Liposome-encapsulated insulin formulations

• US 20040033256A1
• Filed: 08/15/2003
• Published: 02/19/2004
• Est. Priority Date: 10/09/2001
• Status: Abandoned Application

• Current Assignee: Rimona Margalit
• Original Assignee: Rimona Margalit
• Inventors: Margalit, Rimona
• Application Number:
  US10/641,953
• Publication Number:
  US 20040033256A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 38/28 Insulins
• 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: A61K 9/1278 Post-loading, e.g. by ion or pH gradient
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The present invention provides formulations of insulin or insulin analogs encapsulated in a liposome, and methods of producing such formulations. The invention further provides methods of treating hyperglycemia and related disorders by administering a formulation of the invention.

Claims

1. A method for preparing an insulin formulation, the method comprising the steps of:

(a) preparing a solution comprising insulin, wherein the solution has a non-neutral pH;

(b) encapsulating the solution in liposomes at a non-neutral pH; and

(c) neutralizing the liposomes of step (b) to pH of 7.2 to 7.6.

2. The method of claim 1, wherein the solution has a pH between about 2.3 and 3.0 before it is neutralized, and wherein the encapsulation takes place in an acidic environment.

3. The method of claim 1, wherein the solution has a pH between about 7.8 and 9.5 before it is neutralized, and wherein the encapsulation takes place in a basic environment.

4. The method of claim 1, wherein the solution of step (a) comprises 20 to 80 mg/ml insulin.

5. The method of claim 1, wherein the liposomes are between about 0.2 and 3 microns in diameter.

6. The method of claim 1, wherein the liposomes comprise a lipid selected from the group consisting of:

phosphatidylcholine, phosphatidyl ethanolamine, cholesterol, phosophatidyl serine, phosphatidyl glycerol and phosphatidyl inositol.

7. The method of claim 1, wherein the liposomes are unilamellar.

8. The method of claim 1, wherein the liposomes are multilamellar.

13. The composition of claim 1, wherein the solution further comprises a second therapeutic agent.

19. A method of delivering insulin to a lung of an individual, comprising:

preparing an insulin formulation by the method of claim 1;

aerosolizing the insulin formulation to provide aerosol particles having an aerodynamic diameter of about 1 to about 5 microns; and

inhaling the aerosol into the lung of the individual.

9. A composition comprising monomeric insulin encapsulated in liposomes, wherein the monomeric insulin has a molecular weight of about 6,000 Da.

10. The composition of claim 9, wherein the insulin is an insulin analog.

11. The composition of claim 9, wherein the insulin is selected from the group consisting of a superactive insulin analog, a monomeric insulin analog, and a hepatospecific insulin analog.

12. The composition of claim 11, wherein the insulin is insulin lispro.

14. A method for reducing a blood glucose level in a patient, the method comprising administering a formulation comprising monomeric insulin encapsulated in liposomes to the patient.

15. The method of claim 14, wherein the monomeric insulin has a molecular weight of about 6,000 Da.

16. The method of claim 14, wherein the administering is carried out by:

creating an aerosol of the formulation; and

inhaling the aerosol.

17. The method of claim 14, wherein the administering is carried out by:

creating an injectable solution of the formulation; and

injecting the solution.

18. A method for treating a condition related to hyperglycemia in an individual, the method comprising administering a formulation comprising monomeric insulin encapsulated in liposomes to the individual.