Optimisation of Pharmaceutical Cocrystal Dissolution Performance through a Synergistic Precipitation Inhibition.

OBJECTIVES: Polymeric excipients play an important role in a cocrystal formulation to act as precipitation inhibitors to maximize the potential. Otherwise, a stable form of the parent drug will be recrystallized on the dissolving cocrystal surface and/or in the bulk solution during the cocrystal dissolution process, negating the solubility advantage. The objectives of this work were to investigate the potential of using combined polymers to maximise the dissolution performance of surface precipitation pharmaceutical cocrystals. METHODS: The dissolution performance of a highly soluble flufenamic acid and nicotinamide (FFA-NIC) cocrystal has been systematically studied with predissolved or powder mixed with a single polymer, including a surface precipitation inhibitor [i.e., copolymer of vinylpyrrolidone (60%) /vinyl acetate (40%) (PVP-VA)] and two bulk precipitation inhibitors [i.e., polyethylene glycol (PEG) and Soluplus (SLP)], or binary polymers combinations. RESULTS: A single polymer of PVP-VA prevented the FFA surface precipitation for an enhanced dissolution performance of FFA-NIC cocrystal. Unfortunately, it cannot sustain the supersaturated FFA concentration in the bulk solution. A combination of two polymers of PVP-VA and SLP has shown a synergistic inhibition effect to enhance the dissolution advantage of FFA-NIC cocrystal. CONCLUSIONS: The dissolution of a cocrystal with surface precipitation of the parent drug can be described as: i) the cocrystal surface contacting the dissolution medium; ii) the cocrystal surface dissolving; iii) the parent drug precipitation on the dissolving surface; and iv) the parent drug particles redissolving. A combination of two types of polymers can be used to maximise the cocrystal performance in solution.

A Review of the Benefits 3D Printing Brings to Patients with Neurological Diseases.

This interdisciplinary review focuses on how flexible three-dimensional printing (3DP) technology can aid patients with neurological diseases. It covers a wide variety of current and possible applications ranging from neurosurgery to customizable polypill along with a brief description of the various 3DP techniques. The article goes into detail about how 3DP technology can aid delicate neurosurgical planning and its consequent outcome for patients. It also covers areas such as how the 3DP model can be utilized in patient counseling along with designing specific implants involved in cranioplasty and customization of a specialized instrument such as 3DP optogenetic probes. Furthermore, the review includes how a 3DP nasal cast can contribute to the development of nose-to-brain drug delivery along with looking into how bioprinting could be used for regenerating nerves and how 3D-printed drugs could offer practical benefits to patients suffering from neurological diseases via polypill.

Role of release modifiers to modulate drug release from fused deposition modelling (FDM) 3D printed tablets.

Although hot melt extrusion (HME) has been used in combination with fused deposition modelling (FDM) three-dimensional printing (3DP), suitable feedstock materials such as polymeric filaments with optimum properties are still limited. In this study, various release modifying excipients, namely, poly(vinyl alcohol) (PVA), Soluplus®, polyethylene glycol (PEG) 6000, Eudragit® RL PO/RS PO, hydroxypropyl methylcellulose (HPMC) K4M/E10M/K100M, Kollidon® vinyl acetate 64 (VA 64)/17PF/30, were used as a release modulating tool to control the drug release from 3D printed sustained release tablets. Ibuprofen (as the model drug) and ethyl cellulose (as the polymeric matrix), along with various release modifiers, were blended and extruded into filaments through a twin-screw extruder. Then these filaments were printed into cylindrical tablets through FDM 3DP technique and their surface morphology, thermal stability, solid-state, mechanical properties, dose accuracy and drug release behaviors were investigated. The solid-state analysis of 3D printed tablets exhibited the amorphous nature of the drug dispersed in the polymer matrices. Although all these prepared filaments could be successfully printed without failing during the FDM 3DP process, the mechanical characterization showed that the filament stiffness and brittleness could be adjusted significantly by changing the type of release modifiers. Moreover, in vitro drug release studies revealed that the drug release could simply be controlled over 24 h by only changing the type of release modifiers. All ibuprofen (IBP) loaded 3D printed tablets with ethyl cellulose (EC) matrix, especially with PEG as the release modifier, showed great potential in releasing IBP in a zero-order reaction. In conclusion, all the results illustrated that the HME/FDM approach and optimized formulation compositions can be an attractive option for the development of pharmaceutical tablets and implants where adjustable drug release patterns are necessary.

Magnetic Field Triggerable Macroporous PDMS Sponge Loaded with an Anticancer Drug, 5-Fluorouracil.

