L.
To: SILVERGATE PHARMACEUTICALS, INC.
Reel/Frame 070961/0491 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 28, 2025
From: SILVERGATE PHARMACEUTICALS, INC.
To: AZURITY PHARMACEUTICALS, INC.
Reel/Frame 071096/0173 →
CONFIRMATORY GRANT OF SECURITY INTEREST IN UNITED STATES PATENTS Recorded Mar 17, 2025
From: ARBOR PHARMACEUTICALS, LLC; AZURITY PHARMACEUTICALS, INC.; AZURITY PHARMACEUTICALS IRELAND LIMITED; SILVERGATE PHARMACEUTICALS, INC.
To: HPS INVESTMENT PARTNERS, LLC, AS ADMINISTRATIVE AGENT
Reel/Frame 070531/0487 →
Continuity (7)
Continuation 17716505 · Apr 8, 2022
Continuation 17194016 · Mar 5, 2021
Continuation 16927678 · Jul 13, 2020
Continuation 16853380 · Apr 20, 2020
Continuation 15726901 · Oct 6, 2017
Provisional Application 62405455 · Oct 7, 2016
Related Publication 20240390347A1 · Nov 28, 2024
References Cited (108)
US 4879303A · Davison et al. · 1989 [cited by applicant]
US 6057344A · Young · 2000 [cited by applicant]
US 6291490B1 · Young · 2001 [cited by applicant]
US 6333342B1 · Foster · 2001 [cited by applicant]
US 6448275B2 · Young · 2002 [cited by applicant]
US 6451826B2 · Young · 2002 [cited by applicant]
US 6479525B2 · Lemmens et al. · 2002 [cited by applicant]
US 6518288B2 · Lemmens et al. · 2003 [cited by applicant]
US 6538012B2 · Ettema et al. · 2003 [cited by applicant]
US 6600047B2 · Benneker et al. · 2003 [cited by applicant]
US 6646131B2 · Zhang et al. · 2003 [cited by applicant]
US 6653481B2 · Peters et al. · 2003 [cited by applicant]
US 6680334B2 · Bentham et al. · 2004 [cited by applicant]
US 6822099B2 · Senanayake et al. · 2004 [cited by applicant]
US 6846931B2 · Youn et al. · 2005 [cited by applicant]
US 6890944B2 · Cho et al. · 2005 [cited by applicant]
US 6903124B2 · Cho et al. · 2005 [cited by applicant]
US 7015238B2 · Lim et al. · 2006 [cited by applicant]
US 7115638B2 · Lemmens et al. · 2006 [cited by applicant]
US 7199247B2 · Lemmens et al. · 2007 [cited by applicant]
US 7772400B2 · Kim et al. · 2010 [cited by applicant]
US 8158146B2 · Kadosh et al. · 2012 [cited by applicant]
US 8377994B2 · Gray et al. · 2013 [cited by applicant]
US 10695329B2 · Brauer et al. · 2020 [cited by applicant]
US 10799453B2 · Brauer et al. · 2020 [cited by applicant]
US 10894039B2 · Brauer et al. · 2021 [cited by applicant]
US 10952998B2 · Brauer et al. · 2021 [cited by applicant]
US 10959991B2 · Brauer et al. · 2021 [cited by applicant]
US 11364230B2 · Brauer et al. · 2022 [cited by applicant]
US 11471409B2 · Brauer et al. · 2022 [cited by applicant]
US 11484498B2 · Brauer et al. · 2022 [cited by applicant]
US 11701326B2 · Brauer et al. · 2023 [cited by applicant]
US 11918685B2 · Brauer et al. · 2024 [cited by applicant]
US 12053461B2 · Brauer et al. · 2024 [cited by applicant]
US 20020176889A1 · Lemmens et al. · 2002 [cited by applicant]
US 20030199559A1 · Benneker et al. · 2003 [cited by applicant]
US 20050019395A1 · Pragai et al. · 2005 [cited by applicant]
US 20060030602A1 · Laughlin et al. · 2006 [cited by applicant]
US 20060035940A1 · Laughlin et al. · 2006 [cited by applicant]
US 20090098200A1 · Temtsin et al. · 2009 [cited by applicant]
US 20110212169A1 · Bae et al. · 2011 [cited by applicant]
US 20110294860A1 · Tatsumi et al. · 2011 [cited by applicant]
US 20120177733A1 · Joshi et al. · 2012 [cited by applicant]
US 20140024723A1 · Brackhagen et al. · 2014 [cited by applicant]
CN 101416966A · 2009 [cited by applicant]
CN 101843615A · 2010 [cited by applicant]
CN 102018708A · 2011 [cited by applicant]
