Development of a simple paste for 3D printing of drug formulations containing a mesoporous material loaded with a poorly water-soluble drug.

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.

Combinatorial 3D printed dosage forms for a two-step and controlled drug release.

Fused deposition modeling (FDM) and selective laser sintering (SLS) are two of the most employed additive manufacturing (AM) techniques within the pharmaceutical research field. Despite the numerous advantages of different AM methods, their respective drawbacks have yet to be fully addressed, and therefore combinatorial systems are starting to emerge. In the present study, hybrid systems comprising SLS inserts and a two-compartment FDM shell are developed to achieve controlled release of the model drug theophylline. Via the use of SLS a partial amorphization of the drug is demonstrated, which can be advantageous in the case of poorly soluble drugs, and it is shown that sintering parameters can regulate the dosage and release kinetics of the drug from the inserts. Furthermore, via different combinations of inserts within the FDM-printed shell, various drug release patterns, such as a two-step or prolonged release, can be achieved. The study serves as a proof of concept, highlighting the advantages of combining two AM techniques, both to overcome their respective shortcomings and to develop modular and highly tunable drug delivery devices.

Processability of mesoporous materials in fused deposition modeling for drug delivery of a model thermolabile drug.

The incorporation of drug-loaded mesoporous materials in dosage forms prepared with fused deposition modeling (FDM) has shown the potential to solve challenges relating to additive manufacturing techniques, such as the stability of poorly-soluble drugs in the amorphous state. However, the addition of these non-melting mesoporous materials significantly affects the mechanical properties of the filament used in FDM, which in turn affects the printability of the feedstock material. Therefore, in this study a full-factorial experimental design was utilized to investigate different processing parameters of the hot melt extrusion process, their effect on various mechanical properties and the potential correlation with the filaments' printability. The thermolabile, poorly-soluble drug ibuprofen was utilized as a model drug to assess the potential of two mesoporous materials, Mesoporous Magnesium Carbonate (MMC) and a silica-based material (MCM-41), to thermally protect the loaded drug. Factorial and principal components analysis displayed a correlation between non-printable MCM-41 filaments and their mechanical properties where printable filaments had a maximum stress >7.5 MPa and a Young's modulus >83 MPa. For MMC samples there was no clear correlation, which was in large part attributed to the filaments' inconsistencies and imperfections. Finally, both mesoporous materials displayed a thermal protective feature, as the decomposition due to the thermal degradation of a significant portion of the thermolabile drug was shifted to higher temperatures post-loading. This highlights the potential capability of such a system to be implemented for thermosensitive drugs in FDM applications.

Bioactive Silicon Nitride Implant Surfaces with Maintained Antibacterial Properties.

Silicon nitride (Si3N4) is a promising biomaterial, currently used in spinal fusion implants. Such implants should result in high vertebral union rates without major complications. However, pseudarthrosis remains an important complication that could lead to a need for implant replacement. Making silicon nitride implants more bioactive could lead to higher fusion rates, and reduce the incidence of pseudarthrosis. In this study, it was hypothesized that creating a highly negatively charged Si3N4 surface would enhance its bioactivity without affecting the antibacterial nature of the material. To this end, samples were thermally, chemically, and thermochemically treated. Apatite formation was examined for a 21-day immersion period as an in-vitro estimate of bioactivity. Staphylococcus aureus bacteria were inoculated on the surface of the samples, and their viability was investigated. It was found that the thermochemically and chemically treated samples exhibited enhanced bioactivity, as demonstrated by the increased spontaneous formation of apatite on their surface. All modified samples showed a reduction in the bacterial population; however, no statistically significant differences were noticed between groups. This study successfully demonstrated a simple method to improve the in vitro bioactivity of Si3N4 implants while maintaining the bacteriostatic properties.

3D-Printed Mesoporous Carrier System for Delivery of Poorly Soluble Drugs.

