Biomedical subjects

H W Frijlink

Publications and source records attributed to H W Frijlink.

At least 55 records · Page 3Linked to original sources

PubMed2002

Equivalence testing of salbutamol dry powder inhalers: in vitro impaction results versus in vivo efficacy.

The aim of the study was to evaluate several impactors for in vitro equivalence testing of salbutamol with respect to efficacy and to define in vitro equivalence limits validated with in vivo efficacy data. The four impactors described in Supplement 2000 of the European Pharmacopoeia were used: Glass Impinger (GI), Metal Impinger (MI), Multistage Liquid Impinger (MSLI) and Andersen Cascade Impactor (ACI). Three salbutamol dry powder formulations with different fine particle doses (FPDs) were prepared and the aerodynamic particle size distribution was measured. For each impactor also the recovery was determined. The same three preparations were administered to 12 asthmatic patients in a randomized, placebo-controlled, four-way crossover study. Cumulative doses from 50 microg up to 400 microg were given. The FEV(1) was measured at baseline and 15 min after each dose. The in vitro results showed large differences between the FPDs of the three preparations with all impactors, whereas only small differences were observed between the four impactors. Since the recoveries of the MI and GI were low, in vitro equivalence testing should only be performed with the MSLI or ACI. The in vivo measurements did not show significant differences in efficacy between the three active preparations, even at the most discriminatory dose of 50 microg. It is concluded that in case there are no relevant differences between delivered dose, inhalation device and excipients, for salbutamol dry powder inhalers equivalence can be assumed when the 90% confidence interval for the FPD ratio of the test product and reference product is within 0.50-1.20 and each of the two products has a FPD (particles <6 microm) of at least 10 microg.

Adult↗

PubMed2002

Effect of an external resistance to airflow on the inspiratory flow curve.

Inhalation is a convenient way to deliver drugs to the respiratory tract in the treatment of respiratory diseases. For dry powder inhalers (DPI's), the principle of operation is to use the patient-generated inspiratory flow as energy source for emptying of the dose system and the delivery of fine drug particles into the respiratory tract. Resistance to airflow of the inhaler device is a major determinant for the inspiratory flow profile through the dry powder inhaler that can be generated by the patient. Therefore, resistance to airflow is one of the design parameters for DPI's, that could be used to control the inspiratory flow profile, and is one of the parameters to optimise particle deposition in the airways. In this study the effect of resistance to airflow on different parameters of the inspiratory flow curves as generated by healthy subjects, asthmatics and COPD patients was determined. As a result of increased resistance to airflow, the peak inspiratory flow (PIF), the flow increase rate (FIR) and the inhaled volume to reach PIF is decreased. On the other hand, the total inhalation time as well as the 80% dwell time is increased. In general, tuning of the resistance to airflow in the design of a dry powder inhaler may improve the drug deposition in the respiratory tract.

Administration, Inhalation↗

PubMed2002

Pore formation in tablets compressed from binary mixtures as a result of deformation and relaxation of particles.

This paper describes the internal structure of tablets compressed from binary mixtures of sodium chloride and pregelatinised starch. The minimum particle diameter of pregelatinised starch inside tablets compressed from mixtures was calculated from the difference between the initial pore size distribution and the pore size distribution after removal of the starch particles by burning. Subsequently, the tablets were carefully crushed. These powders, consisting of almost only sodium chloride particles, were measured by laser diffraction. It was found that the diameter of the sodium chloride particles hardly changed, whereas the minimum diameter of starch particles strongly decreased during the compaction process. As an effect of the difference in yield pressure, the harder sodium chloride particles cause deformation of the softer starch particles, resulting in a change in particle shape. The pore size distribution of tablets compressed from mixtures of sodium chloride and starch is typically that of viscoelastic materials; the larger pores (>5 microm) change, while the small pores stay constant in number and size. The median pore diameter in tablets compressed from the mixtures is higher than the median pore diameter in tablets compressed from the pure materials. This paper shows that the formation of large pores was the result of the extra porosity expansion of tablets compressed from binary mixtures of sodium chloride and pregelatinised starch.

Chemical Phenomena↗

PubMed2002

The influence of particles of a minor component on the matrix strength of sodium chloride.

