[Characteristics of CMR Appearance in a Case of Cardiac Metastatic Melanoma].

A 53-year-old woman was found "an occupant in the left ciliary body" two years ago and underwent the surgery of "left eye ball removal". Pathological results confirmed the diagnosis of malignant melanoma. The patient was admitted to our hospital again due to newly found heart murmur. With the combination of cardiac magnetic resonance (CMR) imaging characteristics, including high signals on T1-weighted and fat-suppressed T1-weighted images, the high signal on T2-weighted images, uneven first-pass perfusion and late gadolinium enhancement (LGE), as well as PET signal characteristics, the diagnosis of malignant melanoma cardiac metastasis was made. This case suggests that multimodality CMR, including T1-weighted, T2-weighted, first-pass perfusion, late gadolinium enhancement, and cine imaging, can be used to monitor and detect cardiac metastasis of melanoma in a relatively early stage. Therefore, we recommend a routine echocardiography screening for patients diagnosed with melanoma. In addition, CMR examinations and PET/CT may help early detection and timely intervention of melanoma cardiac metastasis, as for their good specificity in detecting, this disease in clinical practice.

[Effect and regulation of drying on quality of traditional Chinese medicine pills].

The dry quality of traditional Chinese medicine pills is the hot spot of pills research, because their quality has a crucial effect on the efficacy and development of dosage forms. Through literature research and statistical analysis, we would review the current problems on the drying of traditional Chinese medicine pills in this paper, and surrounding the evaluation system for traditional Chinese medicine pills, analyze the characteristics of common drying equipment and processes as well as their effect on quality of pills, discuss the problems in drying equipment and process as well as quality, and put forward the corresponding strategies, hoping to provide new ideas and new methods for the quality improvement of traditional Chinese medicine pills and quality standards.

[Status, problems and warranty strategy of quality uniformity for traditional Chinese medicine preparations].

The quality uniformity of traditional Chinese medicine (TCM) preparation is the base for guaranteeing the safety and effectiveness of clinical medication. At present, the quality of TCM preparation is uneven. At present, the same TCM preparation in different manufacturers, TCM preparations in the same manufacturer, and even different batches of a same TCM preparation in the same manufacturer have great differences in quality, which can not reach stability and uniformity. This paper would discuss the possible factors that influence the uniformity of quality in the whole process of pharmacy by means of consulting relevant literature on quality control of Chinese herbal preparations and analyzing the present situation and problems of the quality of TCM preparation. In addition, some strategies such as standardization of cultivation of TCM, processing standardization, standardization of pharmaceutical equipment, mixed batch feeding, and Quality by Design would be also put forward to provide references for the quality uniformity of TCM preparation.

Structural Stabilities and Transformation Mechanism of Rhynchophylline and Isorhynchophylline by Ultra Performance Liquid Chromatography/Time-of-Flight Mass Spectrometry (UPLC/Q-TOF-MS).

To reveal the structural stabilities and transformation mechanism of rhynchophylline (RIN) and isorhynchophylline (IRN), HPLC and UPLC-Q-TOF-MS method were developed for the qualitative and quantitative analysis of the conversion rate. The method was validated for linearity, inter- and intra-day precisions, repeatability and stability. All the quantitative determination method validation results were satisfactory. Under the optimized chromatographic conditions, the effect of various heat temperatures, retention time, and solvent polarities on conversion rate and equilibrium were systematically investigated for the first time. Besides, a model relating the retention yield value and time-temperature was built to predict the t0.5 and Ea of the conversion rate by the Arrhenius equation. The experimental results proved to be in good accordance with the predicted values. Furthermore, UPLC-Q-TOF-MS analysis was performed to verify the transformation mechanism and provide valuable information for stability analysis of the conversion products.

[Status and problem analysis of drying process and equipment for traditional Chinese medicinal materials and preparations].