Fused deposition modelling (FDM) is the most extensively employed 3D-printing technique used in pharmaceutical applications, and offers fast and facile formulation development of personalized dosage forms. In the present study, mesoporous materials were incorporated into a thermoplastic filament produced via hot-melt extrusion and used to produce oral dosage forms via FDM. Mesoporous materials are known to be highly effective for the amorphization and stabilization of poorly soluble drugs, and were therefore studied in order to determine their ability to enhance the drug-release properties in 3D-printed tablets. Celecoxib was selected as the model poorly soluble drug, and was loaded into mesoporous silica (MCM-41) or mesoporous magnesium carbonate. In vitro drug release tests showed that the printed tablets produced up to 3.6 and 1.5 times higher drug concentrations, and up to 4.4 and 1.9 times higher release percentages, compared to the crystalline drug or the corresponding plain drug-loaded mesoporous materials, respectively. This novel approach utilizing drug-loaded mesoporous materials in a printed tablet via FDM shows great promise in achieving personalized oral dosage forms for poorly soluble drugs.

Combined Catalysis for Engineering Bioinspired, Lignin-Based, Long-Lasting, Adhesive, Self-Mending, Antimicrobial Hydrogels.

The engineering of multifunctional biomaterials using a facile sustainable methodology that follows the principles of green chemistry is still largely unexplored but would be very beneficial to the world. Here, the employment of catalytic reactions in combination with biomass-derived starting materials in the design of biomaterials would promote the development of eco-friendly technologies and sustainable materials. Herein, we disclose the combination of two catalytic cycles (combined catalysis) comprising oxidative decarboxylation and quinone-catechol redox catalysis for engineering lignin-based multifunctional antimicrobial hydrogels. The bioinspired design mimics the catechol chemistry employed by marine mussels in nature. The resultant multifunctional sustainable hydrogels (1) are robust and elastic, (2) have strong antimicrobial activity, (3) are adhesive to skin tissue and various other surfaces, and (4) are able to self-mend. A systematic characterization was carried out to fully elucidate and understand the facile and efficient catalytic strategy and the subsequent multifunctional materials. Electron paramagnetic resonance analysis confirmed the long-lasting quinone-catechol redox environment within the hydrogel system. Initial in vitro biocompatibility studies demonstrated the low toxicity of the hydrogels. This proof-of-concept strategy could be developed into an important technological platform for the eco-friendly, bioinspired design of other multifunctional hydrogels and their use in various biomedical and flexible electronic applications.

Multifunctional Polymer-Free Mineral Plastic Adhesives Formed by Multiple Noncovalent Bonds.

Supramolecular adhesives have attracted a great deal of attention in recent years, resulting in their development for different applications. However, creating supramolecular adhesives with reversible and reusable properties is still a challenge. Here, a synthesis route to obtain supramolecular adhesives is presented in which no polymeric compounds are involved in the preparation. The adhesive is formed by intermolecular coulomb forces between amorphous magnesium carbonate nanoparticles and the low-molecular-weight drug ibuprofen, which results in an amorphous composite material that is transparent, shapeable, stretchable, and self-healing, making it reusable. It is demonstrated that this hybrid material provides a simple means of gluing a wide variety of materials, including metals, glass, paper, and plastics, and that is reversible and possesses reusability. The material disrupts the traditional concept of polymer-based adhesives and may be used as a sustainable mineral plastic in applications such as 3D printing.

Thromboinflammation as bioactivity assessment of H2O2-alkali modified titanium surfaces.

The release of growth factors from platelets, mediated by the coagulation and the complement system, plays an important role in the bone formation around implants. This study aimed at exploring the thromboinflammatory response of H2O2-alkali soaked commercially pure titanium grade 2 discs exposed to whole human blood, as a way to assess the bioactivity of the discs. Commercially pure titanium grade 2 discs were modified by soaking in H2O2, NaOH and Ca(OH)2. The platelet aggregation, coagulation activation and complement activation was assessed by exposing the discs to fresh whole blood from human donors. The platelet aggregation was examined by a cell counter and the coagulation and complement activation were assessed by ELISA-measurements of the concentration of thrombin-antithrombin complex, C3a and terminal complement complex. The modified surface showed a statistically significant increased platelet aggregation, coagulation activation and complement activation compared to unexposed blood. The surface also showed a statistically significant increase of coagulation activation compared to PVC. The results of this study showed that the H2O2-alkali soaked surfaces induced a thromboinflammatory response that indicates that the surfaces are bioactive.

Titanium surface modification to enhance antibacterial and bioactive properties while retaining biocompatibility.

