Search

3D printed LEGO®-like designs are an attractive approach for the development of compartmental delivery systems due to their potential for dose personalisation through the customisation of drug release profiles. Additive manufacturing technologies such as Fused Deposition Modelling (FDM) are ideal for the printing of structures with complex geometries and various sizes. This study is a paradigm for the fabrication of 3D printed LEGO® -like tablets by altering the design of the modular units and the filament composition for the delivery of different drug substances. By using a combination of placebo and drug loaded compartments comprising of immediate release (hydroxypropyl cellulose) and pH dependant polymers (hypromellose acetate succinate) we were able to customise the release kinetics of melatonin and caffeine that can potentially be used for the treatment of sleeping disorders. The LEGO® -like compartments were designed to achieve immediate release of melatonin followed by variable lag times and controlled release of caffeine.

Objectives The aim of the work was to introduce 3D printing technology for the design and fabrication of drug-eluting contact lenses (DECL) for the treatment of glaucoma. The development of 3D printed lenses can effectively overcome drawbacks of existing approaches by using biocompatible medical grade polymers that provide sustained drug release of timolol maleate for extended periods. Methods Hot melt extrusion was coupled with fusion deposition modelling (FDM) to produce printable filaments of ethylene-vinyl acetate copolymer–polylactic acid blends at various ratios loaded with timolol maleate. Physicochemical and mechanical characterisation of the printed filaments was used to optimise the printing of the contact lenses Key findings 3D printed lenses with an aperture (opening) and specified dimensions could be printed using FDM technology. The lenses presented a smooth surface with good printing resolution while providing sustained release of timolol maleate over 3 days. The findings of this study can be used for the development of personalised DECL in the future.

The present review aims at identifying the key progress points that have been made on the use of 3D printing to manufacture microneedles in the past 3 years. The advances in the field of photopolymerization and extrusion-based 3D printing are outlined. The study revealed that the printing resolution and the material properties are the two critical parameters that have the most influential effect on the outcome of every microneedle printing endeavour. Finally, the authors attempt to estimate the impact of 3D printing on the transdermal drug delivery market.

Microfluidics is a technology that allows handling small volumes and mixing them in narrow channels. In this study, we used three different 3D printed microfluidics arrays to prepare liposomes by mixing an aqueous phase with an organic phase made of S75 and Cholesterol at ratios of 8:2 and 6:4 respectively. Liposomes were collected at Total Flow Rates of 3, 5 and 10 ml/min.All arrays produced liposomes varying from 40 to 70 nm, the particle size decreases with increasing TFR from 3 to 10 ml/min for all arrays and both FRRs. Zeta values varies from -40.5 to -86.6 mV indicating excellent stability for all nano dispersions. After 4 weeks storage at 4°C, a slight increase in the particle size was observed for both FRRs. Our study demonstrates the successful use of 3D printed microfluidic arrays for the design and development of liposomes.

Three-dimensional (3D) printing is becoming an attractive technology for the design and development of personalized paediatric dosage forms with improved palatability. In this work micro-extrusion based printing was implemented for the fabrication of chewable paediatric ibuprofen (IBU) tablets by assessing a range of front runner polymers in taste masking. Due to the drug-polymer miscibility and the IBU plasticization effect, micro-extrusion was proved to be an ideal technology for processing the drug/polymer powder blends for the printing of paediatric dosage forms. The printed tablets presented high printing quality with reproducible layer thickness and a smooth surface. Due to the drug-polymer interactions induced during printing processing, IBU was found to form a glass solution confirmed by differential calorimetry (DSC) while H-bonding interactions were identified by confocal Raman mapping. IBU was also found to be uniformly distributed within the polymer matrices at molecular level. The tablet palatability was assessed by panellists and revealed excellent taste masking of the IBU's bitter taste. Overall micro-extrusion demonstrated promising processing capabilities of powder blends for rapid printing and development of personalised dosage forms.

Bone is known to have a natural function to heal itself. However, if the bone damage is beyond a critical degree, intervention such as bone grafting may be imperative. In this work, the fabrication of a novel bone scaffold composed of natural bone components and polycaprolactone (PCL) using 3D printing is put forward. α1, 3-galactosyltransferase deficient pigs were used as the donor source of a xenograft. Decellularized porcine bone (DCB) with attenuated immunogenicity was used as the natural component of the scaffold with the aim to promote bone regeneration. The 3D printed DCB-PCL scaffolds combined essential advantages such as uniformity of the interconnected macropores and high porosity and enhanced compressive strength. The biological properties of the DCB-PCL scaffolds were evaluated by studying cell adhesion, viability, alkaline phosphatase activity and osteogenic gene expression of human bone marrow-derived mesenchymal stem cells. The in vitro results demonstrated that the DCB-PCL scaffolds exhibit an enhanced performance in promoting bone differentiation, which is correlated to the DCB content. Furthermore, critical-sized cranial rat defects were used to assess the effect of DCB-PCL scaffolds on bone regeneration in vivo. The results confirm that in comparison with PCL scaffolds, the DCB-PCL scaffolds can significantly improve new bone formation in cranial defects. Thus, the proposed 3D printed DCB-PCL scaffolds emerge as a promising regeneration alternative in the clinical treatment of large bone defects.

