Spray drying lactoferrin produces inhalable antimicrobial particles

The use of antimicrobial peptides and proteins as potential therapeutic agents in the management of multi-drug resistant infections is considered an attractive concept especially since such compounds should theoretically have low immunogenicity, high bioavailability with negligible toxicity. In this study we investigated the potential of developing a dry powder inhaler formulation of lactoferrin (a multifunctional iron binding protein). To achieve this, the protein was spray dried from a water only feedstock with suitably adjusted spray drying parameters. The particle size, degree of crystallinity, moisture content and yield of the spray dried powders along with the minimum bactericidal concentration (MBC) against Pseudomonas aeruginosa strain PAO1, were assessed. Dry powder inhaler formulations were prepared, and in vitro assessment studies using the multistage impinger were carried out to assess the aerosolisation performance of the formulations. Data obtained indicate that spray dried lactoferrin retains activity against biofilms and may be successfully employed in the treatment of chronic airway infections.

Drying of portland cement raw material slurries:predicting the performance of a counter-current spray drier

An extensive review of literature has been carried out concerning the drying of single drops, sprays of droplets and the prediction of spray drier performances. The experimental investigation has been divided into two broad parts mainly: (1) Single Drop Experiments, and (2) Spray Drying and Residence Time Distribution Experiments. The thermal conductivity of slurry cakes from five different sources have been experimentally determined using a modified Lee's Disc Apparatus and the data collected was correlated by the polynominal... Good agreement was observed between the experimental thermal conductivity values and the predicted ones. The fit gave a variance ... for the various samples experimented on. A mathematical model for estimating crust mass transfer coefficient at high drying temperatures was derived.

Carbomer-modified spray-dried respirable powders for pulmonary delivery of salbutamol sulphate

The present study investigates the feasibility of using two types of carbomer (971 and 974) to prepare inhalable dry powders that exhibit modified drug release properties. Powders were prepared by spray-drying formulations containing salbutamol sulphate, 20-50% w/w carbomer as a drug release modifier and leucine as an aerosolization enhancer. Following physical characterization of the powders, the aerosolization and dissolution properties of the powders were investigated using a Multi-Stage Liquid Impinger and a modified USP II dissolution apparatus, respectively. All carbomer 974-modified powders and the 20% carbomer 971 powder demonstrated high dispersibility, with emitted doses of at least 80% and fine particle fractions of approximately 40%. The release data indicated that all carbomer-modified powders displayed a sustained release profile, with carbomer 971-modified powders obeying first order kinetics, whereas carbomer 974-modified powders obeyed the Higuchi root time kinetic model; increasing the amount of carbomer 971 in the formulation did not extend the duration of drug release, whereas this was observed for the carbomer 974-modified powders. These powders would be anticipated to deposit predominately in the lower regions of the lung following inhalation and then undergo delayed rather than instantaneous drug release, offering the potential to reduce dosing frequency and improve patient compliance.

Sustained delivery by leucine-modified chitosan spray-dried respirable powders

The controlled co-delivery of multiple agents to the lung offers potential benefits to patients. This study investigated the preparation and characterisation of highly respirable spray-dried powders displaying the sustained release of two chemically distinct therapeutic agents. Spray-dried powders were produced from 30% (v/v) aqueous ethanol formulations that contained hydrophilic (terbutaline sulphate) and hydrophobic (beclometasone dipropionate) model drugs, chitosan (as a drug release modifier) and leucine (aerosolisation enhancer). The influence of chitosan molecular weight on spray-drying thermal efficiency, aerosol performance and drug release profile was investigated. Resultant powders were physically characterised: with in vitro aerosolisation performance and drug release profile investigated by the Multi-Stage Liquid Impinger and modified USP II dissolution apparatus, respectively. It was found that increased chitosan molecular weight gave increased spray-drying thermal efficiency. The powders generated were of a suitable size for inhalation—with emitted doses over 90% and fine particle fractions up to 72% of the loaded dose. Sustained drug release profiles were observed in dissolution tests for both agents: increased chitosan molecular weight associated with increased duration of drug release. The controlled co-delivery of hydrophilic and hydrophobic entities underlines the capability of spray drying to produce respirable particles with sustained release for delivery to the lung. (c) 2009 Elsevier B.V. All rights reserved.

