A pH-independent instantaneous release of flurbiprofen: a study of the preparation of complexes, their characterization and in vitro/in vivo evaluation.

In this study, furbiprofen/hydroxypropyl-ß-cyclodextrin (HPßCD) inclusion complexes were prepared to improve the drug dissolution and facilitate its application in hydrophilic gels. Inclusion complexes were prepared using a supercritical fluid processing and a conventional optimized co-lypholization method was employed as a reference. The entrapment efficacy and drug loading of both methods were investigated. Evaluation of drug dissolution enhancement was conducted in deionized water as well as buffer solutions of different pH. Carbopol 940 gels of both flurbiprofen and flurbiprofen/HPßCD inclusion complexes, with or without penetration enhancers, were prepared and percutaneous permeation studies were performed using rat abdominal skin samples. Formation of flurbiprofen/HPßCD inclusion complexes was confirmed by Fourier transform-infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. The results obtained showed that SCF processing produced a higher EE (81.91 ± 1.54%) and DL (6.96 ± 0.17%) compared with OCL with values of 69.11 ± 2.23% and 4.00 ± 1.01%, respectively. A marked instantaneous release of flurbiprofen/HPßCD inclusion complexes prepared by SCF processing (103.04 ± 2.66% cumulative release within 5 min, a 10-fold increase in comparison with flurbiprofen alone) was observed. In addition, this improvement in dissolution was shown to be pH-independent (the percentage cumulative release at pH 1.2, 4.5, 6.8 and 7.4 at 5 min was 95.19 ± 1.71, 101.75 ± 1.44, 105.37 ± 4.58 and 96.84 ± 0.56, respectively). Percutaneous permeability of flurbiprofen-in-HPßCD-in-gels could be significantly accelerated by turpentine oil and was related to the water content in the system. An in vivo pharmacokinetic study showed a 2-fold increase in Cmax and a shortened Tmax as well as a comparable relative bioavailability when compared with the commercial flurbiprofen Cataplasms (Zepolas®). With their superior dissolution, these flurbiprofen/HPßCD inclusion complexes prepared by SCF processing could provide improved applications for flurbiprofen.

[Preparation of valsartan nanosuspensions and its in vitro dissolution].

To increase the dissolution rate and extent of valsartan, valsartan nanosuspensions have been prepared. Controlled precipitation assisted with sonication is utilized to prepare valsartan nanosuspensions, the concentration of the drug, stabilizer and costablizer had a great effect on the stability of the preparation according to the pre-experiment. So the method of central composite design-response surface is used to optimize the prescription based on the above three factors and the particle size as the response value. The software Origin 8.0 is used to draw the view of the three-dimensional effects and 2D contour map, to get the optimal prescription area. Valsartan nanosuspensions were prepared. The mean diameter and zeta potential are about 216.6 nm and -57.7 mV, respectively. Compared with the microsuspensions and commercial preparation, the dissolution of valsartan nanosuspensions was faster and the bioavailability can be enhanced to some extent.

[Formulation optimization of ginkgo flavonoids matrix tablets by orthogonal design].

Sustained-release tablet has become one of the hottest research spots in the area of sustained release preparations with its unique advantages. At present, a series of shortcomings were exited in the ordinary ginkgo preparations, which were used for the treatment of cardiovascular and cerebrovascular diseases. In order to avoid these shortcomings, ginkgo flavonoids matrix tablets were prepared in this paper. Furthermore, the amount and varieties of matrix material, adhesives and fillers were investigated. Meanwhile, the formulation was optimized by using the method of orthogonal design, and Zero-order, First-order, Higuchi, Ritger-peppas equation were used for the model fitting and mechanism discussing of drug release.

[Intestinal absorption kinetics of flurbiprofen in rats].

