Effect of surface covering of lactose carrier particles on dry powder inhalation properties of salbutamol sulfate

The effect of the surface covering of lactose carrier particles on the dry powder inhalation properties of salbutamol sulfate was investigated. Lactose carrier surfaces were covered with sucrose tristearate (J-1803F) by a high-speed elliptical-rotor-type powder mixer (Theta-Composer). In the present study, drug/carrier powder mixtures were prepared consisting of micronized salbutamol sulfate and lactose carriers with various particle surface conditions prepared by surface covering. These powder mixtures were aerosolized by a Jethaler), and the in vitro inhalation properties of salbutamol sulfate were evaluated by a twin impinger. Compared with the powder mixed with uncovered lactose carrier, the in vitro inhalation properties of the powder mixture prepared using the surface covering lactose carrier were significantly different, showing that the in vitro inhalation properties of salbutamol sulfate were improved. In vitro inhalation properties increased with the percentage of J-1803F added. Using this surface covering system would thus be valuable for increasing the inhalation properties of dry powder inhalation with lactose carrier particles.     

Preparation of dry powder inhalation with lactose carrier particles surface-coated using a Wurster fluidized bed

An attempt was made to produce carrier particles for dry powder inhalation with lactose carrier particles surface-coated using a Wurster fluidized bed. The lactose carrier particles were coated with lactose aqueous solution containing hydroxypropyl methyl cellulose (HPMC) as a binder using a Wurster coating apparatus. Drug/carrier powder mixtures were prepared consisting of micronized salbutamol sulfate and lactose carriers under various particle surface conditions. These powder mixtures were aerosolized by a Jethaler((R)), and the in vitro deposition properties of salbutamol sulfate were evaluated by a twin impinger. The in vitro inhalation properties of the powder mixture prepared using the coated lactose carrier differed significantly compared with those of the powder mixture prepared using the uncoated lactose carrier, indicating improvements in in vitro inhalation properties of sulbutamol sulfate. In vitro inhalation properties increased with the surface coating time. This surface coating system would thus be valuable for increasing the in vitro inhalation properties of dry powder inhalation with lactose carrier particles.     

Influence of storage humidity on the in vitro inhalation properties of salbutamol sulfate dry powder with surface covered lactose carrier

The influence of storage humidity on the in vitro inhalation properties of salbutamol sulfate dry powder with surface covered lactose carrier was investigated. In the present study, drug/carrier powder mixtures were prepared consisting of micronized salbutamol sulfate and lactose carriers with different particle surface conditions prepared by surface covering. Lactose carrier surfaces were covered with vegetable magnesium stearate (Mg-St-V) by a high-speed elliptical-rotor-type powder mixer (Theta-Composer). These powder mixtures were aerosolized by a Jethaler), and the in vitro inhalation properties of salbutamol sulfate were evaluated by a twin impinger. Compared with the powder mixed with uncovered lactose carrier, the in vitro inhalation properties of the powder mixture prepared using the surface covered lactose carrier were little decreased with increased in relative humidity (RH), showing that the in vitro inhalation properties of salbutamol sulfate were improved at high RH. Using this surface covering technique would thus be valuable for storage humidity of dry powder inhalation (DPI) with lactose carrier particles.     

Effect of surface layering time of lactose carrier particles on dry powder inhalation properties of salbutamol sulfate

The effect of the surface layering time of lactose carrier particles on the dry powder inhalation properties of salbutamol sulfate was investigated. Lactose carrier particles were layered with vegetable magnesium stearate by physical mixing. In the present study, drug/carrier powder mixtures were designed consisting of micronized salbutamol sulfate and lactose carriers with various particle surface conditions prepared by surface layering. These powder mixtures were aerosolized by a Jethaler, and the in vitro deposition properties of salbutamol sulfate were evaluated by a twin impinger. Compared with the powder mixed with unlayered lactose carrier, the in vitro inhalation properties of the powder mixture prepared using the surface layering lactose carrier were significantly different, showing that the in vitro inhalation properties of the drug/carrier powder mixtures were improved. In vitro deposition properties (RP) increased with surface layering time. Using this surface layering system would thus be valuable for increasing the inhalation properties of dry powder inhalation.     

