Controlling Microparticle Morphology in Melt-Jet Printing of Active Pharmaceutical Ingredients through Surface Phenomena.

Achieving homogeneity and reproducibility in the size, shape, and morphology of active pharmaceutical ingredient (API) particles is crucial for their successful manufacturing and performance. Herein, we describe a new method for API particle engineering using melt-jet printing technology as an alternative to the current solvent-based particle engineering methods. Paracetamol, a widely used API, was melted and jetted as droplets onto various surfaces to solidify and form microparticles. The influence of different surfaces (glass, aluminum, polytetrafluoroethylene, and polyethylene) on particle shape was investigated, revealing a correlation between substrate properties (heat conduction, surface energy, and roughness) and particle sphericity. Higher thermal conductivity, surface roughness, and decreased surface energy contributed to larger contact angles and increased sphericity, reaching a near-perfect micro-spherical shape on an aluminum substrate. The integrity and polymorphic form of the printed particles were confirmed through differential scanning calorimetry and X-ray diffraction. Additionally, high-performance liquid chromatography analysis revealed minimal degradation products. The applicability of the printing process to other APIs was demonstrated by printing carbamazepine and indomethacin on aluminum surfaces, resulting in spherical microparticles. This study emphasizes the potential of melt-jet printing as a promising approach for the precise engineering of pharmaceutical particles, enabling effective control over their physiochemical properties.

Full-Spectrum Cannabis Extract Microdepots Support Controlled Release of Multiple Phytocannabinoids for Extended Therapeutic Effect.

The therapeutic effect of the Cannabis plant largely depends on the presence and specific ratio of a spectrum of phytocannabinoids. Although prescription of medicinal Cannabis for various conditions constantly grows, its consumption is mostly limited to oral or respiratory pathways, impeding its duration of action, bioavailability, and efficacy. Herein, a long-acting formulation in the form of melt-printed polymeric microdepots for full-spectrum cannabidiol (CBD)-rich extract administration is described. When injected subcutaneously in mice, the microdepots facilitate sustained release of the encapsulated extract over a two-week period. The prolonged delivery results in elevated serum levels of multiple, major and minor, phytocannabinoids for over 14 days, compared to Cannabis extract injection. A direct analysis of the microdepots retrieved from the injection site gives rise to an empirical model for the release kinetics of the phytocannabinoids as a function of their physical traits. As a proof of concept, we compare the long-term efficacy of a single administration of the microdepots to a single administration of Cannabis extract in a pentylenetetrazol-induced convulsion model. One week following administration, the microdepots reduce the incidence of tonic-clonic seizures by 40%, increase the survival rate by 50%, and the latency to first tonic-clonic seizures by 170%. These results suggest that a long-term full-spectrum Cannabis delivery system may provide new form of Cannabis administration and treatments.

SPHRINT - Printing Drug Delivery Microspheres from Polymeric Melts.

This paper describes a simple, straightforward, and rapid method for producing microspheres from molten polymers by merely printing them in an inkjet-like manner onto a superoleophobic surface (microsphere printing, hence SPHRINT). Similar to 3D printing, a polymer melt is deposited onto a surface; however, in contrast to 2D or 3D printing, the surface is not wetted (i.e. exhibiting high contact angles with liquids, above 150°, due to its low surface energy), resulting in the formation of discrete spherical microspheres. In this study, microspheres were printed using polycaprolactone and poly(lactic-co-glycolic acid) loaded with a model active pharmaceutical ingredient-ibuprofen (IBU). The formation of microspheres was captured by high-speed imaging and was found to involve several physical phenomena characterized by non-dimensional numbers, including the thinning and breakup of highly viscous, weakly elastic filaments, which are first to be described in pure polymer melts. The resulting IBU-loaded microspheres had higher sphericity, reproducible sizes and shapes, and superior drug encapsulation efficiencies with a distinctly high process yield (>95%) as compared to the conservative solvent-based methods used presently. Furthermore, the microspheres showed sustained release profiles.

Bioactive Agarose Carbon-Nanotube Composites are Capable of Manipulating Brain-Implant Interface.

