High-payload long-acting injectables for biologics
Author: Dr. T. Kamperman, July 2026.  Last updated: 20 July 2026
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Long-acting injectable formulations, or LAIs, can reduce dosing frequency, but high biologic payloads create difficult trade-offs between injection volume, particle structure, molecular stability and release control. Engineered microparticle architectures, including core-shell particles and particles with tunable internal morphology, offer potential routes to reducing early burst release while retaining a high payload. IN-AIR MICROFLUIDICS™ provides a channel-free manufacturing approach for creating such structured microparticles at elevated production rates.
This article focuses on the formulation and manufacturing challenges of high-payload biologics encapsulation. For a broader overview of IamFluidics’ work in injectable microparticles and controlled delivery, visit our Controlled Injectables page.
Key takeaways
- High drug loading can create interconnected drug-rich domains that accelerate water ingress and early release.
- A continuous drug-poor shell can reduce surface-associated API and add a controllable diffusion barrier.
- Rapid solidification and phase separation can be used to tune surface density, porosity and internal payload distribution.
- Uniform particle size reduces particle-to-particle variation, but release performance remains formulation-specific.
- Particle morphology alone does not prove sustained release; loading, stability and release must be measured for each API-polymer system.
Why longer-acting biologic formulations matter
Peptides, proteins and antibodies are central to modern pharmaceutical development. The adoption of GLP-1 and dual GIP/GLP-1 receptor agonists for type 2 diabetes and obesity has intensified interest in convenient, long-acting delivery formats. Several commercial peptide therapeutics use structural modification and lipidation to resist enzymatic degradation and support once-weekly administration.[2,3]
Even weekly injections can create treatment, handling and supply-chain burdens. Monthly or longer-acting depots could reduce injection frequency while maintaining therapeutic exposure. Biodegradable polymer microparticles, microcapsules and injectable hydrogels are among the technologies being investigated for this purpose.[4,5]
The central formulation challenge
High payload without uncontrolled early release
High payload requirements
For high-dose biologics, commercially practical injection volumes may require unusually high drug loading. In some development programs, drug content may need to approach or exceed 50% by mass. The necessary loading depends on potency, target exposure, particle density, syringeability, injection volume and intended release duration.
Initial burst release
Initial burst release occurs when drug located at or near the particle surface dissolves rapidly after injection. Water may also penetrate pores and interconnected drug-rich regions within the polymer matrix. This can release a substantial portion of the payload before the intended sustained-release phase begins.
Formation of percolation channels
At high loading, drug-rich regions can become interconnected, forming percolating channels. Water can penetrate these channels, dissolve hydrophilic biologics and accelerate transport through the particle. Drug located at or near the particle surface may also dissolve rapidly. Together, these effects can produce an initial burst that increases early exposure, wastes payload and shortens the remaining release period.[5,6]
Figure 1. Why high payload can increase burst release. At high drug loading, interconnected drug-rich domains may form percolation pathways that promote rapid water ingress and early release. A drug-poor polymer shell can introduce an additional diffusion barrier and reduce surface-associated drug.
Formulation strategies for high-payload biologics
Several complementary formulation strategies can be used to reduce early release while maintaining a high biologic payload. The appropriate route depends on the physicochemical properties of the API, the polymer system and the required release duration.
Hydrophobic ion pairing
Hydrophobic ion pairing temporarily complexes an ionizable biologic with an oppositely charged counter-ion. Lower aqueous solubility may reduce premature diffusion from the polymer matrix. Performance depends on counter-ion selection, complex stability, processing conditions and recovery of active biologic after release.
Core–shell microparticles
A core-shell structure physically separates a drug-rich core from the external environment using a drug-free or drug-poor polymer shell. When the shell is continuous and sufficiently dense, it can reduce surface-associated API and provide an additional barrier to water ingress and drug diffusion. Shell thickness, defects, porosity and degradation behaviour determine the resulting release profile.[5]
Rapid solidification and kinetic trapping
Rapid precipitation or solidification can immobilize the biologic before it migrates to the droplet surface or separates into large drug-rich domains. Solvent exchange, drying conditions and solid-state transitions must be controlled to protect molecular integrity and activity.
How IN-AIR MICROFLUIDICS enables particle engineering
IN-AIR MICROFLUIDICS is a channel-free particle-manufacturing platform in which microscale liquid jets interact and form droplets in air. Published work demonstrated monodisperse emulsions, particles and fibres with diameters of approximately 20–300 µm at rates 10–1000 times higher than the chip-based droplet microfluidic configurations used for comparison.[1]
For sustained-release biologics, the platform is relevant because droplet formation, material distribution and solidification can be controlled without enclosed microchannels. This creates routes to structured particles while reducing the channel-clogging constraints associated with conventional microfluidic chips.
Coaxial processing for core-shell particles
By running concentric fluid streams through an IN-AIR coaxial nozzle, we can encapsulate a dense, biologic-rich inner core directly inside a drug-free outer polymer shell. The polymer shell serves as a physical gatekeeper, reducing the presence of surface-bound drug molecules that typically cause the initial burst release.[7,8,9]
In-flight precipitation and morphology control
Droplets may undergo solvent evaporation, nonsolvent-induced phase separation or another solidification process during or immediately after formation. The competition between external mass transfer and internal molecular diffusion influences whether material accumulates near the surface or remains more uniformly distributed. Under suitable conditions, rapid surface solidification can create a denser outer region surrounding a porous or payload-rich interior.
Mild processing and material-efficient development
IN-AIR MICROFLUIDCIS offers relatively mild, low-shear processing conditions and short residence times, which may help preserve sensitive and high-value materials during particle formation. Its scale-up strategy is based on numbering up individual nozzles in parallel while maintaining comparable operating conditions at each nozzle. This approach may reduce material consumption during feasibility studies and support more predictable process translation toward larger production volumes.
