Liposome in Injectable Drugs

Liposomes are bilayer structures formed by the assembly of hydrophilic and hydrophobic groups. Due to their advantages, such as adjustable particle size, good biocompatibility, low toxicity, and low immunogenicity, as well as the ability to load both hydrophilic and hydrophobic drugs, liposomes have attracted increasing attention in the pharmaceutical field in recent years as a new drug carrier. Liposome injections, as a novel nanodrug delivery system, offer good targeting capabilities, tissue affinity, improved solubility and permeability of poorly soluble drugs, and enhanced drug stability. Liposome injections can overcome the clinical application bottlenecks of traditional injections and are used in the diagnosis and treatment of major diseases, providing new directions and ideas for the development of complex injectable drugs.

What is Liposomal?

The discovery of liposomes dates back to 1964 when British scientist Alec Bangham discovered that phospholipid molecules spontaneously form closed bilayer vesicles in water. He published the electron microscope images of these multilayer vesicles in the Journal of Molecular Biology. Subsequent researchers began to use the affinity of different parts of the vesicle to encapsulate hydrophilic or lipophilic drugs within the internal aqueous phase or bilayer phase of the liposome, introducing liposomes into the fields of drug and gene therapy.

Fig. Liposome hydrophilic load.

Compared to conventional formulations, liposome formulations offer the following advantages: 1) High drug loading and excellent biocompatibility. Liposome injections can encapsulate poorly soluble drugs within lipid nanostructures, increasing drug solubility and stability. Additionally, the lipid structure is degradable in the body, enhancing safety; 2) Targeted action that reduces the drug's toxic side effects. The body's organs have different retention capabilities for particles of varying sizes. By controlling the particle size of liposome injections, a passive targeting effect can be achieved. Furthermore, the surface of liposomes can be modified with ligands for specific receptors, guiding drug-loaded liposomes to actively target specific sites, selectively concentrating the drug at target tissues, organs, cells, or cell structures. This enhances the drug concentration in the lesion area, enabling targeted treatment. It improves drug bioavailability while reducing potential harm to other organs and tissues. Liposome formulations show great promise for various indications. They can be applied in fields such as oncology, infections, neurology, anesthesia, ophthalmology, and diagnostics. Compared to conventional formulations, liposome formulations offer distinct advantages in various disease areas. For example, in oncology, drugs encapsulated in liposomes have 50%-70% lower toxicity compared to free drugs, and liposome formulations show higher anti-cancer activity than free drugs.

Liposomal Structure

Liposomes are formed by dispersing lipids, such as phospholipids, which resemble biological membrane structures, in an aqueous phase. The lipid molecules that make up liposomes can be categorized into classical lipid molecules and novel lipid molecules. Both are amphipathic molecules, typically composed of a hydrophilic head, a hydrophobic tail, and a connecting bond. The membrane wall of liposomes is about 5-7 nm thick, with the vesicle diameter typically ranging from 25-500 nm. Drugs, depending on their lipophilic or hydrophilic properties, can either insert into the lipid bilayer or be encapsulated in the aqueous phase inside the liposome, or attached to the surface of the liposome. Liposomes are closed particles with bilayer membranes that encapsulate an aqueous medium. They can be classified into large, small, multilayered, oligolayered, and unilamellar liposomes, with unilamellar liposomes being the most commonly used in medical applications. In liposomal drugs, the drug is contained within the liposome. Generally, water-soluble drugs are encapsulated in the aqueous compartment, while lipophilic drugs are enclosed within the lipid bilayer of the liposome. Due to their unique drug release mechanisms, liposomes are not only an effective solubilization method but also have potential sustained release or targeting characteristics, making them highly favored by researchers. Liposomes are suitable for various administration routes, including injection, oral administration, ocular administration, pulmonary inhalation, and transdermal delivery. Currently, most liposomal drugs are administered via injection.

