Biomedical subjects

H W Frijlink

Publications and source records attributed to H W Frijlink.

At least 19 recordsLinked to original sources

PubMed2006

Dry powder inhalation of colistin in cystic fibrosis patients: a single dose pilot study.

BACKGROUND: Dry powder inhalation (DPI) may be an alternative to nebulisation of drugs in the treatment of chest infections in cystic fibrosis (CF) patients. In a pilot study the feasibility of a colistin dry powder inhaler (prototype Twincer) by a single dose in CF-patients was assessed and compared to nebulised colistin. METHODS: Ten CF-patients, chronically infected with P. aeruginosa, participated in a randomised cross over study. On two visits to the outpatient clinic, patients inhaled colistin sulphomethate as 25 mg dry powder (Twincer) or as 158 mg nebulised solution (Ventstream nebuliser, PortaNeb compressor). Pulmonary function tests were performed before, 5 and 30 min after inhalation. Serum samples were drawn prior to each dose and at 15, 45 min, 1.5; 2.5; 3.5 and 5.5 h after inhalation. RESULTS: The DPI was well tolerated by the patients: no significant reduction in FEV1 was observed. Relative bioavailability of DPI to nebulisation was approx. 140% based on actual dose and approx. 270% based on drug dose label claim. CONCLUSIONS: The colistin DPI (Twincer inhaler) is well tolerated and appreciated by CF-patients. Optimisation with respect to particle size and internal resistance of the inhaler is necessary to attain equivalent pulmonary deposition to liquid nebulisation.

Administration, Inhalation↗

PubMed2006

Dry powder inhalation of colistin sulphomethate in healthy volunteers: A pilot study.

BACKGROUND: Pulmonary administration of the antimicrobial drugs colistin sulphomethate and tobramycin has been shown to be effective in slowing down pulmonary deterioration in cystic fibrosis (CF) patients. Both drugs are administered by liquid nebulisation, a technique known to have disadvantages. Dry powder inhalation may be an attractive alternative. We investigated inhalation of colistin sulphomethate dry powder using a newly developed Twincer device in healthy volunteers. METHODS: Eight healthy volunteers inhaled a single dose of 25mg colistin sulphomethate dry powder each, using the Twincer inhaler. The median diameter (X(50)) of the dry powder was 1.6 microm (X(10)=0.7 microm, X(90)=3.1 microm), measured by laser diffraction technique. Pulmonary function tests were performed before, 5 and 30 min after inhalation. Serum samples were drawn at t=15 min, 45 min, 1.5h, 2.5h, 3.5h, 5.5h, 7.5h and 24h after inhalation. RESULTS: The colistin sulphomethate dry powder inhaler was well tolerated: no clinically relevant effect on FEV(1) was observed nor did the volunteers experience adverse effects. CONCLUSION: Dry powder inhalation of colistin sulphomethate using the Twincer inhaler is well tolerated by healthy volunteers. A pilot study in cystic fibrosis patients is therefore considered safe in developing a dry powder inhalation of colistin for everyday CF treatment.

Administration, Inhalation↗

PubMed2006

A novel dissolution method relevant to intestinal release behaviour and its application in the evaluation of modified release mesalazine products.

Mesalazine (5-ASA) is a compound being used in the therapy of inflammatory bowel disease (IBD). Considering the fact that 5-ASA is locally active and that the location of inflammation in IBD may vary, it is recognized that the release profile of 5-ASA drugs is the dominant factor for adequate local bioavailability. Furthermore, it is hypothesized that systemic absorption of 5-ASA (mainly in the upper intestinal segments) increases the risk of side effects. These facts relate to the conclusion that a method determining the dissolution profile under biorelevant conditions is a valuable tool for evaluation and comparison of 5-ASA-products. We tested several commercially available products (Salofalk tablets, Salofalk granules, Asacol tablets, Pentasa tablets and granules) in a gastro-intestinal simulation system (GISS). The GISS is based on the pharmacopeial dissolution test. The release profiles of all products are in agreement with their technological concepts. The percentage of the dose released in the simulated colon is small in all products. The GISS is a robust system able to discriminate between products which apply different modified-release technologies. Colon-selectivity of modified-release 5-ASA products might further be improved. The commercially available 5-ASA containing oral dosage forms exhibit different release profiles, which suggests that the optimal product may differ per patient.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2006

The effect of carrier surface treatment on drug particle detachment from crystalline carriers in adhesive mixtures for inhalation.

