Formulation and characterization of spray-dried powders containing nanoparticles for aerosol delivery to the lung

Spray-drying is a common practice of powder preparation for a wide range of drugs. Spray-dried powders can be used to deliver particles to the lungs via a dry powder inhaler (DPI). The present study investigated the feasibility of developing a platform for aerosol delivery of nanoparticles. Lactose was used as the excipient and spray-dried with two different types of nanoparticles: gelatin and polybutylcyanoacrylate nanoparticles. Results showed that some carrier particles were hollow while others had a continuous matrix. Gelatin nanoparticles were incorporated throughout the matrix and sometimes accumulated at one end of the lactose. Polycyanoacrylate nanoparticles mostly clustered in different spots within the lactose carriers. The mean sizes of both nanoparticle types were characterized at two different times: before they were spray-dried and after they were redissolved from the spray-dried powders. Both nanoparticle types remained in the nano-range size after spray-drying. The mean nanoparticle sizes were increased by approximately 30% after spray-drying, though this increase was statistically significant only for the gelatin nanoparticles. Dispersion of the powder with an in-house passive dry powder inhaler and subsequent cascade impaction measurements showed that incorporation of the nanoparticles did not affect the fine particle fraction (FPF) or mass median aerodynamic diameter (MMAD) of the powders. FPF was approximately 40% while MMAD was 3.0+/-0.2 microm, indicating the present formulations yield aerosols of a suitable particle size for efficient lung delivery of nanoparticles.The present work demonstrates that nanoparticles can be delivered to the lungs via carrier particles that dissolve after coming in contact with the aqueous environment of the lung epithelium. This opens the way for new drug-targeting strategies using nanoparticles for pulmonary delivery of drugs and diagnostics.     

Formulation and cytotoxicity of doxorubicin nanoparticles carried by dry powder aerosol particles

Regional drug delivery via dry powder inhalers offers many advantages in the management of pharmaceutical compounds for the prevention and treatment of respiratory diseases. In the present study, doxorubicin (DOX)-loaded nanoparticles were incorporated as colloidal drug delivery system into inhalable carrier particles using a spray-freeze-drying technique. The cytotoxic effects of free DOX, carrier particles containing blank nanoparticles or DOX-loaded nanoparticles on H460 and A549 lung cancer cells were assessed using a colorimetric XTT cell viability assay. The mean geometric carrier particle size of 10+/-4 microm was determined using confocal laser scanning microscopy. DOX-loaded nanoparticles had a particle size of 173+/-43 nm after re-dissolving of the carrier particles. Compared to H460 cells, A549 cells showed less sensitivity to the treatment with free DOX. The DOX-nanoparticles showed in both cell lines a higher cytotoxicity at the highest tested concentration compared to the blank nanoparticles and the free DOX. The cell uptake of free DOX and DOX delivered by nanoparticles was confirmed using confocal laser scanning microscopy. This study supports the approach of lung cancer treatment using nanoparticles in dry powder aerosol form.     

The use of different grades of lactose as a carrier for aerosolised salbutamol sulphate

Five different grades of lactose namely, anhydrous lactose, medium lactose, regular lactose, lactose crystals and foremost lactose were fractionated under similar conditions to obtain a size range of 63-90 microm and were characterised using laser diffraction and time-of-flight particle sizing techniques, scanning electron microscopy, optical microscopy image analysis, thermal gravimetric analysis and differential scanning calorimetry. Each of these lactose fractions were then blended separately with micronised salbutamol sulphate in a ratio of 67.5:1 (w/w). The mixing uniformity and percentage recovery of salbutamol sulphate in the powder blends were analysed using a validated HPLC method. The deposition profiles of the drug were determined using a 5-stage liquid impinger after aerosolisation at 60 l min(-1) via a Rotahaler. Despite the identical processing conditions, the lactose fractions were shown to differ in particle size, size distribution and concentrations of fine particles. The particles from each fraction also exhibited different surface textures and dissimilar DSC thermograms. However, all the blends of the lactose with salbutamol sulphate were found to have a relatively high uniformity of salbutamol sulphate content, as suggested by a coefficient of variation of less than 3.2%. Anhydrous and medium lactose produced a more efficient delivery of salbutamol sulphate when aerosolised from the Rotahaler in comparison to other grades of lactose. For example, the fine particle fraction (FPF) and fine particle dose (FPD) of drug from formulations containing anhydrous lactose were 13.4+/-4.2% and 57.3+/-17.6 microg, respectively, which were approximately two times higher than the respective values of the formulation containing regular lactose. Medium lactose resulted in drug FPF (7. 9+/-2.7%) and FPD (32.4+/-11.8 microg), which were significantly (ANOVA P<0.05) higher than the same parameters obtained using lactose crystals, foremost lactose and regular lactose. More efficient drug delivery from anhydrous lactose may be partly attributed to the relatively higher concentration of fine lactose in this grade of carrier, although it showed a rougher surface than the other grades of lactose. However, the relatively high FPF of the drug from medium lactose may have been due to the relatively small mean particle size and smooth surface of the particles. Therefore, the source and grade of lactose may have a substantial effect on drug delivery from dry powder inhaler formulations and care should be taken in establishing appropriate quality control parameters when selecting an appropriate grade of carrier.     

