1,721,008 research outputs found
The revolutionary technology of 3D printing in the pharmaceutical field
Full text linkFrom when the first 3D printing technology was patented, this manufacturing field has grown exponentially developing new techniques and inventing innovative applications. During the last decade, the interest in its usage for pharmaceutical-related purposes raise dramatically.
3D printing has been explored to produce pharmaceutical forms, medical devices, manufacturing devices, and analytical devices.
In this thesis, the results of the research conducted with the application of 3D printing during my PhD programme has been presented.
As medical device, we were able to efficiently produce a 3D printed intravaginal ring loaded with clotrimazole. This ring showed a sustained release and an efficient killing activity against C. Albicans, the pathogen causing vaginal candidiasis.
Then, as manufacturing devices, we developed 3D printed microfluidic devices firstly using polylactic acid and then polypropylene. Using them, we manufactured lipid and polymer-based nanocarriers in a controllable and tunable manner encapsulating glycyrrhetinic acid, and cannabidiol. These devices resulted resistant to the manufacturing process with a very lower overall cost compared to commercially available microfluidic systems and with the possibility of quick personalization based on the user needs.
Finally, as analytical device, we developed a 3D printed vertical diffusion cell or Franz cell that can be efficiently used instead of glass ones to evaluate drug release and/or permeation.
This thesis provides new insights on the use of 3D printing for pharmaceutical applications, supporting the idea that in the close future 3D printing will be used for the formulation of personalized medicines in pharmacies and that this technology will help the diffusion of personalized and low-cost manufacturing and analytical devices in research laboratories
Nasal vaccination against SARS-CoV-2: Synergistic or alternative to intramuscular vaccines?
Full text linkIt is striking that all marketed SARS-CoV-2 vaccines are developed for intramuscular administration designed to produce humoral and cell mediated immune responses, preventing viremia and the COVID-19 syndrome. They have a high degree of efficacy in humans (70-95%) depending on the type of vaccine. However, little protection is provided against viral replication and shedding in the upper airways due to the lack of a local sIgA immune response, indicating a risk of transmission of virus from vaccinated individuals. A range of novel nasal COVID-19 vaccines are in development and preclinical results in non-human primates have shown a promising prevention of replication and shedding of virus due to the induction of mucosal immune response (sIgA) in upper and lower respiratory tracts as well as robust systemic and humoral immune responses. Whether these results will translate to humans remains to be clarified. An IM prime followed by an IN booster vaccination would likely result in a better well-rounded immune response, including prevention (or strong reduction) in viral replication in the upper and lower respiratory tracts
3D printed clotrimazole intravaginal ring for the treatment of recurrent vaginal candidiasis
Full text linkVulvovaginal candidiasis is a vaginal infection caused by the fungal pathogen Candida albicans that, most commonly, affects women of reproductive age. Its first-line treatment consists in topical applications of conventional drug formulations (e.g., creams, gels, tablets) containing imidazole drugs. The treatment involves single or multiple daily applications and, in the case of recurrences, daily administration of oral antifungal drugs for up to one month. Intravaginal rings are flexible, biocompatible medical devices that, compared to conventional drug formulations, offer the possibility of a controlled vaginal drug delivery over a determined period with a single application, thus increasing patient compliance. Among innovative manufacturing techniques, in recent years, fused deposition modeling 3D printing has emerged in the pharmaceutical field to produce different therapeutics combining drugs and polymers. This technique allows to print objects layer by layer with many different thermoplastic materials after a computer-assisted design. Thermoplastic polyurethanes are flexible and biocompatible materials that can be efficiently employed for the manufacturing of drug release systems, already utilized to prepare vaginal devices. In this work, we produced a clotrimazole-loaded intravaginal ring by fused deposition modeling 3D printing combining the drug with thermoplastic polyurethane using hot melt extrusion. The rings were computer-designed and then printed with two different drug concentrations (i.e., 2% and 10% w/w). The intravaginal rings were first tested in an agar-diffusion test to evaluate their effectiveness against C. albicans; and the 10% loaded ring was selected for further studies. Drug release was evaluated in two different media (i.e., 50% ethanol and vaginal fluid simulant) showing a sustained release over a period of seven days. Next, in vitro time-kill analysis against C. albicans in simulated vaginal fluid was performed and displayed a complete growth inhibition after 5 days, compared to the control. These results suggest a potential application of these 3D printed intravaginal rings for the treatment of vulvovaginal candidiasis and for the long-time treatment of recurrences
An easy 3D printing approach to manufacture vertical diffusion cells for in vitro release and permeation studies