Nanostructure lipid carriers (NLCs) were developed for the delivery of curmumin (CRN), a potent anticancer agent with low bioavailability, for the treatment of prostate cancer. NLCs prepared using high pressure homogenization (HPH) with around 150 nm particle size, − 40 V ζ-potential and excellent long-term stability. Cellular uptake of CRN-SLN showed nanoparticle localization in the cytoplasm around the nucleus. CRN-NLCs were assessed using flow cytometry and found to cause early and late apoptotic events at 100 μg/ml CRN concentrations. CRN-NLC nanoparticles were administrated to nude mice with LNCaP prostate cancer xenografts and demonstrated substantial tumour volume suppression (40%) with no weight loss compared to pure CRN (ethanolic solution). Overall, NLCs were proved a suitable carrier for passive drug delivery and cancer treatment. Graphical abstract

The development of personalised paediatric dosage forms using 3D printing technologies has gained significant interest over the last few years. In the current study extruded filaments of the highly bitter Diphenhydramine Hydrochloride (DPH) were fabricated by using suitable hydrophilic carries such as hydroxypropyl cellulose (Klucel ELFTM) and a non-ionic surfactant (Gelucire 48/16TM) combined with sweetener (Sucralose) and strawberry flavour grades. The thermoplastic filaments were used to print 3D fruit-chew designs by Fused Deposition Modelling (FDM) technology. Physicochemical characterisation confirmed the formation of glass solution where DPH was molecularly dispersed within the hydrophilic carriers. DPH was released rapidly from the 3D printed fruit-chew designs with &gt, 85% within the first 30 min. Trained panellists performed a full taste and sensory evaluation of the sweetener intensity and the strawberry aroma. The evaluation showed complete taste masking of the bitter DPH and revealed a synergistic effect of the sweetener and the strawberry flavour with enhanced sweet strawberry, fruity and aftertaste perception. The findings of the study can be used for the development of paediatric dosage forms with enhanced organoleptic properties, palatability and medication adherence.

Recently, various additive manufacturing (3D printing) approaches have been employed to fabricate dressings such as film scaffolds that possess well defined architecture and orientation at the micro level. In this study, crosslinked chitosan (CH) based film matrices were prepared using 3D printing with genipin (GE) as a crosslinker, with glycerol (GLY) and poly ethylene glycol (PEG) as plasticizer. The 3D printed films were functionally characterized using (tensile, fluid handling, mucoadhesion, drug dissolution, morphological properties and cell viability as well physico-chemical characterization using scanning electron microscopy, Fourier transform infrared spectroscopy and X-ray diffraction. CH-GE-PEG600 3D printed films having the ratio of 1:1 polymer: plasticizer was selected due to their appropriate flexibility. Fourier transform infrared results showed intermolecular interaction between CH, GE and PEG which was confirmed by X-ray diffraction showing amorphous matrix structure. In vitro mucoadhesion studies of CH-GE-PEG600 films showed the capability of the 3D printed film to adhere to the epithelial surface. Scanning electron microscopy images showed that the surface of the plasticised films were smooth indicating content uniformity of CH, GE and PEG whilst micro cracks in unplasticised films confirmed their brittle nature. Plasticised films also showed high swelling capacity which enhanced water absorption. Cytotoxicity (MTT) assay using human skin fibroblast cell lines demonstrated that more than 90% of cells were viable after 48 h confirming non-toxic nature of the 3D printed CH-GE-PEG600 films and therefore promising dressing for chronic wound healing applications.

The current study investigates the development of extemporaneous preparation of hot melt extruded diclofenac sodium (Df-Na) pellets processed with glyceryl dibehenate (Compritol® 888 ATO) and dibasic calcium phosphate anhydrous (Fujicalin®) as carriers for pediatric applications. The extruded lipidic pellets were physicochemically characterized in order to examine the state of the active substance within the extruded formulations where Df-Na was found to retain its crystallinity but partially solubilized by glyceryl dibehenate. Furthermore, the dissolution rates of extemporaneous Df-Na pellets were assessed at gastric (pH 1.1 and simulated gastric fluid pH 1.6) and intestinal conditions (pH 5.5) to investigate the effect of food grades such as yogurt, apple sauce, mashed potato and hypromellose 2910. Extemporaneous compositions appeared to have a significant effect on Df-Na dissolution rates, especially in presence of apple sauce compared to the other food types. Furthermore, storage under long-term and accelerated conditions showed an effect on drug release from pellets.