To study the in situ intestinal absorption kinetics of flrubiprofen in rats, the absorption of flurbiprofen in small intestine (duodenum, jejunum and ileum) and colon of rats was investigated using in situ single-pass perfusion method and the drug content was measured by HPLC. The effects of drug concentration on the intestinal absorption were investigated. The K(a) and P(app) values of flurbiprofen in the small intestine and colon had no significant difference (P > 0.05). Drug concentration (4.0, 10.0 and 16.0 mg x L(-1)) had no significant influence on the K(a) values (P > 0.05). However, when concentration was 4.0 mg x L(-1) and 10.0 mg x L(-1), significant effect on the P(app) values (P < 0.05) was found, but significant effect on the P(app) values was not shown between 10.0 mg x L(-1) and 16.0 mg x L(-1) (P > 0.05). The K(a) and P(app) values of flurbiprofen on the perfusion flow rate had significant difference (P < 0.05). Flurbiprofen could be absorbed at all segments of the intestine in rats and had no special absorption window. The absorption of flurbiprofen complies with the facilitated diffusion in the general intestinal segments, and accompany with the cytopsistransport mechanism probably. The perfusion flow rate had significant effect on the K(a) and P(app).

A novel small peptide as an epidermal growth factor receptor targeting ligand for nanodelivery in vitro.

The epidermal growth factor receptor (EGFR) serves an important function in the proliferation of tumors in humans and is an effective target for the treatment of cancer. In this paper, we studied the targeting characteristics of small peptides (AEYLR, EYINQ, and PDYQQD) that were derived from three major autophosphorylation sites of the EGFR C-terminus domain in vitro. These small peptides were labeled with fluorescein isothiocyanate (FITC) and used the peptide LARLLT as a positive control, which bound to putative EGFR selected from a virtual peptide library by computer-aided design, and the independent peptide RALEL as a negative control. Analyses with flow cytometry and an internalization assay using NCI-H1299 and K562 with high EGFR and no EGFR expression, respectively, indicated that FITC-AEYLR had high EGFR targeting activity. Biotin-AEYLR that was specifically bound to human EGFR proteins demonstrated a high affinity for human non-small-cell lung tumors. We found that AEYLR peptide-conjugated, nanostructured lipid carriers enhanced specific cellular uptake in vitro during a process that was apparently mediated by tumor cells with high-expression EGFR. Analysis of the MTT assay indicated that the AEYLR peptide did not significantly stimulate or inhibit the growth activity of the cells. These findings suggest that, when mediated by EGFR, AEYLR may be a potentially safe and efficient delivery ligand for targeted chemotherapy, radiotherapy, and gene therapy.

Further investigation of nanostructured lipid carriers as an ocular delivery system: in vivo transcorneal mechanism and in vitro release study.

This study was designed to provide further understanding of transcorneal mechanism of nanostructured lipid carriers (NLC). NLC labeled with fluorescent marker rhodamine B or coumarin-6 were produced by a melt emulsification method. By confocal laser scanning microscopy (CLSM), the interaction of NLC with corneal epithelia was traced and evaluated in rabbits in vivo. Thermal stability of the markers and the amorphous state were detected using thermogravimetric analysis (TGA) and differential scanning calorimeter (DSC). The labeled NLC were characterized to be solid spherical in shape with an average diameter of 70 nm and zeta potential of -8 mV by transmission electron microscopy and dynamic light scattering, respectively. CLSM results demonstrated NLC were not directly internalized by corneal epithelia, whereas the markers themselves transferred from NLC to corneal epithelia with subsequent staining of intracellular lipophilic compartments. Furthermore, the in vitro release study using liposome dispersions as mimic biomembranes demonstrated an efficient transfer of fluorescence marker into the liposomes. This implied the deceptive particle uptake was due to a collision-induced process, during which the rapid transfer of fluorescence marker occurred by forming a complex between the nanoparticles and the biomembranes. Thus, these evidences provide further insights into NLC as an ocular delivery system.

In vitro and in vivo evaluation of gliclazide push-pull osmotic pump coated with aqueous colloidal polymer dispersions.

