[Normalization of the ratio of nitric oxide and peroxynitrite by promoting eNOS dimer activity is a new direction for diabetic nephropathy treatment].

Diabetic nephropathy is a microvascular complication of diabetes. Its etiology involves metabolic disorder-induced endothelial dysfunction. Endothelium-derived nitric oxide (NO) plays an important role in a number of physiological processes, including glomerular filtration and endothelial protection. NO dysregulation is an important pathogenic basis of diabetic nephropathy. Hyperglycemia and dyslipidemia can lead to oxidative stress, chronic inflammation and insulin resistance, thus affecting NO homeostasis regulated by endothelial nitric oxide synthase (eNOS) and a conglomerate of related proteins and factors. The reaction of NO and superoxide (O2.-) to form peroxynitrite (ONOO-) is the most important pathological NO pathway in diabetic nephropathy. ONOO- is a hyper-reactive oxidant and nitrating agent in vivo which can cause the uncoupling of eNOS. The uncoupled eNOS does not produce NO but produces superoxide. Thus, eNOS uncoupling is a critical contributor of NO dysregulation. Understanding the regulatory mechanism of NO and the effects of various pathological conditions on it could reveal the pathophysiology of diabetic nephropathy, potential drug targets and mechanisms of action. We believe that increasing the stability and activity of eNOS dimers, promoting NO synthesis and increasing NO/ONOO- ratio could guide the development of drugs to treat diabetic nephropathy. We will illustrate these actions with some clinically used drugs as examples in the present review.

[Real-time UV imaging of chloramphenicol intrinsic dissolution characteristics from ophthalmic in situ gel].

In this paper, chloramphenicol was selected as a model drug to prepare in situ gels. The intrinsic dissolution rate of chloramphenicol from in situ gel was evaluated using the surface dissolution imaging system. The results indicated that intrinsic dissolution rate of chloramphenicol thermosensitive in situ gel decreased significantly when the poloxamer concentration increased. The addition of the thickener reduced the intrinsic dissolution rate of chloramphenicol thermosensitive gel, wherein carbomer had the most impact. Different dilution ratios of simulated tear fluid greatly affected gel temperature, and had little influence on the intrinsic dissolution rate of chloramphenicol from the thermosensitive in situ gel. The pH of simulated tear fluid had little influence on the intrinsic dissolution rate of chloramphenicol thermosensitive in situ gel. For the pH sensitive in situ gel, the dissolution rates of chloramphenicol in weak acidic and neutral simulated tear fluids were slower than that in weak alkaline simulated tear fluid. In conclusion, the intrinsic dissolution of chloramphenicol from in situ gel was dependent on formulation and physiological factors. With advantages of small volume sample required and rapid detection, the UV imaging method can be an efficient tool for the evaluation of drug release characteristics of ophthalmic in situ gel.

Enhancing Oral Performance of Paclitaxel Lipid-Mimic Prodrug via Modulating Type of Fatty Acids.

Owing to the serious clinical side effects of intravenous Taxol, an oral chemotherapeutic strategy is expected to be promising for paclitaxel (PTX) delivery. However, its poor solubility and permeability, high first-pass metabolism, and gastrointestinal toxicity need to be overcome. A triglyceride (TG)-like prodrug strategy facilitates oral drug delivery by bypassing liver metabolism. However, the effect of fatty acids (FAs) in sn-1,3 on the oral absorption of prodrugs remains unclear. Herein, a series of TG-mimetic prodrugs of PTX is explored with different carbon chain lengths and degrees of unsaturation of FAs at the sn-1,3 position in an attempt to enhance oral antitumor effect and to guide the design of TG-like prodrugs. Interestingly, the different FA lengths exhibit great influence on in vitro intestinal digestion behavior, lymph transport efficiency, and up to fourfold differences in plasma pharmacokinetics. The prodrug with long-chain FAs shows a more effective antitumor effect, whereas the degree of unsaturation has a negligible impact. The findings illustrate how FAs structures affect the oral delivery efficiency of TG-like PTX prodrugs and thus provide a theoretical basis for their rational design.