Preparation of dry powder inhalation by surface treatment of lactose carrier particles

An attempt was made to produce carrier particles for dry powder inhalations by the surface treatment of lactose particles with aqueous ethanol solution. Drug/carrier powder mixtures were prepared consisting of lactose carriers with different particle surface properties and micronized salbutamol sulfate. These powder mixtures were aerosolized by Spinhaler, and in vitro deposition properties of salbutamol sulfate were evaluated by twin impinger. The degree of adhesion between drug particles and carrier particles was determined by the ultracentrifuge separation method. In addition, the air jet sieve method was used to evaluate characteristics of the separation of drug particles from carrier particles in airflow. The average adhesion force (F50) between the surface-treated lactose carrier and drug particles was significantly lower than that of powder mixed with the untreated lactose carrier, indicating that the degree of separation (T50) of drug particles from carrier particles was improved when surface-treated lactose carrier was used. This resulted in an improvement of in vitro inhalation properties.     

Evaluation of flow properties of dry powder inhalation of salbutamol sulfate with lactose carrier

The effects of the flow and packing properties of a drug/carrier powder mixture on emission of drug adhering to the carrier from capsules and inhalation devices were investigated. Model powder mixtures were designed consisting of lactose carriers with different particle shapes were prepared by surface treatment and micronized salbutamol sulfate. These powder mixtures were aerosolized by a Spinhaler, and in vitro deposition properties of salbutamol sulfate were evaluated by a twin impinger. The flow properties of the mixed powders were evaluated by the Carr's flowability index (FI) and Hausner's ratio (HR). The packing properties of the mixed powders were determined employing the tapping method. Compared with the powder mixed with the untreated lactose carrier, the FI, HR, and the constant K in Kawakita's equation of the powder mixture prepared using the surface-treated lactose carrier were significantly different, showing that the flow and packing properties of the drug/carrier powder mixture were improved. Using this surface-treated system, the handling of the powder mixture when packing into capsules is improved, which is desirable for handling dry powder inhalants. The fraction (%) of drug emitted from capsules and devices (EM) and the FI of the powder mixture were correlated. As the flow properties improved, the outflow of the powder mixture from capsules and devices became easier, and emission of drug adhering on the carrier from capsules and devices improved. Improvement of the inhalation process, such as the drug particles emitted from the inhalation system, is valuable for increasing inhalation properties of dry powder inhalation.     

Quantification of the surface morphologies of lactose carriers and their effect on the in vitro deposition of salbutamol sulphate

Application of the scanning probe microscopy technique for quantitative measurement of the surface roughness of lactose carriers was evaluated. The roughness values of four different lactose carriers were related to the in vitro deposition results of the drug, salbutamol sulphate. The rugosity values of the lactose carriers were represented by Ra values which were in the order of DCL-40>DCL-11>lactose 325M>lactose 200 M. In vitro deposition results using a twin impinger showed that rougher carrier surfaces generally allowed more drug particles to be emitted from the capsules and inhaler but the availability of the drug to stage 2 was reduced, as detachment of drug particles from the carrier surfaces was more hindered. There was an optimum Ra value for greater delivery of the drug particles to stage 2 of the twin impinger. A balance between adherence and detachment of the drug from the carrier surface was needed in order to optimize the delivery of a drug to the desired target sites using a dry powder inhaler.     

