Introduction:
Nanotechnology in the Pharmaceutical Industry
Part 3 of 4: Lipid-based-Nanoparticles
The cornerstone of nanotechnology’s future is the discovery of new inactive ingredients (excipients) implemented in a drug formulation to overcome the deficiencies of traditional medicines. Unlike the finished drug products, and to some extent the active pharmaceutical ingredient (API), an excipient is not individually approved by the FDA. Novel excipients are only evaluated by the FDA in a New Drug Application (NDA), or a Supplemental New Drug Application (sNDA) in certain situations. This hurdle has created a reluctance to develop and utilize novel excipients. In response, the FDA launched PRIME (Pilot Program for the Review of Innovation and Modernization of Excipients) as a mechanism to de-risk novel excipient development.
We love nanotechnologies and want you to love them too. In this 4-part series, we will introduce some of the well-established nanoparticle technologies, highlighting their benefits. We’ll conclude each part of the series discussing emerging technologies we think are noteworthy. Today in Part 3, we’ll discuss Lipid-based nanoparticles.
Part 3: Lipid-based Nanoparticles
The COVID-19 pandemic thrust lipid-based nanoparticles into the public spotlight with the rapid development, approval, and deployment of the SARS-CoV-2 targeted mRNA vaccines. Prior to the pandemic, lipid-based nanoparticles were predominantly investigated in academic and early-phase clinical settings. The first breakthrough was the 2018 approval of ONPATTRO™ (patisiran), which is an ionizable lipid containing technology—specially a lipid nanoparticle (LNP)—used to delivery transthyretin-directed small interfering RNA (siRNA). Discussed below are the 4 major subtypes of lipid-based nanoparticles used in nanotechnologies.
- Liposomes – The strategy of this nanotechnology is to create spherical vesicles structurally similar to biological membranes. They are comprised of phospholipids that form a bilayer encapsulating an aqueous core. This structure allows for the possibility of entrapping both hydrophobic drugs in the lipid bilayer, or hydrophilic drugs in the aqueous core. Frequently employed components are natural and naturally derived phosphatidylcholines, cholesterol, and mono-, di-, or triacylglycerols. The landmark first approval of a liposomal drug was DOXIL™ (doxorubicin HCl) in 1995 for the treatment of AIDS-related Kaposi’s sarcoma. This liposomal formulation lowered peak plasma levels and reduced entry into heart muscle, thus lowering the cardiotoxicity of doxorubicin.
- Lipid nanoparticles (LNPs) – Evolved from liposomal technology, tailored specifically to deliver nucleic acid payloads. Structurally, LNPs are monolayer and do not have an aqueous core. Another major difference is the components, with LNPs incorporating ionizable lipids not typically found in liposomal formulations. These cationic lipids form electrostatic complexes with negatively charged nucleic acids during the formulation process. The key to LNP technology is pH responsiveness of the ionizable lipids, which are neutral while circulating, but which facilitates cellular uptake and release into the cytosol in response to changes in pH. COMIRNATY™ is the COVID-19 mRNA vaccine developed by Pfizer and BioNTech, which utilizes the synthetic ionizable lipid ALC-0315 which was developed and patented by Acuitas Therapeutics.
- Emulsions – This versatile class of lipid-based nanoparticles can be used to delivery both hydrophilic and hydrophobic drugs, via a broad range of routes of administration, including injectable, ophthalmic, oral, and topical. Characteristics of the emulsion, such as droplet size, charge, and viscosity, can be tuned through manipulation of the composition and formulation technique used. The composition of an emulsion varies greatly, but generally include oil components, aqueous components, in addition to emulsifying and stabilizing agents. An example of an approved injectable emulsion is DIPRIVAN™ (propofol) used as a general anesthetic. The oil component of this emulsion is soybean oil, while purified egg phospholipids act as the emulsifier, and glycerol is added as a tonicity agent.
- Solid lipid nanoparticles (SLNs) – The differentiating feature of this technology is solid state of the lipid core, even at body temperature. This feature can impart increased stability over the other lipid-based nanoparticles. The promise of SLNs is this increased stability offers an extended-release property and makes these particles more resistant to aggregation. SLNs are classically prepared with common surfactants combined with triglycerides and waxes, such as tristearin and cetyl palmitate. This nanotechnology has not enjoyed the clinical success of the other lipid-based nanoparticles. However, a topical gel comprised of a polyacrylic acid polymer (Carbopol™ 934) designed to deliver oxiconazole nitrate has been evaluated clinically to treat fungal infections.
Emerging Technology:
The increased regulatory scrutiny on PEG-based excipients in injectable drug products has created a demand for alternatives. Poly(sarcosine) is a hydrophilic polymer of the naturally occurring amino acid sarcosine (N-methyl glycine) that has gained traction in drug delivery applications. It is biodegradable, biocompatible, and non-immunogenetic, all while maintaining the physiochemical features that have made PEG ubiquitous. Leading the way is Curapath, who has scalable poly(sarcosine)-lipid derivatives which function as shielding lipids in nucleic acid–LNP formulations, offering an alternative to PEG-based lipids such as DMG-PEG.
