Koennings, S. and Sapin, A. and Blunk, T. and Menei, P. and Goepferich, A. (2007) Towards controlled release of BDNF - Manufacturing strategies for protein-loaded lipid implants and biocompatibility evaluation in the brain. JOURNAL OF CONTROLLED RELEASE, 119 (2). pp. 163-172. ISSN 0168-3659,
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It was the aim of this study to establish triglyceride matrices as potential carriers for long-term release of brain-derived neurotrophic factor (BDNF), a potential therapeutic for Huntington's disease. First, four different manufacturing strategies were investigated with lysozyme as a model substance: either lyophilized protein was mixed with lipid powder, or suspended in organic solution thereof (s/o). Or else, an aqueous protein solution was dispersed by w/o emulsion in organic lipid solution. Alternatively, a PEG co-lyophilization was performed prior to dispersing solid protein microparticles in organic lipid solution. After removal of the solvent(s), the resulting powder formulations were compressed at 250 N to form mini-cylinders of 2 mm diameter, 2.2 mm height and 7 mg weight. Protein integrity after formulation and release was evaluated from an enzyme activity assay and SDS-PAGE. Confocal microscopy revealed that the resulting distribution of FITC-lysozyme within the matrices depended strongly on the manufacturing method, which had an important impact on matrix performance: matrices with a very fine and homogeneous protein distribution (PEG co-lyophilization) continually released protein for 2 months. The other methods did not guarantee a homogeneous distribution and either failed in sustaining release for more than I week (powder mixture), completely liberating the loading (s/o dispersion) or preserving protein activity during manufacturing (w/o emulsion, formation of aggregates and 25% activity loss). Based on these results, miniature-sized implants of I mm diameter, 0.8 mm height and I mg weight were successfully loaded by the PEG co-lyophilization method with 2% BDNF and 2% PEG. Release studies in phosphate buffer PH 7.4 at 4 and 37 degrees C revealed a controlled release of either 20 or 60% intact protein over one month as determined by ELISA. SDS-PAGE detected only minor aggregates in the matrix during release at higher temperature. In vivo evaluation of lipid cylinders in the striatum of rat brains revealed a biocompatibility comparable to silicone reference cylinders. (C) 2007 Elsevier B.V. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BIODEGRADABLE PLGA MICROSPHERES; CONTROLLED DRUG-DELIVERY; NEUROTROPHIC FACTOR; SPINAL-CORD; NEURODEGENERATIVE DISEASES; TRIGLYCERIDE MATRICES; NEURONAL SURVIVAL; SUSTAINED-RELEASE; NGF STABILITY; ADULT-RATS; manufacturing strategies; confocal microscopy; protein drugs; lipid matrices; brain biocompatibility |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical Technology (Prof. Göpferich) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Dec 2020 08:52 |
| Last Modified: | 04 Dec 2020 08:52 |
| URI: | https://pred.uni-regensburg.de/id/eprint/32676 |
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