Kevin Taylor

Production of spray dried salbutamol sulphate for use in dry powder aerosol formulation

Salbutamol sulphate particles, for use in dry powder aerosol formulation, were prepared by spray drying, using a Buchi 190 mini spray dryer. The spray drying parameters were investigated in relation to particle size and yield of the resultant powder. Important factors were determined using a 24 factorial statistical design. The four factors investigated were pump speed, aspirator level (the rate at which the drying air is pulled through the dryer), inlet temperature and the concentration of the aqueous salbutamol sulphate solution dried. Spray drying conditions were chosen based on results from the experimental design and working knowledge of the spray dryer, to produce a batch of salbutamol sulphate powder on which further studies were performed. The physicochemical properties of spray dried salbutamol sulphate were compared to those of the micronised drug. Infrared spectroscopy, X-ray diffraction, appearance, particle size analysis (including aerodynamic diameter) and powder flow were investigated. It was found that spray drying produced spherically shaped particles of salbutamol sulphate having a mass median diameter of 4.5 μm (laser diffraction), mean Ferets diameter (image analysis) of 1.58 μm and a mass median aerodynamic diameter of 9.7 μm (cascade impaction), i.e., particles sufficiently small in diameter for use in inhalation formulation. The spray dried material was seen to perform as well as the micronised material in most cases with the exception of powder flow properties, where performance was slightly poorer.

Nebulization of fluids of different physicochemical properties with air-jet and ultrasonic nebulizers

AbstractPurpose. Empirical formulae relate the mean size of primary droplets from jet and ultrasonic nebulizers to a fluids physicochemical properties. Although the size selective “filtering” effects of baffling and evaporation may modify the secondary aerosol produced, this research sought to evaluate whether viscosity and surface tension of nebulized fluids influenced the aerosols size and output characteristics. Methods. Fluid systems of different surface tension and viscosity (glycerol and propylene glycol solutions [10–50% (v/v)] and a range of silicone fluids [200/0.65 cs– l00cs]) were nebulized in three jet and two ultrasonic nebulizers. Secondary aerosol characteristics were measured with a Malvern 2600C laser diffraction sizer and the nebulization times, residual volumes and percentage outputs were determined. Results. While the droplet size appeared to be inversely proportional to viscosity for jet nebulizers, it was directly proportional to viscosity for ultrasonic nebulizers. Although fluid systems with lower surface tensions generally produced slightly smaller MMDs, the relationship between surface tension and droplet size was complex. The more viscous fluids required longer nebulization times and were associated with increased residual amounts (lower outputs). The ultrasonic nebulizers did not effectively, and were on occasion unable to, nebulize the more viscous fluids. Conclusions. It follows that there are cut-off values for viscosity and/or surface tension above or below which ultrasonic devices fail to operate. Moreover, jet nebulizers generated an aerosol with an optimum respirable output from median-viscosity fluids.

The influence of liposomal encapsulation on sodium cromoglycate pharmacokinetics in man.

The pharmacokinetics of pulmonary-administered sodium cromoglycate (SCG) has been studied in five healthy volunteers. SCG, 20 mg, was inhaled as a solution and encapsulated in dipalmitoyl phosphatidylcholine/cholesterol (1:1) liposomes. Liposomal SCG produced detectable drug levels in plasma from four volunteers taken 24 and 25 hr after inhalation. Inhaled SCG solution, although producing peak plasma levels more than sevenfold greater than liposomal drug, was not detectable in 24-hr samples from any volunteer. The decline in plasma levels following inhalation of liposomal SCG (reflecting the absorption phase) was best described by a biexponential equation. The two absorption rate constants differed by more than an order of magnitude. The rapid absorption phase was probably due to free or surface-adsorbed SCG in the liposomal formulation, since the absorption rate constant for this phase did not differ significantly from the absorption rate constant for SCG in solution. The phase of slow drug absorption may then be attributed to absorption of drug released from vesicles. The data indicate that encapsulation of SCG prior to pulmonary administration prolonged drug retention within the lungs and altered its pharmacokinetics.

Thermal analysis of phase transition behaviour in liposomes

Abstract Liposomes are small vesicles having one or more concentric phospholipid bilayers, interspersed with aqueous phase. Thermal analysis, particularly differential scanning calorimetry (DSC) has been used extensively to study the behaviour of hydrated phospholipids within bilayers. On heating, and dependent on the state of hydration, phospholipids undergo a series of phase transitions. This paper reviews investigations of the phase transition behaviour of single component phospholipid systems, bilayers having mixtures of phospholipids and bilayers containing phospholipid-cholesterol mixtures. Liposomes are being extensively studied for use as colloidal drug delivery systems. Inclusion of therapeutic agents into liposomal systems may have pronounced effects on the phospholipid phase transition behaviour and consequently bilayer fluidity. These effects are determined by the location of the therapeutic agent within the bilayer. The interactions of electrolytes and steroids with phospholipids are discussed. The use of DSC studies of drug-liposome interactions as models of drug-cell membrane interactions is also discussed.

Factors affecting the size distribution of liposomes produced by freeze-thaw extrusion.