Modified release of beclometasone dipropionate from chitosan-basedd spray-dried respirable powders

Dry powders for inhalation were prepared by spray drying a 30% v/v aqueous ethanol formulation containing beclometasone dipropionate (BDP), lactose, leucine and chitosan (low, medium or high molecular weight (MW), or combinations thereof). Following physical characterisation of the powders, the aerosolisation and dissolution properties of the powders were investigated using Multi-Stage Liquid Impinger and USP II dissolution apparatus, respectively. The powders were highly dispersible, with emitted doses in excess of 90% of loaded powder aerosolised from a Spinhaler dry powder inhaler. The fine particle fraction (FPF) was observed to decrease, whereas the time for 100% drug release increased, with increasing chitosan MW. For example, the low MW formulation exhibited an FPF of 64% and a 100% dissolution time of 2 h, whereas the high MW formulation demonstrated an FPF of 54% and a dissolution time of 12 h. These powders would be anticipated to deposit predominately in the lower regions of the lung following inhalation, and then undergo delayed rather than instantaneous drug release, offering the potential to reduce dosing frequency and improve patient compliance. (c) 2008 Elsevier B.V. All rights reserved.

Chitosan-based spray-dried respirable powders for sustained delivery of terbutaline sulfate

In this study, we describe the preparation of highly dispersible dry powders for pulmonary drug delivery that display sustained drug release characteristics. Powders were prepared by spray-drying 30% v/v aqueous ethanol formulations containing terbutaline sulfate as a model drug, chitosan as a drug release modifier and leucine as an aerosolisation enhancer. The influence of chitosan molecular weight on the drug release profile was investigated by using low, medium and high molecular weight chitosan or combinations thereof. Following spray-drying, resultant powders were characterised using scanning electron microscopy, laser diffraction, tapped density analysis, differential scanning calorimetry and thermogravitational analysis. The in vitro aerosolisation performance and drug release profile were investigated using Multi-Stage Liquid Impinger analysis and modified USP II dissolution apparatus, respectively. The powders generated were of a suitable aerodynamic size for inhalation, had low moisture content and were amorphous in nature. The powders were highly dispersible, with emitted doses of over 90% and fine particle fractions of up to 82% of the total loaded dose, and mass median aerodynamic diameters of less than 2.5microm. A sustained drug release profile was observed during dissolution testing; increasing the molecular weight of the chitosan in the formulation increased the duration of drug release. (c)2007 Elsevier B.V. All rights reserved.

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 μm. 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. © 2007 by Begell House, Inc.

The influence of formulation components on the aerosolisation properties of spray-dried powders

Dry powders suitable for inhalation containing β-estradiol, leucine as a dispersibility enhancer and lactose as a bulking agent were prepared by spray-drying from aqueous ethanol formulations. The influence of formulation components on the characteristics of the resultant spray-dried powders was examined through the use of a range of ethanol concentrations (10-50% v/v) in the solvent used to prepare the initial formulations. Additionally, the amount of leucine required to act as a dispersibility enhancer was investigated by varying the amount of leucine added to the formulation prior to spray-drying. Following spray-drying, resultant powders were characterised using scanning electron microscopy, laser diffraction and tapped density measurements, and the aerosolisation performance determined using Twin Stage Impinger and Andersen Cascade Impactor analysis. We demonstrate that selection of appropriate solvent systems and leucine concentration allows the preparation of spray-dried powders that display enhanced aerosolisation properties, and would be predicted to exhibit high deposition in the lower regions of the respiratory tract. © 2005 Elsevier B.V. All rights reserved.

The use of amino acids to enhance the aerosolisation of spray-dried powders for pulmonary gene therapy

Background Pulmonary delivery of gene therapy offers the potential for the treatment of a range of lung conditions, including cystic fibrosis, asthma and lung cancer. Spray-drying may be used to prepare dry powders for inhalation; however, aerosolisation of such powders is limited, resulting in poor lung deposition and biological functionality. In this study, we examine the use of amino acids (arginine, aspartic acid, threonine, phenylalanine) to enhance the aerosolisation of spray-dried powders containing model non-viral gene vectors. Methods Lipid/polycation/pDNA (LPD) vectors, in the presence or absence of amino acids, were dispersed in lactose solutions, and spray-dried to produce appropriately sized dry powders. Scanning electron microscopy and laser diffraction were used to determine particle morphology and diameter, respectively. Gel electrophoresis was used to examine the influence of amino acids on the structural integrity of the LPD complex. In vitro cell (A.549) transfection was used to determine the biological functionality of the dry powders, and the in vitro aerosolisation performance was assessed using a multistage liquid impinger (MSLI). Results Both gel electrophoresis and in vitro cell transfection indicated that certain amino acids (aspartic acid, threonine) can adversely affect the integrity and biological functionality of the LPD complex. All amino acids significantly increased the aerosolisation of the powder, with the arginine and phenylalanine powders showing optimal deposition in the lower stages of the MSLI. Conclusions Amino acids can be used to enhance the aerosolisation of spray-dried powders for respiratory gene delivery, allowing the development of stable and viable formulations for pulmonary gene therapy.

