1. Brannon - Peppas L (1997). Med Plast Biomater 4: 34-44; 2. Nitesh K. Kunda & Iman M. A lfagih, Sarah R. Dennison, H M. Tawfeek, S Somavarapu, G A. Hutcheon & I Y. Saleem.

(2014). Pharmaceutical research , 1-13. 3. Thompson C. J., D. Hansford, S. Higgins, C. Rostron, G. A. Hutcheon and D. L. (2009) Munday. Journal of Microencapsulation. 26(8):

676–683; 4. Tawfeek H. M., S.H. Khidr, E.M Samy, S.M Ahmed, M Murphy, A. Mohammed, A. Shabir, G. Hutcheon & I. Saleem.(2011). Pharmaceutical research, 28(9), 2086-2097;

5. C. Pinto Reis et al. Nanomedicine: nanotechnology, biology, and medicine. 2:8-21 (2006).

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 workAggregation 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.

AimThe 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).

050

100150200250300350400450

D1 D2 D4 D7 D14 D21 D28

Siz

e i

n n

m

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

Zeta

po

ten

tial in

mV

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

34

5

6

7

8

9

10

D1 D2 D4 D7 D14 D21 D28

pH

valu

e

Daily interval

PGA-co-PDL PLGA

Fig 3. pH changes over the study time interval of both polymeric NPs