All-stage targeted therapy for the brain metastasis from triple-negative breast cancer

Brain metastasis is a common and serious complication of breast cancer, which is commonly associated with poor survival and prognosis. In particular, the treatment of brain metastasis from triple-negative breast cancer (BM-TNBC) has to face the distinct therapeutic challenges from tumor heterogeneity, circulating tumor cells (CTCs), blood-brain barrier (BBB) and blood-tumor barrier (BTB), which is in unmet clinical needs. Herein, combining with the advantages of synthetic and natural targeting moieties, we develop a "Y-shaped" peptide pVAP-decorated platelet-hybrid liposome drug delivery system to address the all-stage targeted drug delivery for the whole progression of BM-TNBC. Inherited from the activated platelet, the hybrid liposomes still retain the native affinity toward CTCs. Further, the peptide-mediated targeting to breast cancer cells and transport across BBB/BTB are demonstrated in vitro and in vivo. The resultant delivery platform significantly improves the drug accumulation both in orthotopic breast tumors and brain metastatic lesions, and eventually exhibits an outperformance in the inhibition of BM-TNBC compared with the free drug. Overall, this work provides a promising prospect for the comprehensive treatment of BM-TNBC, which could be generalized to other cell types or used in imaging platforms in the future.

Research progress on the preparation and application of flavonoid nanocrystals / 浙江大学学报·医学版

Flavonoids have been reported to possess significant pharmacological activities,such as antioxidant, anti-inflammatory and anticancer effects. However, the low solubility and low bioavailability limits their clinical application. Nanocrystal technology can solve the delivery problems of flavonoids by reducing particle size, increasing the solubility of insoluble drugs and improving their bioavailability. This article summaries nanosuspension preparation methods and the stabilizers for flavonoid nanocrystals, and reviews the drug delivery routes including oral, Injection and transdermal of flavonoid nanocrystals, to provide information for further research on nanocrystal delivery system of flavonoids.

Preparation and in vitro property evaluation of β-cyclodextrin-daidzein/PEG_(20000)/Carbomer_(940) nanocrystals / 中国中药杂志

This study aims to improve the solubility and bioavailability of daidzein by preparing the β-cyclodextrin-daidzein/PEG_(20000)/Carbomer_(940) nanocrystals. Specifically, the nanocrystals were prepared with daidzein as a model drug, PEG_(20000), Carbomer_(940), and NaOH as a plasticizer, a gelling agent, and a crosslinking agent, respectively. A two-step method was employed to prepare the β-cyclodextrin-daidzein/PEG_(20000)/Carbomer_(940) nanocystals. First, the insoluble drug daidzein was embedded in β-cyclodextrin to form inclusion complexes, which were then encapsulated in the PEG_(20000)/Carbomer_(940) nanocrystals. The optimal mass fraction of NaOH was determined as 0.8% by the drug release rate, redispersability, SEM morphology, encapsulation rate, and drug loading. The inclusion status of daidzein nanocrystals was determined by Fourier transform infrared spectroscopy(FTIR), thermogravimetric analysis(TGA), and X-ray diffraction(XRD) analysis to verify the feasibility of the preparation. The prepared nanocrystals showed the average Zeta potential of(-30.77±0.15)mV and(-37.47±0.64)mV and the particle sizes of(333.60±3.81)nm and(544.60±7.66)nm before and after daidzein loading, respectively. The irregular distribution of nanocrystals before and after daidzein loading was observed under SEM. The redispersability experiment showed high dispersion efficiency of the nanocrystals. The in vitro dissolution rate of nanocrystals in intestinal fluid was significantly faster than that of daidzein, and followed the first-order drug release kinetic model. XRD, FTIR, and TGA were employed to determine the polycrystalline properties, drug loading, and thermal stability of the nanocrystals before and after drug loading. The nanocrystals loaded with daidzein demonstrated obvious antibacterial effect. The nanocrystals had more significant inhibitory effects on Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa than daidzein because of the improved solubility of daidzein. The prepared nanocrystals can significantly increase the dissolution rate and oral bioavailability of the insoluble drug daidzein.

