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Mechanistic evaluation of acidic mic...

Ding, Guangbing (Amy).

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Mechanistic evaluation of acidic microclimate pH development in biodegradable poly(lactic-co-glycolic acid) delivery systems.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Mechanistic evaluation of acidic microclimate pH development in biodegradable poly(lactic-co-glycolic acid) delivery systems./
Author:	Ding, Guangbing (Amy).
Description:	244 p.
Notes:	Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5343.
Contained By:	Dissertation Abstracts International66-10B.
Subject:	Health Sciences, Pharmacy. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3192562
ISBN:	9780542364013

Mechanistic evaluation of acidic microclimate pH development in biodegradable poly(lactic-co-glycolic acid) delivery systems.
Ding, Guangbing (Amy).

Mechanistic evaluation of acidic microclimate pH development in biodegradable poly(lactic-co-glycolic acid) delivery systems. - 244 p.

Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5343.

Thesis (Ph.D.)--University of Michigan, 2005.

Copolymers of lactic and glycolic acids (PLGAs) have shown great potential as carriers for controlled delivery of proteins. However, insufficient stability of encapsulated proteins during the extended drug release period has been a principal obstacle for successful development of drug products. Although the acidic microclimate pH (mupH) has been identified as a principal stress for instability of PLGA-encapsulated proteins, little attempt to understand the underlying factors that influence mupH has been reported.

ISBN: 9780542364013Subjects--Topical Terms:

1017737
Health Sciences, Pharmacy.

Mechanistic evaluation of acidic microclimate pH development in biodegradable poly(lactic-co-glycolic acid) delivery systems.
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035 $a (UnM)AAI3192562
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100 1 $a Ding, Guangbing (Amy). $3 1910042
245 1 0 $a Mechanistic evaluation of acidic microclimate pH development in biodegradable poly(lactic-co-glycolic acid) delivery systems.
300 $a 244 p.
500 $a Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5343.
500 $a Chair: Steven P. Schwendeman.
502 $a Thesis (Ph.D.)--University of Michigan, 2005.
520 $a Copolymers of lactic and glycolic acids (PLGAs) have shown great potential as carriers for controlled delivery of proteins. However, insufficient stability of encapsulated proteins during the extended drug release period has been a principal obstacle for successful development of drug products. Although the acidic microclimate pH (mupH) has been identified as a principal stress for instability of PLGA-encapsulated proteins, little attempt to understand the underlying factors that influence mupH has been reported.
520 $a In this study, firstly, we developed an equilibrium mathematical model to attempt for the first time quantitative prediction of mupH. The model successfully predicted mupH measured by a potentiometric method. The mupH model also revealed that mupH kinetics was primarily a function of. (i) kinetics of water-soluble acid content and composition in the polymer matrix, and (ii) polymer-water partition coefficients of water-soluble degradation products, which suggested that controlling mupH can be achieved by the control of (i) acid production, (ii) acid transport out of the polymer matrix, and (iii) acid neutralization with excipients.
520 $a The mupH distribution inside PLGA matrix was then evaluated. The direct quantification of mupH was established by ratiometric measurement of acidic pH sensitive probe by confocal laser scanning microscopy (CLSM). The pH gradient existed over a short distance adjacent to edge of film and its front moved further towards edge with longer incubation times. The coencapsulation with protein (bovine serum albumin) partially neutralized microclimate pH due to the protein's buffering ability.
520 $a The transport behavior of acids was studied by measuring monomer diffusion coefficients in thin PLGA films. Diffusivities of glycolic and lactic acids were concentration-dependent, and could be expressed as an exponential function of concentration for C ≤ 0.5mol/L. Consistent with this behavior, glass transition temperatures of films decreased with increasing concentration, and glycolic acid exhibited higher plasticization effect and diffusivity than observed for lactic acid. Acids also diffused faster in more hydrophilic PLGAs.
520 $a The mupH distribution inside PLGA microspheres formulations were monitored by CLSM. mupH distribution kinetics were significantly affected by polymer MW, composition, microspheres size, and preparation method. PLGA microspheres for bFGF delivery were then prepared accordingly with mupH control and addition of stabilizers. The microspheres prepared from an optimized formulation showed continuous release for over a month in vitro, and the released protein remained bioactive.
520 $a In summary, the findings of the thesis have provided a physical chemical basis for mupH development in PLGA delivery systems in order to optimize delivery of pHsensitive encapsulated molecules (e.g. proteins). The plasticization effect of the monomers on PLGA and its role in monomer diffusion through PLGA has important implications on PLGA erosion and release of drugs.
590 $a School code: 0127.
650 4 $a Health Sciences, Pharmacy. $3 1017737
690 $a 0572
710 2 0 $a University of Michigan. $3 777416
773 0 $t Dissertation Abstracts International $g 66-10B.
790 1 0 $a Schwendeman, Steven P., $e advisor
790 $a 0127
791 $a Ph.D.
792 $a 2005
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3192562