Application of a four-fluid nozzle spray drier to prepare inhalable rifampicin-containing mannitol microparticles.

The purpose of this study was to use a four-fluid nozzle spray drier as a new one-step method for preparing rifampicin (RFP)-containing mannitol microparticles. A RFP-acetone/methanol (2:1) solution and aqueous solutions of mannitol (MAN) were simultaneously supplied through different liquid passages of a four-fluid nozzle spray drier and then dried to obtain MAN microparticles containing RFP. Using a cascade impactor, the in vitro aerosol performance of RFP powder and RFP-MAN microparticles with 1:5, 1:10, and 1:20 ratios was compared. The in vivo retention of RFP in the lungs of rats after intratracheal administration of 1:20 RFP-MAN microparticles was also compared. The RFP-MAN microparticles had better aerosol performance than RFP powder and delivery to the lung stages improved as the fraction of MAN was increased. For the 1:20 RFP-MAN microparticles, deposition in stages 2-7 was approximately 43%, which is sufficient for treatment. Approximately 8% of the RFP-MAN microparticles were deposited in stages 6-7, which corresponds to alveoli containing alveolar macrophages. The initial retention of RFP in the lung following pulmonary delivery of 1:20 RFP-MAN microparticles was higher than following oral or intravenous administration of RFP, but the elimination was rapid, resulting in the disappearance of RFP from the lung within 4 h. The plasma concentration-time profile of RFP after intratracheal administration of 1:20 RFP-MAN microparticles was consistent with the profile for RFP retention in the lung. Addition of cholesterol or phosphatidylcholine to RFP had little effect on its retention in the lung. The RFP-MAN microparticles were effective for delivery of RFP to the lung, but the RFP rapidly removed from the lung into the blood circulation. This study demonstrated that RFP-containing MAN microparticles prepared in one step using the four-fluid nozzle spray drier efficiently deliver RFP to the lung, although methods must be developed to prolong its retention and improve targeting to alveolar macrophages.

Preparation of drug nanoparticle-containing microparticles using a 4-fluid nozzle spray drier for oral, pulmonary, and injection dosage forms.

We prepared microparticles containing nanoparticles of water-insoluble pranlukast hemihydrate (PLH) using a 4-fluid nozzle spray drier. These particles were designed to improve the absorption of PLH and to allow delivery by oral, pulmonary, and injection routes. Mannitol (MAN) was used as a water-soluble carrier for the microparticles. We orally administered suspensions of PLH powder and PLH-MAN microparticles to rats. We also compared the in vitro aerosol performance of the PLH powder and PLH-MAN microparticles using a cascade impactor, and we compared the delivery of PLH by oral administration of PLH powder and pulmonary delivery of PLH-MAN microparticles at PLH/MAN ratios of 1:4 and 1:10. The absorption of PLH was markedly enhanced by pulmonary deliver of PLH-MAN composite microparticles. The area under the plasma concentration-time curve per dose for pulmonary administration of the 1:4 and 1:10 PLH-MAN microparticles was approximately 85- and 100-fold higher, respectively, than for oral administration of PLH powder. Also, we found that PLH rapidly disappeared from the plasma following injection of PLH aqueous solution or PLH-MAN microparticles dissolved in water. The PLH particles remaining after dissolution of MAN from the 1:10 PLH-MAN microparticles were 200 nm in diameter. Therefore, PLH particles may be captured immediately after injection by reticuloendothelial tissues such as the liver and spleen. This study demonstrated that it is possible to use the 4-fluid spray drier to prepare microparticles containing PLH nanoparticles that that improve drug absorption and can be administered by oral, pulmonary, and injection routes.

One-step preparation of drug-containing microparticles to enhance the dissolution and absorption of poorly water-soluble drugs using a 4-fluid nozzle spray drier.