This paper deals with the matrix strength of sodium chloride particles in pure sodium chloride tablets and in tablets compressed from binary mixtures of sodium chloride with low concentrations of pregelatinised starch. Because this study concerns the strength of the sodium chloride matrix, the tablet strength is reflected as a function of the sodium chloride volume fraction in the tablet. Starch particles in the mixture tablets decrease the sodium chloride volume fraction-tensile strength relationship compared with that of pure sodium chloride tablets. To determine the contribution of the sodium chloride matrix to the tablet strength, the starch particles were removed from the mixture tablets by heat treatment. Determination of the strengths of these heat-treated tablets reveals that the sodium chloride matrix strength determines the tablet strength of mixture tablets containing a single matrix of sodium chloride particles. The decrease of the sodium chloride matrix density in the three different tablets (pure sodium chloride tablets, mixture tablets and heat-treated tablets) is reflected by an increase of the median pore size. The matrix in sodium chloride tablets shows a higher tensile strength to median pore size relation than the matrices in the mixture and heat-treated tablets. Based on calculations according to the theory of elastic-brittle fracture, it is suggested that the initial presence of starch particles during tablet compaction causes the pores in the matrices of the mixtures and heat-treated tablets to be relatively more flat and longer. These pores weaken the sodium chloride matrix in the mixture and heat-treated tablets to a larger extent than the shorter, more spherical pores formed during compaction of pure sodium chloride.

Drug Compounding↗

PubMed2002

Breaking of scored tablets: a review.

The literature was reviewed regarding advantages, problems and performance indicators of score lines. Scored tablets provide dose flexibility, ease of swallowing and may reduce the costs of medication. However, many patients are confronted with scored tablets that are broken unequally and with difficulty, reducing compliance and reliance on the drug. Possibilities to reduce breaking difficulties are breaking instructions, tablet-splitters and breaking in advance. Factors influencing the performance of score lines are shape, size, curvature and thickness of the tablet and the form and deepness of the score line. Performance of score lines can be defined by breaking ease, uniformity of mass of subdivided tablets and loss of mass by the subdivision. For breaking ease, an in-vivo reference test and a routinely applicable in-vitro test need to be established. For the uniformity of mass of subdivided tablets a requirement has recently been set by the European Pharmacopoeia. Loss of mass upon breaking can be limited to not more than 1%.

Chemistry, Pharmaceutical↗

PubMed2002

Dry powder inhalation of antibiotics in cystic fibrosis therapy, part 1: development of a powder formulation with colistin sulfate for a special test inhaler with an air classifier as de-agglomeration principle.

The aim of this study was to investigate the pulmonary administration of antibiotics as dry powder to patients with cystic fibrosis (CF), as an alternative for nebulization. This part of the study describes the development of a powder formulation with colistin sulfate as model substance. The aim of the new dosage form was to increase pulmonary deposition, therapeutic efficiency and, by that, compliance by the CF patients. A physical powder mixture of colistin and a size fraction of lactose (106-150 microm) was prepared and the mixture was optimized with respect to colistin content (83.3%) for use in a special test inhaler. A laser diffraction apparatus with special inhaler adapter was applied for analysis of the size distribution of the aerosol cloud from the inhaler. The size distributions of the aerosol clouds from the test inhaler at flow rates between 30 and 60 l/min for the optimized formulation showed nearly the same median diameter as that for the primary drug particles. But the X(100)-value was much lower, because of an effective large particle separation from the inspiratory air by an air classifier in the test inhaler. The results suggest that dry powder inhalation might be a suitable and highly efficient alternative for nebulization of antibiotic drugs in CF therapy.

Administration, Inhalation↗

PubMed2002

Dry powder inhalation of antibiotics in cystic fibrosis therapy: part 2. Inhalation of a novel colistin dry powder formulation: a feasibility study in healthy volunteers and patients.

The aim of the present study was to perform a proof of principle study with a new colistin dry powder inhalation system in six healthy volunteers and five patients with cystic fibrosis. All subjects were asked to inhale 25 mg colistin sulfate dry powder. The patients were also asked to nebulize 160 mg colistin sulfomethate as a solution. Colistin serum concentrations were determined as an indirect parameter to compare both forms of administration. Pulmonary function tests were performed. Peak serum colistin concentrations ranged from 14 to 59 microg/l in volunteers after inhalation of 25 mg as dry powder. In patients, peak concentrations ranged from 18 to 64 microg/l after nebulization of 160 mg colistin sulfomethate solution and from 77 to 159 microg/l after inhalation of 25 mg colistin sulfate dry powder. Pulmonary function tests were not significantly different after inhalation of the dry powder by the volunteers nor after nebulization of the solution by the patients. In some patients a decrease in pulmonary function and moderate to severe cough was observed after inhalation of the dry powder. The new colistin inhaler provides an attractive alternative for nebulized colistin and was highly appreciated by the patients. The decrease in pulmonary function and cough in patients is a drawback, which may be overcome by dose reduction and a further improvement of the new dosage form.

