Optimization, characterization and in vitro/vivo evaluation of azilsartan nanocrystals

Azilsartan(AZL), a poorly soluble drug, was considered to be fit for nanocrystals to improve its solubility. Our study intended to prepare AZL nanocrystals by means of bead milling method. Eight stabilizers or their binary combination and the milling time were set to be variable factors to optimize AZL nanosuspension formulation, and six types of freezedrying supports were investigated to reduce the aggregation of particles during the solidification. AZL nanocrystals with or without sodium deoxycholate(NaDC) as combined stabilizer with Poloxamer 188(F68) were prepared owning mean particle sizes of about 300 nm and 460 nm. During the screening processes, the formulation containing NaDC showed a smaller particle size and better stability during lyophilization. The irregular shape and crystal form changing in AZL nanocrystals were discovered by various characterizations. And with physical mixture as reference, nanocrystals showed its improvement about in-vitro dissolution and in-vivo bioavailability. In conclusion, the nanocrystals of AZL could be prepared well in our study. Additionally, our results suggested that NaDC was an appreciated excipient on the nanocrystals platform, which can exhibit the abilities of size-reduction and stabilitymaintaining on freeze-drying.

Preparation and evaluation of sustained-release diltiazem hydrochloride pellets

In this study,diltiazem hydrochloride(DTZ)pellets were prepared successfully by extrusionespheronization method.Then methacrylic acid and ethylcellulose coating formulations were employed to make the DTZ pellets sustained release.The pellets with different coatings were investigated by in vitro dissolution tests.At last,the pellets with the best coating copolymer were subjected to pharmacokinetic studies in beagle dogs.The dissolution profiles of pellets coated with Eudragit
NE30D were similar to Herbesser
,one of the marketed sustained release capsules.In the bioavailability study,the principal pharmacokinetic parameters of self-made pellets and the marketed ones were comparable;the relative bioavailability of DTZ sustained release capsules compared with Herbesser
was 98.5
36.4%.All the data indicated self-made sustained pellets could prolong the release of DTZ,decrease the fluctuation of drug level in vivo,and increase the compliance of patients.

Preparation and evaluation of tamsulosin hydrochloride sustained-release pellets modified by two-layered membrane techniques

The aim of the present study was to develop tamsulosin hydrochloride sustained-release pellets using two-layered membrane techniques.Centrifugal granulator and fluidizedbed coater were employed to prepare drug-loaded pellets and to employ two-layered membrane coating respectively.The prepared pellets were evaluated for physicochemical characterization,subjected to differential scanning calorimetry(DSC)and in vitro release of different pH.Different release models and scanning electron microscopy(SEM)were utilized to analyze the release mechanism of Harnual■ and home-made pellets.By comparing the dissolution profiles,the ratio and coating weight gain of Eudragit■ NE30D and Eudragit■ L30D55 which constitute the inside membrane were identified as 18:1 and 10%-11%.The coating amount of outside membrane containing Eudragit■ L30D55 was determined to be 0.8%.The similarity factors(f_(2))of home-made capsule and commercially available product(Harnual■)were above 50 in different dissolution media.DSC studies confirmed that drug and excipients had good compatibility and SEM photographs showed the similarities and differences of coating surface between Harnual■ and self-made pellets before and after dissolution.According to Ritger-Peppas model,the two dosage form had different release mechanism.

Preparation and stability investigation of tamsulosin hydrochloride sustained release pellets containing acrylic resin polymers with two different techniques

The objective of this study was to prepare tamsulosin hydrochloride-sustained release(TSH-SR)pellets which showed good release stability with frame-controlled method.TSH was added to Eudragit~?NE30D and Eudragit~?L30D-55 polymers to form drug-loaded inner core.Afterwards,enteric Eudragit~?L30D-55 polymer was modified on the surface of it to the final product.Dissolution studies showed that TSH-SR pellets were more stable during the coating process,different curing temperatures and storage conditions compared with TSH pellets produced by film-controlled technique.Appearances and glass transition temperatures(Tgs)of free films and surface morphologies observed by scanning electron microscopy(SEM)of blank sustained release pellets prepared by different ratios of Eudragit~?NE30D and Eudragit~?L30D-55 further indicated that temperature and relative humidity(RH)were the key factors when Eudragit~?NE30D blended with Eudragit~?L30D-55 were applied to sustained/controlled release preparations.In addition,SEM identified the surface morphologies of TSH-SR pellets before and after dissolution,which showed intact surface structure and great correlation with release curve respectively.