The objective of present work was to design and evaluate gliclazide push-pull osmotic pump (PPOP) coated with aqueous colloidal polymer dispersions-Eudragit(®) RL 30D and Eudragit(®) RS 30D. The influence of diacetin, diethyl phthalate (DEP), dibutyl sebacate (DBS) and triethyl citrate (TEC) on the free Eudragit(®) RL 30D and Eudragit(®) RS 30D films as plasticizers on drug release were studied. Among these four plasticizers, diacetin offered the smoothest surface of the cast films, and it displayed greatest water vapor transmission coefficient. Free RL and RS films with diacetin also exhibited greatest erosion compared with the other three plasticizers. On the other hand, TEC, DEP and DBS showed greater water absorption. When compared with CA-coated gliclazide PPOP, Eudragit-coated ones showed a f(2) factor of 71.7, indicating the similarity between the release profile of the two formulations. The prepared Eudragit-coated gliclazide PPOP showed typical Zero-order release characteristics, with R being 0.9953. In the in vivo evaluation, the mean relative oral bioavailability of Eudragit-coated PPOP compared to CA-coated ones was 106.9%, demonstrating good bioequivalence. Both of their in vitro-in vivo correlation (IVIVC) showed linear relationship, with R(2) being 0.9955 (Eudragit-coated PPOP) and 0.9987 (CA-coated PPOP), respectively. These results suggested that PPOP coated with Eudragit(®) RL 30D and RS 30D could overcome drawbacks of organic solution coating and promote the development of PPOP.

[Optimization of a novel mucoadhesive drug deliver system with ion-exchange resin core loaded with berberine hydrochloride using central composite design methodology].

A novel mucoadhesive microcapsule with drug-resin complex core loaded with berberine hydrochloride (BH) was developed and optimized. Drug-ion exchange resin (IER) complex was prepared by static method which stirring IER in drug solution at certain conditions. The influences of different IERs, different temperature, pH values and concentrations of drug solution on the drug loading were investigated. IER complex was coated by emulsion-solvent evaporation method. The coating fluid formulation was optimized using central composite design-response surface methodology, where the ratio between Carbopol 934 and IER (X1), the ratio between Eudragit and IER (X2) and the ratio between Eudragit RL and RS (X3) were taken as independent variables. Time of cumulative release 85% (Y1) and percentage of gastric retention (Y2) were taken as response variables. Drug loading achieved a high level and more drug available in the condition of IER (IRP 88), 37 degrees C, pH 5 and 1.0 mg x mL(-1) drug solution. When X1 = 0.75, X2 = 0.9, X3 = 0.6, the time of cumulative release reached 85% at 300 min, the highest percentage of gastric retention in the range of this experiment were procured.

[Preparation of PEG-modified nanostructured lipid carriers loaded with hydroxycamptothecin and tissue distribution in mice].

Hydroxycamptothecin (HCPT) loaded PEG modified nanostructured lipid carriers (HCPT-PEG-NLC) and nanostructured lipid carriers (HCPT-NLC) were prepared by melt emulsification and homogenization method. The morphology, particle size and encapsulation efficiency of them were investigated. HCPT concentrations in plasma, heart, liver, spleen, lung, kidney and ovary were determined after iv of HCPT injection, HCPT-PEG-NLC and HCPT-NLC in mice. The targeting indexes of HCPT-PEG-NLC and HCPT-NLC were calculated. The transmission electron microscope imaging showed that HCPT-PEG-NLC and HCPT-NLC exhibited a spherical shape. The particle sizes of them were (88.6 +/- 22.5) and (127.2 +/- 43.4) nm. The encapsulation efficiency were (90.51 +/- 3.29)% and (84.37 +/- 2.81)%, respectively. After iv injection into the tail vein of mice, HCPT plasma concentrations of HCPT-PEG-NLC and HCPT-NLC were higher than that of HCPT injection at each sampling time. They also showed longer elimination time in every tissue. HCPT-NLC accumulated in endothelial system (RES), Re and Ce of it in liver and spleen were significantly higher than HCPT-PEG-NLC. HPCT-PEG-NLC prolonged circulation time and increased bioavailability of HCPT. MRT and AUC0-24 h of it were 19.80 and 17.02 times higher than those of HCPT injection. It also significantly reduced phagocytosis of RES, and showed lung targeting effect (Re and Ce were 14.51 and 41.35). To summarize, HCPT-PEG-NLC could prolong the circulation time of HCPT in vivo, and had the lung targeting effect. It was a promising carrier to increase therapeutic effect of HCPT in treating lung cancer.

