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

• US 10,653,628 B2
• Filed: 03/12/2019
• Issued: 05/19/2020
• 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:
  US16/299,214
• Publication Number:
  US 20200060974A1
• Time in Patent Office: 434 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 solution for use in the lyophilization of a pharmaceutical compound comprising:

an amount of water;

an amount of solubilized arsenic trioxide;

an amount of solubilized alkalizing agent;

an amount of solubilized surfactant; and

,

an amount of an acid;

wherein the amount of solubilized arsenic trioxide is present in the solution at a concentration level of about 6 mg/mL to about 50 mg/mL.

2. The solution of claim 1, wherein the amount of solubilized arsenic trioxide is present in the solution at a concentration level of about 6 mg/ml to about 25 mg/ml.

3. The solution of claim 1, wherein the amount of solubilized arsenic trioxide is present in the solution at a concentration level of about 11 mg/ml to about 50 mg/ml.

4. The solution of claim 1, wherein the amount of solubilized arsenic trioxide is present in the solution at a concentration level of about 11 mg/ml to about 25 mg/ml.

5. The solution of claim 1, wherein the amount of solubilized arsenic trioxide is present in the solution at a concentration level of about 23 mg/ml to about 50 mg/ml.

6. The solution of claim 1, wherein the amount of solubilized arsenic trioxide is present in the solution at a concentration level of about 23 mg/ml to about 25 mg/ml.

7. The solution of claim 1, wherein the weight ratio of the amount of solubilized arsenic trioxide to the amount of solubilized alkalizing agent is in the range of about 10:

1 to 1;

1.

8. The solution of claim 1, wherein the weight ratio of the amount of solubilized arsenic trioxide to the amount of solubilized alkalizing agent is in the range of about of 2:

1 to 1;

1.

9. The solution of claim 1, wherein the weight ratio of the amount of solubilized arsenic trioxide to the amount of solubilized surfactant is in the range of about 10:

1 to 2;

1.

10. The solution of claim 1, wherein the amount of solubilized surfactant is present in the solution in the range of 0.5% to 4.0% v/v of the solution.

11. The solution of claim 1, wherein the amount of solubilized alkalizing agent and the amount of the acid in the solution provides a pH in the range of about 7.0 to 8.2.

12. The solution of claim 1, wherein the solubilized alkalizing agent is sodium hydroxide, sodium carbonate, or a mixture thereof.

13. The solution of claim 1, wherein the solubilized surfactant is sodium lauryl sulfate;

polyoxyethylene sorbitan monooleate;

betacyclodextrin;

poloxamer;

tocopheryl polyethylene glycol succinate (TPGS).

14. The solution of claim 1, wherein the solubilized alkalizing agent is sodium hydroxide and the solubilized surfactant is sodium lauryl sulfate.

15. The solution of claim 1 wherein the amount of solubilized arsenic trioxide is present in the solution at a concentration level of about 11 mg/ml to about 50 mg/ml, and wherein the weight ratio of the amount of solubilized arsenic trioxide to the amount of solubilized alkalizing agent is in the range of about of 2:

1 to 1;

1.

16. The solution of claim 1 wherein the amount of solubilized arsenic trioxide is present in the solution at a concentration level of about 11 mg/ml to about 50 mg/ml, and wherein the weight ratio of the amount of solubilized arsenic trioxide to the amount of solubilized surfactant is in the range of about 10:

1 to 2;

1.