Lactose as a carrier in dry powder formulations: the influence of surface characteristics on drug delivery.

The aim of the study was to investigate the interdependence of carrier particle size, surface treatment of the carrier, and inclusion of fines on the drug delivery from dry power inhaler formulations. Two size fractions (< 63 and 63-90 microm) of alpha-lactose monohydrate were subjected to treatment with 95% (v/v) ethanol to introduce small asperities or cavities onto the otherwise smooth surface without substantially changing the particle shape. After blending with albuterol sulfate [ALB; volume median diameter (VMD), 1.9 microm; geometric standard deviation (GSD), 1.5], the solvent-treated lactose produced a fine particle fraction (FPF; < 6.18 microm) and dispersibility of the drug that was significantly (ANOVA p < 0.01) lower than that which resulted from formulations containing untreated lactose of a similar size fraction, after aerosolization at 60 L min(-1) via a Rotahaler. The two size fractions of the treated lactose resulted in similar deposition profiles of ALB. The effects of such surface asperities or cavities of lactose were offset by introducing a small amount (5% w/w) of smaller-sized lactose (5-10 microm) to the powder formulations. The fine lactose increased the FPF and dispersibility of ALB to such a level that all lactose batches, regardless of particle size or whether solvent treated, produced a similar fraction of aerosolized ALB. The inclusion of recrystallized needle lactose (5-15 microm) was superior to micronized lactose in improving the aerosolization of ALB. The findings of this study indicate that the presence and characteristics of the finer fraction of lactose carrier particles dominate over the particle size and surface smoothness of the carrier particles in determining dispersion and deaggregation of drugs from dry powder formulations for inhalation.     

Size-dependency of nanoparticle-mediated gene transfection: studies with fractionated nanoparticles

Nanoparticles formulated from biodegradable polymers such as poly (lactic acid) and poly (D,L-lactide-co-glycolide) (PLGA) are being extensively investigated as non-viral gene delivery systems due to their sustained release characteristics and biocompatibility. PLGA nanoparticles for DNA delivery are mainly formulated using an emulsion-solvent evaporation technique. However, this formulation procedure results in the formation of particles with heterogeneous size distribution. The objective of the present study was to determine the relative transfectivity of the smaller- and the larger-sized fractions of nanoparticles in cell culture. PLGA nanoparticles containing a plasmid DNA encoding luciferase protein as a marker were formulated by a multiple emulsion-solvent evaporation method (mean particle diameter = 97 +/- 3 nm) and were fractionated using a membrane (pore size: 100 nm) filtration technique. The particles that passed through the membrane were designated as the smaller-sized nanoparticles (mean diameter = 70 +/- 2 nm) and the fraction that was retained on the membrane as the larger-sized nanoparticles (mean diameter = 202 +/- 9 nm). The smaller-sized nanoparticles showed a 27-fold higher transfection than the larger-sized nanoparticles in COS-7 cell line and a 4-fold higher transfection in HEK-293 cell line. The surface charge (zeta potential), cellular uptake, and the DNA release were almost similar for the two fractions of nanoparticles, suggesting that some other yet unknown factor(s) is responsible for the observed differences in the transfection levels. The results suggest that the particle size is an important factor, and that the smaller-sized fraction of the nanoparticle formulation predominantly contributes towards their transfection.     