Administration, Inhalation↗

PubMed2002

The effect of budesonide particle mass on drug particle detachment from carrier crystals in adhesive mixtures during inhalation.

The different fine particle fractions (FPFs) that are obtained, when different dry powder inhalers (DPIs) are used for the same powder formulation at the same flow rate, is the result of different powder de-agglomeration efficiencies for these DPIs. For adhesive mixtures, this is the efficiency with which the kinetic energy of the air flow through the DPI is converted into separation forces that detach drug particles from carrier crystals. We investigated the effect of drug particle diameter (mass) on drug-carrier separation during inhalation with three different inhalers (Sofotec Novolizer, Inhalator Ingelheim and a special test inhaler), at two different flow rates (30 and 60l/min). Two different size fractions were used as carrier material (45-63 and 100-150 microm). We measured decreasing amounts of residual drug on the carrier crystals after inhalation with increasing drug particle mass for all inhalers at both flow rates. The observed trends were the same for both carrier fractions. The decrease in residual drug on carrier is in agreement with increasing FPFs in an Erweka impactor. However, it has been calculated that the magnitude of the effect decreases with increasing de-agglomeration efficiency.

Adhesives↗

PubMed2001

Characterization of human placental alkaline phosphatase by activity and protein assays, capillary electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Placental alkaline phosphatase (PLAP) that had been isolated from human placenta was further purified using subsequent ion-exchange chromatography (IEC), affinity chromatography (AC) and centrifugal membrane concentration (CMC). During the process, the PLAP samples from the different stages of purification were characterized regarding purity and activity. This was accomplished by combining Lowry analysis, enzymatic activity assay, capillary zone electrophoresis (CZE), capillary gel electrophoresis (CGE) and matrix-assisted laser desorption/ionisation time of flight mass spectrometry (MALDI-TOF-MS). The sample obtained after IEC had a rather low specific activity (6.8 U/mg) and appeared to contain several major contaminants, among which was human serum albumin (HSA). AC followed by CMC yielded PLAP with a specific activity of 128 U/mg. The purity and identity of the protein was indicated by MALDI-TOF-MS yielding a spectrum with one major peak at m/z 58,101. Interestingly, CZE of the pure PLAP revealed a cluster of peaks, which probably reflects the presence of various glycoforms and/or oligomers. The same analytical approach was used to characterize commercially available PLAP. This sample showed a moderate specific activity (15 U/mg) and appeared to be highly impure containing various other proteins.

Alkaline Phosphatase↗

PubMed2001

Inulin glasses for the stabilization of therapeutic proteins.

Sugar glasses are widely used to stabilize proteins during drying and subsequent storage. To act successfully as a protectant, the sugars should have a high glass transition temperature (Tg), a poor hygroscopicity, a low crystallization rate, and contain no reducing groups. When freeze drying is envisaged as method of drying, a relatively high Tg of the freeze concentrated fraction (Tg') is preferrable. In this study, whether inulins meet these requirements was investigated. Inulins of various degrees of polymerisation (DP) were evaluated. Trehalose glass was used as a positive control. It was found that the Tg and the Tg' of inulins with a number/weight average DP (DP(n)/DP(w)) higher than 5.5/6.0 were higher than those of trehalose glass. Furthermore, inulin glasses showed a similar hygroscopicity to that of trehalose glass but crystallized less rapidly. Less than 6% of the sugar units of inulins with a DP(n)/DP(w) higher than 5.5/6.0 contained reducing groups. Trehalose contained no reducing groups. Freeze drying of an alkaline phosphatase solution without protectant induced an almost complete loss of the activity of the protein. In contrast, when inulins with a DP(n)/DP(w) higher than 5.5/6.0 or trehalose were used as stabilizer, the activity was fully maintained, also after subsequent storage for 4 weeks at 20 degrees C and 0, 45, or 60% RH, respectively. The stabilizing capacities of inulin with a lower DP and glucose were substantially less pronounced. After storage at 60 degrees C for 6 days, the activity of freeze dried samples containing inulins with a DP(n)/DP(w) higher than 5.5/6.0 was still about 50% whereas the activity of samples containing inulin with a lower DP, glucose, or trehalose was completely lost. It is concluded that inulins with a DP(n)/DP(w) higher than 5.5/6.0 meet the physico-chemical characteristics to successfully act as protectants for proteins. The stabilizing potential of these inulins was clearly shown using alkaline phosphatase as a model protein.

