A. de Boer

Dry powder inhalers for pulmonary drug delivery

The pulmonary route is an interesting route for drug administration, both for effective local therapy (asthma, chronic obstructive pulmonary disease or cystic fibrosis) and for the systemic administration of drugs (e.g., peptides and proteins). Well-designed dry powder inhalers are highly efficient systems for pulmonary drug delivery. However, they are also complicated systems, the the performance of which relies on many aspects, including the design of the inhaler (e.g., resistance to air flow and the used de-agglomeration principle to generate the inhalation aerosol), the powder formulation and the air flow generated by the patient. The technical background of these aspects, and how they may be tuned in order to obtain desired performance profiles, is reviewed. In light of the technical background, new developments and possibilities for further improvements are discussed.

Technological and practical challenges of dry powder inhalers and formulations

In the 50 years following the introduction of the first dry powder inhaler to the market, several developments have occurred. Multiple-unit dose and multi-dose devices have been introduced, but first generation capsule inhalers are still widely used for new formulations. Many new particle engineering techniques have been developed and considerable effort has been put in understanding the mechanisms that control particle interaction and powder dispersion during inhalation. Yet, several misconceptions about optimal inhaler performance manage to survive in modern literature. It is, for example still widely believed that a flow rate independent fine particle fraction contributes to an inhalation performance independent therapy, that dry powder inhalers perform best at 4 kPa (or 60 L/min) and that a high resistance device cannot be operated correctly by patients with reduced lung function. Nevertheless, there seems to be a great future for dry powder inhalation. Many new areas of interest for dry powder inhalation are explored and with the assistance of new techniques like computational fluid dynamics and emerging particle engineering technologies, this is likely to result in a new generation of inhaler devices and formulations, that will enable the introduction of new therapies based on inhaled medicines.

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.

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.

Air classifier technology (ACT) in dry powder inhalation. Part 1: Introduction of a novel force distribution concept (FDC) explaining the performance of a basic air classifier on adhesive mixtures

Air classifier technology (ACT) is introduced as part of formulation integrated dry powder inhaler development (FIDPI) to optimise the de-agglomeration of inhalation powders. Carrier retention and de-agglomeration results obtained with a basic classifier concept are discussed. The theoretical cut-off diameter for lactose of the classifier used, is between 35 and 15 microm for flow rates ranging from 20 to 70 l/min. Carrier retention of narrow size fractions is higher than 80% for flow rates between 30 and 60 l/min, inhalation times up to 6s and classifier payloads between 0 and 30mg. The de-agglomeration efficiency for adhesive mixtures, derived from carrier residue (CR) measurement, increases both with increasing flow rate and inhalation time. At 30 l/min, 60% fine particle detachment can be obtained within 3s circulation time, whereas at 60 l/min only 0.5s is necessary to release more than 70%. More detailed information of the change of detachment rate within the first 0.5s of inhalation is obtained from laser diffraction analysis (LDA) of the aerosol cloud. The experimental results can be explained with a novel force distribution concept (FDC) which is introduced to better understand the complex effects of mixing and inhalation parameters on the size distributions of adhesion and removal forces and their relevance to the de-agglomeration in the classifier.

STUDIES ON TABLETING PROPERTIES OF LACTOSE .3. THE CONSOLIDATION BEHAVIOR OF SIEVE FRACTIONS OF CRYSTALLINE ALPHA-LACTOSE MONOHYDRATE

The consolidation and compaction behaviour of sieve fractions of crystalline α-lactose monohydrate were studied. From mercury porosimetry measurements tablet pore surface areas were derived. At a certain compaction load it appeared that tablets compressed from small particles were generally stronger and showed a larger surface area than compacts prepared from coarse sieve fractions. By plotting compact strength against pore surface area, a unique linear relationship was obtained. From these results it can be concluded that the actual tablet surface area, being a function of both the initial particle size and applied compaction pressure, is responsible for the compact strength.

Studies on tableting properties of lactose. Part 2. Consolidation and compaction of different types of crystalline lactose

Lactose is available in several crystalline forms, which differ in binding properties. A new method of estimating the fragmentation propensity was applied to investigate the consolidation and compaction behaviour of this excipient for direct compression. Mercury porosimetry was used to demonstrate that crystalline lactose fragments during compaction. Tablet strength was found to be dependent on the degree of fragmentation only. This finding indicates that the nature of the actual binding must be the same for the different types of crystalline lactose.

