High surface-area lyophilized compositions comprising arsenic for oral administration in patients

• US 10,272,045 B2
• Filed: 10/01/2018
• Issued: 04/30/2019
• Est. Priority Date: 02/01/2015
• Status: Active Grant

• Current Assignee: Syros Pharmaceuticals, Inc.
• Original Assignee: Orsenix Holdings BV
• Inventors: Vaddi, Krishna, Kurumaddali, Kumar
• Primary Examiner(s): Palenik, Jeffrey T.
• Application Number:
  US16/148,193
• Publication Number:
  US 20190029963A1
• Time in Patent Office: 211 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 33/36 Arsenic; Compounds thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Abstract

The present invention relates to treating malignancies such as tumors or cancers by orally administering lyophilized compositions comprising arsenic to a subject in such need. Malignancies include various hematological malignancies, such as acute myeloid leukemia (AML) including acute promyelocytic leukemia (APL), myelodysplastic syndrome (MDS), multiple myeloma (MM) and lymphomas and solid tumors including glioblastoma multiforme and breast cancer. Arsenic treatment has shown great promise in the treatment of several cancers but requires daily intravenous (IV) administration. This invention relates to a novel formulation comprising a lyophilized compositions comprising arsenic. As a result, the formulation facilitates a systemic bioavailability comparable to that of intravenous (IV) administration of arsenic trioxide currently practiced. The present invention also relates to a method for lyophilizing the arsenic trioxide, preparing the oral formulation comprising lyophilized compositions comprising arsenic, and a method for treating a subject with malignancies using the oral formulation.

Claims

1. A method for preparing a lyophilized composition comprising arsenic (LCCA) comprising:

solubilizing As₂O₃ powder and an alkalizing agent in an aqueous medium to form a solution, wherein the alkalizing agent is sodium hydroxide and the amount added is about 10% to about 100% the amount of the As₂O₃ powder;

adding a surfactant to the solution; and

lyophilizing the solution, wherein the step of lyophilization includes;

freezing the solution to form a frozen As₂O₃ product; and

drying the frozen product to form particles of an LCCA.

2. The method of claim 1, wherein the alkalizing agent is sodium hydroxide and is added at 100% by weight of the amount of As₂O₃ powder.

3. The method of claim 1, wherein the surfactant comprises at least one of sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, betacyclodextrin, poloxamer, tocopheryl polyethylene glycol succinate (TPGS).

4. The method of claim 1, wherein the surfactant is added in amount by weight to the amount by weight of the As₂O₃ powder in the range from about 1:

10 to about 1;

2.

5. The method of claim 1, wherein the surfactant is sodium lauryl sulfate and is added in an amount by weight relative to the As₂O₃ powder of about 1:

2.

6. The method of claim 1, wherein the freezing step comprises freezing the solution at a temperature in the range of from about −

50°

C. to about 0°

C.

7. The method of claim 1, wherein the solution is frozen for at least about 6 hours.

8. The method of claim 1, wherein the solution is frozen for a time period from about 6 hours to about 8 hours.

9. The method of claim 1, wherein the freezing step comprises a freezing sub step of steadily decreasing the temperature for a time frame of about 60 minutes to about 120 minutes to a freezing temperature of −

50°

C.

10. The method of claim 1, wherein the solution is frozen at about −

50°

C. for about 6 hours.

11. The method of claim 1, wherein the drying step comprises a primary drying step and a secondary drying step.

12. The method of claim 11, wherein the primary drying step includes a heating step.

13. The method of claim 12, wherein the heating step comprises heating the frozen product under vacuum from a freezing temperature of about −

50°

C. to about −

30°

C. in a time frame of about 30 minutes to about 60 minutes.

14. The method of claim 12, wherein the primary drying step includes drying the frozen product under vacuum at about −

30°

C.

15. The method of claim 11, wherein the secondary drying step includes a heating step comprising heating the frozen product under vacuum from about −

30°

C. to about 25°

C. in a time frame of about 60 minutes to about 120 minutes.

16. The method of claim 11, wherein the secondary drying step includes drying the LCCA particles under vacuum for about 300 minutes to about 600 minutes.

17. The method of claim 1, wherein the As₂O₃ powder has an average particle size, and wherein the LCCA particles have an average particle size that is from about 10 times to about 50 times smaller than the As₂O₃ powder average particle size.

18. The method of claim 1, wherein the LCCA particles have a D(90) size range of from about 2 micron to 10 micron.

19. The method of claim 1, wherein the As₂O₃ powder has an average BET surface area, and wherein the LCCA particles have an average BET surface area that is from about 2 times to about 80 times greater than the As₂O₃ powder average BET surface area.

20. The method of claim 1, wherein the LCCA particles have a BET surface area in the range of from about 0.5 m²/g to 5 m²/g.

21. The method of claim 1, wherein the As₂O₃ powder has a solubility in cold water or alcohol, and wherein the solubility of the LCCA particles in cold water or alcohol is about 2 times to about 30 times higher than the solubility of the As₂O₃ powder.

22. The method of claim 1, wherein the solubility of the LCCA particles in cold water or alcohol is the range of about 400 mg/ml to about 600 mg/ml.

23. The method of claim 1, wherein the As₂O₃ powder has a dissolution rate in water, and wherein the dissolution rate of the LCCA particles in water as measured by ICP-OES is from about 5 times to about 10 times greater than the dissolution rate of the As₂O₃ powder.

24. The method of claim 1, wherein the As₂O₃ powder has polymorphic form, and wherein the LCCA particles have the same polymorphic form as the As₂O₃ powder as measured XRD diffractogram.

25. The method of claim 1, wherein the solution is frozen at about −

50°

C. for about 4 hours to about 6 hours.

26. The method of claim 1, wherein the solution is frozen at about −

50°

C. for about 3 hours to about 4 hours.