Particle morphologies produced using IN-AIR MICROFLUIDCS
With IN-AIR MICROFLUIDICS process conditions and material combinations can be adjusted to produce a range of particle morphologies for controlled injectable applications. Representative examples include dense particles, porous structures, core–shell microcapsules and monodisperse spherical particles.
Figure 2. Representative particle morphologies produced using IN-AIR MICROFLUIDICS. The images show examples of dense, porous, shell-containing and monodisperse microparticle structures manufactured using IN-AIR MICROFLUIDICS.
How particle morphology may influence release
Particle architecture can influence water transport, API distribution and diffusion distance. These relationships provide useful formulation hypotheses, but each must be confirmed using analytical and release testing.
Figure 3. Formulation-to-function relationships. Dense outer layers may reduce early water ingress, while drug-poor shells may reduce surface-associated API. Porous cores can increase internal volume, shell thickness may alter diffusion distance, and monodisperse particles may reduce particle-to-particle variation.
Potential manufacturing advantages of IN-AIR MICROFLUIDCS
IN-AIR MICROFLUIDICS provides mild, low-shear processing with short residence times, helping protect sensitive and high-value materials during particle formation. Because droplets are generated rapidly and in open air, the process can also reduce material losses during formulation development. Scale-up is achieved by operating multiple nozzles in parallel rather than substantially changing the conditions within each nozzle. This numbering-up approach can reduce material requirements during feasibility studies and make scale-up more predictable and lower risk.
IamFluidics can produce uniform microparticles (with a coefficient of Variation under 5%), ensuring more predictable and reproducible release profiles while offering industrial scale production rates up to 1000x faster than microfluidic devices.
Outlook
High-payload sustained-release biologics require simultaneous control over drug loading, particle architecture, molecular stability and release kinetics. Core-shell structures and rapid in-flight solidification provide promising routes to addressing these competing requirements. IN-AIR MICROFLUIDICS offers a scalable particle-engineering platform through which these strategies can be developed and tested.
Frequently asked questions
What causes initial burst release from polymer microparticles?
Initial burst is commonly associated with API located at or near the particle surface, rapid water ingress, particle porosity and interconnected drug-rich domains. Polymer properties and manufacturing conditions also affect the magnitude of the burst.
Why can high drug loading accelerate release?
At sufficiently high loading, drug-rich regions may connect across the particle and form transport pathways (percolation channels). Water can enter these channels and dissolve hydrophilic API more rapidly. The relevant threshold is formulation-specific.
How can a core-shell particle reduce burst release?
A continuous drug-poor shell can reduce surface-associated API and introduce an additional diffusion barrier. The characteristics of this diffusion barrier depend on shell continuity, thickness and porosity.
Can IN-AIR MICROFLUIDICS manufacture core-shell microparticles?
Structured jet configurations can generate droplets with compositionally distinct core and shell regions. Published research has demonstrated core-shell microcapsule fabrication using in-air jetting approaches.[10]
Does monodispersity guarantee uniform release?
A narrow size distribution removes one source of variability, but internal morphology, loading, polymer properties and defects can still differ between particles.
Developing a high-payload biologic load?
Discuss particle architecture, formulation feasibility and scale-up requirements with the IamFluidics team.
Explore our broader capabilities in controlled injectables and microparticle-based drug delivery
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[1] C. W. Visser, T. Kamperman, L. P. Karbaat, D. Lohse and M. Karperien. “In-air microfluidics enables rapid fabrication of emulsions, suspensions, and 3D modular (bio)materials.” Science Advances 4(1), eaao1175 (2018). DOI: 10.1126/sciadv.aao1175.
[2] Ozempic (semaglutide) injection. United States Prescribing Information. Novo Nordisk. Current label should be checked at publication for dosing and pharmacokinetic wording.
[3] Mounjaro (tirzepatide) injection. United States Prescribing Information. Eli Lilly and Company. Current label should be checked at publication for dosing and pharmacokinetic wording.
[4] Z. Gao, Y. Wei and G. Ma. “A review of recent research and development on GLP-1 receptor agonist-loaded microspheres.” Journal of Materials Chemistry B 11(47), 11184–11197 (2023). DOI:10.1039/D3TB02207B.
[5] J. Yoo, Y.Y. Won. “Phenomenology of the Initial Burst Release of Drugs from PLGA Microparticles.” ACS Biomaterials Science & Engineering, 6053-6062,(2020). DOI:10.1021/acsbiomaterials.0c01228
[6] J. Wang et al. “Semaglutide sustained-release microspheres with single-phase release profile prepared by a novel emulsion-solvent evaporation method.” International Journal of Pharmaceutics 651, 123789 (2024). DOI:10.1016/j.ijpharm.2024.123789.
[7] V. dos Santos et al., "Sustained release of GLP-1 and liraglutide from polymeric microparticles: In vitro and in vivo evaluation," bioRxiv, 2018. DOI:10.1101/262782
[8] J. Wang et al., "Semaglutide sustained-release microspheres with single-phase release profile prepared by a novel emulsion-solvent evaporation method," International Journal of Pharmaceutics, vol. 651, p. 123789, 2024. DOI: 10.1016/j.ijpharm.2024.123789
[9] H. Yoo et al., "Phenomenology of the Initial Burst Release of Drugs from PLGA Microparticles," Journal of Controlled Release, vol. 327, pp. 693-706, 2020. DOI:10.1016/j.jconrel.2020.09.014
[10] J. Jiang et al. “Scalable air-assisted microfluidic system for core-shell microcapsule fabrication via in-air jetting.” Journal of Food Engineering 342, 111354 (2023). DOI:10.1016/j.jfoodeng.2022.111354.