[Study on in vitro release empirical method and the release mechanism of budesonide colonic localization tablet].

The three-step dissolution experiment was established to investigate the in vitro release of budesonide colon-specific tablet and to elucidate the drug release mechanism by fitting to different mathematical models. The physiological parameters of stomach, small intestine and colon such as pH value, intestinal flora, specific organic enzyme, vermiculation and conveying time were mimicked to plot the in vitro dissolution, separately. Sample were taken at predetermined time intervals in 24 h and the accumulated drug releases were determined by using HPLC method. Drug release curves of the localization tablets were fitted to various mathematical models. It shows that no drug release was found in 2 h. About 5% release was determined after 6 h while 77.5% accumulated release was reached within 24 h. Drug release from the in house formulation fitted well into first-order model. The three-step dissolution method could be used to evaluate the colon-specific characteristics of budesonide colonic localization tablet. The drug release behavior of the localization tablet conforms to the drug release mechanisms of controlled porosity osmotic pump where osmotic pressure is the main driving force for controlled delivery of drugs.

Study on the ocular pharmacokinetics of ion-activated in situ gelling ophthalmic delivery system for gatifloxacin by microdialysis.

The poor bioavailability and therapeutic response exhibited by conventional ophthalmic solutions due to rapid precorneal elimination of the drug may be overcome by the use of gel system. The present work was conducted to evaluate the relative bioavailability of ion-activated in situ ophthalmic gel of gatifloxacin by microdialysis. The conventional ophthalmic solution of gatifloxacin was used as reference. The AUC of test group is 3.8-fold vs. the reference group (1.4316 +/- 0.1327 microg.mL(-1).h vs. 0.3756 +/- 0.0380 microg.mL(-1).hr) (P < 0.05), and the C(max) of test group vs. the control group is 3.0-fold (0.3363 +/- 0.0634 microg.mL(-1) vs. 0.1112 +/- 0.0151 microg.mL(-1)) (P < 0.05). The T(max) of test group is longer than that of reference group (2.0 +/- 0.67 hr vs. 0.667 +/- 0.17 hr) (P < 0.1), and K(e) of test group is lower than that of reference group. The developed formulation has a higher bioavailability and longer residence time in aqueous humor than conventional ophthalmic solutions. The developed system is a viable alternative to conventional eye drops.

Preparation of budesonide-poly (ethylene oxide) solid dispersions using supercritical fluid technology.

The purpose of this study was to investigate the possibility of preparing solid dispersions of the poorly soluble budesonide by supercritical fluid (SCF) technique, using poly (ethylene oxide) (PEO) as a hydrophilic carrier. The budesonide-PEO solid dispersions were prepared, using supercritical carbon dioxide (SC CO(2)) as the processing medium, and characterized by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), solubility test and dissolution test in order to understand the influence of the SCF process on the physical status of the drug. The endothermic peak of budesonide in the SCF-treated mixtures was significantly reduced, indicating that budesonide was in amorphous form inside the carrier system. This was further confirmed by SEM and PXRD studies. The enhanced dissolution rates of budesonide were observed from SCF-treated budesonide-PEO mixtures. The amorphous characteristic of the budesonide, the better mixing of drug and PEO powders in the presence of SC CO(2), together with the improved wettability of the drug in PEO, produced a remarkable enhancement of the in vitro drug dissolution rate. Thus, budesonide-PEO solid dispersions with enhanced dissolution rate can be prepared using organic solvent-free SCF process.