A human oral-throat cast integrated with a twin-stage impinger for evaluation of dry powder inhalers

The aim of this study was to investigate the applicability of replacing the glass throat from a twin-stage impinger (TSI) with a human oral-throat cast. Monodisperse aerosols were used to calibrate the human oral cast-TSI at 60 L min(-1) and cut-off in particle size was compared with that of the TSI described in the British Pharmacopoeia which employs a glass throat. The amount of salbutamol sulphate (and lactose) delivered by the Cyclohaler depositing on various elements of the in-vitro model were determined. The calibration of the model containing a human oral-throat cast at 60 L min(-1) gave a particle size cut-off of 5.2 microm which was less than that of the TSI (6.3 microm). The oral-throat cast trapped more drug than the glass throat model with a formulation that employed the larger carrier (63-90 microm; P<0.05) while it trapped a lesser amount of drug with those filled with the lower size carrier (Lactochem, micronised lactose). The greater amount of lactose in the formulation that employed the larger-sized carrier (63-90 microm) was deposited closer to the inlet of the oral-throat cast than to the inlet of the glass throat model. Replacement of the glass throat in the TSI by the human oral-throat cast, leads to a change in deposition efficiency, with the cast having a higher filter efficiency and hence more aerosol particles being captured before their entry into the TSI. This should be investigated further to determine whether such a model might provide a more realistic assessment of the in-vivo characteristics of an aerosol in comparison with the TSI currently being employed, which utilises the glass throat as the portal of entry.     

Pulmonary drug delivery with aerosolizable nanoparticles in an ex vivo lung model

The use of colloidal carrier systems for pulmonary drug delivery is an emerging field of interest in nanomedicine. The objective of this study was to compare the pulmonary absorption and distribution characteristics of the hydrophilic model drug 5(6)-carboxyfluorescein (CF) after aerosolization as solution or entrapped into nanoparticles in an isolated rabbit lung model (IPL). CF-nanoparticles were prepared from a new class of biocompatible, fast degrading, branched polyesters by a modified solvent displacement method. Physicochemical properties, morphology, encapsulation efficiency, in vitro drug release, stability of nanoparticles to nebulization, aerosol characteristics as well as pulmonary dye absorption and distribution profiles after nebulization in an IPL were investigated. CF-nanoparticles were spherical in shape with a mean particle size of 195.3+/-7.1nm, a polydispersity index of 0.225+/-0.017 and a zeta-potential of -28.3+/-0.3mV. Encapsulation efficiencies of CF were as high as about 60% (drug loading of 3% (w/w)); 90% of the entrapped CF were released during the first 50min in vitro. Nanoparticle characteristics were not significantly affected by the aerosolization process utilizing a vibrating mesh nebulizer. After deposition of equal amounts of CF in the IPL, less CF was detected in the perfusate for CF-nanoparticles (plateau concentration 9.2+/-2.4ng/ml) when compared to CF aerosolized from solution (17.7+/-0.8ng/ml). In conclusion, the data suggest that inhalative delivery of biodegradable nanoparticles may be a viable approach for pulmonary drug delivery. Moreover, a targeting effect to the lung tissue is claimed.     

Comparative study of erythritol and lactose monohydrate as carriers for inhalation: atomic force microscopy and in vitro correlation.

The adhesion of micronised salbutamol sulphate to two carrier excipients, lactose monohydrate and erythritol, was investigated using the atomic force microscope (AFM) colloid probe technique and correlated with their respective physico-mechanical properties and aerosolisation performance. The particle size, morphology and moisture sorption properties of the carriers were similar thereby allowing direct comparison of functionality. AFM force measurements (n = 1024 force curves) were obtained between salbutamol sulphate drug probes (n = 4) and the excipients, as 63-90 microm sieve fractions and atomically smooth crystals. In general, significant differences in drug adhesion to lactose monohydrate and erythritol were observed (ANOVA, p<0.05), with erythritol exhibiting relatively greater adhesiveness. A linear relationship between drug probe adhesion to lactose monohydrate and drug probe adhesion to erythritol was established with salbutamol sulphate-lactose monohydrate adhesion being 60-70% of that of the erythritol system. In vitro analysis suggested good correlation with the adhesion measurements. The aerosolisation of salbutamol sulphate from erythritol carrier particles was significantly less (ANOVA, p<0.05) than from lactose monohydrate, with a fine particle dose (<6.4 microm) of 41.9 +/- 7.4 microg and 24.9 +/- 3.1 microg for the lactose monohydrate and erythritol carriers, respectively (n = 3).     