This study aims to prepare, optimize, and characterize magnetic-field-sensitive sugar-templated polydimethylsiloxane (PDMS) sponges for localized delivery of an anticancer drug, 5-fluorouracil (FLU). For this purpose, different concentrations of carbonyl iron (CI) and magnetite Fe3O4 nanopowders were embedded as magnetosensitive materials in PDMS resins for the fabrication of macroporous sponges via a sugar-template process. The process is environmentally friendly and simple. The fabricated interconnected macroporous magnetic particles loaded PDMS sponges possess flexible skeletons and good recyclability because of their recoverability after compression (deformation) without any breakdown. The prepared magnetic PDMS sponges were evaluated for their morphology (SEM and EDS), porosity (absorbency), elastic modulus, deformation under a magnetic field, thermostability, and in vitro cell studies. All physicochemical and magnetomechanical analysis confirmed that the optimized magnetic-field-sensitive PDMS sponge can provide an efficient method for delivering an on-demand dose of anticancer drug solutions at a specific location and timing with the aid of controlled magnetic fields.

Novel 3D printed device with integrated macroscale magnetic field triggerable anti-cancer drug delivery system.

With the growing demand for personalized medicine and medical devices, the impact of on-demand triggerable (e.g., via magnetic fields) drug delivery systems increased significantly in recent years. The three-dimensional (3D) printing technology has already been applied in the development of personalized dosage forms because of its high-precision and accurate manufacturing ability. In this study, a novel magnetically triggerable drug delivery device composed of a magnetic polydimethylsiloxane (PDMS) sponge cylinder and a 3D printed reservoir was designed, fabricated and characterized. This system can realize a switch between "on" and "off" state easily through the application of different magnetic fields and from different directions. Active and repeatable control of the localized drug release could be achieved by the utilization of magnetic fields to this device due to the shrinking extent of the macro-porous magnetic sponge inside. The switching "on" state of drug-releasing could be realized by the magnetic bar contacted with the side part of the device because the times at which 50%, 80% and 90% (w/w) of the drug were dissolved are observed to be 20, 55 and 140 min, respectively. In contrast, the switching "off" state of drug-releasing could be realized by the magnetic bar placed at the bottom of the device as only 10% (w/w) of the drug could be released within 12 h. An anti-cancer substance, 5-fluorouracil (FLU), was used as the model drug to illustrate the drug release behaviour of the device under different strengths of magnetic fields applied. In vitro cell culture studies also demonstrated that the stronger the magnetic field applied, the higher the drug release from the deformed PDMS sponge cylinder and thus more obvious inhibition effects on Trex cell growth. All results confirmed that the device can provide a safe, long-term, triggerable and reutilizable way for localized disease treatment such as cancer.

Drop-On-Powder 3D Printing of Tablets with an Anti-Cancer Drug, 5-Fluorouracil.

This study reports the first case of an innovative drop-on-powder (DoP) three-dimensional (3D) printing technology to produce oral tablets (diameters of 10 mm and 13 mm) loaded with an anticancer model drug, 5-fluorouracil (FLU). For this study, a composition of the powder carrier containing CaSO4 hydrates, vinyl polymer, and carbohydrate was used as the matrix former, whereas 2-pyrrolidone with a viscosity like water was used as a binding liquid or inkjet ink. All tablets were printed using a commercial ZCorp 3D printer with modification. The resultant tablets were subject to coating with various polymeric solutions containing the drug. The composition of the polymeric solutions was adjusted at drug: polymer(s) 1:1 (w/w) ratio. Either Soluplus® (SOL) alone or in combination with polyethylene glycol (PEG) was used to develop the coating solution of 2.5% (w/v) concentration. The particle size analysis, flow test, and particle morphology studies revealed mono-modal narrow size distribution, good flow properties, and porous loosely bound texture (of the tablets), respectively. Moreover, the advanced application of the fluorescence microscopy showed a homogenous distribution of the drug throughout the surface of the 3D printed tablets. The in vitro dissolution studies showed that the tablet compositions, dimensions, and the coating solution compositions influenced the release of the drug from the tablets. It can be concluded that our innovative DoP 3D printing technology can be used to fabricate personalized dosage forms containing optimized drug content with high accuracy and shape fidelity. This is particularly suitable for those drugs that are highly unstable in thermal processing and cannot withstand the heat treatment, such as in fused deposition modeling (FDM) 3D printing.

Formulation and in vivo evaluation of orally disintegrating tablets of clozapine/hydroxypropyl-ß-cyclodextrin inclusion complexes.

The aim of this study was to improve the solubility and oral bioavailability of clozapine (CLZ), a poorly water-soluble drug subjected to substantial first-pass metabolism, employing cyclodextrin complexation technique. The inclusion complexes were prepared by an evaporation method. Phase solubility studies, differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy were used to evaluate the complexation of CLZ with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and the formation of true inclusion complexes. Characterization and dissolution studies were carried out to evaluate the orally disintegrating tablets (ODTs) containing CLZ/HP-ß-CD complexes prepared by direct compression. Finally, the bioavailability studies of the prepared ODTs were performed by oral administration to rabbits. The ODTs showed a higher in vitro dissolution rate and bioavailability compared with the commercial tablets. It is evident from the results herein that the developed ODTs provide a promising drug delivery system in drug development, owing to their excellent performance of a rapid onset of action, improved bioavailability, and good patient compliance.