Poly(lactide-co-glycolide) microsphere formulations of darbepoetin alfa: spray drying is an alternative to encapsulation by spray-freeze drying.
OBJECTIVE
The purpose of this work was to evaluate spray-freeze drying and spray drying processes for encapsulation of darbepoetin alfa (NESP, Aranesp).


METHODS
Darbepoetin alfa was encapsulated in poly(lactide-co-glycolide) by spray-freeze drying and by spray drying. Integrity was evaluated by size-exclusion chromatography and Western blot. Physical properties and in vitro release kinetics were characterized. Pharmacokinetics and pharmacodynamics were evaluated in nude rats.


RESULTS
Microspheres produced by spray drying were larger than those produced by spray-freeze drying (69 microm vs. 29 microm). Postencapsulation integrity was excellent for both processes, with < 2% dimer by size-exclusion chromatography. In vitro release profiles were similar, with low burst (< 25%) and low cumulative protein recovery at 4 weeks (< or = 30%), after which time covalent dimer (< or = 6.5%) and high molecular weight aggregates (< or = 2.3%) were recovered by denaturing extraction. After a single injection, darbepoetin alfa was detected in serum through 4 weeks for all microsphere formulations tested in vivo, although relative bioavailability was higher for spray-freeze drying (28%) compared with spray drying (21%; p = 0.08) as were yields (73-82% vs. 34-57%, respectively). For both processes hemoglobin was elevated for 7 weeks, over twice as long as unencapsulated drug.


CONCLUSIONS
Spray drying, conducted at pilot scale with commercial equipment, is comparable to spray-freeze drying for encapsulation of darbepoetin alfa.
Burke
Paul A
PA
Pharmaceutics and Drug Delivery, Amgen, Inc., One Amgen Center, Drive Thousand Oaks, California 93120, USA. pburke@amgen.com
Klumb
Lisa A
LA
Herberger
John D
JD
Nguyen
Xichdao C
XC
Harrell
Roy A
RA
Zordich
Monica
M
D000818:Animals; D000068256:Darbepoetin alfa; D004339:Drug Compounding; D005612:Freeze Drying; D019344:Lactic Acid / Q000737:chemistry; D008863:Microspheres; D010316:Particle Size; D011098:Polyglactin 910 / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D011108:Polymers / Q000737:chemistry
D011108:Polymers; D000068256:Darbepoetin alfa; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011098:Polyglactin 910