Pulmonary deposition of lactose carriers used in inhalation powders

Dry powder dosage forms are generally formulated by mixing the micronized drug particles with the larger carrier particles. Lactose is a commonly used carrier. Carriers enhance the flowability of powder mixtures and therefore enable low dosing of active substances. During inhalation, the drug particles are dispersed from the surface of carrier particles. The aim of this study was to compare how different qualities of 99mTc-labelled lactose carrier systems deposit in the lungs. The sizes of the labelled and unlabelled alpha-lactose monohydrate particles were compared by using a laser diffraction method. Distribution of radiolabel between different particle size fractions was determined using the Andersen cascade impactor. The in vivo depositions of lactose carrier systems were investigated in ten healthy men using the technique of gammascintigraphy. In addition, redispersion of budesonide from the carrier materials was evaluated by using the Andersen cascade impactor. According to the validation data the particle size of the lactose carriers remained unchanged during the labelling process. Low pulmonary deposition varying between 2.5 and 3.3% was detected. Only a small amount of lactose was deposited in the lungs, thus pulmonary deposition is not a limiting factor for lactose selection. According to in vitro redispersion data the fine particle fraction of the delivered dose in the impactor varied between 10.3 and 26.0%. Thus, the redispersion of the budesonide particles can be altered by the properties of the carrier system.     

Effect of carrier size on the dispersion of salmeterol xinafoate from interactive mixtures

The objective of this study was to determine the influence of lactose carrier size on drug dispersion of salmeterol xinafoate (SX) from interactive mixtures. SX dispersion was measured by using the fine particle fractions determined by a twin stage impinger attached to a Rotahaler. The particle size of the lactose carrier in the SX interactive mixtures was varied using a range of commercial inhalation-grade lactoses. In addition, differing size fractions of individual lactose samples were achieved by dry sieving. The dispersion of SX appeared to increase as the particle size of the lactose carrier decreased for the mixtures prepared from different particle size commercial samples of lactose and from different sieve fractions of the same lactose. Fine particles of lactose (<5 microm) associated with the lactose carrier were removed from the carrier surface by a wet decantation process to produce lactose samples with low but similar concentrations of fine lactose particles. The fine particle fractions of SX in mixtures prepared with the decanted lactose decreased significantly (analysis of variance, p < 0.001) and the degree of dispersion became independent of the volume mean diameter of the carriers (analysis of variance, p < 0.05). The dispersion behavior is therefore associated with the presence of fine adhered particles associated with the carriers and the inherent size of the carrier itself has little influence on dispersion.     

Dry powder aerosol delivery of large hollow nanoparticulate aggregates as prospective carriers of nanoparticulate drugs: effects of phospholipids

The present work details the effects of incorporating phospholipids, a major component of lung surfactants, in the formulation of large hollow nanoparticulate aggregates, which are specifically designed to serve as potential carrier particles in inhaled delivery of nanoparticulate drugs. The large hollow aerosol particles (d(g) approximately 10 microm), whose shells are composed of nanoparticulate aggregates, are manufactured via the spray drying of nanoparticulate suspensions under a predetermined operating condition. Polyacrylate and silica nanoparticles of various sizes (20-170 nm), without loaded drugs, are employed as the model nanoparticles. The effects of increasing the phospholipids concentration in the presence of the nanoparticles, and vice versa, on the degree of hollowness and morphology of the spray-dried particles are investigated. Varying the phospholipids concentration in the presence of a constant amount of nanoparticles is found to influence the degree of hollowness, without significantly affecting the particle size distribution and respirable fine particle fraction, of the aerosol particles. The effects of increasing the phospholipids concentration on the degree of hollowness of the spray-dried particles are found to depend on the size and chemical nature of the nanoparticles.     