Nanocrystals self-stabilized Pickering emulsion loaded with active components of Tongmai prescription: preparation, characterization and evaluation by Caco-2 cell model / 药学学报

It is of great significance to apply the nanocrystals self-stabilized Pickering emulsion (NSSPE) to traditional Chinese medicine (TCM) compounds, and to study the effect of NSSPE on the oral absorption of various components with different solubility and permeability. In the study, NSSPE of Tongmai prescription was prepared by the high pressure homogenization method with nanocrystals of main active components (puerarin, ferulic acid, salvianolic acid B and tanshinone IIA) of Tongmai prescription as solid particle stabilizers and a mixture of Ligusticum chuanxiong essential oil and Labrafil M 1944 CS as oil phase. The NSSPE had better physical stability than nanocrystals suspension and blank emulsion. The adsorption of nanocrystals on the surface of oil droplets was confirmed by scanning electron microscopy and fluorescence microscopy. The surface adsorption rates of puerarin, ferulic acid, salvianolic acid B and tanshinone ⅡA in NSSPE were 15.40% ± 3.19%, 15.39% ± 5.07%, 10.97% ± 3.70% and 31.51% ± 1.60%, respectively. When solid active components were prepared into nanocrystals suspension, the cellular uptake and transport across Caco-2 cells were increased significantly for puerarin and tanshinone IIA. The uptake rates of ferulic acid, ligustilide and tanshinone IIA in NSSPE were further increased compared with the physical mixture of nanocrystals suspension and oil, and the transports of ligustilide and tanshinone IIA were also significantly improved. The main absorption mechanisms of NSSPE were passive diffusion and caveolin-mediated endocytosis, which were determined mainly by the microstructure of NSSPE. In conclusion, NSSPE could be applied to complicated TCM. The "micro" and "nano" synergistic microstructure with drug nanocrystals adsorbed on the surface of micron-sized oil droplets could not only improve the physical stability of NSSPE, but also promote the absorption of various components in NSSPE, which made NSSPE a promising oral drug delivery system for TCM.

Folic acid-modified phospholipid-encapsulated paclitaxel nanocrystals for preoperative chemotherapy of gastric cancer / 药学学报

This paper aims to develop folic acid-modified paclitaxel nanocrystals (PTX NC@FA) with good stability, high drug loading and tumor cell targeting for endoscopic injection for preoperative local chemotherapy of gastric cancer. PTX NC@FA was prepared by the "bottom-up" followed by ultrasonic to study its morphology, particle size, ζ-potential, drug loading, folic acid-modified phospholipid (FA-DSPE-PEG2000) content, crystalline characteristics, stability, in vitro release, cytotoxicity against human gastric cancer cell line SGC-7901, and anti-tumor effect in two different tumor sizes (tumor volume 100 mm3 or 300 mm3) after single peri-tumor injection in a murine subcutaneous SGC-7901 tumor model. Animal experiments were approved by the Experimental Animal Ethics Committee of the School of Pharmacy, Fudan University. The resulting PTX NC@FA was of short rod-like shape, average particle size 175.3 ± 2.5 nm (PDI 0.17 ± 0.02), ζ- potential -2.5 ± 0.2 mV, PTX loading (28.23 ± 0.74) % (w/w) and FA-DSPE-PEG2000 content (4.40 ± 0.60) % (w/w). The size of the PTX NC@FA remained unchanged for 4 days in phosphate buffer with or without serum. Cellular growth inhibition effect on SGC-7901 showed the superiority of PTX NC@FA over nanocrystals without FA modification. PTX NC@FA inhibited tumor growth more efficiently than both nanocrystals without FA modification and commercially available paclitaxel injection (Taxol) 12 days after peri-tumor injection. For model tumor with the volume of 100 mm3, tumors of all animals in the PTX NC@FA group disappeared completely. For model tumor with the volume of 300 mm3, tumors of 3 animals in the PTX NC@FA group completely disappeared and tumors of the rest 4 animals also became significantly smaller with a tumor volume inhibition rate of 90%. PTX NC@FA showed good potential for preoperative chemotherapy of increase the chances of function preserving gastrectomy and improve the quality of life of patients.