This paper describes the development of a protocol for the production of liposomes using a freeze-thaw extrusion methodology. Laser diffraction particle size analysis showed that the median diameter of freeze-thawed egg phosphatidylcholine multilamellar vesicles (eggPC MLVs) was increased when cholesterol was included in the bilayers. Using a freeze-thaw cycle of 3 min freezing in liquid nitrogen at -196 degrees C followed by 3 min thawing at 50 degrees C resulted in an anomalously large particle size for eggPC/cholesterol formulations. When liposomes were repeatedly freeze-thawed a maximum size was achieved after five freeze-thaw cycles. Dispersion of liposomes in sodium chloride solutions promoted size increases following freeze-thawing, suggesting that vesicles had aggregated or fused. Poloxamers P338 and P407 inhibited the size increases observed during freeze-thawing for eggPC MLVs dispersed in 1.0 M NaCl, probably through steric prevention of aggregation and fusion.

Jet nebulisers for pulmonary drug delivery

Abstract Nebulisers are widely used clinically to produce aerosols for a range of applications. This paper reviews the many factors which determine the particle size of the aerosol and drug output and describes their potential usefulness for novel drug delivery. There are numerous commercially available nebulisers, and their design is an important factor governing aerosol size and fluid output. Recent designs have included developments to reduce the proportion of drug lost during exhalation with traditional continuous output nebulisers. The rate of gas flow driving atomization is a major determinant of aerosol size; there being an inverse relationship between droplet size and flow rate, due to the increased shearing forces at higher flow rates. Although droplet size is largely independent of fill volume, the proportion of available drug increases with increased fill volumes, since some fluid is invariably retained within the nebulisation chamber at the end of atomization. During use the temperature of the fluid within the nebuliser significantly decreases. This may result in precipitation of poorly soluble drugs and produce variability in droplet size due to changes in the physicochemical properties of nebuliser fluids. Mean aerosol size is inversely proportional to viscosity. However, although high viscosity fluids produce small droplets, they require longer to nebulise to dryness and are retained to a greater extent. Reducing the surface tension of fluids tends to produce aerosols of smaller size. Thus, the size and dose of aerosol available for inhalation by a patient is a complex function of all these factors, whilst the dose inhaled and deposited in the airways is highly dependent on patient-related factors.

An investigation of some of the factors influencing the jet nebulisation of liposomes.

Multilamellar egg phosphatidylcholine liposomes with or without cholesterol have been aerosolised using four jet nebulisers. The size of aerosols generated from liposome suspensions, as measured by laser diffraction, was independent of liposome size and bilayer composition. However, increasing the phospholipid concentration caused an increase in the median size of the secondary aerosol size, although the extent of this effect was dependent on the design on the nebuliser. The total mass output of liposomal aerosols was similar for the Pari-LC and Sidestream nebulisers, though the rate of output was higher for the Sidestream. In both cases, increasing lipid concentration produced a reduced rate of aerosol output. For all the nebulisers studied, a size selective process was found, resulting in the retention of the largest liposomes.

Liposomes for drug delivery to the respiratory tract

AbstractThis paper provides a review of the current literature pertaining to the pulmonary delivery of liposomes.The technological aspects of delivering liposomes to the lung are discussed, including the characterization of liposome-containing aerosols and the potential advantages and disadvantages of the various methods which have been employed for their generation.Studies have indicated that liposomes can be effectively deposited in the human respiratory tract, wherein they may remain for prolonged periods. A prolonged retention in the airways may markedly alter the pharmacokinetics of liposome associated materials; increasing local concentrations, whilst decreasing levels at sites distant from the lung. The future potential for such systems is discussed, including the possibilities for selective drug delivery to specific cell populations within the lung.

Nebulisers for the generation of liposomal aerosols

Multilamellar liposomes and latex spheres have been atomised using a range of jet and ultrasonic nebulisers. Studies with spheres indicated that relatively large particles can be delivered from nebulisers, although the smaller the suspended particle size, the more efficiently they are delivered from all nebulisers. The size of aerosols generated from liposome suspensions, as measured by laser diffraction, was determined by the lipid concentration and the nebuliser used, but was independent of liposome size and bilayer composition. Generation of aerosols by both jet and ultrasonic nebulisers resulted in damage to liposome structures, with a consequent reduction in the measured vesicle sizes. The Respirgard II jet nebuliser produced aerosols with the smallest median droplet size and caused the greatest damage to liposomes. However, the size of droplets produced by the nebuliser is not the only determinant of liposome stability during atomisation. Relatively fluid EggPC liposomes experienced the greatest disruption during nebulisation. Inclusion of cholesterol or DPPC in the liposome bilayers rendered them more resistant to the disruptive forces to which they were exposed during either jet or ultrasonic nebulisation.

The implications of increasing student numbers for pharmacy education

The number of students recruited into UK schools of pharmacy has increased considerably over recent years and is set to increase further still as new schools of pharmacy begin recruiting from 2003. This increase in student numbers mirrors international trends and reflects both the need to address shortages in the pharmacy workforce and the exercise of market forces within UK higher education. Increased enrolments of less academically able students onto MPharm courses potentially threaten academic standards. Pharmacy schools will need to modify their courses and assessment methods to meet this challenge, whilst at the same time striving to ensure that pharmacy programmes meet the rigorous academic demands of a masters level degree. As staff:student ratios worsen, maintaining the quality of the learning experience will become increasingly difficult, and efficiencies in teaching and assessment will inevitably be sought. Computer-based technology might offer innovative, cost-effective solutions to some logistical problems, but such technology distances the learner from the tutor, and reduces opportunities for students to accrue values and attitudes that form part of their professional socialization. As the numbers of students enrolled into existing schools increase and new pharmacy schools are inaugurated, the already small and diminishing pool of full-time pharmacist academics will be stretched to the point that students will have few opportunities to engage with such staff, limiting their opportunities to absorb the “culture of pharmacy” and hindering their development from student to autonomous professional.