In this study, the effect of lactose carrier surface treatment on drug particle detachment during inhalation has been investigated. Crystals of marketed brands of alpha lactose monohydrate brands normally exhibit a certain surface rugosity and contain natural fines and impurities on their surface, which influence the drug-to-carrier interaction in adhesive mixtures for inhalation. Submersion treatment may change these surface characteristics. Two different sieve fractions (63-90 and 250-355microm) were submerged in mixtures of ethanol and water (96 and 80% v/v, respectively). Microscopic observation and laser diffraction analysis revealed that neither the shape nor the size of the carrier particles was changed by the submersion treatment. However, the specific surface area and the amount of impurities appeared to decrease substantially after submersion, and the magnitude of the decrease was different for the different ethanol-water mixtures. The reduction in specific surface area was attributed particularly to the removal of the adhering lactose fines from the carrier surface. Mixtures with budesonide (in a wide range of carrier payloads) were prepared before and after treatment. Drug particle detachment from the various mixtures was studied with a sieve test and with a cascade impactor analysis at 30 and 60l/min. Two different types of inhalers were used, one generating lift- and drag-forces (ISF inhaler) and one generating inertial forces (test inhaler), respectively. The cascade impactor and sieve test experiments showed that an increase in carrier surface smoothness results in a reduced drug particle detachment during inhalation, which was independent of the type of inhaler used. This reduction could be attributed to the removal of the adhering lactose fines which may provide shelter for the drug particles from press-on forces during mixing.

Bronchodilator Agents↗

PubMed2006

The use of Stokes deformation number as a predictive tool for material exchange behaviour of granules in the 'equilibrium phase' in high shear granulation.

The objective of this study was three-fold; to investigate the different mechanisms of material exchange during the equilibrium phase of the granulation process and whether these mechanisms are consistent with the mechanisms described in the growth regime map, to study how material properties and process conditions affect these exchange mechanisms, and to correlate Stokes deformation number to the exchange mechanisms. Microcrystalline cellulose (MCC), alpha-lactose, microfine cellulose (MFC), and dextrin were granulated using water as a binding agent. Once in the equilibrium phase, 5% (w/w) of the granular mass was replaced with wet tracer granules, after which the granulation process was continued. Granules were typically of a size of approximately 1mm in diameter. Therefore, these granules can also be called pellets. Tracer experiments show indeed solid material exchange can take place in the equilibrium phase of the high shear granulation process. Tracer material was equally dispersed throughout the whole batch for all materials tested. However, the granulation time needed to reach this homogeneous distribution varied with material and granulation conditions. Three different mechanisms of material exchange were identified: exchange by disintegration, where granules are rapidly crushed and formed to granules again; exchange by deformation, where abraded granule fragments immediately fuse with other granules; and exchange by distribution, where there is a prolonged period over which both tracer and standard granules stay intact, followed by uncontrolled growth and exchange of material. It was found that it is possible to shift between the mechanisms by changing the process conditions, e.g., changing viscosity or amount of binder liquid. These observations indicate that by choosing the appropriate process conditions improved distribution of small amounts of insoluble materials in the granules can be obtained. A relation exists between the exchange mechanisms and the growth regime map: the disintegration mechanism resembles 'crumb behaviour', the deformation mechanism resembles 'steady growth', and the distribution mechanism resembles 'nucleation' and 'induction growth'. Unfortunately, Stokes deformation number cannot be used as a predictive tool when low viscosity binders like water are used, due to the importance of viscosity in the equation. However, this number is one of the variables of the growth regime map. Since the exchange mechanisms correspond to the granule growth mechanisms in the regime map, alternatively colour experiments might be used to reveal the granulation regime.

Algorithms↗

PubMed2006

Air classifier technology (ACT) in dry powder inhalation Part 4. Performance of air classifier technology in the Novolizer multi-dose dry powder inhaler.

