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Encapsulation of protein nanoparticles into uniform-sized microspheres formed in a spinning oil film

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Abstract

A new spinning oil film (SOF) solid-in-oil-in-oil emulsion process was developed to produce uniform-sized proteinloaded biodegradable microspheres. A thin SOF on a cylindrical rotor was used to shear droplets from a nozzle tip to control droplet size. The resulting microspheres with low polydispersity (6%) produced a low burst (6%–11%) release even at high loadings (13%–18% encapsulated solids, 8%–12% protein). The SOF process had a high yield and did not require the presence of water, which can cause protein denaturation, or surfactants, which may be unwanted in the final product. Amorphous protein and crystalline excipient solids were encapsulated into 3 different polymers, giving a homogenous drug distribution throughout the microspheres, and an essentially complete protein encapsulation efficiency (average=99%). In contrast, large burst release was observed for polydisperse microspheres produced by a conventional emulsification technique, particularly for microspheres smaller than 25 μm in diameter, which gave 93% burst at 15% loading. The uniform encapsulation of high loadings of proteins into microspheres with low polydispersity in an anhydrous process is of practical interest in the development of controlled-release protein therapeutics.

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References

  1. Sinha VR, Trehan A. Biodegradable microspheres for protein delivery.J Control Release. 2003;90:261–280.

    Article  CAS  Google Scholar 

  2. TAP Pharmaceutical Products Inc. LupronDepot. Available at: http://www.tap.com/prd_ldep.asp. Accessed: September 23, 2004.

  3. Cleland JL, Johnson OL, Putney S, Jones AJS. Recombinant human growth hormone poly(lactic-co-glycolic acid) microsphere formulation development.Adv Drug Deliv Rev. 1997;28:71–84.

    Article  CAS  Google Scholar 

  4. Genentech Inc. Genentech’s Growth Hormone Web site. Available at: http://www.nutropin.com/index.jsp. Accessed: September 23, 2004.

  5. Johnson OL, Tracy MA. Peptide and protein drug delivery. In: Mathiowitz E, ed.Encyclopedia of Controlled Drug Delivery. Vol 2. Hoboken, NJ: John Wiley and Sons; 1999:816–832.

    Google Scholar 

  6. Jain RA. The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices.Biomaterials. 2000;21:2475–2490.

    Article  CAS  Google Scholar 

  7. Perez C, Castellanos IJ, Costantino HR, Al-Azzam W, Griebenow K. Recent trends in stabilizing protein structure upon encapsulation and release from bioerodible polymers.J Pharm Pharmacol. 2002;54:301–313.

    Article  CAS  Google Scholar 

  8. Castellanos IJ, Carrasquillo KG, Lopez JD, Alvarez M, Griebenow K. Encapsulation of bovine serum albumin in poly(lactide-co-glycolide) microspheres by the solid-in-oil-in-water technique.J Pharm Pharmacol. 2001;53:167–178.

    Article  CAS  Google Scholar 

  9. Griebenow K, Klibanov AM. On protein denaturation in aqueousorganic mixtures but not in pure organic solvents.J Am Chem Soc. 1996;118:11695–11700.

    Article  CAS  Google Scholar 

  10. Leach WT, Simpson DT, Val TN, et al. Uniform encapsulation of stable protein nanoparticles produced by spray freezing for the reduction of burst release.J Pharm Sci. 2005;94:56–69.

    Article  CAS  Google Scholar 

  11. Berkland C, Kim K, Pack DW. PLG microsphere size controls drug release rate through several competing factors.Pharm Res. 2003;20:1055–1062.

    Article  CAS  Google Scholar 

  12. Jalil R, Nixon JR. Microencapsulation using poly(L-lactide). II. Preparative variables affecting microcapsule properties.J Microencapsul. 1990;7:25–39.

    Article  CAS  Google Scholar 

  13. Berkland C, Kim K, Pack DW. Fabrication of PLG microspheres with precisely controlled and monodisperse size distributions.J Control Release. 2001;73:59–74.

    Article  CAS  Google Scholar 

  14. Berkland C, King M, Cox A, Kim K, Pack DW. Precise control of PLG microsphere size provides enhanced control of drug release rate.J Control Release 2002;82:137–147.