Application and mechanism of inhalation profile improvement of DPI formulations by mechanofusion with magnesium stearate

In our previous paper, we reported the inhalation properties of dry powder inhaler (DPI) formulations containing Compound A and mechanofusion-processed lactose carriers. The mechanofusion process with magnesium stearate (Mg-St) on the lactose carrier enhanced the fine particle fraction (FPF) value of the Andersen cascade impactor (ACI) study. The increase of FPF seemed to be associated with the increase of the dispersibility of drug particles. The objectives of this study were (1) to evaluate the applicability of lactose carrier mechanofusion-processed with Mg-St and (2) to examine the mechanism of FPF alteration by the mechanofusion process applied on the lactose carrier with or without additive. The inhalation profiles of DPI formulations containing four different pharmaceutical compounds were evaluated with an ACI. The dispersibility of the formulations was observed by particle size distribution measurement in the air stream and the adhesive force was measured bydirect separation method. It was found that higher FPF was obtained with lactose mechanofusion-processed with Mg-St as compared to control lactose carriers for all four compounds. This suggested that mechanofusion process with Mg-St is widely applicable in DPI formulations. The homogenization of surface adhesiveness was attributed to the increased FPF of the DPI including lactose mechanofusion-processed with Mg-St, as suggested by the combination of several physicochemical characteristics. Combination of different characterization methods would be of help to clarify the whole mechanism which defines the inhalation properties of DPI formulations.     

Novel approach to DPI carrier lactose with mechanofusion process with additives and evaluation by IGC

The effect of lactose carrier surface property on the inhalation profile of dry powder inhaler (DPI) was evaluated using a micronized drug (Compound A) by inverse gas chromatography (IGC). Mechanofusion with magnesium stearate (Mg-St) or sucrose stearate increased the fine particle fraction (FPF), considered to be due to decrease in the interaction between Compound A and the lactose carrier. The effect of Compound A concentration on FPF was smaller in mechanofusion-processed lactose compared to intact lactose, especially when processed with Mg-St. The relationship between the IGC parameters of the lactose and FPF was also investigated. FPF increased as both the dispersive component of the surface energy and acidity similarity between the lactose carriers and Compound A increased. Although further investigation is necessary, it could be suggested that acidity similarity decreases the interaction between Compound A and lactose, thus contributing to the increase in the FPF. In conclusion, (1) mechanofusion with Mg-St or sucrose stearate could be an effective method to improve FPF of a DPI drug formulation; (2) IGC would be a valuable method to investigate the interaction between a drug and the DPI carrier; and (3) a relationship between surface acidity and inhalation profile was suggested.     

A study of drug-carrier interactions in dry powder inhaler formulations using the Andersen cascade impactor, X-ray microanalysis and time of flight aerosol beam spectrometry (TOFABS)

The purpose of this study was to determine the in vitro deposition of both drug (albuterol sulfate) and carrier (lactose) particles in relation to each other from a dry powder inhaler formulation using an Andersen cascade impactor (ACI) and time of flight aerosol beam spectrometry (TOFABS). In addition, scanning electron microscopy (SEM) combined with X-ray microanalysis was employed to distinguish albuterol sulfate from lactose. Drug particles apparently penetrated deeper into the impactor than lactose particles contained in the formulation. In some certain stages of impactor, drug particles were separated from lactose particles. Although the TOFABS cannot distinguish between albuterol sulfate and lactose, the TOF spectra obtained from the Aerosizer would appear to be partly indicative of the interactions which exist between drug and carrier. One symmetrical TOF peak was obtained from drug or lactose alone. The TOF peak of the drug was always lower than the TOF of lactose. The times obtained for each powder between experiments were highly reproducible and typical of material and particle size. The use of SEM-X-ray microanalysis also allowed some qualitative characterization of shape and state of association of the two components.     

