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Multiphase and Multilayered Polymeric Particles

Multiphase and Multilayered Polymeric Particles

Evolution from single-layered to quadruple-layered particles fabricated through a patented one-step fabrication technique.

(a) Raman mapping showing polymer and drug distributions (red: high concentration, blue: little or no concentration). (b) Cross-sectional view of a ternary-phase double-layered microparticles. (c) Sequential release of two different drugs.

Controlled and sustained co-delivery of two anticancer drugs (i.e. doxorubicin HCl and paclitaxel) from the multilayered microparticles significantly reduces MCF-7 3D tumor spheroid growth rate, in comparison with single-drug-loaded particles.

Particulate systems have tremendous potential to achieve controlled release and targeted delivery of drugs. However, conventional single-layered (monolithic) particles have several inherent limitations, including initial burst release, the inability to provide a constant release, and a lack of time-delayed or pulsatile release. The development of multiphase or multilayered particles is an important step towards a robust approach in providing a variety of drug delivery kinetics and profiles. We have developed several simple, economical, versatile, highly scalable one-step techniques for multiphase polymeric particles, hydrophilic-hydrophobic (core-shell) particles and hollow particles. Unlike traditional techniques for fabricating the multicompartmented particles involving complicated and multistep processes, the invented one-step techniques reduce the total process time and increase the process yield.

 

Key Features                                                 

  • “Designer” particulate system: Double-layered to quadruple-layered, potentially multilayered structure with controllable particle sizes (micron to sub-micron sizes), layer thicknesses, configurations and localization of drugs

  • Controlled and adjustable drug release kinetics: Reduced burst release, time-delayed release, zero-order release and sequential release of multiple drugs

  • Controlled release of hydrophilic protein or growth factor, while maintaining their bioactivity, through the use of alginate core-hydrophobic shell particles

 

Applications

  • Chemotherapy with multiple anticancer drugs

  • Topical application for wound healing

  • 3D tissue engineering scaffold for delivery of growth factors

  • Vaccination

  • Other drug delivery applications...

 

Selected Publications

  1. W.L. Lee,  W.M. Guo, V.H.B. Ho, A. Saha, H.C. Chong, N.S. Tan, E. Widjaja, E.Y. Tan, S.C.J. Loo, Inhibition of 3-D tumor spheroids by timed-released hydrophilic and hydrophobic drugs from multilayered polymeric microparticles, Small 10 (2014) 3986-3996.

  2. W.L. Lee, C. Loei, E. Widjaja, S.C.J. Loo, Altering the drug release profiles of double-layered ternary-phase microparticles, Journal of Controlled Release 151 (2011) 229-238.

  3. W.L. Lee, E. Widjaja, S.C.J. Loo, One-step fabrication of triple-layered polymeric microparticles with layer localization of drugs as a novel drug-delivery system, Small 6 (2010) 1003-1011.

  4. S.C.J. Loo, W.L. Lee, Multi-phase microparticles and method of manufacturing multi-phase microparticles, Patent (WO/2010/140987) PCT/SG2010/000215, CN Patent No. ZL 2010 8 0034273.8.

  5. S.C.J. Loo, M.P. Lim, W.L. Lee, Methods of manufacturing core-shell microparticles and microparticles formed thereof, Patent (WO/2013/119183) PCT/SG2013/000051.

  6. S.C.J. Loo, S. Kharel, W.L. Lee, Method of preparing hollow microparticles and hollow microparticles prepared thereof, Patent (WO/2016/089309) PCT/SG2015/050483.

 

Microencapsulation of Particles

Monolithic particulate systems would not allow for the loading of multiple drugs into a single carrier due to certain physicochemical considerations, such as possible drug-drug interactions. While the current approach towards designing drug delivery systems largely revolves around polymeric platforms for single drug administration, basic economics and patient compliance are factors that would favour the realization of a single carrier that can house and release multiple drug entities simultaneously. To help achieve a multiple-drug delivery system, through a microencapsulation technique, the fabrication technique of a polymeric hollow microcapsule that can carry a range of different chemically-loaded nano/sub-micron particles was thus developed. This system can reduce burst release and achieve controlled release of multiple drugs, as the shell of acts as a barrier against rapid drug diffusion.

 

Key Features                                                 

  • Bio-imaging dyes or drugs can be concurrently loaded.

  • Drug-drug interactions can be avoided.

  • Retardation of the burst drug release

  • Controlled release of both hydrophilic and hydrophobic drugs

 

Applications

  • Pulmonary delivery

  • Depot delivery

  • Multiple drug combination therapies e.g. HIV, tuberculosis, cancer and lupus

 

Selected Publications

  1. Y.L. Khung, W.L. Lee (co-first author), K.L. Chui, Y. Liu, M.P. Lim, C.L. Huang, S.C.J. Loo, Microencapsulation of dye- and drug-loaded particles for imaging and controlled release of multiple drugs, Advanced Healthcare Materials 1 (2012) 159-163.

