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.

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.

[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.

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.

Nanocarrier improves the bioavailability, stability and antitumor activity of camptothecin.

Camptothecin (CPT) nanosuspension was prepared by anti-solvent precipitation with TPGS as stabilizer to improve the solubility, stability and antitumor activity of CPT. And an increased solubility, stability and dissolution rate was achieved after nanosuspension being prepared. While, enhanced intracellular accumulation and cellular cytotoxicity was also observed for CPT nanosuspension than that of CPT solution.In addition, nanosuspension could increase bioavailability and intratumor accumulation of CPT in vivo after intravenous administration, and then produced a much higher antitumor effect and biocompatibility than that of CPT solution. Meanwhile, an enhanced cellular CPT uptake in hypoxic or acid conditions could also be observed for nanosuspension. As a result, nanosuspension represents a potentially feasible formation for insoluble drug in antitumor research.

[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.

[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.

[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.

Supramolecular micellar nanoaggregates based on a novel chitosan/vitamin E succinate copolymer for paclitaxel selective delivery.

BACKGROUND: Nowadays, many cytotoxic anticancer drugs exhibit low solubility and poor tumor selectivity, which means that the drug formulation is very important. For example, in the case of paclitaxel (PTX), Cremophor EL(®) (BASF, Ludwigshafen, Germany) needs to be used as a solubilizer in its clinical formulation (Taxol(®), Bristol-Myers Squibb, New York, NY), although it can cause serious side effects. Nanomicellar systems are promising carriers to resolve the above problems, and the polymer chosen is the key element. METHODS: In this study, a novel amphiphilic chitosan/vitamin E succinate (CS-VES) copolymer was successfully synthesized for self-assembling polymeric micelles. Proton nuclear magnetic resonance spectroscopy and infrared were used to characterize the molecular structure of the copolymer. The PTX-loaded CS-VES polymeric micelles (PTX-micelles) were characterized by dynamic light scattering, transmission electron microscopy, X-ray diffraction, and differential scanning calorimetry. RESULTS: The critical micelle concentration of CS-VES was about 12.6 µg/mL, with the degree of amino group substitution being 20.4%. PTX-micelles were prepared by a nanoprecipitation/dispersion technique without any surfactant being involved. PTX-micelles exhibited a drug loading as high as 21.37% and an encapsulation efficiency of 81.12%, with a particle size ranging from 326.3 to 380.8 nm and a zeta potential of +20 mV. In vitro release study showed a near zero-order sustained release, with 51.06%, 50.88%, and 44.35% of the PTX in the micelles being released up to 168 hours at three drug loadings of 7.52%, 14.09%, and 21.37%, respectively. The cellular uptake experiments, conducted by confocal laser scanning microscopy, showed an enhanced cellular uptake efficiency of the CS-VES micelles in MCF-7 cells compared with Taxol. The PTX-micelles exhibited a comparable but delayed cytotoxic effect compared with Taxol against MCF-7 cells, due to the sustained-release characteristics of the nanomicelles. More interestingly, blank nanomicelles based on CS-VES copolymer demonstrated significant cytotoxicity against MCF-7 cells. CONCLUSION: The supramolecular micellar aggregates based on CS-VES copolymer is a promising nanocarrier and efficacy enhancer when used as an anticancer drug-delivery system.

Microemulsions as drug delivery systems to improve the solubility and the bioavailability of poorly water-soluble drugs.

IMPORTANCE OF THE FIELD: Microemulsions have been studied extensively as potential drug delivery vehicles for poorly water-soluble drugs. An understanding of the physicochemical and biopharmaceutical characteristics of the microemulsions according to administration routes will provide guidance for designing the formulations of microemulsions. AREAS COVERED IN THIS REVIEW: In this paper, the use and the characteristics of microemulsions as drug delivery vehicles are reviewed. As the formulations of the microemulsion always include a great amount of surfactant and co-surfactant, which may cause hemolysis or histopathological alterations of the tissue, the potential toxicity or the irritancy of microemulsions is also discussed in this paper. WHAT THE READER WILL GAIN: Developments of microemulsions for poorly water-soluble drugs in recent years are included in this review. Several factors limiting the commercial or clinical use of microemulsions are also discussed. TAKE HOME MESSAGE: Considering the potential in enhanced drug uptake/permeation and facing the limitations, their unique properties make microemulsions a promising vehicle for poorly water-soluble drugs.

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.

[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.

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.

[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.

Pharmacokinetic behaviors and oral bioavailability of oridonin in rat plasma.

AIM: To study the intravenous and oral pharmacokinetic behavior of oridonin and its extent of absolute oral bioavailability in rats. METHODS: Oridonin was administered to rats via iv (5, 10 and 15 mg/kg), po (20, 40 and 80 mg/kg) or ip administration (10 mg/kg). The concentrations of oridonin in rat plasma were determined by a high performance liquid chromatography with electrospray ionization mass spectrometric detection (HPLC/ESI-MS) method and the pharmacokinetic parameters were determined by non-compartmental analysis. RESULTS: The plasma concentration of oridonin after intravenous administration decreased polyexponentially, and the pharmacokinetic parameters of oridonin were dose-independent within the examined range. Oridonin was absorbed rapidly after oral gavage with a t(max) of less than 15 min; the extent of absolute bioavailability of oridonin following oral administration was 4.32%, 4.58% and 10.8%. The extent of absolute bioavailability of oridonin following intraperitoneal administration was 12.6%. CONCLUSION: First order rate pharmacokinetics were observed for oridonin within the range of iv doses, while the extent of absolute oral bioavailability was rather low and dose- dependent. The low and dose-dependent extent of oral bioavailability may be due to the saturation of first-pass effects.

[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%.