Cyclodextrins in the production of large porous particles: Development of dry powders for the sustained release of insulin to the lungs

Ungaro, Francesca; Rosa, Giuseppe De; Miro, Agnese; Quaglia, Fabiana; Rotonda, Maria Immacolata La

doi:10.1016/j.ejps.2006.05.005

Cited by 114 publications

(65 citation statements)

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“…8,9) Furthermore, Ungaro et al prepared gas-foamed large porous particles based on poly(lactic-co-glycolic) acid polymer (PLGA) via a double emulsion-solvent evaporation technique. [10][11][12] These reports concluded that spherical particles with hollow or porous internal structures exhibited extremely better flow and aerosolization properties than the normal mechanically micronized crystalline.We previously developed a spray freeze-drying (SFD) method, which is a combination of conventional spray-drying and freeze-drying techniques. 13,14) In this method, a solution of the drug and release-modified excipient is co-sprayed into liquid nitrogen, causing the solution to immediately freeze and form a suspension.…”

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Spray Freeze-Dried Porous Microparticles of a Poorly Water-Soluble Drug for Respiratory Delivery

Niwa

Mizutani

Danjo

2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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Particles of poorly water-soluble drugs were prepared to develop a dry powder inhaler (DPI). Spray freeze-drying (SFD) technique using a four-fluid nozzle (4N), which has been developed by authors, was applied in this research. Ciclosporin and mannitol were used as a poorly water-soluble model drug and a dissolution-enhanced carrier, respectively. The organic solution of ciclosporin and aqueous solution of mannitol were separately and simultaneously atomized through the 4N, and the two solutions were collided with each other at the tip of the nozzle edge. The spray mists were immediately frozen in liquid nitrogen to form a suspension. Then, the iced droplets were freeze-dried to prepare the composite particles of the drug and carrier. tert-Butyl alcohol (t-BuOH) was used as the organic spray solvent due to its relatively high freezing point. The resultant composite particles with varying drug content were characterized depending on their morphological and physicochemical properties. The particles contained amorphous ciclosporin and δ-crystalline mannitol. The characteristic porous structure of SFD particles potentially contributed to their good aerodynamic performance. A series of particles with a similar size distribution and different drug content revealed that the incorporation of mannitol successfully improved the cohesive behavior of ciclosporin, leading to enhanced aerosol dispersion. The dissolution test method using low-volume medium was newly established to simulate the release process from particles deposited on the surface of the bronchus and pulmonary mucosa. The composite with hydrophilic mannitol dramatically improved the in vitro dissolution behavior of ciclosporin in combination with the porous structure of SFD particles.Key words spray freeze-drying; liquid nitrogen; ciclosporin; porous particle; tert-butyl alcohol Inhalation is the most appropriate route to deliver drugs to treat respiratory disorders such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis.1-3) This route directly targets the site of action and reduces the occurrence of systemic adverse effects. In addition, there is increasing interest in the use of pulmonary delivery to administer systemically-acting macromolecules, such as inhaled insulin product.4) The aerodynamic size of drug particles should be 5-6 µm or less for optimal airway deposition.5-7) However, particles in this size range have potentially cohesive property and tend to disperse poorly.One approach to achieve excellent inhalation delivery by simultaneously improving the micromeritic properties and reducing the cohesive properties of agents is to design spherical particles with relative large geometric diameters and low particle mass densities. Inter-particulate cohesion could be reduced by enlarging and spheronizing the individual particle, and aerosol performance could be improved by decreasing the weight of the particles, ultimately like soap bubbles. In particular, particle design focused on particle density has been specifically resear...

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confidence: 99%

Spray Freeze-Dried Porous Microparticles of a Poorly Water-Soluble Drug for Respiratory Delivery

Niwa

Mizutani

Danjo

2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…37 Furthermore, the ED, FPF, and RF values were all high compared to other values reported in the literature. 54,55 While not all of these submit your manuscript | www. aerosol performance parameters are often reported, FPF% values for porous poly(lactic-co-glycolic acid) particles were reported to be in the range of 10.7%-33.8% 5 and sodium alendronate from 34.4% to 62.0%.…”

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Design, physicochemical characterization, and optimization of organic solution advanced spray-dried inhalable dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine poly(ethylene glycol) (DPPE-PEG) microparticles and nanoparticles for targeted respiratory nanomedicine delivery as dry powder inhalation aerosols

