STABILIZED GLUCAGON NANOEMULSIONS

• US 20140378381A1
• Filed: 06/25/2014
• Published: 12/25/2014
• Est. Priority Date: 12/29/2011
• Status: Abandoned Application

• Current Assignee: Latitude Pharmaceuticals Inc.
• Original Assignee: Latitude Pharmaceuticals Inc.
• Inventors: Chen, Andrew Xian, Chen, Hailiang, Orida, Norman Keith, Dang, Hau Huu
• Application Number:
  US14/315,212
• Publication Number:
  US 20140378381A1
• Time in Patent Office: Days
• US Class Current: 514/11.7
• 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 38/26 Glucagons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• 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 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• 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 9/107 Emulsions ; Emulsion preconcentrates; Micelles composition of emulsions A61K47/00
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• 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: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 5/48 of the pancreatic hormones

Abstract

The present invention provides an oil-in-water nanoemulsion containing glucagon, an oily phase, and an aqueous phase, wherein the glucagon is physically and chemically stable and the nanoemulsion is suitable for administration by manual injection or by a pump to treat hypoglycemia.

Claims

1. An oil-in-water nanoemulsion composition comprising:

glucagon,

an oily phase, and

an aqueous phase,

wherein the glucagon is not aggregated and retains no less than 75% of its concentration after 3-7 days storage at 37°

C., and wherein the oily phase is in the form of oil droplets having a mean diameter of less than about 200 nm.

2. The nanoemulsion according to claim 1, wherein the oily phase comprises a phospholipid and an oil.

3. The nanoemulsion according to claim 2, wherein the oily phase is between about 10% and 20% by weight of the nanoemulsion and the phospholipid concentration is no less than the oil concentration.

4. The nanoemulsion according to claim 1, wherein no less than 50% of the glucagon is non-covalently associated with the oily phase.

5. The nanoemulsion according to claim 1, wherein said nanoemulsion is made with egg or soy lecithin having a lysolecithin content of less than 5% of the lecithin weight.

6. The nanoemulsion according to claim 2, wherein the oil is a medium chain oil, a vegetable oil, or a combination thereof.

7. The nanoemulsion according to claim 1, wherein the pH of said nanoemulsion is between about 2.7 to about 7.5.

8. The nanoemulsion according to claim 1, wherein the nanoemulsion is filterable through a 0.2-micron filter.

9. The nanoemulsion according to claim 1, wherein said nanoemulsion further contains at least one antioxidant selected from the group consisting of EDTA, methionine, lactose, fructose, dextrose, cysteine, glutathione or salt or a combination thereof.

10. The nanoemulsion according to claim 1, further comprising an antimicrobial preservative selected from the group consisting of EDTA, benzyl alcohol, a paraben, sodium metabisulfite, a cresol, or a salt or a combination thereof.

11. The nanoemulsion according to claim 1, wherein the composition is provided in a vial, a syringe or auto-injector.

12. The nanoemulsion according to claim 1, wherein the glucagon is administered from a pump or from a syringe via a needle through a subcutaneous, intramuscular or intravenous route.

13. The nanoemulsion according to claim 1, wherein the nanoemulsion is ready-to-inject.

14. A nanoemulsion comprising between about 0.25 and 1.5 mg/mL glucagon, a phospholipid, between about 0.5 and 5% by weight oil, and an aqueous phase, wherein said nanoemulsion the oil droplets have a mean diameter of less than about 200 nm and wherein the glucagon is not aggregated and retains no less than 75% of its concentration after 3-7 days storage at 37°

C.

15. A nanoemulsion comprising about 1 mg/mL glucagon, about 10% by weight lecithin, about 0.5 to 5% by weight medium chain oil, and an aqueous phase, wherein said nanoemulsion the glucagon is not aggregated and retains no less than 75% of its concentration after 3-7 days storage at 37°

C., and wherein the pH is between about 2.7 to about 7.5.

16. A process for preparing a nanoemulsion, the method comprising:

(a) combining glucagon and an aqueous phase;

(b) adding phospholipid and oil;

(c) mixing and homogenizing to form a nanoemulsion having an average droplet size of no more than 200 nm in diameter; and

(d) passing said nanoemulsion through a 0.2-micron filter.