Chitosan-based controlled porosity osmotic pump for colon-specific delivery system: screening of formulation variables and in vitro investigation.

A microbially triggered colon-targeted osmotic pump (MTCT-OP) has been studied. The gelable property at acid condition and colon-specific biodegradation of chitosan were used to: (1) produce the osmotic pressure, (2) form the drug suspension and (3) form the in situ delivery pores for colon-specific drug release, respectively. The scanning electron microscopy (SEM) study and the calculation of membrane permeability were applied to elucidate the mechanism of MTCT-OP. The effects of different formulation variables, including the level of pH-regulating excipient (citric acid) and the amount of chitosan in the core, the weight gain of semipermeable membrane and enteric-coating membrane, and the level of pore former (chitosan) in the semipermeable membrane, have been studied. Results of SEM showed that the in situ delivery pores could be formed in predetermined time after coming into contact with dissolution medium, and the number of pore was dependent on the initial level of pore former in the membrane. The amount of budesonide release was directly proportional to the initial level of pore former, but inversely related to the weight of semipermeable membrane. The effects of variations in the level of citric acid and chitosan in the core formulation on drug release were studied. The different levels of enteric-coating membrane could prevent cellulose acetate membrane (containing chitosan as pore former) from forming pore or rupture before contact with simulated colonic fluid, but had no effect on the drug release. Budesonide release from the developed formulation was inversely proportional to the osmotic pressure of the release medium, confirming that osmotic pumping was the major mechanism of drug release. These results showed that MTCT-OP based on osmotic technology and microbially triggered mechanism had a high potential for colon-specific drug delivery.

[Study on ingredients of essential oils of Curcuma wenyujin extracted by supercritical-CO2 fluid extraction and steam distillation].

OBJECTIVE: To compare the ingredients of essential oils of Curcuma wenyujin extracted by supercritical-CO2 fluid extraction and by steam distillation. METHOD: GC-MS was applied in this experiment. RESULT: The ingredients and physical and chemical properties of essential oils of C. wenyujin extracted by supercritical-CO2 fluid extraction and by steam distillation are similar. CONCLUSION: Supercritical-CO2 fluid extraction is better than steam distillation in extraction time, power consumption, recovery and purity.

Design and evaluation of jingzhiguanxin monolithic osmotic pump tablet.

A monolithic osmotic pump tablet (MOPT) of Traditional Chinese Medicine Compound Recipe (TCMCR) was successfully prepared and active components of Jingzhiguanxin prescription which has been widely used in China and Japan was selected as model drug. Analysis methods of maker compound in vitro of danshensu, paeoniflorin and safflor yellow A were built, and different methods were compared by f2 factors. The results showed that there were fine correlation among them. Finally UV method of safflor yellow A was chosen to determine the release of the drugs, which was fast, convenient, met the need of determination and could represent other methods. During the research, single factor influence selection was studied emphatically. It showed that there were significant influence between different varieties and quantity of osmotic promoting agents, different kind of retardants, different varieties and quantity of PEG (polyethylene glycol) and membrane weight. However, no significant influence existed between different quantity of retardants and SDS, different membrane orifices and methods of dissolution. Based on the single factor influence selection, an optimal formulation was decided, and three maker compounds of Jingzhiguanxin MOPT could isochronous release and at the same time they had good zero order release characteristics to 8 h. Paeoniflorin release in vivo was estimated by deconvolution, the results shown that there were a good in-vitro in-vivo correlation (r=0.9571).

Studies of the pharmacokinetics of paeoniflorin in two Jing-Zhi-Guan-Xin formulations after oral administration to beagle dogs.

