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Spray freeze drying of small nucleic acids as inhaled powder for pulmonary delivery.

ABSTRACT: The therapeutic potential of small nucleic acids such as small interfering RNA (siRNA) to treat lung diseases has been successfully demonstrated in many in vivo studies. A major barrier to their clinical application is the lack of a safe and efficient inhaled formulation. In this study, spray freeze drying was employed to prepare dry powder of small nucleic acids. Mannitol and herring sperm DNA were used as bulking agent and model of small nucleic acid therapeutics, respectively. Formulations containing different solute concentration and DNA concentration were produced. The scanning electron microscope (SEM) images showed that the porosity of the particles increased as the solute concentration decreased. Powders prepared with solute concentration of 5% w/v were found to maintain a balance between porosity and robustness. Increasing concentration of DNA improved the aerosol performance of the formulation. The dry powder formulation containing 2% w/w DNA had a median diameter of 12.5?µm, and the aerosol performance study using next generation impactor (NGI) showed an emitted fraction (EF) and fine particle fraction (FPF) of 91% and 28% respectively. This formulation (5% w/v solute concentration and 2% w/w nucleic acid) was adopted subsequently to produce siRNA powder. The gel retardation and liquid chromatography assays showed that the siRNA remained intact after spray freeze drying even in the absence of delivery vector. The siRNA powder formulation exhibited a high EF of 92.4% and a modest FPF of around 20%. Further exploration of this technology to optimise inhaled siRNA powder formulation is warranted.

SUBMITTER: Liang W

PROVIDER: S-EPMC7032260 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Spray freeze drying of small nucleic acids as inhaled powder for pulmonary delivery.

Liang Wanling W Chan Alan Y L AYL Chow Michael Y T MYT Lo Fiona F K FFK Qiu Yingshan Y Kwok Philip C L PCL Lam Jenny K W JKW

Asian journal of pharmaceutical sciences 20171020 2

The therapeutic potential of small nucleic acids such as small interfering RNA (siRNA) to treat lung diseases has been successfully demonstrated in many <i>in vivo</i> studies. A major barrier to their clinical application is the lack of a safe and efficient inhaled formulation. In this study, spray freeze drying was employed to prepare dry powder of small nucleic acids. Mannitol and herring sperm DNA were used as bulking agent and model of small nucleic acid therapeutics, respectively. Formulat ...[more]

PMID: 32104389

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Project description:While all the siRNA drugs on the market target the liver, the lungs offer a variety of currently undruggable targets which could potentially be treated with RNA therapeutics. Hence, local, pulmonary delivery of RNA nanoparticles could finally enable delivery beyond the liver. The administration of RNA drugs via dry powder inhalers offers many advantages related to physical, chemical and microbial stability of RNA and nanosuspensions. The present study was therefore designed to test the feasibility of engineering spray dried lipid nanoparticle (LNP) powders. Spray drying was performed using 5% lactose solution (m/V), and the targets were set to obtain nanoparticle sizes after redispersion of spray-dried powders around 150 nm, a residual moisture level below 5%, and RNA loss below 15% at maintained RNA bioactivity. The LNPs consisted of an ionizable cationic lipid which is a sulfur-containing analog of DLin-MC3-DMA, a helper lipid, cholesterol, and PEG-DMG encapsulating siRNA. Prior to the spray drying, the latter process was simulated with a novel dual emission fluorescence spectroscopy method to preselect the highest possible drying temperature and excipient solution maintaining LNP integrity and stability. Through characterization of physicochemical and aerodynamic properties of the spray dried powders, administration criteria for delivery to the lower respiratory tract were fulfilled. Spray dried LNPs penetrated the lung mucus layer and maintained bioactivity for >90% protein downregulation with a confirmed safety profile in a lung adenocarcinoma cell line. Additionally, the spray dried LNPs successfully achieved up to 50% gene silencing of the house keeping gene GAPDH in ex vivo human precision-cut lung slices at without increasing cytokine levels. This study verifies the successful spray drying procedure of LNP-siRNA systems maintaining their integrity and mediating strong gene silencing efficiency on mRNA and protein levels both in vitro and ex vivo. The successful spray drying procedure of LNP-siRNA formulations in 5% lactose solution creates a novel siRNA-based therapy option to target respiratory diseases such as lung cancer, asthma, COPD, cystic fibrosis and viral infections.

