Optimization of O/W Emulsion Solvent Evaporation Method for Itraconazole Sustained Release Microspheres.

Itraconazole, a commonly used antifungal drug in the clinic approved by U.S. Food and Drug Administration (FDA), has been gradually found to have anti-tumor, angiogenesis inhibition and other pharmacological activities. However, its poor water solubility and potential toxicity limited its clinical application. In order to improve the water solubility and reduce the side effects caused by the high concentration of itraconazole, a novel preparation method of itraconazole sustained release microspheres was established in this study. Firstly, five kinds of polylactic acid-glycolic acid (PLGA) microspheres loaded with itraconazole were prepared by oil/water (O/W) emulsion solvent evaporation and then characterized by infrared spectroscopy. Then the particle size and morphology of the microspheres were observed by scanning electron microscope (SEM) and transmission electron microscope (TEM). After that, the particle size distribution, drug loading rate, entrapment efficiency, and drug release experiments were evaluated. Our results showed the microspheres prepared in this study had uniform particle size distribution and good integrity. Further study found that the average drug loading of the five kinds of microspheres prepared with PLGA 7505, PLGA 7510, PLGA 7520, PLGA 5020 and PLGA 0020 were 16.88, 17.72, 16.72, 16.57, and 16.64%, respectively, and the encapsulation rate all reached about 100%. More surprisingly, the release experimental results showed that the microspheres prepared with PLGA 7520 did not show sudden release, showing good sustained release performance and high drug release rate. To sum up, this study optimized the preparation method of sustained-release microspheres without sudden release, which provides a new solution for the delivery of itraconazole in the clinic.

Three-dimensional assessment of facial asymmetry in class III subjects, part 2: evaluating asymmetry index and asymmetry scores.

OBJECTIVES: To evaluate the outcomes of corrective surgical treatment for craniofacial asymmetry using four different methods with the aim of developing the best technique for craniofacial asymmetry assessment. MATERIALS AND METHODS: CBCT images of twenty-one class III subjects with surgically corrected craniofacial asymmetry and twenty-one matched controls were analyzed. Twenty-seven hard tissue landmarks were used to quantify asymmetry using the following methodologies: the asymmetry index (AI), asymmetry scores based on the clinically derived midline (CM), Procrustes analysis (PA), and modified Procrustes analysis (MPA). RESULTS: Modified Procrustes analysis successfully identified pre-operative asymmetry and revealed severe asymmetry at the mandibular regions compared to controls, which was comparable to the asymmetry index and clinically derived midline methods, while Procrustes analysis masked the asymmetric characteristics. Likewise, when comparing the post-surgical outcomes, modified Procrustes analysis not only efficiently determined the changes evidencing decrease in facial asymmetry but also revealed significant residual asymmetry in the mandible, which was congruent with the asymmetry index and clinically derived midline methods but contradictory to the results shown by Procrustes analysis. CONCLUSIONS: In terms of quantifying cranio-facial asymmetry, modified Procrustes analysis has evidenced to produce promising results that were comparable to the asymmetry index and the clinically derived midline, making it a more viable option for craniofacial asymmetry assessment. CLINICAL RELEVANCE: Modified Procrustes analysis is proficient in evaluating cranio-facial asymmetry with more valid clinical representation and has potential applications in assessing asymmetry in a wide spectrum of patients, including syndromic patients.

Highly biocompatible thermosensitive nanocomposite gel for combined therapy of hepatocellular carcinoma via the enhancement of mitochondria related apoptosis.

Primary hepatocellular carcinoma (HCC) is a common malignant tumor. Surgery is the main treatment, but HCC patients have a potential risk of tumor recurrence. Besides, many limitations arise during the application of single first-line antitumor drugs. Here, we selected Pluronic F-127 and sodium alginate (SA) to prepare a thermosensitive gel (Gel). The optimal synergistic ratio of PTX and DOX on the SMMC-7721 cells was 1: 2 (w/w), calculated by the Chou-Talalay analysis. Then, PTX and DOX coloaded liposomes (PD-LPs) with such drugs ratios presented enhanced anticancer ability in vitro. Upon local injection, the PD-LPs Gel formed a nanoparticles reservoir at tumor via sol-gel transformation, while exhibiting a long-term effective anti-tumor ability in vivo. The relative tumor volume after the PD-LPs Gel treatment was reduced over 62%. Effective mitochondria related apoptosis induction was observed. Therefore, the local delivery of PD-LPs Gel can be a promising alternative method for the HCC therapy.

