Papers by Jörg Breitkreutz
Pharmaceutics, Oct 26, 2012
Orodispersible dosage forms are promising new approaches for drug delivery. They enable an easy a... more Orodispersible dosage forms are promising new approaches for drug delivery. They enable an easy application, as there is no need to drink high amounts of liquids or swallow large solid dosage forms. The aim of the study was to develop an orodispersible film (ODF) as an alternative to tablets, syrups or suppositories for the treatment of vomiting and nausea, especially for the pediatric population. Formulations were investigated by X-ray diffraction, scanning electron and polarized light microscopy. Additionally, two commercially available electronic taste sensing systems were used to investigate the applied taste-masking strategies. Results obtained from X-ray-diffraction and polarized light microscopy showed no recrystallization of dimenhydrinate in the formulation when cyclodextrin or maltodextrin were used as solubilizing and complexing agent. All ODFs showed fast disintegration depending on the characterization method. In order to get taste information, the dimenhydrinate formulations were analytically compared to pure drug and drug-free formulations by electronic tongues. Results obtained from both systems are comparable and were used together for the first time. It was possible to develop an ODF of dimenhydrinate that is fast disintegrating even in small volumes of liquid. Furthermore, in vitro taste assessment by two electronic tongues revealed taste-masking effects by the excipients.
Expert Opinion on Drug Delivery, Jan 17, 2017
Introduction: The oral mucosa has recently become increasingly important as an alternative admini... more Introduction: The oral mucosa has recently become increasingly important as an alternative administration route for tailor-made, controlled drug delivery. Oromucosal multilayer films, assigned to the monograph oromucosal preparations in the Ph.Eur. may be a promising dosage form to overcome the requirements related to this drug delivery site. Areas covered: We provide an overview of multilayer films as drug delivery tools, and discuss manufacturing processes and characterization methods. We focus on the suitability of characterization methods for particular requirements of multilayer films. A classification was performed covering indication areas and APIs incorporated in multilayer film systems for oromucosal use in order to provide a summary of data published in this field. Expert Opinion: The shift in drug development to high molecular weight drugs will influence the field of pharmaceutical development and delivery technologies. For a high number of indication areas, such as hormonal disorders, cardiovascular diseases or local treatment of infections, the flexible layer design of oromucosal multilayer films provides a promising option for tailor-made, controlled delivery of APIs to or through defined surfaces in the oral cavity. However, there is a lack of discriminating or standardized testing methods to assess the quality of multilayer films in a reliable way.
Journal of Pharmaceutical and Biomedical Analysis, Sep 1, 2013
Performance qualification (PQ) of taste sensing systems is mandatory for their use in pharmaceuti... more Performance qualification (PQ) of taste sensing systems is mandatory for their use in pharmaceutical industry. According to ICH Q2 (R1) and a recent adaptation for taste sensing systems, non-specificity, log-linear relationships between the concentration of analytes and the sensor signal as well as a repeatability with relative standard deviation (RSD) values <4% were defined as basic requirements to pass a PQ. In the present work, the αAstree taste sensing system led to a successful PQ procedure by the use of recent sensor batches for pharmaceutical applications (sensor set #2) and a modified measurement protocol. Log-linear relationships between concentration and responses of each sensor were investigated for different bitter tasting active pharmaceutical ingredients (APIs). Using the new protocol, RSD values <2.1% were obtained in the repeatability study. Applying the visual evaluation approach, detection and quantitation limit could be determined for caffeine citrate with every sensor (LOD 0.05-0.5 mM, LOQ: 0.1-0.5 mM). In addition, the sensor set marketed for food applications (sensor set #5) was proven to show beneficial effects regarding the log-linear relationship between the concentration of quinine hydrochloride and the sensor signal. By the use of our proposed protocol, it is possible to implement the αAstree taste sensing system as a tool to assure quality control in the pharmaceutical industry.
