Biopolymeric 3D printed implantable scaffolds as a potential adjuvant treatment for acute post-operative pain management.

BACKGROUND: Pain is characterized as a major symptom induced by tissue damage occurring from surgical procedures, whose potency is being experienced subjectively, while current pain relief strategies are not always efficient in providing individualized treatment. 3D printed implantable devices hold the potential to offer a precise and customized medicinal approach, targeting both tissue engineering and drug delivery. RESEARCH DESIGN AND METHODS: Polycaprolactone (PCL) and PCL - chitosan (CS) composite scaffolds loaded with procaine (PRC) were fabricated by bioprinting. Geometrical features including dimensions, pattern, and infill of the scaffolds were mathematically optimized and digitally determined, aiming at developing structurally uniform 3D printed models. Printability studies based on thermal imaging of the bioprinting system were performed, and physicochemical, surface, and mechanical attributes of the extruded scaffolds were evaluated. The release rate of PRC was examined at different time intervals up to 1 week. RESULTS: Physicochemical stability and mechanical integrity of the scaffolds were studied, while in vitro drug release studies revealed that CS contributes to the sustained release dynamic of PRC. CONCLUSIONS: The printing extrusion process was capable of developing implantable devices for a local and sustained delivery of PRC as a 7-day adjuvant regimen in post-operative pain management.

Application of 3D printing in early phase development of pharmaceutical solid dosage forms.

Three-dimensional printing (3DP) is an emerging technology, offering the possibility for the development of dose-customized, effective, and safe solid oral dosage forms (SODFs). Although 3DP has great potential, it does come with certain limitations, and the traditional drug manufacturing platforms remain the industry standard. The consensus appears to be that 3DP technology is expected to benefit personalized medicine the most, but that it is unlikely to replace conventional manufacturing for mass production. The 3DP method, on the other hand, could prove well-suited for producing small batches as an adaptive manufacturing technique for enabling adaptive clinical trial design for early clinical studies. The purpose of this review is to discuss recent advancements in 3DP technologies for SODFs and to focus on the applications for SODFs in the early clinical development stages, including a discussion of current regulatory challenges and quality controls.

Development of a new age-appropriate, chewable tablet of mebendazole 500 mg for preventive chemotherapy of soil-transmitted helminth infections in pre-school and school-age children.

The aim of this study was to develop an age-appropriate tablet of mebendazole 500 mg to be used in large donation programs by the World Health Organization (WHO) for preventive chemotherapy of soil-transmitted helminth (STH) infections in pre-school and school-age children living in tropical and subtropical endemic areas. To that end, a new oral tablet formulation was developed that can be either chewed or given to young (≥1 year old) children by spoon after rapid disintegration to a soft mass with the addition of a small amount of water directly on the spoon. Although the tablet was manufactured using conventional fluid bed granulation, screening, blending, and compression processes, one of the main challenges was to combine properties of a chewable, dispersible, and regular (solid) immediate release tablet to meet the predefined requirements. The tablet disintegration time was below 120 s, allowing for administration by the "spoon method". The tablet hardness was higher (160-220 N) than normally applicable for chewable tablets, permitting shipment along a lengthy supply chain in a primary 200-tablet count bottle packaging. In addition, the resulting tablets are stable for 48 months in all climatic zones (I-IV). In this article, several aspects of the development of this unique tablet are described, including formulation, process development, stability, clinical acceptability testing, and regulatory filing.

In-line NIR spectroscopy for the understanding of polymer-drug interaction during pharmaceutical hot-melt extrusion.

The aim was to evaluate near-infrared spectroscopy for the in-line determination of the drug concentration, the polymer-drug solid-state behaviour and molecular interactions during hot-melt extrusion. Kollidon® SR was extruded with varying metoprolol tartrate (MPT) concentrations (20%, 30% and 40%) and monitored using NIR spectroscopy. A PLS model allowed drug concentration determination. The correlation between predicted and real MPT concentrations was good (R(2)=0.97). The predictive performance of the model was evaluated by the root mean square error of prediction, which was 1.54%. Kollidon® SR with 40% MPT was extruded at 105°C and 135°C to evaluate NIR spectroscopy for in-line polymer-drug solid-state characterisation. NIR spectra indicated the presence of amorphous MPT and hydrogen bonds between drug and polymer in the extrudates. More amorphous MPT and interactions could be found in the extrudates produced at 135°C than at 105°C. Raman spectroscopy, DSC and ATR FT-IR were used to confirm the NIR observations. Due to the instability of the formulation, only in-line Raman spectroscopy was an adequate confirmation tool. NIR spectroscopy is a potential PAT-tool for the in-line determination of API concentration and for the polymer-drug solid-state behaviour monitoring during pharmaceutical hot-melt extrusion.