Project description:Microcapsules of ciriguela peel extracts obtained by ultrasound-assisted extraction were prepared by spray drying, whose results were compared with those of freeze-drying as a control. The effects of spray-drying air temperature, feed flow rate and ratio of encapsulating agents (maltodextrin and arabic gum) were studied. Encapsulation efficiency, moisture content, total phenolic compounds (TPC), water activity, hygroscopicity, solubility, colorimetric parameters, phenolic profile by HPLC/DAD, simulated gastrointestinal digestion and morphology of spray-dried and freeze-dried microcapsules were evaluated, as well as their stability of TPC during 90 days storage at 7 and 25 °C. Spray-dried extract showed higher encapsulation efficiency (98.83%) and TPC (476.82 mg GAE g-1) than freeze-dried extract. The most abundant compounds in the liquid extract of ciriguela peel flour were rutin, epicatechin gallate, chlorogenic acid and quercetin. Rutin and myricetin were the major flavonoids in the spray-dried extract, while quercetin and kaempferol were in the freeze-dried one. The simulated gastrointestinal digestion test of microencapsulated extracts revealed the highest TPC contents after the gastric phase and the lowest one after the intestinal one. Rutin was the most abundant compound after the digestion of both spray-dried (68.74 µg g-1) and freeze-dried (93.98 µg g-1) extracts. Spray-dried microcapsules were of spherical shape, freeze-dried products of irregular structures. Spray-dried microcapsules had higher phenolic compounds contents after 90 days of storage at 7 °C compared to those stored at 25 °C, while the lyophilized ones showed no significant difference between the two storage temperatures. The ciriguela agro-industrial residue can be considered an interesting alternative source of phenolic compounds that could be used, in the form of bioactive compounds-rich powders, as an ingredient in pharmaceutical, cosmetic and food industries.

Project description:SARS-CoV-2, the causative agent of COVID-19, predominantly affects the respiratory tract. As a consequence, it seems intuitive to develop antiviral agents capable of targeting the virus right on its main anatomical site of replication. Ivermectin, a U.S. FDA-approved anti-parasitic drug, was originally shown to inhibit SARS-CoV-2 replication in vitro, albeit at relatively high concentrations, which is difficult to achieve in the lung. In this study, we tested the spray-drying conditions to develop an inhalable dry powder formulation that could ensure sufficient antiviral drug concentrations, which are difficult to achieve in the lungs based on the oral dosage used in clinical trials. Here, by using ivermectin as a proof-of-concept, we evaluated spray-drying conditions that could lead to the development of antivirals in an inhalable dry powder formulation, which could then be used to ensure sufficient drug concentrations in the lung. Thus, we used ivermectin in proof-of-principle experiments to evaluate our system, including physical characterization and in vitro aerosolization of prepared dry powder. The ivermectin dry powder was prepared with a mini spray-dryer (Buchi B-290), using a 23 factorial design and manipulating spray-drying conditions such as feed concentration (0.2% w/v and 0.8% w/v), inlet temperature (80 °C and 100 °C) and presence/absence of L-leucine (0% and 10%). The prepared dry powder was in the size range of 1-5 μm and amorphous in nature with wrinkle morphology. We observed a higher fine particle fraction (82.5 ± 1.4%) in high feed concentration (0.8% w/v), high inlet temperature (100 °C) and the presence of L-leucine (10% w/w). The stability study conducted for 28 days confirmed that the spray-dried powder was stable at 25 ± 2 °C/<15% RH and 25 ± 2 °C/ 53% RH. Interestingly, the ivermectin dry powder formulation inhibited SARS-CoV-2 replication in vitro with a potency similar to ivermectin solution (EC50 values of 15.8 µM and 14.1 µM, respectively), with a comparable cell toxicity profile in Calu-3 cells. In summary, we were able to manipulate the spray-drying conditions to develop an effective ivermectin inhalable dry powder. Ongoing studies based on this system will allow the development of novel formulations based on single or combinations of drugs that could be used to inhibit SARS-CoV-2 replication in the respiratory tract.

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Spray freeze drying of small nucleic acids as inhaled powder for pulmonary delivery.

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Spray freeze drying of small nucleic acids as inhaled powder for pulmonary delivery.

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