    Article  CAS  Google Scholar 

  15. Umbanhowar PB, Prasad V, Weitz DA. Monodisperse emulsion generation via drop break off in a coflowing stream.Langmuir. 2000;16:347–351.

    Article  CAS  Google Scholar 

  16. Li YX, Kissel T. Synthesis and properties of biodegradable ABA triblock copolymers consisting of poly(L-lactic acid) or poly(L-lactic-co-glycolic acid) A-blocks attached to central poly(oxyethylene) B-blocks.J Control Release. 1993;54:99–134.

    Google Scholar 

  17. Yu Z III, Garcia AS III, Johnston KP III, Williams RO III. Spray freezing into liquid for highly stable protein nanostructured microparticles.Eur J Pharm Biopharm. 2004;58:529–537.

    Article  CAS  Google Scholar 

  18. Yu Z III, Rogers TL III, Hu J III, Johnston KP III, Williams RO III. Preparation and characterization of microparticles containing peptide produced by a novel process: spray freezing into liquid.Eur J Pharm Biopharm. 2002;54:221–228.

    Article  CAS  Google Scholar 

  19. Sanchez A, Villamayor B, Guo YY, McIver J, Alonso MJ. Formulation strategies for the stabilization of tetanus toxoid in poly (lactide-co-glycolide) microspheres.Int J Pharm. 1999;185:255–266.

    Article  CAS  Google Scholar 

  20. Iwata M, Nakamura Y, McGinity JW. Particle size and loading efficiency of poly(D,L-lactic-co- glycolic acid) multiphase micropheres containing water soluble substances prepared by the hydrous and anhydrous solvent evaporation methods.J Microencapsul. 1999;16:49–58.

    Article  CAS  Google Scholar 

  21. Jiang W, Schwendeman SP. Stabilization of a model formalinized protein antigen encapsulated in poly(lactide-co-glycolide)-based microspheres.J Pharm Sci. 2001;90:1558–1569.

    Article  CAS  Google Scholar 

  22. Jiang W, Schwendeman SP. Stabilization and controlled release of bovine serum albumin encapsulated in poly(D, L-lactide) and poly (ethylene glycol) microsphere blends.Pharm Res. 2001;18:878–885.

    Article  CAS  Google Scholar 

  23. Cleland JL. Solvent evaporation processes for the production of controlled release biodegradable microsphere formulations for therapeutics and vaccines.Biotechnol Prog. 1998;14:102–107.

    Article  CAS  Google Scholar 

  24. Cleland JL, Lim A, Barron L, Duenas ET, Powell MF. Development of a single-shot subunit vaccine for HIV-1.4: optimizing microencapsulation and pulsatile release of MN rgp120 from biodegradable microspheres.J Control Release. 1997;47:135–150.

    Article  CAS  Google Scholar 

  25. Lam XM, Duenas ET, Daugherty AL, Levin N, Cleland JL. Sustained release of recombinant human insulin-like growth factor-I for treatment of diabetes.J Control Release. 2000;67:281–292.

    Article  CAS  Google Scholar 

  26. Wang J, Wang BA, Schwendeman SP. Characterization of the initial burst release of a model peptide from poly(D,L-lactide-co-glycolide) microspheres.J Control Release. 2002;82:289–307.

    Article  CAS  Google Scholar 

  27. Kissel T, Li YX, Unger F. ABA-triblock copolymers from biodegradable polyester A-blocks and hydrophilic poly(ethylene oxide) B-blocks as a candidate for in situ forming hydrogel delivery systems for proteins.Adv Drug Deliv Rev. 2002;54:99–134.

    Article  CAS  Google Scholar 

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Correspondence to Keith P. Johnston.

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Published: December 6, 2005

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Leach, W.T., Simpson, D.T., Val, T.N. et al. Encapsulation of protein nanoparticles into uniform-sized microspheres formed in a spinning oil film. AAPS PharmSciTech 6, 75 (2005). https://doi.org/10.1208/pt060475

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  • DOI: https://doi.org/10.1208/pt060475

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