In this study, the in vitro fine particle deposition from a multi dose dry powder inhaler (Novolizer) with air classifier technology has been investigated. It is shown that different target values for the fine particle fraction (fpf<5 microm) of the same drug can be achieved in a well-controlled way. This is particularly relevant to the application of generic formulations in the inhaler. The well-controlled and predictable fpf is achieved through dispersion of different types of formulations in exactly the same classifier concept. On the other hand, it is shown that air classifier-based inhalers are less sensitive to the carrier surface and bulk properties than competitive inhalers like the Diskus. For 10 randomly selected lactose carriers for inhalation from four different suppliers, the budesonide fpf (at 4 kPa) from the Novolizer varied between 30 and 46% (of the measured dose; R.S.D.=14.2%), whereas the extremes in fpf from the Diskus dpi were 7 and 44% (R.S.D.=56.2%) for the same formulations. The fpf from a classifier-based inhaler appears to be less dependent of the amount of lactose (carrier) fines (<15 microm) in the mixture too. Classifier-based inhalers perform best with coarse carriers that have relatively wide size distributions (e.g. 50-350 microm) and surface discontinuities inside which drug particles can find shelter from press-on forces during mixing. Coarse carrier fractions have good flow properties, which increases the dose measuring accuracy and reproducibility. The fpf from the Novolizer increases with increasing pressure drop across the device. On theoretical grounds, it can be argued that this yields a more reproducible therapy, because it compensates for a shift in deposition to larger airways when the flow rate is increased. Support for this reasoning based on lung deposition modelling studies has been found in a scintigraphic study with the Novolizer. Finally, it is shown that this inhaler produces a finer aerosol than competitor devices, within the fpf<5 microm, subfractions of particles (e.g. <1, 1-2, 2-3, 3-4 and 4-5 microm) are higher.

Adhesiveness↗

PubMed2006

Air classifier technology (ACT) in dry powder inhalation Part 3. Design and development of an air classifier family for the Novolizer multi-dose dry powder inhaler.

In this study, the design of a multifarious classifier family for different applications is described. The main design and development steps are presented as well as some special techniques that have been applied to achieve preset objectives. It is shown by increasing the number of air supply channels to the classifier chamber (from 2 to 8), that the fine particle losses from adhesion onto the classifier walls can be reduced from 75% to less than 5% of the real dose for soft (spherical) agglomerates. By applying a bypass flow that is arranged as a co-axial sheath of clean air around the aerosol cloud from the classifier, the airflow resistance of the classifier can be controlled over a relatively wide range of values (0.023-0.041 kPa(0.5) min l(-1)). This, without affecting the fine particle dose or increasing the fine particle losses in the inhaler. Moreover, the sheath flow can be modelled to reduce the depositions in the induction port to the cascade impactor or in the patient's mouth, which are the result of back flows in these regions. The principle of powder induced pressure drop reduction across a classifier enables assessment of the amount of powder in the classifier at any moment during inhalation, from which classifier loading (from the dose system) and discharge rates can be derived. This principle has been applied to study the residence time of a dose in the classifier as function of the carrier size fraction and the flow rate. It has been found that this residence time can be controlled in order to obtain an optimal balance between the generated fine particle fraction and the inhalation manoeuvre of the patient. A residence time between 0.5 and 2 s at 60 l/min is considered favourable, as this yields a high fine particle dose (depending on the type of formulation used) and leaves sufficient inhaled volume for particle transport into the deep lung.

Adhesiveness↗

PubMed2006

The choice of a suitable oligosaccharide to prevent aggregation of PEGylated nanoparticles during freeze thawing and freeze drying.

