A toolbox for mimicking gastrointestinal conditions in children: Design and evaluation of biorelevant dissolution media for mimicking paediatric gastric- and small intestinal conditions.

The goal of the present work was to develop an in vitro toolbox to evaluate the oral administration of dosage forms to children of different age groups and under different administration conditions (fasted/fed). Based on current data on the gastrointestinal physiology of children, a set of new biorelevant media was designed to mimic the composition and physicochemical properties of resting gastric and resting small intestinal fluid in children of different age groups. In addition, guidelines were developed on how to generate fasted and fed state gastric and small intestinal fluids by combining these media with age-specific drinking volumes or portions of already established simulated paediatric breakfast meals, respectively. These fluids can simulate the conditions in the paediatric stomach and small intestine after administration of a dosage form in the fasting state or after a breakfast. The in vitro toolbox was evaluated using the example of pre-school children with a total of five paediatric medicines. Results from the corresponding set of in vitro studies highlight the importance of addressing patient-specific characteristics rather than downscaling existing adult in vitro models.

Oral drug delivery strategies for development of poorly water soluble drugs in paediatric patient population.

Selecting the appropriate formulation and solubility-enabling technology for poorly water soluble drugs is an essential element in the development of formulations for paediatric patients. Different methodologies and structured strategies are available to select a suitable approach and guide formulation scientists for development of adult formulations. However, there is paucity of available literature for selection of technology and overcoming the challenges in paediatric formulation development. The need for flexible dosing, and the limited knowledge of the safety of many formulation excipients in paediatric subjects, impose significant constraints and in some instances require adaptation of the approaches taken to formulating these drugs for the adult population. Selection of the best drug delivery system for paediatrics requires an efficient, systematic approach that considers a drug's physical and chemical properties and the targeted patient population's requirements. This review is a step towards development of a strategy for the design of solubility enhancing paediatric formulations of highly insoluble drugs. The aim of this review is to provide an overview of different approaches and strategies to consider in order to assist development of paediatric formulation for poorly water-soluble drugs with the provision of examples of some marketed products. In addition, it provides recommendations to overcome the range of challenges posed by these strategies and adaptations of the adult approach/product presentation required to enable paediatric drug development and administration.

A Toolbox for Mimicking Gastrointestinal Conditions in Children: Simulated Paediatric Breakfast Media (SPBM) for Addressing the Variability of Gastric Contents After Typical Paediatric Breakfasts.

Since co-administration of dosage forms with food can impact drug exposure, food effect studies became an integral part of oral drug product development. Studies are usually performed in healthy adults and the dosage form is co-administered with a high-fat high-calorie standard breakfast meal to mimic worst-case dosing conditions. A corresponding study design for children is lacking but would be essential for a proper risk-assessment in this vulnerable patient group. To protect healthy children from unnecessary in vivo studies, it would be even more desirable to predict food effects based on other than in vivo studies in the target age group. In the present study, typical children's breakfasts in different parts of the world were identified, prepared and physicochemical properties were assessed. Subsequently, Simulated Paediatric Breakfast Media (SPBM) resembling breakfast composition and properties were designed and applied in in vitro dissolution experiments mimicking the initial composition of the postprandial stomach after breakfast ingestion. Study results indicate the impact of different simulated gastric conditions on drug release. SPBM enabled to better estimate the variability of in vivo drug release in fed dosing conditions and their use will aid in better assessing food effects in children in different parts of the world.

Characterisation of fasted state gastric and intestinal fluids collected from children.

Fundamental knowledge about the composition of intestinal fluids in paediatric populations is currently unavailable. This study aimed to characterise gastric and intestinal fluid from paediatric populations. Gastric and intestinal fluid samples were obtained during routine clinical endoscopy from paediatric patients at a large teaching hospital. These fluids were characterised to measure the pH; buffer capacity; osmolality; bile acid concentration and composition. A total of 55 children were recruited to the study aged from 11 months to 15 years of age where 53 gastric fluid samples and 40 intestinal fluid samples were obtained. pH values recorded ranged from pH 0.57 to 11.05 (median: 2.50) in gastric fluids and from 0.89 to 8.97 (median: 3.27) in intestinal fluids. The buffer capacity did not change significantly between gastric and intestinal fluids with median values of 12 mM/L/ΔpH for both fluids. Gastric fluid osmolality values ranged from 1 to 615 mOsm/kg, while intestinal fluid values ranged from 35 to 631 mOsm/kg. Gastric fluid bile acid concentrations ranged from 0.002 to 2.3 mM with a median value of 0.017 mM whilst intestinal fluid bile acid concentrations ranged from 0.0008 to 3.3 mM with a median value of 0.178 mM. Glycocholate; taurocholic acid; glycochenodeoxycholate and taurochenodeoxycholate were the most commonly identified bile acids within paediatric intestinal fluids. All compositional components were associated with large inter-individual variability. Further work is required to develop simulated paediatric media and to explore the impact of these media on drug solubility and dissolution.

