Large Porous Particles for Sustained Protection from Carbachol-Induced Bronchoconstriction in Guinea Pigs

Purpose. To determine whether a new formulated albuterol aerosol could sustain inhibition to bronchoconstriction for approximately one day in guinea pigs challenged with carbachol. Methods. Large and porous particles, comprising a combination of endogenous or PDA-approved excipients and albuterol sulfate, were prepared by spray drying using a NIRO portable spray drier. The anesthetized animals inhaled 5 mg of large porous or small nonporous particles by forced ventilation via cannulae inserted in the lumen of their exposed tracheae. At regular intervals over a period of 36 hours after drug delivery, airway resistance was determined in response to carbachol challenge dose. Results. Whereas inhalation of small nonporous albuterol particles protected from the carbachol-induced bronchoconstriction for up to 5 hours, inhalation of large porous albuterol particles produced a significant inhibition of carbachol-induced bronchoconstriction for at least 16 hours. Conclusions. The absence of substantial side effects, verified over a period of 24 hours by evaluating cardio-respiratory parameters as well as pulmonary inflammation, supports the utility of large porous albuterol particles for sustained therapies in asthma and other types of lung disease.Dr. Ben-Jebria is also affiliated with     

Optimization of the aerosolization properties of an inhalation dry powder based on selection of excipients

The aim of this study was to investigate the influence of formulation excipients on physical characteristics of inhalation dry powders prepared by spray-drying. The excipients used were a series of amino acids (glycine, alanine, leucine, isoleucine), trehalose and dipalmitoylphosphatidylcholine (DPPC). The particle diameter and the powder density were assessed by laser diffraction and tap density measurements, respectively. The aerosol behaviour of the powders was studied in a Multi-Stage Liquid Impinger. The nature and the relative proportion of the excipients affected the aerosol performance of the powders, mainly by altering powder tap density and degree of particle aggregation. The alanine/trehalose/DPPC (30/10/60 w/w/w) formulation showed optimal aerodynamic behaviour with a mass median aerodynamic diameter of 4.7 μm, an emitted dose of 94% and a fine particle fraction of 54% at an airflow rate of 100 L/min using a Spinhaler inhaler device. The powder had a tap density of 0.10 g/cm³. The particles were spherical with a granular surface and had a 4 μm volume median diameter. In conclusion, optimization of the aerosolization properties of inhalation dry powders could be achieved by appropriately selecting the composition of the particles.     

Formulation and Physical Characterization of Large Porous Particles for Inhalation

Purpose. Relatively large (>5 µm) and porous (mass density < 0.4 g/cm³) particles present advantages for the delivery of drugs to the lungs, e.g., excellent aerosolization properties. The aim of this study was, first, to formulate such particles with excipients that are either FDA-approved for inhalation or endogenous to the lungs; and second, to compare the aerodynamic size and performance of the particles with theoretical estimates based on bulk powder measurements. Methods. Dry powders were made of water-soluble excipients (e.g., lactose, albumin) combined with water-insoluble material (e.g., lung surfactant), using a standard single-step spray-drying process. Aerosolization properties were assessed with a Spinhaler ^TM device in vitro in both an Andersen cascade impactor and an Aerosizer^TM.. Results. By properly choosing excipient concentration and varying the spray drying parameters, a high degree of control was achieved over the physical properties of the dry powders. Mean geometric diameters ranged between 3 and 15 µm, and tap densities between 0.04 and 0.6 g/cm³. Theoretical estimates of mass mean aerodynamic diameter (MMAD) were rationalized and calculated in terms of geometric particle diameters and bulk tap densities. Experimental values of MMAD obtained from the Aerosizer^TM most closely approximated the theoretical estimates, as compared to those obtained from the Andersen cascade impactor. Particles possessing high porosity and large size, with theoretical estimates of MMAD between 1–3 µm, exhibited emitted doses as high as 96% and respirable fractions ranging up to 49% or 92%, depending on measurement technique. Conclusions. Dry powders engineered as large and light particles, and prepared with combinations of GRAS (generally recognized as safe) excipients, may be broadly applicable to inhalation therapy.     

