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Advances in therapeutic modalities and an increase in molecular complexity have led to the need for an evolution in drug delivery approaches over the years.
Traditionally, drug delivery approaches were primarily aimed at the oral administration of a therapeutic substance that was released immediately. However, as drug molecules have progressed and newer modalities have been investigated, the ‘conventional’ routes of drug delivery proved limiting for formulators as a result of the requirement for higher doses, the need for frequent administration, and the fact that the release of the therapeutic is not controlled. Therefore, novel drug delivery systems (NDDS) that can help overcome the limitations of more conventional approaches have been a key area of focus for bio/pharmaceutical companies (1).
This industry focus is reflected in the market trajectory for NDDS, which, according to research, is projected to grow at a compound annual growth rate of 20.8% between 2021 and 2026, reaching an estimated value of $28.1 billion by the end of the forecast period (2). It is anticipated that this growth will be driven by multiple factors, such as the benefits offered by controlled-release drug delivery, the presence of in-vivo biological barriers that impact various properties of a drug substance, and the increased adoption of controlled-release drug delivery systems by specific patient populations because of non-adherence to treatment regimens.
Between 1950 and 1980, the fundamentals of understanding how drugs are released were underpinned (3). This period saw the first generation of development, with controlled-release mechanisms being approved by regulatory bodies, such as the approval of Spansule (Smith, Kline, & French Laboratories) in 1952—the first controlled-release drug delivery system (4).
In the first generation of drug delivery development, four main drug-release mechanisms were employed—dissolution-control, diffusion-control, osmotic-pressure control, and ion-exchange control (3). Other mechanisms were investigated, but for most commercial products between the 1950s and 1980s, the release-mechanism was based on dissolution or diffusion-control, or a mixture of the two (4). These delivery systems were mainly employed for oral or transdermal administration of therapeutic products.
Moving over to injectables, the first long-acting formulation was approved in 1989 by FDA, forming part of the second generation of drug delivery development (3). The poly(lactic-co-glycolic acid) (PLGA) microparticle formulation—an injectable depot formulation—was designed initially to deliver peptide and protein drugs for a month. This duration of drug release expanded to a period of six months with some ratio and molecular weight adjustments (4). As a result of the known safety of PLGA polymers, approvals of all other polymer-based long-acting injectable formulations have been based on PLGA.
Another significant second-generation development is the process of attaching poly(ethylene glycol) (PEG) to protein molecules—PEGylation (4). Through this process, it is possible for protein molecules to stay in the systemic circulation for longer. However, a potential limitation was realized in subsequent studies where antibodies were produced in the body against the PEG molecules, which led to accelerated blood clearance (5,6). Ultimately, greater understanding of PEGylation is required to ensure this process is used more effectively (4).
Most recently, PEGylation, more specifically lipid nanoparticles containing PEGylated lipid, has been imperative in the messenger RNA (mRNA) vaccines used against COVID-19, a development that has renewed research into the field of lipid nanoparticles (4).
A notable progression, brought to the fore of global attention thanks to the COVID-19 pandemic as mentioned previously, has been the ability to deliver mRNA vaccines (7)—something that was not possible when the medical use of mRNA vaccines was first proposed, approximately 30 years ago (8).
To enable the safe delivery of the sensitive and unstable mRNA, it is first necessary to encapsulate the vaccine molecules in lipid nanoparticles so that they are shielded from destructive enzymes (9). Once the vaccine is
appropriately protected, however, it is then necessary to ensure it can be delivered effectively and escape the endosome to have a therapeutic effect (4). The ability for formulators to rapidly create a functional mRNA delivery system using lipid nanoparticles, as was seen in the COVID-19 pandemic, was only possible thanks to decades of prior research in the area.
Staying with the basic concept of encapsulation, scientists from Nanyang Technological University, Singapore, published a study into the utility of conjugated peptide coacervates—protein-based microdroplet—as a drug delivery vehicle for the intracellular administration of a broad range of macromolecular therapeutics (10,11). Through the use of the protein-based microdroplets, which act as a ‘Trojan Horse’, the therapeutics are able to sneak into the cells. Once inside the cells, the droplets dissolve, allowing the release of the drug-carrying biomolecules.
