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

• US 10,111,836 B2
• Filed: 02/01/2016
• Issued: 10/30/2018
• 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:
  US15/012,355
• Publication Number:
  US 20160235679A1
• Time in Patent Office: 1,002 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 an oral pharmaceutical formulation comprising a lyophilized composition comprising arsenic or lyophilized arsenic trioxide (As₂O₃), said method comprising:

(A) solubilizing As₂O₃ powder in an aqueous medium to form an As₂O₃ solution;

(B) lyophilizing said As₂O₃ solution to generate a lyopremix;

wherein lyophilizing comprises freezing said As₂O₃ solution to generate a frozen As ₂O₃ product and drying said frozen As₂O₃ product, wherein drying includes applying a vaccum to said frozen As₂O₃ product in a range of from about 300 millitorrs to about 1000 millitorrs, for a time in the range of from about 5 minutes to about 500 minutes ;

(C) sifting said lyopremix to generate lyophilized As₂O₃ powder;

(D) optionally, adding at least one bulking agent to said lyophilized As₂O₃ powder;

(E) optionally, adding one or more lubricants to said lyophilized As₂O₃ powder to generate said oral formulation of As₂O₃.

2. The method of claim 1, wherein said solubilizing As₂O₃ powder in an aqueous medium comprises:

(I) adding an alkalizing agent to the As₂O₃ powder in a vessel, with or without stirring and with or without addition of water, to render a pH of about 12 or higher;

(II) adding an acid to said vessel, with or without stirring and with or without addition of water, to adjust the pH to from about 7 to about 8;

(III) optionally, adding a surfactant to said vessel, with or without stirring and with or without addition of water, and

(IV) optionally, adding water to said vessel to generate an As₂O₃ solution with or without stirring.

3. The method of claim 2, wherein said alkalizing agent comprises sodium hydroxide (NaOH), sodium carbonate (Na₂CO₃), or a mixture thereof.

4. The method of claim 2, wherein the amount of said alkalizing agent added is about 10% to about 100% the amount of the As₂O₃ powder.

5. The method of claim 2, wherein said acid comprises hydrochloric acid (HCl).

6. The method of claim 5, wherein said HCl is about 6 M HCl.

7. The method of claim 2, wherein said acid is added to said vessel to adjust the pH to about 7.2.

8. The method of claim 2, wherein said surfactant comprises at least one of sodium lauryl sulfate;

Tween 80®

;

betacyclodextrin;

poloxamer;

tocopheryl polyethylene glycol succinate (TPGS).

9. The method of claim 2, wherein said surfactant is added to about 0.5% v/v to about 4.0% v/v, but does not exceed about 50% As₂O₃ concentration.

10. The method of claim 1, wherein said freezing step comprises freezing said As₂O₃ solution at a temperature in the range of from about −

50°

C. to about 0°

C.

11. The method of claim 10, wherein said As₂O₃solution is frozen at about −

40°

C. for at least about 6 hours.

12. The method of claim 1, wherein said drying further comprises:

(I) drying said frozen As₂O₃product at at least one temperature in the range of from about −

40°

C. to about 50°

C., for the time in the range of from about 5 minutes to about 500 min.

13. The method of claim 1, wherein said drying step comprises

heating said As₂O₃product at about −

30°

C. and about 800 millitorrs for about 60 minutes;

heating said As₂O₃product from the previous step at −

20°

C. and 500 millitorrs for about 120 minutes;

heating said As₂O₃product from the previous step at about −

5°

C. and about 500 millitorrs for about 120 minutes;

heating said As₂O₃product from the previous step at about 10°

C. and about 500 millitorrs for about 60 minutes; and

heating said As₂O₃product from the previous step at about 25°

C. and about 500 millitorrs for the time in the range of from about 180 minutes to 300 minutes.

14. The method of claim 1, wherein said drying step comprises

heating said As₂O₃product to about −

30°

C. and about 800 millitorrs over about 60 minutes and holding at about −

30°

C. and about 800 millitorrs for about 60 minutes;

heating said As₂O₃product from the previous step to about −

20°

C. and about 500 millitorrs over about 60 minutes and holding at about −

20°

C. and about 500millitorrs for about 120 minutes;

heating said As₂O₃product from the previous step to about −

5°

C. and about 500 millitorrs over about 300 minutes and holding at about −

5°

C. and about 500 millitorrs for about 120minutes;

heating said As₂O₃product from the previous step to about 10°

C. and about 500 millitorrs over about 120 minutes and holding at about 10°

C. and about 500 millitorrs for about 60 minutes; and

heating said As₂O₃product from the previous step to about 25°

C. and about 500 millitorrs over about 60 minutes and holding at about 25°

C. and about 500 millitorrs for the time in the range of from about 180 minutes to 300 minutes.

15. The method of claim 1, wherein said bulking agent comprises mannitol;

and/or wherein said one or more lubricants comprises talc and/or magnesium stearate.

16. The method of claim 1, further comprising filling a capsule with said oral formulation.

17. The method of claim 1, wherein said drying further comprises:

drying said frozen As₂O₃ by progressively increasing temperature from at least one first temperature in the range of from about −

40°

C. to about 50°

C. to at least one second temperature in the range of from about −

40°

C. to about 50°

C., for the time in the range of from about 5 minutes to about 500 min, wherein said at least one second temperature is higher than said at least one first temperature.