Bacterial infections associated with metal implants are severe problems affecting a considerable amount of people with dental or orthopedic implants. This study aims to examine the antibacterial effect of a Titanium-peroxy gel layer on the modified surface of commercially pure titanium grade 2. Variations in a multi-step surface modification procedure were tested to determine the best combination that provided an antibacterial effect while enhancing bioactivity without compromising biocompatibility. Soaking the surfaces in 30 wt% hydrogen peroxide held at 80 °C provided antibacterial activity while subsequent surface treatments in concentrated sodium and calcium hydroxide solutions were preformed to enhance bioactivity. Staphylococcus epidermidis was used to determine the antibacterial effect through both direct contact and biofilm inhibition tests while human dermal fibroblast cells and MC3T3 pre osteoblast cells were utilized to test biocompatibility. The greatest antibacterial effect was observed with only hydrogen peroxide treatment, but the resulting surface was neither bioactive nor biocompatible. It was found that subsequent surface treatments with sodium hydroxide followed by calcium hydroxide provided a bioactive surface that was also biocompatible. Additionally, a final treatment with autoclaving showed positive effects with regards to enhanced bioactivity. This multi-step surface modification procedure offers a promising, non-antibiotic, solution for combatting infections associated with biomedical implants.

Debridement of Bacterial Biofilms with TiO2/H2O2 Solutions and Visible Light Irradiation.

OBJECTIVES: The aim of the study was to explore the debridement efficacy of different solutions of H2O2 and rutile particles against Staphylococcus epidermidis and Pseudomonas aeruginosa biofilms attached to titanium surfaces when exposed to visible light. MATERIALS AND METHODS: Titanium discs cultivated with biofilms of Staphylococcus epidermidis or Pseudomonas aeruginosa were subjected for 1 min to suspensions consisting of rutile particles mixed with high (950 mM) or low (2 mM) concentrations of H2O2 under visible light irradiation (405 nm; 2.1 mW/cm2). Discs were rinsed and the degree of debridement was determined through scanning electron microscopy and viability assessment of the remaining bacteria using luminescence measurements and/or a metabolic activity assay. RESULTS: Cleaning mixtures containing the higher concentration of H2O2 showed a significantly improved debridement compared to the negative control in all experiments. The addition of rutile particles was shown to have a statistically significant effect in one test with S. epidermidis. Limited evidence of the catalytic effect of visible light irradiation was seen, but effects were relatively small and statistically insignificant. CONCLUSIONS: H2O2 at a concentration of 950 mM proved to be the strongest contribution to the debridement and bactericidal effect of the cleaning techniques tested in this study.

Amorphous magnesium carbonate nanoparticles with strong stabilizing capability for amorphous ibuprofen.

Formulating active pharmaceutical ingredients (APIs) in the amorphous state can increase their apparent aqueous solubility and dissolution rate and consequently improve their bioavailability. This study demonstrates, for the first time, the ability to stabilize an API in the amorphous state using a solid dispersion of magnesium carbonate nanoparticles within the API. Specifically, high proportions of ibuprofen were able to be stabilized in the amorphous state using as little as 17% wt/wt amorphous magnesium carbonate nanoparticles, and drug release rates 83 times faster than from the crystalline state were achieved. Biocompatibility of the nanoparticles was demonstrated in vitro using human dermal fibroblasts and stability of the nanocomposite formulation was verified with a storage time of six months. The success of this novel formulation provides a promising approach for achieving improved apparent solubility and enhanced bioavailability of drugs.

Ion-crosslinked wood-derived nanocellulose hydrogels with tunable antibacterial properties: Candidate materials for advanced wound care applications.

Development of advanced dressings with antimicrobial properties for the treatment of infected wounds is an important approach in the fight against evolution of antibiotic resistant bacterial strains. Herein, the effects of ion-crosslinked nanocellulose hydrogels on bacteria commonly found in infected wounds were investigated in vitro. By using divalent calcium or copper ions as crosslinking agents, different antibacterial properties against the bacterial strains Staphylococcus epidermidis and Pseudomonas aeruginosa were obtained. Calcium crosslinked hydrogels were found to retard S. epidermidis growth (up to 266% increase in lag time, 36% increase in doubling time) and inhibited P. aeruginosa biofilm formation, while copper crosslinked hydrogels prevented S. epidermidis growth and were bacteriostatic towards P. aeruginosa (49% increase in lag time, 78% increase in doubling time). The wound dressing candidates furthermore displayed barrier properties towards both S. epidermidis and P. aeruginosa, hence making them interesting for further development of advanced wound dressings with tunable antibacterial properties.