3D printing technologies have found several applications within the biomedical sector including in the fabrication of medical devices, advanced visualization, diagnosis planning and simulation of surgical procedures. One of the areas in which of 3D printing is anticipated to revolutionised is the manufacturing of implantable bioresorbable drug-eluting scaffolds (stents). The ability to customize and create personalised tailor-made bioresorbable scaffolds has the potential to help solve many of the challenges associated with stenting, such as inappropriate stent sizing and design, abolish late stent thrombosis and help artery growth; 3D printing offers a rapid prototyping and effective method of producing stents making customization of designs feasible. This review provides an overview of the subjects and summarizes the latest research in the 3D printing technologies employed for the design and fabrication of bioresorbable stents including materials with the required printable and mechanical properties. Finally, we present a regulatory perspective on the development and engineering of 3D printed implantable stents.

The taste of drug substances plays a key role in the development of paediatric formulations with suitable organoleptic properties. The aim of the study was to evaluate the taste masking effectiveness of Smartseal 30D and ReadyMix on a range of bitter drug substances such as diphenhydramine HCl (DPD), ibuprofen lysine (IBU-LS), and phenylephrine HCl (PPH) for the development of paediatric dosage forms. The drugs were microencapsulated in the polymer carriers at 10-20% loadings using spray-drying processing. Spray drying of drug formulations was optimized in terms of percent yield and encapsulation efficiency followed by physicochemical characterization in order to identify the drugs' physical state in the polymer microparticles. The in vivo taste masking efficiency was evaluated using human test panel and showed noticeable reduction of drug's bitterness at all loadings in comparison to the bulk substances.

Prostate cancer is one of the prominent causes of cancer mortality in men all over the world and a challenge to treat. In this study, transferrin (Tf) bioconjugated solid lipid nanoparticles (SLNs) were developed and loaded with curcumin (CRC) for active targeting of prostate cancer cells. Curcumin is an anticancer agent, but its clinical applications are impeded due to the poor water solubility and bioavailability. Prepared blank Tf-SLNs showed minimal cytotoxicity while Tf-CRC-SLNs demonstrated significant in-vitro anti-proliferative activity compared to CRC-SLNs alone. Cellular uptake of Tf-CRC-SLNs were found to be significantly higher (p < 0.05/=0.01) compared to unconjugated SLNs or pure drug alone. Bioconjugated Tf-CRC-SLNs also showed improved early apoptotic and late apoptotic or early necrotic populations (6.4% and 88.9% respectively) to CRC-SLNs and CRC solution. Most importantly, in-vivo studies with Tf-CRC-SLNs in mice bearing prostate cancer revealed significant tumour regression (392.64 mm3 after 4 weeks, p < 0.001) compared to the control group. The findings of this work encourage future investigations and further in-vivo clinical studies on the potential of bioconjugated SLNs for cancer cure.

Twin-screw granulation (TSG) is a pharmaceutical process that has gained increased interest from the pharmaceutical industry for its potential for the development of oral dosage forms. The technology has evolved rapidly due to the flexibility of the equipment design, the selection of the process variables and the wide range of processed materials. Most importantly, TSG offers the benefits of both batch and continuous manufacturing for pharmaceutical products, accompanied by excellent process control, high product quality which can be achieved through the implementation of Quality by Design (QbD) approaches and the integration of Process Analytical Tools (PAT). Here, we present basic concepts of the various twin-screw granulation techniques and present in detail their advantages and disadvantages. In addition, we discuss the detail of the instrumentation used for TSG and how the critical processing paraments (CPP) affect the critical quality attributes (CQA) of the produced granules. Finally, we present recent advances in TSG continuous manufacturing including the paradigms of modelling of continuous granulation process, QbD approaches coupled with PAT monitoring for granule optimization and process understanding.

The aim of the study was the manufacturing and scale-up of theophylline-nicotinamide (THL-NIC) pharmaceutical cocrystals processed by hot-melt extrusion (HME). The barrel temperature profile, feed rate and screw speed were found to be the critical processing parameters with a residence time of approximately 47 s for the scaled-up batches. Physicochemical characterization using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction of bulk and extruded materials revealed the formation of high purity cocrystals (98.6%). The quality of THL-NIC remained unchanged under accelerated stability conditions.

