Methods and compositions for pulmonary delivery of insulin

• US 7,521,069 B2
• Filed: 07/01/2003
• Issued: 04/21/2009
• Est. Priority Date: 03/07/1994
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Patton, John S., Foster, Linda S., Platz, Robert M.
• Primary Examiner(s): Kishore; Gollamudi S
• Application Number:
  US10/612,376
• Publication Number:
  US 20040096400A1
• Time in Patent Office: 2,121 Days
• Field of Search: 424 43- 46, 424489-502, 424/434, 514/21, 514/2, 514/3, 514/866, 514/8, 128/200.14, 128/200.18
• US Class Current: 424/499
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• 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 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• 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

Systemic delivery of insulin to a mammalian host is accomplished by inhalation of a dry powder of insulin. It has been found that dry insulin powders are rapidly absorbed through the alveolar regions of the lungs.

Claims

1. A method for preparing a dry powder insulin composition, said method comprising:

dissolving insulin in an aqueous buffer at a concentration in the range from 0.01% to 1% to form a solution; and

spray drying the solution to produce particles having an average size below 10 μ

m.

2. A method as in claim 1, wherein the insulin is dissolved in an aqueous buffer together with a pharmaceutical carrier, wherein a dry powder having insulin present in individual particles at from 5% to 99% by weight is produced upon spray drying.

3. A method as in claim 2, wherein the pharmaceutical carrier is a carbohydrate, organic salt, amino acid, peptide, or protein which produces a powder upon spray drying.

4. A method as in claim 3, wherein the pharmaceutical carrier is a carbohydrate selected from the group consisting of mannitol, raffinose, lactose, maltodextrin and trehalose.

5. A method as in claim 2, wherein the pharmaceutical carrier is an organic salt selected from the group consisting of sodium citrate, sodium acetate, and sodium ascorbate.

19. A method as in claim 1, wherein the composition is substantially free from penetration enhancers.

20. A method as in claim 1, wherein the particles are substantially amorphous.

6. An insulin composition for pulmonary delivery, said composition comprising a dry powder of individual particles which include insulin present at from 20% to 80% by weight in a pharmaceutical carrier material, wherein the particles have an average size below 10 μ

m.

7. An insulin composition as in claim 6, wherein the composition is substantially free from penetration enhancers.

8. An insulin composition as in claim 6, wherein the pharmaceutical carrier material comprises a carbohydrate selected from the group consisting of mannitol, raffinose, lactose, maltodextrin, and trehalose.

9. An insulin composition as in claim 6, wherein the pharmaceutical carrier material comprises an organic salt selected from the group consisting of sodium citrate, sodium gluconate, and sodium ascorbate.

21. A composition as in claim 6, wherein the composition is substantially amorphous.

10. A method for preparing a dry powder insulin composition, said method comprising:

providing an aqueous solution of insulin and a pharmaceutical carrier dissolved in an aqueous buffer, wherein the insulin is present at 0.01% to 1% by weight and comprises from 20% to 80% of the total weight of insulin and pharmaceutical carrier in the solution; and

spray drying the solution to produce particles comprising both the insulin and the pharmaceutical carrier having an average size below 10μ

m and a moisture content below 10%.

11. A method as in claim 10, wherein the pharmaceutical carrier is a carbohydrate, organic salt, amino acid, peptide, or protein which produces a powder upon spray drying.

12. A method as in claim 11, wherein the carbohydrate carrier is selected from the group consisting of mannitol, raffinose, lactose, maltodextrin and trehalose.

13. A method as in claim 10, wherein the carrier is an organic salt selected from the group consisting of sodium citrate, sodium acetate, and sodium ascorbate.

22. A method as in claim 10, wherein the particles have a moisture content less than about 5% by weight.

23. A method as in claim 10, wherein the particles are substantially amorphous.

14. An insulin composition for pulmonary delivery, said composition comprising:

a dry powder of individual particles including both insulin and a pharmaceutical carrier, wherein the particles comprise from 20% to 80% insulin by weight, have an average particle size below 10μ

m, and have a moisture content below 10%.

15. An insulin composition as in claim 14, wherein the particles consist essentially of the insulin and the pharmaceutical carrier.

16. An insulin composition as in claim 14, wherein the composition is substantially free from penetration enhancers.

17. An insulin composition as in claim 14, wherein the pharmaceutical carrier comprises a carbohydrate selected from the group consisting of mannitol, raffinose, lactose, maltodextrin, and trehalose.

18. An insulin composition as in claim 14, wherein the pharmaceutical carrier comprises an organic salt selected from the group consisting of sodium citrate, sodium gluconate, and sodium ascorbate.

24. An insulin composition as in claim 14, wherein the particles have a moisture content less than about 5% by weight.

25. An insulin composition as in claim 14, wherein the particles are substantially amorphous.

26. An insulin composition for pulmonary delivery, said composition comprising a dry powder of individual particles including insulin present at from 5% to 80% by weight in a pharmaceutical carrier material, wherein the particles have an average size below 10 μ

m.

27. An insulin composition as in claim 26, wherein the composition is substantially free from penetration enhancers.

28. An insulin composition as in claim 26, wherein the pharmaceutical carrier material comprises a carbohydrate selected from the group consisting of mannitol, raffinose, lactose, maltodextrin, and trehalose.

29. A composition as in claim 26, wherein the composition is substantially amorphous.

30. A composition as in claim 26, wherein the particles have a moisture content less than about 10% by weight.

31. A composition as in claim 26, wherein the particles have a moisture content less than about 5% by weight.

32. A method for preparing a dry powder insulin composition, said method comprising:

providing an aqueous solution of insulin and a pharmaceutical carrier dissolved in an aqueous buffer, wherein the insulin is present at 0.01% to 1% by weight and comprises from 5% to 80% of the total weight of insulin and pharmaceutical carrier in the solution; and

spray drying the solution to produce particles comprising both the insulin and the pharmaceutical carrier having an average size below 10 μ

m and a moisture content below 10%.

33. A method as in claim 32, wherein the particles have a moisture content less than about 5% by weight.

34. A method as in claim 32, wherein the particles are substantially amorphous.