Alkaline Phosphatase↗

PubMed2001

Effect of molecular weight and glass transition on relaxation and release behaviour of poly(DL-lactic acid) tablets.

Different molecular weight grades of poly(DL-lactic acid) were applied as release controlling excipients in tablets for oral drug administration. The role of molecular weight and glass transition in the mechanism of water-induced volume expansion and drug release of PDLA tablets was investigated. Modulated differential scanning calorimetry (MDSC) was used to determine the glass transition temperature of both dry and hydrated PDLA samples. The absorption rate and total amounts of sorbed water by the polymer were determined by dynamic vapour sorption (DVS). Expansion behaviour of PDLA tablets was measured using thermal mechanical analysis (TMA). At 95% relative humidity all molecular weight grades of PDLA sorbed 1.1-1.3% w/w water, as was determined with DVS. MDSC showed glass transition temperature reductions of 10-11 degrees C for all molecular weight grades of PDLA in water. Volume expansion studies using TMA showed that the molecular relaxation time and equilibrium porosity of the tablets increased with molecular weight. The mean relaxation time increased exponentially with the temperature interval T(g)-T. The onset temperature of shape recovery of hydrated tablets was approximately 8 degrees C lower than for dry samples. Drug release was only slightly affected by molecular weight. It is concluded that volume expansion of compressed PDLA tablets is related to the glass transition behaviour, originates from water-induced and thermally stimulated shape memory behaviour and is therefore highly dependent on the molecular weight of PDLA.

Lactic Acid↗

PubMed2001

Plasticisation of amylodextrin by moisture. Consequences for compaction behaviour and tablet properties.

PURPOSE: Amylodextrin, a starch-based controlled release excipient, spontaneously absorbs moisture during storage. The aim of this study was to investigate plasticisation of amylodextrin by moisture and its effect on compaction and tablet characteristics. METHODS: The glass transition temperature (T(g)) of amylodextrin powders with moisture fractions (x(w)) 0.070<x(w)<0.40 was studied by conventional and modulated DSC. Elastic modulus and yield stress were determined from compressive stress-strain experiments. Compaction behaviour was studied at 3 and 300 mm/s using a compaction simulator. RESULTS: The T(g) of amylodextrin-water blends showed a smooth reduction with increasing x(w), equalling room temperature at x(w)=0.19. Experimentally obtained T(g) values were close to temperatures as predicted by the Gordon-Taylor/Kelley-Bueche model and the modified Couchman-Karasz model. The elastic modulus decreased steeply between x(w)=0.17 and 0.23. Compaction experiments showed that moisture facilitated consolidation due to increasing powder compressibility and reduced compact relaxation. However, at x(w)=0.23, compressibility was reduced and relaxation significantly higher due to the rubbery character of this powder. Consequently, the lowest tablet porosities were obtained around x(w)=0.15. Although decreasing porosities enhanced tablet strengths, the maximum obtainable tablet strengths decreased with moisture due to reduced particle bonding and lowering of the elastic modulus. CONCLUSION: Moisture largely affects the visco-elastic and compaction characteristics of amylodextrin. Hence, control over moisture content is essential to produce tablets with reproducible porosity, strength and dissolution characteristics.

Calorimetry, Differential Scanning↗

PubMed2000

Plasticisation of amylodextrin by moisture: consequences for drug release from tablets.

Moisture influences the consolidation behaviour of amylodextrin powders and the porosity and mechanical strength of compacts thereof. The aim of this study is to relate moisture content and compact properties to drug release characteristics of amylodextrin tablets. Therefore, amylodextrin tablets containing theophylline monohydrate were prepared and their release characteristics were studied as a function of moisture content and initial porosity. Drug release from amylodextrin tablets occurs through a leaching mechanism in which cracks are progressively formed in the hydrated part of the matrix leading to almost constant release rates. Small variations in moisture content resulted in large changes of the release rate. A unique relationship between porosity and release rate, which was independent on moisture content and compaction pressure, was observed. Above a critical porosity of 0.075 crack formation was followed by disintegration and fast release. Below this critical porosity, tablets stayed intact despite of the formation of cracks, and sustained release was observed. It is concluded that control over moisture content is essential for the production of amylodextrin tablets with reproducible release characteristics. Using amylodextrin containing 10-17%, moisture, tablets with a constant release behaviour can be obtained if sufficient compaction pressure ( > 300 MPa) is applied. Lubrication of amylodextrin powders reduces the effect of porosity significantly and improves the robustness of amylodextrin tablets as a release controlling excipient in tablets largely.

