I.What Problems Does "Formulation and Delivery" Solve in Research Settings?
The "pharmaceutical formulation and delivery" discussed in this paper is exclusively oriented to scientific research and experimental methodology (e.g., in vitro models, cell/tissue models, material-biological interface research, development of analytical and process methods, etc.), and is not intended for human use or any clinical applications.
In scientific research, "formulation and delivery" is a process objective:
How to ensure that an active molecule stably exists in the target experimental medium, remains measurable/characterizable, and achieves controllable presentation (release/localization/uptake, etc.) in the model system, with reproducible results.
Such problems are far from niche. Modern pharmaceutical and bioactive molecules are becoming increasingly diverse (small molecules, peptides/proteins, nucleic acids, complexes, etc.), with significant differences in their solubility, stability and interfacial behavior; therefore, "delivery technology" is widely used to control dissolution, dose presentation and delivery parameters, and has gradually become an integral part of the R&D system.
Many experimental failures are not caused by "inactive molecules", but by system-level issues. Typical problems include:
1. The formulation can be prepared, but becomes turbid/precipitated/adhered to the vessel wall after a short period of time: supersaturation collapse, aggregation, container adsorption, and destabilization caused by ionic strength or proteins.
2. Large batch-to-batch variations: inconsistent microstructures resulting from different mixing sequences, shear history, and temperature/time windows.
3. Concentrations can be detected, but the effects cannot be explained: unclear free/bound ratio; drifts in "effective exposure" due to structural changes of carriers.
4. The system can enter cells/models, but the readout is unstable: label interference, high background, entrapment after endocytosis, and misalignment between the release and readout time windows.
Therefore, the real problem to be solved is not a "specific carrier platform", but to achieve the controllability of the system in the three dimensions of "medium-interface-time".
II.Basic Definitions
1) Formulation
Formulation is defined as the combination of an active molecule with solvents/excipients/materials to form a system with a defined composition, microstructure and process history, such that it meets preset quality objectives (e.g., dissolution/dispersion state, stability, particle size distribution, measurability, reproducibility). This goal-oriented approach—identifying critical quality attributes and engineering quality into the product through processes and materials—is consistent with the framework for Pharmaceutical Development outlined in ICH Q8(R2).
2) Delivery
In a research context, delivery refers to the control of how a sample is "perceived" by the model system, including:
a) The extent of perception (available fraction/effective concentration)
b) The location of perception (medium phase, interface, intracellular/extracellular space, specific structural domains)
c) The timing of perception (temporal windows such as rapid/delayed/sustained/pulsatile presentation)
In other words, delivery is the control of presentation mode, while formulation is the means to achieve such control.
3) Carrier / Delivery System
A carrier/delivery system is a toolkit that utilizes materials and structures to achieve loading-protection-presentation (including lipid-based systems, polymer-based systems, gels/microparticles/nanostructures, conjugation and functionalized systems, etc.). Modern delivery research is typically organized and compared by material category + target level (tissue/cell/organelle) + mechanism of action.
III.From Research Objectives to Controllable Variables
In scientific research, pharmaceutical formulation and delivery is not a matter of "selecting a single carrier", but of rendering the system controllable, measurable and reproducible across the three dimensions of medium, interface and time. This can be achieved through a structured and effective framework, following these steps:
1. First, clearly define the target profile (what the model is intended to "perceive", where and when);
2. Second, list the Critical Quality Attributes (CQAs) (the measurable indicators that must be controlled within acceptable ranges);
3. Finally, identify a small set of key adjustable parameters (Critical Material Attributes (CMAs) + Critical Process Parameters (CPPs)), and prioritize stabilizing the most critical indicators or common problem points first.
Note: The framework for organizing research methodology here draws on the core logic of ICH Q8/Q9 (objective → attribute → risk-oriented control), and is not applicable to any clinical applications.
