Stable spray-dried protein formulations
Spray-dried particles having improved protein stability are produced by spray-drying a mixture including a protein, a phospholipid and an organic-aqueous co-solvent. Spray-dried particles which include at least 1 weight % phospholipid, having a tap density of less than 0.4 g/cm 3 can be prepared. The particles can be delivered to the pulmonary system of a patient.
1 . A method for producing spray-dried particles having improved stability of a protein comprising:
(a) combining a protein, buffer, a phospholipid and a co-solvent, said co-solvent including an aqueous solvent and an organic solvent, to form a mixture; and
(b) spray-drying said mixture to produce spray-dried particles having improved stability of the protein;
wherein the particles consist essentially of protein, buffer and the phospholipid and the protein is insulin.
2 . The method of claim 1 , wherein the spray-dried particles consist of insulin, buffer and the phospholipid.
3 . The method of claim 1 , wherein the phospholipid is selected from the group consisting of phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols and combinations thereof.
4 . The method of claim 1 , wherein the phospholipid is dipalmitoylphosphatidylcholine.
5 . The method of claim 1 , wherein the protein is present in the spray-dried particles in an amount ranging from about 1 to about 90 weight %.
6 . The method of claim 1 , wherein the phospholipid is present in an amount of at least 10 weight %.
7 . The method of claim 1 , wherein the spray-dried particles retain at least about 70% protein integrity when stored at about 25° C. and about 60% relative humidity conditions for six weeks.
8 . The method of claim 1 , wherein the spray-dried particles retain at least about 50% protein integrity when stored at about 40° C. and about 75% relative humidity conditions for six weeks.
9 . The method of claim 1 , wherein the protein and phospholipid concentration in said mixture is at least 0.1 weight/volume %.
10 . The method of claim 1 , wherein the co-solvent includes an alcohol.
11 . The method of claim 1 , wherein the organic solvent is present in the co-solvent in a concentration of at least 50 volume %.
12 . The method of claim 1 , wherein the spray-dried particles have a tap density less than about 0.4 g/cm 3 .
13 . The method of claim 12 wherein the spray-dried particles have a tap density less than about 0.1 g/cm 3 .
14 . The method of claim 12 , wherein the spray-dried particles have a tap density less than about 0.05 g/cm 3 .
15 . The method of claim 1 , wherein the spray-dried particles have a median geometric diameter of between about 5 microns and about 30 microns.
16 . The method of claim 1 , wherein the spray-dried particles have an aerodynamic diameter of between about 1 micron and about 5 micron.
17 . The particles produced by the method of claim 1 .
18 . A method comprising administering to the respiratory tract of a patient in need of treatment, prophylaxis or diagnosis an effective amount of the spray-dried particles produced by the method of claim 1.