Optimization of the aerosolization properties of an inhalation dry powder based on selection of excipients

The aim of this study was to investigate the influence of formulation excipients on physical characteristics of inhalation dry powders prepared by spray-drying. The excipients used were a series of amino acids (glycine, alanine, leucine, isoleucine), trehalose and dipalmitoylphosphatidylcholine (DPPC). The particle diameter and the powder density were assessed by laser diffraction and tap density measurements, respectively. The aerosol behaviour of the powders was studied in a Multi-Stage Liquid Impinger. The nature and the relative proportion of the excipients affected the aerosol performance of the powders, mainly by altering powder tap density and degree of particle aggregation. The alanine/trehalose/DPPC (30/10/60 w/w/w) formulation showed optimal aerodynamic behaviour with a mass median aerodynamic diameter of 4.7 μm, an emitted dose of 94% and a fine particle fraction of 54% at an airflow rate of 100 L/min using a Spinhaler inhaler device. The powder had a tap density of 0.10 g/cm³. The particles were spherical with a granular surface and had a 4 μm volume median diameter. In conclusion, optimization of the aerosolization properties of inhalation dry powders could be achieved by appropriately selecting the composition of the particles.     

Spray-dried powders for pulmonary drug delivery

Powders for inhalation are traditionally prepared using a destructive micronization process such as jet milling to reduce the particle size of the drug to 2-5 mum. The resultant particles are typically highly cohesive and display poor aerosolization properties, necessitating the addition of a coarse carrier particle to the micronized drug to improve powder flowability. Spray-drying technology offers an alternative, constructive particle production technique to the traditional destructive approach, which may be particularly useful when processing biotechnology products that could be adversely affected by high-energy micronization processes. Advantages of spray drying include the ability to incorporate a wide range of excipients into the spray-drying feedstock, which could modify the aerosolization and stability characterizations of the resultant powders, as well as modify the drug release and absorption profiles following inhalation. This review discusses some of the reasons why pulmonary drug delivery is becoming an increasingly popular route of administration and describes the various investigations that have been undertaken in the preparation of spray-dried powders for pulmonary drug delivery.     

The influence of amino acids on aztreonam spray-dried powders for inhalation

The dry powder inhalation of antibiotics for the treatment of lung infections has attracted drastically increasing attention as it offers rapid local therapy at lower doses and minimal side effects. In this study, aztreonam (AZT) was used as the model antibiotic and spray-dried to prepare powders for inhalation. Amino acids of glycine (GLY), histidine (HIS) and leucine (LEU) were used as excipients to modify the spray-dried particles. It was demonstrated that the GLY-AZT spray-dried powders formed huge agglomerates with the size of 144.51 µm, which made it very difficult to be delivered to the lungs (FPF: 0.29% w/w only). In comparison with the AZT spray-dried powders, HIS-modified spray-dried powders showed increased compressibility, indicating larger distance and less cohesion between particles; while the LEU-modified spray-dried particles showed a hollow structure with significantly decreased densities. The fine particle fraction for HIS- and LEU-modified powders was 51.4% w/w and 61.7% w/w, respectively, and both were significantly increased (one-way ANOVA, Duncan's test, P <0.05) compared to that of AZT spray-dried powders (45.4% w/w), showing a great potential to be applied in clinic.     

Physicochemical factors governing the performance of nedocromil sodium as a dry powder aerosol

Previous investigations have found that the in vitro aerosol performance of nedocromil sodium is poor. A study has been undertaken to gain a better understanding of the physicochemical properties of the drug particles together with the factors governing the aerosol performance of inhalation systems containing this drug. Material previously passed through a hammer mill only and particles subsequently passed through a micronizer were characterized, and the information gathered was correlated with the in vitro aerosol performance of the pure drug systems. Optimization of particle sizing procedures revealed that both sets of materials were ultrafine powders with a volume median diameter of approximately 1 microm. It is concluded that the processing stages, employed in the manufacture of these batches of fine particle nedocromil sodium trihydrate, may not in fact be primary particle size reduction stages but instead deaggregation stages and that these govern the aerosol performance. The in vitro aerosol performance of samples of the "micronized" nedocromil sodium stored over a range of relative humidities (RHs) was characterized. Storage RHs in the range 12-76% (where nedocromil sodium is stable as the trihydrate) did not have a dramatic effect on the in vitro aerosol performance of the drug. However, conversion to the heptahemihydrate (following storage of the drug at 86% RH) significantly decreased the deaggregation performance in an in vitro model.     

