Transfer of a rational formulation and process development approach for 2D inks for pharmaceutical 2D and 3D printing.

The field of pharmaceutical 3D printing is growing over the past year, with Spitam® as the first 3D printed dosage form on the market. Showing the suitability of a binder jetting process for dosage forms. Although the development of inks for pharmaceutical field is more trail and error based, focusing on the Z-number as key parameter to judge the printability of an ink. To generate a more knowledgeable based ink development an approach from electronics printing was transferred to the field of pharmaceutical binder jetting. Therefore, a dimensionless space was used to investigate the limits of printability for the used Spectra S Class SL-128 piezo print head using solvent based inks. The jettability of inks could now be judged based on the capillary and weber number. Addition of different polymers into the ink narrowed the printable space and showed, that the ink development purely based on Z-numbers is not suitable to predict printability. Two possible ink candidates were developed based on the droplet momentum which showed huge differences in process stability, indicating that the used polymer type and concentration has a high influence on printability and process stability. Based on the study a more knowledgeable based ink design for the field of pharmaceutical binder jetting is proposed, to shift the ink design to a more knowledgeable based and process-oriented approach.

3D printing of amorphous solid dispersions: A comparison of fused deposition modeling and drop-on-powder printing.

Nowadays, a high number of pipeline drugs are poorly soluble and require solubility enhancement by e.g., manufacturing of amorphous solid dispersion. Pharmaceutical 3D printing has great potential in producing amorphous solid oral dosage forms. However, 3D printing techniques differ greatly in terms of processing as well as tablet properties. In this study, an amorphous formulation, which had been printed via Fused Deposition Modeling and drop-on-powder printing, also known as binder jetting, was characterized in terms of solid-state properties and physical stability. Solid state assessment was performed by differential scanning calorimetry, powder X-ray diffraction and polarized microscopy. The supersaturation performance of the amorphous solid dispersion was assessed via non-sink dissolution. We further evaluated both 3D printing techniques regarding their processability as well as tablet uniformity in terms of dimension, mass and content. Challenges and limitations of each 3D printing technique were discussed. Both techniques are feasible for the production of amorphous formulations. Results indicated that Fused Deposition Modeling is better suited for production, as the recrystallization tendency was lower. Still, filament production and printing presented a major challenge. Drop-on-powder printing can be a viable alternative for the production of amorphous tablets, when a formulation is not printable by Fused Deposition Modeling.

Development and Application of a Dissolution-Transfer-Partitioning System (DTPS) for Biopharmaceutical Drug Characterization.

A variety of in vitro dissolution and gastrointestinal transfer models have been developed aiming to predict drug supersaturation and precipitation. Further, biphasic, one-vessel in vitro systems are increasingly applied to simulate drug absorption in vitro. However, to date, there is a lack of combining the two approaches. Therefore, the first aim of this study was to develop a dissolution-transfer-partitioning system (DTPS) and, secondly, to assess its biopredictive power. In the DTPS, simulated gastric and intestinal dissolution vessels are connected via a peristaltic pump. An organic layer is added on top of the intestinal phase, serving as an absorptive compartment. The predictive power of the novel DTPS was assessed to a classical USP II transfer model using a BCS class II weak base with poor aqueous solubility, MSC-A. The classical USP II transfer model overestimated simulated intestinal drug precipitation, especially at higher doses. By applying the DTPS, a clearly improved estimation of drug supersaturation and precipitation and an accurate prediction of the in vivo dose linearity of MSC-A were observed. The DTPS provides a useful tool taking both dissolution and absorption into account. This advanced in vitro tool offers the advantage of streamlining the development process of challenging compounds.

Drop-on-powder 3D printing of amorphous high dose oral dosage forms: Process development, opportunities and printing limitations.

Drop-on-powder 3D printing is able to produce highly drug loaded solid oral dosage forms. However, this technique is mainly limited to well soluble drugs. The majority of pipeline compounds is poorly soluble, though, and requires solubility enhancement, e.g., via formation of amorphous solid dispersions. This study presents a detailed and systematic development approach for the production of tablets containing high amounts of a poorly soluble, amorphized drug via drop-on-powder 3D printing (also known as binder jetting). Amorphization of the compound was achieved via hot-melt extrusion using the exemplary system of the model compound ketoconazole and copovidone as matrix polymer at drug loadings of 20% and 40%. The milled extrudate was used as powder for printing and the influence of inks and different ink-to-powder ratios on recrystallization of ketoconazole was investigated in a material-saving small-scale screening. Crystallinity assessment was performed using differential scanning calorimetry and polarized light microscopy to identify even small traces of crystallinity. Printing of tablets showed that the performed small-scale screening was capable to identify printing parameters for the development of amorphous and mechanically stable tablets via drop-on-powder printing. A stability study demonstrated physically stable tablets over twelve weeks at accelerated storage conditions.