[Preparation and characterization of dihydroartemisinin/ hydroxypropyl-beta-cyclodextrin inclusion complex].

To optimize the preparation method of the complex of dihydroartemisinin (DHA) included by hydroxypropyl-beta-cyclodextrin (HP-beta-CD), the molar ratio of DHA and HP-beta-CD, inclusion temperature and inclusion time were optimized by the orthogonal design method with the inclusion drug yield and drug loading as the evaluation indexes. The IR spectrum, DSC and PXRD analyses were employed to characterize the complex and the molecular simulation was processed to investigate the tendency of complex formation. The optimized molar ratio of DHA and HP-beta-CD was 1 : 5, and the optimized preparation was performed under 50 degrees C for 1 h. The IR spectrum, DSC and PXRD analyses indicated the formation of the complex. The low binding free energy and the high solvent accessible surface obtained by molecular simulation showed that DHA could be included by HP-beta-CD and its solubility could be improved significantly. In conclusion, the optimized conditions for the preparation of DHA-HP-beta-CD complex provide a theoretical and experimental basis for further scale-up research.

Long chain triglyceride-lipid formulation promotes the oral absorption of the lipidic prodrugs through coincident intestinal behaviors.

Oral administration of chemotherapy agents, such as docetaxel (DTX), is expected to reduce side effects significantly and increase dosing frequency. However, they often suffer from poor oral bioavailability, impeding their oral application. Dietary lipids such as triglycerides favor lymphatic transport nor vein system, bypassing the first-pass metabolism. Inspired by this concept, we developed a triglyceride-like prodrug of DTX (named as OATG) and explored the effect of lipid types on the OATG oral delivery. The plasma profile in rats revealed that long chain triglyceride (LCT)-based lipid formulations (LBLF) were more promising for OATG delivery than medium chain triglyceride (MCT) ones. The OATG LBLF elicited a markedly enhanced absorption compared with oral Taxotere or DTX LBLF, resulting in relative bioavailability 6.11 or 2.47-fold higher, respectively. The coincident intestinal behaviors of lipid excipients and TG-like prodrug facilitate the oral absorption of the prodrug. The effectiveness of the prodrug formulation was also examined in beagles with absolute bioavailability up to 41.08%, in sharp contrast to that of control DTX group (8%). Besides, the OATG oral formulation could be schedule-intensively administrated with no hypersensitivity, gastrointestinal and hematological toxicity. The current strategy provides an effective lipid formulation and a promising chance for chemotherapy at home.

[Pharmaceutical evaluation of hydroxycamptothecin nanosuspensions with the action of inhibiting P-gp].

Oral hydroxycamptothecin nanosuspension (HCPT-Nano) with high supersaturated dissolution level, high permeation and well physical stability, was manufactured by microprecipitation-high press homogenization method. Its pharmaceutical properties were investigated, such as size and distribution, zeta potential, particle shape, physical existence condition, supersaturated dissolution level and so on. Particle size was measured by laser diffraction, and the mean diameters before and after lyophilization were 138 +/- 11.72 nm and 175 +/- 12.74 nm, respectively, for HCPT-Nano. Zeta potentials of HCPT-Nano was over -20 mV. The nanoparticles, being observed by transmission electron microscopy (TEM), were claviform or column in shape. DSC and X-ray diffraction revealed that HCPT existed in the form of crystal for HCPT-Nano. And HCPT-Nano could maintain higher supersaturated dissolution level for long time. So it supplied the possibility of improving oral bioavailability of HCPT when combining together admoveatur of P-gp inhibitor, CsA.

Probing the new strategy for the oral formulations of taxanes: changing the method with the situation.