Pharmaceutical salt formation is the most preferred and effective method to enhance the physicochemical properties of an active pharmaceutical ingredient (API) such as solubility, bioavailability, stability, and processability. Salts are defined as crystalline materials composed of two or more different molecules, typically, drug and salt formers in the same crystal lattice, where the components in the crystal lattice are in an ionized state and interact via ionic interactions. Conventionally, the solvent-mediated process is used to manufacture the salts, where the use of a vast amount of solvent has a detrimental effect on the environment. Recently, there have been very few solvent-free methods reported for pharmaceutical salt manufacturing salt. In this article, recent trends and advances in synthesis and manufacturing of salts are reviewed. Furthermore, the operational principles of commonly employed salt manufacturing technologies are discussed including their benefits and drawbacks in terms of purity, stability, throughput, and limitations in large-scale production. The final section is devoted to reviewing the regulatory issues in terms of the patent application for the salt form of an API compared to other multicomponent forms.

3D printing has emerged as a powerful manufacturing technology and has attracted significant attention for the fabrication of microneedle (MN)-mediated transdermal systems. In this work, we describe an optimisation strategy for 3D-printed MNs, ranging from the design to the drug delivery stage. The key relationships between design and manufacturing parameters and quality and performance are systematically explored. The printing and post-printing set parameters were found to influence quality and material mechanical properties, respectively. It was demonstrated that the MN geometry affected piercing behaviour, fracture, and coating morphology. The delivery of insulin in porcine skin by inkjet-coated MNs was shown to be influenced by MN design.

The advancement of drug delivery devices is critical for the individualization of patient treatment and the improvement of healthcare. Here, we introduce the 3DMNMEMS, a novel device that combines 3D printing, microneedles (MNs) and Microelectromechanical Systems (MEMS), allowing versatile and controllable by the user transdermal drug delivery. Hollow MNs were designed and 3D printed using Stereolithography, followed by integrating into a MEMS. By employing advanced imaging techniques, we monitored the distribution of liquid delivered by the device within skin tissue in real-time. In vivo testing revealed that the delivery of insulin using the 3DMNMEMS achieved improved glycemic control to diabetic animals compared to subcutaneous injections. These results demonstrated the potential of the 3DMNMEMS as a universal transdermal drug delivery system for personalized care.

ObjectivesDesign and examine the effect of sirolimus-PEGylated (Stealth) liposomes for breast cancer treatment. In this study, we developed conventional and Stealth liposome nanoparticles comprising of distearoylphosphatidylcholine (DSPC) or dipalmitoyl-phosphatidylcholine (DPPC) and DSPE-MPEG-2000 lipids loaded with sirolimus as an anticancer agent. The effect of lipid grade, drug loading and incubation times were evaluated.MethodsParticle size distribution, encapsulation efficiency of conventional and Stealth liposomes were studied followed by cytotoxicity evaluation. The cellular uptake and internal localisation of liposome formulations were investigated using confocal microscopy.Key findingsThe designed Stealth liposome formulations loaded with sirolimus demonstrated an effective in vitro anticancer therapy compared with conventional liposomes while the length of the acyl chain affected the cell viability. Anticancer activity was found to be related on the drug loading amounts and incubation times. Cell internalization was observed after 5 h while significant cellular uptake of liposome was detected after 24 h with liposome particles been located in the cytoplasm round the cell nucleus. Sirolimus Stealth liposomes induced cell apoptosisConclusionsThe design and evaluation of sirolimus-loaded PEGylated liposome nanoparticles demonstrated their capacity as drug delivery carrier for the treatment of breast cancer tumours.

The aim of this study was to investigate suitability of natural and synthetic smectite clay matrices as a drug delivery carrier for the development of amorphous solid dispersions (ASD). Indomethacin (IND) was processed with two different smectite clays, natural-magnesium aluminium and synthetic-lithium magnesium sodium silicates, using Hot Melt Extrusion (HME) to prepare solid dispersions. Scanning electron microscopy (SEM), Powdered X-ray diffraction (PXRD), Differential scanning calorimetry (DSC) were used to examine the physical form of the drug. Energy dispersive X-ray spectroscopy (EDX) was used to investigate the drug distribution and Attenuated Total Reflectance-Fourier transform infrared (ATR-FTIR) spectroscopic analysis was done to detect any chemical interaction between these two kinds. Both, PXRD and DSC analysis showed that drug-clay solid dispersion contained IND in amorphous form. Energy dispersive X-ray (EDX) analysis showed a uniform IND dispersion in the extruded powders. ATR-FTIR data presented possible drug and clay interactions via hydrogen bonding. In-vitro drug dissolution studies revealed a lag time of about two hours in the acidic media and a rapid release of IND at pH 7.4. The work demonstrated that preparation of amorphous solid dispersion using inorganic smectite clay particles can effectively increase the dissolution rate of IND.