The morphology of spray-dried particles

Samples of Various industrial or pilot plant spray-dried materials were obtained from manufacturers together with details of drying conditions and feed concentrations. The samples were subjected to qualitative and semi-quantitative examination to identify structural and morphological features. The results were related to measured bulk physical properties and to drying conditions. Single particles were produced in a convective drying process Analogous to spray drying, in which different solids or mixtures of solids were dried from solutions, slurries or pastes as single suspended droplets. The localized chemical and physical structures were analysed and in some cases the retention of volatiles monitored. The results were related to experimental conditions, viz.; air temperature, initial solids concentration and the degree of feed aeration. Three distinct categories of particle morphology were identified, i.e.; crystalline, skin-forming and agglomerate. Each category is evidence of a characteristic drying behaviour which is dependent on initial solids concentration. the degree of feed aeration, and drying temperature. Powder flow ability, particle and bulk density, particle-size, particle friability, and the retention of volatiles bear a direct relationship to morphological structure. Morphologies of multicomponent mixtures were complex, but the respective migration rates of the solutes were dependent on drying temperature. Gas-film heat and SDSS transfer coefficients of single pure liquid droplets were also measured over a temperature range of 50•C to 200•C under forced convection. Balanced transfer rates were obtained attributed to droplet instability or oscillation within the airflow, demonstrated in associated work with single free-flight droplets. The results are of relevance to drier optimisation and to the optimisation of product characteristics, e.g.; particle strength and essential volatiles-retention, in convective drying.

A study of the drying of single droplets in free-flight

The literature relating to evaporation from single droplets of pure liquids and the drying of solution and slurry droplets, and of droplet sprays has been reviewed. The heat and mass transfer rates for individual droplets suspended in free-flight, were investigated using a specially-designed vertical wind tunnel, to simulate conditions in a spray drier. The technique represented a unique alternative method for investigating evaporation from unrestrained single droplets with variable residence times. The experiments covered droplets of pure liquid allowbreak (water, isopropanol) allowbreak and of significantly different solutions (sucrose, potassium sulphate) over a range of temperatures of 37oC to 97oC, initial concentrations of 5 to 40wt/wt% , and initial drop sizes of 2.8 to 4.6mm. Drop behaviour was recorded photographically and dried particles were examined by Scanning Electron Microscopy. Correlations were developed for mass transfer coefficients for pure water droplets in free-flight; (i) experiencing oscillations, rotation and deformation, Sh = -105 + 3.9 [Ta - Td/Tamb]0.18Re0.5Sc033 for Re approx. > 1380 (ii) when these movements had ceased or diminished, Sh = 2.0 + 0.71 [Ta - Td/Tamb]0.18Re0.5Sc033 for Re approx. < 1060. Data for isopropanol drops were correlated resonably well by these equations. The heat transfer data showed a similar transition range. The drying rate curves for drops of sucrose and potassium sulphate solution exhibited three distinct stages; an initial increase in the drying rate as drop temperature reduced to the wet-bulb temperature, a short constant-rate period and a falling-rate period characterised by formation of a crust which controlled the mass transfer rate. Due to drop perturbation the rates in the high Re number region were up to 5 times greater than predicted from theory for spherical droplets. In the case of sucrose solution a `skin' formed over the drop surface prior to crust formation. This provided an additional resistance to mass transfer and resulted in extended drying times and a smooth crust of low porosity. The relevance of the results to practical spray drying operations is discussed.

Spray drier simulation and air flow pattern studies

The literature pertaining to the key stages of spray drying has been reviewed in the context of the mathematical modelling of drier performance. A critical review is also presented of previous spray drying models. A new mathematical model has been developed for prediction of spray drier performance. This is applicable to slurries of rigid, porous crust-forming materials to predict trajectories and drying profiles for droplets with a distribution of sizes sprayed from a centrifugal pressure nozzle. The model has been validated by comparing model predictions to experimental data from a pilot-scale counter-current drier and from a full-scale co-current drier. For the latter, the computed product moisture content was within 2%, and the computed air exit temperature within 10oC of experimental data. Air flow patterns have been investigated in a 1.2m diameter transparent countercurrent spray tower by flow visualisation. Smoke was introduced into various zones within the tower to trace the direction, and gauge the intensity, of the air flow. By means of a set of variable-angle air inlet nozzles, a variety of air entry configurations was investigated. The existence of a core of high rotational and axial velocity channelling up the axis of the tower was confirmed. The stability of flow within the core was found to be strongly dependent upon the air entry arrangement. A probe was developed for the measurement of air temperature and humidity profiles. This was employed for studying evaporation of pure water drops in a 1.2m diameter pilot-scale counter-current drier. A rapid approach to the exit air properties was detected within a 1m distance from the air entry ports. Measured radial profiles were found to be virtually flat but, from the axial profiles, the existence of plug-flow, well-mixed-flow and some degree of air short-circuiting can be inferred. The model and conclusions should assist in the improved design and optimum operation of industrial spray driers.