CN 102114017A · 2011 [cited by applicant]
CN 102370965A · 2012 [cited by applicant]
CN 102746215A · 2012 [cited by applicant]
EP 2676660A1 · 2013 [cited by applicant]
EP 2952207A1 · 2015 [cited by applicant]
EP 3773574A1 · 2021 [cited by applicant]
EP 3522872B1 · 2021 [cited by applicant]
EP 3960158A1 · 2022 [cited by applicant]
WO WO02053134A1 · 2002 [cited by applicant]
WO WO2005079772A2 · 2005 [cited by applicant]
WO WO2005099699A1 · 2005 [cited by applicant]
WO WO2006059217A1 · 2006 [cited by applicant]
WO WO2008001341A1 · 2008 [cited by applicant]
WO WO2010070705A1 · 2010 [cited by applicant]
WO WO2012142815A1 · 2012 [cited by applicant]
WO WO2018067959A1 · 2018 [cited by applicant]
WO WO2019200143A1 · 2019 [cited by applicant]
Advisory Action with Examiner Initiated Interview Summary and AFCP 2.0 Decision dated Mar. 17, 2020 for U.S. Appl. No. 16/381,575. [cited by applicant]
Allen, Jr., Allen V.: Amlodipine 1 mg/mL Oral Liquid. Cardiovascular. US Pharm. 39(2):55-56 2014. [cited by applicant]
Ananchenko, G. et al.: Chapter 2—Amlodipine Besylate. Britain, Profiles of Drug Substances, Excipients, and Related Methodology 37 (2012). [cited by applicant]
Bellay, R. et al.: Stability of 5 mg/mL Nitrendipine Oral Suspension in Syrspend® SF PH4. Pharmaceutical Technology in Hospital Pharmacy 3(1):31-37 (2018). [cited by applicant]
Bernard et al.: Spectrophotometric method of estimation of Amlodipine besylate using hydrotropic solubilization; Journal of Applied Pharmaceutical Science 01 (09); 177-180 (2011). [cited by applicant]
Blowey: Update on the pharmacologic treatment of hypertension in pediatrics. Journal of Clinical Hypertension 14(6), 383-387 (2012). [cited by applicant]
Dhapte et al.: Advances in hydrotropic solutions: An updated review. St. Petersburg Polytechnical University Journal; Physics and Mathematics, vol. 1, Issue 4, pp. 424-436 (2015). [cited by applicant]
EP21190149.1 European Examination Report dated Apr. 23, 2024. [cited by applicant]
Extended European Search Report dated Apr. 21, 2020 for EP Application No. 17859269.7. [cited by applicant]
Extended European Search Report issued in European Patent Application No. 19784696.7 on Jan. 28, 2022. [cited by applicant]
Ferreira, A.O. et al.: Feasibility of amlodipine besylate, chloroquine phosphate, dapsone, phenytoin, pyridoxine hydrochloride, sulfadiazine, sulfasalazine, tetracycline hydrochloride, trimethoprim and zonisamide in Syr… [cited by applicant]
Final Office Action dated Dec. 31, 2019, for U.S. Appl. No. 16/381,575. [cited by applicant]
Final Office Action dated Nov. 15, 2019, for U.S. Appl. No. 15/726,901. [cited by applicant]
Flynn, J.T. et al.: Calcium channel blockers: pharmacology and place in therapy of pediatric hypertension, Pediatr Nephrol 15:302-316 (2000). [cited by applicant]
Friciu, M. et al.: Stability of Diazoxide in Extemporaneously Compounded Oral Suspensions. PLoS One 11(10):1-12 (2016). [cited by applicant]
Friciu, M. et al.: Stability of Extemporaneously Compounded Amlodipine Besylate Oral Suspensions, CJHP 69(4):327-329 (2016). [cited by applicant]
Gad, S.C. et al.: Tolerable Levels of Nonclinical Vehicles and Formulations Used in Studies by Multiple Routes in Multiple Species With Notes on Methods to Improve Utility. Int J Toxicol. 35(2):95-178 (2016). [cited by applicant]
International Search Report and Written Opinion dated Dec. 28, 2017, for PCT/US17/055576. [cited by applicant]