Influence of peak inspiratory flow rates and pressure drops on inhalation performance of dry powder inhalers

The aim of this study was to reveal the relationship between human inspiratory flow patterns and the concomitant drops in pressure in different inhalation devices, and the influence of the devices on inhalation performance. As a model formulation for inhalers, a physically mixed dry powder composed of salbutamol sulfate and coarse lactose monohydrate was selected. The drops in pressure at 28.3?L/min of three inhalation devices, Single-type, Dual-type, and Reverse-type, was 1.0, 5.1, and 8.7?kPa, respectively. Measurements of human inspiratory patterns revealed that although the least resistant device (Single) had large inter- and intra-individual variation of peak flow rate (PFR), the coefficients of variation of PFR of the three devices were almost the same. In tests with a human inspiratory flow simulator in vitro, inhalation performance was higher, but the variation in inhalation performance in the range of human flow patterns was wider, for the more resistant device. To minimize the intra- and inter-individual variation in inhalation performance for the model formulation in this study, a formulation design that allows active pharmaceutical ingredient to detach from the carrier with a lower inhalation flow rate is needed.     

Preparation of functional composite particles of salbutamol sulfate using a 4-fluid nozzle spray-drying technique

A previous study on spray-drying demonstrated that it could promote the solubility of poorly water-soluble drugs using water-soluble polymers. Here, the preparation of composite particles of salbutamol sulfate (Sb) with water-insoluble polymers, such as Eudragit RS (RS) or Eudragit RL (RL) as a carrier, was examined. Despite the water insolubility of both polymers, the permeability of water was low in the former but high in the latter. We attempted to prepare controlled release composite particles by exploiting the characteristics of these carriers. The composite particles of the three components (Sb, RS, and RL) were prepared using a 4-fluid nozzle spray-dryer, and their physico-chemical and dissolution properties were compared with physical mixtures. Examination of particle morphology by scanning electron microscopy (SEM) revealed that the particles from the spray-drying process had atomized to several microns and were spherical. Analysis by X-ray diffraction and differential scanning calorimetry revealed that diffraction peaks and heat of fusion of Sb in the spray-dried samples decreased, indicating that the drug was amorphous and formed a solid dispersion. FT-IR analysis suggested that the amino group of Sb and a carbonyl group of the polymers formed a hydrogen bond. A dissolution test of Sb-RS-RL particles prepared using the 4-fluid nozzle spray-drying method showed that release rates were depressed significantly compared to the physical mixture at pH 1.2 and 6.8, and the depression was greater when RS was used instead of RL, presumably because of the permeability difference. The compression of these particles into tablets revealed that desirable controlled released dosage forms could be prepared. In addition, Sb was used to simulate an anti-asthmatic drug. For this an Andersen cascade impactor for dry powder inhalers was used to investigate delivery to the lungs.     

Development of dry salbutamol sulfate powder with high inhalation performance independent of inhalation patterns

While dry powder inhalations are commonly used to treat pulmonary diseases, their clinical performance depends on patient inspiratory flow patterns. The purpose of this study was to develop a new powder with high and stable therapeutic performance for various patients. We applied the supercritical antisolvent (SCF) method to salbutamol sulfate (SS) to prepare a bulky SS particle (SS-SCF). Tests of in vitro inhalation performance with a human inspiratory flow simulator revealed SS-SCF to be less susceptible to inspiratory flow patterns than milled SS. When inspired, the unique structure seemed to be broken resulting in small fragments that could be delivered to the lungs. However, stability tests under physical stress showed tolerance for transportation and handling. In addition, optimization of the concentration of the SS solution applied to SCF method improved the in vitro inhalation performance of SS-SCF. These results indicated that a unique bulky SS powder prepared by the SCF method was useful for dry powder inhalation.     

Scanning white-light interferometry as a novel technique to quantify the surface roughness of micron-sized particles for inhalation