IgG particle formation during filling pump operation: a case study of heterogeneous nucleation on stainless steel nanoparticles

This study investigated factors associated with vial filling with a positive displacement piston pump leading to formation of protein particles in a formulation of an IgG. We hypothesized that nanoparticles shed from the pump's solution-contact surfaces nucleated protein aggregation and particle formation. Vials of IgG formulation filled at a clinical manufacturing site contained a few visible particles and about 100,000 particles (1.5-3 microm) per mL. In laboratory studies with the same model (National Instruments FUS-10) of pump, pumping of 20 mg/mL IgG formulation resulted in about 300,000 particles (1.5-3 microm) per mL. Pumping of protein-free formulation resulted in 13,000 particles (1.5-15 microm) per mL. More than 99% of the particles were 0.25-0.95 microm in size. Mixing of protein-free pumped solution with an equal volume of 40 mg/mL IgG resulted in 300,000 particles (1.5-15 microm) per mL. Also, mixing IgG formulation with 30,000/mL stainless steel nanoparticles resulted in formation of 30,000 protein microparticles (1.5-15 microm) per mL. Infrared spectroscopy showed that secondary structure of IgG in microparticles formed by pumping or mixing with steel nanoparticles was minimally perturbed. Our results document that nanoparticles of foreign materials shed by pumps can serve as heterogeneous nuclei for formation of protein microparticles.     

Design of ciprofloxacin-loaded nano-and microcomposite particles for dry powder inhaler formulations: preparation,in vitro characterisation,and antimicrobial efficacy

Abstract

In this study, ciprofloxacin hydrochloride (CIP)-loaded poly-ε-caprolactone (PCL) nanoparticles were prepared for pulmonary administration. CIP-loaded PCL nanoparticles were prepared using solid-in-oil-in-water (s/o/w) emulsion solvent evaporation method, and the effects of various formulation parameters on the physicochemical properties of the nanoparticles were investigated. PCL nanoparticles showed spherical shapes with particle sizes around 143–489?nm. Encapsulation efficiency was found to be very low because of water-solubility properties of CIP. However, the surface modification of nanoparticles with chitosan caused an increase in the encapsulation efficiency of nanoparticles. At drug release study, CIP-loaded PCL nanoparticles showed initial burst effect for 4?h and then continuously released for 72?h. Nanocomposite microparticles containing CIP-loaded PCL nanoparticles were prepared freeze-drying method and mannitol was used as carrier material. Tapped density and MMADt results show that nanocomposite microparticles have suitable aerodynamic properties for pulmonary administration. Antimicrobial efficacy investigations showed that CIP-encapsulated PCL nanoparticles and nanocomposite microparticles inhibited the growth of bacteria. Also, when the antimicrobial activity of the nanoparticles at the beginning and at the sixth month was examined, it was found that the structure of the particulate system was still preserved. These results indicated that nanocomposite microparticles containing CIP-loaded PCL nanoparticles can be used for pulmonary delivery.     

Nimodipine loaded PLGA nanoparticles: formulation optimization using factorial design, characterization and in vitro evaluation

The present study was aimed at developing a sustained release formulation of Nimodipine (NIM) nanoparticles using the biodegradable polymers, poly (lactide-co-glycolide) (PLGA 50:50 and 85:15) as carrier. NIM is a widely used calcium channel blocker which has to be administered as an intravenous infusion for a prolonged period of 1-2 weeks in the treatment of cerebral vasospasm. A sustained release biodegradable formulation would serve to replace this conventional therapy of continuous intravenous administration. PLGA nanoparticles were prepared by a modified precipitation method using high pressure homogenizer at 10,000 to 14,000 psi. A 3(2) factorial design was applied for optimization of the formulation parameters and for studying the effect of two independent variables [drug: polymer ratio and concentration of surfactant (Pluronic F 127)] on entrapment efficiency and mean particle size (response variables). Contour plots were plotted which gave a visual representation of the two variables on the dependent variables and also indicated non-linear relationship between them. The nanoparticles had particle size of 131+/-1.9 nm for PLGA 50:50 and 196+/-2.2 nm for PLGA 85:15. Scanning Electron Microscopy studies indicated that nanoparticles had spherical shape with a regular surface. The nanoparticles had high entrapment efficiency (96.42+/-2.09% for PLGA 50:50 and 94.50+/-1.25% for PLGA 85:15). DSC thermograms indicated that NIM was dispersed as an amorphous state in the nanoparticles. In vitro drug release from the lyophilized nanoparticles showed 94.35 +/- 3.8% NIM release from PLGA (50:50) nanoparticles and 63.32 +/- 4.6% release from PLGA (85:15) nanoparticles in 25 days. The release was first ordered and fickian diffusion kinetics in both the cases. These preliminary results indicate that NIM loaded PLGA nanoparticles could be effective in sustaining its release for a prolonged period. However, further studies are needed to confirm its performance in vivo.     

