Study on the preparation of nifedipine-loaded oral copolymer micelles and its pharmacokinetics in rats.

The objective of this paper was to prepare nifedipine-loaded oral copolymer micelles and to improve bioavailability of hydrophobic drugs. The methoxy poly(ethylene glycol)-b-polycaprolactone diblock copolymer (mPEG-b-PCL) we developed was the research object; solvent evaporation method was utilized to prepare nifedipine-loaded copolymer micelles, and the drug concentration, drug-loaded amount, and entrapment efficiency were also determined. Transmission electron microscopy and dynamic light scattering were used to characterize the morphology and size distributions of micelles, and the in vivo pharmacokinetics were studied in rats with the research objects of nifedipine-loaded oral copolymer micelles. The drug concentration, drug-loaded amount, and entrapment efficiency of mPEG-b-PCL-nifedipine micelles were (69.39 ± 4.33) µg mL(-1), (3.35 ± 0.21)%, and (8.67 ± 0.54)%, respectively. The micelles were globular shaped with a narrow size distribution and a mean diameter of (34.8 ± 3.2) nm, and the relative bioavailability of the micelles we developed was 246.20% when compared with the tablets available in the market. The mPEG-b-PCL-nifedipine oral copolymer micelles can improve the bioavailability of hydrophobic drugs. Oral polymer micelles drug delivery system has a good prospect.

[Advances in the study of polymeric micelles used in oral administration].

Polymeric micelles which are self-assembled from amphiphilic copolymers are thermodynamically stable, and they can solubilize hydrophobic drugs by the hydrophilic core. Many excellent active compounds are confined because of general low oral bioavailability due to poor solubility. Take into account from the two points above, polymeric micelles may be used as proper oral carrier to improve the dissolubility of hydrophobic drugs, and enhance the permeation though gastrointestinal tract, therefore, the pharmacodynamics is elevated. Meanwhile, the segments in copolymers are multivariate, so many kinds of micelles can be obtained, such as, pH- or thermo- sensitive as well as mucoadhesive ones. The modified micelles can alter drug release profiles while solubilizing them, that is why the oral bioavailability increase further. In this review, recent progress of polymeric micelles used in oral administration is summarized, and the prospect of polymeric micelles' application in this field is also evaluated.

DOX-loaded PEG-PLGA and Pluronic copolymer composite micelles enhances cytotoxicity and the intracellular accumulation of drug in DOX-resistant tumor cells.

In the present study, doxorubicin (DOX) loaded polyethyleneglycol-poly (DL-lactic-co-glycolic acid) micelle as well as composite micelles composed polyethyleneglycol- poly(DL-lactic-co-glycolic acid) (PEG-PLGA) and Pluronic 105 (P105) were constructed. The micelles, with diameter around 106 nm and 85 nm respectively, were prepared by solvent evaporation method. The results showed that the encapsulation of DOX in micelles could significantly enhance its cytotoxicity in a DOX resistant tumor cell line, K562/DOX. The combination of PEG-PLGA and Pluronic further improved both the tumor-suppressive activity and the intracellular accumulation of DOX, indicating that the composite micelles would be potential to reverse the multidrug resistance in tumor cells.

[Optimization of ligustrazine phosphate thermosensitive gel formulation by central composite design-response surface methodology].

OBJECTIVE: To optimize the formulation of ligustrazine phosphate thermosensitive gel by the central composite design-response surface methodology (RSM plus CCD). METHODS: In the formulation design using RSM plus CCD, independent variables were the amounts of poloxamer 407 and poloxamer 188, and gel temperature was dependent variable. Multilinear and quadratic models were used to estimate the relationship between the dependent and the independent variables, select the optimal formulations and validate. RESULTS: The quantitative relationships between two factors and evaluation index were characterized, quadratic model had better prediction capability than multilinear model. CONCLUSION: Quadratic model is performed in the optimization of formulation due to the statistical confidence. The optimization of ligustrazine phosphate thermosensitive gel formulation can be achieved by the central composite design and response surface methodology.

[Pharmacokinetics of pingyangmycin hydrochloride in rabbits determined by microdialysis coupled with RP-HPLC].

Microdialysis coupled with RP-HPLC was used to study the blood pharmacokinetics of pingyangmycin hydrochloride in rabbits. Supelco RP-amide C16 column was adopted for the analysis of pingyangmycin hydrochloride. The data was analyzed with 3P87 program. The calibration curve was linear in the concentration range from 1.04 to 66.56 microg x mL(-1) (r2 = 0.999 4). The in vivo recovery of microdialysis probe was (42.8 +/- 3.4)% (n = 4). The concentration-time curve of pingyangmycin hydrochloride was fitted to two-compartment model. T1/2 alpha and T1/2 beta were 14.9 and 60.3 min, respectively. The method is proved to be accurate, simple and suitable for the pharmacokinetics study of pingyangmycin hydrochloride in rabbits.