Development of injection moulded matrix tablets based on mixtures of ethylcellulose and low-substituted hydroxypropylcellulose.

The objective of this study was to produce sustained-release matrix tablets by means of injection moulding and to evaluate the influence of matrix composition, process temperature and viscosity grade of ethylcellulose on processability and drug release by means of a statistical design. The matrix tablets were physico-chemically characterized and the drug release mechanism and kinetics were studied. Formulations containing metoprolol tartrate (30%, model drug), ethylcellulose with dibutylsebacate (matrix former and plasticizer) and L-HPC were extruded and subsequently injection moulded into tablets (375mg, 10mm diameter, convex-shaped) at different temperatures (110, 120 and 130 degrees C). Dissolution tests were performed and tablets were characterized by means of DSC, X-ray powder diffraction studies, X-ray tomography, porosity and hardness. Tablets containing 30% metoprolol and 70% ethylcellulose (EC 4cps) showed an incomplete drug release within 24h (<50%). Formulations containing L-HPC and EC in a ratio of 20/50 and 27.5/42.5 resulted in nearly zero-order drug release, while the drug release rate was not constant when 35% L-HPC was included. Processing of these formulations was possible at all temperatures, but at higher processing temperatures the drug release rate decreased and tablet hardness increased. Higher viscosity grades of EC resulted in a faster drug release and a higher tablet hardness. The statistical design confirmed a significant influence of the EC and L-HPC concentration on drug release, while the processing temperature and EC viscosity grade did not affect drug release. Tablet porosity was low (<5%), independent of the formulation and process conditions. DSC and XRD demonstrated the formation of a solid dispersion. The hydration front in the tablets during dissolution was visualized by dynamic X-ray tomography, this technique also revealed an anisotropic pore structure through the tablet.

Evaluation of injection moulding as a pharmaceutical technology to produce matrix tablets.

The aim of this study was to develop sustained-release matrix tablets by means of injection moulding and to evaluate the influence of process temperature, matrix composition (EC and HPMC concentration) and viscosity grade of ethylcellulose (EC) and hydroxypropylmethylcellulose (HPMC) on processability and drug release. The drug release data were analyzed to get insight in the release kinetics and mechanism. Formulations containing metoprolol tartrate (30%, model drug), EC with dibutyl sebacate (matrix former and plasticizer) and hydrophilic polymer HPMC were extruded and subsequently injection moulded into tablets (375 mg, 10 mm diameter, convex-shaped) at temperatures ranging from 110 to 140 degrees C. Tablets containing 30% metoprolol and 70% ethylcellulose (EC 4mPa s) showed an incomplete drug release within 24 h (<50%). Increasing production temperatures resulted in a lower drug release rate. Substituting part of the EC fraction by HPMC (HPMC/EC-ratio: 20/50 and 35/35) resulted in faster and constant drug release rates. Formulations containing 50% HPMC had a complete and first-order drug release profile with drug release controlled via the combination of diffusion and swelling/erosion. Faster drug release rates were observed for higher viscosity grades of EC (Mw>20 mPa s) and HPMC (4000 and 10,000 mPa s). Tablet porosity was low (<4%). Differential scanning calorimetry (DSC) and X-ray powder diffraction studies (X-RD) showed that solid dispersions were formed during processing. Using thermogravimetrical analysis (TGA) and gel-permeation chromatography no degradation of drug and matrix polymer was observed. The surface morphology was investigated with the aid of scanning electron microscopy (SEM) showing an influence of the process temperature. Raman spectroscopy demonstrated that the drug is distributed in the entire matrix, however, some drug clusters were identified.