The osteogenic niche-targeted arsenic nanoparticles prevent colonization of disseminated breast tumor cells in the bone

Up to 70% of patients with late-stage breast cancer have bone metastasis. Current treatment regimens for breast cancer bone metastasis are palliative with no therapeutic cure. Disseminated tumor cells (DTCs) colonize inside the osteogenic niches in the early stage of bone metastasis. Drug delivery into osteogenic niches to inhibit DTC colonization can prevent bone metastasis from entering its late stage and therefore cure bone metastasis. Here, we constructed a 50% DSS6 peptide conjugated nanoparticle to target the osteogenic niche. The osteogenic niche was always located at the endosteum with immature hydroxyapatite. Arsenic-manganese nanocrystals (around 14 nm) were loaded in osteogenic niche-targeted PEG-PLGA nanoparticles with an acidic environment-triggered arsenic release. Arsenic formulations greatly reduced 4T1 cell adhesion to mesenchymal stem cells (MSCs)/preosteoblasts (pre-OBs) and osteogenic differentiation of osteoblastic cells. Arsenic formulations also prevented tumor cell colonization and dormancy via altering the direct interaction between 4T1 cells and MSCs/pre-OBs. The chemotactic migration of 4T1 cells toward osteogenic cells was blocked by arsenic in mimic 3D osteogenic niche. Systemic administration of osteogenic niche-targeted arsenic nanoparticles significantly extended the survival of mice with 4T1 syngeneic bone metastasis. Our findings provide an effective approach for osteogenic niche-specific drug delivery and suggest that bone metastasis can be effectively inhibited by blockage of tumor cell colonization in the bone microenvironment.

Advances in nanocrystal technology and its application to improve the pharmacological efficacy for poorly-water soluble drugs / 药学学报

In order to solve the problems of erratic drug absorption and low bioavailability after oral administration for poorly-water soluble drugs due to low solubility, a series of novel pharmaceutical dosage forms as solid dispersion, liposome, microemulsion, vesicle, cyclodextrin inclusion complexes and drug nanocrystal have been developed in recent years. Among which drug nanocrystal attracts more attentions for its simpler preparation method, higher drug loading and easier manufacturing technology in the design of dosage forms suitable for different administration routes. In this paper, the nanocrystals of the poorly-water soluble drugs prepared based on bottom-up and top-down technologies were introduced. The characteristics and applications of the nanocrystal-based dosage forms as suspension, tablet and capsule were also introduced and carefully evaluated with the focus on their pharmacokinetics, pharmacodynamics and tissue targeted drug distribution after delivery by oral administration, intravenous injection and pulmonary inhalation. The advantages of drug nanocrystals in their therapeutics effects over the bulk drugs were discussed together with the inherent mechanism. Finally, the problems existing in basic research and scaled-up manufacture of drug nanocrystal as well as the possible ways of solution were listed out so as to make the nanocrystal-based preparations exert their maximum therapeutic effect after clinical application.

Research progress on preparation technology of nanocrystal drugs / 药学学报

Nanocrystal drugs have many advantages, such as no carrier materials, easy industrialization, diversified dosage forms, and can significantly improve the solubility and bioavailability of insoluble drugs, so many drugs have been on the market. The traditional nanocrystal preparation technology has the problems of low preparation efficiency and process limitation of the smallest achievable particle size. With the progress of pharmaceutical preparation technology, the preparation technology of nanocrystal drugs is constantly improving, and new preparation technologies are constantly emerging. The emergence of new technologies has greatly shortened the process time and makes it possible to prepare nanocrystal drugs with smaller particle diameters. In this paper, the preparation technologies of nanocrystal drugs, especially the new preparation technologies such as high gravity controlled precipitation, microfluidic reaction technology and various combination technologies, are reviewed from three aspects: "Top-down" technology, "Bottom-up" technology and combination technology. This article also prospects the development of new preparation technologies, hoping to provide reference for the related research of nano-preparations.

