Successful Drug Development with Synthetic Lipids: Critical Aspects and Strategies

pharma’s almanac – September 29, 2020 PAP-Q3-20-CL-024 – Shiksha Mantri, Ph.D. – Adela Kasselkus, Ph.D.

Lipid-based drug delivery systems offer several advantages, including improving the stability, solubility, bioavailability, and toxicity profiles of active pharmaceutical ingredients (APIs). It is essential to select the optimal lipid excipients with the appropriate characteristics for each specific API and application and to ensure that they can be produced using high-quality production methods that are scalable for GMP manufacturing. Working with the right supplier that offers consistent, high-quality products and has expertise in the drug development process and the regulatory environment is essential for the successful development and commercialization of lipid-based drug products.

Why Lipid-Based Drug Delivery?

Lipid-based formulations have shown significant promise in drug development and delivery. In addition to enhancing the stability of the API in vivo, they boost the bioavailability of both hydrophilic and hydrophobic drugs. Lipid-based formulations also improve the toxicity profile of the entrapped API via passively targeting inflamed or tumor tissues or certain organs and enable the delivery of difficult APIs, such as RNA, that are prone to instability, nuclease-mediated lysis, strong immune responses, and an inability to reach the site of action. They also facilitate patient compliance by reducing dosing frequency and/or increasing tolerability.

These benefits can be realized for patients with a wide range of disease indications. In addition, lipid-based drug-delivery systems (LBDDSs) can be used to formulate drugs in the most common dosage forms, including topical, oral, pulmonary, or parenteral administration.

Several Approvals and Many Lipid-Based Drugs in Development

The first lipid-based drug, Doxil®, comprising liposome-encapsulated doxorubicin, was approved by the U.S. Food and Drug Administration (FDA) in 1995. Figure 1 shows the marketed liposomal formulations in six therapeutic categories, with the most lipid-based drugs indicated for the treatment of cancer.

Currently, 18 lipid-based drugs have received marketing approval, and hundreds more are in clinical trials for a wide range of ailments. There is active work in developing generics of off-patent lipid-based drugs, and the FDA has issued product-specific guidances to aid in the development of a range of generic lipid-based products.
The latest developments in lipid-based drug delivery have been in the field of nucleic acid delivery involving APIs such as short RNAs for gene silencing or activation (short interfering (siRNA), micro (miRNA), short activating (saRNA)) and long RNA (messenger RNA (mRNA)) for applications in cancer therapy, enzyme replacement therapy, vaccines, and others.
In 2018, the first lipid-based drug for gene therapy encapsulating siRNA, Onpattro®, was approved by the FDA for the treatment of hereditary transthyretin amyloidosis (hATTR). Lipid-based RNA formulations are also finding their use as vaccines for infectious diseases. There is rapid development of mRNA-based COVID-19 vaccines, where an mRNA encoding a SARS-COV-2 virus protein is encapsulated in a lipid nanoparticle. The success of an RNA vaccine for COVID-19 will catalyze this field, leading to the approval of many more gene therapy drugs using lipids in the next few years.

Advantages of Synthetic Lipids

Lipid type, source, and quality/purity have a direct impact on the impurity profile and properties of final liposome formulations, such as the particle characteristics, bilayer structure, stability, and drug-release profile. For reproducible results, it is essential to synthesize lipids using only high-quality raw materials with optimal material characteristics and consistent quality.

Chemically synthesized lipids are advantageous over natural lipids, because they consist of a single lipid of known quality, whereas tissue-derived lipids are usually a mixture of egg-derived or bovine-derived lipids. Unlike tissue-derived lipids, synthetic lipids do not show batch-to-batch variability or risk of viral or protein contamination.

The purity of synthetic lipids can be optimized by selecting high-quality starting materials and optimizing the manufacturing processes and purification techniques. Raw materials should have a low level of by-products, defined stereochemistry (D/L) and isomeric purity (cis/trans), low bioburden and endotoxin levels, and be plant derived with bovine spongiform encephalopathy (BSE)/transmissible spongiform encephalopathy (TSE) and non-genetically modified organism (GMO) certificates and produced using only class II or III solvents. Class I solvents should be avoided based on guidelines from the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) in ICH Q3C. Continue reading on Successful Drug Development with Synthetic Lipids: Critical Aspects and Strategies

List of Synthetic Lipid Excipients