Drying is the critical link during pharmaceutical process of traditional Chinese medicine (TCM), which is directly related to the quality of drugs. The key to technology upgrading of pharmaceutical equipment in Chinese materia medica enterprise is the development of new drying techniques, which concerns the modernization of TCM. The study provides new ideas for the drying technology and equipment by means of reviewing the research status of drying process for the traditional Chinese medicinal materials and preparations, and analyzing the traditional and modern drying methods and equipment, as well as their existing problems and corresponding measures for the drying processes and equipment. In addition, this paper expounds the development trend of traditional Chinese medicinal materials and preparations of drying process and equipment.

A novel high-pressure precipitation tandem homogenization technology for drug nanocrystals production - a case study with ursodeoxycholic acid.

To overcome the limitations of the conventional particle size reduction technologies, a novel combinative particle size reduction method for the effective production of homogeneous nanosuspensions was investigated. Ursodeoxycholic acid, a poorly soluble drug representative, was tried to prepare nanosuspension by homogenization technology and high-pressure precipitation tandem homogenization technology. It was shown that the combinative approach could significantly improve the particle size reduction effectiveness over conventional homogenization approach. The Box-Behnken design analysis for process optimization revealed that the acceptable UDCA-NS was obtained wherein the optimal values of A, B, C and D were 10%, 500 bar, 0.125 and 600 bar, respectively. SEM results demonstrated that no significant aggregation or crystals growth could be observed in the freeze-dried UDCA nanocrystals. The DSC and XRD results showed that UDCA remained in a crystalline state. Dissolution velocities of the freeze-dried UDCA-NS powder were distinctly superior compared to those of the crude powder and physical mixture. The high-pressure precipitation tandem homogenization technology can be a good choice for nanosuspension preparation of poorly soluble UDCA, due to high efficiency of particle size reduction.

[Advance in studies on establishment methods of responsive drug delivery system].

Responsive drug delivery system can release drug at specific time and sites, and effectively overcome the drug resistance of organisms. With such advantages as drug protection, local targeting, inhibition of enzymatic activity, memory and expression, it has good prospect of application. So far, many chemical preparations have been launched in the market. This article mainly summarizes the advance in studies on establishment methods of responsive drug delivery system, while proposing research ideas for the traditional Chinese medicine component-based responsive drug delivery system according to the multi-component, multi-link and multi-target characteristics, in the expectation of providing reference and thought for the development of the drug delivery system.

Process optimization by response surface design and characterization study on geniposide pharmacosomes.

The objective of this study was to prepare and characterize geniposide-pharmcosomes (GP-PMS) and optimize the process and formulation variables using response surface methodology. Tetrahydrofuran was used as a reaction medium, GP and phospholipids were resolved into the medium, and GP-PMS was formed after the organic solvent was evaporated off under vacuum condition. The process and formulation variables were optimized by central composite design (CCD) of response surface methodology (RSM). The phospholipid-to-drug ratio (X(1)), reaction temperature (X(2)) and the drug concentration (X(3)) were selected as independent variables and the yield (%) of GP 'present as a complex' in the PMS was used as the dependent variable. The physico-chemical properties of the complex obtained by optimal parameters were investigated by means of Fourier transform infrared spectrophotometry (FT-IR), differential scanning calorimetry, n-octanol/water partition coefficient (P) and particle size analysis. Multiple linear regression analysis for optimization by CCD revealed that the higher the yield of GP 'present as a complex' in the GP-PMS was obtained wherein the optimal settings of X(1), X(2) and X(3) are 3, 50°C and 5.5 mg/mL, respectively. The DSC and IR studies of GP-PMS by the optimal settings demonstrated that GP and phospholipids in the GP-PMS were combined by non-covalent bond, not forming a new compound. GP-PMS could significantly increased the lipophilicify of GP, and P of GP-PMS in n-octanol and water was about 20 multiples more than that of GP material. Pharmacosomes could be an alternative approach to improve the absorption and permeation of biologically active constituents.

[The research progress of preparation methods of solid nanocrystal delivery system].

