Hongzhuo Liu

Enhanced oral bioavailability of tacrolimus in rats by self-microemulsifying drug delivery systems.

A new self-microemulsifying drug delivery system (SMEDDS) has been developed to increase the solubility, dissolution rate and oral bioavailability of tacrolimus (TAC). The formulations of TAC-SMEDDS were optimized by solubility assay, compatibility tests, and pseudo-ternary phase diagrams analysis. In order to inhibit the efflux of P-glycoprotein (P-gp) for tacrolimus, which is the substrate of P-gp, the excipients which show the inhibition effect to P-gp, such as tocopheryl polyethylene glycol succinate (TPGS) and Cremophor EL40, were chosen in the SMEDDS formulations. According to particle size and the rate of self-emulsification, two optimized formulations were selected: Miglyol 840 as oil phase, Transcutol P as cosurfactant, TPGS as surfactant (TPGS-SMEDDS) or Cremophor EL40 as surfactant (Crem-SMEDDS), respectively. The ratio of oil phase, surfactant and cosurfactant is 1:7.2:1.8. The mean droplet size distribution of the optimized SMEDDS was less than 20u2009nm. The in vitro dissolution test indicated a significant improvement in release characteristics of TAC. The prepared SMEDDS was compared with the homemade solution by administering the hard capsule to fasted rats. The absorption of TAC from TPGS-SMEDDS and Crem-SMEDDS form resulted in about sevenfold and eightfold increase in bioavailability compared with the homemade solution. Our study illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds, such as TAC by the oral route.

Bicontinuous Cyclosporin a loaded Water-AOT/Tween 85-isopropylmyristate microemulsion: Structural characterization and dermal pharmacokinetics in vivo

Topical delivery of Cyclosporin A (CysA) is of great interest for the treatment of autoimmune skin disorders. Microemulsion systems prepared by AOT/Tween85/isopropyl myristate (IPM)/water possessing a potentially improved skin bioavailability of CysA were designed. The structure of microemulsions was investigated by diffusion-ordered NMR spectroscopy (DOSY) and differential scanning calorimetry (DSC) measurements. The DOSY measurements indicated the presence of bicontinuous and water-in-oil microemulsions depending on microemulsion composition. The DSC measurement confirmed that the microemulsion containing 30.0 wt% water was bicontinuous type, in agreement with the DOSY findings. We also evaluated the therapeutic advantage of dermal administration of CysA in rat model. Local (subcutaneous and skin), systemic concentrations and organ distribution (liver and kidney) were evaluated serially following topical and oral application of the drug. In rat dermal applied with the bicontinuous microemulsion containing CysA, the deposition of the drug into skin and subcutaneous fat was respectively almost 30 and 15-fold higher than the concentrations compared with oral administration. Systemic distribution in blood, liver and kidney was much lower following topical administration than that of following oral administration. With high local concentrations and minimal distribution to other organs via the circulation, topical microemulsion vehicle loaded with CysA might deliver maximal therapeutic effect to local tissue while avoiding side effects seen with systemic therapy. The histopathological findings revealed that the new bicontinuous microemulsion was a safe vehicle for topical drug delivery of CysA.

Cloud point extraction-HPLC method for determination and pharmacokinetic study of flurbiprofen in rat plasma after oral and transdermal administration

A method based on cloud-point extraction (CPE) was developed for the determination of flurbiprofen (FP) in rat plasma after oral and transdermal administration by high-performance liquid chromatography coupled with UV detection (HPLC-UV). The non-ionic surfactant Genapol X-080 was chosen as the extract solvent. Variables parameter affecting the CPE efficiency were evaluated and optimized. Chromatography separation was performed on a Diamond C(18) column (4.6 mm i.d. x 250 mm, 10 microm particle size) by isocratic elution with UV detection at 254 nm. The assay was linear over the range of 0.2-50 and 0.1-10 microg/ml for oral and transdermal administration, respectively, and the lower limit of quantification (LLOQ) was 0.1 microg/ml. The extraction recoveries were more than 84.5%, the accuracies were within +/-3.8%, and the intra- and inter-day precisions were less than 10.1% in all cases. After strict validation, the method indicated good performance in terms of reproducibility, specificity, linearity, precision and accuracy, and it was successfully applied to the pharmacokinetic study of flurbiprofen in rats after oral and transdermal administration.