Full text linkVertical diffusion cells are commonly used in the pharmaceutical and cosmetic fields to study the release and permeation of active ingredients through synthetic or biological membranes. Nevertheless, the commercially available glass-based systems are expensive and need to be carefully handled due to their fragility. Fused deposition modeling 3D printing is an additive manufacturing technique that allows producing objects layer by layer using different thermoplastic materials. Among them, polypropylene is a robust, flexible, and chemically inert polymer that can resist to many organic solvents. In this work, we designed and printed a vertical diffusion cell following pharmacopeia requirements by using polypropylene in a fused deposition modeling 3D printer. To keep the system thermostated, the developed model fits in a heating block to avoid the use of water recirculating system. The vertical diffusion cells were leak-free and presented chemical resistance and no interaction with model molecules (i.e., caffeine, diclofenac sodium, and glycyrrhetinic acid). The 3D printed cells were compared to commercially available glass cells and then two different types of synthetic membranes (i.e., PDMS and Strat-M®) were used to evaluate the permeation of a caffeine hydrogel. The developed 3D printed testing system could represent an efficient alternative to the glass-based equipment
Microfluidic production of protein loaded chimeric stealth liposomes
No full textThe addition of polyethylene glycol (PEG) on the surface of liposomes increases their circulation time when administered intravenously. However, the inclusion of PEG using PEGylated phospholipids could result in a possible micelles formation. The development of chimeric systems mixing synthetic biocompatible and biodegradable PEG-containing copolymers with lipids is a strategy to obtain as well PEGylated liposomes. Microfluidics is an innovative manufacturing technology easy to scale up that presents high reproducibility, low batch-to-batch variation, and better control over particles characteristics. Taking advantage of this technique, in this research work, chimeric stealth liposomes were produced mixing five different synthesized methoxy-poly(ethylene glycol)-block-poly(δ-decalactone) (mPEG-PDL, varying in polymer length) with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and cholesterol. The obtained chimeric formulations were around 150 nm in size with a narrow distribution and an almost neutral surface charge. Ovalbumin (OVA) was used as a model protein to evaluate the loading potential reaching an encapsulation efficiency of 41±4 %. The prepared systems showed no cytotoxicity in vitro on THP-1 cell with an uptake up to 89±4 % after 3 h. Finally, protein integrity after encapsulation was confirmed with DQ-OVA. In this work, we demonstrated that using microfluidics, it is possible to produce stable and highly protein-loaded chimeric stealth liposomes with good physicochemical characteristics, no toxicity, protein integrity, and effective uptake by endocytosis
Poly(3-hydroxybutyrate): A potential biodegradable excipient for direct 3D printing of pharmaceuticals
Full text linkDuring the past decades, 3D printing has revolutionised different areas of research. Despite the considerable progress achieved in 3D printing of pharmaceuticals, the limited choice of suitable materials remains a challenge to overcome. The growing search for sustainable excipients has led to an increasing interest in biopolymers. Poly(3-hydroxybutyrate) (PHB) is a biocompatible and biodegradable biopolymer obtained from bacteria that could be efficiently employed in the pharmaceutical field. Here we aimed to demonstrate its potential application as a thermoplastic material for personalised medicine through 3D printing. More specifically, we processed PHB by using direct powder extrusion, a one-step additive manufacturing technique. To assess and denote the feasibility and versatility of the process, a 3D square model was manufactured in different dimensions (sidexheight: 12x2 mm; 18x2 mm; 24x2 mm) and loaded with increasing percentages of a model drug (up to 30% w/w). The manufacturing process was influenced by the drug content, and indeed, an increase in the amount of the drug determined a reduction in the printing temperature, without affecting the other parameters (such as the layer height). The composition of the model squares was investigated using Fourier-transform infrared spectroscopy, the resulting spectra confirmed that the starting materials were successfully incorporated into the final formulations. The thermal behaviour of the printed systems was characterized by differential scanning calorimetry, and thermal gravimetric analysis. Moreover, the sustained drug release profile of the formulations was performed over 21 days and showed to be dependent on the dimensions of the printed object and on the amount of loaded drug. Indeed, the formulation with 30% w/w in the dimension 24x2 mm released the highest amount of drug. Hence, the results suggested that PHB and direct powder extrusion technique could be promising tools for the manufacturing of prolonged release and personalised drug delivery forms
Fascinating strategies of marine benthic organisms to cope with emerging pollutant: Titanium dioxide nanoparticles
No full text: Titanium dioxide nanoparticles (NPs) have numerous applications, and their demands have increased as an alternative for banned sunscreen filters. However, the underlying mechanisms of their toxicity, remain largely unknown. Here, we investigate the mechanism of TiO2 NP cytotoxicity and detoxification through time-course experiments (1, 6, and 24 h) based on cellular observations and single-cell transcriptome analyses in a marine benthic foraminifer strain, derived from a common unicellular eukaryotic organism worldwide. After exposure for 1 h, cells enhanced the production of reactive oxygen species (ROS) in acidic endosomes containing TiO2 NPs as well as in mitochondria. In acidic endosomes, ROS were produced through the Fenton reaction on the surface of charged TiO2 NPs. In mitochondria, ROS were associated with porphyrin synthesis that chelated metal ions. Glutathione peroxide and neutral lipids acted as a sink for free radicals, whereas lipid peroxides were excreted to prevent further radical chain reactions. By 24 h, aggregated TiO2 NPs were encapsulated in organic compounds, possibly ceramide, and excreted as mucus, thereby preventing their further uptake. Thus, we reveal that foraminifers can tolerate the toxicity of TiO2 NPs and even prevent their further phagocytosis and uptake by trapping TiO2 NPs inside mucus. This previously unknown strategy could be applied in bioremediation to sequester NPs from the marine environment and can guide management of TiO2 pollution