Intracellular uptake of nanocrystals: Probing with aggregation-induced emission of fluorescence and kinetic modeling

Nanocrystal formulations have been explored to deliver poorly water-soluble drug molecules. Despite various studies of nanocrystal formulation and delivery, much more understanding needs to be gained into absorption mechanisms and kinetics of drug nanocrystals at various levels, ranging from cells to tissues and to the whole body. In this study, nanocrystals of tetrakis (4-hydroxyphenyl) ethylene (THPE) with an aggregation-induced emission (AIE) property was used as a model to explore intracellular absorption mechanism and dissolution kinetics of nanocrystals. Cellular uptake studies were conducted with KB cells and characterized by confocal microscopy, flow cytometry, and quantitative analyses. The results suggested that THPE nanocrystals could be taken up by KB cells directly, as well as in the form of dissolved molecules. The cellular uptake was found to be concentration- and time-dependent. In addition, the intracellular THPE also could be exocytosed from cells in forms of dissolved molecules and nanocrystals. Kinetic modeling was conducted to further understand the cellular mechanism of THPE nanocrystals based on first-order ordinary differential equations (ODEs). By fitting the kinetic model against experimental measurements, it was found that the initial nanocrystal concentration had a great influence on the dynamic process of dissolution, cellular uptake, and exocytosis of THPE nanocrystals. As the nanocrystal concentration increased in the culture media, dissolution of endocytosed nanocrystals became enhanced, subsequently driving the efflux of THPE molecules from cells.

Preparation and characterization of armodafinil nanocrystals / 国际药学研究杂志

Objective: To prepare and characterize armodafinil nanocrystals, and investigate its release in vitro. Methods: Anti-solvent precipitation technology was used to prepare the armodafinil nanocrystals. The formulation and preparation process of the armodafinil nanosuspension were optimized by the orthogonal design experiment with the average particle diameter as the evaluation index. The suspension was prepared into nanocrystals by freeze-drying technology. The particle size and the polydispersity coefficient of the armodafinil nanocrystals were measured. The X-ray powder diffraction method was used to investigate the crystal form transition of the armodafinil. The dissolution behavior of the armodafinil nanocrystals and raw substances was investigated and compared with each other by the slurry method. Results: The prepared amodafinil nanocrystals had a quite uniformly distributed particle size around 100 nm. The nanocrystals appeared to be in irregular form. After amodafinil was made into nanocrystals, the solubility and dissolution were significantly improved. The crystal form of amodafinil significantly changed after nanocrystallization. Conclusion: The preparation of a small and uniformly distributed particle size of amodafinil nanocrystals could significantly improve the dissolution performance of amodafinil, which is beneficial to improving the bioavailability of insoluble drugs.

Research progress of Pickering emulsion drug delivery systems / 药学学报

Pickering emulsion is a new type of emulsion which is stabilized by the adsorption of solid particles on the interface of emulsion droplets. In recent years, its applications in pharmacy have attracted more and more attention because of its higher resistance to coalescence and better safety than traditional surfactant emulsions. The Pickering emulsion was first used for topical administration to reduce skin irritation of surfactants and promote transdermal absorption of drugs. Recently, new oral and injectable Pickering emulsions have also been reported, which can promote oral absorption of insoluble drugs, improve stability of drugs, control drug release, targeted-delivery drugs, and serve as the carrier for novel immunological adjuvants. All these studies show Pickering emulsion a promising drug delivery system. However, its development in pharmacy is still in its infancy. There are many factors influencing the preparation of Pickering emulsions. But there is no systematic analysis of these factors up to now. In this review, we gave an overview of Pickering emulsions from their application in pharmaceutical field, preparation and evaluation, focusing on the effects of solid particles, oil phase, preparation technology and interaction of various factors on the fabrication of Pickering emulsions. The challenges and future directions of this exciting and rapidly expanding research area were further commented on, in order to provide reference for the in-depth study of Pickering emulsion drug delivery systems.

Preparation of baicalin solid nanocrystal using glycyrrhizic acid as a natural stabilizer / 中草药

Objective To prepare baicalin solid nanocrystal (BCN-SN) stabilized by glycyrrhizic acid (GA) and determine its in vitro release characteristics. Methods The high-speed shearing-high pressure homogenization technology was adopted in the preparation of BCN nanosuspension, and then BCN nanosuspension was solidified into BCN-SN by freeze-drying. The formula and process of BCN-SN were optimized by the single factor experiment with average particle size and polydispersity index (PDI) as indicator. BCN-SN were prepared under the optimal conditions and characterized for crystal-linity and particle size. In vitro release of BCN-SN was also determined. Results The particle size of BCN-SN stabilized by GA and protected by mannitol-GA was (478.0 ± 6.5) nm, and the polydispersity index (PDI) was 0.230 ± 0.015, respectively. The results of SEM showed that BCN-SN was irregular spherical and DSC showed that BCN-SN was amorphous after being prepared into solid nanocrystal. In the in vitro dissolution test, BCN-SN showed a significantly increased dissolution. Conclusion The method employed to prepare the BCN-SN stabilized by GA is simple and low-cost. BCN-SN can significantly improve the dissolution of BCN, which has a broad application.

