Nanocarrier-integrated multilayer films produced by 3D printing for improved skin adhesion and curcumin photostability

Additive manufacturing can be regarded as a game-changing approach for paediatric drug development, as children have special drug-related requirements which are rarely met by conventional technologies. Traditional dosage forms have considerable drawbacks, among them dose, excipient safety, and taste issues, which can be resolved by using three-dimensional (3D) printing. Ease of swallowing and an appealing design are among the improvements brought forth by 3D printing techniques. Techniques that have been thoroughly researched in the paediatric field include hot-melt extrusion (HME) coupled with fused deposition modelling (FDM), direct powder extrusion (DPE) and semisolid extrusion (SSE) 3D printing. Selective Laser Sintering (SLS) 3D bioprinting and binder-jet (BJ) 3D printing are other less known but highly useful techniques. A number of studies focus on significant subjects for the paediatric medicine domain, such as the acceptability of the produced formulations, the size of tablets, the design, the concealment of bitter API flavour, and the stability of the dosage forms. The 3D-printed oral formulations are varied: conventional-sized tablets, miniaturised tablets, chewable tablets, and orodispersible films or tablets. Most of the drugs used in the presented studies are essential medicines for children, for which commercial products with flexible doses and age-appropriate characteristics are often lacking. The practical implications of currently published studies and future directions for paediatric pharmaceutical 3D printing are described. Although there is a substantial amount of technical and in vitro data as well as paediatric engagement work on this subject, its translation into clinical practice is still limited. The clinical efficacy of 3D-printed dosage forms has to be further researched, since only a few studies have targeted this aspect.

Semisolid extrusion (SSE) 3D printing is an emerging technology in personalized medicine. To address clinical multi-dose requirements, SSE has been explored to manufacture new preparations. In this study, amlodipine besylate (AMB) was the model drug, and SSE was the pharmaceutical strategy. We developed semisolids suitable for SSE and AMB chewable tablets with six strengths (1.5–5 mg) to meet the needs of 2–16-year-old patients. First, the semisolid extrudability was evaluated by texture analyzer, and then the amounts of carboxymethyl cellulose sodium, sodium starch glycolate, and glycerin were optimized by full factorial design. Then, rheological tests were performed to evaluate the properties of the semisolid and the effect of starch sodium glycolate on printability. Finally, the amount of corrigents was optimized using the electronic tongue. Laboratory amplified semisolids and 3D printed tablets can be stored for a few months, and the whole SSE process had no effect on crystal type. This study validated the feasibility of SSE 3D printing, and tablets with appropriate taste and cartoon appearance can meet or even exceed the traditional preparations. Our study provides a new strategy for multi-dose solid preparations and effectively meet the need for personalized amlodipine medicine.

Anxiety disorders are the most prevalent psychiatric disorders and are associated with a high burden of illness. Combining synthetic and native-origin compounds in treating such disorders could provide true benefits in terms of therapeutic efficacy. In the present study, we combined triazolobenzodiazepine and motherwort (Leonurus cardiaca L.) dry extract for such applications. The aim. The aim of this study was to develop aqueous polyethylene oxide (PEO) composite gels loaded with 1,2,3-triazolo-1,4-benzodiazepine nanofibers and a valine-modified motherwort herb dry extract for semi-solid extrusion (SSE) 3D printing. The printability of such gels and the physicochemical properties of the final 3D-printed drug preparations were investigated. Materials and methods. A new drug substance, 1,2,3-triazolo-1,4-benzodiazepine (MA-253) was synthesized and used to formulate oleogels and electrospun nanofibers for 3D printing. The plant-origin dry extract was prepared from a motherwort tincture and valine. The aqueous PEO gels loaded with a synthetic drug (MA-253) containing nanofibers and a valine-modified motherwort extract were prepared and subsequently used in the SSE 3D printing experiments. The homogeneity, viscosity and 3D printability of composite PEO gels were verified. The phytochemical assay of flavonoids in the 3D-printed drug preparations was conducted with the European pharmacopoeia spectrophotometric method. Research results. Three experimental gel formulations loaded with 1,2,3-triazolo-1,4-benzodiazepine nanofibers and a valine-modified motherwort dry extract were developed and tested for the SSE 3D printing applications. The present three gels showed good SSE 3D printability without any significant printing flaws. The SSE 3D-printed lattices prepared from the aqueous PEO gels containing 100 mg/ml of motherwort extract showed the most promising 3D printing performance. The 3D-printed drug preparations were entirely dissolved in purified water (22±2 °C) within 20 minutes, thus suggesting their applicability in oral administration. Conclusions. Novel aqueous PEO gel formulations loaded with nanofibrous 1,2,3-triazolo-1,4-benzodiazepine nanofibers and valine-modified motherwort herb extract are feasible for pharmaceutical SSE 3D printing. The present composite PEO gels enable the preparation of printed oral immediate-release drug delivery systems for new triazolobenzodiazepine derivatives and a drug therapy supportive plant extract

