Lipid nanoparticles offer a safe and efficient method for delivering poorly soluble drugs and RNA. There has been an increased interest in LNP delivery in recent years, which was further accelerated by the COVID-19 pandemic and the resulting mRNA vaccines, but scaling such drugs to market presents a number of challenges. Still, using lipid nanoparticles for drug delivery is a promising area of research, and the clinical pipeline is filled with lipid nanoparticle products that provide innovative solutions unmatched by traditional drug delivery systems.
What Are Lipid Nanoparticles?
Lipid nanoparticles (LNPs) are a novel nanoparticle drug delivery system that can be used to deliver a wide range of therapeutic agents, including nucleic acids such as DNA, siRNA, and mRNA. First approved in 2018 for the siRNA drug Onpattro, lipid nanoparticles are usually (but not always) spherical and have an average diameter between 10 and 1,000 nanometers.
LNPs are made of ionizable lipids; these lipids are positively charged at a low pH, but neutral at physiological pH. Their unique properties and nano size mean that lipid nanoparticles are taken into cells by the invagination of its membranes, forming a vacuole (endocytosis). Once absorbed by cells, the LNPs release their payload into the cytoplasm.
How Are Lipid Nanoparticles Used?
Lipid nanoparticles are commonly used for the intracellular delivery of nucleic acids, but they can also be used to deliver more traditional therapeutics, including small molecules, peptides, and proteins. Lipid nanoparticles can also be used for intravascular delivery of nucleic acids. This is a promising method for brain drug delivery and cancer therapies, as it allows for precise targeting of tumor cells.
In addition, lipid nanoparticles can be used as a delivery method for inoculations, as with the recent COVID-19 vaccines. This is because lipid nanoparticles are optimal for delivering mRNA to cells (and protecting mRNA before delivery), resulting in high levels of vaccine efficacy.
Benefits of LNP Delivery
Delivering drugs via lipid nanoparticles has a number of advantages over traditional methods. These include:
More Efficient Delivery for a Variety of Drugs
Lipid nanoparticles can be used to deliver a wide range of therapeutic agents, including hydrophilic and hydrophobic molecules. With so many poorly soluble drugs in the clinical pipeline, LNPs have proven to be an excellent solution.
Advanced Targeting
Lipid nanoparticles can be targeted to specific cells or tissues, making them ideal for cancer therapies and other diseases that require targeted drug delivery. Among the benefits of targeted delivery is fewer unwanted side effects.
Biocompatibility and Biodegradability
The lipids used in LNPs are biocompatible and biodegradable; this is another factor that helps avoid the risk of side effects and adverse events.
Non-Immunogenicity
Lipid nanoparticles are non-immunogenic, meaning they will not elicit an immune response when administered to humans. This makes lipid nanoparticles an attractive option for delivering vaccines and other immunotherapies.
Low Toxicity
Lipid nanoparticles for drug delivery have low toxicity, so they are safe for use in humans. This is in contrast to other nanoparticles, such as metals, which may have toxicity when used topically (as in sunscreens) or inhaled.
Versatility
By using a variety of lipids, surfactants, and excipients, lipid nanoparticles can be easily formulated to meet the specific needs of a given application.
Types of Lipid Nanoparticles
When we talk about lipid nanoparticles, we're really talking about two different types of products: solid lipid nanoparticles and nano-structured lipid carriers.
Solid Lipid Nanoparticles
Solid lipid nanoparticles, or SLNs, have a good release profile, physical stability, and they allow for targeted drug delivery. SLNs overcome many of the challenges of other colloidal carriers like emulsions, liposomes, and polymeric nanoparticles.
As their name suggests, solid lipid nanoparticles are formulated to be solid at body temperature. These lipids have a perfect crystalline structure and are stabilized by emulsifiers.
There are some downsides to SLNs, though. Their structure means they have low drug loading efficiency, and drug expulsion may occur during storage. Their initial burst release is another obstacle.
Nano-Structured Lipid Carriers
Nano-structured lipid carriers (NLCs) are similar to solid lipid nanoparticles, but they contain both a solid and liquid lipid. They are considered the next generation of lipid nanoparticles because they have improved stability and capacity loading. Unlike SLNs with their perfect crystalline structure, NLCs have an unstructured matrix.
This unstructured matrix helps prevent drug expulsion during storage, and it also gives NLCs a higher drug loading capacity. Another difference between NLCs and SLNs is that they have better controlled release and they increase drug solubility.