Preparation and Quality Evaluation of Magnolol Nano-crystal Suspension / 中国药房

OBJECTIVE： To prepare Magnolol nano-crystal suspension （MAG-NS）， and to conduct quality evaluation. METHODS： The preparation technology of MAG-NS was optimized by central composite design-response surface methodology with OD value of particle size and polydispersity coefficient as evaluation indexes， using volume ratio of organic phase to water phase， ratio of excipient to drug， concentration of magnolol as factors and conduct validation tests. The quality of MAG-NS prepared optimal technology was evaluated. RESULTS： Optimized technology included that the volume ratio of organic phase to water phase was 1 ∶ 5， mass ratio of excipient to drug was 4 ∶ 1， concentration of magnolol was 2 mg/mL. In 3 times of validation tests， average OD value was 0.940 0 （RSD＝0.08％）， relative error of which to predicted value 0.977 7 was 3.86％. magnolol nano-crystals of MAG-NS prepared by the optimal technology were spherical， uniform in size， smooth in surface， with particle size of （34.88±0.33） nm， polydispersity coefficient of 0.032±0.001 and drug loading amount of （17.83±0.92）％. CONCLUSIONS： Established preparation method is simple and feasible. Prepared MAG-NS is in line with quality requirements. It can provide reference for further development and utilization of MAG-NS.

Nanocristais de flubendazol: preparação e caracterização físico-química / Flubendazole nanocrystals: preparation and physical-chemical characterization

Os nanocristais são partículas de fármacos cristalinos, com tamanho médio na faixa de submicrons, geralmente entre 200 e 500 nm, estabilizados por agentes estéricos ou eletrostáticos adsorvidos na superfície das partículas do fármaco. Sua dimensão reduzida proporciona propriedades especiais, como a adesividade às mucosas e o aumento de área superficial e da solubilidade de saturação, o que melhora significativamente a biodisponibilidade de fármacos pouco solúveis em água. Outra aplicação emergente dos nanocristais é na melhoria da entrega e da retenção de fármacos em tecidos e células tumorais. Estudos demonstraram que o flubendazol é um fármaco capaz de induzir a morte celular em tumores malignos e retardar o seu crescimento, por meio da alteração que provoca na estrutura dos microtúbulos e pela inibição da polimerização da tubulina. Foi demonstrada sua atividade antiproliferativa em linhagens de leucemia, mieloma, câncer intestinal, câncer de mama e neuroblastoma. O flubendazol é também um fármaco eficaz contra os helmintos, demonstrando atividade superior na eliminação dos vermes adultos, quando comparado com a dietilcarbamazina. Embora o flubendazol pareça ser uma molécula promissora, é um fármaco praticamente insolúvel em água (0,005 mg/mL). Para atingir o efeito terapêutico desejado, é necessário o desenvolvimento de uma formulação com melhores solubilidade e biodisponibilidade. Nesse sentido, o presente trabalho apresenta o preparo e a caracterização físico-química de nanocristais de flubendazol por meio da microfluidização. Foram realizados ensaios exploratórios para avaliar a performance de diferentes agentes estabilizantes nas suspensões: o polissorbato 80, o polaxamer 188 e o D-α tocoferol polietilenoglicol 1.000 succinato (TPGS). A avaliação da distribuição do tamanho de partícula foi realizada por espalhamento de luz laser (LLS), espalhamento de luz dinâmica (DLS), análise de rastreamento de nanopartículas (NTA) e microscopia eletrônica de varredura (MEV). A utilização do TPGS favoreceu a obtenção de uma nanossuspensão com o menor diâmetro hidrodinâmico médio das partículas, de 253,9 ± 3,0 nm. Nos estudos exploratórios, também foram determinados os parâmetros ótimos de moagem do microfluidizador, sendo estabelecidos: 35.000 psi de pressão, temperatura do produto de 30°C (± 5°C) e tempo de recirculação de 2 horas/100 gramas. Objetivando alcançar o menor diâmetro hidrodinâmico médio dos nanocristais, executou-se um planejamento estatístico no qual foi avaliada a influência da concentração de flubendazol (% p/p) e de TPGS (% p/p) na formulação. A análise revelou a significativa influência da concentração do TPGS na redução do tamanho de partícula e na estabilidade físico-química da nanossuspensão. Ensaios complementares de solubilidade demonstraram que o nanocristal proporcionou incremento na solubilidade de 2,3 e 3,2 e 5,2 vezes em HCl 0,1 N, tampão fosfato pH 6,8 e tampão fosfato salino pH 7,4, respectivamente. No ensaio de dissolução conduzido em HCl 0,1 N e 0,1% TPGS, observou-se significativo incremento, de 41% de fármaco dissolvido após 60 minutos, quando comparado com o flubendazol micronizado. As características do estado sólido do nanocristal foram avaliadas por meio de análise térmica (calorimetria exploratória diferencial e termogravimetria) e difratometria de raios X, não sendo observadas significativas alterações da estrutura cristalina. O presente trabalho também avaliou a efetividade dos nanocristais de flubendazol em tumores de pulmão, demonstrando sua expressiva capacidade de retardar o crescimento e diminuir o tamanho desses tumores em camundongos xenotransplantados

