In-vitro degradation of polymeric carriers of PLGA, PGA-co-PDL polymers

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References
N. M. Osman1,2, K. Sin1, J. Jaffer1, K. Ritchie1, I. Y. Saleem1, G. A. Hutcheon1,
1 School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
2 Forensic Medicine & Clinical Toxicology Dep., Sohag University, Sohag, Egypt
Introduction
Formulation & Drug
Delivery Research
DEGRADATION OF PLGA AND PGA-co-PDL POLYMERIC CARRIERS IN SIMULATED LUNG FLUID FOR
PULMONARY DRUG DELIVERY
Results and Discussion
Conclusions and Future work
Aggregation of PGA-co-PDL NPs made it difficult to determine any size reduction due to degradation. PLGA NPs reduced in size indicating some degradation
occurred under the stated experimental conditions. PGA-co-PDL NPs produced a less acidic environment compared with PLGA NPs hence less inflammation
may occur in vivo. Determination of changes in polymer molecular weight by GPC analysis and observation of the particles using Transmission Electron
Microscopy are currently in progress which will increase our understanding of the stability and degradation of these particles.
Acknowledgements
Nashwa Osman would like to thank the Egyptian Educational and Cultural Bureau for funding this project and thank LJMU staff and technicians for their kind support.
Successful drug delivery systems are able to deliver an active
therapeutic agent to a specific targeted site in the duration of time with
minimal side effects1. Aliphatic polyesters are widely used for drug delivery
applications, the most common being poly (lactic-co-glycolic acid), PLGA .
The main drawbacks of using PLGA are the initial burst release and the bulk
degradation that produces acidic products resulting in a reduction in pH at
the site of drug action.
A novel aliphatic polyester, poly (glycerol adipate-co-w-
pentadecalactone), (PGA-co-PDL), synthesized from the lipase catalysed
poly-condensation and ring-opening polymerization reaction with the
potential to overcome these drawbacks has recently been investigated2,3.
These aliphatic polyesters achieve the controlled-release of drugs by bulk
degradation which leads to uniform disintegration of the drug delivery system
with a decrease in molecular weight (MWt) and size until complete
dissolution. The degradation products consist of the parent alcohol and acid
monomeric units which can create an acidic environment depending on their
chemistry. In vivo these products then enter Kreb’s cycle to decompose to
CO2 and H2O.
Rate-control of drug release can by achieved by controlling the
degradation rate of polymer chemistry; monomeric ratio, MWt and
hydrophobicity, particle characters; size, core, coating or matrix thickness
and its formulation, and with the target physicochemical environment.
Aim
The aim of this study was to evaluate the stability and degradation of
polymeric nanoparticles (NPs) prepared from PLGA and PGA-co-PDL
under in-vitro simulated pulmonary physiologic conditions as a suspension
in simulated lung fluid (SLF) at 37 o C.
Materials and Methods
Acid terminated PLGA (50:50) with a MWt of 7000- 17000 KDa (Sigma
Aldrich) and PGA-co-PDL (synthesized and characterized as previously
reported by Thompson et al3) were used to prepare NPs by the single
emulsion solvent evaporation method5 using poly vinyl alcohol as an
emulsifier. NPs were centrifuged twice at 78,000g, and 4ºC for 40 min. Initial
MWt of both polymers were analyzed using Gel Permeation
Chromatography (GPC)3 (Viscoteck TDA Model 300 operating OmniSEC3
software) calibrated with polystyrene standards.
PLGA and PGA-co-PDL NPs (10 mg) were stored at 37oC as a
suspension in SLF (Gamble’s solution) at pH 7.4 with axial rotation of 15
rpm. At specified time points between 1-28 days the pH of the suspension
was measured. NPs were characterized for size and zeta potential using
Malvern Zetasizer ZS.
The initial polymer MWt was 17.57 and 14.73 KDa for PLGA and PGA-co-
PDL respectively. NPs were successfully formulated with a size of 157.9 ±
2.19 nm and 179.8 ± 3.91 nm for PLGA and PGA-co-PDL respectively. The
zeta potentials of PLGA and PGA-co-PDL NPs were -8.9 ± 0.5 and -9.72 ±
1.0 mV. The initial pH of the NPs suspension was 8.7 and 7.46 for PGA-co-
PDL and PLGA NPs respectively
NP size: The size of the PGA-co-PDL NPs increased over time with a
corresponding increase in polydispersity suggesting the particles were
aggregating. The PLGA NP decreased in size over time confirming their
degradation without aggregation (Fig 1).
0
50
100
150
200
250
300
350
400
450
D1 D2 D4 D7 D14 D21 D28
Sizeinnm
Daily interval
PGA-co-PDL PLGA
Fig 1. Size changes over the study time interval of both polymeric NPs
NP zeta potential: The zeta potential was initially negative. After day 4,
the negativity of the PGA-co-PDL NPs increased where-as little change was
observed with PLGA NPs over time (Fig 2).
-30.0
-25.0
-20.0
-15.0
-10.0
-5.0
0.0
D1 D2 D4 D7 D14 D21 D28
ZetapotentialinmV
Daily interval
PGA-co-PDL PLGA
Fig 2. Zeta potential changes over the study time interval of both polymeric NPs
pH analysis : The pH changes observed (Fig 3) confirmed that as the NPs
degraded, the solution containing the NPs became more acidic. PLGA NPs
showed a greater change in acidity indicating that the degradation products
were more acidic. In vivo this may cause localized acidity promoting an
inflammatory response.
0
1
2
3
4
5
6
7
8
9
10
D1 D2 D4 D7 D14 D21 D28
pHvalue
Daily interval
PGA-co-PDL PLGA
Fig 3. pH changes over the study time interval of both polymeric NPs