The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response

Clopidogrel is a prodrug that has to be converted in vivo to its active metabolite by cytochrome (CYP)P450 iso-enzymes. As calcium channel blockers (CCBs) are inhibitors of CYP3A4, concomitant use of these drugs might play a role in the wide inter-individual variability in the response to clopidogrel. However, some CCBs also have strong inhibitory effects on the drug transporter P-glycoprotein (Pgp), which mediates clopidogrels intestinal absorption. It was the aim of this study to evaluate the effect of co-administration of Pgp-inhibiting and non-Pgp-inhibiting CCBs on on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective percutaneous coronary intervention (PCI). In a total of 623 consecutive patients undergoing elective PCI treated with clopidogrel and aspirin, platelet reactivity to 5 and 20 muM adenosine diphospate (ADP) and clopidogrel poor-response (defined as > 70% platelet aggregation to 20 muM ADP) were evaluated by light transmittance aggregometry. A total of 222 patients (35.6%) were on CCB treatment, of which 98 used Pgp-inhibiting CCBs (verapamil, nifedipine, diltiazem, barnidipine) and 124 patients used the non-Pgp-inhibiting CCB amlodipine. Adjusted mean ADP-induced on-clopidogrel platelet reactivity was significantly higher in both users of Pgp-inhibiting CCBs and amlodipine as compared to CCB non-users (all p<0.05). However, only the use of amlodipine was significantly associated with a 2.3-fold increased risk of clopidogrel poor-response. This study demonstrates that concomitant use of Pgp-inhibiting CCBs and amlodipine increases on-clopidogrel platelet reactivity. Only amlodipine was associated with clopidogrel poor-response. The drug-drug interaction between clopidogrel and amlodipine might be more clinically relevant as compared to P-glycoprotein-inhibiting CCBs.

Agreement between self‐reported antihypertensive drug use and pharmacy records in a population‐based study in The Netherlands

From 1987 to 1991, over 36,000 men and women aged 20‐59 years have been examined in the Monitoring Project on Cardiovascular Disease Risk Factors in The Netherlands. Classification of the treatment status of hypertensives in this population‐based study was based on self‐administered questionnaires. In order to assess the accuracy of self‐reported antihypertensive drug use we compared the questionnaire information with computerized pharmacy records from a sample of 372 hypertensive subjects. Most antihypertensive drugs that were mentioned in the questionnaire were present in the pharmacy medication history (93%). However, this percentage was less (76%) when a comparison was made with the calculated duration of use based on the number of units prescribed and the directions for use in the pharmacy records. About 94% of the hypertensive subjects who were using an antihypertensive drug according to the pharmacy records, also mentioned at least one antihypertensive drug in the questionnaire. Agreement between self‐reported antihypertensive drug use and pharmacy records was consistently high for all classes of antihypertensive drugs. Among 321 (86%) subjects, the number and types of self‐reported antihypertensive drugs were exactly the same as in the pharmacy records. In conclusion, the agreement between self‐reported antihypertensive drug use and pharmacy records was high, and the self‐reported questionnaire information on antihypertensive drug use can be reliably used for the classification of treatment status of hypertensive subjects in this population‐based study.

Bi-phasic composition of trans-root electrical potential in roots of Plantago species: involvement of spatially separated electrogenic pumps.

The effect of oxygen on the trans-root potential (TRP) of excised roots in Plantago media L. and P. maritima L. was investigated. Two distinct reactions were found. In some experiments (type A roots) the reaction of TRP to anoxia was bi-phasic, and this reaction fits well into a model, assuming the presence of two spatially separated proton pump sites in the roots: one at the plasmalemma of epidermal and cortical cells and the other at the symplast/xylem interface. The two pumps work in opposite directions. In other experiments (type B roots) no hyperpolarization as a response to anoxia at the inner symplast membrane was observed. There is evidence that the inner pump is also present in these roots, but only in an inactive or electroneutral state. It is concluded that O2-deficiency prevails more often in the central part of the root than in epidermal and cortical cells, when roots are brought gradually under anoxia. This causes the pump located at the symplast/xylem interface to be inhibited more quickly than the other at decreasing O2-concentrations in the bathing solution.