Construction of hollow polydopamine nanoparticle based drug sustainable release system and its application in bone regeneration

Nanomaterial-based drug sustainable release systems have been tentatively applied to bone regeneration. They, however, still face disadvantages of high toxicity, low biocompatibility, and low drug-load capacity. In view of the low toxicity and high biocompatibility of polymer nanomaterials and the excellent load capacity of hollow nanomaterials with high specific surface area, we evaluated the hollow polydopamine nanoparticles (HPDA NPs), in order to find an optimal system to effectively deliver the osteogenic drugs to improve treatment of bone defect. Data demonstrated that the HPDA NPs synthesized herein could efficiently load four types of osteogenic drugs and the drugs can effectively release from the HPDA NPs for a relatively longer time in vitro and in vivo with low toxicity and high biocompatibility. Results of qRT-PCR, ALP, and alizarin red S staining showed that drugs released from the HPDA NPs could promote osteogenic differentiation and proliferation of rat bone marrow mesenchymal stem cells (rBMSCs) in vitro. Image data from micro-CT and H&E staining showed that all four osteogenic drugs released from the HPDA NPs effectively promoted bone regeneration in the defect of tooth extraction fossa in vivo, especially tacrolimus. These results suggest that the HPDA NPs, the biodegradable hollow polymer nanoparticles with high drug load rate and sustainable release ability, have good prospect to treat the bone defect in future clinical practice.

Biorelevant In Vitro Skin Permeation Testing and In Vivo Pharmacokinetic Characterization of Lidocaine from a Nonaqueous Drug-in-Matrix Topical System

Recently, lidocaine topical systems utilizing nonaqueous matrices have been developed and provide efficient lidocaine delivery through the skin, such that lower concentrations of drug provide equivalent or greater drug delivery than drug-in-matrix hydrogel lidocaine patches. This study characterizes drug delivery from a nonaqueous lidocaine topical system with increasing drug load both in vitro and in vivo. Topical systems formulated with either 1.8% or 5.4% lidocaine were applied to healthy volunteers’ backs (n = 15) for 12 h in a single-center, open-label, four-treatment, four-period crossover pharmacokinetic study. Subjects were dosed with either three 1.8% systems or one, two, or three 5.4% systems in each period. Blood was collected for up to 48 h, and plasma lidocaine levels were measured with a validated HPLC method. In parallel, human and mouse skin models characterized the in vitro skin permeation profile. The pharmacokinetic profile was linear between one, two, and three lidocaine 5.4% applications. Application of three lidocaine 1.8% systems (108 mg lidocaine) was bioequivalent to one lidocaine 5.4% system (108 mg lidocaine). Both topical systems remained well adhered to the skin and irritation was mild. The 5.4% system had approximately threefold higher skin permeability than the 1.8% system in the mouse and human skin models. The results indicate increasing the drug load by three times results in triple the drug delivery both in vivo and in vitro. The relationship between the in vitro permeation and in vivo absorption correlates and is nonlinear.

Dissolution profile of Curcumin from solid dispersion prepared at a high drug load of Curcumin using Poloxamer 407 as the carrier

Introduction: Curcumin, a BCS II drug, suffers from poor bioavailability. Increasing curcumin dissolution is a way to increase its bioavailability. Solid dispersion formulation can be used to improve curcumin dissolution. However, the successful curcumin solid dispersion is limited to a relatively low drug load (< 20%). Objective: This study aimed to investigate the dissolution behaviour of curcumin at a higher drug load (27.9%, 42.3%, and 56.6%) using a surfactant carrier of poloxamer 407. Methods: The solvent evaporation method was employed to prepare high drug load solid dispersion of curcumin. A physical mixture of the corresponding solid dispersion formulation was prepared as a control. Drug load, dissolution behaviour in 180 minutes, and dissolution efficiency (DE180) were determined. Results: The results showed that incorporating curcumin into a poloxamer 407 solid dispersion significantly improves the dissolution rate of curcumin. In the solid dispersion formula, the dissolution behaviour of curcumin was found to be carrier-dependent.

