title: Modulation of the sustained delivery of myelopoietin (Leridistim) encapsulated in multivesicular liposomes (DepoFoam).
abstract: Myelopoietins (MPO) are novel chimeric growth factors containing IL-3 and G-CSF receptor agonists that enhance the biological properties of both cytokines. These cytokines, like many therapeutic proteins, clear rapidly from circulation and must be administered daily to provide efficacy. Therefore, a controlled and sustained delivery system comprised of a biocompatible and biodegradable matrix, would offer important therapeutic advantages in the clinic, such as significantly reducing dose frequency and providing efficacy without toxicity. We report here the encapsulation of Leridistim (a protein from the MPO family) in multivesicular liposomes (DepoFoam) for sustained delivery, and demonstrate that a single injection of DepoFoam-encapsulated Leridistim results in elevated neutrophil counts for 10 days, in contrast to only 2 days for un-encapsulated Leridistim. Moreover, varying the lipid content of the DepoFoam matrix modulated the duration of elevated neutrophils from 2-3 to 9-10 days. The encapsulated Leridistim was released in vivo from the multivesicular liposomes in a uniform manner, consistent with its pharmacodynamic duration. Finally, a reproducible pharmacodynamic effect was observed with several batches of a DepoLeridistim formulation, indicating consistency of the manufacturing process of the DepoFoam delivery system. The capability of altering the release rates by varying the lipid composition provides maximum flexibility for controlled delivery of cytokine therapeutics.
authors.affiliation: SkyePharma Inc., 10450 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Melissa V
authors.initials: MV
authors.lastname: Langston
authors.forename: Mysore P
authors.initials: MP
authors.lastname: Ramprasad
authors.forename: Tugrul T
authors.initials: TT
authors.lastname: Kararli
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Galluppi
authors.forename: Nandini V
authors.initials: NV
authors.lastname: Katre
mesh_terms: D000818:Animals; D002214:Capsules; D002853:Chromatography, Liquid; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods; D004355:Drug Stability; D016179:Granulocyte Colony-Stimulating Factor / Q000819:agonists* / Q000138:chemical synthesis / Q000235:genetics / Q000493:pharmacokinetics*; D006801:Humans; D007377:Interleukin-3 / Q000819:agonists* / Q000138:chemical synthesis / Q000235:genetics / Q000493:pharmacokinetics*; D008081:Liposomes / Q000493:pharmacokinetics*; D051381:Rats; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D013997:Time Factors; D014280:Triglycerides / Q000493:pharmacokinetics
chemical_list: D002214:Capsules; D003692:Delayed-Action Preparations; D007377:Interleukin-3; D008081:Liposomes; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014280:Triglycerides; D016179:Granulocyte Colony-Stimulating Factor; C400711:leridistim