A Novel Gel-Forming Solution Based on PEG-DSPE/Solutol HS 15 Mixed Micelles and Gellan Gum for Ophthalmic Delivery of Curcumin.

Curcumin (Cur) is a naturally hydrophobic polyphenol with potential pharmacological properties. However, the poor aqueous solubility and low bioavailability of curcumin limits its ocular administration. Thus, the aim of this study was to prepare a mixed micelle in situ gelling system of curcumin (Cur-MM-ISG) for ophthalmic drug delivery. The curcumin mixed micelles (Cur-MMs) were prepared via the solvent evaporation method, after which they were incorporated into gellan gum gels. Characterization tests showed that Cur-MMs were small in size and spherical in shape, with a low critical micelle concentration. Compared with free curcumin, Cur-MMs improved the solubility and stability of curcumin significantly. The ex vivo penetration study revealed that Cur-MMs could penetrate the rabbit cornea more efficiently than the free curcumin. After dispersing the micelles in the gellan gum solution at a ratio of 1:1 (v/v), a transparent Cur-MM-ISG with the characteristics of a pseudoplastic fluid was formed. No obvious irritations were observed in the rabbit eyes after ocular instillation of Cur-MM-ISG. Moreover, Cur-MM-ISG showed a longer retention time on the corneal surface when compared to Cur-MMs using the fluorescein sodium labeling method. These findings indicate that biocompatible Cur-MM-ISG has great potential in ophthalmic drug therapy.

Biocompatible Fe-Based Micropore Metal-Organic Frameworks as Sustained-Release Anticancer Drug Carriers.

Sustained-release preparation is a hot spot in antitumor drug research, where the first task is to select suitable drug carriers. Research has revealed that carboxylic acid iron metal⁻organic frameworks (MOFs), constructed from iron (Fe) ions and terephthalic acid, are nontoxic and biocompatible. Due to the breathing effect, the skeleton of this mesoporous material is flexible and can reversibly adapt its pore size through drug adsorption. Therefore, we chose one kind of Fe-MOF, MIL-53(Fe), as a carrier for the anticancer drug oridonin (Ori). In this work, we report the design and synthesis of MIL-53(Fe) and explore its ability as a transport vehicle to deliver Ori. MIL-53(Fe) is characterized by scanning electron microscopy and X-ray powder diffraction. A loading capacity of 56.25 wt % was measured by high performance liquid chromatography. This carrier was safe and nontoxic (cell viability > 95.27%), depending on the results of 3-(4,5-dimethylthiazol-2-yl)--2,5-diphenyltetrazolium bromide assays, lactate dehydrogenase assays, and Annexin V-fluoresce isothiocyanate/propidium iodide double-staining assays. After loading the drug, the structure of the MIL-53(Fe) was not destroyed, and Ori was amorphous in MIL-53(Fe). Based on an analysis of the Ori release profile, results suggest that it lasts for more than seven days in vitro. The cumulative release rate of Ori at the seventh day was about 82.23% and 91.75% in phosphate buffer saline solution at 37 °C under pH 7.2 and pH 5.5, respectively. HepG2 cells were chosen to study the cytotoxicity of Ori@MIL-53(Fe), and the results show that the anticancer ratio of Ori@MIL-53(Fe) system reaches 90.62%. Thus, MIL-53 can be used as a carrier for anticancer drugs and Ori@MIL-53(Fe) is a promising sustained-release drug delivery system for the cancer therapy.

Morphology and mechanical performance of dental crown designed by 3D-DCGAN.

OBJECTIVES: This study utilised an Artificial Intelligence (AI) method, namely 3D-Deep Convolutional Generative Adversarial Network (3D-DCGAN), which is one of the true 3D machine learning methods, as an automatic algorithm to design a dental crown. METHODS: Six hundred sets of digital casts containing mandibular second premolars and their adjacent and antagonist teeth obtained from healthy personnel were machine-learned using 3D-DCGAN. Additional 12 sets of data were used as the test dataset, whereas the natural second premolars in the test dataset were compared with the designs in (1) 3D-DCGAN, (2) CEREC Biogeneric, and (3) CAD for morphological parameters of 3D similarity, cusp angle, occlusal contact point number and area, and in silico fatigue simulations with finite element (FE) using lithium disilicate material. RESULTS: The 3D-DCGAN design and natural teeth had the lowest discrepancy in morphology compared with the other groups (root mean square value = 0.3611). The Biogeneric design showed a significantly (p < 0.05) higher cusp angle (67.11°) than that of the 3D-DCGAN design (49.43°) and natural tooth (54.05°). No significant difference was observed in the number and area of occlusal contact points among the four groups. FE analysis showed that the 3D-DCGAN design had the best match to the natural tooth regarding the stress distribution in the crown. The 3D-DCGAN design was subjected to 26.73 MPa and the natural tooth was subjected to 23.97 MPa stress at the central fossa area under physiological occlusal force (300 N); the two groups showed similar fatigue lifetimes (F-N curve) under simulated cyclic loading of 100-400 N. Designs with Biogeneric or technician would yield respectively higher or lower fatigue lifetime than natural teeth. SIGNIFICANCE: This study demonstrated that 3D-DCGAN could be utilised to design personalised dental crowns with high accuracy that can mimic both the morphology and biomechanics of natural teeth.

