Design of porous microparticles with single-micron size by novel spray freeze-drying technique using four-fluid nozzle

Niwa, Toshiyuki; Shimabara, Hiroko; Kondo, Masahiro; Danjo, Kazumi

doi:10.1016/j.ijpharm.2009.08.011

Cited by 50 publications

(26 citation statements)

References 25 publications

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“…Cic0% particle composed of only mannitol had a tight network structure, which is characteristic morphology of SFD particles as reported in previous papers (Fig. 3A1), 13,14) however, the surface morphology became smooth at higher drug content (Figs. 3B1, 3C1).…”

Section: Preparation Of Composite Particles By Sfd Processsupporting

confidence: 83%

“…The schematic diagram of the entire apparatus and procedure for the current SFD technique was also reported in our previous paper. 13) The formulations of the spray solutions in this study are summarized in Table 1. Six types of particles with different drug content (0%, 5%, 10%, 20%, 50%, and 100%) were prepared by changing the loading amounts of ciclosporin and mannitol, and abbreviated to Cic0%, Cic5%, Cic10%, Cic20%, Cic50%, and Cic100%, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…13,14) These reports indicated that the resultant SFD composite particles had a porous and spherical morphology with a low particle density. The fluffy characteristics based on this unique internal structure prompted us to apply the particles to dry powder inhalation.…”

Section: Preparation Of Composite Particles By Sfd Processmentioning

confidence: 99%

“…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. Then, the iced droplets are lyophilized by a freeze-dryer to prepare composite particles, which are then characterized by fine porous structure producing a large specific surface area; this method is extremely attractive for the development of particles for dry powder inhaler (DPI) because of their specific low density.…”

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confidence: 99%

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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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Section: Preparation Of Composite Particles By Sfd Processsupporting

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Section: Preparation Of Composite Particles By Sfd Processmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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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“…20) In addition, SFD technique was further improved by adopting four-fluid nozzle (4N) to expand its application in pharmaceutical industry. 21) In the conventional process both API and a hydrophilic excipient, called drug and carrier in this report respectively, are necessary to be dissolved in common spray solution because two-fluid nozzle (2N) has only one liquid-supplying line. Using a common solvent would sometimes lead to restricted combination between API and the carrier.…”

mentioning

confidence: 99%

Novel Spray Freeze-Drying Technique Using Four-Fluid Nozzle-Development of Organic Solvent System to Expand Its Application to Poorly Water Soluble Drugs

Niwa

Shimabara

Danjo

2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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A significant number of active pharmaceutical ingredients (APIs) being discovered exhibit expected therapeutic behaviors, but unfortunately have undesirable drug-like properties such as low solubility and poor ADME performance, making formulation into an effective drug product challenging. In fact, more than 40% of the pharmaceutical candidates in the development pipelines are reported to be categorized as poorly soluble.1,2) These compounds are classified as biopharmaceutical classification system (BCS) class II for which their maximum bioavailability is limited by their rate of dissolution. 3,4) Improving the dissolution rate of these compounds is achieved through various approaches of formulation technology. These include particle size reduction/ milling, [5][6][7][8] solution-based precipitation, solid dispersion by hot melt extrusion 9) or spray-drying, 10,11) complexation with cyclodextrins 12,13) and so on, as also described extensively in reviews. 14,15) Cryogenic technologies such as freeze drying 16) and spray freezing into liquid (SFL), [17][18][19] in particular, have lately attracted considerable attention for BCS class II compounds. These processes use cryogen, particularly liquid nitrogen, to form a solid dispersion composed of nano-dispersed domains of API within the hydrophilic polymer matrix. In order to increase universality of unique lyophilization technique in SFL, authors have developed spray freeze-drying (SFD) technique before, which is combined the conventional spraydryer with freeze-dryer, both equipments are available in market. 20) In addition, SFD technique was further improved by adopting four-fluid nozzle (4N) to expand its application in pharmaceutical industry. 21) In the conventional process both API and a hydrophilic excipient, called drug and carrier in this report respectively, are necessary to be dissolved in common spray solution because two-fluid nozzle (2N) has only one liquid-supplying line. Using a common solvent would sometimes lead to restricted combination between API and the carrier. 4N having two liquid passages allows API and the carrier to be dissolved in separate solvents, overcoming this problem. In this research, the organic/aqueous co-solvent spray system was newly established in 4N-SFD process in which the poorly water-soluble drug was dissolved in organic solvent and the dissolution-modified carrier was dissolved in water, which is likely frequent combination for solubilization. Acetonitrile was selected as an organic spray solvent due to its good solvent property for many drugs, its relatively high melting point (Ϫ43.8°C) among organic solvents and its easily evaporated behavior with higher vapor pressure. Phenytoin and ciclosporin were used as a poorly water-soluble drug and two types of carrier were used as a dissolution modifier. In case using phenytoin, which is dissolved in aqueous alkaline solution as well as acetonitrile, 1) aqueous spray system (phenytoin dissolved in aqueous alkaline solution and the carrier dissolved in water; called 4N-SFD-aqua)...

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Spray Freeze Drying

Ishwarya

Anandharamakrishnan

Stapley

2017

Handbook of Drying for Dairy Products

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Design of porous microparticles with single-micron size by novel spray freeze-drying technique using four-fluid nozzle

Cited by 50 publications

References 25 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

Novel Spray Freeze-Drying Technique Using Four-Fluid Nozzle-Development of Organic Solvent System to Expand Its Application to Poorly Water Soluble Drugs

Spray Freeze Drying

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