Pressure-assisted microsyringe 3D printing of oral films based on pullulan and hydroxypropyl methylcellulose.

Oral films (OFs) continue to attract attention as drug delivery systems, particularly for pedatric and geriatric needs. However, immiscibility between different polymers limits the full potential of OFs from being explored. One example is pullulan (PUL), a novel biopolymer which often has to be blended with other polymers to reduce cost and alter its mechanical properties. In this study, the state-of-the-art in fabrication techniques, three-dimensional (3D) printing was used to produce hybrid film structures of PUL and hydroxypropyl methylcellulose (HPMC), which were loaded with caffeine as a model drug. 3D printing was used to control the spatial deposition of films. HPMC was found to increase the mean mechanical properties of PUL films, where the tensile strength, elastic modulus and elongation break increased from 8.9 to 14.5 MPa, 1.17 to 1.56 GPa and from 1.48% to 1.77%, respectively. In addition, the spatial orientation of the hybrid films was also explored to determine which orientation could maximize the mechanical properties of the hybrid films. The results revealed that 3D printing could modify the mechanical properties of PUL whilst circumventing the issues associated with immiscibility.

3D printed tablets loaded with polymeric nanocapsules: An innovative approach to produce customized drug delivery systems.

The generation of multi-functional drug delivery systems, namely solid dosage forms loaded with nano-sized carriers, remains little explored and is still a challenge for formulators. For the first time, the coupling of two important technologies, 3D printing and nanotechnology, to produce innovative solid dosage forms containing drug-loaded nanocapsules was evaluated here. Drug delivery devices were prepared by fused deposition modelling (FDM) from poly(ε-caprolactone) (PCL) and Eudragit® RL100 (ERL) filaments with or without a channelling agent (mannitol). They were soaked in deflazacort-loaded nanocapsules (particle size: 138nm) to produce 3D printed tablets (printlets) loaded with them, as observed by SEM. Drug loading was improved by the presence of the channelling agent and a linear correlation was obtained between the soaking time and the drug loading (r2=0.9739). Moreover, drug release profiles were dependent on the polymeric material of tablets and the presence of the channelling agent. In particular, tablets prepared with a partially hollow core (50% infill) had a higher drug loading (0.27% w/w) and faster drug release rate. This study represents an original approach to convert nanocapsules suspensions into solid dosage forms as well as an efficient 3D printing method to produce novel drug delivery systems, as personalised nanomedicines.

Comparative survival of commercial probiotic formulations: tests in biorelevant gastric fluids and real-time measurements using microcalorimetry.

The large number of probiotic products now available makes the decision about which product to choose difficult both for the consumer and for the specialist providing dietary/nutritional advice. Data on the viability of the bacteria in these products, in an in vivo situation, are therefore important. This study was designed to explore the comparative health and survival of probiotic species in various commercial formulations, using more realistic test systems. This might allow further understanding of factors that must be controlled to optimise the delivery of live healthy bacteria to the lower gut. A total of eight commercially available probiotic preparations were selected for enumeration tests and in vitro gastric tolerance tests. Tolerance assays were conducted in porcine gastric fluid (PGF) fed and fasted state (pH 3.4±0.04), simulated gastric fluid (SGF, pH adjusted to 1.2 and 3.4) and fasted state simulated gastric fluid (FaSSGF, pH adjusted to 1.6 and 3.4). Isothermal microcalorimetry was also used to measure real-time growth of probiotics after exposure to simulated gastric fluid. Results from the enumeration tests indicated that recovery of viable organisms per dose is the same as or better than the stated label claims for liquid-based formulations, but lower than the stated claim for freeze-dried products. Results from the in vitro tolerance tests overall suggest that the PGF provided a harsher environment than the simulated systems at similar pH. In general, liquid-based products tested tended to give superior results in terms of survival compared with the freeze-dried products tested. Results from tests in the fed state in PGF suggested that food greatly affects viability. Microcalorimetric data showed that for some products probiotic species were able to grow following exposure to gastric fluid, suggesting that viable bacteria reach the gut in vivo.

The use of dynamic mechanical analysis (DMA) to evaluate plasticization of acrylic polymer films under simulated gastrointestinal conditions.

