As most of polypeptides are marginally stable, a mild formulation procedure would be beneficial for the activities of these drugs. The objective of the present study was to develop a novel pH-sensitive nanoparticle system that was suitable for entrapment of hydrophilic insulin but without affecting its conformation. Chitosan was incorporated as a positively charged material, and one of the three poly(methylmethacrylate/methylmethacrylic acid) copolymers, consisting of Eudragit L100-55, L100, and S100, was used as a negatively charged polymer for preparation of three insulin nanoparticles, respectively. Three nanoparticles obtained were spherical. The mean diameters were in the range from 200 nm to 250 nm, and the entrapment efficiencies, from 50% to 70%. The surface analysis indicated that insulin was evenly distributed in the nanoparticles. Polymer ratio of chitosan to Eudragit was the factor which influenced the nanoparticles significantly. Characterization results showed that the electrostatic interactions existed, thus providing a mild formulation procedure which did not affect the chemical integrity and the conformation of insulin. In vitro release studies revealed that all three types of the nanoparticles exhibited a pH-dependant characteristic. The modeling data indicated that the release kinetics of insulin was nonlinear, and during the release process, the nanoparticles showed a polynomial swelling. On overall estimation, the insulin chitosan-Eudragit L100-55 nanoparticles may be better for the oral delivery. This new pH-sensitive nanoparticle formulation using chitosan and Eudragit L100-55 polymer may provide a useful approach for entrapment of hydrophilic polypeptides without affecting their conformation.

Simvastatin is a translational drug that may be used to induce local bone formation. In this study, simvastatin microcrystals were made by a wet media milling method, and then we verified the osteogenic effect of the microcrystals in rat ovariectomy (OVX)–induced osteoporosis and femur defect models. For the osteoporosis model, we delivered simvastatin microcrystals to the tibia with poloxamer hydrogels via an intraosseous injection. Bone mineral density and the ultimate force of the treated tibia were significantly improved after injection of simvastatin microcrystals at 0.5 and 1 mg compared with the OVX or 0‐mg control groups. For the femur defect model, simvastatin microcrystals were incorporated in clinically used calcium phosphate cements (CPCs) as an implant. Quantitative analysis of bone regeneration by microcomputed tomography (μCT) showed improved bone morphology with simvastatin microcrystals at 50 and 100 μg, compared with the CPC vehicle. A semiquantitative scale for histology assessment further demonstrated a higher bone regeneration score in the drug‐loaded groups. Our study shows that simvastatin microcrystals can promote bone formation by local delivery using a poloxamer hydrogel or CPC, which may be translationally useful.

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To investigate the effect of different enteric polymers on the characteristics of pH-sensitive nanoparticles, Rhodamine 6G (Rho) was incorporated in various pH-sensitive nanoparticles. The different patterns of pH-dependent release profiles were observed, although some polymers have the same dissolving pH. The distribution, adhesion and transition of different nanoparticles in rat gut showed significant difference, closely related to the release characteristics of nanoparticles, and their release behaviour are dependent on the dissolving pH and the structure of the polymers, as well as the drug property.Most nanoparticle formulations decreased the distribution and adhesion of Rho in the stomach but increased these values in the intestine. The nanocarriers also control the drug release sites and release rate in the GI tract. In conclusion, pH-sensitive nanoparticles seem favourable for drug absorption and it is important to choose the proper materials to obtain the suitable characteristics for the oral pH-sensitive nanoparticles.

To investigate the effect of different enteric polymers on the characteristics of pH-sensitive nanoparticles, Rhodamine 6G (Rho) was incorporated in various pH-sensitive nanoparticles. The different patterns of pH-dependent release profiles were observed, although some polymers have the same dissolving pH. The distribution, adhesion and transition of different nanoparticles in rat gut showed significant difference, closely related to the release characteristics of nanoparticles, and their release behaviour are dependent on the dissolving pH and the structure of the polymers, as well as the drug property.Most nanoparticle formulations decreased the distribution and adhesion of Rho in the stomach but increased these values in the intestine. The nanocarriers also control the drug release sites and release rate in the GI tract. In conclusion, pH-sensitive nanoparticles seem favourable for drug absorption and it is important to choose the proper materials to obtain the suitable characteristics for the oral pH-sensitive nanoparticles.

