PMID- 17428570
OWN - NLM
STAT- MEDLINE
DCOM- 20070710
LR  - 20070521
IS  - 1873-4995 (Electronic)
IS  - 0168-3659 (Linking)
VI  - 119
IP  - 2
DP  - 2007 Jun 4
TI  - Towards controlled release of BDNF--manufacturing strategies for protein-loaded 
      lipid implants and biocompatibility evaluation in the brain.
PG  - 163-72
AB  - 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 1 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 1 mm diameter, 0.8 mm height and 1 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.
FAU - Koennings, S
AU  - Koennings S
AD  - Department of Pharmaceutical Technology, University of Regensburg, 
      Universitaetsstr, 31, 93040 Regensburg, Germany.
FAU - Sapin, A
AU  - Sapin A
FAU - Blunk, T
AU  - Blunk T
FAU - Menei, P
AU  - Menei P
FAU - Goepferich, A
AU  - Goepferich A
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070220
PL  - Netherlands
TA  - J Control Release
JT  - Journal of controlled release : official journal of the Controlled Release 
      Society
JID - 8607908
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Delayed-Action Preparations)
RN  - 0 (Drug Implants)
RN  - 0 (Lipids)
RN  - EC 3.2.1.17 (Muramidase)
SB  - IM
MH  - Animals
MH  - Brain/drug effects/*metabolism
MH  - Brain-Derived Neurotrophic Factor/administration & dosage/*pharmacokinetics
MH  - Chemistry, Pharmaceutical/methods
MH  - Chickens
MH  - Delayed-Action Preparations/administration & dosage/pharmacokinetics
MH  - Drug Delivery Systems/*methods
MH  - Drug Evaluation, Preclinical/methods
MH  - Drug Implants
MH  - Female
MH  - Lipids/administration & dosage/*pharmacokinetics
MH  - Materials Testing/methods
MH  - Muramidase/administration & dosage/*pharmacokinetics
MH  - Rats
MH  - Rats, Inbred F344
EDAT- 2007/04/13 09:00
MHDA- 2007/07/11 09:00
CRDT- 2007/04/13 09:00
PHST- 2006/09/25 00:00 [received]
PHST- 2007/01/31 00:00 [revised]
PHST- 2007/02/05 00:00 [accepted]
PHST- 2007/04/13 09:00 [pubmed]
PHST- 2007/07/11 09:00 [medline]
PHST- 2007/04/13 09:00 [entrez]
AID - S0168-3659(07)00076-4 [pii]
AID - 10.1016/j.jconrel.2007.02.005 [doi]
PST - ppublish
SO  - J Control Release. 2007 Jun 4;119(2):163-72. doi: 10.1016/j.jconrel.2007.02.005. 
      Epub 2007 Feb 20.