Meenach¹,

Vogt²,

Anderson³

et al. 2013

IJN

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Novel advanced spray-dried and co-spray-dried inhalable lung surfactant-mimic phospholipid and poly(ethylene glycol) (PEG)ylated lipopolymers as microparticulate/ nanoparticulate dry powders of biodegradable biocompatible lipopolymers were rationally formulated via an organic solution advanced spray-drying process in closed mode using various phospholipid formulations and rationally chosen spray-drying pump rates. Ratios of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine PEG (DPPE-PEG) with varying PEG lengths were mixed in a dilute methanol solution. Scanning electron microscopy images showed the smooth, spherical particle morphology of the inhalable particles. The size of the particles was statistically analyzed using the scanning electron micrographs and SigmaScan ® software and were determined to be 600 nm to 1.2 µm in diameter, which is optimal for deep-lung alveolar penetration. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were performed to analyze solid-state transitions and long-range molecular order, respectively, and allowed for the confirmation of the presence of phospholipid bilayers in the solid state of the particles. The residual water content of the particles was very low, as quantified analytically via Karl Fischer titration. The composition of the particles was confirmed using attenuated total-reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy and confocal Raman microscopy (CRM), and chemical imaging confirmed the chemical homogeneity of the particles. The dry powder aerosol dispersion properties were evaluated using the Next Generation Impactor™ (NGI™) coupled with the HandiHaler ® dry powder inhaler device, where the mass median aerodynamic diameter from 2.6 to 4.3 µm with excellent aerosol dispersion performance, as exemplified by high values of emitted dose, fine particle fraction, and respirable fraction. Overall, it was determined that the pump rates defined in the spray-drying process had a significant effect on the solid-state particle properties and that a higher pump rate produced the most optimal system. Advanced dry powder inhalers of inhalable lipopolymers for targeted dry powder inhalation delivery were successfully achieved. Dovepresssubmit your manuscript | www.dovepress.com

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“…Chitosan has the ability to modify the particle morphology and surface of drugs, subsequently, increase the deposition of drug in the lungs due to the improved aerosolization properties. 19) What is more, the bioadhesive effect of chitosan particles may be useful in enhancing drug absorption subsequent to inhalation.…”

Section: Optimization and Characterization Of Dry Powder Of Fanhuncaomentioning

confidence: 99%

Optimization and Characterization of Dry Powder of Fanhuncaoin for Inhalation Based on Selection of Excipients

Yang

Wang

Pan

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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Regular ArticleDrug delivery to the lungs is highly desirable, especially in patients with specific pulmonary diseases such as chronic pulmonary infections. It can reduce systemic side effects and increase doses of the applicable medication at the site of drug action. It's also a good idea to choose inhalation for systemic therapies because the respiratory region of the lung has an enormous surface area (80-100 m 2 /adult), a highly permeable membrane (0.1-0.2 mm) for the absorption of medication into the blood and a blood flow about 5 l/min, which rapidly transports molecules throughout the body. 1) Large protein molecules, which degrade in the terrible gastrointestinal conditions, can be delivered via the pulmonary route. In addition, it is a needle-free delivery system capable of increasing the compliance of patients.The 1-5 mm aerodynamic diameter range is needed for particles to be inhaled in order to avoid deposition in the oropharynx and maximize deposition in the lower respiratory tract.2) Generally, drugs for inhalation in dry powder inhaler (DPI) systems are micronized to achieve the requisite size; however, particles in this size range show strong interparticulate cohesion, leading to poor powder flow properties.3,4) In addition, factors that are known to influence the aerosolization properties of dry powders, such as particle morphology, density and surface composition, can not be well controlled by the micronization process. 5)Spray drying, an alternative approach to the generation of potentially respirable powders with respect to local pulmonary drug delivery, offers advantages to manipulate and control a variety of parameters such as temperature and relative humidity, solute concentration, solvent composition, solution and gas feed rate, droplet size, etc. This allows optimization of particle characteristics such as particle size, size distribution, density and morphology, and then macroscopic powder properties such as bulk density, flowability and dispersibility. 6)Senecio cannabifolius LESS. (Kuan Ye Fan Hun Cao in Chinese), as one species of Senecio genus of Compositae family, shows the effects on dispelling ecchymoma, anastalsis and algesic. As one kind of folk medicine, it's usually used to treat the diseases, such as virus influenza and many kinds of inflammatories. Unfortunately, In 2004, the importing of many kinds of preparations made from the species of Senecio genus from China had been prohibited by American and Europe drug administrative departments, because of the existence of one of its chemical constituents named pyrrolizidine alkaloids, which exhibited the chronical hepatotoxicity (liver toxicity) and cancerigenic possibility to the human beings. In order to deal with the contradiction between the toxicity and efficiency on the treatment, 52 compounds were obtained from the herb by many kinds of isolation method, such as silica gel chromatography, Lobar column, semi-preparative HPLC (PHPLC) and so on. Among the 52 compounds, 14 of them were isolated from the Senecio genus for the f...

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Cyclodextrins in the production of large porous particles: Development of dry powders for the sustained release of insulin to the lungs

Cited by 114 publications

References 29 publications

Spray Freeze-Dried Porous Microparticles of a Poorly Water-Soluble Drug for Respiratory Delivery

Spray Freeze-Dried Porous Microparticles of a Poorly Water-Soluble Drug for Respiratory Delivery

Optimization and Characterization of Dry Powder of Fanhuncaoin for Inhalation Based on Selection of Excipients

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