<b><i>Introduction:</i></b> The mixture of etomidate and propofol is widely used in clinical practice to improve efficacy of general anesthesia and to minimize side effects. As a thermodynamically unstable system, emulsion is prone to destabilization through mechanisms including coalescence, flocculation, and creaming. Such unwanted phenomenon can induce fat embolism after intravenous administration. This study was aimed to investigate the physical and chemical stability of the mixture of etomidate and propofol in the dosage form of emulsion. <b><i>Methods:</i></b> This compatibility study focused on the critical quality attributes (CQAs) of drug-containing emulsions, such as appearance, pH, particle size and distribution, <i>zeta</i> potential, the observation under centrifugation, and drug content and impurity. <b><i>Results:</i></b> As the results, there were no significant changes in the CQAs of the mixed emulsions up to 24 h after mixing at refrigeration temperature (4°C), room temperature (25°C), and body temperature (37°C). <b><i>Conclusions:</i></b> These results demonstrate that etomidate emulsion is physically and chemically compatible with propofol emulsions up to 24 h at 4°C, 25°C, and 37°C, suggesting that etomidate and propofol can be administrated in mixture without adversely affecting product characteristics, at least in vitro.

Background: Currently, drugs for local bone formation are very limited in clinic. Simvastatin is one of most potential translational drugs by repositioning for its significant osteogenic effect and its history as a safe lipid-lowering medicine. In this study, we prepared the pre-clinical simvastatin microcrystals which could be potentially translated and industrialized. Methods: Simvastatin microcrystals were made by wet media milling method. Characterization of microcrystal particles were evaluated by laser particle size analyzer and high-performance liquid chromatography (HPLC). Furthermore, we verified the osteogenic effect in rat ovariectomy(OVX)-induced osteoporosis model and femur defect model. For osteoporosis model, we delivered simvastatin microcrystals to tibia with poloxamer hydrogel by intraosseous injection. Bone mineral density (BMD) and ultimate force were assessed after treatment. For femur defect model, simvastatin microcrystal was incorporated in clinically used calcium phosphate cements (CPCs) as an implant. Histology and μCT were used for evaluation of the healing. Results: The D 10 , D 50, and D 90 showed size of the most particles ranged from 0.226-3.425 μm. The mean particle size of the microcrystals is determined as 1.365 μm which demonstrated a successful preparation. For osteoporosis model, BMD and the ultimate force of the treated tibia were significantly improved in osteoporosis rat after injection of 0.5 mg and 1 mg simvastatin microcrystals compared with OVX or 0 mg groups. There were no differences observed in BMD and ultimate force between 0.5 mg, 1 mg simvastatin microcrystals group and bone morphogenetic protein (BMP) 5 ug group. For femur defect model, quantitative analysis of bone regeneration by μCT showed bone volume/tissue volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) were significantly increased in simvastatin microcrystals 50ug (SIM-C 50 ug), SIM-C 100 ug and BMP 5 ug group compared with CPC vehicle group. Trabecular separation (Tb.Sp), and cement volume/tissue volume (CV/TV) were decreased in SIM-C 50 ug, SIM-C 100 ug and BMP 5 ug groups compared with CPC vehicle group. Semiquantitative scale for histology assessment further demonstrated a higher bone regeneration score in drug loaded groups compared with CPC group.Conclusions: Our study shows that simvastatin microcrystals were successfully prepared by wet media milling method and the microcrystals can promote bone formation by local delivery by poloxamer hydrogel or CPC, which is of great translational potential.