Self-assembled L-alanine derivative organogel as in situ drug delivery implant: characterization, biodegradability, and biocompatibility.

Objective: The purpose of this work is to prepare and characterize the novel in situ forming implants, obtained through self-assembling of N-stearoyl-L-alanine methyl ester (SAM) in pharmaceutical oils, and to evaluate the biodegradability and biocompatibility of this organogel system. Methods: Minimum gelation concentration was used to measure the gelling ability of gelator SAM in different oils to select the optimal oil for further research. Phase transition temperatures of SAM/soybean oil organogels were determined by differential scanning calorimetry. Comparative studies on the in vitro degradation and in vivo degradation of SAM/soybean oil organogels in mice were investigated. Cytotoxicity tests and histological analysis of SAM/soybean oil organogels were studied by using mouse fibrosarcoma cells and mouse, respectively. Results: As an organogelator, SAM could gel a variety of oils at different minimum gelation concentration. Among them, it had the best-gelling ability in soybean oil, and the SAM/soybean oil organogel could be turned into gels abruptly at body temperature when the concentration of SAM was higher than 5% (w/v) to be used as an injectable system. The in vitro degradation rate of organogel was inversely proportional to the organogelator concentration, whereas the degradation rate in vivo was much higher than in vitro, and gels were almost disappeared after 6 weeks. The selected formulation showed excellent biocompatibility as tested by in vitro cytotoxicity and in vivo histological evaluation. Conclusion: SAM/soybean oil organogel has excellent biodegradability and biocompatibility, which indicates that it has a great potential for safe in situ forming drug delivery.

Increased dissolution rate and oral bioavailability of hydrophobic drug glyburide tablets produced using supercritical CO2 silica dispersion technology

The aim of this study was to design a silica-supported solid dispersion of a water-insoluble drug, glyburide, to increase its dissolution rate and oral absorption using supercritical fluid (SCF) technology. DSC and PXRD results indicated that the encapsulated drug in the optimal solid dispersion was in an amorphous state and the product was stable for 6 months. Glyburide was adsorbed onto the porous silica, as confirmed by the SEM images and BET analysis. Furthermore, FT-IR spectroscopy confirmed that there was no change in the chemical structure of glyburide after the application of SCF. The glyburide silica-based dispersion could also be compressed into tablet form. In vitro drug release analysis of the silica solid dispersion tablets demonstrated faster release of glyburide compared with the commercial micronized tablet. In an in vivo test, the AUC of the tablets composed of the new glyburide silica-based solid dispersion was 2.01 times greater than that of the commercial micronized glyburide tablets. In conclusion, SCF technology presents a promising approach to prepare silica-based solid dispersions of hydrophobic drugs because of its ability to increase their release and oral bioavailability.

Effect of intratumoral injection on the biodistribution and therapeutic potential of novel chemophor EL-modified single-walled nanotube loading doxorubicin

The purpose of this study is to evaluate in vivo efficacy and loco-regional distribution of a doxorubicin (DOX)-loaded Polyoxyl 35 Castor Oil (Cremophor EL, CrEL) noncovalent modified single-walled carbon nanotubes (SWNTs) formulation in a sarcoma tumor model after intratumoral injection. The drug loaded SWNTs were successfully prepared via physical absorption, which was confirmed by UV-vis-NIR absorbance spectra and dynamic light scattering assay. Solid tumor models were obtained by injecting mouse sarcoma 180 cells into the thighs of ICR mice. CrEL-SWNTs-DOX, CrEL-SWNTs, free DOX and saline (control) were intratumorally injected after 5 days post transplantation. The biodistribution studies demonstrated that intratumoral delivery of CrEL-SWNTs-DOX resulted in longer drug retention time in tumor, higher tumor level (27.6-fold than that of free DOX), as well as less accumulation in other solid tissues, especially in heart. Furthermore, in vivo anti-tumor activity results showed that CrEL-SWNTs-DOX could effectively suppress the tumor growth than free DOX and the control, attributing to its enhanced intratumoral DOX level. The histopathological findings revealed that the new carbon nanomaterials were a safe vehicle for topical drug delivery systems. It is concluded that this noncovalent modification of carbon nanotubes by CrEL for anticancer agents might be a promising alternative for cancer treatment.