In vitro and in vivo dose delivery characteristics of large porous particles for inhalation

The purpose of this study was to evaluate the in vitro and in vivo dose delivery characteristics of two large porous particle placebo formulations with different mass median aerodynamic diameters (MMAD approximately equal to 3 and 5 microm). In vitro dose delivery characteristics were measured using the multistage liquid impinger (MSLI). In vitro lung deposition was predicted by calculating the extrathoracic deposition using the ICRP model, with the remaining fraction assumed to deposit in the lungs. Healthy subjects were trained to inhale through the AIR delivery system at a target peak inspiratory flow rate (PIFR) of 60 l/min, The in vivo dose delivery of large porous particles were obtained by gamma-scintigraphy and was characterized by high ( approximately 90%), reproducible emitted doses for both the small and large MMAD powders. The mean in vivo lung deposition relative to the total metered dose were 59.0 and 37.3% for 3 and 5 microm MMAD powders, respectively. The AIR delivery system produced high in vivo lung deposition and low intersubject CVs (approximately 14%) across the range of PIFRs obtained in the study (50-80 l/min), This is relative to a variety of dry powder inhalers (DPI) that have been published in the literature, with in vivo lung deposition ranging from 13 to 35% with intersubject CVs ranging from 17 to 50%. The ICRP model provided a good estimate of the mean in vivo lung deposition for both powders. Intersubject variability was not captured by the ICRP model due to intersubject differences in the morphology and physiology of the oropharyngeal region. The ICRP model was used to predict the regional lung deposition, although these predictions were only considered speculative in the absence of experimental validation.     

Spray freeze drying to produce a stable Delta(9)-tetrahydrocannabinol containing inulin-based solid dispersion powder suitable for inhalation.

The purpose of this study is to investigate whether spray freeze drying produces an inhalable solid dispersion powder in which Delta(9)-tetrahydrocannabinol (THC) is stabilised. Solutions of THC and inulin in a mixture of tertiary butanol (TBA) and water were spray freeze dried. Drug loads varied from 4 to 30 wt.%. Various powder characteristics of the materials were determined. Stability of THC was determined and compared with freeze dried material. The powders, dispersed with an inhaler based on air classifier technology, were subjected to laser diffraction analysis and cascade impactor analysis. Highly porous particles having large specific surface areas (about 90 m(2)/g) were produced. At high drug loads, THC was more effectively stabilised by spray freeze drying than by freeze drying. Higher cooling rates during spray freeze drying result in improved incorporation. Fine particle fractions of up to 50% were generated indicating suitability for inhalation. It was concluded that spray freeze drying from a water-TBA mixture is a suitable process to include lipophilic drugs (THC) in inulin glass matrices. High cooling rates during the freezing process result in effective stabilisation of THC. The powders can be dispersed into aerosols with a particle size appropriate for inhalation.     

Sustained release of insulin from insoluble inhaled particles

Conventional slow‐acting insulin preparations for subcutaneous injection, e.g., suspensions of the complex with protamine and/or zinc, were reformulated as dry powders for inhalation and the insoluble aerosol tested for providing sustained insulin plasma levels. Large porous particles made of lactose, albumin, and dipalmitoylphosphatidylcholine, and incorporating insulin, protamine, and/or zinc chloride were prepared using spray‐drying. Integrity of insulin after spray‐drying and insulin insolubilization in spray‐dried particles was verified in vitro. The pharmacokinetic profile of the formulation delivered by inhalation and subcutaneous injection was assessed in vivo in the rat. The formulation process of insulin as dry powders did not alter insulin integrity and did not impede, in most cases, insulin insolubilization by protamine and/or zinc. Large porous insulin particles presented 7 μm mass mean geometric particle diameters, 0.1 g/cm³ bulk powder tap densities and theoretical aerodynamic diameters suitable for deep lung deposition (in the range of 2.2–2.5 μm). The dry powders exhibited 40% respirable fractions in the Andersen cascade impactor and 58–75% in the Aero‐Breather™. Insoluble inhaled insulin provided sustained insulin plasma levels for half a day, similar to injected insulin, and exhibited a bioavailability of 80.5% relative to subcutaneous injection of the same formulation. Drug Dev. Res. 48:178–185, 1999. ©1999 Wiley‐Liss, Inc.     