Nanocrystal suspensions drug delivery system is used to solve the delivery difficulty of poorly soluble drug. However, the physical stability of liquid nanocrystal suspensions is very bad. Solid nanocrystal delivery system as a novel technology, can improve the thermokinetics stability of nanocrystal suspensions and have good clinical compliance, which can achieve stabilization of nanocrystal suspension systems as an ideal delivery system. In this paper, we reviewed the research progress of nanotechnology and solidification technology of solid nanocrystal suspension delivery system, which will give the new mirrors and thoughts on the development of solid nanocrystal delivery system.

Essential oil of Ligusticum chuanxiong Hort. Regulated P-gp protein and tight junction protein to change pharmacokinetic parameters of temozolomide in blood, brain and tumor.

ETHNOPHARMACOLOGICAL RELEVANCE: The existence of the blood-brain barrier/blood tumor barrier (BBB/BTB) severely restricts the effectiveness of anti-tumor drugs, thus glioma is still an incurable disease with a high fatality rate. Chuanxiong (Ligusticum chuanxiong Hort., Umbelliferae) was used as a messenger drug to increase the distribution of drugs in brain tissue, and its application in Chinese herbal formula for treating glioma was also the highest. AIM OF THE STUDY: Our previous researches showed that essential oil (EO) of chuanxiong could promote temozolomide (TMZ) entry into glioma cells in vitro and enhance TMZ-induced anticancer efficiency in vivo, and therefore, the aim of this study was to investigate whether EO could increase the concentration accumulation of TMZ in brain or tumor of C6 glioma rats and the related mechanisms. MATERIALS AND METHODS: The pharmacokinetics were conducted in C6 glioma rats by administering either TMZ alone or combined with EO through oral routes. TMZ concentration in blood, brain and tumor was detected using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and then pharmacokinetic parameters were calculated. The changed expressions of P-gp protein, tight junction occludin, claudin-5 and zonula occludens-1 (ZO-1) in brain of glioma rats were studied by Western blot to clarify the mechanism. Finally, the chemical composition of EO was analyzed by gas chromatography-massspectrometry (GC-MS). RESULTS: The results showed that EO significantly affected the pharmacokinetic parameters such as Tmax, Cmax and CL (p < 0.01), but did not significantly change the AUC(0→∞) of TMZ in blood (p > 0.05). However, EO markedly improved the AUC(0→∞)of TMZ in brain and tumor (p < 0.01). The calculate drug targeting index was greater than 1, indicating that EO could promote the distribution of TMZ to the brain and tumor. Western blot analysis showed that EO significantly inhibited the expression of P-gp, tight junction protein claudin-5, occludin and ZO-1. And meanwhile, the expressions of P-gp, claudin-5 and occludin also markedly down-regulated in EO-TMZ co-administration treatment. GC-MS analysis of the TIC component of EO was (E)-Ligustilide (36.93%), Terpinolene (7.245%), gamma-terpinene (7.225%) etc. CONCLUSION: EO could promote the distribution of TMZ in the brain and tumor of C6 glioma rats, which may attribute to down-regulate the expression of P-gp, claudin-5 and occludin.

["Total amount" release kinetics evaluation of traditional Chinese medicine sustained-release preparations based on material rough set theory].

The release kinetics research of sustained-release formulations of traditional Chinese medicines (TCM) is an inalienable part of the chain of TCM modernization, which plays an important role in the development of modern compound TCM preparation. However, the research method or pattern in line with the specific characteristics of TCM, i.e., multi-component and multi-target, is still lacking. On the basis of material rough set theory, this paper reviewed the advantages and disadvantages of the existing evaluation patterns and methods, a tentative idea about the "total amount" release characteristics evaluation on TCM compound sustained-release preparation has suggested so as to evaluate the release kinetics and to promote the development of evaluation methodology on TCM sustained-release preparations.

Preparation of Puerarin Chitosan Oral Nanoparticles by Ionic Gelation Method and Its Related Kinetics.