Lipids for Liposomes

BOC Sciences has extensive experience in liposome preparation and is able to provide high-quality lipid materials for research institutions and industrial clients. We offer a wide range of phospholipids and cholesterol derivatives, including natural phospholipids (such as soy lecithin, egg lecithin) and high-purity synthetic phospholipids (such as DSPC, DPPC), to meet the needs of various applications. Additionally, we provide modified lipids, such as PEG-lipid for long-circulating liposome preparation, as well as functionalized lipids conjugated with targeting ligands for precise drug delivery. All products comply with strict quality control standards to ensure high purity and stability. Furthermore, BOC Sciences offers customized services and can design special formulations based on customer requirements, supporting innovative applications of liposomes in drug delivery, vaccine development, and gene therapy.

What is a Liposomal Injection?

Liposome injections are among the most successful injectable formulations that enhance drug therapeutic effects and reduce drug toxicity using nanotechnology. Since the first liposome injection containing doxorubicin was launched, new technologies and products related to liposomes have been continuously emerging. Nanoliposomes are spherical vesicles formed by natural, non-toxic lipid molecules such as phospholipids and cholesterol, arranged in an ordered manner to create a structure with an aqueous core and a lipid bilayer. In 1965, Alec Bangham first proposed liposomes as a model for studying biological membranes. Later, due to their advantages such as adjustable particle size, good biocompatibility, low toxicity and immunogenicity, and the ability to encapsulate both hydrophilic and hydrophobic drugs, liposomes evolved from being an artificial cell model to a successful drug delivery system now widely used in clinical applications. According to statistics, between 1973 and 2015, the FDA processed 359 nanomedicine product applications (including IND, NDA, and ANDA), with liposomes accounting for the largest share (33%), followed by nanocrystals (23%). Various drug delivery routes for liposome formulations have been developed (such as injection, oral, transdermal, nasal, pulmonary, ocular, etc.), with injection still being the most commonly used in commercial and clinical research settings.

Advantages of Liposome Injections

• High Load Capacity and Biocompatibility: Approximately 40% of marketed drugs globally belong to Biopharmaceutics Classification System (BCS) Class II or IV, which have solubility or permeability issues. Liposome injections improve the solubility and stability of poorly soluble drugs by encapsulating them in lipid nanostructures or by covalently conjugating them to form drug-lipid complexes. Furthermore, the lipid structure is biodegradable in the body, making it safer.
• Efficient Targeting: Liposomes can be modified in terms of size and functionality. The body's organs have different retention capacities for particles of varying sizes, and the particle size of liposome injections can be controlled to achieve passive targeting effects. Additionally, the surface of liposomes can be modified with ligands such as membrane proteins and sugars that have corresponding receptors in the body, enabling active targeting of drug-loaded lipid nanoparticles to specific sites, increasing drug concentration at the target site.
• Scalable Production: The preparation technology for liposome injections is straightforward, and scaling up production is feasible. Various methods have been developed for the mass production of liposome injections. For example, the dynamic high-pressure micro-jet method uses high-pressure jet and impact flow technology to transport lipid fluid into an oscillating reactor. After shear through microchannels, the fluid is impacted at high speed in a collision chamber, with high-frequency ultrasound waves generated by oscillating chips aiding in emulsification and homogenization of the lipid fluid. The supercritical fluid method utilizes supercritical gases to extract lipids, which then undergo supersaturation and precipitation to form lipid nanoparticles. The dual-asymmetric centrifugation method uses a dual-centrifugal axis to enhance the homogenization of lipids, creating a highly concentrated lipid dispersion. The membrane contactor method uses hollow fiber tubes with nano-porous membranes as the water-oil contact zone, where lipid-containing organic solutions penetrate through the membrane into the aqueous phase to form uniformly sized lipid nanoparticles.

Liposomal Injections Approved by FDA

Currently, most FDA-approved liposome injections are traditional liposomes, with long-circulating and cationic liposomes accounting for only a small fraction. Liposome injections are primarily used in fields such as oncology, antifungal treatment, and pain relief. Each product has improved the therapeutic effect of the drug through unique methods based on the specific properties of the drug.

