Mika Vidgren

Effect of powder inhaler design on drug deposition in the respiratory tract

Abstract Disodium cromoglycate particles were labelled with pure γ-radiator, 99m Tc, using the co-precipitation technique based on spray drying. Radioactive drug particles were mixed with lactose carrier and filled into hard gelatin capsules. Seven healthy volunteers inhaled drug doses using Spinhaler I.S.F., Berotec, and Rotahaler dry powder devices. The fractional deposition of drug particles in the upper airways and lung region were monitored using a gamma camera. The fraction of the dose retained in the powder inhaler was the smallest for I.S.F. and especially for Berotec inhalers. These devices have narrower air channel constructions with a smaller wall surface area than the Spinhaler and Rotahaler devices. Thus the sticking of the drug particles onto the plastic walls was less probable for the first-mentioned devices. The drug particles from all the dry powder inhalers seemed to be more able to follow the inspired air stream without depositing in the upper airways than previously documented for pressurized metered dose aerosols. I.S.F. and Berotec inhalers with narrow air channels gave the greatest lung deposition of the inhaled drug particles. Thus the design of the dry powder inhaler was noticed to have a remarkable effect both on the emptying of the capsules as well as on the redispersion of the powder mixture.

Starch Acetates—Multifunctional Direct Compression Excipients

Native starch grains contain polymers consisting in varying ratios of linear amylose and branched amylopectin, which are composed of glucose monomers. Glucose monomers are linked to each other mainly by a-1,4 glucosidic bonds. A glucose monomer contains three hydroxyl groups, which can be, in the present case, acetylated. Native starch grains are insoluble in water, but they are hydroscopic materials which swell in the presence of water. Starches from various natural origins and their common derivates are well-known, safe, and have been extensively investigated in tablet formulations for various purposes. Native starches are used as disintegrants, diluents, and wet binders. However, their poor flow and high lubricant sensitivity make them less favoured in direct compression. Different chemical, mechanical, and physical modifications of native starches have been used to improve both their direct compression and controlled release properties (1– 5). Although, various starches and their derivatives have been studied extensively, there is still much to examine about their mechanical properties as compacts. Furthermore, starchbased formulations are usually multicomponent formulations which increase the risks of incompatibility. In the present study, novel direct compression excipients are introduced as starch acetates (6). The preparation of these acetates was accomplished, and their chemical properties were evaluated. The effects of substitution on the starch acetates were investigated according to physical and tablet properties. The resulting starch acetates were compared to commercially available direct compression excipients.

Effects of physical properties for starch acetate powders on tableting

The aim of the study was to investigate particle and powder properties of various starch acetate powders, to study the effect of these properties on direct compression characteristics, and to evaluate the modification opportunity of physical properties for starch acetate powders by using various drying methods. At the end of the production phase of starch acetate, the slurry of starch acetate was dried using various techniques. Particle, powder, and tableting properties of end products were investigated. Particle size, circularity, surface texture, water content and specific surface area varied according to the particular drying method of choice. However, all powders were freely flowing. Bulk and tapped densities of powders varied in the range of 0.29 to 0.44 g/cm3 and 0.39 to 0.56 g/cm3, respectively. Compaction characteristics revealed that all powders were easily deformed under compression, having yield pressure values of less than 66 MPa according to Heckel analysis. All powders possessed a significant interparticulate bond-forming capacity during compaction. The tensile strength values of tablets varied between 10 and 18 MPa. In conclusion, physical properties of starch acetate could be affected by various drying techniques. A large specific surface area and water content above 4% were favorable properties by direct compression, especially for small, irregular, and rough particles.

Double-labelling technique in the evaluation of nasal mucoadhesion of disodium cromoglycate microspheres

Abstract 99m Tc-labelled disodium cromoglycate particles and 111 In-labelled microspheres of disodium cromoglycate and polyacrylic acid were administered simultaneously to the nasal cavities of four healthy volunteers. The initial deposition patterns of the inhaled powder mixture as well as the drug removal due to the mucociliary clearance were monitored by a gamma camera. The double-labelling technique enabled in vivo comparison of simultaneously administered plain drug particles and polyacrylic acid microspheres of disodium cromoglycate. After administration, both the plain drug particles and the microspheres distributed equally effectively. On average, 27% of the 99m Tc-labelled plain drug particles and 50% of the 111 In-labelled microspheres were retained at the initial site of deposition 30 min after inhalation. Thus, the removal of microspheres from the nasal cavities was clearly impeded by polyacrylic acid.