The first-generation taxanes (including paclitaxel and docetaxel) are widely used for the treatment of various cancers in clinical settings. In the past decade, a series of new-generation taxanes have been developed which are effective in the inhibition of tumor resistance. However, intravenous (i.v.) infusion is still the only route of administration, and may result in serious adverse reactions with respect to the utilization of Cremophor EL or Tween-80 as solvent. Besides, the dosing schedule is also limited. Therefore, oral administration of taxanes is urgently needed to avoid the adverse reactionss and increase dosing frequency. In this review, we first outlined the discovery and development of taxane-based anticancer agents. Furthermore, we summarized the research progress on the oral formulations of taxanes and proposed some thoughts on the future development of oral taxane formulations.

Influence of ion-pairing and chemical enhancers on the transdermal delivery of meloxicam.

PURPOSE: To investigate the influence of ion pairing and chemical enhancers on the transdermal delivery of meloxicam. METHOD: We examined the increased permeation of meloxicam produced by ion pair formation with six organic bases, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, and N-(2'-hydroxyethanol)-piperidine, and four normal permeation enhancers, oleic acid, menthol, azone, and N-methyl-2-pyrrolidone. The cumulative permeation was markedly increased in the presence of either a counter ion or chemical enhancers. In particular, we proved the formation of a meloxicam/amine ion-pair in solution by (13)C-NMR (nuclear magnetic resonance). RESULTS AND CONCLUSION: The cumulative permeation was markedly increased in the presence of either a counter ion or chemical enhancers. These results suggest that the degree of enhancement possibly depends on the structure and hydrophilicity of the counter ions.

[Preparation of in situ gel systems for the oral delivery of ibuprofen and its pharmacokinetics study in beagle dogs].

The in situ gel systems can form gel in situ after administration to achieve sustained release, thus provides a promising strategy for drug delivery systems. The aim of this study was to design and prepare in situ gel systems for the oral delivery of ibuprofen (IBU-ISG) and study its pharmacokinetics in Beagle dogs. The characteristics of the basic material of gellan gum (Kelcogel, Kel) and sodium alginate (Manugel, M) were studied through investigating the complex viscosity of the Kel or M solution with or without different concentrations of calcium ion or sodium citrate to ascertain the amount range of the excipients. The measurement of complex viscosity of the solution (0. 5% Kel and 1% M) with different concentrations of sodium citrate and calcium ion was carried out to select the suitable proportion of calcium ion and sodium citrate. The formulation of binary IBU-ISG was optimized by monitoring the complex viscosity before gelling in vitro release property. The optimized formulation contains 1.0% sodium alginate, 0.5% gellan gum, 0. 21% sodium citrate and 0.056% calcium chloride. A single oral dose of IBU-ISG and reference formulation (IBU suspension) were given to each of the 6 healthy Beagle dogs, ibuprofen in plasma at different sampling times was determined by RP-HPLC. The pharmacokinetics parameters in 6 Beagle dogs were calculated. The Tmax of IBU-ISG and reference formulation were (1.8 +/- 0.6) and (0.4 +/- 0. 1) h. The Cmax values were (29.2 +/- 7.6) and (37.8 +/- 2.2) microg x mL(-1). The T(1/2) were (2.3 +/- 0.5) and (2.0 +/- 0.9) h, and the AUC(0-t) were (131.0 +/- 38.6) and (117.3 +/- 23.1) microg x mL(-1) x h, respectively. The binary IBU-ISG was successfully prepared.

Preparation of the traditional Chinese medicine compound recipe Shuxiong sustained-release capsules by multiparticulate time-controlled explosion technology.

