Development of porous particles using dextran as an excipient for enhanced deep lung delivery of rifampicin

Kadota, Kazunori; Yanagawa, Yuko; Tachikawa, Tomoko; Deki, Yuto; Uchiyama, Hiromasa; Shirakawa, Yoshiyuki; Tozuka, Yuichi

doi:10.1016/j.ijpharm.2018.11.055

Cited by 51 publications

(23 citation statements)

References 67 publications

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“…Conventional DPIs use the first strategy, whereas large porous particles provide an example of the second strategy [ 6 , 7 ]. Large porous particles are recently becoming popular as the technique for both local and systemic applications by the pulmonary route to the lungs [ 8 , 9 , 10 , 11 , 12 ]. A major advantage of large porous particles compared to conventional DPIs is their aerosolization performance [ 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Simple Method to Measure the Aerodynamic Size Distribution of Porous Particles Generated on Lyophilizate for Dry Powder Inhalation

et al. 2020

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Recently, statistical techniques such as design of experiments are being applied for efficient optimization of oral formulations. To use these statistical techniques for inhalation formulations, efficient methods for rapid determination of the aerodynamic particle size distribution of many samples are needed. Therefore, we aimed to develop a simple method to measure aerodynamic particle size distribution that closely agrees with the results of inhalation characteristic tests. We added attachments for dispersion to the aerodynamic particle sizer (APS) so that formulations could be dispersed under the same condition as for multi-stage liquid impinger (MSLI) measurement. Then, we examined the correlation between MSLI and APS using lyophilizate for dry powder inhalation formulations that generate porous particles just on inhalation. It is difficult to obtain the accurate aerodynamic particle size distribution of porous particles by APS because the particle density is difficult to estimate accurately. However, there was a significant correlation between MSLI and APS when the particle density settings for APS measurement was calculated by a conversion factor based on the result of MSLI. The APS with dispersion attachments and this conversion factor can measure a number of samples in a short time, thereby enabling more efficient optimization of dry powder inhalers.

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Section: Introductionmentioning

confidence: 99%

Simple Method to Measure the Aerodynamic Size Distribution of Porous Particles Generated on Lyophilizate for Dry Powder Inhalation

et al. 2020

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“…This effect is particularly relevant in the 3:1 formulations, as dextran becomes enriched on the droplet surface during solvent evaporation where it reaches saturation and precipitates [ 17 ]. Since increasing dextran concentration in water has been found to increase the solution viscosity [ 32 ], incorporating more dextran within the formulation physically prevented mannitol from diffusing towards the droplet surface. As a result, mannitol can closely interact with AdHu5 in the particle core to provide stabilization though hydrogen bonding.…”

Section: Resultsmentioning

confidence: 99%

“…Since the molecular weight of dextran does not impact crystallinity, its impact on AdHu5 partitioning within the particle is diffusion controlled. Using a higher molecular weight dextran may further increase viscosity during drying [ 32 ], impeding molecular movement of the adenovirus that might otherwise lead to viral aggregation. However, at the 3:1 ratio, the 500 kDa dextran led to a slightly higher viral titre log loss than the 40 kDa formulation, suggesting that the molecular weight of dextran was less influential on viscosity than its concentration in the droplet.…”

Section: Resultsmentioning

confidence: 99%

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Dextran Mass Ratio Controls Particle Drying Dynamics in a Thermally Stable Dry Powder Vaccine for Pulmonary Delivery