We studied the use of a 4-fluid nozzle spray drier as a new one-step method for preparing drug-containing microparticles to enhance the dissolution and absorption of poorly water-soluble drugs. We employed ethenzamide (EZ) and flurbiprofen (FP) as poorly water-soluble drugs and lactose (LAC) and mannitol (MAN) as water-soluble carriers for microparticles. EZ-ethanol or FP-acetone/methanol (2:1) solutions and aqueous solutions of LAC or MAN were simultaneously supplied through different liquid passages of a 4-fluid nozzle spray drier and then dried to obtain LAC or MAN microparticles containing EZ or FP. The dissolution of EZ from the EZ/LAC and EZ/MAN microparticles was much faster than that from EZ powder. The dissolution of EZ was more rapid from the EZ/MAN microparticles than the EZ/LAC microparticles. The dissolution of FP from the FP/MAN microparticles was greatly enhanced because of large effective surface area of FP dispersed in microparticles following rapid dissolution of MAN. The absorption of FP after oral administration of the FP/MAN microparticles to rats was markedly increased. The results demonstrate that the 4-fluid nozzle spray drier can be used for the one-step preparation of drug-containing microparticles that enhance the dissolution and absorption of poorly water-soluble drugs and that overcome the problem of finding a common solvent for drugs and carriers.

Preparation of polymeric submicron particle-containing microparticles using a 4-fluid nozzle spray drier.

PURPOSE: We studied a novel method for preparing polymeric submicron particle-containing microparticles using a 4-fluid nozzle spray drier. METHOD: Ethylcellulose (EC) and poly(lactic-co-glycolic acid) (PLGA), either alone or in combination with polyethylenimine (PEI), were used as polymers to produce submicron particles, and mannitol (MAN) was used as a water-soluble carrier for the microparticles. The polymer and MAN solutions were supplied through different liquid passages of a 4-fluid nozzle and then dried to obtain MAN microparticles containing EC or PLGA submicron particles. The polymer/MAN ratio was controlled by changing the concentration of the polymer and MAN solutions. EC or PLGA microparticles were observed via scanning electron microscopy, and the size of microparticles was determined by image analysis. The particle size distribution of EC or PLGA submicron particles was measured with a super dynamic light scattering spectrophotometer. RESULTS: The method generated submicron-sized (<1 microm) particles of EC and PLGA. The mean diameters of EC and PLGA particles at a polymer/MAN ratio of 1:10 were 631 and 490 nm, respectively. The mean diameter of PLGA particles decreased as the PLGA/MAN ratio was reduced, reaching approximately 200 nm at a PLGA/MAN ratio of 1:100. The mean diameter of PLGA/PEI particles at PLGA/PEI/MAN ratios of 1:0.5:10 and 1:0.5:100 were 525 and 223 nm, respectively, and their zeta potentials were +50.8 and +58.2 mV, respectively. The size of EC submicron particles could be controlled by varying the spray conditions. CONCLUSIONS: This study demonstrated that it is possible to prepare polymeric submicron particles dispersed in MAN microparticles in a single process using the 4-fluid nozzle spray drying method. Cationic PLGA particles with a diameter of approximately 200 nm could be prepared by adding PEI, suggesting the possibility of its use as a carrier for delivering DNA into cells. The precipitation of EC may occur by the mutual dispersion and mixing of solvents after collision of EC and MAN mists by antisolvent effect, thereby producing MAN microparticles containing EC submicron particles.

Preparation of two-drug composite microparticles to improve the dissolution of insoluble drug in water for use with a 4-fluid nozzle spray drier.

In this study, we used a novel 4-fluid nozzle spray drier to prepare composite microparticles of a water-insoluble drug, flurbiprofen (FP), and a water-soluble drug, sodium salicylate (SS), for the purpose of improving the water solubility of FP. An ethanol solution of FP and an aqueous SS solution were simultaneously introduced through different liquid passages in the 4-fluid nozzle spray drier and then spray-dried. Quantitative elemental analysis suggested that the FP/SS ratio in each composite microparticle was nearly the same as the formulation ratio. We also found that SS and FP exist in a low crystallinity state in the composite particles. Release of FP from dissolved composite microparticles was markedly improved because of an increase in the effective surface area following rapid dissolution of SS. This study shows that it is possible to prepare FP-SS composite microparticles using a 4-fluid nozzle spray drier in single process and that this can improve the ability of FP to dissolve in water.