In this study the traditional Chinese medicine compound recipe (TCMCR) Shuxiong sustained-release capsules (SXSRC) were prepared by multiparticulate time-controlled explosion technology. First, Shuxiong pellets were prepared with the refined medicinal materials containing in the recipe of Shuxiong tablets. Then, the pellets were coated sequentially with an inner swelling layer containing low-substituted hydroxypropylcellulose as the swelling agent and an outer rupturable layer of ethylcellulose. Finally, SXSRC were developed by encapsulating five kinds of pellets whose respective coating level of outer layer was 0%, 9%, 15%, 18% and 20% at equivalent ratio in hard gelatin capsules. Under the simulated gastrointestinal pH conditions, the in vitro release test of SXSRC was carried out. The value of similarity factor (f2) of hydroxysafflor yellow A and Panax notoginseng saponins, hydroxysafflor yellow A and ferulic acid, Panax notoginseng saponins and ferulic acid was 90.1, 77.3, 87.0, respectively. The release profiles of these three compositions from SXSRC showed a characteristic of obvious sustained-release and no significant difference between them. The results indicated that using multiparticulate time-controlled explosion technology various components in TCMCR with vastly different physicochemical properties could be released synchronously while sustained-releasing. That complies with the organic whole conception of compound compatibility of TCMCR.

[A new method for quantitative assessment of mechanisms of partitioning and absorption of drugs: linear solvation energy relationships].

Linear solvation energy relationships are of a great value in investigating quantitative structure-retention relationship and quantitative structure-activity relationship, and predicting chromatographic retention indices of drugs. Several quantitative relationships in different in vitro biomembrane-mimetic models between retention factors and molecular descriptors have been established successfully and used to clarify drug-membrane interaction mechanisms. Quantitative structure-activity relationships also have been established to predict drug intestinal absorption, permeation of skin and blood-brain barrier. This review focused on the significance and widely application of linear solvation energy relationships in quantitative assessment for mechanisms of partitioning and absorption of drugs. The discrepancy and limits of linear solvation energy relationships were also discussed, which gives us a better insight into investigation of partitioning and absorption of drugs.

[Percutaneous absorption of meloxicam patches in hairless mouse].

Meloxicam concentration in skin was determined following topical administration of meloxicam patches in hairless mouse. Samples were analysized by HPLC coupled with microdialysis sampling technique, in which in vivo recovery of probe was characterized by the retrodialysis method. It was indicated that the in vivo recovery of the probe was 14.0%. The range of steady state concentration of meloxicam in dialysate was 24-50 ng x mL(-1), and that was 170-360 ng x mL(-1) in the hairless mouse skin. Steady state concentration of meloxicam was reached shortly after the application of meloxicam patches, which was maintained during the period of experiment.

[Assessment of Pueraria lobata isoflavone with self-microemulsifying drug delivery systems in vitro and in vivo].

OBJECTIVE: To evaluate the self-microemulsifying ability and dissolution behavior of pueraria lobata isoflavone in vitro and the pharmacokinetic behavior in rats. METHODS: The self-microemulsifying rate was evaluated by the self-microemulsifying time and the self-microemulsifying efficiency was evaluated by the particle size of resultant microemulsions. The plasma concentrations were evaluated by HPLC and dissolution and pharmacokinetic behavior of self-microemulsifying drug delivery systems were evaluated by comparison with commercial tablets. RESULTS: The system was self-microemulsified in 2 min and the particle size was less than 50 nm. The dis- solution of SMESC in distilled water was more than 90% at 10 min, while those of the commercial tablet were less than 50% at 120 min. 82% increase in the relative bioavailability was observed for the self microemulsifying drug delivery systems compared with Yufengningxin tablets. Tmax was smaller in the self-microemulsifying drug delivery systems compared with Yufengningxin tablets. CONCLUSION: The self-microemulsifying drug delivery systems can increase drug dissolution in vitro and absorption in vivo significantly.

[Studies on preparation of sustained-release Shuxiong formulation, a traditional Chinese medicine compound recipe, using time-controlled release techniques].

