Xing Tang

Development of a chemically stable 10-hydroxycamptothecin nanosuspensions

The purpose of this study was to prepare and characterize nanosuspensions loading the active lactone form of 10-hydroxycamptothecin (10-HCPT). Nanosuspensions were prepared in terms of microprecipitation-high-pressure homogenization method. As for the preparation processes, three important parameters, i.e. the agitation rate of stabilizer solution, homogenization pressure and cycle numbers, were investigated and optimized, and the optimal values were 1000 rpm, 1000 bar and 20 times, respectively. The particle size and zeta potential of the 10-HCPT-nanosuspensions were 131 nm and -25.5 mV. The particle morphology was determined by transmission electron microscopy and the 10-HCPT nanoparticles were baculine or trabecular in shape. The solid state of 10-HCPT in nanoparticles was analyzed using X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC). The XRD and the DSC results both indicated that 10-HCPT was present as an amorphous state in the lyophilized powders for nanosuspension. The chemical stability tests demonstrated that near 90% lactone form of 10-HCPT was present in the nanosuspensions but it was easily transferred to the carboxylate form in the solution at pH 7.0-8.0. In vitro dissolution tests showed the dissolution rate of nanosuspensions, compared with the coarse suspensions, had been significantly increased.

In vitro and in vivo evaluation of fenofibrate solid dispersion prepared by hot-melt extrusion

Objective: This article aimed to develop fenofibrate solid dispersion with high bioavailability using hot-melt extrusion and compare the difference of Eudragit® E100 and polyvinylpyrrolidone-vinyl acetate copolymer S630 (PVP-VA) in dissolution. Methods: Solid dispersion with carrier of Eudragit E100 or PVP-VA was prepared by hot-melt extrusion and then characterized by differential scanning calorimetry (DSC), X‐ray diffraction, in vitro dissolution test, and in vivo bioavailability study. Results: Fenofibrate exited as noncrystal state in these two kinds of solid dispersions that can be proved by DSC and X-ray diffraction. Eudragit E100 1:2 solid dispersion has the dissolution of 84% and 65% at 60 minutes in 0.1M HCl and water, respectively. Eudragit E100 1:4 solid dispersion has lower dissolution in 0.1M HCl and higher dissolution in water; the values are 73.6% and 87.3%. PVP-VA 1:2 solid dispersion has the dissolution of 60% and 65% at 60 minutes in 0.1M HCl and water, respectively. PVP-VA 1:4 solid dispersion has higher dissolution in 0.1M HCl and lower dissolution in water; the values are 64% and 53%. The different dissolution of fenofibrate from the two polymers is because of their different solubility and gelling tendency. When Eudragit E100 1:4 solid dispersion was administrated to beagle dogs, its relative bioavailability to micronization Lipanthyl capsule was 177.1%. Conclusion: Hot-melt extrusion is an excellent method to improve the dissolution and therefore the bioavailability of fenofibrate.

Nimodipine semi-solid capsules containing solid dispersion for improving dissolution.

The aim of this study was to improve the dissolution and, therefore, bioavailability of the poorly water-soluble and highly permeable drug nimodipine (NMD). Present research involved the preparation of a solid dispersion (SD) consisting of NMD, Eudragit-E100 and Plasdone-S630 by hot-melt extrusion (HME). Compared with pure drug and physical mixture, the dissolution of NMD was enhanced dramatically (about 80% within 30min). Adding the nimodipine solid dispersion (NMD-SD) powder to a mixture of Plasdone-S630 and PEG400, and then transferring it to hard HPMC capsules, resulted in nimodipine semi-solid capsules (NMD-SSC). The dissolution from NMD-SSC was increased further (about 95% in 20min). In addition, the relative bioavailability of the NMD-SSC (test) and Nimotop (reference) was determined in beagle dogs after a single dose (120mg NMD) in a randomized crossover, own-control study. The results suggested that there was no significant difference in the areas under the plasma concentration-time curve and the mean peak concentration between NMD-SSC (AUC(0-infinity)=2488+/-433nghmL(-1), Cmax=321+/-78ngml(-1)) and Nimotop (AUC0-infinity=2272+/-398nghmL(-1), Cmax=293+/-73ngmL(-1)) (P>0.05). However, the apparent rate of absorption of NMD from NMD-SSC (tmax=1.3h) was markedly faster than that from Nimotop (tmax=3.1h) (P<0.05), which indicates that as a fast release preparation, NMD-SSC is well absorbed.