Table 1 Research Task Mapping: Each research validation objective corresponds to a set of prioritized CQAs
Research Task/Readout Objective (Experimental Scenario) | Most Common Failure Modes | Prioritized CQAs | Prioritized Adjustable Parameters | Key Validation Combinations |
Maintaining stable and measurable samples in the medium (cell culture medium/buffer/salt-containing/protein-containing medium) | Turbidity, precipitation, wall adhesion; system collapse upon medium change | Appearance/turbidity; particle size/distribution; effective concentration (supernatant/filtered); short-term stability (0–24 h) | pH/ionic strength; cosolvent ratio/addition sequence; type and dosage of surfactants/polymer stabilizers | ① Particle size at time points; ② Supernatant concentration; ③ Vessel adsorption control (different materials/BSA blocking, etc.) |
Enabling interpretable free/bound states (explaining biological effects rather than only reporting total concentration) | Detectable concentration but erratic effects; inconsistent "effective exposure" between batches | Free/bound ratio; carrier integrity (no disintegration) | Carrier crosslinking/assembly strength; surface charge/hydrophilic layer (e.g., PEGylation); protein corona sensitivity (need for precoating conditions) | ① Free state separation methodology control (validate one method from ultrafiltration/dialysis/SEC first); ② Structural integrity over time |
Directing spatial perception in the model system (interface/intracellular/extracellular/specific compartments) | Label interference, high background; apparent internalization yet actual mucosal/wall/surface adsorption | Localization readout (colocalization/fractional extraction); non-specific adsorption background; cytotoxicity/stress baseline (avoid readout artifacts) | Surface chemistry (charge, hydrophobicity, ligand density); particle size window; washing/incubation conditions | ① Label-free/empty carrier control; ② 4°C endocytosis inhibition control (distinguish adsorption vs. uptake); ③ Imaging/flow cytometry gating and background correction |
Achieving temporal window control (rapid/delayed/sustained/pulsatile presentation) | Mismatch between readout time points and release; early release causing high background, late release leading to undetectable signals | Release profile (relative trend sufficient); structural stability vs. trigger responsiveness | Crosslink density/hydrophobic domain strength; pH/enzyme/reduction trigger sites; loading method (encapsulation/adsorption/covalent conjugation) | ① Release trend at a minimum of 3 time points; ② Structural changes under the same conditions (select one from particle size/scattering/electron microscopy) |
Ensuring system reproducibility (the core of methodology development) | Large batch-to-batch variations, shear history sensitivity, inconsistent results with altered mixing sequence | Inter-batch consistency (particle size/distribution, effective concentration); process window (temperature/shear/time) | Mixing sequence; shear intensity and duration; temperature and maturation time | ① Process recording template (sequence/time/temperature/rotational speed); ② Retesting at key time points (0 h/2 h/24 h post-preparation) |
Abbreviation Notes: Definitions of CQA / CMA / CPP
1. CQA (Critical Quality Attribute): The measurable indicators that must be controlled to ensure the reliability of experimental conclusions (e.g., effective concentration, particle size distribution, short-term stability, free state ratio).
2. CMA (Critical Material Attribute): The key material-specific characteristics that drive system performance differences (e.g., polymer molecular weight/charge density, lipid phase transition temperature, thickness of surface hydrophilic layer).
3. CPP (Critical Process Parameter): The preparation parameters that exert the most significant impact on the system’s microstructure (e.g., mixing sequence, shear force, temperature, maturation time).
IV.Experimental Cases: Core Logic and Solutions for Formulation and Delivery
Molecular Type & Delivery Scenario | Core Logic + Key Solutions |
mRNA Formulation and Delivery | Core logic: Achieve stable protection, targeted delivery and efficient intracellular release of mRNA. Key solutions: LNP carriers (ionizable lipids + helper lipids + cholesterol + PEGylated lipids) + mRNA chemical modification (pseudouridine) + microfluidic preparation process; ligand-targeted modification to address liver tropism issues. |
Protein Formulation and Delivery | Core logic: Realize precise delivery of drugs to target cells via targeting, and exert efficacy through receptor-mediated endocytosis and lysosomal release. Key solutions: PEGylation for enhanced stability + cell-penetrating peptides (CPPs) to overcome transmembrane barriers + responsive nanocarriers to reduce immunogenicity; site-specific conjugation technology adopted for ADCs. |
Small Molecule Formulation and Delivery | Core logic: Improve the solubility of poorly soluble small molecules and enhance bioavailability. Key solutions: Salt form screening/crystal engineering to optimize physicochemical properties; nanocrystals (prepared by high-pressure homogenization)/polymer micelles to increase specific surface area; supercritical fluid preparation to improve formulation homogeneity. |
V.Cutting-Edge Technologies and Trends
Technical Direction & Research Dimension | Core Logic + Key Solutions |
Development of Novel Carrier Materials | Core logic: Improve delivery efficiency and safety through biomimetic material design, responsive regulation and biocompatibility optimization. Key solutions: ① Biomimetic nanoparticles (cell membrane coating / virus-like particles (VLPs) / bacteria-mimetic carriers); ② Stimuli-responsive materials (pH-responsive / thermo-responsive PNIPAM / enzyme-responsive hyaluronic acid); ③ Biodegradable materials (PLGA (FDA-approved) / polycarbonates / natural polysaccharides). |
Innovation in Formulation Preparation Technologies | Core logic: Achieve formulation precision and industrialization through microscale control, personalized customization and technology integration. Key solutions: ① Microfluidic technology (high-precision particle size control with PDI ≤ 0.05 / high-throughput 1000-channel chips); ② 3D printing technology (personalized drugs / complex pulsatile drug release systems / porous formulations for poorly soluble drugs); ③ Technology integration (4D printing of intelligent responsive formulations / AI-assisted formulation optimization with a prediction accuracy of > 90%). |
Upgrading of Targeted and Intelligent Delivery | Core logic: Break through the targeting limitations and passive release of traditional delivery to realize "on-demand precise delivery". Key solutions: ① Active targeting (ligand modification: transferrin / folic acid / antigen recognition); ② Passive targeting (utilizing the EPR effect of tumors); ③ Intelligent responsive release (microenvironmental pH/temperature/enzyme triggering + timed/quantitative pulsatile release). |
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