Os nanocristais são partículas de fármacos cristalinos, com tamanho médio na faixa de submicrons, geralmente entre 200 e 500 nm, estabilizados por agentes estéricos ou eletrostáticos adsorvidos na superfície das partículas do fármaco. Sua dimensão reduzida proporciona propriedades especiais, como a adesividade às mucosas e o aumento de área superficial e da solubilidade de saturação, o que melhora significativamente a biodisponibilidade de fármacos pouco solúveis em água. Outra aplicação emergente dos nanocristais é na melhoria da entrega e da retenção de fármacos em tecidos e células tumorais. Estudos demonstraram que o flubendazol é um fármaco capaz de induzir a morte celular em tumores malignos e retardar o seu crescimento, por meio da alteração que provoca na estrutura dos microtúbulos e pela inibição da polimerização da tubulina. Foi demonstrada sua atividade antiproliferativa em linhagens de leucemia, mieloma, câncer intestinal, câncer de mama e neuroblastoma. O flubendazol é também um fármaco eficaz contra os helmintos, demonstrando atividade superior na eliminação dos vermes adultos, quando comparado com a dietilcarbamazina. Embora o flubendazol pareça ser uma molécula promissora, é um fármaco praticamente insolúvel em água (0,005 mg/mL). Para atingir o efeito terapêutico desejado, é necessário o desenvolvimento de uma formulação com melhores solubilidade e biodisponibilidade. Nesse sentido, o presente trabalho apresenta o preparo e a caracterização físico-química de nanocristais de flubendazol por meio da microfluidização. Foram realizados ensaios exploratórios para avaliar a performance de diferentes agentes estabilizantes nas suspensões: o polissorbato 80, o polaxamer 188 e o D-α tocoferol polietilenoglicol 1.000 succinato (TPGS). A avaliação da distribuição do tamanho de partícula foi realizada por espalhamento de luz laser (LLS), espalhamento de luz dinâmica (DLS), análise de rastreamento de nanopartículas (NTA) e microscopia eletrônica de varredura (MEV). A utilização do TPGS favoreceu a obtenção de uma nanossuspensão com o menor diâmetro hidrodinâmico médio das partículas, de 253,9 ± 3,0 nm. Nos estudos exploratórios, também foram determinados os parâmetros ótimos de moagem do microfluidizador, sendo estabelecidos: 35.000 psi de pressão, temperatura do produto de 30°C (± 5°C) e tempo de recirculação de 2 horas/100 gramas. Objetivando alcançar o menor diâmetro hidrodinâmico médio dos nanocristais, executou-se um planejamento estatístico no qual foi avaliada a influência da concentração de flubendazol (% p/p) e de TPGS (% p/p) na formulação. A análise revelou a significativa influência da concentração do TPGS na redução do tamanho de partícula e na estabilidade físico-química da nanossuspensão. Ensaios complementares de solubilidade demonstraram que o nanocristal proporcionou incremento na solubilidade de 2,3 e 3,2 e 5,2 vezes em HCl 0,1 N, tampão fosfato pH 6,8 e tampão fosfato salino pH 7,4, respectivamente. No ensaio de dissolução conduzido em HCl 0,1 N e 0,1% TPGS, observou-se significativo incremento, de 41% de fármaco dissolvido após 60 minutos, quando comparado com o flubendazol micronizado. As características do estado sólido do nanocristal foram avaliadas por meio de análise térmica (calorimetria exploratória diferencial e termogravimetria) e difratometria de raios X, não sendo observadas significativas alterações da estrutura cristalina. O presente trabalho também avaliou a efetividade dos nanocristais de flubendazol em tumores de pulmão, demonstrando sua expressiva capacidade de retardar o crescimento e diminuir o tamanho desses tumores em camundongos xenotransplantados

