Towards point-of-care manufacturing and analysis of immediate-release 3D printed hydrocortisone tablets for the treatment of congenital adrenal hyperplasia.

Hydrocortisone (HC) is the preferred drug in children with congenital adrenal hyperplasia due to its lower potency as well as fewer reports of side effects. Fused deposition modelling (FDM) 3D printing holds the potential to produce low-cost personalised doses for children at the point of care. However, the compatibility of the thermal process to produce immediate-release bespoke tablets for this thermally labile active is yet to be established. This work aims to develop immediate-release HC tablets using FDM 3D printing and assess drug contents as a critical quality attribute (CQA) using a compact, low-cost near-infrared (NIR) spectroscopy as a process analytical technology (PAT). The FDM 3D printing temperature (140 °C) and drug concentration in the filament (10%-15% w/w) were critical parameters to meet the compendial criteria for drug contents and impurities. Using a compact low-cost NIR spectral device over a wavelength of 900-1700 nm, the drug contents of 3D printed tablets were assessed. Partial least squares (PLS) regression was used to develop individual calibration models to detect HC content in 3D printed tablets of lower drug contents, small caplet design, and relatively complex formula. The models demonstrated the ability to predict HC concentrations over a wide concentration range (0-15% w/w), which was confirmed by HPLC as a reference method. Ultimately, the capability of the NIR model had preceding dose verification performance on HC tablets, with linearity (R2 = 0.981) and accuracy (RMSECV = 0.46%). In the future, the integration of 3DP technology with non-destructive PAT techniques will accelerate the adoption of on-demand, individualised dosing in a clinical setting.

The use of near-infrared as process analytical technology (PAT) during 3D printing tablets at the point-of-care.

Fused deposition modelling (FDM) is one of the most researched 3D printing technologies that holds great potential for low-cost manufacturing of personalised medicine. To achieve real-time release, timely quality control is a major challenge for applying 3D printing technologies as a point-of-care (PoC) manufacturing approach. This work proposes the use of a low-cost and compact near-infrared (NIR) spectroscopy modality as a process analytical technology (PAT) to monitor a critical quality attribute (drug content) during and after FDM 3D printing process. 3D printed caffeine tablets were used to manifest the feasibility of the NIR model as a quantitative analytical procedure and dose verification method. Caffeine tablets (0-40 % w/w) were fabricated using polyvinyl alcohol and FDM 3D printing. The predictive performance of the NIR model was demonstrated in linearity (correlation coefficient, R2) and accuracy (root mean square error of prediction, RMSEP). The actual drug content values were determined using the reference high-performance liquid chromatography (HPLC) method. The model of full-completion caffeine tablets demonstrated linearity (R2 = 0.985) and accuracy (RMSEP = 1.4 %), indicated to be an alternative dose quantitation method for 3D printed products. The ability of the models to assess caffeine contents during the 3D printing process could not be accurately achieved using the model built with complete tablets. Instead, by building a predictive model for each completion stage of 20 %, 40 %, 60 % and 80 %, the model of different completion caffeine tablets displayed linearity (R2 of 0.991, 0.99, 0.987, and 0.983) and accuracy (RMSEP of 2.22 %, 1.65 %, 1.41 %, 0.83 %), respectively. Overall, this study demonstrated the feasibility of a low-cost NIR model as a non-destructive, compact, and rapid analysis dose verification method enabling the real-time release to facilitate 3D printing medicine production in the clinic.

Creating Acceptable Tablets 3D (CAT 3D): A Feasibility Study to Evaluate the Acceptability of 3D Printed Tablets in Children and Young People.

3D printing (3DP) has been proposed as a novel approach for personalising dosage forms for children and young people (CYP). Owing to its low cost and the lack of need for finishing steps, fused deposing modelling (FDM) 3DP has been heavily researched in solid dosage forms (SDFs) manufacturing. However, the swallowability and overall acceptability of 3D printed dosage forms are yet to be established. This work is the first to evaluate the acceptability of different sized 3D printed placebo SDFs in CYP (aged 4-12 years). All participants had previously participated in a feasibility study (CAT study) that assessed the swallowability and acceptability of different sized GMP manufactured placebo conventional film-coated tablets, and therefore only attempted to swallow one 3D printed tablet. The participants assessed the swallowability, acceptability, mouthfeel, volume of water consumed, and taste of the sample using a 5-point hedonic facial scale on a participant questionnaire. A total of 30 participants were recruited, 87% of whom successfully swallowed the 3D printed tablet that they attempted to take. Attributes of the 3D printed tablets were scored as acceptable by the following percentage of participants-swallowability (80%), mouthfeel/texture (87%), the volume of water consumed (80%), taste (93%), and overall acceptability (83%). Overall, 77% of children reported they would be happy to take the tablet every day if it was a medicine. Participants were also asked which tablets felt better in the mouth-the film-coated tablets or the 3D printed tablets, and the most popular response (43%) was that both were acceptable. This study shows that FDM-based 3D printed SDFs may be a suitable dosage form for children aged 4-12 years. The results from this feasibility study will be used to inform a larger, definitive study looking at the acceptability of 3D printed tablets in children.