3D-printed microfluidic chip for the preparation of glycyrrhetinic acid-loaded ethanolic liposomes
No full text18-α-Glycyrrhetinic acid (GA) is a bioactive compound extracted from licorice that exhibits many biological and pharmacological effects such as anti-inflammatory and antioxidant activities on the skin. However, its lipophilic nature results in poor bioavailability that limits clinical applications. Liposomes, presenting the ability to carry both hydrophobic and hydrophilic payloads and a good cytocompatibility, are effective to overcome this barrier. Furthermore, the addition of permeation enhancers such as ethanol into liposomal formulations helps the diffusion of these systems through the skin barrier. Here, we aimed to formulate GA-loaded ethanolic liposomes, using a natural soybean lecithin via a microfluidic approach. Using an FDM 3D printer we customized a microfluidic chip, and manufactured vesicles that presented spherical shape with a size of 202±5.2 nm, a good size distribution and good stability over a period of 30 days. After reaching a drug encapsulation efficiency of 63.15±2.2%, liposomes were evaluated for their cytocompatibility and skin permeation potentiality after hydrogelation using xanthan gum. The in vitro release and permeation studies were performed using Franz diffusion cells comparing two different media and three synthetic membranes including a polymeric skin-mimicking membrane. The selected formulation presented no cytotoxicity and an increased permeation compared to GA saturated hydrogel. It could perform therapeutically better effects than conventional formulations containing free GA, as prolonged and controlled release topical dosage form, which may lead to improved efficiency and better patient compliance
Microfluidics for nanomedicines manufacturing: An affordable and low-cost 3D printing approach
Full text linkDuring the last decade, an innovative lab on a chip technology known as microfluidics became popular in the pharmaceutical field to produce nanomedicines in a scalable way. Nevertheless, the predominant barriers for new microfluidics users are access to expensive equipment and device fabrication expertise. 3D printing technology promises to be an enabling new field that helps to overcome these drawbacks expanding the realm of microfluidics. Among 3D printing techniques, fused deposition modeling allows the production of devices with relatively inexpensive materials and printers. In this work, we developed two different microfluidic chips designed to obtain a passive micromixing by a "zigzag" bas-relief and by the presence of "split and recombine" channels. Computational fluid dynamics studies improved the evaluation of the mixing potential. A fused deposition modeling 3D printer was used to print the developed devices with polypropylene as manufacturing material. Then, two different model nanocarriers (i.e., polymeric nanoparticles and liposomes), loading cannabidiol as model drug, were formulated evaluating the influence of manufacturing parameters on the final nanocarrier characteristics with a design of experiments approach (2-level full factorial design). Both the chips showed an effective production of nanocarriers with tunable characteristics and with an efficient drug loading. These polypropylene-based microfluidic chips could represent an affordable and low-cost alternative to common microfluidic devices for the effective manufacturing of nanomedicines (both polymer- and lipid-based) after appropriate tuning of manufacturing parameters
Optimized microfluidic blow spinning process for single-step manufacturing of crosslinked chitosan nanofilaments using a quality-by-design approach
Full text linkNanofibrous patches composed of chitosan (CS) present promising solutions for wound healing by supporting cell growth and enabling controlled drug release. This study introduces a new single-step microfluidic blow-spinning process that blends CS with polyethylene oxide (PEO) and crosslinks it with tripolyphosphate (TPP) using a series of laminar flow chips integrated into a blow-spinning apparatus. The microfluidic mixing between PEO and CS solutions at different concentrations was simulated with computational fluid dynamics (CFD). This manufacturing process was optimized through a Design of Experiment Approach (DOE) consisting of a 24 full-level screening design followed by a Box-Behnken optimization design. Design spaces correlating the CS concentration, the flow rate ratio between TPP solution and CS/PEO solution, and the air pressure with the filaments' mean diameter, diameter distribution, and deposition time were defined." These design spaces were used to select the process conditions suitable to obtain filaments with a mean diameter of 295 nm, a diameter distribution width approaching 150 nm, and a deposition time higher than 30 min. The good agreement between the predicted and experimental properties validated the design spaces. The crosslinked sample presented a higher water stability than the uncrosslinked one, retaining the fibrous structure with a swelling ratio of 470 ± 60 %. The cytotoxicity test on HaCaT keratinocyte cells showed no significant reduction in cell viability or protein content, confirming the patch's safety and compatibility for biomedical applications
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