Composite electrodes made of the polysaccharide agarose and carbon nanotube fibers (A-CNE) have shown potential to be applied as tissue-compatible, micro-electronic devices. In the present work, A-CNEs were functionalized using neuro-relevant proteins (laminin and alpha-melanocyte stimulating hormone) and implanted in brain tissue for 1 week (acute response) and 4 weeks (chronic response). Qualitative and quantitative analysis of neuronal and immunological responses revealed significant changes in immunological response to implanted materials depending on the type of biomolecule used. The potential to manipulate tissue response through the use of an anti-inflammatory protein, alpha-melanocyte stimulating hormone, was shown in the reduction of astroglia presence near the implant site during the glial scar formation. These results suggest that A-CNEs, which are soft, flexible, and easily made bioactive, have the ability to modify brain tissue response through surface modification as a function of the biomolecule used.

Molecular design and evaluation of biodegradable polymers using a statistical approach.

The challenging paradigm of bioresorbable polymers, whether in drug delivery or tissue engineering, states that a fine-tuning of the interplay between polymer properties (e.g., thermal, degradation), and the degree of cell/tissue replacement and remodeling is required. In this paper we describe how changes in the molecular architecture of a series of terpolymers allow for the design of polymers with varying glass transition temperatures and degradation rates. The effect of each component in the terpolymers is quantified via design of experiment (DoE) analysis. A linear relationship between terpolymer components and resulting Tg (ranging from 34 to 86 °C) was demonstrated. These findings were further supported with mass-per-flexible-bond analysis. The effect of terpolymer composition on the in vitro degradation of these polymers revealed molecular weight loss ranging from 20 to 60 % within the first 24 h. DoE modeling further illustrated the linear (but reciprocal) relationship between structure elements and degradation for these polymers. Thus, we describe a simple technique to provide insight into the structure property relationship of degradable polymers, specifically applied using a new family of tyrosine-derived polycarbonates, allowing for optimal design of materials for specific applications.

Biohybrid Carbon Nanotube/Agarose Fibers for Neural Tissue Engineering.

We report a novel approach for producing carbon nanotube fibers (CNF) composed with the polysaccharide agarose. Current attempts to make CNF's require the use of a polymer or precipitating agent in the coagulating bath that may have negative effects in biomedical applications. We show that by taking advantage of the gelation properties of agarose one can substitute the bath with distilled water or ethanol and hence reduce the complexity associated with alternating the bath components or the use of organic solvents. We also demonstrate that these CNF can be chemically functionalized to express biological moieties through available free hydroxyl groups in agarose. We corroborate that agarose CNF are not only conductive and nontoxic, but their functionalization can facilitate cell attachment and response both in vitro and in vivo. Our findings suggest that agarose/CNT hybrid materials are excellent candidates for applications involving neural tissue engineering and biointerfacing with the nervous system.

Computational modeling of in vitro biological responses on polymethacrylate surfaces.

The objective of this research was to examine the capabilities of QSPR (Quantitative Structure Property Relationship) modeling to predict specific biological responses (fibrinogen adsorption, cell attachment and cell proliferation index) on thin films of different polymethacrylates. Using 33 commercially available monomers it is theoretically possible to construct a library of over 40,000 distinct polymer compositions. A subset of these polymers were synthesized and solvent cast surfaces were prepared in 96 well plates for the measurement of fibrinogen adsorption. NIH 3T3 cell attachment and proliferation index were measured on spin coated thin films of these polymers. Based on the experimental results of these polymers, separate models were built for homo-, co-, and terpolymers in the library with good correlation between experiment and predicted values. The ability to predict biological responses by simple QSPR models for large numbers of polymers has important implications in designing biomaterials for specific biological or medical applications.

The fate of ultrafast degrading polymeric implants in the brain.

We have recently reported on an ultrafast degrading tyrosine-derived terpolymer that degrades and resorbs within hours, and is suitable for use in cortical neural prosthetic applications. Here we further characterize this polymer, and describe a new tyrosine-derived fast degrading terpolymer in which the poly(ethylene glycol) (PEG) is replaced by poly(trimethylene carbonate) (PTMC). This PTMC containing terpolymer showed similar degradation characteristics but its resorption was negligible in the same period. Thus, changes in the polymer chemistry allowed for the development of two ultrafast degrading polymers with distinct difference in resorption properties. The in vivo tissue response to both polymers used as intraparenchymal cortical devices was compared to poly(lactic-co-glycolic acid) (PLGA). Slow resorbing, indwelling implant resulted in continuous glial activation and loss of neural tissue. In contrast, the fast degrading tyrosine-derived terpolymer that is also fast resorbing, significantly reduced both the glial response in the implantation site and the neuronal exclusion zone. Such polymers allow for brain tissue recovery, thus render them suitable for neural interfacing applications.