In a previous study we have shown that the oligosaccharide inulin can prevent aggregation of poly(ethylene glycol) (PEG) coated plasmid DNA/cationic liposome complexes ("PEGylated lipoplexes") during freeze thawing and freeze drying [Hinrichs et al., 2005. J. Control. Release 103, 465]. By contrast, dextran clearly failed as stabilizer. These results were ascribed to the fact that inulin and PEG are compatible while dextran and PEG are not. In this study the stabilizing capacities of inulin and dextran (of various molecular weights) during freeze thawing and freeze drying of four different types of nanoparticles, each type with different amounts of PEG at their surface, were investigated. Freeze drying and freeze thawing of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/dioleoyl-phosphatidyl-ethanolamine (DOPE) liposomes and egg phosphatidyl choline (EPC)/cholesterol (CHOL) liposomes showed that inulins are excellent stabilizers even for highly PEGylated liposomes while (especially higher molecular weight) dextrans dramatically lost their stabilizing capacity when increasing the degree of PEGylation of the liposomes. The same results were obtained for plasmid DNA/DOTAP/DOPE complexes. Finally, both inulin and dextran could prevent full aggregation of plasmid DNA/polyethylenimine (PEI) complexes independent whether PEI was PEGylated or not. It is concluded that inulins are preferred as stabilizers over dextrans for various types of PEGylated nanoparticles due to their compatibility with PEG.

Cholesterol↗

PubMed2006

Characterization of the molecular distribution of drugs in glassy solid dispersions at the nano-meter scale, using differential scanning calorimetry and gravimetric water vapour sorption techniques.

The molecular distribution in fully amorphous solid dispersions consisting of poly(vinylpyrrolidone) (PVP)-diazepam and inulin-diazepam was studied. One glass transition temperature (T(g)), as determined by temperature modulated differential scanning calorimetry (TMDSC), was observed in PVP-diazepam solid dispersions prepared by fusion for all drug loads tested (10-80 wt.%). The T(g) of these solid dispersions gradually changed with composition and decreased from 177 degrees C for pure PVP to 46 degrees C for diazepam. These observations indicate that diazepam was dispersed in PVP on a molecular level. However, in PVP-diazepam solid dispersions prepared by freeze drying, two T(g)'s were observed for drug loads above 35 wt.% indicating phase separation. One T(g) indicated the presence of amorphous diazepam clusters, the other T(g) was attributed to a PVP-rich phase in which diazepam was dispersed on a molecular level. With both the value of the latter T(g) and the DeltaC(p) of the diazepam glass transition the concentrations of molecular dispersed diazepam could be calculated (27-35 wt.%). Both methods gave similar results. Water vapour sorption (DVS) experiments revealed that the PVP-matrix was hydrophobised by the incorporated diazepam. TMDSC and DVS results were used to estimate the size of diazepam clusters in freeze dried PVP-diazepam solid dispersions, which appeared to be in the nano-meter range. The inulin-diazepam solid dispersions prepared by spray freeze drying showed one T(g) for drug loads up to 35 wt.% indicating homogeneous distribution on a molecular level. However, this T(g) was independent of the drug load, which is unexpected because diazepam has a lower T(g) than inulin (46 and 155 degrees C, respectively). For higher drug loads, a T(g) of diazepam as well as a T(g) of the inulin-rich phase was observed, indicating the formation of amorphous diazepam clusters. From the DeltaC(p) of the diazepam glass transition the amount of molecularly dispersed diazepam was calculated (12-27 wt.%). In contrast to the PVP-diazepam solid dispersions, DVS-experiments revealed that inulin was not hydrophobised by diazepam. Consequently, the size of diazepam clusters could not be estimated. It was concluded that TMDSC enables characterization and quantification of the molecular distribution in amorphous solid dispersions. When the hygroscopicity of the carrier is reduced by the drug, DVS in combination with TMDSC can be used to estimate the size of amorphous drug clusters.

Adsorption↗

PubMed2005

Stability of influenza sub-unit vaccine. Does a couple of days outside the refrigerator matter?

In this study 27 full scale production batches of influenza sub-unit vaccine were evaluated on their stability. The batches varied with respect to the strains they contained and regarding the presence of the preservative thiomersal in the solution. The stability study showed that haemagglutinin content was the most sensitive parameter. An increase in the storage temperature strongly increased the degradation rate of haemagglutinin. The degradation rate of the haemagglutinin differed for the different strains tested. However, statistical evaluation of the data obtained for the most sensitive strain tested showed that even exposure during a 2 week period of the vaccine to room temperature would not adversely affect the shelf life claim of the influenza subunit vaccine of 1 year in the refrigerator. Moreover, this study showed that the presence of thiomersal in the solution has no effect on the stability of the vaccine.

