Jörg Breitkreutz

Paediatric and geriatric drug delivery

Age-adapted drug formulations are a challenge in drug development. This paper describes the special requirements of paediatric and geriatric patients, and new ideas to solve the most prominent problems in the application of drugs to these patients. Most requirements are very similar in each subpopulation, but there are also some particularities. In neonates and infants, the immaturity of enzymes may determine the pharmacokinetics of the excipients, which must be carefully selected. Pharmacokinetics in the elderly are strongly influenced by co-morbidity, multiple-drug use or reduced organ functions. The drug handling and the readability of the product information are key issues in both subpopulations. Children and the elderly show difficulties in swallowing solid dosage forms for oral use. In both patient groups, small sized particulates or liquid dosage forms are superior to classic tablets or capsules. The main problem with using liquids is the palatability of the solution, especially when considering that taste sensation differs age-dependently and interindividually. Recent technological developments such as the dose sipping technology, promise improvements. The new EU legislation for the development of new paediatric drugs may also stimulate the research into drug delivery for the elderly.

Taste sensing systems (electronic tongues) for pharmaceutical applications.

Electronic tongues are sensor array systems able to detect single substances as well as complex mixtures by means of particular sensor membranes and electrochemical techniques. Two systems are already commercially available, the Insent taste sensing system and the αAstree electronic tongue. In addition, various laboratory prototype versions exist. Besides the successful use in food industry, the implementation for pharmaceutical purposes has strongly grown within the recent years. A reason for this is the increased interest of developing palatable formulations, especially for children. As taste assessment of drugs comes along with challenges due to possible toxicity and subjectivity of the taste assessors, electronic tongues could offer a safe and objective alternative. In order to provide guidance on the use of these systems, possible fields of interest are presented in this review, as for example, system qualification, quality control, formulation development, comparison between marketed drug products, and the validation of the methods used. Further, different approaches for solid and liquid dosage forms are summarized. But, also the difficulty to obtain absolute statements regarding taste was identified and the need of more validated data was discussed to offer guidance for the next years of research and application of electronic tongues for pharmaceutical applications.

Advances in orodispersible films for drug delivery

Introduction: Orodispersible films for oral delivery are gaining popularity. Whereas breath-fresheners and over-the-counter products have already become quite common in the US, the first prescription drug films were introduced into the EU and US markets only very recently. Already considered as a unique Rx (prescription drug) dosage form by the FDA (oral soluble film), such products are not substitutable by conventional oral dosage forms. The official term defined by the European Medicines Agency is orodispersible film (ODF). Areas covered: This review gives an overview on the benefits of ODFs, typical excipients and products already available on the market. ODFs are defined and differentiated from other films and dosage forms. Possible manufacturing methods are described. As ODFs are not yet listed in one of the pharmacopoeias, possible methods for characterization and quality control are discussed. Required characteristics, advantages and disadvantages are elaborated. Biopharmaceutical considerations are provided because such films can also be used to enhance bioavailability of a drug. Expert opinion: The magnitude of variants of ODF technology and the advantages over conventional dosage forms promise more applications and more marketed products with ODFs in the near future. Therefore, the authorities have to publish a monograph for ODFs as soon as possible to standardize characterization methods and quality specifications.

Challenges of developing palatable oral paediatric formulations.

Material Sciences and Oral Products Centre of Emphasis, Pfizer Global Research and Development, United Kingdom Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine University Düsseldorf, Germany Pharmaceutical and Analytical Development, Novartis Pharma AG, Switzerland Royal Liverpool Children’s NHS Trust, United Kingdom Medicines for Children Research Network, University of Liverpool, United Kingdom The School of Pharmacy, Department of Pharmaceutics, University of London, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom

Swallowing dysfunction and dysphagia is an unrecognized challenge for oral drug therapy

There is evidence that swallowing issues and dysphagia are an increasing problem of the aging population in the coming decades that is affecting oral medication administration. There is a variety of clinical expressions of swallowing dysfunction caused by aging, acute or chronic disease conditions, decline in physiological functions and adverse drug reactions. About one third of patients in long term care facilities experience serious difficulties with swallowing solid oral dosage forms (SODF). Manipulations of the solid oral drug products occur frequently in nursery homes leading to medication errors and potential changes in drug product performance. The alteration of the drug products is performed with the best intention of the care giver to help the patients but bears concerns about safety and lawfulness. Alternative SODF and drug delivery technologies should be considered in the development of new and generic products and their prescription to overcome medication administration problems in patients with swallowing difficulties of SODF.

A comparative study on two electronic tongues for pharmaceutical formulation development.

