Excipients for Protein Stabilization

• US 20110046052A1
• Filed: 11/17/2008
• Published: 02/24/2011
• Est. Priority Date: 11/16/2007
• Status: Active Grant

• Current Assignee: Guohan Yang
• Original Assignee: Guohan Yang
• Inventors: Yang, Guohan
• Granted Patent: US 8,642,532 B2
• Time in Patent Office: Days
• US Class Current: 514/6.4
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/08 containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin

Abstract

This invention is a method of using a class of excipients for protein formulation to reduce and/or eliminate protein aggregation in solutions or solids. This class of compounds contains carbonyl group(s) to form Schiff base(s) with amino groups of proteins and also contains moieties to keep protein molecules spatially separated. This method has never been disclosed anywhere in the literature.

Claims

1. A method of minimizing or preventing protein aggregation comprising reacting compounds bearing carbonyl group(s) and charges or bulky group(s) with proteins and forming reversible Schiff bonds with amino groups of the protein surface.

2. A compound comprising the Formula I:

3. A method of manufacturing a protein formulation comprising reacting a protein with the compound of claim 2.

4. The method of claim 3 further comprising forming a solid by crystallizing, precipitating, spray drying, spray-freeze drying, or lyophilizing said protein formulation.

5. A method of manufacturing a protein formulation comprising reacting a protein with more than one compound of claim 2 or one or more compounds of claim 2 and one or more other appropriate excipients.

6. Use of one or more compounds of claim 2 to protect or prolong the on-shelf life span of therapeutic protein drugs.

7. Use of one or more compounds of claim 2 in purifying a protein or manufacturing a protein formulation.

8. Use of one or more compounds of claim 2 in a protein formulation for bulk storage.

9. Use of one or more compounds of claim 2 in a protein formulation to reduce viscosity and/or foaming of a protein solution and/or of a reconstituted solution.

10. A stabilized protein formulation comprising one or more compounds of claim 2 and a protein or proteins wherein, said formulation is stable for a prolonged storage time under refrigerated and/or non-refrigerated conditions.

11. A stabilized protein formulation comprising one or more compounds of claim 2 and a protein or proteins wherein, said protein or proteins are soluble.

12. Use of one or more compounds of claim 2 to re-constitute a solid formulation into a solution prior to drug administration.

13. A stabilized formulation comprising zinc insulin, zinc-free insulin, or insulin analogs with or without zinc and one or more compounds of claim 2 wherein said formulation is a liquid or solid.

14. The formulation of claim 13, delivered to a subject by means of a nasal spray, or pulmonary and/or nebulized inhalation, or injection.

15. A stabilized insulin liquid formulation comprising insulin and one or more compounds of claim 2, wherein said insulin liquid formulation is stable when stored for a prolonged time under refrigerated and/or non-refrigerated conditions.

16. A stabilized insulin solid formulation comprising insulin and one or more compounds of claim 2 wherein, said insulin solid formulation is stable when stored for a prolonged time under refrigerated and/or non-refrigerated conditions.

17. Use of one or more compounds of claim 2 to re-constitute an insulin solid formulation into a solution prior to drug administration.