The effect of cephalexin in influencing the pharmacokinetics of a novel drug–5’-valyl-cytarabine hydrochloride

The aim of this study is to investigate the pharmacokinetics of 5′-valyl-cytarabine hydrochloride(OPC) when co-administered with cephalexin, which are both the substrates of PepT 1.The drugs were administered orally by gavage. Blood samples were collected from the orbital plexus of the rats after oral administration of drug solutions. A new high-performance liquid chromatographic method was validated and used for determination of the two drugs. Pharmacokinetic parameters were calculated using DAS 2.1.1 software with noncompartmental analysis. After oral administration of OPC and co-administration of OPC and cephalexin,there were significant differences in the main pharmacokinetic parameters. The main pharmacokinetic parameters for the OPC group and the co-administrative group were as follows:AUC0-10(18,168.7 ± 2561.4) ng·h/ml and(13,448.5 ± 2544.73) ng·h/ml, AUC0-∞(18,683.1 ± 3066.5)ng·h/ml and(13,721.1 ± 2683.0) ng·h/ml, Cmax(6654.8 ± 481.3) ng/ml and(4765.1 ± 928.9) ng/ml, respectively. The results showed that the bioavailability of OPC could be reduced when co-administered with cephalexin, suggesting that the efficacy of a novel drug might be reduced when it came to combination use of β-lactam antibiotics.

Preparation and evaluation of taste masked oral suspension of arbidol hydrochloride

The purpose of this study was to cover the bitter taste of arbidol hydrochloride(ARB)and develop dry suspension with combination of solid dispersion and flavors.Taste masking was successfully done by solid dispersion using octadecanol as the carrier by fusion method.Suspending agents,carriers and other excipients were selected.Differential scanning calorimetry(DSC)and Fourier transform infrared spectroscopy(FTIR)were performed to identify the physicochemical interaction between drug and carrier,DSC analysis indicated that ARB was amorphous in the solid dispersion,FTIR spectroscopy showed no interaction between drug and carrier.Taste masking was evaluated on six volunteers with a score of 4.9.The results demonstrated successful taste masking.Water was used to study the in vitro dissolution performance of the three formulations of commercial tablet,capsule and self-made suspension.The self-made suspension showed a lower and slower release,the insoluble carrier octadecanol blocked the drug dissolving from the solid dispersion.It was indicated from the primary stability study,the self-made suspensions were sensitive to high temperature,high humidity and strong light conditions,they should be stored in sealed containers away from heat,light and humidity.

Preparation, characterization, and in vitro/vivo evaluation of polymer-assisting formulation of atorvastatin calcium based on solid dispersion technique

Due to low solubility and bioavailability, atorvastatin calcium is confronted with challenge in conceiving appropriate formulation. Solid dispersion of atorvastatin calcium was prepared through the solvent evaporation method, with Poloxamer 188 as hydrophilic carriers. This formulation was then characterized by scanning electron microscopy, differential scanning calorimetry, powder X-ray diffraction and fourier transform infrared spectroscopy. Moreover, all these studies suggested the conversion of crystalline atorvastatin calcium. In addition, the drug solubility studies as well as dissolution rates compared with bulk drug and market tablets Lipitor were also examined. Furthermore, the study investigated the pharmacokinetics after oral administration of Lipitor and solid dispersion. And the AUC 0–8 h and C max increased after taking ATC-P188 solid dispersion orally compared with that of Lipitor. All these could be demonstrated that ATC-P188 solid dispersions would be prospective means for enhancing higher oral bioavailability of ATC.