Protein Inhalation Powders: Spray Drying vs Spray Freeze Drying

Purpose. To develop a new technique, spray freeze drying, for preparing protein aerosol powders. Also, to compare the spray freeze-dried powders with spray-dried powders in terms of physical properties and aerosol performance. Methods. Protein powders were characterized using particle size analysis, thermogravimetric analysis, scanning electron microscopy, X-ray powder diffractometry, and specific surface area measurement. Aerosol performance of the powders was evaluated after blending with lactose carriers using a multi-stage liquid impinger or an Anderson cascade impactor. Two recombinant therapeutic proteins currently used for treating respiratory tract-related diseases, deoxyribonuclase (rhDNase) and anti-IgE monoclonal antibody (anti-IgE MAb), were employed and formulated with different carbohydrate excipients. Results. Through the same atomization but the different drying process, spray drying (SD) produced small (3 m), dense particles, but SFD resulted in large (8–10 m), porous particles. The fine particle fraction (FPF) of the spray freeze-dried powder was significantly better than that of the spray-dried powder, attributed to better aerodynamic properties. Powders collected from different stages of the cascade impactor were characterized, which confirmed the concept of aerodynamic particle size. Protein formulation played a major role in affecting the powder's aerosol performance, especially for the carbohydrate excipient of a high crystallization tendency. Conclusions. Spray freeze drying, as opposed to spray drying, produced protein particles with light and porous characteristics, which offered powders with superior aerosol performance due to favorable aerodynamic properties.     

Measurement of the Particle Size of Tablet Excipients with the Aid of Video Recording

A method for the determination of the particle size of tablet excipients involving the use of video recording of microscopic examination of powders is described. The projected area of the particle profile was measured, and Feret's diameter and shape factors such as the elongation ratio, bulkiness factor, and surface factor were determined. Starch particles are the smallest among the excipients studied. Primojel particles are two to three times larger (Feret's diameter) and have up to 10 times greater projected areas. Particles of Avicel PH101, Ac-Di-Sol, Nymcel ZSD16 and ZSB10, and Polyplasdone XL have an irregular surface which results in large differences between the projected area diameter and the perimeter diameter. Particles of Nymcel and Ac-Di-Sol have the highest elongation ratio because of their cylindrical shape. Both Primojel and Starch have a low surface factor because of their spherical shape. This video-recording method is a simple system to observe, record, store, and retrieve particle-size data from microscopic examination of tablet excipients.     

Improvement of dissolution rates of poorly water soluble APIs using novel spray freezing into liquid technology

Purpose. To develop and demonstrate a novel particle engineering technology, spray freezing into liquid (SFL), to enhance the dissolution rates of poorly water-soluble active pharmaceutical ingredients (APIs). Methods. Model APIs, danazol or carbamazepine with or without excipients, were dissolved in a tetrahydrofuran/water cosolvent system and atomized through a nozzle beneath the surface of liquid nitrogen to produce small frozen droplets, which were subsequently lyophilized. The physicochemical properties of the SFL powders and controls were characterized by X-ray diffraction, scanning electron microscopy (SEM), particle size distribution, surface area analysis, contact angle measurement, and dissolution. Results. The X-ray diffraction pattern indicated that SFL powders containing either danazol or carbamazepine were amorphous. SEM micrographs indicated that SFL particles were highly porous. The mean particle diameter of SFL carbamazepine/SLS powder was about 7 m. The surface area of SFL danazol/poloxamer 407 powder was 11.04 m²/g. The dissolution of SFL danazol/poloxamer 407 powder at 10 min was about 99%. The SFL powders were free flowing and had good physical and chemical stability after being stored at 25°C/60%RH for 2 months. Conclusions. The novel SFL technology was demonstrated to produce nanostructured amorphous highly porous particles of poorly water soluble APIs with significantly enhanced wetting and dissolution rates.     