PURPOSE: Glass transition temperature (T(g)) measurements of polymers are conventionally conducted in the dry state with little attention to the environment they are designed to work in. Our aim was to develop the novel use of dynamic mechanical analysis (DMA) to measure the T(g) of enteric polymethacrylic acid methylmethacrylate (Eudragit L and S) polymer films formulated with a range of plasticizers in the dry and wet (while immersed in simulated gastric media) states. METHODS: Polymer films were fabricated with and without different plasticizers (triacetin, acetyl triethyl citrate, triethyl citrate, polyethylene glycol, propylene glycol, dibutyl phthalate, dibutyl sebacate). T(g) was measured by a dynamic oscillating force with simultaneous heating at 1 °C/min. This was conducted on films in the dry state and while immersed in 0.1M HCl to simulate the pH environment in the stomach. RESULTS: The T(g) of unplasticized Eudragit L and S films in the dry state was measured to be 150 and 120 °C, respectively. These values were drastically reduced in the wet state to 20 and 71 °C for Eudragit L and S films, respectively. The plasticized films showed similar falls in T(g) in the wet state. The fall in T(g) of Eudragit L films to below body temperature will have far-reaching implications on polymer functionality and drug release. CONCLUSIONS: Immersion DMA provides a robust method for measuring T(g) of polymer films in the wet state. This allows better prediction of polymer behaviour in vivo.

Stability assessment of pharmaceuticals and biopharmaceuticals by isothermal calorimetry.

The assessment of stability (of actives, excipients and/or formulated products) is an important, and often time-consuming, part of pharmaceutical product development. Conventionally, HPLC is used to quantify the concentrations of a parent compound and any degradation products as a function of storage time. HPLC, however, is relatively insensitive to small changes in concentration and it is often the case that stability assays are conducted under stress conditions, in order to accelerate any degradation processes. The Arrhenius relationship is then employed to give an initial prediction of stability under storage conditions while long-term studies, under storage conditions, are conducted to confirm these predictions. The properties of isothermal calorimetry, such as its intrinsic sensitivity to small changes in heat and invariance to the physical form of a sample, make it ideally suited for stability assessment because it obviates the need for an Arrhenius analysis. In addition, the ability to conduct titration or gas perfusion experiments vastly increases its range of applications. Recent advances in instrumental design and data analysis have made it easier to analyse data quantitatively for complex systems. It is the purpose of this review to highlight some of these developments, discuss them in the context of pharmaceutical and biopharmaceutical examples and explore some of the future challenges and applications of the technique.

Application of solution calorimetry in pharmaceutical and biopharmaceutical research.

In solution calorimetry the heat of solution (Delta(sol)H) is recorded as a solute (usually a solid) dissolves in an excess of solvent. Such measurements are valuable during all the phases of pharmaceutical formulation and the number of applications of the technique is growing. For instance, solution calorimetry is extremely useful during preformulation for the detection and quantification of polymorphs, degrees of crystallinity and percent amorphous content; knowledge of all of these parameters is essential in order to exert control over the manufacture and subsequent performance of a solid pharmaceutical. Careful experimental design and data interpretation also allows the measurement of the enthalpy of transfer (Delta(trans)H) of a solute between two phases. Because solution calorimetry does not require optically transparent solutions, and can be used to study cloudy or turbid solutions or suspensions directly, measurement of Delta(trans)H affords the opportunity to study the partitioning of drugs into, and across, biological membranes. It also allows the in-situ study of cellular systems. Furthermore, novel experimental methodologies have led to the increasing use of solution calorimetry to study a wider range of phenomena, such as the precipitation of drugs from supersaturated solutions or the formation of liposomes from phospholipid films. It is the purpose of this review to discuss some of these applications, in the context of pharmaceutical formulation and preformulation, and highlight some of the potential future areas where solution calorimetry might find applications.

Pharmaceutical microcalorimetry: applications to long-term stability studies.

Calorimetry has been a mainstay of stability analyses for some time in the form of differential scanning microcalorimetry (DSC). This technique exploits high (relatively) temperature studies of pure materials and of formulations to accelerate any degradation or interactions. The behaviour of the material at storage or ambient conditions is then estimated via extrapolation from the Arrhenius equation. Recent developments in isothermal microcalorimetry allow the direct determination of both kinetic and thermodynamic parameters for long, slow reactions from studies conducted at appropriate temperatures and under designated environmental control (pH, pO2, RH etc.). This review introduces the kinetic analysis of microcalorimetric data and, through selected examples, shows applications of the method.