Determination of feed forces to improve process understanding of Fused Deposition Modeling 3D printing and to ensure mass conformity of printed solid oral dosage forms.

Fused Deposition Modeling is a suitable technique for the production of personalized solid oral dosage forms. For widespread application, it is necessary to be able to print a wide range of different formulations to address individual therapeutic needs. Due to the complexity of formulation composition (e.g., due to different compounds, excipients for enhancement of release and mechanical properties) and limited mechanical understanding, determination of suitable printing parameters is challenging. To address this challenge, we have developed a feed force tester using a Texture Analyser setup that mimics the actual printing process. Feed force data were compared to the mass of tablets printed from technical materials as well as pharmaceutical filaments containing ketoconazole at high drug loads of 20% and 40% and polyvinyl alcohol. By determining a feed force limit for the 3D printer from feed force data of several formulations printed, it was possible to specify the operable printing range, where printing is reproducible and printed mass corresponds the target mass. Based on these results, rational optimization of the printing process in terms of speed, time and temperature for different materials and formulations is possible.

Quality of FDM 3D Printed Medicines for Pediatrics: Considerations for Formulation Development, Filament Extrusion, Printing Process and Printer Design.

3d printing is capable of providing dose individualization for pediatric medicines and translating the precision medicine approach into practical application. In pediatrics, dose individualization and preparation of small dosage forms is a requirement for successful therapy, which is frequently not possible due to the lack of suitable dosage forms. For precision medicine, individual characteristics of patients are considered for the selection of the best possible API in the most suitable dose with the most effective release profile to improve therapeutic outcome. 3d printing is inherently suitable for manufacturing of individualized medicines with varying dosages, sizes, release profiles and drug combinations in small batch sizes, which cannot be manufactured with traditional technologies. However, understanding of critical quality attributes and process parameters still needs to be significantly improved for this new technology. To ensure health and safety of patients, cleaning and process validation needs to be established. Additionally, adequate analytical methods for the in-process control of intermediates, regarding their printability as well as control of the final 3d printed tablets considering any risk of this new technology will be required. The PolyPrint consortium is actively working on developing novel polymers for fused deposition modeling (FDM) 3d printing, filament formulation and manufacturing development as well as optimization of the printing process, and the design of a GMP-capable FDM 3d printer. In this manuscript, the consortium shares its views on quality aspects and measures for 3d printing from drug-loaded filaments, including formulation development, the printing process, and the printed dosage forms. Additionally, engineering approaches for quality assurance during the printing process and for the final dosage form will be presented together with considerations for a GMP-capable printer design.

Influence of the geometry of 3D printed solid oral dosage forms on their swallowability.

3D printing can be used to realise a wide variety of geometries of oral dosage forms. In this work, the swallowability of 3D-printed dosage forms with comparable size and different shape using fused deposition modelling (FDM) from isomalt was investigated in a controlled, randomised crossover study design. To produce the required number of dosage forms, a commercial 3D printer was modified with regard to product safety and production time. The modifications carried out permit the printing of 4 pharmaceutical forms simultaneously as well as the printing of rigid filaments. Six 3D-printed placebo objects and two compressed placebo reference objects were tested by 12 subjects in a blinded design. A questionnaire was used to assess swallowability, foreign body sensation at the moment of swallowing, persistent foreign body sensation after swallowing and pain after swallowing. Furthermore, the amount of additional water drunk after administration was documented. With the modified printer, the required 576 test objects could be printed within a few days with good reproducibility. In all questions, the best results were obtained for the printed and compressed oblong tablets, followed by the printed and compressed round tablets, the football and the sphere. The worst results were obtained for the pyramid closely followed by the cuboctahedron. The study shows that the variety of shapes of oral dosage forms made possible by 3D printing needs to be tested in swallowability studies, as not every shape is also easy to swallow.

Brittle polymers in Fused Deposition Modeling: An improved feeding approach to enable the printing of highly drug loaded filament.