Tooth Alignment Network Based on Landmark Constraints and Hierarchical Graph Structure.

Automatic tooth alignment target prediction is vital in shortening the planning time of orthodontic treatments and aligner designs. Generally, the quality of alignment targets greatly depends on the experience and ability of dentists and has enormous subjective factors. Therefore, many knowledge-driven alignment prediction methods have been proposed to help inexperienced dentists. Unfortunately, existing methods tend to directly regress tooth motion, which lacks clinical interpretability. Tooth anatomical landmarks play a critical role in orthodontics because they are effective in aiding the assessment of whether teeth are in close arrangement and normal occlusion. Thus, we consider anatomical landmark constraints to improve tooth alignment results. In this paper, we present a novel tooth alignment neural network for alignment target predictions based on tooth landmark constraints and a hierarchical graph structure. We detect the landmarks of each tooth first and then construct a hierarchical graph of jaw-tooth-landmark to characterize the relationship between teeth and landmarks. Then, we define the landmark constraints to guide the network to learn the normal occlusion and predict the rigid transformation of each tooth during alignment. Our method achieves better results with the architecture built for tooth data and landmark constraints and has better explainability than previous methods with regard to clinical tooth alignments.

TSegNet: An efficient and accurate tooth segmentation network on 3D dental model.

Automatic and accurate segmentation of dental models is a fundamental task in computer-aided dentistry. Previous methods can achieve satisfactory segmentation results on normal dental models; however, they fail to robustly handle challenging clinical cases such as dental models with missing, crowding, or misaligned teeth before orthodontic treatments. In this paper, we propose a novel end-to-end learning-based method, called TSegNet, for robust and efficient tooth segmentation on 3D scanned point cloud data of dental models. Our algorithm detects all the teeth using a distance-aware tooth centroid voting scheme in the first stage, which ensures the accurate localization of tooth objects even with irregular positions on abnormal dental models. Then, a confidence-aware cascade segmentation module in the second stage is designed to segment each individual tooth and resolve ambiguities caused by aforementioned challenging cases. We evaluated our method on a large-scale real-world dataset consisting of dental models scanned before or after orthodontic treatments. Extensive evaluations, ablation studies and comparisons demonstrate that our method can generate accurate tooth labels robustly in various challenging cases and significantly outperforms state-of-the-art approaches by 6.5% of Dice Coefficient, 3.0% of F1 score in term of accuracy, while achieving 20 times speedup of computational time.

[Swelling property of common hydrophilic polymers and their use in push-pull osmotic-pump tablets].

OBJECTIVE: To investigate the feasibility of swelling hydrogel instead of polyethylene oxide as swelling polymer in push-layer of push-pull osmotically controlled-release tablets. METHOD: The swelling patterns of tablets made of pure polymers were studied by immerging the tablets into purified water and testing their size at different time points. The push-pull osmotic-pump tablets were prepared and their release patterns in vitro were studied and compared by their similar factor (f2). RESULT: Tablets with different swelling materials all showed satisfying release pattern in vitro and their release ratio at 12 h were all above 80%. CONCLUSION: With its release rate and cumulative release percentage at 12 h, the mixture of HPMC K15M and CMCNa in ratio of 1:1 is the best choice instead of polyethylene oxide as swelling polymer in push-layer.

Strategy to prevent cardiac toxicity induced by polyacrylic acid decorated iron MRI contrast agent and investigation of its mechanism.