Drug Stability↗

PubMed2005

The effect of powder blend and tablet structure on drug release mechanisms of hydrophobic starch acetate matrix tablets.

This study investigates the release mechanism of a hydrophilic drug (caffeine) from hydrophobic matrix tablets composed of starch acetate. Different particle size fractions of starch acetate were mixed with caffeine (22% V/V) to obtain various mixture organisations in the powder, as well as in the final tablet. The organisation of powder mixtures was calculated by the carrier payload of starch acetate particles, while the pore size distributions in tablets were measured by mercury intrusion porosimetry. A carrier payload below 1 indicated the existence of a free starch acetate particle surface, while numbers greater than 1 pointed to a complete occupation of the starch acetate particle surface area by caffeine particles. The carrier payload calculations gave a good prediction for the existence of a starch acetate matrix in the tablet structures. Caffeine matrices in tablets compressed from the mixtures could be detected by mercury intrusion porosimetry measurements. The existence of different matrices, as well as different pore networks, determined the physical changes of the tablets and the release mechanism of caffeine during dissolution tests. When a tablet contained only a caffeine matrix, rapid tablet disintegration and immediate release of the total amount of caffeine occurred. A single matrix of starch acetate resulted in tablets that remained intact, although cracks were formed. The co-existence of matrices of both materials created surface erosion of the tablet. The caffeine release profiles of tablets that remained intact or showed erosion were fitted by an equation containing both diffusional and relaxational factors to describe the effect of tablet porosity on drug release.

Caffeine↗

PubMed2005

A critical evaluation of the relevant parameters for drug redispersion from adhesive mixtures during inhalation.

In this paper, the parameters that are relevant to the drug redispersion from adhesive mixtures during inhalation are discussed and evaluated. The results obtained with air classifier technology give strong evidence for a dominating influence of carrier surface properties on the fraction of drug detached during inhalation at a low carrier payload (< or =1%, w/w), versus a dominating effect of carrier bulk properties at higher payloads. Furthermore, the results indicate that there is a fundamental difference between so-called active carrier sites and large surface discontinuities. The difference refers to the saturation concentrations, the rates of saturation and their effects on drug detachment during inhalation. The degree of saturation of the active sites appears to be proportional with the square root of the carrier surface payload (after 10 min mixing time in a Turbula mixer at 90 rpm). The storage volume of the discontinuities seems largely independent of the carrier diameter for particles derived from the same batch of crystalline lactose. Saturation of these discontinuities is completed at a much lower carrier surface payload than saturation of the active sites. Relatively large discontinuities are beneficial to de-agglomeration principles that make use of inertial separation forces during inhalation, as they provide shelter from inertial and frictional press-on forces during mixing which increase the strength of the interparticulate bonds in the powder mixture. For de-agglomeration principles generating frictional, drag or lift forces, carrier surface depressions and projections are disadvantageous however, as they also provide shelter from these removal forces.

Adhesives↗

PubMed2005

Inulin is a promising cryo- and lyoprotectant for PEGylated lipoplexes.