International Search Report and Written Opinion dated Jun. 27, 2019, for PCT/US19/27044. [cited by applicant]
Jain et al.: Spectrophotometric Method Development and Validation for Quantitative Estimation of Amlodipine Besylate in Bulk Drug and Their Dosage Forms by Using Hydrotropic Agent; Eurasian J. Anal. Chem. 5(3); 212-217 … [cited by applicant]
Meyers et al.: Pharmacotherapy Review of Chronic Pediatric Hypertension. Clinical Therapeutics 33(10):1331-1356 (2011). Database: CAPLUS, DOI:10.1016/j.clinthera.2011.09.003. [cited by applicant]
Nahata et al.: Stability of Amlodipine Besylate; Research; Journal of the American Pharmaceutical Association; 375-377: 39(3) (1999). [cited by applicant]
Niazi, Sarfaraz K.: Handbook of Pharmaceutical Manufacturing Formulations: Liquid Products, vol. 3, Second edition. New York: Informa Healthcare USA, Inc., 2009, 400 pages. [cited by applicant]
Non-Final Office Action dated Aug. 7, 2020, for U.S. Appl. No. 16/927,678. [cited by applicant]
Non-Final Office Action dated May 14, 2020 for U.S. Appl. No. 16/381,575. [cited by applicant]
Notice of Allowance dated Mar. 27, 2020 for U.S. Appl. No. 15/726,901. [cited by applicant]
Notice of Allowance of U.S. Appl. No. 18/203,266 issued Dec. 7, 2023. [cited by applicant]
Nunn et al.: Formulation of medicines for children. British Journal of Clinical Pharmacology, 59:6, pp. 674-676 (2005). [cited by applicant]
Office Action dated Aug. 15, 2023 issued in U.S. Appl. No. 18/203,266. [cited by applicant]
PCT/US2017/055576 International Search Report and Written Opinion dated Dec. 28, 2017. [cited by applicant]
Pfizer, “NORVASC—amlodipine besylate” Pfizer Labs, 2011. Reference ID: 2943634. [cited by applicant]
Rivero, N.L. et al.: Amlodipine in pediatric patient with uncontrolled multifactorial hypertension; formulation of amlodipine oral suspension. European Review for Medical and Pharmacological Sciences 16:1117-1119 (2012). [cited by applicant]
Rosemont Pharmaceuticals Limited, Yorkdale Industrial Park, Braithwaite Street Leeds, LS11 9XE, United Kingdom, “Pharmaceutical product sheet for Amlodipine 1mg/ml Oral Solution,” https://www.medicines.org.uk/emc/medici… [cited by applicant]
Salma, et al.: The relevancy of controlled nanocrystallization on rifampicin characteristics and cytotoxicity. International Journal of Nanomedicine 2209-2222 (2016). [cited by applicant]
Seikaly: Hypertension in children: an update on treatment strategies. Current Opinion in Pediatrics, 19:170-177, 2007. [cited by applicant]
Standing et al.: Paediatric formulations-Getting to the heart of the problem. International Journal of Pharmaceutics 300(1-2):56-66 (2005). Database: CAPLUS. [cited by applicant]
Tallian, K.B. et al.: Efficacy of amlodipine in pediatric patients with hypertension Pediatr. Nephrol. 13:304-310 (1999). [cited by applicant]
U.S. Appl. No. 15/726,901 Final Office Action dated Dec. 21, 2018. [cited by applicant]
U.S. Appl. No. 15/726,901 Office Action dated May 16, 2019. [cited by applicant]
U.S. Appl. No. 15/726,901 Office Action dated May 3, 2018. [cited by applicant]
U.S. Appl. No. 16/381,575 Office Action dated Jun. 25, 2019. [cited by applicant]
U.S. Appl. No. 17/716,505 Notice of Allowance dated May 30, 2024. [cited by applicant]
U.S. Appl. No. 18/420,901 Office Action dated Aug. 14, 2024. [cited by applicant]
Van Der Vossen et al.: Design and stability study of an oral solution of amlodipine besylate for pediatric patients. European Journal of Pharmaceutical Sciences 92:220-223 (2016). [cited by applicant]