Amorphous Solid Dispersions: Role of the Polymer and Its Importance in Physical Stability and In Vitro Performance.

Amorphous solid dispersions stabilized by one or more polymer(s) have been widely used for delivering amorphous drugs with poor water solubilities, and they have gained great market success. Polymer selection is important for preparing robust amorphous solid dispersions, and considerations should be given as to how the critical attributes of a polymer can enhance the physical stability, and the in vitro and in vivo performances of a drug. This article provides a comprehensive overview for recent developments in the understanding the role of polymers in amorphous solid dispersions from the aspects of nucleation, crystal growth, overall crystallization, miscibility, phase separation, dissolution, and supersaturation. The critical properties of polymers affecting the physical stability and the in vitro performance of amorphous solid dispersions are also highlighted. Moreover, a perspective regarding the current research gaps and novel research directions for better understanding the role of the polymer is provided. This review will provide guidance for the rational design of polymer-based amorphous pharmaceutical solids with desired physicochemical properties from the perspective of physical stability and in vitro performance.

Influence of molecular weight and concentration of carboxymethyl chitosan on biomimetic mineralization of collagen.

The objective of the present study was to systematically investigate the influence of molecular weight (MW) and concentration of carboxymethyl chitosan (CMC), which served as non-collagenous protein (NCP) surrogates, on biomimetic mineralization of type I collagen. Supersaturated CMC-stabilized amorphous calcium-phosphate (CMC-ACP) dispersions containing different MWs (20 kDa, 60 kDa, 150 kDa) and concentrations (25, 50, 100, 200, 400 µg ml-1) of CMC were prepared. After mineralization in the aforementioned dispersions for 7 days, the pattern and extent of biomimetic mineralization of collagen scaffolds were investigated. Our study showed that increasing CMC concentration resulted in increasing stability and decreasing particle size of CMC-ACP dispersions. Images from scanning and transmission electron microscopy revealed that intrafibrillar mineralization of collagen was obtained with 20k-200, 60k-100, 60k-200 and 150k-200 CMC-ACP dispersions, with hydroxyapatite (HAp) formation confirmed by Fourier transform infrared spectroscopy and X-ray diffraction measurements, whereas HAp formed extrafibrillar clusters in other collagen scaffolds. Thermogravimetric analysis showed that the combined effect of MW and concentration of CMC contributed to different extents of biomimetic mineralization, and was correlated with the stability and particle size of CMC-ACP dispersions, and the size-exclusion characteristics of type I collagen. The results of this work support the effective function of CMC as NCP analogs, and provide parameters of MWs and concentrations of CMC for applications in hard tissue engineering as well as insights into intersections of mechanisms in biomimetic mineralization.

Use of experimental-resin-based materials doped with carboxymethyl chitosan and calcium phosphate microfillers to induce biomimetic remineralization of caries-affected dentin.

This study investigated carboxymethyl chitosan (CMC)-induced biomimetic mineralization of collagen fibrils, with the aim of synthesizing experimental resins doped with CMC and calcium phosphate microfillers to remineralize artificial caries-affected dentin (ACAD) and enhance resin-dentin bonding durability. A size exclusion test provided evidence for the rejection of CMC (Mw 150 kDa) by collagen fibrils. Transmission electron microscopy and selected area electron diffraction conducted on reconstituted two-dimensional collagen showed typical deposition of needle-like hydroxyapatite crystals within collagen fibrils through CMC-induced biomimetic mineralization. The Vickers hardness test revealed significant improvement (P < 0.001) of the hardness of ACAD treated with CMC-containing experimental resins. Confocal laser scanning microscopy showed reduced dentin permeability and defect sites after biomimetic mineralization. On microtensile bond strength testing, the CMC-remineralized ACAD had better bonding with resin than ACAD and traditionally remineralized ACAD in both self-etch and etch-and-rinse bonding modes (P < 0.001). In conclusion, CMC is efficient in directing the biomimetic mineralization of collagen fibrils. The experimental resins containing CMC can induce dentin biomimetic remineralization and improve the bonding performance of ACAD.

LL-37 inhibits LPS-induced inflammation and stimulates the osteogenic differentiation of BMSCs via P2X7 receptor and MAPK signaling pathway.

Oral diseases, such as periapical periodontitis and periodontitis, are characterized by inflammation-induced bone loss. LL-37, a human antimicrobial peptide (AMP), has multiple biological functions and the potential to promote osteogenesis. Therefore, this study aimed to investigate the regulatory effects of LL-37 within normal and inflammatory microenvironments. The roles of P2X7 receptor (P2X7R) and mitogen-activated protein kinase (MAPK) signaling pathway were also demonstrated. The results showed that LL-37 promoted bone marrow stromal cell (BMSC) proliferation, migration and osteogenic differentiation. LL-37 inhibited the expression of the inflammatory cytokines interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and receptor activator of nuclear factor kappa-B ligand (RANKL) at both protein and gene levels, and attenuated the lipopolysaccharide (LPS)-induced inhibition of osteogenesis. Immunofluorescence (IF) confirmed P2X7R expression in BMSCs. BBG, a P2X7R antagonist, significantly attenuated LL-37-promoted osteogenesis. The phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase (JNK) increased after LL-37 stimulation, which did not affect p38 phosphorylation. The effects of LL-37 on osteogenesis-related gene expression were markedly attenuated by selective inhibitors of ERK1/2 and JNK. Furthermore, a mouse model of LPS-stimulated calvarial osteolysis was established, and results showed that LL-37 markedly inhibited osteoclastic bone resorption. In conclusion, we speculate that LL-37 inhibits inflammation and promotes BMSC osteogenesis via P2X7R and MAPK signaling pathway.