Single-use plastic films, made of single or multilayer plastic derived from fossil-based polymers, present serious recycling problems [1]. One major challenge in their recycling is that multilayer film laminations are inseparable, leading to poor properties when recovered and remelted. Multilayer packaging thereby contributes to the landfill-waste and exacerbates environmental pollution [2]. The combination of watersoluble and biodegradable polymers is presented in this work as a potential strategy to obtain high barrier performance and trigger degradable properties in multilayer films, eliminating solid-waste problems (Figure 1). Multilayer films composed of melt-extrudable poly (vinyl alcohol) (PVOH) as the core layer and poly (butylene adipate terephthalate) (PBAT) as the outer skin layers for packaging applications were produced by the co-extrusion process. The optimal processing conditions for the multilayer coextruded films (both blown film and cast film) yielding the best combination of properties, performance and potential biodegradability of the flexible plastic films were explored. PBAT/PVOH multilayer films displayed excellent adhesion between the two interlayers in the polymer structure. The interlayer microstructure and chemical composition analysis was performed using SEM morphology, FTIR and NMR characterization methods. The crystallinity of the PVOH grade plays a crucial role in facile processing and ultimately determining the thermal, mechanical and barrier properties of the co-extruded multilayer films. Moreover, these PBAT/PVOH multilayer films exhibited superior barrier properties with an oxygen permeability of 3.5 cc.mil/m2-day at 0% relative humidity (RH), over monolayer PBAT with an oxygen permeability of 15.8 cc.mil/m2-day at 0% RH. Finally, biodegradation experiments using aqueous dissolution of the PVOH from multilayer films followed by enzyme deconstruction of the remaining film components (mainly PBAT) demonstrated an effective and ecofriendly method for biodegrading and bio-recycling of multilayer plastic films at a large scale. Given all the components are biodegradable, the final polymer films will also biodegrade in compost conditions, thereby creating another sustainable end-of-life option.

Semi-solid extrusion 3D printing in drug delivery and biomedicine: Personalised solutions for healthcare challenges

Semi-solid extrusion (SSE) 3D printing offers a versatile platform for preparing personalised pharmaceutical dosage forms. We investigated the applicability of the three different grades of poloxamers combined with polyethylene oxide (PEO) in pharmaceutical SSE 3D printing. The binary mixtures of poloxamers (F68, F87, and F108) and PEO at a ratio of 55:45 (w/w) were used in preparing the aqueous gels for SSE 3D printing. Acetylsalicylic acid (ASA) was used as a model drug in the concentrations 5%, 7%, and 9% (w/w). The physicochemical properties, printability, geometric accuracy, structural fidelity, and in-vitro drug-release behaviour of SSE 3D-printed 4 × 4 grids and axially perforated tablets were studied. We found that poloxamer F108 as a co-printed carrier polymer (with PEO) formed high-viscosity gels, which were feasible for SSE 3D-printing. The poloxamer F68- and F87-based gel formulations in turn showed reduced print fidelity. FTIR spectroscopy analysis confirmed compatibility between ASA, PEO, and all three poloxamers studied. The SSE 3D-printed grid preparations exhibited immediate-release behaviour with an initial burst release of the drug (ASA), followed by a diffusion- and erosion-controlled drug release in vitro. The release rates decreased in order of poloxamer grade: F87 > F68 > F108. Overall, poloxamer grade F108 was the most feasible carrier polymer to be combined with PEO for the SSE 3D printing of ASA-loaded dosage forms. The present poloxamer and PEO co-printed formulations provide an alternative printing platform for aqueous-based SSE 3D printing of immediate-release oral drug preparations applicable in personalized medicine or compounding settings.