Electronic tongues are sensor array systems which are able to determine single substances as well as complex mixtures of various substances. They are increasingly used for taste assessment of pharmaceutical formulations. Two systems are available on the market, the AlphaMOS electronic tongue Astree2 and the Insent taste sensing system TS-5000Z. Both systems measure based on potentiometry but sensor technologies are different. Therefore, these electronic tongue systems were compared to each other with respect to general aspects like software handling, sensors, and measurement procedure, but also on the basis of analytical experiments in order to figure out the applicability and limitations for use in the pharmaceutical field. By investigation of substances with different ionic character, like sodium saccharin, acetaminophen, ibuprofen, quinine, and caffeine, it was shown for both systems that ionic substances are easier to detect than neutral ones. Further, the performance qualification could only be done for the TS-5000Z, whereas the validation step, a correlation to human taste assessment, was passed by both systems. The results were even more reproducible than those from the panel. Taste masking by complexation of ibuprofen and quinine hydrochloride by maltodextrin, could be evaluated by both systems. Data from the Astree2 system have to be normalized in order to compare inter-day results, while the Insent taste sensing system refers each measurement to a standard solution and therefore reaches better inter-day results. Both systems offer the opportunity to be used for the development of taste-masked pharmaceutical formulations.

Comparative investigations on different polymers for the preparation of fast-dissolving oral films.

Objectives The aim was to compare different film‐forming materials used for the preparation of fast‐dissolving oral films.

Oral drug delivery in personalized medicine: unmet needs and novel approaches.

Increasing knowledge into personalized medicine has demonstrated the need for individual dosing. Drug dosage forms are urgently needed enabling an individual therapy, especially for oral drug delivery. This review is focusing on approaches for solid and liquid oral dosage forms for individual dosing. The proposed dosage forms and devices may be distinguished into assembling and partition concepts and have been categorized regarding their applicability, costs, dose flexibility and potential benefits. Opportunities, challenges and further unmet needs are elaborated and critically discussed. Liquid dosage forms can be accurately dosed by novel dropping tubes or oral syringes, but less precisely by dosing spoons and cups. Breaking scored tablets into fragments show major risks such as inaccurate dosing, formation of potent dust and stability issues of the residual segments. Novel approaches are proposed for solid dosage forms enabling a flexible and appropriate therapy such as various dispensers for multiparticulate drug formulations. However, most of the proposals still have to prove their applicability in practice. Promising concepts are the solid dosage pen and drug-loaded oral films which can be cut in individual sections enabling freely selectable doses. Further research and development are required for novel dosage forms and medical devices appropriate for individualized therapy.

Favorable acceptance of mini-tablets compared with syrup: a randomized controlled trial in infants and preschool children.

OBJECTIVE To evaluate acceptability of 2 mm solid dosage forms (mini-tablets) as an alternative administration modality in young children in comparison with syrup. STUDY DESIGN Three hundred six pediatric in- and outpatients aged 6 months-5 years (51 in each of 6 age groups) were recruited. An open, randomized cross-over study was conducted to compare acceptability and capability to swallow 2 mm uncoated or coated mini-tablets vs 3 mL syrup. RESULTS In the overall patient population of 306 children, the acceptability of uncoated mini-tablets was superior to syrup (difference in proportions 14.8%, 95% CI 10.2-19.4; P < .0001). In line with this finding, the level of capability to swallow was higher for uncoated mini-tablets compared with syrup as well (difference in proportions 12.3%, 95% CI 5.4-19.3; P = .0008). All 3 pharmaceutical formulations were well tolerated, and none of the 306 children inhaled or coughed because of the syrup or the uncoated mini-tablet; only 2 of the 306 children (both in age group 0.5-1 year) coughed because of the coated mini-tablet, in both cases without clinical relevance. CONCLUSIONS Mini-tablets are a valuable alternative to syrup for children 6 months-6 years of age and are more acceptable compared with liquid formulation. Regulatory bodies such as Food and Drug Administration and European Medicine Agency are encouraged to take our data into account for guideline updates and future drug approval processes.

Prediction of Intestinal Drug Absorption Properties by Three-Dimensional Solubility Parameters

AbstractPurpose. The purpose of this study was to investigate the use of solubility parameters for the prediction of gastrointestinal absorption sites and absorption durations of drugs. Methods. Three-dimensional solubility parameters of drug substances were calculated using an advanced parameter set based on the group contribution methods of Fedors and Van Krevelen/Hoftyzer. The results of the calculations were illustrated via Bagley diagram and related to absorption data reported in the literature. Results. Solubility parameters of drugs which are known to be absorbed over a long period in humans digestive tract were found in a limited area within the Bagley diagram. From the three-dimensional solubility parameters of these substances, a region for optimal absorption with the centre coordinates δv = 20.3 (J ⋅ cm−3)0.5 and δh = 11.3 (J ⋅ cm−3)0.5 could be derived. Drugs with absorption sites along the whole gastrointestinal tract were found in this area. Drugs which are preferably absorbed from upper parts of the intestine are located in another typical region with partial solubility parameters δh of more than 17 (J ⋅ cm−3)0.5. Conclusions. The method which is presented in this paper appears as a simple but effective method to estimate the absorption behaviour of new substances in drug research and development.