Development of a laser diffraction method for the determination of the particle size of aerosolised powder formulations

Impactor data are an essential component of marketing authorisation for new dry powder aerosol formulations. However such data are time-consuming to obtain and therefore impede the rapid screening of pilot formulations. In this phase of development it would be of considerable benefit to employ a technique where data acquisition was more rapid, such as laser diffraction, to predict the fine particle fraction. It was the aim of this study to investigate whether this is a feasible premise. Five different formulations were prepared, each containing 1.5% (w/w) micronised salbutamol base (volume median diameter: 2.42 microm) blended with the sieved fraction (63-90 microm) of one of the following sugars: regular crystalline lactose, spray dried lactose "Zeparox", sorbitol, maltose and dextrose monohydrate. A Perspex box was constructed to contain particles released from a glass inhaler and allow the particles to be measured by laser diffraction at different flow rates. After being validated using monodisperse aerosols, this assembly was then employed to measure the particle size distributions of each powder formulation and its respective sugar carrier at flow rates ranging from 28.3 to 100 l min(-1). Aerodynamic particle size distribution of salbutamol base from each formulation was also measured after aerosolisation at 28.3 l min(-1) from the glass inhaler into an Andersen cascade impactor. The flight of monodisperse particles with diameters (2-6 microm) in the desired size range of dry powders for inhalation could be contained and the size distribution determined by laser diffraction using the assembly at all flow rates investigated. Treatment of the particle size distributions measured by laser diffraction, i.e. examining only the aerosol particles with diameter <60 microm, highlighted the fine fraction (<5 microm) and enabled the aerosolisation of different blends to be feasibly compared at a range of different flow rates. The blends containing the following excipients could be placed in the following order of increasing fine fraction: spray-dried lactose相似文献   

Influence of fine lactose and magnesium stearate on low dose dry powder inhaler formulations

The behaviour of dry powder blends for inhalation, depending on the amount of fine lactose particles smaller than 10microm and the presence of magnesium stearate (MgSt), was studied in this work. A laser light diffraction method was developed to determine accurately size and volume fraction of these fine lactose particles in coarse carrier lactose (x(50) approximately 220microm). A linear relationship between measured volume fraction undersize at 10microm Q(3)(10microm) and added fine lactose could be established. Aerodynamic particle size distribution analysis of lactose showed that the fine lactose was attached to the coarse particles. In the presence of MgSt this interaction was increased. Consequently, the number of free active sites on the carrier surface was reduced and the investigated drug (formoterol fumarate dihydrate) was more effectively delivered. Addition of fine lactose and MgSt improved the aerodynamic performance the drug, as determined by resulting fine particle fraction, by 3% (for each 1% of added fine lactose) and 10%, respectively. Stability tests indicated that added MgSt was the most relevant of the studied parameter to achieve a stable aerodynamic performance. Its ability to protect the moisture uptake into the system was considered as rational for this effect.     

Influence of polymerization technique and experimental variables on the particle properties and release kinetics of methotrexate from poly(butylcyanoacrylate) nanoparticles

Poly(butylcyanoacrylate) nanoparticles were prepared by dispersion polymerization (DP) and emulsion polymerization (EP) of n-butyl cyanoacrylate monomer. The particles were characterized by infrared spectroscopy, differential scanning calorimetry, X-ray diffractometry and transmission electron microscopy. Particle properties such as size and zeta potential were determined for nanoparticles prepared by DP and EP techniques and compared. EP technique resulted in a low particle size compared to the DP. A high zeta potential was observed for nanoparticles prepared by the DP method. Incorporation of methotrexate resulted in a decrease in zeta potential in both types of nanoparticles, the decrease being greater in DP nanoparticles. Effect of experimental variables such as monomer concentration, polymerization time and temperature on drug entrapment and particle size was studied. Both types of nanoparticles showed an increase in drug entrapment with increased monomer concentrations. Variable polymerization time did not influence the drug entrapment of EP nanoparticles. Polymerization at 60 +/- 2 degrees C resulted in a decrease of drug entrapment and a great increase in the particle size of both types of nanoparticles. In vitro drug release studies showed a comparatively high release of methotrexate from DP nanoparticles suggesting the channelizing effect of dextran chains incorporated into nanoparticles during polymerization. Though the release profiles of nanoparticles appeared similar, a significant difference in release rates was found for DP and EP nanoparticles in 0.1 mol L(-1) HCl and pH 7.4 phosphate buffer (p < 0.01). Drug release data indicate that the release of methotrexate from DP and EP nanoparticles followed Fickian diffusion in 0.1 mol L(-1) HCl, while the mechanism was found anomalous in pH 7.4 phosphate buffer. An effort was also made to critically correlate the properties of nanoparticles synthesized by the above two techniques, and emphasize the importance of these characteristics in targeted drug delivery.     