Nanosuspension for the delivery of a poorly soluble anti-cancer kinase inhibitor.

We hypothesized that nanosuspensions could be promising for the delivery of the poorly water soluble anti-cancer multi-targeted kinase inhibitor, MTKi-327. Hence, the aims of this work were (i) to evaluate the MTKi-327 nanosuspension for parenteral and oral administrations and (ii) to compare this nanosuspension with other nanocarriers in terms of anti-cancer efficacy and pharmacokinetics. Therefore, four formulations of MTKi-327 were studied: (i) PEGylated PLGA-based nanoparticles, (ii) self-assembling PEG750-p-(CL-co-TMC) polymeric micelles, (iii) nanosuspensions of MTKi-327; and (iv) Captisol solution (pH=3.5). All the nano-formulations presented a size below 200 nm. Injections of the highest possible dose of the three nano-formulations did not induce any side effects in mice. In contrast, the maximum tolerated dose of the control Captisol solution was 20-fold lower than its highest possible dose. The highest regrowth delay of A-431-tumor-bearing nude mice was obtained with MTKi-327 nanosuspension, administered intravenously, at a dose of 650 mg/kg. After intravenous and oral administration, the AUC0₋∞ of MTKi-327 nanosuspension was 2.4-fold greater than that of the Captisol solution. Nanosuspension may be considered as an effective anti-cancer MTKi-327 delivery method due to (i) the higher MTKi-327 maximum tolerated dose, (ii) the possible intravenous injection of MTKi-327, (iii) its ability to enhance the administered dose and (iv) its higher efficacy.

Statistical analysis of the effects of polyethylene glycol concentration and molecular weight on the sedimentation and resuspendability behavior of model aqueous dispersions.

This work investigates the flocculation effect of polyethylene glycol (PEG) on typical aqueous dispersions, such as O/W emulsions and solid/liquid suspensions. Hereby, sunflower oil and flubendazole were selected as model ingredients, whereas microfluidization at variable driving air pressure was used to enable particle size distribution variations for both systems. The molecular weight of PEG varied from 2000 to 12,000g/mol while its concentration ranged from 50 to 100mg/ml. Statistical analysis revealed that both PEG concentration and molecular weight showed a flocculation enhancing effect. Hereby the inhibiting effect of particle size toward the formation of voluminous and easily resuspendable sediment could at least partially be overcome by selecting appropriate PEG characteristics.

Sedimentation and resuspendability evaluation of pharmaceutical suspensions by low-field one dimensional pulsed field gradient NMR profilometry.

In order to study the sedimentation of pharmaceutical suspensions using low-field one dimensional pulsed field gradient nuclear magnetic resonance (1D pfg NMR) profilometry, the accuracy of signal acquisition as well as the spatial resolution of a commercial spectrometer operating at 23.4 MHz was investigated. The use of a solid Teflon spacer revealed that the accuracy of signal acquisition was independent of spatial position (height). The standard deviation of distance determinations was less than 150 µm, whereas the accuracy of water content determination was within 2% in the central part of the detection zone and deteriorated to 4% in the outer parts. The study of aqueous paramagnetic MnCl2 solutions indicated an exponential relationship between the relative signal intensity and the transverse relaxation decay constant. From this relationship, the relative water content of suspensions could be derived from their signal intensity relative to that of water. Using concentrated paliperidone palmitate dispersions as model suspensions, low-field 1D pfg NMR profilometry has been proven to be suitable for the evaluation of both the sedimentation and resuspendability behavior of viscous, opaque suspensions, for which visual detection of homogeneity may be difficult.

In situ nondestructive sediment characterization and resuspendability evaluation of concentrated aqueous paliperidone palmitate suspensions in prefilled syringes by low-field one-dimensional pulsed-field gradient NMR profilometry.

This work aims to demonstrate the usefulness of a low-field one-dimensional pulsed-field gradient NMR (1D pfg NMR) profilometry technique to enable in situ nondestructive sediment characterization and resuspendability quantification of concentrated prefilled injectable suspensions. Aqueous paliperidone palmitate suspensions were used as model samples and low-intensity centrifugation was evaluated as a long-term gravity simulation approach. The low-field 1D pfg NMR technique allowed a detection zone of 2.5 cm in height for water content measurement of syringe samples using a Teflon syringe holder. Thus, the sediment compactness could be deduced from its water content. Quantitative evaluation of resuspendability was realized by front tracking of the NMR profile signals, which yielded the exponential sediment volume decay constant as a resuspendability quantification parameter. The study shows that both active ingredient particle size distribution and storage temperature had significant effects on the sedimentation rate and the resuspendability of the suspensions. The centrifugation method proved to be useful as a long-term gravity simulation and screening method, although the results should be interpreted with caution due to its higher acceleration and compression force imposed on the active ingredient particles.