Organic degradation potential of a TiO2/H2O2/UV-vis system for dental applications.

OBJECTIVES: The combination of TiO2 and H2O2 under light activation constitutes a promising method for disinfection of dental prosthetics and implants, due to production of reactive oxygen species (ROS). The aim of this work was to investigate the organic degradation ability of TiO2 particles in combination with H2O2 and under light activation utilizing the organic dye rhodamine B (RhB). METHODS: Five different types of TiO2 particles, consisting of anatase, rutile, or a mixture of these crystalline phases, were combined with H2O2 and RhB, and subsequently exposed to UV (365nm) or visible (405nm) light at an irradiance of 2.1mW/cm2. RESULTS: It was found that rutile in combination with low concentrations of H2O2 (1.0-3.5mM) resulted in a degradation of RhB of 96% and 77% after 10min exposure to 365nm and 405nm light, respectively, which was the highest degradation of all test groups. Control measurements performed without light irradiation or irradiation at 470nm, or without TiO2 particles resulted in little or no degradation of RhB. CONCLUSIONS: Low H2O2 concentrations (1.0mM-3.5mM) and visible light (405nm) used in combination with rutile TiO2 particles showed the highest RhB degradation capacity. CLINICAL SIGNIFICANCE: A combination of TiO2 particles and H2O2 exposed to low energy UV or high energy visible light has an organic degradation capability that could be utilized in applications to kill or inactivate bacteria on medical devices such as dental implants for treatment against, e.g., peri-implantitis.

Enhanced release of poorly water-soluble drugs from synergy between mesoporous magnesium carbonate and polymers.

The need to combat poor water solubility has increased interest in supersaturating drug delivery systems. In this study, amorphous mesoporous magnesium carbonate (MMC) was used as a drug carrier to achieve supersaturation of tolfenamic acid and rimonabant, two drug compounds with low aqueous solubility. The potential synergy between MMC and hydroxypropyl methylcellulose (HPMC), a polymer commonly included as a precipitation inhibitor in drug delivery systems, was explored with the aim of extending the time that high supersaturation levels were maintained. Release was studied under physiological conditions using USP-2 dissolution baths. A new small-scale method was developed to enable measurement of the initial drug release occurring when the MMC is immersed in the water phase. It was shown that MMC and HPMC together resulted in significant supersaturation and that the polymer enabled both the achievement of a higher API concentration and extension of the supersaturation period. The new small-scale release method showed that the release was linearly increasing with the dose and that similar release rates were observed for the two model compounds. It was hence concluded that the MMC release was diffusion limited for the compounds explored.

Dynamics of water confined in mesoporous magnesium carbonate.

We have measured the dynamics of water confined in a porous magnesium carbonate material, Upsalite®, using the high-resolution neutron backscattering spectrometer SPHERES. We found quasielastic scattering that does not flatten out up to 360 K, which means that the dynamics of water are much slower than in other matrix materials. Specifically, a single Lorentzian line could be fitted to the quasielastic part of the acquired spectra between 220 and 360 K. This, accompanied by an elastic line from dynamically frozen water present at all experimental temperatures, even above the melting point, signaled a significant amount of bound or slow water.

Supersaturation of poorly soluble drugs induced by mesoporous magnesium carbonate.

This work investigates whether the solubility of poorly soluble compounds can be improved by using mesoporous magnesium carbonate (MMC) as the drug delivery system. A solvent evaporation method was used to load structurally diverse model drugs (celecoxib, cinnarizine and griseofulvin) into the pores of MMC. The drug-loaded carrier system was then characterized in terms of porosity, crystallinity, and release profiles by a variety of experimental techniques, including X-ray diffraction, nitrogen adsorption analysis, differential scanning calorimetry, infrared spectroscopy, UV absorption spectroscopy, and thermogravimetric analysis. All three drugs were in a non-crystalline state after loading into the pores of MMC. The concentrations of the drugs in solution over time (a measure of the release rates from loaded MMC) were higher than the corresponding concentrations (dissolution rates) of equal amounts of the crystalline drugs. The release rates were five (celecoxib), three (cinnarizine) and two times (griseofulvin) higher than the dissolution rates of their crystalline counterparts. Supersaturation release profiles were also observed; the areas under the concentration-time curves (0-240min) were 25- (celecoxib), 5- (cinnarizine) and 2-fold (griseofulvin) greater than those of the crystalline drugs. Hence, MMC shows promise as a general drug delivery vehicle for increasing the bioavailability of compounds with dissolution rate- or solubility-limited absorption.