Preparation of Novel Cationic Copolymer Microspheres and Evaluation of Their Function by In Vitro and In Vivo tests as Ph-Sensitive Drug Carrier Systems

ABSTRACT Novel pH-sensitive copolymer microspheres containing methylacrylic acid and styrene cross-linking with divinylbenzene were synthesized by free radical polymerization. The microspheres that were formed were then characterized by Fourier-Transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), size analysis, and X-ray analysis. The copolymer microspheres showed pulsatile swelling behavior whenthe pH of the media changed. The pH-sensitive microspheres were loaded with diltiazem hydrochloride (DH). The release characteristics of the free drug and the drug-loaded microspheres were studied under both simulated gastric conditions and intestinal pH conditions. The in vivo evaluation of the pulsatile preparation was subsequently carried out using beagle dogs as experimental subjects. The results demonstrated that the drug release exhibited a pulsatile character both in vitro and in vivo.

Loading and Release of Amine Drugs by Ion-Exchange Fibers: Role of Amine Type

With more production and application of ion-exchange fibers (IEFs), it becomes necessary to understand the interaction between IEFs and amine compounds, an important group of organic drugs and structural components of large organic molecules in biological systems. However, so far few experimental studies have been conducted to systematically investigate the exchanging mechanism of amine compounds to IEFs. Therefore, 15 amine drugs were selected to investigate the effect of amine type on the loading and release of them from the related IEFs. Loading affinity of these drugs by IEFs decreased in the order of secondary, tertiary, and primary. The following items: basicity, aromaticity, molar volume, rotatability, and so on, were emphatically discussed to address the underlying mechanism of drug loading and releasing extent and rate of IEFs. It was evident that strong alkaline drugs strengthened the ionic bond between the amine groups and IEFs, and thus the loading affinity. These results will advance the understanding of the exchanging behavior of IEFs in the drug delivery system.

In vivo assessment of novel furosemide gastro-mucoadhesive delivery system based on a kind of anion ion-exchange fiber.

A novel gastro-mucoadhesive delivery system based on a kind of anion ion-exchange fiber has been developed. Furosemide (FM), which is site-specifically absorbed from the upper gastrointestinal (GI) tract, was used as model drug. A novel-modified dissolution system, which can also be called “flow through diffusion cell,” was used to study the drug release from the drug fibers. The GI transit studies of the FM fiber complexes in rats and gamma imaging studies in volunteers were carried out to evaluate the gastro-mucoadhesive behavior of the fiber. The pharmacokinetic profile and parameters of the FM suspension and FM fiber in fasted and fed rats were measured, respectively. Studies on rats and volunteers provided evidence for the validity of the hypothesis that the drug fiber provided better gastro-mucoadhesive properties in vivo.

Design and evaluation of enteric-coated tablets for rifampicin and isoniazid combinations

In order to improve the bioavailability of rifampicin (RIF) from rifampicin and isoniazid (INH) combination formulations, the physicochemical characteristics of RIF, stability of RIF in different pH buffers in the presence of INH, as well as the effect of particle size of RIF materials on the dissolution rate were investigated. On the basis of the above examinations, enteric-coated tablets for RIF and INH combinations were designed and prepared. RIF showed low solubility and high apparent distribution coefficient in the intestinal pH (pH 4.0–7.4). With the decrease in pH, the degradation of RIF increase and the presence of INH deepen the degradation. Enteric-coated tablets were prepared after grinding the RIF materials by dry granulation technique. The pharmacokinetics of RIF and INH of self-made enteric-coated tablets in dogs were studied by comparing with the reference tablets. The AUC0–48 of RIF in both reference and test tablets were 304.77 ± 42.27 and 353.79 ± 31.63 µg·h·mL−1, respectively. The AUC0–48 of INH in both reference and test tablets were 17.14 ± 8.59 and 19.62 ± 10.57 µg·h·mL−1, respectively. Enteric-coated tablets may minimize the decomposition of RIF in gastrointestinal tract and improve the bioavailability.