The Case for Sustained Release at the Nanoscale
Many therapeutic molecules have pharmacokinetic profiles that are poorly suited to their intended use. A drug that clears from circulation within a few hours may need to be dosed multiple times daily to maintain therapeutic concentrations, creating peaks and troughs in exposure that lead to toxicity at Cmax and loss of efficacy at Ctrough. For chronic conditions requiring long-term treatment, the dosing burden affects patient adherence and quality of life.
Polymeric nanoparticles address this by encapsulating the drug within a biodegradable polymer matrix that releases its payload gradually as the polymer degrades or the drug diffuses through the matrix wall. Release profiles ranging from days to weeks can be engineered by selecting the polymer composition, molecular weight, and drug loading, providing a level of pharmacokinetic control that is difficult to achieve with conventional extended-release oral formulations for many drug classes.
PLGA: The Workhorse Polymer for Sustained Release Nanoparticles
Poly(lactic-co-glycolic acid) (PLGA) is the most widely used biodegradable polymer in pharmaceutical nanoparticle formulations. It is approved for use in parenteral drug products, has a well-characterised safety profile, and degrades in vivo by hydrolysis to lactic acid and glycolic acid, both naturally occurring metabolic products. The FDA’s guidance on biodegradable drug products provides the framework for the characterisation and safety data required for PLGA-based products.
The degradation rate of PLGA depends on the ratio of lactic to glycolic acid monomer units, the molecular weight of the polymer, and the end-group chemistry. High glycolic acid content and low molecular weight produce faster degradation; high lactic acid content and high molecular weight produce slower degradation. This tunability allows the release profile to be tailored across a wide range by selecting the appropriate PLGA grade.
Release Mechanisms in Polymeric Nanoparticles
| Release Mechanism | How It Works | Polymer System | Typical Release Profile |
| Surface erosion | Polymer degrades from outside in; drug released as surface layers are removed | Polyanhydrides; surface-eroding PLGA formulations | Near zero-order release; sustained over weeks |
| Bulk erosion | Polymer absorbs water and degrades throughout the matrix simultaneously | PLGA (predominant mechanism); PLA | Biphasic: initial burst followed by sustained release as matrix erodes |
| Diffusion | Drug diffuses through the intact polymer matrix to the surface | Dense polymer cores; crosslinked hydrogels | Rate depends on drug size, matrix porosity, and diffusion path length |
| Swelling and diffusion | Polymer swells on water uptake; drug diffuses through swollen matrix | HPMC; polyacrylates; hydrophilic matrices | Relatively constant release rate; suitable for hydrophilic drugs |
Formulation Variables That Control Release Rate
Polymer Molecular Weight and Composition
As discussed above, PLGA molecular weight and L:G ratio are the primary handles for controlling the bulk degradation rate and thus the drug release profile. A PLGA 50:50 (equal lactic and glycolic acid) degrades significantly faster than a PLGA 75:25 or PLGA 85:15. Within a given composition, higher molecular weight polymers degrade more slowly. Matching polymer selection to the target release duration is the starting point for any polymeric nanoparticle formulation design.
Drug Loading and Drug-Polymer Interactions
Higher drug loading can increase the initial burst release if the drug is present at the particle surface, and can affect matrix integrity and degradation rate if the drug-polymer interaction alters the physical properties of the matrix. Drug loading is typically optimised alongside release profile in early development to identify the combination that achieves the target exposure profile without compromising physical stability or manufacturability.
Particle Size
Smaller particles have a larger surface area to volume ratio, which generally increases the rate of surface-mediated drug release and can enhance the initial burst. For sustained release applications where a prolonged low-level release is desired, larger particles or core-shell architectures may better suppress the burst release component.
Analytical Characterisation of Polymeric Sustained Release Nanoparticles
In addition to the standard nanoparticle CQAs of particle size, PDI, and zeta potential, sustained release polymeric nanoparticle products require drug content assay, in vitro release testing, and polymer characterisation including molecular weight distribution by gel permeation chromatography (GPC). In vitro release testing for parenteral sustained release nanoparticles is technically challenging because standard dissolution apparatus is not designed for nanoparticle systems; sample and separate methods, membrane diffusion cells, and dialysis-based approaches are all used, and the choice of method affects the release profile observed.
Ardena’s Polymeric Nanoparticle Capabilities at Oss
Ardena’s nanomedicine team at Oss has formulation expertise in polymeric nanoparticle systems including PLGA, PLA, and other biodegradable polymer platforms. Development programmes include polymer selection, drug loading optimisation, in vitro release method development, and physicochemical characterisation using DLS, NTA, and GPC.
