Drug/lactose co-micronization by jet milling to improve aerosolization properties of a powder for inhalation

Giry, Karine; Péan, Jean-Manuel; Giraud, L.; Marsas, S.; Rolland, Hervé; Wüthrich, Patrick

doi:10.1016/j.ijpharm.2006.05.009

Cited by 43 publications

(12 citation statements)

References 8 publications

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“…4). In accordance with commonly recognized, 27,28) the jet-milled ciclosporin particles (described as "Cic bulk") were highly adhesive, resulting in the highest residual amount in capsule and the highest deposition on the device and throat components. It was assumed that the bulk particles tend to be trapped in the oropharyngeal region when inhaled.…”

Section: Preparation Of Composite Particles By Sfd Processsupporting

confidence: 64%

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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Section: Preparation Of Composite Particles By Sfd Processsupporting

confidence: 64%

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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“…It has been recognized in several earlier studies that the efficiency of a dry powder formulation is highly dependent on the size distribution of the lactose carrier used 21,22 and the content of fine lactose. 23 Two binary and four ternary 5-FU dry powder inhaler formulations with different fine lactose ratios were prepared ( Table 2).…”

Section: Preparation Of 5-fluorouracil Dry Powder Formulationsmentioning

confidence: 99%

Preparation of 5-fluorouracil nanoparticles by supercritical antisolvents for pulmonary delivery

Kalantarian

Najafabadi²,

Haririan

et al. 2010

IJN

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This study concerns the supercritical antisolvent process which allows single-step production of 5-fluorouracil (5-FU) nanoparticles. This process enhances the physical characteristics of 5-FU in order to deliver it directly to the respiratory tract. Several mixtures of methanol with dichloromethane, acetone, or ethanol were used for particle preparation, and their effects on the physical characteristics of the final products were studied. The conditions of the experiment included pressures of 100 and 150 bar, temperature of 40°C, and a flow rate of 1 mL/min. The particles were characterized physicochemically before and after the process for their morphology and crystallinity. In spite of differences in size, the particles were not very different regarding their morphology. The resulting particles were of a regular shape, partly spherical, and appeared to have a smooth surface, whereas the mechanically milled particles showed less uniformity, had surface irregularities and a high particle size distribution, and seemed aggregated. Particles of 5-FU precipitated from methanol-dichloromethane 50:50 had a mean particle size of 248 nm. In order to evaluate the aerodynamic behavior of the nanoparticles, six 5-FU dry powder formulations containing mixtures of coarse and fine lactose of different percentages were prepared. Deposition of 5-FU was measured using a twin-stage liquid impinger and analyzed using a validated high pressure liquid chromatography method. Addition of fine lactose improved the aerodynamic performance of the drug, as determined by the fine particle fraction.

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“…In situ micronization and microcrystallization are suitable methods for the production of micron-sized drugs (5)(6)(7). Compared with milled products, drug properties are optimized, the particle size is more uniformly distributed, and the powder is less cohesive (5)(6)(7)(8)(9)(10)(11)(12)(13). Gliclazide (GL), 3-(7-azabicyclo [3.3.0] oct-7-yl)-1-(4-methylphenyl)sulfonylurea is a second-generation sulfonylurea, widely used for the treatment of non-insulin-dependent diabetes mellitus.…”

Section: Introductionmentioning

confidence: 99%

Gliclazide Microcrystals Prepared by Two Methods of In Situ Micronization: Pharmacokinetic Studies in Diabetic and Normal Rats

et al. 2010

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Abstract. The low water-solubility of gliclazide (GL) leads to a low dissolution rate and variable bioavailability. The aim of this study was to investigate the effect of micronization on the absorption and pharmacokinetics of GL after oral administration in rats. GL microcrystals were prepared using solventchange and pH-shift methods. Scanning electron microscopy showed considerable changes in the shape and size of crystals using both methods. In the optimized formulation of each method, the particle size of treated GL was reduced about 30 (from 290 to 9.9 μm) and 61 times (to 4.76 μm) by solvent-change and pH-shift methods, respectively. Recrystallized samples showed faster dissolution rate than untreated GL particles. Glucose-lowering effect, C max , and area under the drug concentration-time profile (area under the curve (AUC)) were compared in diabetic and normal rats. AUC and C max were increased by microcrystals in both groups of animals. Administration of 40 mg/kg of GL in the form of untreated drug and microcrystals obtained by solvent-change and pH-shift methods caused 12.49% and 21.04% enhancement in glucose-lowering effect of GL in diabetic rats, respectively.

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Drug/lactose co-micronization by jet milling to improve aerosolization properties of a powder for inhalation

Cited by 43 publications

References 8 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

Preparation of 5-fluorouracil nanoparticles by supercritical antisolvents for pulmonary delivery

Gliclazide Microcrystals Prepared by Two Methods of In Situ Micronization: Pharmacokinetic Studies in Diabetic and Normal Rats

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