Review and prospect on preparation technology of drug nanocrystals in the past thirty years / 药学学报

Nanocrystals is a hot topic of poorly soluble drug delivery system under development. Nanocrystals is different from the nanoparticles for drug unloading in polymer materials, and nanocrystals is different from solid dispersion system, in which the drug maintains crystals state. Nanocrystals has a simple preparation process, represents an effective technology in the improvement of solubility and bioavailability of poorly soluble drugs, and has a very promising industrialization application and development potential. In this paper, we retrospect the development history of drug nanocrystals technology, review development of the preparation methods of nanocrystals, and analyze the existing problems to provide a reference to the development of drug nanocrystals preparation.

Preparation and evaluation of progesterone injection with different particle size / 国际药学研究杂志

Objective To compare the release rate and bioavailability of progesterone injection with different particle sizes. Methods The preparation of progesterone nano sized injection and micron sized injection were performed by power X-ray diffraction (PXRD)and Fourier trensform infrared spectooscory(FTIR). The dissolution rate of two preparations and progesterone was compared by dialysis Method. HPLC-MS method was used to determine the progesterone concentration of plasma in rats after intramuscular injec-tion of different preparations,and the main pharmacokinetic parameters were calculated and analyzed statistically. Results Based on the analysis of PXRD and FTIR,there were no crystal structure changes between the two preparations and progesterone. The complete release of progesterone nano sized injection and micron sized injection required 2 and 4 h in the PBS solution,respectively,while the release of progesterone required nearly 40 h. In the pharmacokinetic experiment,compared with progesterone injection,the Cmax of pro-gesterone nano sized injection and micron sized injection were increased by 1.8 and 1.7 times,respectively;the AUC0-t were increased by 2.95 and 1.63 times,respectively. The bioavailability of both was higher than that of progesterone injection. Conclusion The re-lease rate bioavailability of progesterone nano sized injection and micron sized injection is higher than that of progesterone and proges-terone injection. Bioavailability of progesterone nano sized injection is higher than that of progesterone micron sized injection.

Preparation and property of gelatin hydrogel loaded with AgSD-nanocrystal / 国际药学研究杂志

Objective To prepare a silver sulfadiazine(AgSD)-nanocrystal loaded hydrogel with gelatin as the main raw mate-rial,genipin as crosslinker,and test its physicochemical property and drug release characteristics. Methods AgSD-nanocrystal was prepared by ball milling,the particle size and polydispersity index were determined,the solubility was studied by an ultra perfor-mance liquid chromatography(UPLC)method and the microstructure was observed with transmission electron microscope(TEM);drug loaded gelatin hydrogel in different crosslinking degrees were prepared,the dissolution rate was studied in the same way as AgSD-nanocrystal and the possible dissolution mechanism was analyzed by fitting curves;the microstructure was observed by scanning elec-tron microscope(SEM). After 6 weeks,with the same method,all the above mentioned properties of drug loaded hydrogel and AgSD-nanocrystal suspension were determined repeatedly,and at the same time their stability was tested. Results After nanocrystalliza-tion,the polydispersity index of AgSD was 0.211,the mean particle size was about 267.8 nm,the dissolution rate greatly increased within 6 hours compared with that of AgSD bulk powder. There was a negative correlation between dissolution rate and crosslinking de-gree,and the nanoparticle gel's curve was higher than that of the bulk. In terms of stability,AgSD-nanocrystal in hydrogel was almost in the original state in SEM,while those in suspention had an increasing particle size and decreasing dissolution rate. Conclusion The stability and dissolution of the new drug loaded hydrogel are good,and its data can be used as reference for relevant study.