In this paper, as an active ingredient, puerarin chitosan nanoparticles (Pur-CS/TPP-NPs) are prepared by an ionic gelation method. The chitosan (CS) concentration, pH of the CS solution, sodium tripolyphosphate (TPP) concentration, stirring speed, stirring time, ultrasonic power, and dosage are used as single factors for investigation, and the encapsulation efficiency, drug loading capacity, particle size, and polydispersity index (PDI) are used as indicators for investigation. The optimal prescription is determined using the Box-Behnken effect surface design method. The characterization of the best formulation, which is determined via an in vitro release assay and liquid chromatography/tandem mass spectrometry (LC-MS/MS) analysis methods, is used here for pharmacokinetic studies. An in situ single-pass intestinal perfusion model is used to investigate drug absorption in the intestine. After characterization, the morphologies of the nanoparticles are intact. It can be seen from the in vitro release experiments that the equation fitted by the nanoparticles is the Higuchi model, the nanoparticle release process is very stable and without sudden release, indicating that the nanoparticles are well-released in vitro. The pharmacokinetic results and the in situ single-pass intestinal perfusion model study show that the bioavailability and absorption of Pur-CS/TPP-NPs were significantly higher than Pur. Thus, all the results show that the prepared nanoparticles can significantly improve the bioavailability of Pur, and we hope to lay the foundation for the development of new products of Pur.

The study on the entrapment efficiency and in vitro release of puerarin submicron emulsion.

The entrapment efficiency (EE) and release in vitro are very important physicochemical characteristics of puerarin submicron emulsion (SME). In this paper, the performance of ultrafiltration (UF), ultracentrifugation (UC), and microdialysis (MD) for determining the EE of SME were evaluated, respectively. The release study in vitro of puerarin from SME was studied by using MD and pressure UF technology. The EE of SME was 86.5%, 72.8%, and 55.8% as determined by MD, UF, and UC, respectively. MD was not suitable for EE measurements of puerarin submicron oil droplet, which could only determine the total EE of submicron oil droplet and liposomes micelles, but it could be applied to determine the amount of free drug in SMEs. Although UC was the fastest and simplest to use, its results were the least reliable. UF was still the relatively accurate method for EE determination of puerarin SME. The release of puerarin SME could be evaluated by using MD and pressure UF, but MD seemed to be more suitable for the release study of puerarin emulsion. The drug release from puerarin SME at three drug concentrations was initially rapid, but reached a plateau value within 30 min. Drug release of puerarin from the SME occurred via burst release.

Preparation, characterization, and bioavailability of ursodeoxycholic acid-phospholipid complex in vivo.

The aim of this study was to prepare ursodeoxycholic acid-phospholipid complex (UDCA-PLC) to enhance oral bioavailability of UDCA, and the physicochemical properties of the complex were studied. Compared with those of UDCA tablet after oral administration in rats, the main pharmacokinetic characteristics and bioavailability of UDCA-PLC orally administered were evaluated. Tetrahydrofuran was used as a reaction medium, UDCA and phospholipids were resolved into the medium, and UDCA-PLC was formed after the organic solvent was evaporated off under vacuum condition. The physicochemical properties of the complex were evaluated using scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction, particle size distribution analysis, and n-octanol/water partition coefficient (P) study. The blood concentrations of UDCA-PLC and UDCA tablet at different time points after oral administration in rats were assayed by high-performance liquid chromatography (HPLC) after derivatization. The pharmacokinetic parameters were computed by software program 3p87. The X-ray diffraction and DSC studies showed that UDCA and phospholipids in the UDCA-PLC were combined by noncovalent bond, not forming a new compound, and n-octanol/water partition coefficient (P) of UDCA-PLC was effectively enhanced. The mean serum concentration-time curves of UDCA after oral administration of UDCA-PLC and UDCA tablet in rats were both in accordance with open two-compartment model. Pharmacokinetic parameters of UDCA tablet and the PLC in rats were T(max) 1.9144 and 1.5610 h, C(max) 0.0576 and 0.1346 microg/mL, and AUC(0-infinity) 4.736 and 11.437 microg h/mL, respectively. The bioavailability of UDCA in rats was significantly different (p < .05) compared with those of UDCA tablet after administration. The UDCA-PLC would be more prospective formulation in future.