In vitro antibacterial properties and UV induced response from Staphylococcus epidermidis on Ag/Ti oxide thin films.

Implanted materials are susceptible to bacterial colonization and biofilm formation, which can result in severe infection and lost implant function. UV induced photocatalytic disinfection on TiO2 and release of Ag(+) ions are two promising strategies to combat such events, and can be combined for improved efficiency. In the current study, a combinatorial physical vapor deposition technique was utilized to construct a gradient coating between Ag and Ti oxide, and the coating was evaluated for antibacterial properties in darkness and under UV light against Staphylococcus epidermidis. The findings revealed a potent antibacterial effect in darkness due to Ag(+) release, with near full elimination (97%) of viable bacteria and visible cell lysis on Ag dominated surfaces. The photocatalytic activity, however, was demonstrated poor due to low TiO2 crystallinity, and UV light irradiation of the coating did not contribute to the antibacterial effect. On the contrary, bacterial viability was in several instances higher after UV illumination, proposing a UV induced SOS response from the bacteria that limited the reduction rate during Ag(+) exposure. Such secondary effects should thus be considered in the development of multifunctional coatings that rely on UV activation.

Investigation of the Antibacterial Effect of Mesoporous Magnesium Carbonate.

Mesoporous magnesium carbonate (MMC) was first presented in 2013, and this material is currently under consideration for use in a number of biotechnological applications including topical formulations. This study presents the first evaluation of the antibacterial properties of the material with mesoporous silica and two other magnesium-containing powder materials used as references. All powder materials in this study are sieved to achieve a particle size distribution between 25 and 75 µm. The Gram-positive bacterium Staphylococcus epidermidis is used as the model bacterium due to its prevalence on human skin, its likelihood of developing resistance to antibiotics, for example, from routine exposure to antibiotics secreted in sweat, and because it is found inside affected acne vulgaris pores. Quantification of bacterial viability using a metabolic activity assay with resazurin as the fluorescent indicator shows that MMC exerts a strong antibacterial effect on the bacteria and that alkalinity accounts for the major part of this effect. The results open up for further development of MMC in on-skin applications where bacterial growth inhibition without using antibiotics is deemed favorable.

Reactive combinatorial synthesis and characterization of a gradient Ag-Ti oxide thin film with antibacterial properties.

The growing demand for orthopedic and dental implants has spurred researchers to develop multifunctional coatings, combining tissue integration with antibacterial features. A possible strategy to endow titanium (Ti) with antibacterial properties is by incorporating silver (Ag), but designing a structure with adequate Ag(+) release while maintaining biocompatibility has been shown difficult. To further explore the composition-structure-property relationships between Ag and Ti, and its effects against bacteria, this study utilized a combinatorial approach to manufacture and test a single sample containing a binary Ag-Ti oxide gradient. The sample, sputter-deposited in a reactive (O2) environment using a custom-built combinatorial physical vapor deposition system, was shown to be effective against Staphylococcus aureus with viability reductions ranging from 17 to above 99%, depending on the amount of Ag(+) released from its different parts. The Ag content along the gradient ranged from 35 to 62 wt.%, but it was found that structural properties such as varied porosity and degree of crystallinity, rather than the amount of incorporated Ag, governed the Ag(+) release and resulting antibacterial activity. The coating also demonstrated in vitro apatite-forming abilities, where structural variety along the sample was shown to alter the hydrophilic behavior, with the degree of hydroxyapatite deposition varying accordingly. By means of combinatorial synthesis, a single gradient sample was able to display intricate compositional and structural features affecting its biological response, which would otherwise require a series of coatings. The current findings suggest that future implant coatings incorporating Ag as an antibacterial agent could be structurally enhanced to better suit clinical requirements.