Pulmonary Deposition and Clinical Response of99mTc-Labelled Salbutamol Delivered from a Novel Multiple Dose Powder Inhaler

Pulmonary deposition of 99mTc-labelled sulbutamol was determined after delivery from a novel multiple dose powder inhaler (Easyhaler®). The clinical efficacy of the inhalation powder, evaluated simultaneously with gamma camera detection, was compared with that obtained after drug delivery from a metered dose inhaler-spacer combination. The study was performed as an open, non-randomized cross-over trial. A single dose of radiolabelled inhalation powder was inhaled on the first and the inhalation aerosol, as control, on the second study day. Sulbutamol sulphate was labelled with 99mtechnetium, and the inhalation powder was formulated by mixing radioactive drug particles with carrier material. Aerodynamic properties of the radiolabelled inhalation powder were similar to those of the unlabelled salbutamol powder. Delivered dose from the breath-actuated powder inhaler was adjusted to be equal to two puffs from a conventional aerosol actuator with a short plastic mouthpiece. Twelve non-smoking asthmatic patients participated in the trial. The mean pulmonary deposition of 24% was obtained after drug delivery from Easyhaler® powder inhaler. Clinical efficacy of the medications was similar in terms of area under the FEV1 curve, maximum FEV1 and the improvement ratio. Thus it can be suggested that powder delivery from Easyhaler® powder inhaler and the aerosol delivery through the spacer are equally effective.

Radiotracer evaluation of the deposition of drug particles inhaled from a new powder inhaler

Abstract Deposition of 99m Tc-labelled particles of disodium cromoglycate in the human respiratory tract after inhalation either from the conventional metered dose aerosol or from the new Ingelheim powder inhaler (FO II) was compared. Fractional deposition in the whole lung area, in the upper airways and in the device was measured using a gamma camera. Eight healthy informed volunteers participated in the inhalation test. The lung deposition of the inhaled drug was about 9% using the conventional aerosol actuator with the short plastic mouthpiece whereas, using the Ingelheim powder inhaler, on average 20% deposition in the whole lung area was achieved. In addition, with the Ingelheim inhaler drug particles seemed to be deposited in the more peripheral parts of the respiratory tract. The upper airway deposition was also reduced with the Ingelheim powder inhaler. On the other hand, a larger fraction of the drug dose was retained in the Ingelheim inhaler than in the aerosol actuator.

Dose of inhaled β2-agonists in asthma

exerted no discernible effect on the L-arginine-induced hypotension. To examine if NO was responsible for the observed hypotension we measured plasma concentrations of L-arginine and L-citrulline’ (by high-performance liquid chromatography), cyclic guanosine monophosphate (cGMP), and several hormones (atrial natriuretic peptide, plasma renin activity, aldosterone arginine vasopressin, noradrenaline, and adrenaline) by radioimmunoassay. The mean plasma concentration of L-arginine after L-arginine infusion was lower than others predicted.3 L-citrulline, the by-product of NO synthesis from L-arginine and cGMP, the second messenger for NO,5 significantly increased:

Gastrointestinal transit of 99mTc-labelled oral dosage forms of sucralfate in healthy volunteers

Abstract In this study the deposition and gastrointestinal transit of a conventional uncoated tablet, a chewable tablet, as well as an effervescent preparation containing 1 g of 99m Tc-labelled sucralfate were evaluated over 180 min using a gamma camera. Each preparation was administered by five healthy volunteers after 10 h fasting. The conventional tablet and the effervescent preparation seemed to distribute immediately in the whole stomach area. With the chewable tablet, the initial deposition of sucralfate in the mouth and oesophagus was also detected. The transit of sucralfate into the intestinal area was noted for the conventional tablet and for the effervescent preparation as early as after 10 min, whereas the increase in sucralfate concentration in the intestinal area after administration of chewable tablets was observed after 30 min. After 60 min the amount of sucralfate remaining in the stomach was about 40% for the conventional tablet, about 20% for the effervescent preparation and about 80% for the chewable tablet. Thus, the effervescent preparation of sucralfate, administered as a suspension, was transported more rapidly into the intestine than the solid oral dosage forms. After 180 min almost all of the sucralfate liberated from the conventional and effervescent formulations was transported from the stomach into the intestine, whereas 21% of that liberated from chewable tablets was still present in the stomach. The dosage form of sucralfate seemed to have a significant effect on the gastrointestinal distribution and transit of sucralfate.