International Journal of Pharmaceutics, Aug 1, 2015
The use of solid oral dosage forms is typically favored with regard to stability and ease of admi... more The use of solid oral dosage forms is typically favored with regard to stability and ease of administration. The aim of this study was to investigate whether cyclodextrins (CD) or ion exchange resins (IER) could be used to taste-mask cetirizine HCl when formulated in a freeze-dried oral formulation. The oral lyophilisates were produced using the Zydis(®) technology that offer the opportunity to produce the dosage form directly in the aluminum laminate blister packs. This study confirmed that a pre-formed resinate of cetirizine HCl and various cyclodextrins can be successfully incorporated into the Zydis(®) oral lyophilisate. A chemically stable product with acceptable release profile was obtained in the case of cyclodextrin. This study has also demonstrated that the Insent(®) taste sensing system is a useful technique for predicting the taste-masking potential of Zydis(®) formulations. The electronic taste sensing system (e-tongue) data can be used to provide guidance on the selection of taste-masked formulations. Principal component analysis (PCA) of sensor data by plotting the PCA scores revealed the effects of used taste-masking techniques on the e-tongue sensors, indicating the successful taste improvement. The PCA plot of the taste sensor data revealed larger distances between the non-taste-masked sample and the CD- and IER-loaded samples, and the shift toward the drug-free formulations and excipient signals indicates a modification of the product taste. The human taste trial confirms the acceptability of the selected promising formulations. The taste evaluation results showed that an effectively taste-masked formulation has been achieved using β-cyclodextrin and cherry/sucralose flavor system with over 80% of volunteers finding the tablet to be acceptable.
Advanced Drug Delivery Reviews, Jun 1, 2014
The development of paediatric medicines can be challenging since this is a diverse patient popula... more The development of paediatric medicines can be challenging since this is a diverse patient population with specific needs. For example, the toxicity of excipients may differ in children compared to adults and children have different taste preferences. Acceptable palatability of oral paediatric medicinal products is of great importance to facilitate patient adherence. This has been recognised by regulatory authorities and so is becoming a key aspect of paediatric pharmaceutical development studies. Many active pharmaceutical ingredients (APIs) have aversive taste characteristics and so it is necessary to utilise taste masking techniques to improve the palatability of paediatric oral formulations. The aim of this review is to provide an overview of different approaches to taste masking APIs in paediatric oral dosage forms, with a focus on the tolerability of excipients used. In addition, where possible, the provision of examples of some marketed products is made.
International Journal of Pharmaceutics, Feb 1, 2018
Orodispersible dosage forms are promising new approaches for drug delivery. They enable an easy a... more Orodispersible dosage forms are promising new approaches for drug delivery. They enable an easy application, as there is no need to drink high amounts of liquids or swallow large solid dosage forms. The aim of the study was to develop an orodispersible film (ODF) as an alternative to tablets, syrups or suppositories for the treatment of vomiting and nausea, especially for the paediatric population. Formulations were investigated by x-ray diffraction, scanning electron and polarized light microscopy. Disintegration time of the films was determined by two different methods. Additionally, two commercially available electronic taste sensing systems (electronic tongues) were used to investigate the applied taste-masking strategies. Different excipients enhancing the solubility of dimenhydrinate were investigated to avoid recrystallization in the film. Furthermore, they were shown to improve the taste attributes of the formulation by interacting with the drug substance. Results obtained from x-ray-diffraction and polarized light microscopy showed no recrystallization of dimenhydrinate in the formulation when cyclodextrin or maltodextrin were used as solubilizing agent. All ODFs disintegrated in an appropriate time (< 120 s) depending on the characterization method. In order to get taste information, the dimenhydrinate formulations were analytically compared to pure drug and drug-free formulations by the electronic tongues. Results obtained from both systems are comparable, but can also be used complementary. Taste masking effects could be detected by both electronic tongues. Merging data of both systems by multivariate data analysis showed improved discrimination between different drug formulations. It was possible to develop an ODF of dimenhydrinate that is fast disintegrating even in small volumes of liquid. Non-human taste assessment by two electronic tongues was successfully performed.