Effects of different preparation technologies on concentrations of puerarin and catalpol in plasma and brain of rats after oral administration / 中国中药杂志

To compare the effects of different preparation technologies on the concentrations of puerarin and catalpol in plasma and brain of rats after oral administration, in order to lay an experimental basis for developing new oral Zige preparations. The nanocrystal, self-microemulsions (tween-80 and Cremophor RH-40 as emulsifiers) and inclusion complex of HP-β-CD containing puerarin and catalpol were prepared. The concentrations of puerarin and catalpol in plasma and brain of rats after oral administration were determined by HPLC-MS/MS method. The pharmacokinetic parameters and brain target index were compared. The results showed that preparation technologies had different influences on the concentrations of puerarin and catalpol in plasma and brain. The self-microemulsion (tween-80) could significantly increase the oral absorption of puerarin than other technologies(P<0.05), and inclusion complex could remarkably increase the oral absorption of catalpol than nanocrystal(P<0.01). For puerarin, the brain targeting index of inclusion complex was the highest (P<0.05); but for catalpol, the brain targeting index of inclusion complex and self-microemulsions were both higher than nanocrystal (P<0.05). The self-microemulsion(tween-80) had the highest AUCbrain of puerarin than other groups (P<0.01); the inclusion complex had the highest AUCbrain for catalpol, but there was no significant difference compared with self-microemulsions. In conclusion, the self-microemulsion (tween-80) technology could increase the amount of puerarin and catalpol in brain, and was expected to be used in new oral Zige preparations.

Preparation of hyperoside solid nanocrystal and evaluation of its in vitro release / 中草药

Objective: To prepare the hyperoside solid nanocrystal (Hyp-SN) and to determine the in vitro release. Methods: The high pressure homogenization technology was applied to preparing Hyp nanosuspension, and then Hyp-NS was solidificated into Hyp-SN by freeze-drying. The fomulation and process of Hyp-SN were optimized by the single factor experiment. Dried powders were prepared under the optimal condition and characterized for crystallinity and particle size. In vitro dissolution of Hyp-SN was also determined. Results: The particle size of Hyp-SN protected by tert-butyl alcohol was (405.2 ± 14.6) nm, as well as the polydispersity index (PI) was 0.25 ± 0.08. The results of SEM showed that Hyp-SN powder was irregular rod and XRD showed Hyp was crystalline in both coarse powder and nanosuspensions. In the in vitro dissolution test, Hyp-SN showed an increased dissolution markedly. Conclusion: The method employed to prepare the Hyp-SN is simple and feasible. Hyp-SN could significantly improve the dissolution of Hyp. It has a broad application prospects.

Dissolution detection of progesterone nanocrystal capsule by HPLC / 国际药学研究杂志

Objective To establish an HPLC method to determine the dissolution of progesterone nanoerystal eapsule. Methods The dissolution was determined by the first method described in Chinese pharmacopoeia (ChP) 2010. Totalis 900 ml of 0.25% sodium lauryl sulfate solution were used as dissolution media, and the rotation speed was 75 r/min. The dissolution lime was 45 min and the dissolution was determined by HPLC. The HPLC column was Agilent TC C18 column (150 mm×4.6 mm.5 µ.rn). The mobile phase was methanol-acetonitrile-water (35-40-25, V/V/V), with a flow rate of 1.0 ml/min and the detection wavelength of 241 nm. The column temperature was 25°C and the injection volume was 20 µ1. Results The average recovery of the method was about 100.02%(n=15 ), and the stability of working solutions was acceptable in 24 h (RSD=0.92%, n=8). The calibration curves showed good linearity (r= 1,n=6) within ranges of 2.78-66.7 µg/ml. Conclusion The method is convenient and sensitive in the dissolution letermination ol progesterone nanncrvstal capsule.