A novel approach of measuring the surface roughness of spherical and flat micron-sized drug particles using scanning white-light interferometry was applied to investigate the surface morphology of micron-sized active pharmaceutical ingredients (APIs) and excipient particles used for inhalation aerosols. Bovine serum albumin (BSA) and alpha-lactose monohydrate particles were chosen as model API and excipient particles, respectively. Both BSA and lactose particles were prepared with different degrees of surface corrugation using either controlled spray drying (four samples of BSA) or decantation (two samples of lactose). Particle size distributions were characterized by laser diffraction, and particles were imaged by scanning electron microscopy (SEM). Surface roughness of the BSA and lactose particles was quantified by white-light optical profilometry using vertical scanning interferometry (VSI) at full resolution using a 50x objective lens with 2.0x and 0.5x fields of view for BSA and lactose, respectively. Data were analyzed using Vision software (version 32, WYKO), and surface roughness values are expressed as root-mean-square roughness ( Rrms). Furthermore, data were compared to topographical measurements made using conventional atomic force microscopy. Analysis of the optical profilometry data showed significant variation in BSA roughness ranging from 18.58 +/- 3.80 nm to 110.90 +/- 13.16 nm for the smoothest and roughest BSA particles, respectively, and from 81.20 +/- 15.90 nm to 229.20 +/- 68.20 nm for decanted and normal lactose, respectively. The Rrms values were in good agreement with the AFM-derived values. The particle morphology was similar to SEM and AFM images. In conclusion, scanning white-light interferometry provides a useful complementary tool for rapid evaluation of surface morphology and roughness in particles used for dry powder inhalation formulation.     

Preparation and properties of inhalable nanocomposite particles: effects of the temperature at a spray-dryer inlet upon the properties of particles

To overcome the disadvantages both of microparticles and nanoparticles for inhalation, we have prepared nanocomposite particles as drug carriers targeting lungs. The nanocomposite particles having sizes about 2.5 μm composed of sugar and drug-loaded PLGA nanoparticles can reach deep in the lungs, and they are decomposed into drug-loaded PLGA nanoparticles in the alveoli. Sugar was used as a binder of PLGA nanoparticles to be nanocomposite particles and is soluble in alveolar lining fluid. The primary nanoparticles containing bioactive materials were prepared by using a probe sonicator. And then they were spray dried with carrier materials, such as trehalose and lactose. The effects of inlet temperature of spray dryer were studied between 60 and 120 °C and the kind of sugars upon properties of nanocomposite particles. When the inlet temperatures were 80 and 90 °C, nanocomposite particles with average diameters of about 2.5 μm are obtained and they are decomposed into primary nanoparticles in water, in both sugars are used as a binder. But, those prepared above 100 °C are not decomposed into nanoparticles in water, while the average diameter was almost 2.5 μm. On the other hand, nanocomposite particles prepared at lower inlet temperatures have larger sizes but better redispersion efficiency in water. By the measurements of aerodynamic diameters of the nanocomposite particles prepared with trehalose at 70, 80, and 90 °C, it was shown that the particles prepared at 80 °C have the highest fine particle fraction (FPF) value and the particles are suitable for pulmonary delivery of bioactive materials deep in the lungs. Meanwhile the case with lactose, the particles prepared at 90 °C have near the best FPF value but they have many particles larger than 11 μm.     

Lactose as a low molecular weight carrier of solid dispersions for carbamazepine and ethenzamide

Solid dispersions of carbamazepine or ethenzamide were prepared by melting and rapid cooling with liquid nitrogen using lactose as a carrier. The physical characteristics of these solid dispersions were investigated by powder X-ray diffraction, differential scanning calorimetry, and dissolution rate analysis. The degree of crystallinity of the drugs in solid dispersions decreased with decreases in the molar ratio of the drugs to lactose. Fourier-transform infrared (FT-IR) analysis demonstrated the presence of intermolecular hydrogen bonds between the primary amide group of carbamazepine and lactose. Dissolution studies indicated that the dissolution rate was markedly increased in solid dispersions compared with physical mixtures and pure drugs. These results indicated that lactose is useful as a carrier for the production of solid dispersions of drugs having a primary amide group in their structures.     