Semi-solid extrusion (SSE) 3D printing has recently attracted increased attention for its pharmaceutical application as a potential method for small-batch manufacturing of personalised solid dosage forms. It has the advantage of allowing ambient temperature printing, which is especially beneficial for the 3D printing of thermosensitive drugs. In this study, the effects of polymeric compositions (single hydroxypropyl methylcellulose (HPMC) system and binary HPMC + polyvinylpyrrolidone (PVP) system), disintegrant (silicon oxide (SiO2)), and active pharmaceutical ingredients (tranexamic acid (TXA) and paracetamol (PAC)) on the printability of semisolid inks and the qualities of SSE printed drug-loaded tablets were investigated. Printability is defined by the suitability of the material for the process in terms of its physical properties during extrusions and post-extrusion, including rheology, solidification time, avoiding slumping, etc. The rheological properties of the inks were investigated as a function of polymeric compositions and drug concentrations and further correlated with the printability of the inks. The SSE 3D printed tablets were subjected to a series of physicochemical properties characterisations and in vitro drug release performance evaluations. The results indicated that an addition of SiO2 would improve 3D printing shape fidelity (e.g., pore area and porosity) by altering the ink rheology. The pores of HPMC + PVP + 5PAC prints completely disappeared after 12 hours of drying (pore area = 0 mm2). An addition of SiO2 significantly improved the pore area of the prints which are 3.5 ± 0.1 mm2. It was noted that the drug release profile of PAC significantly increased (p < 0.05) when additive SiO2 was incorporated in the formulation. This could be due to a significantly higher porosity of HPMC + PVP + SiO2 + PAC (70.3 ± 0.2%) compared to HPMC + PVP + PAC (47.6 ± 2.1%). It was also likely that SiO2 acted as a disintegrant speeding up the drug release process. Besides, the incorporation of APIs with different aqueous solubilities, as well as levels of interaction with the polymeric system showed significant impacts on the structural fidelity and subsequently the drug release performance of 3D printed tablets.

Context: Pharmaceutical 3D printing is a promising technology for preparing next-generation patient-specific drug delivery systems (DDSs) for oral administration. Rosmarinic acid (RA) was first isolated from the Rosmarinus officinalis plant, and currently, it is a well-known plant-origin active pharmaceutical ingredient (API) with anti-oxidative, hypoglycemic, antiviral, neuroprotective, and hepatoprotective effects. The therapeutic efficacy of RA, however, is dose-dependent, and it is sparingly soluble in water, which greatly limits the oral administration and bioavailability of this plant-origin API. Aims: To develop RA-loaded polyethylene oxide (PEO) aqueous gels for semi-solid extrusion (SSE) 3D printing and to investigate the performance of such 3D-printed oral solid DDSs intended for pharmaceutical applications. Methods: For SSE 3D printing, aqueous PEO gel formulations loaded with RA at different concentrations were prepared, and the physical appearance, homogeneity, and viscosity of the aqueous PEO gels were investigated. Results: The RA-PEO gels were printed to lattice- and round-shaped solid DDSs with a head speed of 0.5 mm/s, and the weight (mass uniformity) and effective surface area of the printed DDSs were determined. We found that the maximum concentration of RA loadable in the PEO gel for SSE 3D printing was 100 mg/mL. The optimal ratio of RA and surface-active agent (eumulgin) was 1 to 1.5. The key process parameters of the SSE 3D printing were identified and verified. The printing quality of RA-PEO DDSs was very good, thus showing the compatibility of a plant-origin substance and a carrier polymer (PEO). Conclusions: The SSE 3D-printed preparations obtained from aqueous PEO gels disintegrated rapidly within 15-20 minutes, suggesting their potential applicability as an oral immediate-release delivery system for RA.

Poorly soluble drugs represent a substantial portion of emerging drug candidates, posing significant challenges for pharmaceutical formulators. One promising method to enhance the drug’s dissolution rate and, consequently, bioavailability involves transforming them into an amorphous state within mesoporous materials. These materials can then be seamlessly integrated into personalized drug formulations using Additive Manufacturing (AM) techniques, most commonly via Fused Deposition Modeling. Another innovative approach within the realm of AM for mesoporous material-based formulations is semi-solid extrusion (SSE). This study showcases the feasibility of a straightforward yet groundbreaking hybrid 3D printing system employing SSE to incorporate drug-loaded mesoporous magnesium carbonate (MMC) into two different drug formulations, each designed for distinct administration routes. MMC was loaded with the poorly water-soluble drug ibuprofen via a solvent evaporation method and mixed with PEG 400 as a binder and lubricant, facilitating subsequent SSE. The formulation is non-aqueous, unlike most pastes which are used for SSE, and thus is beneficial for the incorporation of poorly water-soluble drugs. The 3D printing process yielded tablets for oral administration and suppositories for rectal administration, which were then analyzed for their dissolution behavior in biorelevant media. These investigations revealed enhancements in the dissolution kinetics of the amorphous drug-loaded MMC formulations. Furthermore, an impressive drug loading of 15.3 % w/w of the total formulation was achieved, marking the highest reported loading for SSE formulations incorporating mesoporous materials to stabilize drugs in their amorphous state by a wide margin. This simple formulation containing PEG 400 also showed advantages over other aqueous formulations for SSE in that the formulations did not exhibit weight loss or changes in size or form during the curing process post-printing. These results underscore the substantial potential of this innovative hybrid 3D printing system for the development of drug dosage forms, particularly for improving the release profile of poorly water-soluble drugs.