et al. 2022

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Purpose Thermally stable, spray dried vaccines targeting respiratory diseases are promising candidates for pulmonary delivery, requiring careful excipient formulation to effectively encapsulate and protect labile biologics. This study investigates the impact of dextran mass ratio and molecular weight on activity retention, thermal stability and aerosol behaviour of a labile adenoviral vector (AdHu5) encapsulated within a spray dried mannitol-dextran blend. Methods Comparing formulations using 40 kDa or 500 kDa dextran at mass ratios of 1:3 and 3:1 mannitol to dextran, in vitro quantification of activity losses and powder flowability was used to assess suitability for inhalation. Results Incorporating mannitol in a 1:3 ratio with 500 kDa dextran reduced viral titre processing losses below 0.5 log and displayed strong thermal stability under accelerated aging conditions. Moisture absorption and agglomeration was higher in dextran-rich formulations, but under low humidity the 1:3 ratio with 500 kDa dextran powder had the lowest mass median aerodynamic diameter (4.4 µm) and 84% emitted dose from an intratracheal dosator, indicating strong aerosol performance. Conclusions Overall, dextran-rich formulations increased viscosity during drying which slowed self-diffusion and favorably hindered viral partitioning at the particle surface. Reducing mannitol content also minimized AdHu5 exclusion from crystalline regions that can force the vector to air-solid interfaces where deactivation occurs. Although increased dextran molecular weight improved activity retention at the 1:3 ratio, it was less influential than the ratio parameter. Improving encapsulation ultimately allows inhalable vaccines to be prepared at higher potency, requiring less powder mass per inhaled dose and higher delivery efficiency.

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“…In addition, the respiratory tract provides a less harsh and low enzymatic environment with minimal hepatic first-pass metabolism [14]. These unique hallmarks render pulmonary delivery an attractive non-invasive alternative route of administration for delivering small molecules and biological therapeutics for various potential treatments, such as antiviral, antibacterial, anti-inflammatory, anti-asthma, anti-hypertensive, and anticancer [14][15][16][17][18][19][20][21][22][23][24][25]. However, it should be noted that most of the marketed antiviral drugs are administered orally, which implies a significant proportion of drug is distributed to systemic circulation besides the lung.…”

Section: Introductionmentioning

confidence: 99%

Rational Development of a Carrier-Free Dry Powder Inhalation Formulation for Respiratory Viral Infections via Quality by Design: A Drug-Drug Cocrystal of Favipiravir and Theophylline

Wong

Weng

et al. 2022

Pharmaceutics

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Formulating pharmaceutical cocrystals as inhalable dosage forms represents a unique niche in effective management of respiratory infections. Favipiravir, a broad-spectrum antiviral drug with potential pharmacological activity against SARS-CoV-2, exhibits a low aqueous solubility. An ultra-high oral dose is essential, causing low patient compliance. This study reports a Quality-by-Design (QbD)-guided development of a carrier-free inhalable dry powder formulation containing a 1:1 favipiravir–theophylline (FAV-THP) cocrystal via spray drying, which may provide an alternative treatment strategy for individuals with concomitant influenza infections and chronic obstructive pulmonary disease/asthma. The cocrystal formation was confirmed by single crystal X-ray diffraction, powder X-ray diffraction, and the construction of a temperature–composition phase diagram. A three-factor, two-level, full factorial design was employed to produce the optimized formulation and study the impact of critical processing parameters on the resulting median mass aerodynamic diameter (MMAD), fine particle fraction (FPF), and crystallinity of the spray-dried FAV-THP cocrystal. In general, a lower solute concentration and feed pump rate resulted in a smaller MMAD with a higher FPF. The optimized formulation (F1) demonstrated an MMAD of 2.93 μm and an FPF of 79.3%, suitable for deep lung delivery with no in vitro cytotoxicity observed in A549 cells.

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Development of porous particles using dextran as an excipient for enhanced deep lung delivery of rifampicin

Cited by 51 publications

References 67 publications

Simple Method to Measure the Aerodynamic Size Distribution of Porous Particles Generated on Lyophilizate for Dry Powder Inhalation

Simple Method to Measure the Aerodynamic Size Distribution of Porous Particles Generated on Lyophilizate for Dry Powder Inhalation

Dextran Mass Ratio Controls Particle Drying Dynamics in a Thermally Stable Dry Powder Vaccine for Pulmonary Delivery

Rational Development of a Carrier-Free Dry Powder Inhalation Formulation for Respiratory Viral Infections via Quality by Design: A Drug-Drug Cocrystal of Favipiravir and Theophylline

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