Spray Freeze Dried Lyospheres® for Nasal Administration of Insulin.

Tuğrul Mert Serim,Ayşe Nurten Özdemir,Yann Pellequer,Jan Kožák,Alf Lamprecht,Annika Rautenberg

doi:10.3390/pharmaceutics13060852

Tuğrul Mert Serim, Ayşe Nurten Özdemir + Show 4 more

Open Access

https://doi.org/10.3390/pharmaceutics13060852

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Abstract

Pharmacologically active macromolecules, such as peptides, are still a major challenge in terms of designing a delivery system for their transport across absorption barriers and at the same time provide sufficiently high long-term stability. Spray freeze dried (SFD) lyospheres® are proposed here as an alternative for the preparation of fast dissolving porous particles for nasal administration of insulin. Insulin solutions containing mannitol and polyvinylpyrrolidone complemented with permeation enhancing excipients (sodium taurocholate or cyclodextrins) were sprayed into a cooled spray tower, followed by vacuum freeze drying. Final porous particles were highly spherical and mean diameters ranged from 190 to 250 µm, depending on the excipient composition. Based on the low density, lyospheres resulted in a nasal deposition rates of 90% or higher. When tested in vivo for their glycemic potential in rats, an insulin-taurocholate combination revealed a nasal bioavailability of insulin of 7.0 ± 2.8%. A complementary study with fluorescently labeled-dextrans of various molecular weights confirmed these observations, leading to nasal absorption ranging from 0.7 ± 0.3% (70 kDa) to 10.0 ± 3.1% (4 kDa). The low density facilitated nasal administration in general, while the high porosity ensured immediate dissolution of the particles. Additionally, due to their stability, lyospheres provide an extremely promising platform for nasal peptide delivery.

Highlights

The therapeutic use of biologicals has been gaining increasing importance and with the increasing number of such complex molecules like peptides, proteins, and antibodies, related delivery approaches become of major importance
Confocal microscopy of fluorescein isothiocyanate (FITC)-labeled insulin Spray freeze dried (SFD) revealed a homogenous distribution of insulin throughout the SFD matrix along the lamellae and confirmed the same porous structural entities that were observed in SEM cross-sections (Figure 2)
The SEC measurements revealed absence of aggregate or fragment peaks which showed that insulin is present after redissolving of the formulations as a monomer, and comparable insulin content was quantified by the pharmacopoeia RP-HPLC method (Ta120 ble 3)

Summary

Introduction

The therapeutic use of biologicals has been gaining increasing importance and with the increasing number of such complex molecules like peptides, proteins, and antibodies, related delivery approaches become of major importance. They require parenteral administration, which is in case of a long-term/lifelong therapy accompanied with low patient compliance and with further complications caused by the repetitive invasive administration (e.g., infections, thrombosis). Nasal route has been found to be a promising non-invasive delivery route for peptide drugs as the permeability of the epithelial barrier permits a significant transport of such compounds [1].

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