Advanced formulations for intranasal delivery of biologics

doi:10.1016/j.ijpharm.2018.10.029

International Journal of Pharmaceutics

Volume 553, Issues 1–2, 20 December 2018, Pages 8-20

https://doi.org/10.1016/j.ijpharm.2018.10.029 Get rights and content

Abstract

Introduction

The global biologics market has been ever increasing over the last decades and is predicted to top Euro 350 by 2020. Facing this scenario, the parenteral route of biologics administration as hitherto standard route is inconvenient for the future. Among the alternatives, the intranasal delivery of therapeutic biologicals seems to be most promising but researchers are still facing challenges as indicated by the scarce number of successfully marketed peptide drugs.

Areas covered

This review article is a compilation of current research focusing on achievements in the field of auxiliary agents for biologics delivery. First, the key benefits of the nose as most promising alternative route of drug administration are highlighted.

Then, the potential of the different auxiliary agents in preclinical research is in detail discussed. Moreover, the most used permeation enhancing agents, mucolytic agents, mucoadhesive agents, in situ gelling agents and enzyme inhibiting agents in the formulation of nasal drug delivery systems are described.

Thus, the overall purpose of this review is to highlight recent achievements in nasal delivery of biologics and to encourage researchers to work in the direction of needle-free nasal administration of biologics.

Expert opinion

The nasal epithelium is a promising route for biologics administration, which is reflected in a number of well-established products on the market treating chronic diseases as well as a large number of clinical trials currently in progress. The nasal route of drug administration might be a chance to improve therapy of biologics however break-through advances, especially for very complex molecules, such as antibodies, are still needed.

Graphical abstract

Introduction

Since the discovery of recombinant DNA technology in 1973 by Boyer and Cohen, the last five decades have seen extensive research in the field of biotechnologically engineered drugs (Cohen et al., 1973). The market approval of Humilin ® in the early 1980s as first recombinant therapeutic for human use prepared the path for today’s research and development of biologics (Banks et al., 2012, Barrett et al., 1999). Since then, the global biologics market has been growing and is predicted to top Euro 350 billion by 2020 (Limaye, 2020). The numbers send a clear message. The glorious era of biologics is smoothly reaching its summit as the first candidates have been running out of patent, thus providing comparably cheap APIs for biosimilar development (Senior, 2015).

The standard route of biologics administration is to date parenteral, however, in light of the elderly getting patients more patient friendly routes of drug administration are highly demanded. Among the various non-invasive routes of drug administration, the intranasally one is the most viable and most favourable (Zhang et al., 2014). However, intranasal delivery of therapeutic peptide and protein remains a challenge as pointed out by the scarce number of biologics on the marked.

The aim of the review is the evaluation of the nasal route as alternative route for the administration of biologics with attention to the last achievements obtained in this field. Moreover, the review give a view of nasally administered biologics on the market and in clinical trials. Furthermore, the scope of this review is to contribute to a better understanding of the role of auxiliary agents in nasal delivery of biologics.

Section snippets

Nasal cavity and its key benefits for delivery of biologics

Even though the parental route is hitherto the standard route of administration of biologics, the nasal route is gaining more and more attention as alternative route as it offers numerous advantages. These advantages are releated to the advoidance of needles, a comparatively high drug uptake in the systemic circulation due to the high vascularization of the nasal mucosa and a minor presystemic methabolism and direct access to the cerebrospinal fluid with by-pass of the blood-brain-barrier

Nasally administered biologics currently on the market and in clinical trials

Screening of the data base drugbank provides an overview on the scarce number of successfully marketed biologics as represented in Table 2 (Wishart et al., 2006). Most of marketed drugs are hormones marking the first milestone in nasal delivery of biologics decades ago. The gonadotropin-releasing hormone (GnRh) analogue buserelin for instance is nasally used for treatment of hormone dependent advanced carcinoma of the prostate gland. The nasal spray is available on the market under the brand

Auxiliary agents to improve drug delivery in preclinical studies

For a successful intranasal delivery of biologics, the selection of the appropriate auxiliary agents is crucial. The harsh environment of the nasal tissue, aiming to protect the body from pathogens, is a challenge for delivery of highly complex structured biologics (Critchley et al., 1994, Ding and Kaminsky, 2003, Ding and Xie, 2003). For a comprehensive overview of different pathways of protein degradation and inactivation see the article of Goldberg (Goldberg, 2003). This review is focused on

Conclusion

It seems that nasal biologics delivery resembles solving the magic cube (Fig. 3). A limited choice of small molecular weight peptides or oligopeptides merit their fundamental place on the pharmaceutical market since decades, like for example intranasally applied calcitonin in the therapy of osteoporosis. Beneath bioavailability issues, biologics are highly sensitive towards physical and chemical changes such as pH, ion concentrations and oxidative stress to mention some of the most important

Conflicts of interest

None.

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ReviewAdvanced formulations for intranasal delivery of biologics

Abstract

Introduction

Areas covered

Expert opinion

Graphical abstract

Introduction

Section snippets

Nasal cavity and its key benefits for delivery of biologics

Nasally administered biologics currently on the market and in clinical trials

Auxiliary agents to improve drug delivery in preclinical studies

Conclusion

Conflicts of interest

Eur. J. Pharm. Biopharm.

Pharmacol. Ther.

FEBS Lett.

Adv. Drug Deliv. Rev.

Eur. J. Pharm. Sci.

J. Control. Release

J. Control. Release

Peptides

Int. J. Pharm.

Pharmacol. Ther.

Int. J. Pharm.

Int. J. Pharm.

Adv. Drug Deliv. Rev.

Int. J. Pharm.

Eur. J. Pharm. Biopharm.

Int. J. Pharm.

Eur. J. Pharm. Biopharm.

Drug Discov. Today

J. Control. Release

Int. J. Pharm.

Eur. J. Pharm. Biopharm.

Biomaterials

Int. J. Pharm.

Int. J. Pharm.

J. Biol. Chem.

Eur. J. Pharm. Biopharm.

J. Control. Release

Toxicol. In Vitro

Int. J. Pharm.

J. Control. Release

J. Pharm. Sci.

Int. J. Pharm.

Eur. J. Pharm. Sci.

Adv. Drug Deliv. Rev.

J. Control. Release

Acta Biomater.

Int. J. Pharm.

J. Control. Release

J. Control. Release

Int. J. Pharm.

Eur. J. Pharmaceut. Sci.

J. Pharm. Sci.

Eur. J. Pharm. Biopharm.

Adv. Drug Deliv. Rev.

Eur. J. Pharm. Biopharm.

Eur. Polym. J.

Int. J. Pharm.

Int. J. Pharm.

Int. J. Pharm.

J. Control. Release

Review
Advanced formulations for intranasal delivery of biologics