International Journal of Pharmaceutics, Sep 1, 2016
Monatsschrift Kinderheilkunde, Aug 1, 2005
Zusammenfassung Im Rahmen einer vergleichenden Untersuchung von auf dem deutschen Markt verfügbar... more Zusammenfassung Im Rahmen einer vergleichenden Untersuchung von auf dem deutschen Markt verfügbaren Amoxicillintrockensäften wurden die Stabilität der gebrauchsfertigen Säfte bei Lagerung im Kühlschrank und bei Raumtemperatur, das Sedimentationsverhalten sowie die Dosierungsgenauigkeit der beigefügten Dosierhilfen untersucht. Während mit einem ganzen Löffel noch relativ genau dosiert werden konnte, zeigten sich erhebliche Überdosierungen bei Entnahme von Viertel- und Halblöffeldosen. Im Gegensatz zu Amoxicillin
Powder Technology, 2015
ABSTRACT In pharmaceutical industry dry granulation by roll compaction (RC) gains in importance s... more ABSTRACT In pharmaceutical industry dry granulation by roll compaction (RC) gains in importance since the process is cost-effective and continuous. Additionally, mannitol as excipient received more and more attention due to its numerous advantages becoming apparent particularly in orodispersible drug formulation. So far, RC behavior of the commonly used fillers microcrystalline cellulose and lactose has been described in several studies. The purpose of this project was to investigate and to compare RC behavior of both pre-processed d-mannitol grades and unprocessed δ-d-mannitol. Therefore, two granulated mannitol qualities were dry granulated and the compactability of the granules was determined subsequently. It could be shown that the use of granulated raw material leads to granules with acceptable particle size distribution and amounts of particles ≤ 90 μm. Robust tablets with acceptable tensile strength (2 kN/cm batch, mannitol type A 1.39 ± 0.19 N/mm2, mannitol type B 1.27 ± 0.06 N/mm2, applying 115 MPa compression pressure) were produced. Compared to a spray-dried mannitol, granulated raw material leads to tablets with inferior mechanical resistance. One reason for this observation is the smaller specific surface area of granulated raw material (0.46 ± 0.03 m2/g and 0.38 ± 0.04 m2/g, respectively to 3.27 ± 0.03 m2/g) and the resulting granules. Unprocessed d-mannitol in the δ-modification exhibits lower compactability than both pre-processed grades. Higher specific compaction forces (10 kN/cm) during dry granulation have to be applied to achieve granules with adequate flowability (ffc-value 10.13 ± 1.15). Tablets with low abrasion and appropriate disintegration time could be still produced.
The Journal of Pediatrics, Oct 1, 2018
Objectives To assess the acceptability and swallowability of several minitablets when administere... more Objectives To assess the acceptability and swallowability of several minitablets when administered as a unit dose compared with an equivalent dose of syrup in children aged 6 months to 5 years. Study design The acceptability and swallowability of multiple drug-free minitablets in comparison with glucose syrup was assessed in 372 children of 2 age groups (186 in age group 1 [6-23 months of age] and 186 in age group 2 [2-5 years of age]) in a randomized, 3-way, single administration cross-over study. Age group 1 received 25 minitablets, 100 minitablets, and 5 mL syrup. Age group 2 received 100 minitablets, 400 minitablets, and 10 mL syrup. Results Superiority was demonstrated in age group 1 for acceptability (25 minitablets, P < .017; 100 minitablets, P < .0001) and swallowability (25 minitablets and 100 minitablets, both P < .0001) compared with syrup. In age group 2, noninferiority of acceptability was found only for 400 minitablets (P < .0003), not for 100 minitablets. Subgroup analysis revealed a strong sequential effect. For swallowability, noninferiority could be demonstrated for 100 minitablets (P < .01) but not for 400 minitablets. Conclusions Administration of ≥25 minitablets is well-tolerated, feasible, and safe in children aged from 6 months, and was superior to the equivalent dose of syrup. Children aged >1 year accept ≤400 minitablets even better than the equivalent dose of syrup. Minitablets open the perspective for introducing small-sized solid drug formulations for all children, thus, further shifting the paradigm from liquid toward small-sized solid drug formulations.