Liposomes for Injection

Liposome injection preparation technology involves the clever combination of drugs and lipids, optimizing the preparation process to achieve efficient drug encapsulation, stable storage, and precise release. Currently, liposome injection preparation technologies mainly include the thin-film dispersion method, ultrasound method, extrusion method, and microfluidic technology. These methods each have advantages in terms of particle size control, uniformity, and stability. With continuous development in lipid modification and process innovation, many novel liposome technologies can alter the pharmacokinetics and in vivo biodistribution characteristics of drugs by adjusting the lipid composition, structure, charge, and other properties of traditional liposomes, opening new directions for modern drug delivery technology.

Long-Circulating Liposomes

Long-circulating liposomes are one of the most extensively studied liposomes. Polyethylene glycol derivatives of distearoylphosphatidylethanolamine (PEG-DSPE) are incorporated into the surface of liposomes, creating spatial steric hindrance. The high hydrophilicity and flexibility of this derivative interfere with the hydrophobic interaction between the liposome and plasma proteins, reducing the absorption of liposomes by the reticuloendothelial system, thereby achieving long circulation in the body. The world's first anti-tumor liposome product, Doxil (Doxorubicin Liposome Injection), has a half-life of 0.2 h for free doxorubicin, with an AUC of 3.81 µg·h/mL, while the half-life of Doxil is 41-70 h with an AUC of 902 µg·h/mL. Clinical studies have shown that it reduces drug release in the myocardium, thereby lowering the cardiotoxicity of doxorubicin.

Cationic Liposomes

Cationic liposomes are generally composed of cationic hydrophilic lipids and neutral lipids. Their structure and properties are key factors influencing cell toxicity and transfection efficiency. Cationic lipids carry nucleic acids via electrostatic interactions, while neutral lipids serve as stabilizing agents through functionalization. Due to the positive charge of cationic liposomes interacting with the negative charges in the body, they effectively address the problem of gene drugs not being able to interact with diseased sites due to anionic aggregation, greatly enhancing their bioaffinity. They are primarily used as gene drug carriers. Alnylam Pharmaceuticals used the cationic lipid MC3 to prepare the world's first siRNA drug, Onpattro (Patisiran Cationic Liposome Injection), which was approved for market in 2018. Recent studies on cationic liposomes focus mainly on targeted ligand modifications and the co-delivery of nucleic acids with chemical drugs. By modifying cationic liposomes with stearylamine, the development of phosphatedzamine cationic liposomes greatly improves their targeting and affinity.

Microenvironment-Sensitive Liposomes

With the rise of novel nanocarrier materials, liposome formulations that respond to microenvironment changes such as pH, enzymes, and physical conditions like light and heat are widely studied and reported. Celsion's ThermoDox (Doxorubicin Thermosensitive Liposome) is the first heat-sensitive liposome formulation available for clinical use. When heated to its phase transition temperature, pore channels form on the lipid bilayer, enabling more efficient drug release (e.g., 80% drug release within 20 seconds at 42 °C). pH-sensitive liposomes, based on the difference in pH between tumor and normal tissues, can be used for the targeted delivery of anti-tumor drugs. By inserting synthetic pH-sensitive materials into PEG-modified egg phosphatidylcholine liposomes, the modified liposomes show a 2.5-fold increase in uptake efficiency at tumor sites. Currently, many environment-sensitive liposomes are still in the preclinical research stage and demonstrate excellent targeted drug delivery capabilities, with promising application prospects.

Ligand-Targeted Liposomes

By incorporating functional ligands such as antibodies, peptides, proteins, and carbohydrates onto the surface of liposomes, these liposomes can be selectively absorbed by cells that overexpress the corresponding receptors. This improves the accumulation of drugs at the disease site and reduces off-target toxicity, thereby enhancing therapeutic effects. For example, many tumor cells overexpress folate receptors (FR) and transferrin receptors (TfR). Corresponding ligands can specifically bind to these receptors to achieve active targeting. Gazzano et al. prepared folate-modified nitrated doxorubicin liposomes (LNDF), which more effectively target Dox-resistant, FR-positive/P-gp-positive breast cancer cells. Moreover, the mitochondrial localization function of nitrated doxorubicin causes its accumulation in mitochondria, damaging mitochondrial energy metabolism and triggering mitochondrial-dependent apoptosis.

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