Tuesday, 26 January 2016 14:48

Does PLGA microparticle swelling control drug release?

Written by Hanane Gasmi
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Background

Poly(lactic-co-glycolic acid) (PLGA)-based microparticles offer a great potential as parenteral controlled drug delivery systems [1]. Different types of drug release patterns can be obtained from PLGA microparticles, in particular mono-, bi-, or tri-phasic drug release kinetics. Interestingly, yet the underlying mass transport mechanisms in PLGA microparticles are not fully understood, despite their great practical importance. This can be attributed to the complexity of the involved mass transport mechanisms. The aim of this study was to better understand the mass transport mechanisms controlling drug release from PLGA microparticles. Importantly, new insight was gained based on the experimental monitoring of the swelling kinetics of single microparticles.

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Microparticles preparation and physico-chemical characterization

Initially, PLGA microparticles loaded with ketoprofen were prepared using O/W emulsion extraction / evaporation solvent method while keeping the other parameters constant for different formulations. The only parameter which was varied is the viscosity of the organic phase. The aim is to get a range of microparticles having the same size. The obtained microparticles were thoroughly characterized using several techniques such as GPC, DSC and X-ray powder diffraction. The in vitro drug release studies were performed in phosphate buffer pH 7.4 (containing 0.02 % Tween 80) at 37 ° C with horizontal shaking. At predetermined time intervals, samples were withdrawn, replaced with fresh medium and analyzed by appropriate method. Swelling studies were monitored in 96-well standard microplates in the same conditions as the release studies.

Key properties of microparticles

The obtained results showed that the encapsulation efficiency of the investigated ketoprofen-loaded microparticles substantially increased (from 50 to 90%) when increasing the theoretical drug content from 1 to 50 %. The release studies showed two types of release profiles as it can be seen in Figure 1.

(reprinted with permission from [4])

At low drug loadings, tri-phasic drug release patterns were observed: After an initial rapid release phase (“burst release”), a release period with a more or less constant drug release rate was observed, followed by a third (and again rapid) drug release phase. With increasing drug loadings the onset of this third release phase was shifted to earlier time points. At high drug loadings, it was difficult to clearly distinguish different drug release phases; the profiles were more or less bi- or mono-phasic. To better understand why these pronounced differences in the drug release patterns were observed and in order to elucidate the underlying mass transport mechanisms controlling ketoprofen release from these PLGA microparticles, the latter were thoroughly characterized before and after exposure to the release medium. The X-ray powder diffraction patterns of the PLGA, ketoprofen and the different types of drug loaded PLGA microparticles were performed before exposure to the release medium. Clearly, the ketoprofen powder as received was highly crystalline, whereas neither the PLGA powder (as received), nor any of the ketoprofen-loaded PLGA microparticles showed X-ray diffraction peaks indicating crystallinity. This means that the ketoprofen, which was dissolved in the organic phase during microparticle preparation, did not re-crystallize upon solvent evaporation, but was probably molecularly dispersed in the PLGA matrix (dissolved) and optionally partially precipitated in an amorphous form within the system (depending on the practical drug loading). DSC measurements with dry, ketoprofen-loaded microparticles confirmed this hypothesis: The pure ketoprofen powder (as received) showed a sharp melting peak at about 95 °C, whereas none of the investigated ketoprofen-loaded PLGA microparticles showed any thermal event in this temperature range. This is also in good agreement with data reported by Ricci et al. [2]. Furthermore, the DSC studies revealed that ketoprofen is an efficient plasticizer for PLGA. Figure 2 shows how the glass transition temperature (Tg) of the polymer significantly decreased upon addition of up to around 25% ketoprofen. Blasi et al. attributed these plasticizing effects to hydrogen bonding [3].