Paeoniflorin is the principal bioactive component of Paeoniae Radix. The traditional chinese medicine compound recipe (TCMCR) tablets of Jing-Zhi-Guan-Xin (JZGX), which is composed of Radix Salviae Miltiorrhizae, Radix Paeoniae Rubrae, Rhizoma Chuan-xiong, Flos Carthami and Lignum Dalbergiae Odorafera, have been widely used in China and Japan. The plasma concentrations of paeoniflorin in beagle dogs after oral administration of two Jing-Zhi-Guan-Xin formulations (the dose used in the two formulations were both 200 mg paeoniflorin) were measured using a simple and rapid HPLC method. The mean terminal half-lives (t1/2) of JZGX tablet and JZGX elementary osmotic pump tablet (EOPT) formulations of paeoniflorin were 147.52 +/- 28.98 and 276.60 +/- 24.24 min, the maximum plasma concentrations (Cmax) of paeoniflorin were 210.49 +/- 23.89 and 94.36 +/- 14.01 ng/ml, times to reach maximum concentrations (tmax) were 130.00 +/- 30.98 and 280.00 +/- 48.99 min, the area under the plasma concentration-time curves (AUC0-infinity) were 43066.50 +/- 10119.51 and 42266.87 +/- 2654.90 ng min/ml, the mean residence times (MRT) were 212.87 +/- 41.82 and 399.14 +/- 34.98 min, respectively, and the relative bioavailability (Fr) of JZGX EOPT compared with JZGX tablet was 101.8 +/- 18.8%. These results, compared with the pharmacokinetic parameters of paeoniflorin after oral administration of Paeoniae Radix extract alone, indicated that the absorption of paeoniflorin after oral administration of the two JZGX formulations was significantly greater than that after oral administration of Paeoniae Radix extract alone.

[The pharmacokinetics and bioequivalence of acipimox sustained-release tablets after a single and multiple oral administration in healthy dogs].

AIM: To study the pharmacokinetics and bioequivalence of acipimox sustained-release tablets (SRT) after a single and multiple oral dose in healthy dogs. METHODS: The plasma concentrations of of SRT and reference capsules with a single and multiple oral doses. RESULTS: The drug concentration-time profiles fitted to a noncompartment model. After a single dose administration of sustained-release tablets and capsules, the pharmacokinetic parameters were as follows: AUC were (158 +/- 30) and (147 +/- 37) microg x h x mL(-1); Tmax were (4.3 +/- 0.8) and (2.6 +/- 1.3) h; Cmax were (29 +/- 6) and (42 +/- 10) microg x mL(-1); T(1/2) were (2.3 +/- 0.7) and (1.60 +/- 0.10) h; MRT were (6.0 +/- 0.8) and (3.9 +/- 0.7) h, respectively. The relative bioavailability of the sustained-release tablet was (108 +/- 16) %. After a multiple oral administration of sustained-release tablets and capsules, the pharmacokinetic parameters were as follows: AUC were (209 +/- 23) and (195 +/- 26) microg x h x mL(-1); Tmax were (6.3 +/- 0.8) and (3.4 +/- 1.5) h; Cmax were (27 +/- 4) and (36 +/- 5) microg x mL(-1); Cmmin were (2.2 +/- 1.0) and (0.20 +/- 0.20) microg x mL(-1); Cav were (8.7 +/- 1.0) and (8.1 +/- 1.1) micro x mL(-1); FI were (293 +/- 73) % and (448 +/- 91) % , respectively. The relative bioavailability of the sustained-release tablet was (114 +/- 19) %. CONCLUSION: The results of two one-side test from single dose administration shown that two preparations were bioequivalent. The Cmax of sustained-release tablet was lower than that of capsules, while the Tmax and MRT of sustained-release tablet were higher than that of capsule, which indicating a good retarding effect. The results from multiple dose administration also shown that two preparations were bioequivalent and the DF of sustained-release tablet was significant lower than that of capsule.