The aim of this study was to investigate whether the oligosaccharides dextran and inulin are able to prevent aggregation of lipoplexes based on 1,2-dioleoyl-3-trimethylammonium-propane and dioleoylphosphatidyl-ethanolamine with and without distearoylphosphatidylethanolamine-polyethyleneglycol (PEGylated and nonPEGylated lipoplexes, respectively) during storage. The lipoplexes, dispersed in the oligosaccharide solution were frozen and subsequently stored at subzero temperature or freeze dried and subsequently stored at 37 degrees C. When lipoplexes in frozen dispersions were stored below the glass transition temperature of the maximally freeze concentrated fraction (Tg') of the oligosaccharide solutions severe aggregation of the nonPEGylated lipoplexes was prevented for 3 months by both inulin and dextran. However, while dextran failed to stabilize the frozen PEGylated lipoplexes (as in most cases full aggregation occurred in short time) inulin successfully protected them against aggregation. Compared to dextran, inulin was also a superior lyoprotectant of PEGylated lipoplexes: during freeze drying and subsequent storage at 37 degrees C of the dried powders for 3 months the PEGylated lipoplexes maintained their original size when dispersed in inulin matrices while in dextran matrices they fully aggregated in most cases. It is hypothesized that the aggregation of the PEGylated lipoplexes in dextran solutions is caused by the well known incompatibility between dextrans and PEG. This is further supported by the observation that inulins and PEG are compatible. It is concluded that oligosaccharides can prevent severe aggregation of nonPEGylated lipoplexes. The same holds for PEGylated lipoplexes provided that the oligosaccharide is compatible with PEG. Finally, this work also shows that the higher Tg' of oligosaccharides makes them more versatile cryoprotectants than disaccharides like sucrose or trehalose as the frozen dispersions can be stored at higher temperatures for prolonged periods of time. Furthermore, it is proposed that oligosaccharides are also more versatile lyoprotectants than the disaccharides because they can be exposed to higher relative humidities without passing the glass transition temperature.

Drug Stability↗

PubMed2005

The effect of the amount of binder liquid on the granulation mechanisms and structure of microcrystalline cellulose granules prepared by high shear granulation.

The structure of granules changes during the high shear granulation process. The purpose of this research was to investigate the effect of the amount of binder liquid on the structure of the granules and the structural changes which occur during the granulation process, using microcrystalline cellulose (MCC) and water as the model system. The structure is the result of the granulation mechanism; therefore, conclusions can be drawn about the latter by studying the former. X-ray microtomography and scanning electron microscopy (SEM) were applied in order to visualise the densification process of granules, which were first freeze dried in order to preserve their structure. Variations in their porosity were quantified by applying image analysis to the tomography results. In order to link the granule mechanical properties to their structural differences, a micromanipulation technique was used to measure granule resistance to deformation. MCC granules granulated with 100% (w/w) water showed increased densification with time, as expected; detailed examination showed that densification is more pronounced in the core of the granule; whereas the outer part remained more porous. Increased densification reduces deformability, so that granules become more resistant to breakage. The lower deformability of the densified granules in the final stages of granulation might result in establishment of equilibrium between attrition and growth, without substantial gross breakage. On the other hand, when more water was used (125%, w/w), densification was hardly observed; the porosity of the granule core was still high even after prolonged granulation times. This may be explained by the fact that higher water content increases the ease of deformation of granules. This increased deformability led to significant granule breakage even during the final phases of the granulation process. Therefore, for these granules a final equilibrium between breakage and coalescence might be established. This also explains why more granules produced with 125% granulation liquid were composed of fragments of irregular shape. Our results establish the link between the granulation behaviour of MCC in the latter stages and the material structure of these granules, which is determined by their liquid content. The process conditions (amount of liquid) to be chosen depend largely on the final purpose for which the granular material is produced.

Cellulose↗

PubMed2005

The relation between granule size, granule stickiness, and torque in the high-shear granulation process.

PURPOSE: To investigate the background of the observed relationship between measured torque and granule size in high-shear granulation processes. METHODS: Torque was measured during the granulation process; the behavior of individual wet granules during compaction was investigated using micromanipulation. Surface properties of wet granules were manipulated by coating them with talc. RESULTS: The torque-granule size relationship could not be explained by the rise in mass of the individual granules; it occurs rather through an increase in stickiness of the granules when the moisture content is increased. Obviously, the increased stickiness that causes the granules to grow also increases the torque. Increased stickiness was shown to be the result of an increased deformability of the granules at higher moisture contents, in combination with a change in surface properties. The elastic-plastic behavior (ratio of elastic to plastic deformation) was found to change at increasing moisture contents. CONCLUSIONS: Our results imply that changes in the stickiness of the granular material that may be caused by changes in composition shift the torque-size relationship. This may be of particular importance when, for example, granulation results from placebo batches are used to predict the granule size of drug-containing batches.

Particle Size↗

PubMed2005

Compaction mechanism and tablet strength of unlubricated and lubricated (silicified) microcrystalline cellulose.