Influence of Drug Load on the Printability and Solid-State Properties of 3D-Printed Naproxen-Based Amorphous Solid Dispersion

Fused deposition modelling-based 3D printing of pharmaceutical products is facing challenges like brittleness and printability of the drug-loaded hot-melt extruded filament feedstock and stabilization of the solid-state form of the drug in the final product. The aim of this study was to investigate the influence of the drug load on printability and physical stability. The poor glass former naproxen (NAP) was hot-melt extruded with Kollidon® VA 64 at 10–30% w/w drug load. The extrudates (filaments) were characterised using differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and thermogravimetric analysis (TGA). It was confirmed that an amorphous solid dispersion was formed. A temperature profile was developed based on the results from TGA, DSC, and DMA and temperatures used for 3D printing were selected from the profile. The 3D-printed tablets were characterised using DSC, X-ray computer microtomography (XµCT), and X-ray powder diffraction (XRPD). From the DSC and XRPD analysis, it was found that the drug in the 3D-printed tablets (20 and 30% NAP) was amorphous and remained amorphous after 23 weeks of storage (room temperature (RT), 37% relative humidity (RH)). This shows that adjusting the drug ratio can modulate the brittleness and improve printability without compromising the physical stability of the amorphous solid dispersion.

An Investigation into Mechanical Properties and Printability of Potential Substrates for Inkjet Printing of Orodispersible Films

Inkjet printing is novel approach in drug manufacturing that enables dispensing precise volumes of ink onto substrates. Optimal substrate properties including suitable mechanical characteristic are recognized as crucial to achieve desired dosage form performance upon administration. Identification of relevant quality attributes and their quantification is subject of intensive scientific research. The aim of this work was to explore applicability of different materials as printing substrates and explore contribution of the investigated substrate properties to its printability. Substrates were characterized with regards to uniformity, porosity, disintegration time, mechanical properties and drug dissolution. Experimentally obtained values were mathematically transformed and the obtained results were presented as relevant radar charts. It was shown that structurally different substrates may be employed for orodispersible films inkjet printing. Main disadvantage of single-polymer films was low drug load, and their printability was dependent on film flexibility and mechanical strength. Structured orodispersible film templates exhibited favorable mechanical properties and drug load capacity. Wafer edible sheets were characterized with high mechanical resistance and brittleness which somewhat diminished printability, but did not hinder high drug load. Obtained results provide insight into application of different materials as printing substrates and contribute to understanding of substrate properties which can affect printability.

Affibody-Derived Drug Conjugates Targeting HER2: Effect of Drug Load on Cytotoxicity and Biodistribution

Affibody molecules hold great promise as carriers of cytotoxic drugs for cancer therapy due to their typically high affinity, easy production, and inherent control of the drug molecules’ loading and spatial arrangement. Here, the impact of increasing the drug load from one to three on the properties of an affibody drug conjugate targeting the human epidermal growth factor receptor 2 (HER2) was investigated. The affibody carrier was recombinantly expressed as a fusion to an albumin-binding domain (ABD) for plasma half-life extension. One or three cysteine amino acids were placed at the C-terminus to which cytotoxic mcDM1 molecules were conjugated. The resulting drug conjugates, ZHER2–ABD–mcDM1 and ZHER2–ABD–mcDM13, were characterized in vitro, and their biodistribution in mice carrying HER2-overexpressing SKOV3 xenografts was determined. Increasing the drug load from one to three led to a decrease in affinity for HER2, but a significantly more potent cytotoxic effect on SKOV3 cells with high HER2 expression. The difference in cytotoxic effect on other cell lines with high HER2 expression was not significant. In vivo, an increase in drug load led to a 1.45-fold higher amount of cytotoxic mcDM1 delivered to the tumors. The increase in drug load also led to more rapid hepatic clearance, warranting further optimization of the molecular design.