Bronchodilator Agents↗

PubMed2000

Tensile strength of tablets containing two materials with a different compaction behaviour.

The tensile strength of tablets compressed from binary mixtures is in general not linearly related to the strength of tablets prepared from single materials; in many cases it shows a decreased tensile strength relative to interpolation. The materials used in this study, sodium chloride and pregelatinised starch, are both plastically deforming materials, but have a different densification and relaxation behaviour. The yield pressure of the binary mixtures shows an almost linear relationship. As an effect of their lower yield pressure, starch particles yield earlier than sodium chloride particles. The following enclosure prevents some sodium chloride particles to yield or crack. The relaxation of the tablets is higher than the relaxation calculated by linear interpolation of the relaxation behaviour of the two pure materials. The difference between the measured porosity expansion and the data obtained by linear interpolation can be considered as a measure for the reduced interparticle bonding. SEM-photographs indicate that the reduced interparticle bonding is caused by the low adhesive forces. The measured decrease of the tensile strength of the tablets is also considered to be the result of reduced interparticle bonding. In this paper it is shown that there exists a similar relationship between the tensile strength reduction and the percentage of starch on the one hand and the extra porosity expansion and the starch percentage on the other hand.

Pressure↗

PubMed2000

Clinical efficacy, safety and pharmacokinetics of a newly developed controlled release morphine sulphate suppository in patients with cancer pain.

OBJECTIVE: To compare the efficacy, safety and pharmacokinetics of a newly developed controlled-release suppository (MSR) with MS Contin tablets (MSC) in cancer patients with pain. METHODS: In a double-blind, randomised, two-way cross-over trial, 25 patients with cancer pain were selected with a morphine (M) demand of 30 mg every 12 h. Patients were divided into two groups. Group 1 received active MSC (30 mg) and placebo MSR, followed by placebo MSC and active MSR (30 mg) each for a period of 5 days. Group 2 started with active MSR and placebo MSC, followed by active MSC and placebo MSR, each for a period of 5 days. Blood for determination of plasma concentration of morphine (M) and its 3- and 6-glucuronides (M3G, M6G) was collected, and area under the plasma concentration-time curve (AUC)0-12 h, peak plasma concentration (Cmax), time to reach Cmax (tmax), and CO and C12 of M, M6G and M3G were determined on day 5 and day 10. Intensity of pain experienced by each patient was assessed every 2 h on a 0-10 scale, while side effects and rescue medication were recorded. RESULTS: Twenty patients (ten patients in each group) completed the study. A pronounced inter-patient variability in plasma concentrations of M, M3G and M6G was observed after administration of both forms. Apart from the C0 and C12, no significant differences in AUC0-12 h, tmax and Cmax of morphine between the rectal and oral route of administration were found. In the case of the metabolites, it was found that AUC0-12 h and Cmax of M6G, and AUC0-12 h, Cmax, C0 and C12 of M3G after rectal administration were significantly lower than after oral administration. However, apart from the tmax of M6G, none of the pharmacokinetic parameters of M, M6G or M3G met the criteria for bioequivalence. There were no significant (P = 0.44) differences in pain intensity score between the oral and rectal forms within the two groups, regardless of the treatment sequence. No treatment differences in nausea, sedation or the demand on escape medication (acetaminophen tablets) between the rectal and oral forms were observed. CONCLUSION: The newly developed controlled-release M suppository is safe and effective and may be a useful alternative for oral morphine administration in patients with cancer pain.

Adult↗

PubMed2000

A review of the technical aspects of drug nebulization.