This paper describes the differences in compaction properties between microcrystalline cellulose (MCC) and microcrystalline cellulose co-processed with colloidal silicon dioxide (SMCC). The different compaction parameters are not only compared for the pure materials, but also for the lubricated powders with magnesium stearate. Neither magnesium stearate, nor colloidal silicon dioxide, facilitates extensively the densification of (silicified) microcrystalline cellulose during compaction. The difference in tablet relaxation of MCC and SMCC indicates a small negative effect of colloidal silicon dioxide on the interparticle bonding strength of unlubricated MCC. However, for lubricated MCC a larger increase in tablet relaxation at a high compression speed was found than for lubricated SMCC tablets. Accordingly, the decrease in tablet strength was larger for the MCC tablets than for the SMCC tablets when lubrication was applied. The examination of the tablet strengths of tablets compressed from physical mixtures of MCC with increasing concentrations of colloidal silicon dioxide proved the slightly negative influence of silicon dioxide on the tablet strength of unlubricated MCC tablets and the positive effect of colloidal silicon dioxide addition on the tensile strength of lubricated MCC tablets. Co-processing of MCC with colloidal silicon dioxide showed no extra contribution on the tablet strength of lubricated tablets above the physical mixtures. The interactions between the different materials were further supported by the interaction parameters based on partial solubility parameters.

Cellulose↗

PubMed2005

The interaction between carrier rugosity and carrier payload, and its effect on drug particle redispersion from adhesive mixtures during inhalation.

The effectiveness of press-on forces (defined as the adhesive forces between drug and carrier particles) in relation to carrier payload as the result of collisions between carrier particles during the mixing process of an adhesive mixture, has been investigated. Three different carriers of the same size fraction (250-355 microm), but with completely different surface rugosity were studied. It could be shown that this effectiveness depends on the carrier rugosity. The fraction of drug detached from the carrier particles during inhalation appeared to decrease faster with increasing carrier payload for crystalline carriers than for granular carriers. Apparently, increasing the volume of the carrier surface cavities increases the drug mass that can find shelter from the press-on forces during mixing. By measuring the size distribution in the aerosol, it could also be shown that the press-on forces may increase the size of the particles that are detached. This seems to be the result of drug particle re-agglomeration on the carrier surface during mixing. On the other hand, when press-on forces are highly ineffective, an increase in the size of detached particles may also be the result of incomplete break-up of natural drug agglomerates. Finally, it could be shown that when the press-on forces are highly effective, the effect of mixing time is small.

Adhesives↗

PubMed2004

An investigation into the predictive value of cascade impactor results for side effects of inhaled salbutamol.

The aim of this study was to compare the Multistage Liquid Impinger (MSLI) and the Andersen Cascade Impactor (ACI) with respect to their power to predict differences in side effects of salbutamol delivered by a dry powder inhaler. Three preparations with the same nominal dose and the same inhaler device but generating aerosols with different aerodynamic particle size distributions were administered to six healthy volunteers in a randomized, placebo-controlled, four-way crossover study. Cumulative doses from 400 up to 1600 microg were given. The serum potassium level (K+-serum) and the heart rate (HR) were measured at baseline and 15 min after each dose. Both the MSLI and ACI showed large differences between the aerodynamic particle size distributions of the three preparations. The decrease in K+-serum revealed significant differences between the three active preparations and was significant for doses of 800 microg and higher. The HR results showed differences between the active preparations only at a nominal dose of 1600 microg and only for the preparation with the highest fine particle dose (FPD) compared to the other two preparations. The K+-serum appears to be a more sensitive measure for side effects than the HR. In vivo-in vitro correlations (IVIVCs) were established between the amounts of salbutamol deposited on the various cumulative impactor stages and the K+-serum. The best IVIVCs were obtained in the FPD range, resulting in correlation coefficients of at least 0.78. It is concluded that cascade impactor results in the FPD range of the MSLI as well as the ACI correlate well with the K+-serum. Cascade impactor analysis thus provides a clinically meaningful tool in the development and the quality control of salbutamol inhalation powders.

Administration, Inhalation↗