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Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies

Key Points

  • Biopharmaceutical drugs such as antibodies, peptides and recombinant proteins have high specificity and potency compared to small molecules. These features arise from their macromolecular composition, which provides the structural complexity that is often required for specificity.

  • However, this structural complexity means that biopharmaceutical drugs are large and susceptible to degradation, which makes it challenging to formulate and deliver them. These drugs also have reduced permeation across biological barriers, which complicates their delivery to specific sites or intracellular targets.

  • In this Review we highlight recent advances in formulation and delivery strategies that have facilitated the transformation of product portfolios and development pipelines by this class of compounds. These advances include the use of microsphere-based sustained-release technologies, protein modification methods that make use of polyethylene glycol and other polymers, as well as genetic manipulation of biopharmaceutical drugs such as Fc- and albumin-fusions.

  • We also highlight current and emerging delivery routes that provide alternatives to injection, including transdermal, oral and pulmonary delivery.

  • Current areas of formulation and delivery research show promise for the application of biopharmaceutical drugs to tumour immunotherapy using nanoparticle technology, tissue engineering and enhanced approaches to cell-based therapy.

  • These delivery methods could be used for the targeted delivery of proteins to the brain, which could have implications in the treatment of a wide range of central nervous system disorders. These technologies could potentially increase the effectiveness of conventional approaches that have not yet translated to the clinic, although they have had promising preclinical results.

  • Intracellular delivery of proteins and peptides is a new frontier in delivery research, which could dramatically augment the breadth of targets amenable to biopharmaceutical drug therapy.

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.

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Figure 1: Key parameters of polymer microparticle design.
Figure 2: Hurdles associated with nanoparticle-mediated delivery.
Figure 3: Modes of biopharmaceutical modification.
Figure 4: FcRn recycling mechanism.
Figure 5: Alternative routes of biopharmaceutical delivery.
Figure 6: A summary of intracellular targets for biopharmaceutical drugs.
Figure 7: Various means to access the central nervous system for therapeutic delivery.

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Acknowledgements

The research of S.M. is supported by the US National Institutes of Health (NIH) grant R01DK097379. The research of R.L. is supported by the NIHR37-EB000244 grant (MIT #6928649). The authors thank M. Citron for helpful discussions during the preparation of this Review.

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Correspondence to Samir Mitragotri or Robert Langer.

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Competing interests

R.L. and S.M. are shareholders of, R.L., S.M. and P.A.B. are consultants to, and R.L. and S.M. are recipients of research grants from several drug delivery, pharmaceuticals and biotechnology companies, including those whose technologies and products are discussed in this article. The authors are inventors on several patents in the field of drug delivery/formulations that are owned by their current or former employers. The views presented here should not be considered as endorsements of any specific product or company.

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Supplementary information

Supplementary information S1 (table)

Product examples for half-life extension / decreased dosing frequency Products based on depot formulations (PDF 565 kb)

Glossary

Solvent evaporation

A process for microencapsulating drugs or other substances whereby an oil-in-water emulsion is formed, followed by the removal of the organic solvent by its evaporation from the emulsion mixture, resulting in the solidification of the oil phase to form microspheres.

Atomization

A process for microencapsulating drugs or other substances whereby a polymer solution containing the drugs is broken up into droplets, followed by the removal of the polymer solvent by evaporation or other means, resulting in the formation of solid microspheres.

Burst release

The quick release of drugs (usually within minutes to 24 hours) that are encapsulated in microspheres; the drug is associated with the microsphere surface and so is not completely protected from release by the microsphere structure.

Core-shell nanoparticles

Microspheres or precipitates containing a core of one polymer that is surrounded by the shell of another polymer.

Particulate formulations

Formulations comprising microspheres prepared from a polymer or other materials to encapsulate and release proteins.

Implantable depots

Formulations that are too large in volume to be injected, and are instead administered by other means (for example, by insertion through a surgical incision).

Injectable monoliths

A type of depot formulation that is fabricated as a contiguous solid mass, such as a cylinder, and can be administered by positive displacement from a syringe needle without the use of a suspending vehicle.

Biosimilars

A biopharmaceutical drug that is demonstrated to be similar to, or interchangeable with, a licensed biological product, based on the absence of clinically meaningful differences in safety, purity and potency.

New molecular entity

A drug product containing an active moiety or moieties that have not been previously approved by a regulatory authority, either as a single ingredient or as part of a combination product.

Hydrodynamic radius

The effective hydrated radius of a biopharmaceutical drug, which dictates its rate of diffusion in solution and tissues.

FcRn recycling

A process that is mediated by the neonatal Fc receptor (FcRn), which involves the transcytosis of maternal immunoglobulin G (IgG) across the placental membrane. This process is responsible for the long circulating half-lives of IgG and serum albumin throughout life, through a mechanism of protective vesicular trafficking.

Cmax

The maximum plasma or serum concentration of a drug following administration.

Living polymerization

A technique for synthesizing polymers where chain termination and transfer reactions are absent, and the rate of chain initiation substantially exceeds that of chain propagation. The resulting polymer chains have very similar lengths compared to traditional polymerization techniques.

K d

The dissociation constant; a type of equilibrium constant that characterizes the propensity of a complex to separate reversibly into its constituents.

Implantable pumps

Small devices that can be placed within the body and used to deliver a drug. The pumps carry a drug reservoir (which, in some cases, can be refilled through a port, thus avoiding the need for surgical intervention), a control mechanism to regulate delivery, and the delivery catheter.

Insulin patch pumps

A wearable infusion pump that is attached to the skin and delivers insulin into the subcutaneous space.

Liquid jet injections

A type of injection that enables the delivery of drugs into the skin and subdermal tissues — without using needles — by accelerating a stream of drug solution to high velocities.

Absorption enhancers

Chemicals that increase the absorption of drugs across biological barriers such as the skin, intestinal epithelium or cell membrane.

Chitosans

Linear polysaccharides of randomly arranged glucosamine and acetyl glycosamine.

Therapeutic index

A measure of the safety of a particular drug, typically represented by the ratio of the dose causing overt toxicity to the dose providing a therapeutic effect. A drug with a large therapeutic index can be administered with low risk of eliciting a toxic effect.

Tau

A highly soluble microtubule-associated protein found in neurons. Misfolded tau is associated with a variety of neurodegenerative disorders, including Alzheimer's disease, in which interneuronal hyperphosphorylated tau tangles are a common pathological feature.

Stapled peptides

A class of α-helical peptides incorporating α-methylation and hydrocarbon-based macrocyclic bridging features for increased hydrophobicity and conformational stabilization of the helix, resulting in improved membrane permeation.

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Mitragotri, S., Burke, P. & Langer, R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov 13, 655–672 (2014). https://doi.org/10.1038/nrd4363

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