Brittleness is often described as a restricting material property for the processability of filaments via Fused Deposition Modeling. Especially filaments produced from approved pharmaceutical polymers often tend to fracture between feeding gears, the commonly employed feeding mechanism. In order to enhance their mechanical properties, usually extensive formulation development is performed. This study presents a different strategy to enable the printing of brittle filaments without the use of additional excipients by adapting the feeding mechanism to piston feeding. The polymers Soluplus®, Kollidon® VA64 and Eudragit® E PO were used, which have been reported to be brittle. Ketoconazole was used as model compound at 40% drug load and the influence on the mechanical properties was investigated using the three-point flexural test. In order to gain a better understanding of the mechanism affecting brittleness, filaments were analyzed in terms of crystallinity and miscibility of the components using polarized microscopy, differential scanning calorimetry and X-ray diffraction. Printing was performed with the aim to obtain immediate release tablets. The addition of Ketoconazole resulted in filaments even more brittle than placebo filaments. Nevertheless, the adaption of the feeding mechanism enabled the successful manufacturing of uniform tablets from all formulations.

Design and characterization of a novel 3D printed pressure-controlled drug delivery system.

The aim of the present work was to explore the feasibility of 3D printing via fused deposition modeling (FDM) in the manufacturing of a pressure-controlled drug delivery system. Eudragit® RS, a brittle polymer with pH-independent solubility, was chosen to be a suitable excipient for the 3D printing of a pressure-sensitive, capsule-like dosage form. A self-constructed piston extruder was used for hot melt extrusion (HME) of filaments made from Eudragit® RS that could be used for 3D printing. Subsequently, the printing parameters were experimentally optimized with the aid of a self-programmed software. This G-code generator allowed the simple adjustment of printing speed, temperature, extrusion multiplier and layer height. By this, capsule-shaped dosage forms with the desired mechanical properties could be obtained. The effect of physiological pressure events on the drug release behaviour from the novel dosage form was finally tested by using a biorelevant stress test device. These in vitro experiments demonstrated the rapid and quantitative release of the probe drug after applying realistic pressure events. This work illustrated that 3D printing can be an interesting technique for the production of pressure-controlled dosage forms as a new concept of oral drug delivery.

Influence of the test method on in vitro drug release from intravitreal model implants containing dexamethasone or fluorescein sodium in poly (d,l-lactide-co-glycolide) or polycaprolactone.

Sustained intravitreal dexamethasone (DX) administration with the FDA and EMA approved Ozurdex® implant is indicated for the treatment of macular edema and non-infectious uveitis. Since drug release after intravitreal application cannot be determined in vivo in human eyes, the characterization of drug release in vitro in addition to animal models is of great importance. The aim of this study was to provide information about the influence of the test method on the in vitro drug release from intravitreal model implants. The following test methods were used: a shaking incubator experiment in reagent tubes, the small volume USP apparatus 7, the Vitreous Model (VM) and a system simulating the impact of movement on the VM (Eye Movement System, EyeMoS). Cylindrical model implants composed of DX and PLGA (poly (d,l-lactide-co-glycolide)) and additional polycaprolactone (PCL) implants containing fluorescein sodium (FS) as a model substance were produced by hot melt extrusion and were cut to a length of approximately 6 mm. Drug release was studied in ringer buffer pH 7.4 and in a modified polyacrylamide gel (PAAG) as vitreous substitute. In combination with the VM, the shape, the gel structure and a partial liquefaction (50%) were simulated in vitro. Swelling, disintegration, fragmentation, surface enlargement and changes in shape of the PLGA model implants were observed during the drug release study. We experienced that not each of the test methods and media were suitable for drug release studies of the PLGA implants. Marked differences in the release profiles were observed depending on the employed test method. These results emphasize the necessity to understand the underlying in vivo processes and to transfer the knowledge about the release determining factors into reliable in vitro test systems.

Distribution of fluorescein sodium and triamcinolone acetonide in the simulated liquefied and vitrectomized Vitreous Model with simulated eye movements.

