Opportunity and challenges of nasal powders: Drug formulation and delivery

https://doi.org/10.1016/j.ejps.2017.09.027Get rights and content

Abstract

In the field of nasal drug delivery, among the preparations defined by the European Pharmacopoeia, nasal powders facilitate the formulation of poorly water-soluble active compounds. They often display a simple composition in excipients (if any), allow for the administration of larger drug doses and enhance drug diffusion and absorption across the mucosa, improving bioavailability compared to nasal liquids. Despite the positive features, however, nasal products in this form still struggle to enter the market: the few available on the market are Onzetra Xsail® (sumatriptan) for migraine relief and, for the treatment of rhinitis, Rhinocort® Turbuhaler® (budesonide), Teijin Rhinocort® (beclomethasone dipropionate) and Erizas® (dexamethasone cipecilate).

Hence, this review tries to understand why nasal powder formulations are still less common than liquid ones by analyzing whether this depends on the lack of (i) real evidence of superior therapeutic benefit of powders, (ii) therapeutic and/or commercial interest, (iii) efficient manufacturing methods or (iv) availability of suitable and affordable delivery devices. To this purpose, the reader's attention will be guided through nasal powder formulation strategies and manufacturing techniques, eventually giving up-to-date evidences of therapeutic efficacy in vivo. Advancements in the technology of insufflation devices will also be provided as nasal drug products are typical drug-device combinations.

Introduction

Nowadays, the majority of nasal pharmaceutical products on the market are liquids, delivered as sprays or drops (less frequently), regardless of whether they are for local or systemic action. In this area, product development focuses on simple formulation strategy and convenience of the delivery system. However, chemical and microbiological instability, the relatively high formulation's volume administered to ensure the drug dosage, and the rapid clearance from the nasal cavity are significant drawbacks of nasal liquids. When it comes to peptide and protein delivery, nasal formulations need additives and stabilizing agents, and proper storage conditions to assure the intended shelf life. Moreover, when administered in solution, the absorption of some drugs across the nasal biological barrier was demonstrated low and variable, with bioavailability not exceeding 10% for small molecular weight drugs such as alniditan and morphine, and < 1% for peptides such as insulin and leuprolide (Illum et al., 2002).

It is known that solid dosage forms, which for nasal administration are mainly represented by powders, are more stable than liquids. Formulation-wise, powders denote a simpler composition in excipients (if any), allowing for the administration of larger drug doses. Powders also facilitate the formulation of poorly water-soluble compounds (Buttini et al., 2012, Pozzoli et al., 2016, Vasa et al., 2015). Moreover, nasal powder dosage forms can enhance drug diffusion and absorption across the mucosa, thus improving drug bioavailability at the site of action compared to liquids (Vasa et al., 2017). In a study in humans comparing different formulations of desmopressin, a nasal powder was superior to a commercial nasal liquid spray and also to a sublingual tablet with respect to both bioavailability and patient's compliance (Fransén et al., 2009).

Despite the above-listed positive features, however, nasal powders still struggle to enter the market. The only approved product for systemic action is Onzetra Xsail® (Avanir Pharmaceuticals Inc., Aliso Viejo, CA, USA), containing sumatriptan for migraine (approved by the Food and Drug Administration, FDA, in January 2016) (Silberstein, 2017). In Europe, Rhinocort® Turbuhaler® (budesonide, AstraZeneca, London, UK) is marketed for topical treatment of seasonal and perennial allergic and vasomotor rhinitis and of nasal polyps. Other two locally-acting products, Teijin Rhinocort® (beclomethasone dipropionate, Teijin, Tokyo, Japan) and Erizas® (dexamethasone cipecilate, Nippon Shnyaku, Kyoto, Japan), are commercially available in Japan.

Thus, some questions may be raised: is there a lack of therapeutic and/or commercial interest? Isn't there yet a real evidence of a superior therapeutic benefit of nasal powders? Is it difficult to manufacture a nasal powder? Is a suitable and affordable delivery device still not available?

Many remarkable reference papers have already illustrated the anatomy and physiology of the nasal cavity with respect to drug delivery via this route (Dhuria et al., 2010, Illum, 2003, Illum, 2002, Pires et al., 2009). The present review aims to focus on the opportunities and challenges of developing powders for nasal drug delivery and answer the above questions. Nasal powder formulation strategies and manufacturing techniques will be illustrated, eventually giving up-to-date evidence of therapeutic efficacy in vivo. Advancements in the technology of insufflation devices will be addressed too, as nasal drug products are typical drug-device combinations. No nasal formulation works by itself without its paired delivery device. Since the delivery technologies for nasal dry powder vaccines have been treated recently, readers are referred elsewhere for further information (Hickey et al., 2014).

Section snippets

Powder engineering

Nasal powders are defined in the European Pharmacopoeia (Ph. Eur, 9th Ed.) as powders for insufflation into the nasal cavity by means of a suitable device. Despite such quite general definition, nasal powders comprise a number of dosage forms spacing from the pure active pharmaceutical ingredient (API) raw material to micronized powders, where the API can be formulated alone or with excipients (Colombo et al., 2016, Dalpiaz et al., 2015, Gavini et al., 2006) (Fig. 1A–B). Moreover, both the raw

Proof-of-concept of the efficacy of nasal powders in vivo

Particularly for systemic therapeutic action, the literature widely reports on the improvements of in vivo drug absorption and bioavailability obtained using nasal powder formulations compared to liquid dosage forms that in some cases are already marketed. Some studies also compare the nasal administration of powders with other administration routes. Examples are provided in the following sections, not only considering drugs, but also non-pharmacologically active substances.

Nasal powder manufacturing methods

Nasal powders can be manufactured by means of various techniques. For example, different chitosan-based microspheres have been produced by emulsification-cross linking (Patil et al., 2010, Varshosaz et al., 2004), spray drying (Gavini et al., 2011, Gavini et al., 2005, Martinac et al., 2005), precipitation (Abdel Mouez et al., 2014) or solvent evaporation processes (Jain et al., 2004, Lim et al., 2000, Nagda et al., 2011). Any method should work to obtain a powder whose size falls in the

Delivery devices for nasal powder insufflation

According to the Ph. Eur. definition of nasal powders, the formulation must be combined with a device for nasal insufflation for use. Table 2 lists the marketed products with their respective device.

The joint effect of nasal powder properties and device design and mechanism of insufflation is largely responsible for the nasal drug bioavailability, due to the influence on particle deposition in the nasal cavity. Fig. 5 qualitatively shows device-dependent coverage of the various regions of the

Conclusions

This review confirms that nasal delivery of active compounds has been and still is of great interest for locally/systemically acting drugs and also for drugs targeting the central nervous system via the nose-to-brain transport. Many studies and clinical evidence have corroborated the advantages of nasal powder dosage forms. The higher stability over liquids eliminates the need for preservatives in the formulation, increasing safety (Bortolotti et al., 2009). In addition, drug bioavailability in

Author disclosure statement

The authors declare no conflict of interest.

Acknowledgments

This article is based upon work from COST Action MP1404 SimInhale ‘Simulation and pharmaceutical technologies for advanced patient-tailored inhaled medicines’, supported by COST (European Cooperation in Science and Technology) www.cost.eu

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    Present address: Hospital Pharmacy, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy.

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