Microparticle Formulations for Delivery to the Lower and Central Respiratory Tract and Methods of Manufacture
Microparticle formulations of a sialidase fusion protein are produced by contacting an aqueous solution of a protein or other active agent with an organic solvent, a counterion and a scavenging agent, and chilling the solution. The microparticles are useful for preparing stable, uniform pharmaceuticals of predetermined defined dimensions.
1 .- 78 . (canceled)
79 . A method for preparing a pharmaceutical composition comprising DAS181, the method comprising:
a) providing microparticles comprising DAS181 having the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:2, wherein the microparticles are about 60-70% wt/wt DAS181, 7-15% wt/wt histidine, 7-11% wt/wt trehalose, 4-8% wt/wt magnesium sulfate, and 8-12% wt/wt water; and
b) combining the microparticles with a pharmaceutically acceptable aqueous solution.
80 . The method of claim 79 wherein the microparticles are 62% to 68% (wt/wt) DAS181.
81 . The method of claim 79 wherein the microparticles have a Mass Median Aerodynamic Diameter (MMAD) of 1-8 microns, 2-8 microns or 3-8 microns.
82 . The method of claim 79 wherein the microparticles have a Geometric Standard Deviation (GSD) of 1.5-1.7, 1.3-1.6, or 1.4-1.6.
83 . The method of claim 79 wherein the weight percent of microparticles having a fine particle fractionation (FPF) below 5 microns is less than 10%.
84 . A method for preparing a pharmaceutical composition comprising DAS181, the method comprising:
a) providing microparticles comprising DAS181 having the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:2, wherein the microparticles are about 69-74% wt/wt DAS181, 9-17% wt/wt histidine, 8-12% wt/wt trehalose, and 4-8% wt/wt magnesium sulfate; and
b) combining the microparticles with a pharmaceutically acceptable aqueous solution.
85 . The method of claim 84 wherein the microparticles have a GSD of 1.5-1.7, 1.3-1.6, or 1.4-1.6.
86 . The method of claim 84 wherein the weight percent of microparticles having a FPF below 5 microns is less than 10%.
87 . A method for preparing a pharmaceutical composition comprising DAS181, the method comprising:
a) providing microparticles comprising DAS181 having the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:2, wherein the microparticles are about 80-90% wt/wt DAS181, 1.5-3.5% wt/wt sodium sulfate, and 8-12% water; and
b) combining the microparticles with a pharmaceutically acceptable aqueous solution.
88 . The method of claim 87 wherein the microparticles have a GSD of 1.2-1.8, 1.3-1.7 or 1.4-1.6
89 . The method of claim 87 wherein the weight percent of microparticles having a fine particle fractionation (FPF) below 5 microns is less than 10%.
90 . The method of claim 79 wherein the microparticles comprise 3-6% wt/wt histidine free base and 5-9% wt/wt histidine hydrochloride.
91 . The method of claim 84 wherein the microparticles comprise 3-8% wt/wt histidine free base and 5-9% wt/wt histidine hydrochloride.
92 . A method for preparing a pharmaceutical composition comprising DAS181, the method comprising:
a) providing microparticles comprising DAS181 having the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:2, wherein the microparticles are about 60-70% wt/wt DAS181, 8-15% wt/wt histidine, 7-11% wt/wt trehalose, 4-8% wt/wt magnesium sulfate, and 8-12% water; and
b) combining the microparticles with a pharmaceutically acceptable aqueous solution.
93 . A method for preparing a pharmaceutical composition comprising DAS181, the method comprising:
(a) providing microparticles comprising DAS181 having the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:2, wherein the microparticles are about 69-74% wt/wt DAS181, 7-17% wt/wt histidine, 8-12% wt/wt trehalose, and 4-8% wt/wt magnesium sulfate; and
b) combining the microparticles with a pharmaceutically acceptable aqueous solution.