The Journal of Pediatrics, Oct 1, 2015
Objective To evaluate the suitability of drug-free solid dosage forms (2 mm mini-tablets) as an a... more Objective To evaluate the suitability of drug-free solid dosage forms (2 mm mini-tablets) as an alternative administration modality in neonates in comparison with syrup. Study design A total of 151 neonates (inpatients; aged 2-28 days; median 4 days) were recruited. An open, randomized, prospective cross-over study was conducted to compare the acceptability and swallowability of 2 mm uncoated mini-tablets compared with .5 mL syrup. Results All neonates (N = 151) accepted the uncoated mini-tablet as well as the syrup (both formulations 100%; 95% CI 97.6%-100.0%; primary objective). The level of swallowability of uncoated mini-tablets was not inferior (P < .0001), in fact even higher (difference in proportions 10.0%; 95% CI 1.37%-19.34%; P = .0315) compared with syrup. Both pharmaceutical formulations were well tolerated, and in none of the 151 neonates, serious adverse events occurred; particularly none of the neonates inhaled or coughed in either of the formulations.
International Journal of Pharmaceutics, Oct 1, 2015
Different types of printing methods have recently attracted interest as emerging technologies for... more Different types of printing methods have recently attracted interest as emerging technologies for fabrication of drug delivery systems. If printing is combined with different oral film manufacturing technologies such as solvent casting and other techniques, multifunctional structures can be created to enable further complexity and high level of sophistication. This review paper intends to provide profound understanding and future perspectives for the potential use of printing technologies in the preparation of oral film formulations as novel drug delivery systems. The described concepts include advanced multi-layer coatings, stacked systems, and integrated bioactive multi-compartments, which comprise of integrated combinations of diverse materials to form sophisticated bio-functional constructs. The advanced systems enable tailored dosing for individual drug therapy, easy and safe manufacturing of high-potent drugs, development and manufacturing of fixed-dose combinations and product tracking for anti-counterfeiting strategies. 2015 Published by Elsevier B.V.
Archives of Disease in Childhood, Jan 17, 2012
To explore the acceptance of uncoated drug-free mini-tablets 2 mm in diameter in children aged 0.... more To explore the acceptance of uncoated drug-free mini-tablets 2 mm in diameter in children aged 0.5-6 years and their ability to swallow the mini-tablets. 60 children aged 0.5-6 years (10 subjects per year of life) were enrolled in our prospective, open random, two-way cross-over exploratory pilot study. The children were administered either an uncoated drug-free mini-tablet 2 mm in diameter with a beverage of their choice or 3 ml of glucose syrup 15% followed by the other formulation. Deglutition was visually assessed for the two different dosage forms using a predefined criteria list. The study hypothesis was that children would accept the liquid formulation better than the solid mini-tablets. Surprisingly, the authors found that the acceptance of the mini-tablets, defined as immediate swallowing or chewing first with subsequent swallowing, was higher or at least equal to that of the syrup. Very young children (6-12 months) were fully capable of swallowing the mini-tablets and may even accept them better than the sweet liquid formulation. Some children aged between 2 and 4 years chewed the tablets before swallowing, but still accepted them quite well. The acceptance rate of the mini-tablets in the different age groups was much higher than expected. Uncoated mini-tablets seem to be a very promising alternative to liquid formulations and could be used at an earlier age in paediatric drug therapy than previously anticipated.
International Journal of Pharmaceutics, Aug 1, 2011
European Journal of Pharmaceutics and Biopharmaceutics, Apr 1, 2014
Bilayered oromucosal film preparations (buccal films) offer a promising way to enable drug admini... more Bilayered oromucosal film preparations (buccal films) offer a promising way to enable drug administration via the oral cavity. Adding a non-soluble or slowly eroding/dissolving backing layer to a mucoadhesive drug-loaded layer enables unidirectional drug delivery. The aim of this study was to investigate different approaches to the manufacture of bilayered films and to examine their properties by applying different characterization methods including an optimized experimental setup for the study of drug release from bilayered films. A solvent suitability study was performed screening over 15 polymers with respect to their feasibility for viscous film formation for film preparation by solvent casting method. Two methods (double-casting and pasting) were found as suitable methods for bilayered film manufacturing. Results from drug release experiments indicated that slowly eroding hypromellose backing layer films revealed the best shielding of the drug-loaded layer to enable unidirectional drug release. In summary, manufacturing of bilayered films using the described methods was feasible. Furthermore, the use of an optimized experimental setup for drug dissolution studies enabled monitoring of drug release without delays in sampling.