According to the Singapore-based researchers, the microdroplets are a promising platform for delivery of a variety of therapeutics, including proteins, peptides, and mRNAs (10). Additionally, the scientists report that it would be possible to recruit and deliver a single or a combination of macromolecular therapeutics using the microdroplets.
In June 2021, a global specialist HIV company that is majority owned by GlaxoSmithKline, ViiV Healthcare, announced its partnership with biopharmaceutical company, Halozyme Therapeutics, for the development of “ultra long-acting” medicines to treat HIV (12). The collaboration agreement granted ViiV Healthcare exclusive access to Halozyme’s ENHANZE drug delivery technology—recombinant human hyaluronidase PH20 enzyme (rHuPH20)—for four specific HIV medicine targets.
The technology works through the PH20 enzyme, which has the ability to break down hyaluronan (HA)—a substance found under the skin. Once HA is broken down, a greater volume of fluid can be injected subcutaneously and dispersed, which has the potential to reduce treatment burden (12).
Another partnership, this time between Janssen Biotech, a Pharmaceutical Company of Johnson & Johnson, and Bioasis Technologies, has been formed to develop drugs that can traverse the blood-brain barrier (BBB) (13). Under the terms of the agreement, Janssen will have access to Bioasis’ proprietary xB3 platform technology, which is based on a human transport protein that can be found in low levels in blood.
According to Bioasis, the platform has shown efficacy in its ability to shuttle molecules of varying sizes and types, such as monoclonal antibodies, enzymes, small molecules, and gene therapies, across the BBB. Once the molecules have traveled into the brain, it is possible for them to reach the appropriate targets through a process called receptor-mediated transcytosis (14).
Finally, BioNTech has linked up with Matinas BioPharma to evaluate novel delivery technology for mRNA-based vaccines (15). The exclusive research collaboration will assess the combination of mRNA formats and Matinas’ proprietary lipid nanocrystal (LNC) platform technology.
The companies are hopeful that, through the collaboration and the promising capabilities of the LNC delivery platform, they will potentially have the opportunity to develop mRNA vaccines that can be delivered orally.
1. F. Laffleur and V. Keckeis, Int. J. Pharm, 590, 119912 (2020).
2. Research and Markets, Novel Drug Delivery Systems (NDDS)—Global Market Trajectory and Analytics, Market Report (February 2022).
3. Y.H. Yun, B.K. Lee, and K. Park, J. Control. Release, 219, 2–7 (2015).
4. H. Park, A. Otte, and K. Park, J. Control. Release, 342, 53–65 (2022).
5. K. Park, J. Control Release, 142, 147–148 (2010).
6. K. Park, J. Control Release, 287, 257 (2018).
7. G. Quaglio with M. Fernández. Álvarez, “What If New Drug Delivery Methods Revolutionized Medicine?” European Parliamentary Research Service, Scientific Foresight (October 2021).
8. N. Pardi, et al., Nat. Rev. Drug Discov., 17, 261–279 (2018).
9. Editorial, Nat. Rev. Mater., 6, 99 (2021).
10. Y. Sun, et al., Nat. Chem., 14, 274–283 (2022).
11. Nanyang Technological University, Singapore, “Sneaking Large Drug-Carrying Biological Molecules into Cells,” Press Release, ntu.edu.sg, Mar. 16, 2022.
12. GSK, “ViiV Healthcare and Halozyme Enter Global Collaboration and License Agreement for ENHANZE Drug Delivery Technology to Enable Development of ‘Ultra Long-Acting’ Medicines for HIV,” Press Release, June 22, 2021.
13. Bioasis, “Bioasis Enters into Research Collaboration with Janssen,” Press Release, April 11, 2022.
14. Bioasis, “Platform,” Science Information Page [Accessed April 22, 2022].
15. BioNTech, “BioNTech and Matinas BioPharma Announce Exclusive Research Collaboration to Evaluate Novel Delivery Technology for mRNA-Based Vaccines,” Press Release, April 11, 2022.
Felicity Thomas is senior editor of Pharmaceutical Technology.
Volume 46, Number 5
When referring to this article, please cite it as F. Thomas, “An Evolving Approach to Drug Delivery,” Pharmaceutical Technology 46 (5) 2022.