Nebulizers are widely used for the inhalation of drug solutions in a variety of respiratory diseases. The efficacy of nebulizer therapy is influenced by a great number of factors, including the design of the device and the characteristics of the drug solution. Incorrect cleaning, maintenance and disinfection procedures may change the nebulizer performance in time, whereas patient factors can influence the lung deposition of the generated aerosol. In this review the technical aspects of nebulization of drug solutions will be discussed. Two main parameters are generally used to evaluate the performance of nebulizers: the droplet size distribution of the aerosol and the drug output rate. The droplet size distribution and the drug output rate are basically determined by the design and user conditions of the nebulizer. A higher gas flow of the compressor in a jet nebulizer or a higher vibration frequency of the piezo electric crystal in an ultrasonic nebulizer, decreases the droplet size. The choice of the type of nebulizer for nebulization of a certain drug solution may initially be based on laboratory evaluation. The major part of the mass or volume distribution should preferably correspond with aerodynamic particle diameters in the range of 1 to 5 micrometer. The intended drug output must be realized within a reasonable nebulization time (less than 30 min). From the drug output only a minor fraction will be deposited in the lung. The relation between in vitro and in vivo deposition is only partly understood and to date it has not been possible to predict drug delivery only from in vitro studies on nebulizers. Therefore, studies in patients should be performed before a drug solution for nebulization can be recommended for clinical practice. The mechanical properties of nebulizers are likely to change during use. An average utilization time of nebulizers is not available. Therefore, the performance of nebulizers should be checked periodically. Patient compliance in nebulizer therapy is relatively low. This is partly due to the fact that, at present, drug solutions for nebulizers cannot be administered efficiently within a short period of time. More efficient systems should be developed. If possible, nebulizers should be substituted to more efficient systems, e.g. dry powder inhalers or metered dose inhalers.

Administration, Inhalation↗

PubMed1999

Inhalation of tobramycin in cystic fibrosis. Part 1: the choice of a nebulizer.

Forteen commercially available jet and ultrasonic nebulizers were investigated with the aim to select the most suitable type of apparatus for the inhalation of a 10% tobramycin solution. Two different techniques for measurement of particle size distribution were evaluated: laser diffraction and cascade impactor analysis. The final selection of the nebulizers is based on particle size distribution, output and stable performance during nebulization. All 14 nebulizers (eight jet and six ultrasonic) were filled with a solution of 10% m/v tobramycin (as sulphate) in water. The volume in the tested devices ranged from 4.5 to 10 ml (=450-1000 mg tobramycin) in accordance with the prescribed usage by the suppliers. The nebulizers were connected with a special designed adapter to a laser diffraction analyser in order to measure particle size distribution of the aerosol. Inhalation was simulated with a static flow of 40 l/min. The particle size distribution (expressed as X(10), X(50), and X(90)) was determined after 10 s, 1.5, 3, 4.5, 6, 9 and 12 min of nebulization. Furthermore, the tobramycin solutions were assayed for tobramycin content before and after nebulization. For all nebulizers, the mean particle size distribution, depicted as X(50), was within the range of 1-5 mm. There were no relevant differences between the nebulizers in concentration or particle size distribution during nebulization. The output of the nebulizers is a result of both nebulization and evaporation. The output, expressed as volume of tobramycin solution, ranged from 0.06 to 0.50 ml/min. The output of tobramycin ranged from 1.2 to 39.5 mg/min. For clinical practice 300-600 mg have to be nebulized within 20-30 min. It was concluded that only three jet nebulizers [Porta-Neb Sidestream (PNS), Porta-Neb Ventstream (PNV) and Pariboy Pari LC+ (PLC)] have a reasonable output and an acceptable particle size distribution for the administration of a 10% tobramycin solution in the therapeutic dosage range.

Administration, Inhalation↗

PubMed1999

Inhalation of tobramycin in cystic fibrosis. Part 2: optimization of the tobramycin solution for a jet and an ultrasonic nebulizer.

The inhalation of tobramycin is part of current cystic fibrosis (CF) therapy. Local therapy with inhaled antibiotics has demonstrated improvements in pulmonary function. Current inhalation therapy is limited by the available drug formulations in combination with the nebulization time. The aim of this study is to develop a highly concentrated tobramycin solution for inhalation. Several tobramycin solutions, ranging from 5 to 30% (m/v), were compared after aerosolation with a jet and with an ultrasonic nebulizer. Laser diffraction and cascade impactor analysis were used for characterization of the aerosolized solutions. The output rate was determined in volume and mass output per minute. From the output rate measurements, it was concluded that a 20% tobramycin solution is the optimal and maximal concentration to be aerosolized. The jet nebulizer was most suitable. Using the jet nebulizer and the 20% solution, it is possible to administer a dosage of 1000 mg tobramycin by inhalation within 30 min.

Administration, Inhalation↗