The studies of PLGA nanoparticles loading atorvastatin calcium for oral administration in vitro and in vivo

A biodegradable poly(lactic-co-glycolic acid) loading atorvastatin calcium(AC) nanoparticles(AC-PLGA-NPs) were prepared by probe ultrasonication and evaporation method aiming at improving the oral bioavailability of AC. The effects of experimental parameters, including stabilizer species, stabilizer concentration and pH of aqueous phase, on particle size were also evaluated. The resultant nanoparticles were in spherical shape with an average diameter of 174.7 nm and a narrow particle size distribution. And the drug loading and encapsulation efficiency were about 8% and 71%, respectively. The particle size and polydispersion were almost unchanged in 10 days. The release curves of AC-PLGA-NPs in vitro displaying sustained release characteristics indicated that its release mechanisms were matrix erosion and diffusion. The pharmacokinetic study in vivo revealed that the Cmax and AUC0-∞ of AC-PLGA-NPs in rats were nearly 3.7-fold and 4.7-fold higher than that of pure atorvastatin calcium suspension. Our results demonstrated that the delivery of AC-PLGANPs could be a promising approach for the oral delivery of AC for enhanced bioavailability.

Preparation and evaluation of duloxetine hydrochloride enteric-coated pellets with different enteric polymers

The main purpose of the present study was to prepare duloxetine hydrochloride(DXH) entericcoated pellets using different enteric polymers. Three layers(drug-loaded layer, barrier layer,and enteric-coated layer) were applied to the inert core pellets, successively. The optimal formulation was manufactured by employing suspension layering method in fluidized bed processor(FBP) with varieties of enteric polymers like Aqoat? AS-LF, Eudragit? L30D55 and HPMCP-HP55. The prepared pellets were measured for physical characterization and the in vitro dissolution profile. Scanning electron microscopy(SEM) was conducted to observe the morphology of pellets, and different kinetic models were applied to analyze the release mechanism of Cymbalta? and home-made pellets. The coating weight gain of enteric-coated layer containing Eudragit? L30D55, Aqoat? AS-LF and HP-55 were determined to be 35%, 26% and 24%, respectively. The similarity factors(f2) of self-made capsules with above polymers and commercially available capsules(Cymbalta?) were above 50 in the dissolution medium of pH 6.8 phosphate buffer solution(PBS). SEM figures showed the smooth surfaces of selfprepared pellets using Eudragit? L30D55 and Aqoat? AS-LF, whereas rough surface was found in the HP-55 pellets at day 0, and an impurity was appearing in the condition of 40 ℃/75% relative humidity for 1 month. In conclusion, the pellets prepared by utilizing Eudragit? L30D55 and Aqoat?AS-LF were the optimal preparations based on the dissolution profile and stability.

Evaluation of pharmacokinetics underlies the collaborated usage of lamivudine and oxymatrine in beagle dogs

Combinational therapy of lamivudine and oxymatrine has been employed in the battle against hepatitis B virus in clinical setting. However, the pharmacokinetic behavior of the drug or active metabolism in intravenous/oral co-administration regime is poorly investigated. Herein,we evaluated the pharmacokinetic characteristic through a tailor-designed 3 way crossoverLatin square experiment in adult male beagle dogs. Six dogs were randomly treated by intravenous administration of lamivudine(2.5 mg/kg), oxymatrine(15 mg/kg) and combinational dosage, named as intravenous regime. Meanwhile the other six dogs were orally administrated with lamivudine(2.5 mg/kg), oxymatrine(15 mg/kg) and combinational dosage,named as oral regime. The pharmacokinetic feature in simultaneous oral treatment appeared to have no significant difference when compared with individual administration,even including matrine, the active metabolite of oxymatrine. In intravenous regime, the main pharmacokinetic parameters of simultaneous administration were nearly consistent with intravenous regime remedy. The collaborated application of lamivudine and oxymatrine contributed to non-distinctive pharmacokinetic fluctuations of beagle dogs in intravenous/oral regime, compared with individual employment, which established a vital base for the clinical co-administration against hepatitis B. Furthermore, the present study demonstrated that the determination of pharmacokinetics between combinational and individual therapy might assist in the development of drug compatibility in clinical therapy.