Polyelectrolyte modified iron oxide nanoparticles have great potential applications for clinical magnetic resonance imaging (MRI) and anemia treatments, however, possible associated heart toxicity is rarely reported. Here, polyacrylic acid (PAA)-coated Fe3O4 nanoparticles (PION) were synthesized and lethal reactions appeared when it was applied in vivo. The investigation of underlying mechanism showed that PION could break electrolyte balance and further resulted in serious heart failure, which was observed under color doppler ultrasound and dynamic vector blood flow technique. The results demonstrated that PION had a strong absorption tendency for divalent ions and the maximum tolerated dose (MTD) was lower than 100 mg/kg. From electrocardiography (ECG), PION presented an obvious impact on CaV1.2 ion channel, which leading to fatal arrhythmia. An appropriate solution for preventing this deadly effect was pre-chelation Ca2+ (n (Ca): n (COOH) = 3: 8) to PION (PION-Ca), which displayed much higher cardiac and electrophysiological safety when sealing the binding point of divalent cation ions with PAA. The injection in Beagle dogs further confirmed the safety of PION-Ca. This study explored the mechanism and offered a solution for cardiac toxicity induced by PAA-coated nanoparticles, which guides for enhancing the safety of such polyelectrolyte decorated nanoparticles and provides assurance for clinical applications.

Mucus adhesion- and penetration-enhanced liposomes for paclitaxel oral delivery.

Low aqueous solubility and intestinal permeability limit the oral chemotherapy efficacy of paclitaxel (PTX). Traditional nanodrug delivery systems show excellent aqueous solubility improved ability of PTX. However, gastrointestinal (GI) mucus limits the improvement of intestinal permeability in traditional nanodrug delivery systems. A novel mucus adhesion- and penetration-functionalized chitosan-thioglycolic acid-Pluronic F127 (CS-TGA-PF) liposome system was developed for PTX oral delivery. The optimized formulation of PTX-loaded CS-TGA-PF liposomes showed particle size of 121.4 nm and zeta potential of 50.2 mV. CS-TGA-PF liposomes were more stable than unmodified liposomes and demonstrated a sustained-release manner of PTX incubated in simulated gastric fluid and intestinal fluid. CS-TGA-PF liposomes absorbed a three-fold amount of mucin compared with that of unmodified liposomes, which would prolong the residence time of liposomes on the mucosal surface in the intestinal tract. The intestinal mucus adhesion- and penetration-enhanced efficacy of CS-TGA-PF liposomes for intestinal PTX delivery was studied by observing the intestinal absorption and distribution. Results exhibited increased liposome uptake by the GI mucosa and improved drug intestinal absorption. In conclusion, the dual functional CS-TGA-PF liposomes with mucus adhesion- and permeation-enhanced properties could be used as a promising nanodrug delivery system for PTX oral delivery.

Novel bilayer wound dressing composed of SIS membrane with SIS cryogel enhanced wound healing process.

Full-thickness skin damage is a server issue and sometimes even dangerous to life. Many researches have been done toward full-thickness wound dressing. In this study, we demonstrated a facile and one-step procedure of SIS bilayer wound dressing. The top layer could protect the wound from bacterial infection and provide a moist environment suitable for wound healing, while the cryogel layer could promote cell proliferation. The SIS bilayer wound dressing has sufficient mechanical properties to protect wound from second damage and can maintain a moist environment for cell proliferation and migration at wound site. Bacterial permeation testing demonstrated that the bilayer scaffold had high efficiency in blocking bacteria at the wound site. In vivo tests and qRT-PCR results revealed that the bilayer group possessed a higher tendency toward keratinocyte proliferation and migration. The SIS bilayer has a high potential to use as full-thickness wound dressing.

Enhanced skin permeation of glabridin using eutectic mixture-based nanoemulsion.

This study aimed to investigate the performance of the eutectic mixture of menthol and camphor (1:1, w/w) in nanoemulsion formulation for enhanced transdermal penetration of water-insoluble glabridin. Glabridin solubility in different media was determined by a shaking bottle method. The pseudoternary phase diagrams of the oil phase (drug-loaded eutectic mixture or IPM), the surfactant (Tween 80:glycerol = 2:1, w/w), and water were constructed using the aqueous titration method. The obtained glabridin nanoemulsions were characterized and compared on their particle sizes, in vitro and in vivo penetration performance on rat skin, and storage stability. The nanoemulsion formulation was optimized as 0.25% glabridin, 5% oil phase, 10% Tween 80, 5% glycerol, and 79.75% water. The obtained nanoemulsions showed a mean droplet size of nearly 100 nm for different oil phases. And the stability of both formulations was similar after storage for 3 months. In vitro skin permeation study showed that the nanoemulsion formulation with eutectic mixture exhibited higher skin permeability (28.26 µg/cm2) than that with IPM (9.94 µg/cm2) or the drug solution formulation (3.82 µg/cm2), which was further confirmed by in vivo skin permeation tests on the rat skin and human skin. The eutectic mixture is a preferable solvent for glabridin, and its nanoemulsion can be used as an excellent nanocarrier for enhanced transdermal delivery of glabridin.

