PLGA microcapsule synthesis

In this Application Note, PLGA shell/aqueous core microcapsules are obtained using the Secoya Raydrop Double emulsion, a capillary based microfluidic device equipped with a 3D printed injection nozzle simplifying the generation of double emulsion when used in combination with pressure based flow controllers. The influence of the fluidic parameters on the microcapsule size and release from the oil across the shell are explored in this application note.

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Introduction

monodisperse plga double emulsion

Encapsulation of Active Pharmaceutical Compounds in core-shell microcapsules is of great interest for several purposes including: taste and odor masking as well as controlled release of drugs. In pharmaceutics the possibility to encapsulate drugs, nutrients, and living cells that can be protected by a solid biocompatible shell can be used to target a specific site for therapy. [1]

In this context, microcapsules with a PLGA shell and aqueous core have been widely studied because PLGA microcapsules appear to be successful new drug delivery systems (DDS). Due to the good biocompatibility and biodegradability of PLGA, microcapsules can be used in various applications such as long-term drug release systems, vaccine adjuvants, and in tissue engineering [2].

Materials and methods

System setup

The production of droplets has been performed with the Complex Emulsions Production Platform, a lab system integrating all the components needed to produce simple and double emulsions.

plga microcapsule setup
plga platform

System component

Reagents

Core phase (and collect phase):

  • Phosphate Buffered Saline buffer (PBS, pH=7,28 Sigma-Aldrich) containing blue food dye

Shell phase 1: Priming and cleaning phase

  • Ethyl acetate (EtOAc, Merck)

OR

  • Isopropyl acetate (IPAc, Sigma-Aldrich)

Shell phase 2:

  • Ethyl acetate (EtOAc, Merck) containing 10% Poly(D,L-lactide-co-glycolide) (PLGA, Resomer® RG 7555S ester terminated, Sigma-Aldrich)

OR

  • Isopropyl acetate (IPAc, Sigma-Aldrich) containing 10% Poly(D,L-lactide-co-glycolide) (PLGA, Resomer® RG 7555S ester terminated, Sigma-Aldrich)

Continuous phase:

  • Water containing 1% Poly(vinyl alcohol) (PVA, Sigma-Aldrich)

Synthesis of PLGA capsules

Monodisperse PLGA capsule synthesis is performed in 2 main steps:

  • Generation of monodisperse double emulsion in the Raydrop
  • Capsule formation by precipitation of the PLGA shell

1. Droplet generation

To generate droplets easily, the system must first be started with pure solvent in the shell phase (here IPAC). Once droplet formation is stabilized, the shell phase is switched to the solution containing the PLGA. This avoids possible clogging issues during the transient phase. 

plga double emulsion production
Figure 4: Generation of double emulsion in the Raydrop
monodisperse plga double emulsion
Figure 5: Double emulsion water/IPAC/PBS obtained at the output, observed under the microscope

2. Microcapsule formation

After being generated, the droplets are collected in a glass Petri dish. IPAc contained in the shell phase diffuses into the continuous phase so the PLGA precipitates. As a result, droplets are solidified and become PLGA capsules.

plga microcapsule
15s after formation
plga microcapsule
200s after formation

Figure 6: PLGA microcapsules in the PBS solution. On the left, 15 seconds after the creation in the Raydrop. On the right, 200s in the PBS solution after the creation in the Raydrop. The shell thickness decreases, as the IPAc contained in the shell phase diffuses in the continuous phase.

Partial results

In this Application Note, different parameters have been studied. Firstly, the evolution of the droplets over time have been observed. Then, the release rate of the capsules was measured.

Evolution of the droplet diameter during the precipitation process

Once formed, the droplets are collected in the same solution used in the core of droplets to match the osmolarity of inner and outer aqueous phases. An analysis of the size of the capsules is performed using a microscope and measurement software. For a given sample, several measurements of the capsule diameter are made at different times. The evolution of the diameter is highlighted in Figure 7 and the operating conditions are shown in Table 1.


Continuous phase Shell Core
Composition Water + 1% PVA EtOAc + 10% PLGA PBS pH = 7,28 + dye
Pressure (mbar) 214 2404 104
Flow rate (µL/min) 10916.59.1

Table 1: Operating conditions for the evaluation of the diameter of capsules
size of plga capsules
Figure 7: Size of PLGA capsules as a function of time. PLGA shell stop shrinking after 300s. A cut between 300sec and 3500s  has been made in the graph for better understanding.

The capsules have a diameter ranging from 312 µm to 230 µm. Moreover, we observe that during the precipitation process, the diameter of the capsules decreases. Indeed, a diameter of 312 µm is obtained 20 seconds after droplet formation, while a diameter of 230 µm is obtained 300 seconds after droplet formation. After 300s we observed that microcapsules are reaching a steady state and do not decrease further.

Conclusion

The production of stable monodispersed microcapsules with a solid PLGA shell and an aqueous core using a microfluidic has been successfully achieved. The microfluidic platform  allows one to optimize not only the core diameter but also vary the shell thickness by adjusting the flow rates of the different fluids. These microcapsules can be used in a wide range of applications, like the encapsulation of active ingredients such as specific drugs, which will be delivered according to the pH acidity [3].  

References

[1] LEE, Myung Han, HRIBAR, Kolin C., BRUGAROLAS, Teresa, KAMAT, Neha P., BURDICK, Jason A. and LEE, Daeyeon, 2012. Harnessing Interfacial Phenomena to Program the Release Properties of Hollow Microcapsules. Advanced Functional Materials. 11 January 2012. Vol. 22, no. 1, p. 131–138. DOI 10.1002/adfm.201101303.

[2] Qi, F., Wu, J., Li, H., & Ma, G. (2018). Recent research and development of PLGA / PLA

microspheres / nanoparticles: A review in scientific and industrial aspects

[3] MONTAZERI, Leila, BONAKDAR, Shahin, TAGHIPOUR, Mojtaba, RENAUD, Philippe and BAHARVAND, Hossein, 2016. Modification of PDMS to fabricate PLGA microparticles by a double emulsion method in a single microfluidic device. Lab on a Chip. 2016. Vol. 16, no. 14, p. 2596–2600. DOI 10.1039/C6LC00437G.

[4] TU, Fuquan and LEE, Daeyeon, 2012. Controlling the Stability and Size of Double-Emulsion-Templated Poly(lactic- co -glycolic) Acid Microcapsules. Langmuir. 3 July 2012. Vol. 28, no. 26, p. 9944–9952. DOI 10.1021/la301498f.

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