Development of Liposome containing sodium deoxycholate to enhance oral bioavailability of itraconazole

The aim of this study was to enhance oral bioavailability of itraconazole(ITZ) by developing Liposome containing sodium deoxycholate(ITZ-Lip-NaDC). The liposome, consisting of egg yolk lecithin and sodium deoxycholate, was prepared by thin-film dispersion method.Differential Scanning Calorimetry(DSC) results indicated an amorphous state in the liposome. The physicochemical characteristics including particle size, morphology, entrapment efficiency, dissolution properties were also investigated. The performance of single-pass intestinal infusion exhibited that the transport order of intestinal segment was jejunum,duodenum, colon and ileum, and that all the segments participated in the absorption of ITZ in intestinal tract. The bioavailability study in rats showed that the AUC0-72 of the liposome was nearly 1.67-fold higher than that of commercial capsules(SPORANOX) in terms of oral administration, and the RSD of AUC0-72 of ITZ-Lip-NaD C was also decreased. Our results indicated that ITZ-Lip-NaDC liposome was facilitated to improve dissolution efficiency,augment transmembrane absorption, and then enhance the oral bioavailability of ITZ,successfully.

UPLCeMS/MS for the determination of azilsartan in beagle dog plasma and its application in a pharmacokinetics study

The purpose of the study is to develop an ultra performance liquid chromatographytandem mass spectrometry(UPLCeMS/MS)to determinate the concentration of azilsartan in the dog plasma.After precipitated by methanol,the plasma sample containing azilsartan and diazepam(internal standard,IS)was determined by UPLCeMS/MS.The mobile phase consisted of acetonitrile-water was pumped at a flow rate of 0.3 ml/min in gradient elution.Kinetex 2.6 m XB-C18 column(50
2.1 mm,100Å;Phenomenex,USA)were used for LC separations.The column temperature was 30℃ and the injection volume was 5 ml.The electrospray ionization(ESI)and multiple reaction monitoring(MRM)were applied at the transitions of m/z 457/279(azilsartan)and m/z 285/193(diazepam),respectively.The developed method was identified a good linearity over a concentration range of 2.5e5000 ng/ml.The lower limit of quantitation(LLOQ)was 2.5 ng/ml.The intraday and inter-day precision(relative standard deviation,RSD%)were less than 10%and accuracy(relative error,RE%)was less than 5%at three quality control levels.The extraction recovery of azilsartan at three quality control levels were 82.41±0.68%,98.66±11.00%,102.43±0.82%.And the recovery for IS(100 ng/ml)was 91.75±0.54%.A validated UPLCeMS/MS method was firstly developed for the quantification of azilsartan in dog plasma and it was applied to the pharmacokinetics study.

Artificial tumor microenvironment regulated by first hemorrhage for enhanced tumor targeting and then occlusion for synergistic bioactivation of hypoxia-sensitive platesomes

The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity.Given the amplified characteristics of TME regulated by vascular disrupting agents(VDAs),nanomedicines may achieve unexpected improved efficacy.Herein,we fabricate platelet membrane-fusogenic liposomes(PML/DP&PPa),namely“platesomes”,which actively load the hypoxia-activated pro-prodrug DMG-PR104A(DP)and physically encapsulate the photosensitizer pyropheophorbide a(PPa).Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate(CA4P),PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P.First,CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention(EPR)effect,and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa.Besides,CA4P-induced vascular occlusion inhibits oxygen supply,followed by photodynamic therapy-caused acute tumor hypoxia.This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis.Thus,such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation,and provides a preferable solution to high-efficiency cancer therapy.