A Novel Multilayer Natural Coating for Fed-State Gastric Protection.

Several nutraceutical products require gastric protection against the hostile environment in the stomach. Currently marketed synthetic and semi-synthetic coatings suffer from major shortcomings such as poor gastric protection, slow-release response to pH change, and the use of artificial ingredients. The challenge of coating natural products is further exacerbated by the relatively high gastric pH in the fed state. In this work, a novel natural enteric coating is presented as a breakthrough alternative to current solutions. Two coating systems were devised: (i) a triple-layer coating that comprises a wax layer embedded between two alginate-based coatings, and (ii) a double-layer coating, where an overcoat of organic acids (fumaric or citric acid) is applied to an alginate-based coating. The multi-layer architecture did not impact the pH-responsive nature of the coating even when more biologically relevant Krebs bicarbonate buffer of lower buffer capacity was used. Interestingly, the gastric protection barrier of organic acid-based coating remained resistant at elevated gastric pH 2, 3, or 4 for 2 h. This is the first report of using an alginate-based coating to provide gastric protection against fed-state stomach conditions (pH 2-4). Being biodegradable, naturally occurring, and with no limit on daily intake, the reported novel coating provides a superior platform to current coating solutions for pharmaceutical and nutraceutical products.

Can filaments be stored as a shelf-item for on-demand manufacturing of oral 3D printed tablets? An initial stability assessment.

3D printing of oral solid dosage forms is a recently introduced approach for dose personalisation. Fused deposition modelling (FDM) is one of the promising and heavily researched 3D printing techniques in the pharmaceutical field. However, the successful application of this technique relies greatly on the mass manufacturing of physically and chemically stable filaments, that can be readily available as a shelf item to be 3D printed on-demand. In this work, the stability of methacrylate polymers (Eudragit EPO, RL, L100-55 and S100), hydroxypropyl cellulose (HPC SSL) and polyvinyl pyrrolidone (PVP)-based filaments over 6 months were investigated. Filaments manufactured by hot melt extrusion (HME) were stored at either 5 °C or 30 °C + 65 %RH with/without vacuuming. The effects of storage on their dimensions, visual appearance, thermal properties, and 'printability' were analysed. Theophylline content, as well as in vitro release from the 3D printed tablets were also investigated. The filaments were analysed before storage, then after 1, 3 and 6 months from the manufacturing date. Storing the filaments at these conditions had a significant effect on their physical properties, such as shape, dimensions, flexibility and hence compatibility with FDM 3D printing. In general, the methacrylate-based filaments were more physically stable and compatible with FDM 3D printing following storage. Owing to their hygroscopic nature, cellulose- and PVP-based filaments demonstrated a reduction in their glass transition temperature upon storage, leading to increased flexibility and incompatibility with FDM 3D printer. Theophylline contents was not significantly changed during the storage. This work provides preliminary data for the impact of polymer species on the long-term stability of filaments. In general, storage and packaging conditions have a major impact on the potential of on-demand manufacturing of 3D printed tablets using hot melt extruded filaments.

Solvent-free temperature-facilitated direct extrusion 3D printing for pharmaceuticals.

