Elsevier

Powder Technology

Volume 379, February 2021, Pages 144-153
Powder Technology

Microfluidic spray dried and spray freeze dried uniform microparticles potentially for intranasal drug delivery and controlled release

https://doi.org/10.1016/j.powtec.2020.10.061Get rights and content

Highlights

  • Complexation with spray (freeze) drying for producing uniform nasal powder.

  • Enhanced resveratrol dissolubility over 1800 times the pure resveratrol.

  • Excellent antioxidant activity with Net AUC value exceeding 60.

  • Chitosan-induced controlled resveratrol release and good particle-mucin adhesion.

Abstract

Microparticulate formulations of intranasal drug administration, i.e. nasal powder, have aroused widespread interest in academia and industry. However, low drug bioavailability due to poor hydrophilicity and rapid clearance of nasal mucosa remains an important challenge. Herein, with resveratrol as poorly water-soluble model drug, hydroxypropyl-β-cyclodextrin as complexation agent and excipient, chitosan as mucoadhesive enhancer, a series of uniform microparticles were fabricated using a self-designed microfluidic spray granulation platform. The effects of feed solution composition and process technique on particle size, morphology, density and flowability were investigated. The obtained powder presented the significantly enhanced resveratrol dissolubility over 1800 times pure resveratrol and the excellent antioxidant activity with Net AUC value exceeding 60. Chitosan played an important role in adjusting resveratrol release behavior and improving particle mucoadhesive property. This study shows promise for facile and scalable production of high-quality nasal powder using combined complexation method with spray drying and spray freeze drying technique.

Introduction

Intranasal drug delivery (INDD) [[1], [2], [3]] is a noninvasive administration manner for treating both local and systemic diseases with high safety, well patient compliance and rapid onset of action. Especially for the treatment of central nervous disorders, INDD is very promising as allowing direct access of drug to brain through the olfactory region, which would avoid the Blood-Brain Barrier (BBB), gastrointestinal metabolism and hepatic elimination [[4], [5], [6], [7]]. The majority of current commercially-available nasal pharmaceuticals are in liquid form [8], but nasal powders have attracted increasingly more attention, mainly due to the slower elimination in the nasal cavity compared to the liquids, which enhances drug diffusion and absorption across the mucosa, and thus improving bioavailability [[9], [10], [11], [12]]. Besides solid dosage form is generally of better physicochemical and biological stabilities, as well as ease of transportation and storage [13]. More importantly, for poorly water-soluble active pharmaceutical ingredients (APIs) and biopharmaceuticals, such as protein and peptide, nasal powders facilitate the formulation of larger drug doses by selecting appropriate excipients acting as fillers, solubilizers, mucoadhesive agents, permeation and absorption enhancers for promoting drug efficacy [[14], [15], [16]].

Nasal powders can be manufactured using a few technologies, primarily including emulsification and solidification [17,18], spray drying (SD) [19], freeze drying (FD) [20], and spray freeze drying (SFD) [21]. Among those, SD is a continuous and easy to up-scale process, while FD is superior for heat-sensitive compounds. SFD combines the advantages of both SD and FD, facilitating production of thermolabile ingredients in powder form, and yet has to still withstand non-continuous process and high cost [22]. It is noted that any method should obtain particles with properties, including size, morphology, density, API dosage, etc., as controllable as possible [[23], [24], [25]]. Conventional techniques, however, often produce polydisperse particles with a wide performance distribution even in the same batch, which also have poor reproducibility and low yield. To tackle such challenges, our research group has developed a specially self-designed micro-fluidic spray granulation technology platform, including micro-fluidic spray (hot air) dryer (MFSD) [[26], [27], [28], [29], [30], [31], [32], [33], [34]] and spray freeze tower (MFSFT) [35,36], which provides scalable and efficient means to produce uniform microparticles with tailored characteristics and functionalities.

In this study, both MFSD and MFSFT were utilized to prepare a series of uniform microparticles potentially as the nasal powders for the first time. Resveratrol was chosen as poorly water-soluble model drug (ca. 0.03 mg/mL) that have showed therapeutic effect on CNS disorders due to its anti-inflammatory and anti-oxidant capabilities [17,37,38]. Hydroxypropyl-β-cyclodextrin was selected as complexation agent and excipient [14,39,48], while chitosan as mucoadhesive agent in order to control the resveratrol release and enhance the particle residence time on the nasal mucosa [16]. The effects of feed solution compositions and process conditions were investigated on the particle size, morphology, density and structure characterized by scanning electron microscope. The possible interactions among ingredients molecules were evaluated using powder X-ray diffraction, Fourier transform infrared spectrometer and nuclear magnetic resonance, in order to interpret the release behaviors via dissolution tests in both deionized water and simulated nasal mucus. The antioxidant activities were determined using the method of Oxygen Radical Absorbance Capacity (ORAC). Atomic force microscope was used to quantify the microparticle mucosal adhesion.

Section snippets

Materials

Resveratrol (Res; trans-3,4′,5-trihydroxystilbene) and Hydroxypropyl-β-cyclodextrin (CD; purity >99%, MS, 1541.54) were purchased from Suzhou Byno Biotechnology Co., Ltd. (Suzhou, China). The chitosan with low molecular weight (CS; deacetylated degree >95%) was obtained from Shanghai Aladdin Biochemical Technology Co., Ltd. (Shanghai, China). Porcine gastric mucin was purchased from Suzhou Kechuang Biotechnology Co., Ltd. AAPH [(2,2′-azobis(2-methylpropionamidine) dihydrochloride, 98%)] and Na3

Effects of feed solution composition and process technique on particle structure

Uniform microparticles were successfully produced by spray drying and spray freeze drying the feed solution of various formula (Table 1) via the MFSD and MFSFT, respectively, as shown in Fig. 1. Table 2 summaries the quantified sample physical properties, including particle geometric size, aerodynamic size, moisture content, density and Carr's index (CI). Narrow particle size distribution (within ±5%) and nearly identical morphology for every individual samples were presented, and meanwhile the

Conclusions

A serious of uniform SD and SFD microparticles were successfully fabricated using MFSD and MFSFT, respectively. The SD microparticles were buckled and dense with the size from 55.97 to 115.12 μm. The TSC of feed solution played a determinant role in particle size of SD samples, and those samples mostly containing CD were of very similar morphology resulted from uneven shrinkage of the droplets during spray drying process. The SFD microparticles were spherical and porous with larger size of

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work is financially supported by the National Natural Science Foundation of China (No. 21878197), the Natural Science Foundation of Jiangsu Province (No. BK20180096) and Jiangsu Higher Education Institutions (No. 18KJA530004), and the Suzhou Municipal Science and Technology Bureau (No. SYG201810). The support from the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions is also appreciated.

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