Simultaneously manufactured nano-in-micro (SIMANIM) particles for dry-powder modified-release delivery of antibodies

Simultaneously Manufactured Nano-In-Micro (SIMANIM) particles for the pulmonary delivery of antibodies have been prepared by the spray-drying of a double-emulsion containing human IgG (as a model antibody), lactose, poly(lactide-co-glycolide) (PLGA) and dipalmitoylphosphatidylcholine (DPPC). The one-step drying process involved producing microparticles of a diameter suitable for inhalation that upon contact with aqueous media, partially dissolved to form nanoparticles, ～10-fold smaller than their original diameter. Continuous release of the model antibody was observed for 35 days in pH 2.5 release media, and released antibody was shown to be stable and active by gel electrophoresis, field-flow fractionation and enzyme linked immunosorbent assay. Adding 1% L-leucine to the emulsion formulation, and blending ‘SIMANIM’ particles with 1% magnesium stearate, achieved a fine particle fraction of ～60%, when aerosolised from a simple, capsule-based, dry powder inhaler device. ‘SIMANIM’ particles could be beneficial for the delivery of antibodies targeted against inhaled pathogens or other extracellular antigens, as well as having potential applications in the delivery of a wide range of other biopharmaceuticals and certain small-molecule drugs. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4055–4068, 2009     

Inhalable alginate nanoparticles as antitubercular drug carriers against experimental tuberculosis

Pharmacokinetic and chemotherapeutic studies have been carried out with aerosolised alginate nanoparticles encapsulating isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA). The nanoparticles were prepared by cation-induced gelification of alginate and were 235.5 +/- 0 nm in size, with drug encapsulation efficiencies of 70-90% for INH and PZA and 80-90% for RIF. The majority of particles (80.5%) were in the respirable range, with mass median aerodynamic diameter of 1.1 +/- 0.4 microm and geometric standard deviation of 1.71 +/- 0.1 microm. The relative bioavailabilities of all drugs encapsulated in alginate nanoparticles were significantly higher compared with oral free drugs. All drugs were detected in organs (lungs, liver and spleen) above the minimum inhibitory concentration until 15 days post nebulisation, whilst free drugs stayed up to day 1. The chemotherapeutic efficacy of three doses of drug-loaded alginate nanoparticles nebulised 15 days apart was comparable with 45 daily doses of oral free drugs. Thus, inhalable alginate nanoparticles can serve as an ideal carrier for the controlled release of antitubercular drugs.     

Liposomal amphotericin B dry powder inhaler: effect of fines on in vitro performance

The aim of the present investigation was to improve in vitro pulmonary deposition of amphotericin B (AMB) liposomal dry powder inhaler (LDPI) formulations. Liposomes with negative (AMB1) and positive (AMB2) charge were prepared by the reverse phase evaporation (REV) technique, extruded to reduce size, separated from unentrapped drug and lyophilized using an optimized cryoprotectant to achieve maximum drug retention. Lactose carrier (Sorbolac 400) in varying mass ratio with or without addition of fines (500# sieved Pharmatose 325M) in different mixing sequence were used to formulate AMB LDPI formulations. In vitro evaluation was done with twin stage impinger (TSI) for fine particle fraction. The lactose carrier containing 10% fines was found to be optimum blend at 1:6 mass ratio of liposome: lactose. The addition of fines and order of mixing fines were found to influence the fine particle fraction (FPF) significantly. FPF of LDPI formulations using a Rotahaler (Cipla, India) as delivery device at 30, 60 and 90 L/min were found to be 23.1 +/- 1.5 percent and 17.3 +/- 2.2 percent; 25.3 +/- 1.8 percent and 19.6 +/- 1.5 percent and 28.4 +/- 2.1 percent and 22.9 +/- 1.9 percent for AMB1 and AMB2 respectively.