  2. S.C.J. Loo, Y.L. Khung, W.L. Lee, Method for encapsulating particles, Patent (WO/2012/071013) PCT/SG2011/000413, US Patent No. 9,616,031.

(a) Cross-section of microcapsules, subsequent magnification revealing smaller particles residing within the hollow space; (b) Confocal images of a cross-sectional plane of a microcapsule encapsulating dye-loaded particles: (i) Brightfield, (ii) emission of the Coumarin-6 dye, (iii) emission of the Rhodamine-6G dye and (iv) an overlaid representation of all components.

Microencapsulation of Particles

Multi-Drug-Loaded Gastric-Floating Capsules

Multi-Drug-Loaded Gastric-Floating Capsules

Schematic illustration of the encapsulation procedure for the preparation of floating microcapsules and the release of multiple drugs within the gastric region.

(a) Photo showing all microcapsules remained afloat in simulated gastric fluid after 24 h; (b) Release profiles of three different cardiovascular drugs from a floating microcapsule in gastric fluid for 5 h followed by release in intestinal fluid at 37 degC. Controlled and sustained release of multiple drugs with different properties and solubilities is shown.

Floating gastro-retentive drug delivery systems have the potential to improve oral bioavailability and reduce drug wastage. A single carrier or “tablet” that encapsulates various multiple drugs would allow for a reduction in the number of oral tablets to be taken, as well as dosing frequency (i.e. pill burden), which in turn may improve patient medical compliance. We have invented a fabrication technique to encapsulate a variety of drug-loaded particles (nano/micron-sized) within a larger floating microcapsule for rate-controlled oral drug delivery. In this present technique, high compression forces and elevated temperatures are not required, as compared with other common methods of producing floating tablets. The microcapsules offer greater versatility in fine-tuning the drug release profiles through the manipulation of capsule/particle parameters, such as shell thickness, drug loading within the particles and polymer types.

 

Key Features                                                 

  • Excellent buoyancy in gastric fluid

  • Controlled and sustained release of multiple drugs with different properties (e.g. hydrophilic, hydrophobic, amphiphilic)

 

Applications

  • “Single pill” approach towards treatment of chronic diseases that require polypharmacy approach

  • Treatment of chronic cardiovascular diseases through controlled release of three different cardiovascular drugs (i.e. blood pressure, glucose, cholesterol)

  • Treatment of gastric Helicobacter pylori infections and peptic ulcers

  • Other rate-controlled oral drug delivery applications

 

Selected Publications

  1. W.L. Lee, J.W.M. Tan, C.N. Tan, S.C.J. Loo, Modulating drug release from gastric-floating microcapsules through spray-coating layers, PLoS One 9 (2014) e114284.

  2. W.L. Lee, P. Wee, C. Nugraha, S.C.J. Loo, Gastric-floating microcapsules provide controlled and sustained release of multiple cardiovascular drugs, Journal of Materials Chemistry B 1 (2013) 1090-1095.

  3. S.C.J. Loo, W.L. Lee, P. Wee, Floating capsules encapsulating particles loaded with one or more drugs, Patent (WO/2014/027956) PCT/SG2013/000282, US Patent No. 9,381,163.

Micro- and Nanopatterned Shape Memory Polymer Surfaces

Micro- and nanoscale surface textures, when optimally designed, present a unique surface engineering approach to improve surface functionalities. Geometrical effects such as shapes and length scale are important parameters in surface texture designs. Coupling surface texture with shape memory polymer may be a useful approach to generate reversibly tunable surface properties. In this work, a shape memory polyetherurethane is used to prepare various surface textures through thermal nanoimprinting process. The mechanical deformation via shape programming and recovery of the shape memory surface texture are investigated as a function of length scales and shapes. Rational geometrical design of shape memory surface pattern can be applied to create a reconfigurable surface where the surface properties (e.g. wettability, mechanical properties, optical effects) can be tuned reversibly.

 

Key Features                                                 

  • Reversibly deformable surface patterns and switchable surface properties without changing materials or needing continuous external stress or energy inputs

  • Versatility in tuning deformed patterns and the corresponding surface properties through varying the applied mechanical strain levels

 

Applications

  • Fluidic devices

  • Nanoparticle assembly

  • Water collection

  • Transfer of microdroplets

  • Tissue engineering (cell adhesion, differentiation)

  • Biosensors

 

Selected Publications

  1. W.L. Lee, H.Y. Low, C. Ortiz, Geometry-dependent compressive responses in nanoimprinted submicron-structured shape memory polyurethane, Soft Matter 13 (2017) 3314-3327.

  2. W.L. Lee, H.Y. Low, Geometry- and length scale-dependent deformation and recovery on micro- and nanopatterned shape memory polymer surfaces, Scientific Reports 6 (2016) 23686.

The surface texture can be temporarily deformed and the resulting wetting properties can be fixed without the need for continuous input of external stresses; they can also be reprogrammed by manipulating the geometries and the deformation of the surface patterns.

Micro- and Nanopatterned Shape Memory Polymer Surfaces
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