In an era moving towards digital health, 3D printing has successfully proven its applicability in providing personalised medicine through a technology-based approach. Among the different 3D printing techniques, direct extrusion 3D printing has been demonstrated as a promising approach for on demand manufacturing of solid dosage forms. However, it usually requires the use of elevated temperatures and/or the incorporation of an evaporable solvent (usually water). This can implicate the addition of a drying step, which may compromise the integrity of moisture- or temperature-sensitive drugs, and open the door for additional quality control challenges. Here, we demonstrate a new approach that simplifies direct extrusion 3D printing process with the elimination of the post-printing drying step, by merely adding a fatty glyceride, glyceryl monostearate (GMS), to a model drug (theophylline) and permeable water insoluble methacrylate polymers (Eudragit RL and RS). Indeed, rheological studies indicated that the addition of a combination of a plasticiser, (triethyl citrate), and GMS to theophylline: methacrylate polymer blends significantly reduced the extensional viscosity (to <2.5 kPa·Sec) at 90 °C. Interestingly, GMS demonstrated a dual temperature-dependant behaviour by acting both as a plasticiser and a lubricant at printing temperature (90-110 °C), while aiding solidification at room temperature. X-ray powder diffraction indicated incomplete miscibility of GMS within the polymeric matrix at room temperature with the presence of a subtle diffraction peak, at 2(Θ) = 20°. The 3D printed tablets showed acceptable compendial weight and content uniformity as well as sufficient mechanical resistance. In vitro theophylline release from 3D printed tablets was dependant on Eudragit RL:RS ratio. All in all, this work contributes to the efforts of developing a simplified, facile and low-cost 3D printing for small batch manufacturing of bespoke tablets that circumvents the use of high temperature and post-manufacturing drying step.

An innovative wax-based enteric coating for pharmaceutical and nutraceutical oral products.

In this work, a novel enteric coating based on natural waxes and alginate was reported. Initially, theophylline tablets were coated with emulsified ceresin wax in heated aqueous alginate solution using a fluidised bed coating technology. A coating level of 10% proved sufficient to prevent tablets from uptaking gastric medium (<5%) and produced a delayed release profile that complies to the pharmacopeial criteria of enteric coating release. Then, a wide range of emulsions based on other natural waxes (white beeswax, yellow beeswax, cetyl palmitate, carnauba wax or rice bran wax) yielded coatings with similar disintegration times and release profiles. Interestingly, the ceresin-based coating showed a superior performance at inhibiting acid uptake and enabling highly pH-responsive drug release in comparison to different commercially available GRAS enteric coating products (Eudraguard® Control, Swanlac® ASL10, and Aquateric™ N100). The coating was stable for 6 months at 30 °C and 65% RH. This innovative approach of applying hot O/W emulsion of natural waxes yielded an aesthetically attractive and stable coating with gastric protection and pH-sensitive release properties. The novel coating can be an efficient and promising alternative to overcome the shortcomings of current GRAS grade enteric coating products.

Temperature and solvent facilitated extrusion based 3D printing for pharmaceuticals.

On demand manufacturing of patient-specific oral doses provides significant advantages to patients and healthcare staff. Several 3D printing (3DP) technologies have been proposed as a potential digital alternative to conventional manufacturing of oral tablets. For an additive manufacturing approach to be successful for on-demand preparation, a facile process with minimal preparation steps and training requirements is needed. A novel hybrid approach to the 3D printing process is demonstrated here based on combining both a solvent and heating to facilitate extrusion. The system employed a moderate elevated temperature range (65-100 °C), a brief drying period, and a simple set-up. In this approach, a compact material cylinder is used as a pharmaceutical ink to be extruded in a temperature-controlled metal syringe. The process proved compatible with hygroscopic polymers [Poly(vinyl alcohol (PVA) and polyvinylpyrrolidone (PVP)] and a number of pharmaceutical fillers (lactose, sorbitol and D-mannitol). The fabricated tablets demonstrated acceptable compendial weight and content uniformity as well as mechanical resistance. In vitro drug release of theophylline from 3D printed tablets was dependent on the nature of the polymer and its molecular weight. This reported approach offers significant advantages compared to other 3DP technologies: simplification of pre-product, the use of a moderate temperature range, a minimal drying period, and avoiding the use of mechanically complicated machinery. In the future, we envisage the use of this low-cost and facile approach to fabricate small batches of bespoke tablets.

A novel natural GRAS-grade enteric coating for pharmaceutical and nutraceutical products.

In this study, enteric coatings based exclusively on naturally occurring ingredients were reported. Alginate (Alg) and pectin (Pec) blends with or without naturally occurring glyceride, glycerol monostearate (GMS), were initially used to produce solvent-casted films. Incorporating GMS in the natural polymeric films significantly enhanced the acid-resistance properties in gastric medium. Theophylline tablets coated with Alg-Pec blends without GMS disintegrated shortly after incubation in gastric medium (pH 1.2), leading to a premature and complete release of theophylline. Interestingly, tablets coated with Alg-Pec blends that contain the natural glyceride (GMS) resisted the gastric environment for 2 h with minimal drug release (<5%) and disintegrated rapidly following introduction to the intestinal medium, allowing a fast and complete drug release. Furthermore, the coating system proved to be stable for six months under accelerated conditions. These findings are particularly appealing to nutraceutical industry as they provide the foundation to produce naturally-occurring GRAS based enteric coatings.