Design of fine particles for pulmonary drug delivery

Particle design for inhalation is characterized by advances in particle processing methods and the utilization of new excipients. Processing methods such as spray drying allow control over critical particle design features, such as particle size and distribution, surface energy, surface rugosity, particle density, surface area, porosity and microviscosity. Control of these features has enabled new classes of therapeutics to be delivered by inhalation. These include therapeutics that have a narrow therapeutic index, require a high delivered dose, and/or elicit their action systemically. Engineered particles are also being utilized for immune modulation, with exciting advances being made in the delivery of antibodies and inhaled vaccines. Continued advances are expected to result in ‘smart’ therapeutics capable of active targeting and intracellular trafficking.     

Design of fine particles for pulmonary drug delivery

Particle design for inhalation is characterized by advances in particle processing methods and the utilization of new excipients. Processing methods such as spray drying allow control over critical particle design features, such as particle size and distribution, surface energy, surface rugosity, particle density, surface area, porosity and microviscosity. Control of these features has enabled new classes of therapeutics to be delivered by inhalation. These include therapeutics that have a narrow therapeutic index, require a high delivered dose, and/or elicit their action systemically. Engineered particles are also being utilized for immune modulation, with exciting advances being made in the delivery of antibodies and inhaled vaccines. Continued advances are expected to result in 'smart' therapeutics capable of active targeting and intracellular trafficking.     

Constant size, variable density aerosol particles by ultrasonic spray freeze drying

This work provides a new understanding of critical process parameters involved in the production of inhalation aerosol particles by ultrasonic spray freeze drying to enable precise control over particle size and aerodynamic properties. A series of highly porous mannitol, lysozyme, and bovine serum albumin (BSA) particles were produced, varying only the solute concentration in the liquid feed, c(s), from 1 to 5 wt%. The particle sizes of mannitol, BSA, and lysozyme powders were independent of solute concentration, and depend only on the drop size produced by atomization. Both mannitol and lysozyme formulations showed a linear relationship between the computed Fine Particle Fraction (FPF) and the square root of c(s), which is proportional to the particle density, ρ, given a constant particle size d(g). The FPF decreased with increasing c(s) from 57.0% to 16.6% for mannitol and 44.5% to 17.2% for lysozyme. Due to cohesion, the BSA powder FPF measured by cascade impaction was less than 10% and independent of c(s). Ultrasonic spray freeze drying enables separate control over particle size, d(g), and aerodynamic size, d(a) which has allowed us to make the first experimental demonstration of the widely accepted rule d(a)=d(g)(ρ/ρ(o))(1/2) with particles of constant d(g), but variable density, ρ (ρ(o) is unit density).     

Effect of degree of methoxylation and particle size on compression properties and compactibility of pectin powders

This study examines the effect of the degree of methoxylation (DM) and particle size on compression properties and compactibility of pectin powders. A powder classification system based on sequential handling of compression parameters was applied. A single size fraction (90-125 μm) of pectin powders with DM values ranging from 5-72% was studied. For DM 25%, the effect of different particle size fractions (180-250, 125-180, 90-125, 63-90, 45-63, <45 μm) were investigated. Compression parameters were derived based on time-resolved force-displacement data using Heckel, Kawakita and Shapiro equations. Volume-specific surface area was estimated for powders and tablets. Tablet tensile strength was determined. It was found that all pectin powders displayed low degrees of particle rearrangement and relatively low degrees of fragmentation (class IIA materials). Pectin particles were found to be relatively soft, with a tendency towards softer particles for pectins of higher DM. The overall variation in fragmentation and deformation behavior was limited. Both DM and initial particle size affected the tensile strength of pectin tablets. The difference in surface hydrophobicity caused by the DM was suggested as being responsible for the variation in the mechanical strengths. The study shows that pectin grades with DM ≤ 40% are potential direct compression excipients.     

