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Pharmaceutical Research

, Volume 31, Issue 10, pp 2844–2856 | Cite as

Computer Modeling Assisted Design of Monodisperse PLGA Microspheres with Controlled Porosity Affords Zero Order Release of an Encapsulated Macromolecule for 3 Months

  • Filis Kazazi-Hyseni
  • Mariana Landin
  • Audrey Lathuile
  • Gert J. Veldhuis
  • Sima Rahimian
  • Wim E. Hennink
  • Robbert Jan Kok
  • Cornelus F. van Nostrum
Research Paper

ABSTRACT

Purpose

The aim of this study was the development of poly(D,L-lactide-co-glycolide) (PLGA) microspheres with controlled porosity, to obtain microspheres that afford continuous release of a macromolecular model compound (blue dextran).

Methods

PLGA microspheres with a size of around 40 μm and narrow size distribution (span value of 0.3) were prepared with a double emulsion membrane emulsification method. Gene expression programming (GEP) analysis was applied to design and formulate a batch of microspheres with controlled porosity that shows continuous release of blue dextran.

Results

Low porous microspheres with a high loading efficiency were formed at high polymer concentrations (30% w/w in the oil phase) and were characterized with a burst release <10% and a three-phasic release profile of blue dextran. Increasing porosity (10% w/w polymer concentrations), a sustained release of blue dextran was obtained albeit with up to 40% of burst release. The desired formulation, calculated by GEP, resulted in microspheres with 72% loading efficiency and intermediate porosity. Blue dextran was indeed released continuously in almost a zero order manner over a period of 3 months after an initial small burst release of 9%.

Conclusions

By fine-tuning the porosity, the release profile of PLGA microspheres for macromolecules can be predicted and changed from a three-phasic to a continuous release.

KEY WORDS

controlled release membrane emulsification microspheres PLGA porosity 

Abbreviations

ANNs

Artificial neural networks

GEP

Gene expression programing

LC

Loading capacity

LE

Loading efficiency

ME

Membrane emulsification

PLGA

Poly(D,L-lactide-co-glycolide)

PVA

Polyvinyl alcohol

TL

Theoretical loading

d4,3

Volume-weighted mean droplet diameter

dd

Droplet diameter

dp

Membrane pore diameter

ε

Membrane porosity

Fb

The buoyancy force

Fc

The drag force of the continuous phase flow

Fd

The inertial force of the dispersed phase flow

Fγ

The interfacial tension force

γ

Interfacial tension

Jd

Dispersed phase flux

k

Fraction of active membrane pores

ηd

Viscosity of the dispersed phase

\( {\overline{P}}_c \)

Continuous phase pressure

Pc,in; Pc,out

Pressure of the continuous phase at the inlet and outlet of the main channel

Pctm

Critical transmembrane pressure

Pd

Dispersed phase pressure

ΔPtm

Transmembrane pressure

q

Dispersed phase flow rate

R2

Correlation coefficient

Rm

Hydraulic membrane resistance

rp

Radius of the membrane pore

td

Period of drop detachment

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

This research forms part of the Project P3.02 DESIRE of the research program of the BioMedical Materials institute, co-funded by the Dutch Ministry of Economic Affairs. ML thanks the Spanish Government for financial support (SAF 2012- 39878-C02-01).

Supplementary material

11095_2014_1381_MOESM1_ESM.docx (8.9 mb)
ESM 1 (DOCX 9078 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Filis Kazazi-Hyseni
    • 1
  • Mariana Landin
    • 2
  • Audrey Lathuile
    • 3
  • Gert J. Veldhuis
    • 3
  • Sima Rahimian
    • 1
  • Wim E. Hennink
    • 1
  • Robbert Jan Kok
    • 1
  • Cornelus F. van Nostrum
    • 1
  1. 1.Department of Pharmaceutics, Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
  2. 2.Department of Pharmacy and Pharmaceutical TechnologyUniversity of SantiagoSantiago de CompostelaSpain
  3. 3.Nanomi B.V.OldenzaalThe Netherlands

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