In vitro and in vivo evaluation of ofloxacin sustained release pellets

Being a sustained release dosage form, pellets allow ofloxacin to exhibit improved release and absorption profiles. In this paper, the centrifugal granulation method was employed to prepare ofloxacin pellets. Then the pellets were subjected to a coating process with methacrylic acid copolymers to produce sustained release characteristics. The pellets with different coatings were investigated by release tests in vitro. Finally, pellets with the best coating suspension were subjected to a multiple doses pharmacokinetic study in beagle dogs. The in vitro release profiles showed that pellets coated with Eudragit NE30D and Eudragit L30D55, at a ratio of 1:8 (w/w) and a coating level of 8% with diethyl phthalate (DEP) as plasticizer equivalent to 10% of solid material in the coating suspension were suitable for sustained release. In the bioavailability study, the principal pharmacokinetic parameters showed there were differences between the sustained release pellets and the conventional ofloxacin capsules. The relative bioavailability of ofloxacin sustained release pellets compared with conventional ofloxacin capsules was 116.35+/-33.31%. All the statistics indicate that the preparation has a sustained release effect with many advantages over conventional preparations.

Determination of azithromycin by ion-pair HPLC with UV detection

An ion-pair reversed phase high performance liquid chromatographic method with UV detection was developed for the determination of azithromycin using sodium heptanesulfonate as an ion-pair reagent. The mobile phase consisted of a mixture of ammonium dihydrogen phosphate (0.045 M, pH 3.0 adjusted by phosphoric acid):acetonitrile 47:15 (v/v) and the concentration of sodium heptanesulfonate in the aqueous phase was 0.002 M. UV detection was performed at 210 nm. The chromatographic column was Dikma Technologies Diamonsil C18 column, 5 microm 150 mm x 4.6 mm, which was maintained at 25 degrees C. Applying the method to a stability study of azithromycin eye drops, it was found that the related substance could be detected and the profile of the AZM peak was symmetrical and the column efficiency was high. Accordingly, it is suitable for the routine analysis and stability testing of azithromycin preparations.

Determination of entrapment efficiency and drug phase distribution of submicron emulsions loaded silybin.

This paper compared the performance of ultrafiltration (UF), ultracentrifugation (UC) and microdialysis (MD) for determining the entrapment efficiency (EE) of submicron emulsions (SE) loaded with a model drug, silybin (SB). Also, a novel way was created to evaluate the drug phase distribution of SE. The EE of SEI, SEII and SEIII with a range of particle sizes (109.8, 171.7 and 213.2 nm) and the drug phase distribution of SEII and SEIII were separately determined by the three methods. The EEs of SEI were 99.8%, 91.1%, 84.4% determined by MD, UF, UC, respectively, and the EEs of SEII and SEIII were 99.5%, 86.4%, 72.1% and 99.4%, 84.3%, 66.3%, separately. The accuracy of MD to determine EE of SE is much less than that of UF. Although UC is the fastest and most simple to use, its results are the least reliable. The sequence of the amount of drug in SE is as follows: O/W interface, aqueous phase and oil phase. Over 80% of SB was in the O/W interface of SEII and SEIII individually. The method created is reliable for quantifying the phase distribution of drug in submicron emulsions.

Preparation and in vitro evaluation of gliclazide sustained-release matrix pellets: formulation and storage stability

Objective: Gliclazide-loaded matrix pellets consisting of ethylcellulose, microcrystalline cellulose (MCC), and sodium carboxymethyl starch were prepared by extrusion-spheronization. Method: To control the initial fast release of the matrix pellets, three coating methods were used: hot-melt coating, polymer aqueous dispersion film coating, and MCC powder coating. An orthogonal experiment (L9(3)4) was applied to optimize the key process variables of MCC-powder coating. The in vitro dissolution profiles of the coating pellets were compared with the commercial tablets Diamicron® by the similarity factor (f 2). The storage stability was measured to choose the best coating method. Result: Initial fast release was overcome by using the three coating methods. Rotation speed of friction plate and time of coating (addition of binder/coating agents) were both found to have the more important influence to drug release. The f 2 values between the three coated pellets and the commercial product were all greater than 50. The results of storage-stability tests suggest that the pellets prepared by MCC-powder-coating method are stable for at least 6 months under stress conditions (40°C/75%RH), whereas the others failed. Conclusion: The MCC-powder-coating method offered the advantage of a one-step procedure compared with film coating and hot-melt coating.

