Quality attributes for printable emulsion gels and 3D-printed tablets: Towards production of personalized dosage forms.

3D-printing technology offers a flexible manufacturing platform with the potential to address the need of personalized dosage forms. However, quality aspects of such small-scale, on-demand production of pharmaceutical products intended for personalization is still limited. The aim of this study was therefore to study critical quality control attributes of lipid tablets produced by semi-solid extrusion (SSE) 3D printing from emulsion gels incorporating a poorly water-soluble drug. Quality attributes for both the printable emulsion gel and the printed dosage forms were assessed. The emulsion gel was shown to be printable with accurate dosing for at least one month of storage at 4 °C. Tablets were 3D printed in different sizes and a correlation, R2 value of 0.99, was found between the weight and the drug content. The 3D-printed tablets complied with the mass and drug content uniformity requirements described in the European Pharmacopoeia.. Solid-state characterization of the tablets during short-term storage revealed no signs of crystallinity of the drug. Lastly, the lipid digestion and drug release were unchanged after short-term storage of the tablets. This study demonstrates the potential of SSE 3D printing for personalized dosing of a lipid-based formulation strategy and discusses central quality attributes for the printable formulation and the 3D-printed dosage form.

Synergistic stabilization of emulsion gel by nanoparticles and surfactant enables 3D printing of lipid-rich solid oral dosage forms.

Pharmaceutical formulation of oral dosage forms is continuously challenged by the low solubility of new drug candidates. Pickering emulsions, emulsions stabilized with solid particles, are a promising alternative to surfactants for developing long-term stable emulsions that can be tailored for controlled release of lipophilic drugs. In this work, a non-emulsifying lipid-based formulation (LBF) loaded with fenofibrate was formulated into an oil-in-water (O/W) emulsion synergistically stabilized by stearic acid and silica (SiO2) nanoparticles. The emulsion had a droplet size of 341 nm with SiO2 particles partially covering the oil-water interface. In vitro lipid digestion was faster for the emulsion compared to the corresponding LBF due to the larger total surface area available for digestion. Cellulose biopolymers were added to the emulsion to produce a gel for semi-solid extrusion (SSE) 3D printing into tablets. The emulsion gel showed suitable rheological attributes for SSE, with a trend of higher viscosity, yield stress, and storage modulus (G'), compared to a conventional self-emulsifying lipid-based emulsion gel. The developed emulsion gel allows for a non-emulsifying LBF to be transformed into solid dosage forms for rapid lipid digestion and drug release of a poorly water-soluble drug in the small intestine.

Manipulations and age-appropriateness of oral medications in pediatric oncology patients in Sweden: Need for personalized dosage forms.

Due to the lack of age-appropriate formulations for children, healthcare professionals and caregivers frequently manipulate dosage forms to facilitate oral administration and obtain the required dose. In this study, we investigated drug manipulation and age-appropriateness of oral medications for pediatric oncology patients with the aim of identifying the therapeutic needs for personalized dosage forms. An observational study at a pediatric oncology ward, combined with analysis of the age-appropriateness of the oral medications, was performed. Nurses frequently manipulated solid dosage forms to administer them via enteral feeding tubes. Of the active pharmaceutical ingredients (APIs) assessed for age-appropriateness, 74% (29 of 39) were identified to need personalization, either because of lack of child-friendly dosage form, suitable dosage strength, or both. Most APIs, due to limited solubility, were sensitive to formulation changes, such as drug manipulation. This study demonstrates problems and therapeutic needs regarding oral dosage forms in treatment of children with cancer. Expertise in formulation design, new manufacturing technologies, and patient-centered information are needed to address age-appropriate formulations for children.

3D-printing of solid lipid tablets from emulsion gels.

Interest in 3D-printing technologies for pharmaceutical manufacturing of oral dosage forms is driven by the need for personalized medicines. Most research to date has focused on printing of polymeric-based drug delivery systems at high temperatures. Furthermore, oral formulation development is continuously challenged by the large number of poorly water-soluble drugs, which require more advanced enabling formulations to improve oral bioavailability. In this work, we used semi-solid extrusion (SSE) printing of emulsion gels with three types of emulsified lipid-based formulations (LBFs) to produce solid lipid tablets incorporating the poorly water-soluble drug, fenofibrate. Tablets were successfully 3D-printed from emulsion gels using SSE at room temperature, making the methodology particularly useful for thermolabile compounds. The tablets were well-defined in mass and disintegrated rapidly (<15 min). Importantly, the oil droplet size reconstituted after dispersion of the tablets and subsequent lipid digestion was similar to traditional liquid LBFs. This work demonstrates the successful use of SSE for fabricating solid lipid tablets based on emulsion gels. The method is further promising for on demand production of personalized dosage forms, necessary for flexible dosage adjustment in e.g., pediatric patients, when poorly water-soluble compounds constitute the core of the therapy.

Impact of Drug Physicochemical Properties on Lipolysis-Triggered Drug Supersaturation and Precipitation from Lipid-Based Formulations.

In this study we investigated lipolysis-triggered supersaturation and precipitation of a set of model compounds formulated in lipid-based formulations (LBFs). The purpose was to explore the relationship between precipitated solid form and inherent physicochemical properties of the drug. Eight drugs were studied after formulation in three LBFs, representing lipid-rich (extensively digestible) to surfactant-rich (less digestible) formulations. In vitro lipolysis of drug-loaded LBFs were conducted, and the amount of dissolved and precipitated drug was quantified. Solid form of the precipitated drug was characterized with polarized light microscopy (PLM) and Raman spectroscopy. A significant solubility increase for the weak bases in the presence of digestion products was observed, in contrast to the neutral and acidic compounds for which the solubility decreased. The fold-increase in solubility was linked to the degree of ionization of the weak bases and thus their attraction to free fatty acids. A high level of supersaturation was needed to cause precipitation. For the weak bases, the dose number indicated that precipitation would not occur during lipolysis; hence, these compounds were not included in further studies. The solid state analysis proved that danazol and griseofulvin precipitated in a crystalline form, while niclosamide precipitated as a hydrate. Felodipine and indomethacin crystals were visible in the PLM, whereas the Raman spectra showed presence of amorphous drug, indicating amorphous precipitation that quickly crystallized. The solid state analysis was combined with literature data to allow analysis of the relationship between solid form and the physicochemical properties of the drug. It was found that low molecular weight and high melting temperature increases the probability of crystalline precipitation, whereas precipitation in an amorphous form was favored by high molecular weight, low melting temperature, and positive charge.