Safety of Lipid Nanoparticles for Drug Delivery
Lipid nanoparticles are safe for use in humans. They are biocompatible and biodegradable, with low toxicity and non-immunogenic properties.
The safety of lipid nanoparticles has been extensively studied, and COVID-19 vaccinations themselves are certainly the most wide scale “trial” of LNPs for drug delivery to-date. We know that lipid nanoparticles delivering nucleic acids, RNA, and poorly soluble drugs have fewer side effects than other methods because they offer precision targeting, and the incidence of severe adverse effects is reduced as well.
Lipid Nanoparticle Formulation
Lipid nanoparticle formulation is a new and developing field, which means the methods we use for formulation today may be replaced a decade from now. The most commonly used LNP formulation methods include:
High-Pressure Homogenization
High-pressure homogenization (HPH) can be hot or cold. With hot HPH, the lipid is melted, then the drug is dissolved or melted into it. A hot aqueous surfactant solution is added and dispersed with a high shear mixing device. The pre-emulsion is homogenized to reach the desired particle size, then the nano emulsion is cooled. During the cooling process, liquid droplets crystallize and form solid matrix LNPs.
Cold HPH is a similar process, but after the lipid and drug are combined, the mixture is cooled with dry ice or liquid nitrogen. This is milled into microparticles, which are then homogenized into lipid nanoparticles.
Emulsion-Sonification
Lipid nanoparticles can also be prepared by emulsion-sonification, which is similar to HPH. Once the mixture is dispersed, though, a probe solicitor ultrasonicates the emulsion to form nanoparticles. When the emulsion is cooled, lipid nanoparticles form.
Microemulsion
In this method, solid lipids are melted, then the drug is dispersed into them. An aqueous surfactant-cosurfactant solution is added; when agitated, the mixture forms a microemulsion.
The microemulsion is dispersed into cold water with mild agitation, which forms ultra-fine nanoemulsion droplets that crystallize into solid lipid nanoparticles.
Solvent Emulsification-Evaporation
Solvent emulsification-evaporation involves dissolving lipids into an organic solvent, then emulsifying them into an aqueous phase with surfactants. Once the solvent evaporates, the lipids precipitate.
Solvent Diffusion
Partially water-miscible organic solvents are used in solvent diffusion. These solvents are saturated with water, creating thermodynamic equilibrium. The oil-in-water emulsion passes into water, which solidifies the dispersed phase and forms lipid nanoparticles from the diffused organic solvent.
Solvent Injection
Similar to solvent diffusion, solvent injection involves administering dissolved lipids into an aqueous solution of surfactants using a needle.
Double Emulsion
Double emulsion is a method reserved for lipid nanoparticles that are delivering hydrophilic drugs. A drug is encapsulated in an inner aqueous phase, then a stabilizer is added to prevent the drug from moving to the outer aqueous phase once the solvent evaporates. These liposphere formulations have a larger particle size than other solid lipid nanoparticles.
Manufacturing Lipid Nanoparticles
Because lipid nanoparticles are a relatively new technology, not all CMOs and CDMOs have the knowledge, equipment, and staff to develop and manufacture these drugs. Choosing a partner that can scale from development to manufacturing is key. Ascendia Pharmaceuticals has proven experience in LNPs, including for COVID-19 treatment.
There are four steps involved in LNP manufacturing, no matter the method or equipment used for production. First, a crude liposome suspension must be formed. Then, the particle size is reduced via solvent dilution and rapid mixing or extrusion. Next, solvents and impurities are removed through purification. The final step is sterile filtration and aseptic filling.
Leading the Way in Lipid Nanoparticle Drug Delivery Systems
In the field of scalable LNP production, Ascendia Pharmaceuticals is a pioneer. We are a one-stop shop for the formulation and production of lipid nanoparticles thanks to our experienced team and proprietary nano-technologies. In our capacity as a CDMO, we manage the entire drug development process for you, starting with initial formulation and moving all the way through to first-in-man trials. When you're prepared to scale up and bring your drug to market, we can serve as your Partner of Choice, just as we have for many other clients. We will implement our BEST approach to help make the seemingly impossible, possible.
Ascendia is known for its expertise and leadership in using advanced nanotechnology solutions for low bioavailability and poorly soluble drugs. We have the capacity to provide nano formulations via bead-milling, microfluidization, and homogenization for both solid dosage forms or suspended for injection. Ascendia also has the ability to formulate self-emulsifying lipid systems, dispersed amorphous systems, and nano-emulsions to create dosage forms that can be administered parenterally, topically, or orally.
To learn more about partnering with Ascendia, contact us today.
