Liposomes
Advanced and well-established drug delivery for small molecules in oncology drug discovery and development
Overview
Despite significant technological advancements, there are still many challenges to small molecule anticancer drug development. Novel therapeutic approaches such as Targeting Protein Degrader (TPD) continue to emerge for targets previously considered undruggable. However, the design of small molecules for these difficult targets must overcome significant difficulties in order to harmonize high target affinity, pharmacokinetics, biodistribution, and safety. Liposomes encapsulate small molecules in stable lipid nanocapsule particles. This simple but effective drug delivery system has the potential to address the challenges of emerging small molecule anticancer drugs.
Fujifilm’s CDMO services offers these technologies for partners in the field of small molecule oncology drug discovery and development.
Formulation
Liposomes are nanoscale, artificial lipid-based structures consisting of a lipid bilayer that can be used to encapsulate a wide range of small molecule APIs or as drug delivery systems (DDS) for injectable drugs.
Liposomal formulations improve the pharmacokinetics and biodistribution of payload APIs, increasing drug efficacy and safety, and enhance the combined effects of drugs with different mechanisms of action such as immune checkpoint inhibitors and PARP inhibitors.
High-stability liposome development: DHSM-based liposomes
Liposomes are formulated to be stable carriers, prolonging plasma half-life of the encapsulated API and improving biodistribution for targeted drug delivery. Extended stability (> 2 years) during refrigerated storage is also desirable for logistics and application considerations in commercial use.
Conventional formulations use hydrogenated soy phosphatidyl choline (HSPC) as the main lipid bilayer component. Our use of synthetic dihydrosphingomyelin (DHSM) results in higher stability.
DHSM-based liposomes enhance plasma retention and biodistribution of the encapsulated API
Ester bonds in HSPC used in conventional liposome formulations can be degraded by hydrolysis, whereas the presence of a non-hydrolyzable amide bond and hydroxyl group in DHSM confers a structural advantage, leading to higher stability of the liposome capsule itself during long-term storage in liquid suspension. The amide and hydroxyl groups can also form intermolecular hydrogen bonds between DHSM molecules or through cholesterol, which combined with the hydrophobic interaction of the acyl groups, enables the formation of a tight lipid bilayer that is resistant to leakage of the loaded API, enhancing plasma retention and biodistribution in vitro and in vivo.
API Encapsulation Success Rate
A free service to predict liposome encapsulation efficiency based on molecular structure is available prior to start of CDMO services. Try our liposome encapsulation prediction service.
Case Studies
Two liposome investigational drugs designed and manufactured by Fujifilm are in clinical trials:
Case Study
Liposomal topotecan: FF-10850
A case of topotecan: improved pharmacokinetics and efficacy-safety profile via liposomal formulation
Designed and manufactured by Fujifilm, FF-10850 is an injectable formulation of DHSM-based liposomal topotecan. In contrast with topotecan’s high permeability or “leakage” from conventional HSPC-based liposomes, encapsulation in DHSM-based liposomes enables refrigerated storage for more than three years. FF-10850 is now in clinical trials in the United States.
DHSM-based liposomal topotecan has demonstrated high drug efficacy and safety in vivo, and high combination effect with PD-1 Ab.
Case Study
Liposomal gemcitabine: FF-10832
A case of gemcitabine: Enhanced combination effect with immune checkpoint inhibitor (ICI) via liposomal formulation
Designed and manufactured by Fujifilm, FF-10832 is the only gemcitabine-containing liposomal formulation that has entered clinical trials in the United States, with demonstrated stability of more than 3 years under refrigerated conditions.
Liposomal encapsulation of gemcitabine greatly enhances its combined effect with CTLA-4 immune checkpoint inhibitor (ICI) by a two-fold effect: high API accumulation in tumor tissue via the enhanced permeability and retention (EPR) effect, as well as a decrease in M2 macrophages and increase in M1 macrophages and CD8-positive T cells in the tumor microenvironment.
Liposome GMP Manufacturing
Fujifilm has developed a high-speed stirring dispersion method for liposome production that results in homogeneous particles with a sharp size distribution. The process parameters of dispersion (mixer geometry, vessel form, temperature, solvent composition, mixer speed) have been well studied, enabling excellent repeatability and scale-up. Our nanoparticle formation step does not use nanopore membranes, circumventing conventional extruder challenges associated with membrane clogging.
Learn more about our one-stop formulation development and manufacturing support for small molecule liposomes.
Analytical Services
Analytical capabilities to streamline the success of liposome, LNP, and mRNA programs
Liposomes and LNPs are complex preparations, requiring dedicated quality assurance specifications and analytical method development.
Fujifilm can provide a full range of analytical services to support drug development and ensure compliance with:
- Liposome drug products, Guidance for Industry (April 2018, FDA)
- Drug Products, Including Biological Products, that Contain Nanomaterials, Guidance for Industry (April 2022, FDA)
- ICH Q6A (Global specifications for new drug substances and products)
Fujifilm has the required equipment and skilled chemists to develop a range of analytical and QC tests for GMP batch release testing of liposomes.
Equipment & Capabilities
- Particle size and distribution
- Zeta potential, pH, osmolality
- Lipid & API analysis by HPLC (UV, CAD, TripleQ MS, TOF MS)
- Residual solvent analysis by GC (FID)
- Ion analysis (IC)
- Metal analysis (ICP-MS)
- Spectroscopy (UV, IR, Fluorescence, NMR )
- Particulate matter (Accusizer®)
- Non-GMP cryo-TEM imaging
- Sterility and endotoxin testing
- Karl Fischer, polarimeter
Specifications
- Appearance
- Identification test (API)
- Identification test (lipid)
- pH
- Osmolality
- API-related impurities
- Lipid-related impurities
- Residual solvents
- Elemental impurities
- Endotoxin
- Sterility
- Particulate matter (in injections)
- Insoluble foreign matter
- In-vitro release
- Mean particle size
- Particle size distribution
- Container content
- Total API content
- Free API content
- Lipid content
- Lipid composition
Blue: liposome-specific items required by related guidelines.
Drug Products, Including Biological Products, that Contain Nanomaterials, Guidance for Industry (April 2022, FDA)
ICH Q6A, Specifications
In cases where no analytical specifications or methods are outlined in the guidelines, Fujifilm’s Analytical Services has the expertise to overcome this technical challenge.
Examples of in-house method development for liposome analysis include:
High-recovery separation method for liposome-encapsulated APIs
OBJECTIVE
Control API adsorption onto separation devices during In Vitro Release (IVR) assay preparation
- Encapsulated and unencapsulated API are separated during sample preparation for analysis
- APIs can adsorb to separation devices such as ultrafiltration filters and solid phase extraction (SPE) cartridges
- Fujifilm has developed a novel device-coating method that achieves ~100% API recovery
Development of a modified IVR assay
OBJECTIVE
Control loss of API during IVR assay preparation
Guidance requires > 85% API release
Conventional method
Loss of API via:
- Rapid degradation of released API
- Adsorption of API onto separation devices
Fujifilm-refined method
Meets guidance:
- Uses proprietary device-coating method to reduce API adsorption
- Provides direct measurement of remaining API in liposome