Enhanced encapsulation and bioavailability of breviscapine in PLGA microparticles by nanocrystal and water-soluble polymer template techniques.

Poly (lactide-co-glycolide) (PLGA) microparticles are widely used for controlled drug delivery. Emulsion methods have been commonly used for preparation of PLGA microparticles, but they usually result in low loading capacity, especially for drugs with poor solubility in organic solvents. In the present study, the nanocrystal technology and a water-soluble polymer template method were used to fabricate nanocrystal-loaded microparticles with improved drug loading and encapsulation efficiency for prolonged delivery of breviscapine. Breviscapine nanocrystals were prepared using a precipitation-ultrasonication method and further loaded into PLGA microparticles by casting in a mold from a water-soluble polymer. The obtained disc-like particles were then characterized and compared with the spherical particles prepared by an emulsion-solvent evaporation method. X-ray powder diffraction (XRPD) and confocal laser scanning microscopy (CLSM) analysis confirmed a highly-dispersed state of breviscapine inside the microparticles. The drug form, loading percentage and fabrication techniques significantly affected the loading capacity and efficiency of breviscapine in PLGA microparticles, and their release performance as well. Drug loading was increased from 2.4% up to 15.3% when both nanocrystal and template methods were applied, and encapsulation efficiency increased from 48.5% to 91.9%. But loading efficiency was reduced as the drug loading was increased. All microparticles showed an initial burst release, and then a slow release period of 28days followed by an erosion-accelerated release phase, which provides a sustained delivery of breviscapine over a month. A relatively stable serum drug level for more than 30days was observed after intramuscular injection of microparticles in rats. Therefore, PLGA microparticles loaded with nanocrystals of poorly soluble drugs provided a promising approach for long-term therapeutic products characterized with preferable in vitro and in vivo performance.

Sophoridine-loaded PLGA microspheres for lung targeting: preparation, in vitro, and in vivo evaluation.

Lung-targeting sophoridine-loaded poly(lactide-co-glycolide) (PLGA) microspheres were constructed by a simple oil-in-oil emulsion-solvent evaporation method. The obtained microspheres were systematically studied on their morphology, size distribution, drug loading, encapsulation efficiency, in vitro release profile, and biodistribution in rats. The drug-loaded microparticles showed as tiny spheres under SEM and had an average size of 17 µm with 90% of the microspheres ranging from 12 to 24 µm. The drug loading and encapsulation efficiency were 65% and 6.5%, respectively. The in vitro drug release behavior of microspheres exhibited an initial burst of 16.6% at 4 h and a sustained-release period of 14 days. Drug concentration in lung tissue of rats was 220.10 µg/g for microspheres and 6.77 µg/g for solution after intraveneous injection for 30 min, respectively. And the microsphere formulation showed a significantly higher drug level in lung tissue than in other major organs and blood samples for 12 days. These results demonstrated that the obtained PLGA microspheres could potentially improve the treatment efficacy of sophoridine against lung cancer.

Comparative studies on the properties of glycyrrhetinic acid-loaded PLGA microparticles prepared by emulsion and template methods.

The O/W emulsion method has been widely used for the production of poly (lactide-co-glycolide) (PLGA) microparticles. Recently, a template method has been used to make homogeneous microparticles with predefined size and shape, and shown to be useful in encapsulating different types of active compounds. However, differences between the template method and emulsion method have not been examined. In the current study, PLGA microparticles were prepared by the two methods using glycyrrhetinic acid (GA) as a model drug. The properties of obtained microparticles were characterized and compared on drug distribution, in vitro release, and degradation. An encapsulation efficiency of over 70% and a mean particle size of about 40µm were found for both methods. DSC thermograms and XRPD diffractograms indicated that GA was highly dispersed or in the amorphous state in the matrix of microparticles. The emulsion method produced microparticles of a broad size distribution with a core-shell type structure and many drug-rich domains inside each microparticle. Its drug release and matrix degradation was slow before Day 50 and then accelerated. In contrast, the template method formed microparticles with narrow size distribution and drug distribution without apparent drug-rich domains. The template microparticles with a loading efficiency of 85% exhibited a zero-order release profile for 3 months after the initial burst release of 26.7%, and a steady surface erosion process as well. The same microparticles made by two different methods showed two distinguished drug release profiles. The two different methods can be supplementary with each other in optimization of drug formulation for achieving predetermined drug release patterns.