OBJECTIVE: To prepare a sustained-release formulation of traditional Chinese medicine compound recipe by adopting time-controlled release techniques. METHOD: Shuxiong tablets were chosen as model drug. The prescription and technique of core tablets were formulated with selecting disintegrating time and swelling volume of core tablets in water as index. The time-controlled release tablets were prepared by adopting press-coated techniques, using PEG6000, HCO and EVA as coating materials. The influences of compositions, preparation process and dissolution conditions in vitro on the lag time (T(lag)) of drug release were investigated. RESULT: The composition of core tablets was as follow: 30% of drug, 50% MCC and 20% CMS-Na. The T(lag) of time-controlled release tablets was altered remarkably by PEG6000 content of the outer layer, the amount of outer layer and hardness of tablet. The viscosity of dissolution media and basket rotation had less influence on the T(lag) but more on rate of drug release. CONCLUSION: The core tablets pressed with the optimized composition had preferable swelling and disintegrating properties. The shuxiong sustained-release formulations which contained core tablet and two kinds of time-controlled release tablets with 3 h and 6 h of T(lag) could release drug successively at 0 h, 3 h and 6 h in vitro. The technique made it possible that various components with extremely different physicochemical properties in these preparations could release synchronously.

[Preparation of Shuxiong micropellets by centrifugal granulation technology].

OBJECTIVE: To prepare shuxiong micropellets. METHOD: Shuxiong micropellets were prepared by using a centrifugal granulator. The formulation composition and process factors were optimized investigated by adopting several indices such as size distribution, repose angle, bulk density and friability as indexes. RESULT: The optimal process parameters were as follows. The ratio of fine intermediate product and MCC was 3:1 (w/w), the adhesive agent was 3% HMPC solution, the rotating rate of plate was 200 r x min(-1), the blower rate was 15 x 20 L x min(-1), the rate of air flow was 15 L x min(-1), the spray air pressure was 0.5 MPa, the rotating of spray solution pump was 5-25 r x min(-1) and the rotating rate of powder feed machine was 5-25 r x min(-1). CONCLUSION: Under the optimal conditions, micropellets prepared by using centrifugal granulator hadpossessed prefect shape and surface characteristics and the yield of shuxiong pellets was 90.5%.

Impact of release characteristics of sinomenine hydrochloride dosage forms on its pharmacokinetics in beagle dogs.

AIM: To investigate the effect of release behavior of sustained-release dosage forms of sinomenine hydrochloride (SM.HCl) on its pharmacokinetics in beagle dogs. METHODS: The in vitro release behavior of two SM.HCl dosage forms, including commercial 12-h sustained-release tablets and 24-h sustained-release pellets prepared in our laboratory, was examined. The two dosage forms were orally administrated to beagle dogs, and then the in vivo SM.HCl pharmacokinetics was investigated and compared. RESULTS: The optimal SM.HCl sustained-release formulation was achieved by mixing slow- and rapid-release pellets (9:1, w/w). The SM.HCl release profiles of the sustained-release pellets were scarcely influenced by the pH of the dissolution medium. Release from the 12-h sustained-release tablets was markedly quicker than that from the 24-h sustained-release pellets, the cumulative release up to 12-h was 99.9% vs 68.7%. From a pharmacokinetic standpoint, the 24-h SM.HCl sustained-release pellets had longer tmax and lower Cmax compared to the 12-h sustained-release tablets, the tmax being 2.67+/-0.52 h vs 9.83+/-0.98 h and the Cmax being 1 334.45+/-368.76 ng/mL vs 893.12+/-292.55 ng/mL, respectively. However, the AUC(0-tn) of two SM.HCl dosage forms was comparable and both preparations were statistically bioequivalent. Furthermore, the two preparations had good correlations between SM.HCl percentage absorption in vivo and the cumulative percentage release in vitro. CONCLUSION: The in vitro release properties of the dosage forms strongly affect their pharmacokinetic behavior in vivo. Therefore, managing the in vitro release behavior of dosage forms is a promising strategy for obtaining the optimal in vivo pharmacokinetic characteristics and safe therapeutic drug concentration-time curves.

[The solubilization effect of 2-hydroxypropyl-beta-cyclodextrin on paeonolum].