Intravitreal administration is the method of choice for drug delivery to the posterior segment of the eye with special emphasis on the vitreous body and its surrounding retinal vasculature. In order to gain a better understanding of the underlying distribution processes, an in vitro model simulating the vitreous body (Vitreous Model, VM) and a system simulating the impact of movement on the VM (Eye Movement System, EyeMoS) was previously developed. In the study reported here, these systems were modified in regard to a standardized injection procedure, the diversity of simulated eye movements, extended periods of investigation, the opportunity to simulate the state after vitrectomy and in considering the physiological temperature. Fluorescein sodium (FS) and triamcinolone acetonide (TA) were used as (model) drugs to examine the drug distribution within the VM. Vitrectomy was simulated by replacing half the volume of the polyacrylamide gel that was used as vitreous substitute with the clinically used Siluron® 5000 whereas for a simulated liquefaction half the volume of the gel was replaced by buffer. A simulated liquefaction caused a 12-fold faster distribution of FS compared to the simulated juvenile VM, which was most likely caused by convective forces and mass transfer. Also, the injection technique (injection into the gel or into the buffer compartment) influenced the resulting distribution pattern. Without any liquefaction, the previously described initial injection channel occurred with both (model) drugs and, in the case of TA, remained almost unchanged during the investigation period of 72h. Simulating vitrectomized eyes, TA did not spread uniformly, but either remained in the depot or strongly sedimented within the VM suggesting that a homogenous distribution of a TA suspension is highly unlikely in vitrectomized eyes. High variabilities were observed with ex vivo animal eyes, demonstrating the limited benefit of explanted tissues for such distribution studies. The combination of the modified VM and EyeMoS seems a valuable tool for characterizing intravitreal dosage forms in a reproducible simulation of diversified eye movements and a partially liquefied or vitrectomized vitreous body.

Assessment of different polymers and drug loads for fused deposition modeling of drug loaded implants.

The 3D printing technique of fused deposition modeling® (FDM) has lately come into focus as a potential fabrication technique for pharmaceutical dosage forms and medical devices that allows the preparation of delivery systems with nearly any shape. This is particular promising for implants administered at application sites with a high anatomical variability where an individual shape adaption appears reasonable. In this work different polymers (Eudragit®RS, polycaprolactone (PCL), poly(l-lactide) (PLLA) and ethyl cellulose (EC)) were evaluated with respect to their suitability for FDM of drug loaded implants and their drug release behaviour was evaluated. The fluorescent dye quinine was used as a model drug to visualize drug distribution in filaments and implants. Quinine loaded filaments were produced by solvent casting and subsequent hot melt extrusion (HME) and model implants were printed as hollow cylinders using a standard FDM printer. Parameters were found at which model implants (hollow cylinders, outer diameter 4-5mm, height 3mm) could be produced from all tested polymers. The drug release which was examined by incubation of the printed implants in phosphate buffered saline solution (PBS) pH 7.4 was highly dependent on the used polymer. The fastest relative drug release of approximately 76% in 51days was observed for PCL and the lowest for Eudragit®RS and EC with less than 5% of quinine release in 78 and 100days, respectively. For PCL further filaments were prepared with different quinine loads ranging from 2.5% to 25% and thermal analysis proved the presence of a solid dispersion of quinine in the polymer for all tested concentrations. Increasing the drug load also increased the overall percentage of drug released to the medium since nearly the same absolute amount of quinine remained trapped in PCL at the end of drug release studies. This knowledge is valuable for future developments of printed implants with a desired drug release profile that might be controlled by the choice of the polymer and the drug load.

Simulation of drug distribution in the vitreous body after local drug application into intact vitreous body and in progress of posterior vitreous detachment.

Intravitreal injections and drug-loaded implants are current approaches to treat diseases of the posterior eye. To investigate the release of active agents and their distribution in the vitreous body, a new test system was developed that enables a realistic simulation of eye motions. It is called the eye movement system (EyeMoS). In combination with a previously developed model containing a polyacrylamide gel as a substitute for the vitreous body, this new system enables the characterization of the influence of eye motions on drug distribution within the vitreous body. In the presented work, the distribution of fluorescence-tagged model drugs of different molecular weight within the simulated vitreous was examined under movement with the EyeMoS and without movement. By replacing a part of the gel in the simulated vitreous body with buffer, the influence of the progress of posterior vitreous detachment (PVD) on the distribution of these model substances was also studied. The results indicate that convective forces may be of predominate influence on initial drug distribution. The impact of these forces on drug transport increases with simulated progression of PVD. Using the EyeMoS, the investigation of release and distribution from intravitreal drug delivery systems becomes feasible under biorelevant conditions.