Use of the co-grinding method to enhance the dissolution behavior of a poorly water-soluble drug: generation of solvent-free drug-polymer solid dispersions

The solid dispersion (SD) technique is the most effective method for improving the dissolution rate of poorly water-soluble drugs. In the present work, SDs of the Ca2+ channel blocker dipfluzine (DF) with polyvinylpyrrolidone K30 (PVP) and poloxamer 188 (PLXM) were prepared by the powder solid co-grinding method under a solvent-free condition. The properties of all SDs and physical mixtures were investigated by X-ray diffraction, Fourier-transform infrared, differential scanning calorimetry, scanning electron microscopy, dissolution test, and particles size determination. Eutectic compounds were produced between the DF and PLXM matrix during the co-grinding process, whereas glass suspension formed in the SDs with PVP carrier. Hydrogen bond formation was not observed between DF and carriers and DF was microcrystalline state in the PVP and PLXM matrices. The solubility of DF in different concentration of carriers at 25, 31, and 37°C was investigated; the values obtained were used to calculate the thermodynamic parameters of interaction between DF and carriers. The Gibbs free energy (ΔrGθ) values were negative, indicating the spontaneous nature of dispersing DF into the carriers. Moreover, entropy is the drive force when DF disperses into the matrix of PVP, while, enthalpy-driven dispersing encounters in the PLXM carrier. All the SDs of DF/carriers showed a considerably higher dissolution rate than pure DF and the corresponding physical mixtures. The cumulative dissolution rate at 10?min of the SD with a 1?:?3 DF/carrier ratio increased 5.1-fold for PVP and 5.5-fold for PLXM.     

Spray freeze-dried porous microparticles of a poorly water-soluble drug for respiratory delivery

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.     

Formulation optimization and in vitro antibacterial ability investigation of azithromycin loaded FDKP microspheres dry powder inhalation

Azithromycin loaded fumaryl diketopiperazine(FDKP) dry powder inhalation was designed and prepared for the treatment of community-acquired pneumonia.The solubility of FDKP and stability of azithromycin solution was investigated.Formulation of azithromycin loaded FDKP microparticle was investigated and optimized by the single factor experiment.High-pressure homogenization and spray drying conditions were also optimized to prepare the particles by spray drying azithromycin dissolved FDKP microparticle suspension at pH 4.5.The in vitro antibacterial efficiency and in vitro dispersion performance was also investigated to confirm the antibacterial efficiency,dispersion and deposition behavers.FDKP/azithromycin mass ratio(3:2) was the optimized formulation of azithromycin loaded FDKP microparticle with the maximal drug loading efficiency.High-pressure homogenization and spray drying conditions were also optimized.The in vitro antibacterial results indicated that only with the antibiotic concentration higher than mutant prevention concentration could totally inhibit the reproduction of bacteria.In vitro dispersion performance of azithromycin loaded FDKP microparticles(AZM@FDKP-MPs) also shows remarkable improvement of dispersion and deposition behavers of AZM.AZM@FDKP-MPs dry powder inhalation as a targeting delivery route has better potential for lung infection treatment.     

The surface composition of spray-dried protein—lactose powders

The surface composition of spray-dried mixtures of lactose-protein and lactose-glycine were estimated by means of electron spectroscopy for chemical analysis (ESCA). The results show that even with a low concentration of protein (0.01 wt.%) in the solution to be dried, protein starts to appear on the surface of the powder. At a protein/lactose ratio of 1/99 the protein starts to dominate the powder surface. At a protein/lactose ratio of 20/80, about 70% of the surface is covered by protein. The results are similar for the proteins sodium caseinate and bovine albumin.

The spray drying of mixtures of lactose and glycine gives a different result. In this case, the surface composition of the powder reflects the composition of the mixture to be dried.

The surface tensions of the solutions show that the proteins have a higher surface activity than lactose, since even a small amount of protein added to a lactose solution lowers the surface tension considerably. Glycine affects the surface tension only to a minor extent.

These results show that the composition of the air-water interface of the drying droplets is reflected in the surface composition of the dried powder. In addition, scanning electron micrographs show that the changes in the powder structure when protein is added to the solution are associated with the presence of protein on the surface. When the surface coverage of protein increases, dents start to appear in the particles. The powders made from lactose-glycine solutions are highly agglomerated regardless of the glycine concentration.