OBJECTIVE: To study the solubilization effect of 2-hydroxypropyl-beta-cyclodextrin(HPCD) on paeonolum at various pH value. METHOD: Phase-solubility method was adopted to study the solubilization effect at 25 degrees C and UV spectrohotometer was used to determine paeonolum content. RESULTS: The apparent solubility of paeonolum was significantly enhanced by increased HPCD concentration. The apparent stability constant of paeonolum compounds was calculated up to 1 425 in which pH was 3 and HPCD concentration was 133.33 mmol x L(-1). The solubility of paeonolum came up to 10 mg x mL(-1). CONCLUSION: HPCD is an ideal solubilizer for paeonolum.

HPLC analyses and pharmacokinetic studies of baicalin and oxymatrine in rabbits.

In the present study two simple RP-HPLC methods were developed to determine baicalin and oxymatrine in rabbit serum. Separation was performed on a Diamonsil C18 column (200 mm x 4.6 mm I.D., 5 microm) with UV detector at 277 nm for baicalin and 220 nm for oxymatrine. The mobile phase was methanol-water-phosphoric acid 50:50:0.2 v/v for baicalin and acetonitrile-water (20:80, v/v, 5 mmol/L sodium octanesulfonate was contained and pH was adjusted to 3.2 with phosphoric acid for oxymatrine. p-Nitrobenzoic acid and phenacetin were used as internal standards for baicalin and oxymatrine, respectively. The standard curves were linear from 0.5 to 200.0 mg/L for baicalin and from 0.5 to 100.0 mg/L for oxymatrine with correlation coefficients of 0.9994 and 0.9965, respectively. The intra-day and inter-day RSD were less than 5.4% and 7.2% for baicalin and 6.6% and 13.8% for oxymatrine. The mean recoveries were 100.1% for baicalin and 99.1% for oxymatrine. The methods were applied to a pharmacokinetic study of baicalin and oxymatrine in rabbits. The pharmacokinetic parameters were determined after intravenous injections of baicalin and oxymatrine (40 mg/kg) separately and together to rabbits. They all fit to the two-compartment open model. Student's t test shows that there is no significant difference in the main pharmacokinetic parameters including AUC(0-infinity), when alpha and beta, when baicalin and oxymatrine were administered separately or together.

[Comparative study of lipophilicity from immobilized artificial chromatography and n-octanol/buffer systems].

AIM: To compare lipophilicity measuring scale stemmed from immobilized artificial membrane chromatography and n-octanol/buffer systems. METHODS: A test set consisted of 27 structurally diverse compounds. The lipophilicity of these were evaluated by both immobilized artificial membrane chromatography (IAMC) and n-octanol/buffer systems, which were expressed as lg kIAM and lg DO/W,7.4, respectively. RESULTS: With regard to each individual group, good correlation coefficient (r2) over 0.81 was obtained (0.82 for acid; 0.88 for neutral, 0.81 for base and 0.92 for ampholyte, respectively). However, a smaller r2 (0.62) was acquired for all compounds studied than that of each individual group. CONCLUSION: IAMC and n-octanol/buffer systems were shown to be different in lipophilicity.

[Evaluation of interaction between drugs and ordered phospholipid membrane by immobilized artificial membrane chromatography].

AIM: To investigate the interaction between drugs and ordered phospholipid membrane using immobilized artificial membrane chromatography (IAMC). METHODS: IAMC was used to determine the interaction drugs with phospholipid membrane, expressed as membrane affinity (lg kIAM). An n-octanol/buffer system was also employed as the reference hydrophobicity (lg Do/w,7.4). RESULTS: Within the range of used acetonitrile percentages (phi) 0-30% in mobile phase, retention index (lg kIAM) showed excellent correlation with phi. Intercepts of fitted straight lines between lg kIAM and phi were comparable but slopes were much different for the three organic modifiers (acetonitrile, ethanol and methanol). Effects by adding CH2 substituent on lipophilicity difference (delta lg kIAM and delta lg Do/w,7.4) were similar for p-hydroxyl benzoic methyl ester to butyl ester, whereas different for p-hydroxylbenzoic acid to methyl ester. CONCLUSION: IAMC system is a convenient, efficient and rapid tool for determining membrane interaction.