(reprinted with permission from [4])

Figure 3 illustrates the impact of the initial practical ketoprofen loading on PLGA degradation in the investigated microparticles upon exposure to the release medium. As it can be seen, the polymer degradation rate substantially increased with increasing initial drug content. This can be attributed to the fact that ketoprofen is an acid and PLGA degradation is catalyzed by protons [4]. Importantly, the polymer molecular weight can be expected to be potentially decisive for key properties of the microparticles, such as their mechanical stability and swelling behavior.

 (reprinted with permission from [4])

Swelling kinetics of individual microparticles and correlation with drug release

The microscopic pictures in Figure 4 show ensembles of microparticles, which were exposed to phosphate buffer pH 7.4 (containing 0.02% Tween 80) at 37 °C for 7, 10 and 14 d, respectively. Importantly, the spatial arrangements of the microparticles in the wells remained about constant, so that it was possible to follow the changes in the size of individual microparticles during the entire drug release period. 

(reprinted with permission from [4])

The diagram in Figure 4 shows 3 examples: The swelling kinetics of a small microparticle (initially 55 μm in diameter), of a medium-sized microparticle (initially 83 μm in diameter) and of a large microparticle (initially 109 μmin diameter) are illustrated. Clearly, the microparticle size remained about constant during the first 7 d, and then substantially increased, irrespective of the microparticle size. This is likely attributable to the fact that after a certain lag-time, a critical PLGA molecular weight is reached, at which polymer swelling is less hindered. Initially, the degree of polymer chain entanglement is very high and effectively prevents substantial microparticle swelling. Upon contact with water, the polyester chains are more and more cleaved by hydrolysis and as soon as the degree of macromolecular entanglement becomes insufficient to prevent substantial particle swelling, the PLGA matrix can increase in volume. Also, the degradation products are creating a steadily increasing osmotic pressure within the system, attracting more and more water into the microparticles. Importantly, the observed dramatic changes in the microparticles' size result in tremendous changes in the systems' composition: the water content of the polymeric particles fundamentally increases. This can be expected to have major impact on the conditions for drug transport in the systems: The mobility of dissolved ketoprofen molecules is likely to substantially increase with the onset of significant microparticle swelling.

The same phenomenen was observed with microparticles loaded with 1.9 to 8.3 % of ketopofen. The lag-time was about 6 to 2 days, respectively and then the diameter of microparticles increased which coincide with the onset of the third drug release phase and the morphological changes are visible during this time period. In the case of microparticles loaded with 11.7 % to 35.0 % of ketoprofen (Figure 5), the onset of the third drug release phase was shifted to earlier time points when the drug loading increased and this can be probably due to the accelerates PLGA degradation in presence of hight amount of acidic drug.

(reprinted with permission from [4])

Conclusion

The presented results suggest that the swelling kinetics of PLGA microparticles can play a decisive role in the control of drug release: The onset of the often observed third (and again rapid) drug release phase form these systems might be a consequence of the penetration of substantial amounts of water into the particles, leading to a fundamental increase in drug mobility. During the second drug release phase, the polymer chain entanglement is too high to allow for significant particle swelling and, thus, results in limited water contents and limited drug mobility, resulting in a relatively low drug release rate.

References:

[1] S.P. Schwendeman, R.B. Shah, B.A. Bailey, A.S. Schwendeman, Injectable controlled  release depots for large molecules., J. Control. Release 190 (2014) 240–253.

[2] M. Ricci, P. Blasi, S. Giovagnoli, C. Rossi, G. Macchiarulo, G. Luca, et al., Ketoprofen controlled release from composite microcapsules for cell encapsulation: effect on post-transplant acute inflammation. J. Control. Release 107 (2005) 395-407.

[3] P. Blasi, A. Schoubben, S. Giovagnoli, L. Perioli, M. Ricci, C. Rossi, Ketoprofen poly(lactideco-glycolide) physical interaction., AAPS PharmSciTech 8 (2007) (Article 37).

[4] H. Gasmi, F. Danede, J. Siepmann, F. Siepmann, Does PLGA microparticle swelling control drug release? New insight based on single particle swelling studies. J. Control. Release 213 (2015) 120-127.

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