Preparation of fenofibrate immediate-release tablets involving wet grinding for improved bioavailability

Objective: The purpose of this study was to investigate the dissolution and oral bioavailability of an immediate-release tablet involving wet grinding of a poorly water-soluble drug, fenofibrate. Methods: The milled suspension was prepared using a Basket Dispersing Mill in the presence of a hydrophilic polymer solution and then granulated with common excipients, and compressed into an immediate-release tablet with blank microcrystalline cellulose granules. Results: Compared with unmilled tablets (56% within 30 minutes), the dissolution of wet-milled tablets (about 98% in 30 minutes) was markedly enhanced. No significant decrease in the dissolution rate (96% in 30 minutes) of the wet-milled tablet was observed after 3 months under 40°C and 75% relative humidity storage. In addition, the oral bioavailability of the wet-milled tablets (test) and Lipanthyl® supra-bioavailability tablets (reference) was determined in beagle dogs after a single dose (160 mg fenofibrate) in a randomized crossover, own-control study. The results suggested that both the area under the plasma concentration–time curve (AUC(0−t) = 46.83 ± 11.09 μg/mL h) and the mean peak concentration of the test (Cmax = 4.63 ± 1.71 μg/mL) were higher than the reference (AUC(0−t) = 35.12 ± 10.97 μg/mL h, Cmax = 2.11 ± 0.08 μg/mL). The relative bioavailability of the wet-milled tablet was approximately 1.3-fold higher. Furthermore, the apparent rate of absorption of fenofibrate from the wet-milled tablet (Tmax = 2.63 hours) was faster than that from Lipanthyl® (Tmax = 3.75 hours). Conclusion: These results indicated that the dissolution and the bioavailability of fenofibrate were significantly enhanced by wet-grinding process. So, this shows that wet grinding is a powerful technique to improve the bioavailability for poorly water-soluble drugs, especially for Biopharmaceutics Classification System Class II compounds.

Evaluation ofin-vitro dissolution andin-vivo absorption for two different film-coated pellets of clarithromycin

The aim of this study was to compare two formulations of film-coated pellets containing clarithromycin after single oral dose study in healthy male volunteers. Two formulations with different coating polymers were prepared: formulation-1 (F-1) was prepared by incorporating three kinds of pH-dependent gradient-release coated pellets into capsules and formulation-2 (F-2) was prepared by coated with an insoluble semiosmotic film. Release profiles of film-coated pellets were evaluated using paddle method under different conditions. Pharmacokinetic profiles of these formulations were obtained in three healthy male volunteers and compared to commercially available immediate release (IR) tablets. The relative bioavailability based on the AUC0–24 h was found to be 96.2% and 58.7% for F-1 and F-2 compared with IR, and the Tmax was delayed.

An oral controlled release system for amroxol hydrochloride containing a wax and a water insoluble polymer

This study was carried out to develop and optimize oral sustained-release formulations for Ambroxol hydrochloride matrix pellets using a combination of wax and water-insoluble polymer, glyceryl behenate (Compritol 888 ATO) and Ethylcellulose (EC7 FP). It involved three factors: the content of Compritol 888 ATO (X1), EC7 FP (X2), and the matrix formation methods (X3), as independent variables. The drug release percentages at 1, 2 and 4u2009h were the target responses and were restricted to 15–45% (Y1), 45–80% (Y2) and 80–100% (Y3), respectively. The final blend formulation prepared by extrusion spheronization, was achieved with 27.00% (w/w) Ambroxol hydrochloride, 48.70% (w/w) Compritol 888 ATO, and 24.30% (w/w) EC7 Fp with 40°C for 12u2009h. Comparing the single matrix materials consisting of just the wax or water-insoluble in the complex matrix system containing wax and water-insoluble polymer, the release of the drug can be far more retarded, when the formulations have undergone the process of heat treatment. Furthermore, the combination of the two polymers, with flexible matrix formation methods, will offer a very promising way of producing matrix pellets instead of coated controlled-release pellets to meet various demands of drug release.