Process optimization, characterization and pharmacokinetic evaluation in rats of ursodeoxycholic acid-phospholipid complex.

The purpose of this research was to study whether the bioavailability of ursodeoxycholic acid could be improved by administering ursodeoxycholic acid-phospholipid complex (UDCA-PLC) orally to rats. A central composite design approach was used for process optimization in order to obtain the acceptable UDCA-PLC. The physicochemical properties of the complex obtained by optimal parameters were investigated by means of scanning electron microscopy and X-ray diffraction. The pharmacokinetic parameters and bioavailability studies were conducted in rats of UDCA after oral administration of UDCA-PLC and UDCA tablet. Multiple linear regression analysis for process optimization revealed that the acceptable UDCA-PLC was obtained wherein the optimal values of X(1), X(2) and X(3) were 3, 60 degrees C and 3 h, respectively. The XRD studies of UDCA-PLC obtained by the optimal parameters demonstrated that UDCA and phospholipids in the UDCA-PLC were combined by non-covalent bonds, not form new compounds. But pharmacokinetic parameters of the complex in rats were T(max) 1.6 h, C(max) 0.1346 microg/ml, AUC(0-infinity) 11.437 microg x h/ml, respectively. The relative bioavailability of UDCA of UDCA-PLC was increased by 241%,compared with the reference ursodeoxycholic acid tablet.

Preparation, characterization, and pharmacokinetic evaluation of puerarin submicron emulsion.

A novel formulation of puerarin was studied. Puerarin submicron emulsion was prepared by complex phase inversion-high-pressure homogenization technology. Characterization, distribution of drug in emulsion, short-term stability, and pharmacokinetics of emulsion were evaluated. The mean diameter and zeta potential of puerarin emulsion were 188.14 nm and -29.45 mv, respectively. The distribution range of puerarin emulsion was very narrow. The concentration of puerarin in the interfacial surface, oil droplet, water, and liposome-micelles were 7.821, 1.079, 0.637 and 0.423 mg/mL, respectively. Puerarin submicron emulsion was stable for a period of 3 months. The area under the whole blood concentration-time curve of rabbits after intravenous administration of puerarin emulsion was 1.718-fold higher than that of rabbits of intravenous administration of puerarin (P < 0.05). And compared with the puerarin group, the elimination rate of puerarin emulsion group was significantly decreased (P < 0.05), and the biological half-life and the mean retention time of puerarin emulsion were markedly increased (P < 0.05).

[Preparation and characterization of the puerarin submicron emulsion].

To decrease the hemolysis side effect of puerarin, the basic formula and preparation of puerarin submicron emulsion were optimized and the physicochemical properties were evaluated. Puerarin submicron emulsions were prepared by phase inversion-ultrasound combining with phospholipids complexes technology. The effects of preparative parameters, such as emulsification time, stirring velocity and ultrasound time, on mean diameter, span of dispersity, entrapment efficiency and overall desirability were investigated. The three dimensional response surface graphs were produced by second-order polynomial and liner equation, which predict the optimal experiment conditions. All response variables were found to be greatly dependent on three independent variables. Second-order polynomial equations were fitter than liner equations for this study. The optimal emulsification time, stirring velocity and ultrasound time was 15 min, 2 000 r x min(-1), 30 min, respectively. The mean diameter, span of dispersity, entrapment efficiency, drug content and zeta potential of emulsions prepared by the method were 228.23 nm, 0.628 4, 84. 32%, 9.98 mg x mL(-1), - 29.03 mV, respectively. Puerarin submicron emulsion was prepared by the optimized preparation method. The narrow particle diameter distribution, high envelopment efficacy and good stability were obtained. The physicochemical properties were suitable for the requirement of the intravenous emulsion.