Acute severe ulcerative colitis (ASUC) is a growing health burden that often requires treatment with multiple therapeutic agents. As inflammation is localised in the rectum and colon, local drug delivery using suppositories could improve therapeutic outcomes. Three-dimensional (3D) printing is a novel manufacturing tool that permits the combination of multiple drugs in personalised dosage forms, created based on each patient's disease condition. This study, for the first time, demonstrates the feasibility of producing 3D printed suppositories with two anti-inflammatory agents, budesonide and tofacitinib citrate, for the treatment of ASUC. As both drugs are poorly water-soluble, the suppositories' ability to self-emulsify was exploited to improve their performance. The suppositories were fabricated via semi-solid extrusion (SSE) 3D printing and contained tofacitinib citrate and budesonide in varying doses (10 or 5 mg; 4 or 2 mg, respectively). The suppositories displayed similar dissolution and disintegration behaviours irrespective of their drug content, demonstrating the flexibility of the technology. Overall, this study demonstrates the feasibility of using SSE 3D printing to create multi-drug suppositories for the treatment of ASUC, with the possibility of titrating the drug doses based on the disease progression.

Three-dimensional (3D) printing, also known as additive manufacturing (AM), has emerged as a transformative technology in the pharmaceutical field, enabling the precise fabrication of dosage forms through a layer-by-layer approach. Over the past three decades, it has evolved from a prototyping tool into a promising platform for personalized medicine and advanced drug delivery systems. 3D printing allows for the customization of drug dosage, geometry, and release profiles, offering solutions for patient-specific treatment, especially in paediatrics, geriatrics, and complex diseases. Various printing techniques—including Fused Deposition Modelling (FDM), Selective Laser Sintering (SLS), Semi-Solid Extrusion (SSE), and Inkjet Printing—enable the fabrication of oral tablets, implants, microneedles, and biomedical devices with controlled release characteristics. Despite these advantages, challenges persist related to the selection of suitable pharmaceutical-grade excipients, mechanical strength, regulatory approval, and Good Manufacturing Practice (GMP) compliance.Future perspectives include integrating 3D printing with nanotechnology, artificial intelligence (AI), and bioprinting for on-demand drug manufacturing, tissue engineering, and regenerative medicine. Overall, 3D printing holds immense potential to revolutionize the pharmaceutical industry by facilitating personalized, cost-effective, and sustainable drug development tailored to individual patient needs.

Three kinds of low-fluorine YB2Cu3O7−x (YBCO) starting sols with F/Ba = 6, 4 and 2 were applied to fabricate multilayer YBCO films on LaAlO3 substrates by multi-coating technique. Influence of the fluorine content in the sols and the thickness of single-coated layer on the properties of multilayer YBCO films was discussed in detail. The critical current density (J c) of multilayer YBCO films derived from F/Ba = 6 and 4 sols dropped sharply with thickness. However, using sol with F/Ba = 2, the J c of multilayer films decreased slowly with thickness. Moreover, the thinner the single-coated film, the less the amount of a-axis-oriented grains inside the multilayer films, resulting in the improvement in J c of the final thick films. Through multi-coating technique, YBCO films as thick as 1.1–1.2 μm were prepared. The J c of the optimized thick YBCO films reached a high value of 4.23MA/cm2 at 77 K, 0T. Compared with the YBCO films derived from other low-fluorine sols, the YBCO films prepared using the ultralow-fluorine sol with mole ratio of F/Ba = 2 show the higher superconducting current transportation ability. Using this solution, the “thickness effect” of multilayer thick YBCO films is degraded obviously. Moreover, lowering the thickness of every layer film through controlling the withdrawal speed can also suppress the formation of a-axis grains, thus enhancing the critical current density of final thick YBCO films.

Semi-solid extrusion 3D-printing of eucalypt extract-loaded polyethylene oxide gels intended for pharmaceutical applications

Background/Objectives: Semi-solid extrusion (SSE) 3D printing is an innovative method utilized for preparation of various drug dosage forms, allowing for individualization by means of incorporation of one or multiple drugs in adjustable doses. SSE provides repeatable results and can be conveniently utilized in small batch production. This study aimed to develop a chewable formulation for pediatric patients which could be easily printed using SSE. Methods: Pectin and gelatin were utilized as gel-forming agents, polyvinylpyrrolidone as a thickener, glycerol as a plasticizer, citric acid as a pH modifier, and potassium sorbate as a conserving agent. Obtained tablets were evaluated for mass and content homogeneity and their mechanical properties compared to the long-time market standard for gummies. Results: Gummy formulation with texture properties comparable to the selected standard and mass homogeneity were prepared. The linear correlation between the model size and ondansetron content was proven. Conclusions: SSE 3D printing thus presents a suitable method of gummy formulation production with possible adjustment of dose by defining the object size.

Pharmaceutical 3D-printing of nanoemulsified eucalypt extracts and their antimicrobial activity