Embedded 3D Printing of Novel Bespoke Soft Dosage Form Concept for Pediatrics.

Embedded three-dimensional printing (e-3DP) is an emerging method for additive manufacturing where semi-solid materials are extruded within a solidifying liquid matrix. Here, we present the first example of employing e-3DP in the pharmaceutical field and demonstrate the fabrication of bespoke chewable dosage forms with dual drug loading for potential use in pediatrics. LegoTM-like chewable bricks made of edible soft material (gelatin-based matrix) were produced by directly extruding novel printing patterns of model drug ink (embedded phase) into a liquid gelatin-based matrix (embedding phase) at an elevated temperature (70 °C) to then solidify at room temperature. Dose titration of the two model drugs (paracetamol and ibuprofen) was possible by using specially designed printing patterns of the embedded phase to produce varying doses. A linearity [R2 = 0.9804 (paracetamol) and 0.9976 (ibuprofen)] was achieved between percentage of completion of printing patterns and achieved doses using a multi-step method. The impact of embedded phase rheological behavior, the printing speed and the needle size of the embedded phase were examined. Owning to their appearance, modular nature, ease of personalizing dose and geometry, and tailoring and potential inclusion of various materials, this new dosage form concept holds a substantial promise for novel dosage forms in pediatrics.

'Temporary Plasticiser': A novel solution to fabricate 3D printed patient-centred cardiovascular 'Polypill' architectures.

Hypertension and dyslipidaemia are modifiable risk factors associated with cardiovascular diseases (CVDs) and often require a complex therapeutic regimen. The administration of several medicines is commonly associated with poor levels of adherence among patients, to which World Health Organisation (WHO) proposed a fixed-dose combination unit (polypill) as a strategy to improve adherence. In this work, we demonstrate the fabrication of patient-specific polypills for the treatment of CVDs by fused deposition modelling (FDM) 3D printing and introduce a novel solution to meet critical quality attributes. The construction of poly(vinyl alcohol) (PVA)-based polypills containing four model drugs (lisinopril dihydrate, indapamide, rosuvastatin calcium and amlodipine besylate) was revealed for the first time. The impact of tablet architecture was explored using multi-layered and unimatrix structures. The novel approach of using distilled water as a 'temporary co-plasticiser' is reported and was found to significantly lower the extruding (90 °C) and 3D printing (150 °C) temperatures from 170 °C and 210 °C respectively, with consequent reduction in thermal stress to the chemicals. XRD indicated that lisinopril dihydrate and amlodipine besylate maintained their crystalline form while indapamide and rosuvastatin calcium were essentially in amorphous form in the PVA tablets. From the multilayer polypills, the release profile of each drug was dependent on its position in the multilayer. In addition to the multilayer architecture offering a higher flexibility in dose titration and a more adaptive solution to meet the expectations of patient-centred therapy, we identify that it also allows orchestrating the release of drugs of different physicochemical characteristics. Adopting such an approach opens up a pathway towards low-cost multidrug delivery systems such as tablets, stents or implants for wider range of globally approved actives.

On demand manufacturing of patient-specific liquid capsules via co-ordinated 3D printing and liquid dispensing.

A method for the production of liquid capsules with the potential of modifying drug dose and release is presented. For the first time, the co-ordinated use of fused deposition modelling (FDM), 3D printing and liquid dispensing to fabricate individualised dosage form on demand in a fully automated fashion has been demonstrated. Polymethacrylate shells (Eudragit EPO and RL) for immediate and extended release were fabricated using FDM 3D printing and simultaneously filled using a computer-controlled liquid dispenser loaded with model drug solution (theophylline) or suspension (dipyridamole). The impact of printing modes: simultaneous shell printing and filling (single-phase) or sequential 3D printing of shell bottom, filling and shell cap (multi-phase), nozzle size, syringe volume, and shell structure has been reported. The use of shell thickness of 1.6 mm, and concentric architecture allowed successful containment of liquid core whilst maintaining the release properties of the 3D printed liquid capsule. The linear relationship between the theoretical and the actual volumes from the dispenser reflected its potential for accurate dosing (R2 = 0.9985). Modifying the shell thickness of Eudragit RL capsule allowed a controlled extended drug release without the need for formulation change. Owing to its low cost and versatility, this approach can be adapted to wide spectrum of liquid formulations such as small and large molecule solutions and obviate the need for compatibility with the high temperature of FDM 3D printing process. In a clinical setting, health care staff will be able to instantly manufacture in small volumes liquid capsules with individualised dose contents and release pattern in response to specific patient's needs.