Formulation and characterization of microspheres loaded with imatinib for sustained delivery

F. Ramazani, W. Chen, C.F. van Nostrum, Gerrit Storm, F. Kiessling, Twan Gerardus Gertudis Maria Lammers, Wim E. Hennink, R.J. Kok

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The aim of this study was the development of imatinib-loaded poly(d,l-lactide-co-glycolide) (PLGA) microspheres with high loading efficiency which can afford continuous release of imatinib over a prolonged period of time. Imatinib mesylate loaded PLGA microspheres with a size of 6–20 μm were prepared by a double emulsion (W1/O/W2) method using dichloromethane as volatile solvent. It was found that the microspheres were spherical with a non-porous surface; imatinib loading efficiency (LE) was highly dependent on the pH of the external water phase (W2). By increasing the pH of W2 phase above the highest pKa of imatinib (pKa 8.1), at which imatinib is mainly uncharged, the LE increased from 10% to 90% (pH 5.0 versus pH 9.0). Conversely, only 4% of its counter ion, mesylate, was retained in the microspheres at the same condition (pH 9.0). Since mesylate is highly water soluble, it is unlikely that it partitions into the organic phase. We demonstrated, using differential scanning calorimetry (DSC), that imatinib was molecularly dispersed in the polymeric matrix at loadings up to 8.0%. At higher drug loading, imatinib partially crystallized in the matrix. Imatinib microspheres released their cargo during three months by a combination of diffusion through the polymer matrix and polymer erosion. In conclusion, we have formulated imatinib microspheres with high LE and LC. Although we started with a double emulsion of imatinib mesylate, the obtained microspheres contained imatinib base which was mainly molecularly dispersed in the polymer matrix. These microspheres release imatinib over a 3-month period which is of interest for local treatment of cancer.
Original languageUndefined
Pages (from-to)123-130
JournalInternational journal of pharmaceutics
Volume482
Issue number1-2
DOIs
Publication statusPublished - 2015

Keywords

  • METIS-315202
  • IR-99929

Cite this

Ramazani, F. ; Chen, W. ; van Nostrum, C.F. ; Storm, Gerrit ; Kiessling, F. ; Lammers, Twan Gerardus Gertudis Maria ; Hennink, Wim E. ; Kok, R.J. / Formulation and characterization of microspheres loaded with imatinib for sustained delivery. In: International journal of pharmaceutics. 2015 ; Vol. 482, No. 1-2. pp. 123-130.
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Formulation and characterization of microspheres loaded with imatinib for sustained delivery. / Ramazani, F.; Chen, W.; van Nostrum, C.F.; Storm, Gerrit; Kiessling, F.; Lammers, Twan Gerardus Gertudis Maria; Hennink, Wim E.; Kok, R.J.

In: International journal of pharmaceutics, Vol. 482, No. 1-2, 2015, p. 123-130.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Formulation and characterization of microspheres loaded with imatinib for sustained delivery

AU - Ramazani, F.

AU - Chen, W.

AU - van Nostrum, C.F.

AU - Storm, Gerrit

AU - Kiessling, F.

AU - Lammers, Twan Gerardus Gertudis Maria

AU - Hennink, Wim E.

AU - Kok, R.J.

N1 - Particulate Systems in Nanomedicine — Selected papers from a 2014 EWPS Workshop

PY - 2015

Y1 - 2015

N2 - The aim of this study was the development of imatinib-loaded poly(d,l-lactide-co-glycolide) (PLGA) microspheres with high loading efficiency which can afford continuous release of imatinib over a prolonged period of time. Imatinib mesylate loaded PLGA microspheres with a size of 6–20 μm were prepared by a double emulsion (W1/O/W2) method using dichloromethane as volatile solvent. It was found that the microspheres were spherical with a non-porous surface; imatinib loading efficiency (LE) was highly dependent on the pH of the external water phase (W2). By increasing the pH of W2 phase above the highest pKa of imatinib (pKa 8.1), at which imatinib is mainly uncharged, the LE increased from 10% to 90% (pH 5.0 versus pH 9.0). Conversely, only 4% of its counter ion, mesylate, was retained in the microspheres at the same condition (pH 9.0). Since mesylate is highly water soluble, it is unlikely that it partitions into the organic phase. We demonstrated, using differential scanning calorimetry (DSC), that imatinib was molecularly dispersed in the polymeric matrix at loadings up to 8.0%. At higher drug loading, imatinib partially crystallized in the matrix. Imatinib microspheres released their cargo during three months by a combination of diffusion through the polymer matrix and polymer erosion. In conclusion, we have formulated imatinib microspheres with high LE and LC. Although we started with a double emulsion of imatinib mesylate, the obtained microspheres contained imatinib base which was mainly molecularly dispersed in the polymer matrix. These microspheres release imatinib over a 3-month period which is of interest for local treatment of cancer.

AB - The aim of this study was the development of imatinib-loaded poly(d,l-lactide-co-glycolide) (PLGA) microspheres with high loading efficiency which can afford continuous release of imatinib over a prolonged period of time. Imatinib mesylate loaded PLGA microspheres with a size of 6–20 μm were prepared by a double emulsion (W1/O/W2) method using dichloromethane as volatile solvent. It was found that the microspheres were spherical with a non-porous surface; imatinib loading efficiency (LE) was highly dependent on the pH of the external water phase (W2). By increasing the pH of W2 phase above the highest pKa of imatinib (pKa 8.1), at which imatinib is mainly uncharged, the LE increased from 10% to 90% (pH 5.0 versus pH 9.0). Conversely, only 4% of its counter ion, mesylate, was retained in the microspheres at the same condition (pH 9.0). Since mesylate is highly water soluble, it is unlikely that it partitions into the organic phase. We demonstrated, using differential scanning calorimetry (DSC), that imatinib was molecularly dispersed in the polymeric matrix at loadings up to 8.0%. At higher drug loading, imatinib partially crystallized in the matrix. Imatinib microspheres released their cargo during three months by a combination of diffusion through the polymer matrix and polymer erosion. In conclusion, we have formulated imatinib microspheres with high LE and LC. Although we started with a double emulsion of imatinib mesylate, the obtained microspheres contained imatinib base which was mainly molecularly dispersed in the polymer matrix. These microspheres release imatinib over a 3-month period which is of interest for local treatment of cancer.

KW - METIS-315202

KW - IR-99929

U2 - 10.1016/j.ijpharm.2015.01.043

DO - 10.1016/j.ijpharm.2015.01.043

M3 - Article

VL - 482

SP - 123

EP - 130

JO - International journal of pharmaceutics

JF - International journal of pharmaceutics

SN - 0378-5173

IS - 1-2

ER -