Preparation and characterization of spray-dried tobramycin powders containing nanoparticles for pulmonary delivery

Using high-pressure homogenization and spray-drying techniques, novel formulations were developed for manufacturing dry powder for inhalation, composed of a mixture of micro- and nanoparticles in order to enhance lung deposition. Particle size analysis was performed by laser diffraction. Spray-drying was applied in order to retrieve nanoparticles in dried-powder state from tobramycin nanosuspensions. The aerolization properties of the different formulations were evaluated by a multi-stage liquid impinger. Suspensions of nanoparticles of tobramycin containing Na glycocholate at 2% (w/w) relative to tobramycin content and presenting a mean particle size about 200 nm were produced. The results from the spray-dried powders showed that the presence of nanoparticles in the formulations improved particle dispersion properties during inhalation. The fine particle fraction (percentage of particles below 5 microm) increased from 36% for the raw micronized tobramycin material to about 61% for the most effective formulation. These new nanoparticle-containing tobramycin DPI formulations, based on the use of very low level of excipient and presenting high lung deposition properties, offer very important perspectives for improving the delivery of drugs to the pulmonary tract.     

Optimization of formulation components and characterization of large respirable powders containing high therapeutic payload

The aim of the study was to optimize and characterize high therapeutic payload large respirable powders prepared by spray-drying technique for maximum fine particle fraction with minimum quantities of excipients. Influence of formulation components was optimized by a three-factor, five-level central composite design having different proportions of L-leucine (X1), tobramycin sulfate (X2), and poloxamer-188 (X3) as the independent variables and fine particle fraction as a response variable (Y). Large respirable powders were characterized for particle size, size distribution, moisture, crystallinity, and morphology. In vitro aerosol performance of powders was determined by an eight-stage Andersen cascade impactor using the Rotahaler. Mathematical model elucidated for Y was Y = 56.2068 + 5.7481 X1 - 3.0531 X2 + 0.8468 X3 + 1.1737 X1 X2 - 0.5012 X1 X3 - 0.7412 X2 X3 - 0.7149 X1(2) - 1.9212 X2(2) - 1.6187X3(2). The component of greatest influence on product performance (response variable) was found to be L-leucine. Lack of fit was not significant (p = 0.08), and regression equation predicted response for Y was in reasonably good agreement with experimental values (p = 0.01; R2 = 0.92). The optimal model predicted with a fine particle fraction of 62.8 +/- 2.6% with X1, X2, X3 levels of 20, 45.71, and 5.51 respectively. Large respirable powders with TB load of 45.7% w/w were prepared; they had smooth surface texture, dimpled spherical shape, roundness value close to 1(1.048 +/- 0.032) and were found to possess bulk tap densities of 0.04 g/cc, geometric particle sizes of 6-7 micro m, and emitted dose of 92%. The results of the studies suggest that in vitro aerosol performance was affected significantly by small and deliberate change of specific formulation components and its proportions. It may be concluded that appropriate type and proportion of excipients is necessary to obtain maximum fine particle fraction of large respirable powders containing high therapeutic payloads.     

Effect of process variables on morphology and aerodynamic properties of voriconazole formulations produced by thin film freezing

The particle engineering process, thin film freezing (TFF), was used to produce particulate voriconazole (VRC) formulations with enhanced properties. The effect of various processing parameters on the solid state properties and aerodynamic performance of the TFF-processed powders was investigated in order to evaluate the suitability of these formulations for dry powder inhalation and to optimize the aerodynamic properties. Thin film freezing of VRC solution without stabilizing excipients resulted in microstructured, crystalline low density aggregate particles with specific surface areas of approximately 10m(2)/g. Thin film freezing of VRC-PVP solutions produced nanostructured, amorphous low density aggregate particles with specific surface areas ranging from 15 to 180m(2)/g, depending on the solvent system composition, polymer grade, and drug to polymer ratio utilized. VRC formulations manufactured with 1,4-dioxane, with and without PVP K12, resulted in the lowest specific surface areas but displayed the best aerodynamic properties. Using a Handihaler(?) dry powder inhaler (DPI), microstructured crystalline TFF-VRC and nanostructured amorphous TFF-VRC-PVP K12 (1:2) displayed total emitted fractions of 80.6% and 96.5%, fine particle fractions of 43.1% and 42.4%, and mass median aerodynamic diameters of 3.5 and 4.5μm, respectively.