Pharmacokinetic comparative study of gastrodin after oral administration of Gastrodia elata Bl. extract and its compatibility with the different indigents of Ligusticum chuanxiong Hort. to rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Da Chuan Xiong Decoction Compound preparation (DCXDCP) is a classic TCM formula of an aqueous extract made from Chuanxiong Rhizoma (Ligusticum chuanxiong Hort., umbelliferae) and Tianma Rhizoma (Gastrodia elata Bl., Orchidaceae). Gastrodin (GAS), a bioactive component of tianma, its pharmacokinetic (PK) behavior significantly changed after oral administration of DCXDCP compared with the extract of tianma. However, little is known about how the ingredients of chuanxiong influenced on the PK of GAS. AIM OF THE STUDY: To study the possible PK behavior differences of GAS after individually oral administration of tianma extract and tianma extract mixed with different active ingredients of chuanxiong to rats, as well as explore whether there were some herb-herb interactions. MATERIALS AND METHODS: Different DCXDCP suspensions were prepared by mixing tianma extract with different active ingredients of chuanxiong. The rats were randomly assigned to six groups and were orally treated with different DCXDCP. At different predetermined time points after administration, the concentrations of GAS in the rat plasma were determined using HPLC, and the main PK parameters were investigated. RESULTS: The results showed that tetramethylpyrazine had no significant effects on the PK parameters of GAS (p>0.05), whereas ferulic acid (FA), total phenolic acids and total alkaloids significantly increased AUC0-∞ (p<0.05). In general the observed changes in the PK parameters of GAS in DCXDCP could be closely related to the total phenolic acids and total alkaloids. CONCLUSION: It could be shown that total phenolic acids and total alkaloids present in Ligusticum chuanxiong in addition to other components not tested yet play an important role in affecting the PK of gastrodin in DCXDCP.

Study on formability of solid nanosuspensions during solidification: II novel roles of freezing stress and cryoprotectant property.

The freezing stress and cryoprotectants were known to be the crucial factors for solidification formability of nanosuspensions during freeze-drying. However, there has been controversy as to whether an aggressive or conservative freezing stress (freezing temperature or freezing rate) prevents from irreversible aggregation of nanosuspensions. And the screening of cryoprotectants for solidification formability of nanosuspensions has largely relied on empirical approaches. A systematic investigation was presented herein regarding the effect of both the freezing stress and property of cryoprotectants on solidification formability of drug nanosuspensions during freeze-drying. It was found that at different freezing stresses (-20 °C, -80 °C, and -196 °C), the redispersibility of BCN, NGN, RCN, and RVL nanosuspensions stabilized, respectively, by seven stabilizers, was RDI(-20 °C)>RDI(-80 °C)>RDI(-196 °C). But the redispersibility of UDCA and OCA nanosuspensions stabilized, respectively, by seven stabilizers, was RDI(-20 °C)

Study on formability of solid nanosuspensions during nanodispersion and solidification: I. Novel role of stabilizer/drug property.

Few or no attempts have been made so far to understand the feasibility of solid nanosuspension formulation during nanodispersion and solidification in terms of drug properties and stabilizer characterizations. In order to establish a knowledge base about the effect of physicochemical property of drug compounds and stabilizers on solid nanosuspension production during nanodispersion and solidification, a comparative study was firstly performed on 10 different stabilizers at 3 concentrations for 8 structurally different drug compounds. Synthetic polymers (HPMC, PVP K30, CMS-Na and MC) displayed a poor stabilizing performance (10% success rate on average) during nanodispersion, but polymers showed better potential when higher concentrations was applied during freezing and lyophilization. Meanwhile, an effect for the surfactants group was even more pronounced during nanodispersion. However, the solid nanosuspension stabilized by surfactants showed the worst formability potential when be applied in setted concentrations during freezing and lyophilization. From the point of view of drug property, it was found that the surface hydrophobicity and cohesive energy of drug, were responsible for the formability of the solid nanosuspension during nanodispersion and solidification. Wetting index (k) and ΔE were concluded to have a direct correlation on the feasibility of formation of a stable solid nanosuspension, which can give a formulation design strategy from where candidate drugs and stabilizers with a set of properties.