The pulmonary administration of pharmaceutical aerosols to patients is affected by age-dependent ... more The pulmonary administration of pharmaceutical aerosols to patients is affected by age-dependent variations in the anatomy of the upper airways and the inhalation pattern. Considering this aspect, different upper airway models, representing the geometries of adults and preschool children, and a conventional induction port according to the European Pharmacopeia were used for in vitro testing of dry powder inhalers with single dosed capsules (Cyclohaler ® , Handihaler ® and Spinhaler ®). Deposition measurements were performed using steady flow rates of 30 and 60 L/min for the Handihaler ® /Spinhaler ® and 30, 60 and 75 L/min for the Cyclohaler ®. The inhalation volume was set at 1 L. For the Cyclohaler ® , the in vitro testing was supplemented by a pediatric inhalation profile. Slight differences of pulmonary deposition between the idealized adult (11%-15%) and pediatric (9%-11%) upper airway model were observed for the Cyclohaler ®. The applied pediatric inhalation profile resulted in a reduction of pulmonary deposition by 5% compared to steady conditions and indicated the influence of the inhalation pattern on the amount of pulmonary deposited particles. The comparison of two pediatric upper airway models showed no differences. The performance of the Handihaler ® was similar to the Cyclohaler ®. The Spinhaler ® showed an insufficient performance and limited reproducibility in our investigations.
Contemporary Clinical Trials Communications, 2019
Introduction: Treatment of paediatric heart failure is based on paradigms extensively tested in t... more Introduction: Treatment of paediatric heart failure is based on paradigms extensively tested in the adult population assuming similar underlying pathophysiological mechanisms. Angiotensin converting enzyme inhibitors (ACEI) like enalapril are one of the cornerstones of treatment and commonly used off-label in children. Dose recommendations have been extrapolated from adult experience, but the relationship between dose and pharmacokinetics (PK) in (young) children is insufficiently studied. Furthermore, appropriate paediatric formulations are lacking. Within the European collaborative project LENA, a novel formulation of enalapril orodispersible minitablets (ODMT), suitable for paediatric administration, will be tested in (young) children with heart failure due to either dilated cardiomyopathy or congenital heart disease in two pharmacokinetic bridging studies. Paediatric PK data of enalapril and its active metabolite enalaprilat will be obtained. In a follow-up study, the safety of enalapril ODMTs will be demonstrated in patients on long-term treatment of up to 10 months. Furthermore, additional information about pharmacodynamics (PD) and ODMT acceptability will be collected in all three studies. Methods and Analysis: Phase II/III, open-label, multicentre study. Children with dilated cardiomyopathy (DCM) (n = 25; 1 month to less than 12 years) or congenital heart disease (CHD) (n = 60; 0 to less than 6 years) requiring or already on ACEI will be included. Exclusion criteria include severe heart failure precluding ACEI use, hypotension, renal impairment, hypersensitivity to ACEI. For those naïve to ACEI up-titration to an optimal dose will be performed, those already on ACEI will be switched to an expected equivalent dose of enalapril ODMT and optimised. In the first 8 weeks of treatment, a PK profile will be obtained at the first dose (ACEI naïve patients) or when an optimal dose is reached. Furthermore, population PK will be done with concentrations detected over the whole treatment period. PD and safety data will be obtained at least at 2-weeks intervals. Subsequently, an intended number of 85 patients will be followed-up up to 10 months to demonstrate long-term
Archives of Disease in Childhood, 2019
BackgroundACE-inhibitors are first choice treatment for adult and paediatric patients with heart ... more BackgroundACE-inhibitors are first choice treatment for adult and paediatric patients with heart failure. Since there are no systematic data on pharmacokinetics and safety in the young heart failure population, the EU funded a drug development program1 to fill those gaps for the ACE-inhibitor enalapril. An age appropriate paediatric formulation was also required.MethodsA paediatric patient cohort with heart failure was recruited to fulfil the paediatric investigation plan (PIP) requirements. The PIP required a total of 85 evaluable patients from birth to less than 12 years of age with a subset cohort of 25 patients with heart failure due to dilated cardiomyopathy and a subset of 60 heart failure patients of congenital heart disease. Out of these, 54% of patients must be aged below 12 months to provide a substantial amount of young patients.ResultsThe LENA consortium recruited 102 children from birth to 12 years. Out of those, 89 patients fulfilled relevant protocol criteria and coul...
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Papers by Jörg Breitkreutz