Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies

Abstract

The formulation and delivery of biopharmaceutical drugs, such as monoclonal antibodies and recombinant proteins, poses substantial challenges owing to their large size and susceptibility to degradation. In this Review we highlight recent advances in formulation and delivery strategies--such as the use of microsphere-based controlled-release technologies, protein modification methods that make use of polyethylene glycol and other polymers, and genetic manipulation of biopharmaceutical drugs--and discuss their advantages and limitations. We also highlight current and emerging delivery routes that provide an alternative to injection, including transdermal, oral and pulmonary delivery routes. In addition, the potential of targeted and intracellular protein delivery is discussed.

Figure 1. Key parameters of polymer microparticle design

The chemical functionalities of the polymer affect essentially all aspects of microparticle performance, including the efficiency of drug encapsulation, the rate of polymer degradation and drug release, and toxicity at the injection site. a | The porous structure of the polymer alllows penetration of water and facilitates its degradation and subsequent drug release. The porosity of the polymer also affects the diffusion of the drug. b | The size of the microsphere particles affects the duration of drug release (in general, larger particles lead to more prolonged release) and the size of the needle required for administration (smaller needles are required for smaller particles). c | Polydispersity of particle size may introduce variability in the release rates. d | Particle surface properties affect their interactions with the surroundings at the injection site, especially immune cells. Modification of the surface with polymers such as polyethylene glycol (PEG) is used to modulate the interactions of the microsphere with immune cells. e | The shape of the polymer affects the interactions of particles with macrophages; elongated particles exhibit orientation-dependent internalization by macrophages.

Figure 2. Hurdles associated with nanoparticle-mediated delivery

The figure depicts various hurdles involved in the delivery of therapeutic nanoparticles to targeted tissues. Nanoparticles injected into the bloodstream are cleared by the reticuloendothelial system, including the liver and spleen, especially by the resident macrophages in these organs. Circulating nanoparticles need to cross the vascular endothelium of the diseased tissue and penetrate into the diseased tissue, both of which pose a considerable hurdle. The vascular endothelium possesses low permeability to nanoparticles, except in some cases — such as tumours — where the endothelium is poorly formed and allows the passage of nanoparticles (known as the enhanced permeation-retention effect). Nanoparticles that escape the blood vessel still need to diffuse through the dense extracellular matrix to reach relevant target cells embedded deep within the tissue. Upon arriving at the surface of the target cells, nanoparticles need to enter the cells via endocytosis. Nanoparticles that are internalized by the cells are trafficked within endosomes and sometimes need to escape the endosome to release the active drug cargo.

Figure 3. Modes of biopharmaceutical modification

Two general types of protein modification are used to extend half-life; conjugation with hydrophilic polymers (parts a–d) and genetic constructs or fusion approaches (parts e–g). Conjugation approaches include protein modification with polymers such as polyethylene glycol (PEG) and hyaluronic acid. The advantages of the conjugation approach include: the availability of a variety of established chemistries; ease of evaluation at a discovery stage using well-known approaches such as N-hydroxy succinimide or maleimide chemistries; reduction of protein immunogenicity; and a proven history with multiple products. Their limitations include the creation of a new molecular entity, polydispersity and potential immunogenicity of polymers. Fusions offer the advantage of being developed and formulated as conventional protein therapeutics, avoiding additional downstream processing such as encapsulation and associated costs. In addition, there is a proven history of several products based on this approach. Their limitations include the creation of a new molecular entity and the associated safety issues and testing, the possibility of generating an immune response to the modified protein and potential formulation challenges owing to the increased molecular complexity.

Figure 4. FcRn recycling mechanism

Neonatal Fc receptor (FcRn) recycling has a crucial role in the biological activity of Fc- and albumin-fusion proteins. Fc-fusion protein drugs or albumin-fusion protein drugs bind to FcRn on the endothelium. Receptor-bound proteins are internalized into endocytic vesicles. End osomes are acidified and undergo sorting of FcRn. Non-receptor-bound proteins are degraded in the lysosomal compartment and receptor-bound proteins are recycled back to the cell membrane. The protein therapeutic is subsequently released back into the blood. FcRn-mediated recycling leads to prolonged circulation of Fc-fusion and albumin-fusion protein therapeutics. IgG, immunoglobulin G.

Figure 5. Alternative routes of biopharmaceutical delivery

Various alternative routes to needle-based injections have been proposed for the delivery of biopharmaceutical drugs. These include oral, transdermal, pulmonary, nasal, vaginal, sublingual, rectal and ocular delivery routes. The figure summarizes some of the approved products that are administered via these routes and those that are in clinical trials. Examples listed in the figure indicate the high level of activity in alternative routes of drug administration. IgG1, immunoglobulin G1; LHRH, luteinizing hormone-releasing hormone; mAb, monoclonal antibody; PTH, parathyroid hormone; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

Figure 6. A summary of intracellular targets for biopharmaceutical drugs

The cell interior is the site of numerous potential drug targets where biopharmaceuticals may be attractive candidates provided they can be delivered successfully. Approaches to the intracellular delivery of biopharmaceuticals include increasing their membrane permeability (particularly in the case of peptides) and active transport via internalizing receptors on the cell surface, such as the asialoglycoprotein receptor on hepatocytes. Potential intracellular targets include those associated with mitochondria, the nucleus and the cytoplasm. Intracellular pathogens are another potential application. These include the liver stages of Plasmodium spp. mycobacteria in alveolar macrophages and associated granuloma, and amastigotes of Leishmania spp. in infected macrophages and various tissues including the liver and bone marrow. GPCR, G protein-coupled receptor; HSP90, heat shock protein 90.

Figure 7. Various means to access the central nervous system for therapeutic delivery

Delivery of biopharmaceutical drugs into the central nervous system (CNS) is highly challenging. Intracerebroventricular injections offer a direct mode of drug delivery into the brain; however, this approach is limited by its invasive nature. Systemic delivery in the vascular compartment is another option. Although this approach is easy, its use is limited by the low permeability of the blood-brain barrier. Specifically, endothelial cells in the brain possess highly regulated tight junctions that limit passive diffusion of drugs. Biopharmaceutical drugs must exhibit active uptake in order to cross the endothelium. Intrathecal administration provides an optimal blend of ease of use and access to the cerebrospinal compartment, although diffusion within the brain can be a limiting factor.