[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.

Application of microdialysis to study the in vivo release of pingyangmycin from in situ gels in rabbits.

Microdialysis was used together with HPLC to monitor the local concentration of pingyangmycin hydrochloride (PYM) after embolizing rabbit ear-veins with an injectable sustained release formulation, PYM-Zein/PYM-Zein-sucrose acetate isobutyrate (SAIB), in situ gel. The dialysis probe was perfused at 2 microL/min. The in vivo recovery was 46.6 3.1% (n = 4). The samples were injected directly into HPLC. PYM was detected using UV detector at 291 nm. Separation from other components in the dialysate was performed using a Discovery((R)) RP-Amide C(16) column within 12 min. The response for PYM in the dialysate was linear (r(2) > 0.996) over the range of 2.5-212 microg/mL. The limit of detection and limit of quantitation of PYM in the dialysate were 0.4 and 1.5 microg/mL, respectively. The results demonstrated that the in situ gel of PYM-Zein-SAIB could extend the release of PYM to 4 days. SAIB could significantly cut down the initial burst of PYM from the in situ gels (p < 0.05).

Pharmacokinetics of timolol in aqueous humor sampled by microdialysis after topical administration of thermosetting gels.

In order to develop a thermosetting gel-based formulation, the ocular pharmacokinetics of timolol was studied utilizing microdialysis sampling technique after topical administration. A linear microdialysis probe was characterized and implanted in the anterior chamber of a rabbit. Dialysate samples collected from the aqueous humor (AH) were directly injected into the HPLC system without any pre-treatment and no interference was observed in the blank sample. The measured in vitro recovery of the probe was 57.67%; however, the in vivo recovery significantly decreased to 16.78% when assessed by the retrodialysis method, which was used to calculate the timolol concentration in AH. Although in the initial 15 min the drug concentrations in AH were comparable to that of the timolol solution, increased Cmax and significantly improved ocular bioavailability were obtained for the gel. When sodium deoxycholate (DC) was incorporated in the gel as a penetration enhancer, a 2-fold increment in the ocular bioavailability was achieved with an increased Cmax and significantly suspended Tmax. The results demonstrated that microdialysis coupled to HPLC is a powerful tool to investigate the ocular pharmacokinetic, and hence facilitates the design of ophthalmic formulations.

Expression of matrix metalloproteinase 2 and its tissue inhibitor in oral squamous cell carcinoma.

The aim of this study is to investigate the expression of matrix metalloproteinase 2 (MMP-2) and the tissue inhibitor of metalloproteinase 2 (TIMP-2) in oral squamous cell carcinoma (OSCC) and adjacent normal tissues, and explore the role of MMP-2 and TIMP-2 in carcinoma metastasis and invasion. Expression of MMP-2 and TIMP-2 was evaluated in 40 cases with semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemical techniques. The values of MMP-2/beta-actin and TIMP-2/beta-actin in OSCC were significantly higher than those in adjacent normal tissues 2 cm and > or = 5 cm from carcinoma tissues (p<0.05). The results of immunohistochemical analysis show that the positive expression of MMP-2 and TIMP-2 protein in tumor tissues (60.0 and 52.5%) was higher than that in adjacent normal tissues 2 cm (30.0 and 22.5%) and 5 cm (22.5 and 25.0%) from cancer tissues, and the difference was significant p<0.05). The expression of MMP-2 and TIMP-2 was related to the differentiation degree of tumor cells, metastatic lymph node status and stage of carcinoma, but not related to the age and gender of patients, or location of the carcinoma. Therefore, MMP-2 and TIMP-2 may play important roles in the invasion and metastasis of OSCC.

[Cutaneous permeation kinetics and pharmacodynamics of topical lidocaine gel in rat].

AIM: To study the cutaneous permeation kinetics and pharmacodynamics of lidocaine gel. METHODS: The concentration of lidocaine in dermis following topical application in rats was determined by the cutaneous microdialysis technique and related parameters were calculated; the pharmacodynamics of the gel was evaluated by electric stimulation method with EMLA (eutectic mixture of local anesthetics) cream as a control. RESULTS: The peak of percutaneous absorption kinetic profile of lidocaine gel across rat skin occurred at 1.25 h; the onset time of local anesthetic action of lidociane gel was similar to that of EMLA, but both the duration and depth of anesthetic effect were superior to EMLA cream. CONCLUSION: Lidocaine gel showed good anesthetic effect. The minimum effective concentration of lidocaine in dermis is 12 mg.L-1.

[Enhancement of gastrointestinal absorption of chitosan-coated insulin-loaded poly (lactic-co-glycolic acid) nanoparticles].

AIM: To study chitosan-coated poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) on enhancing gastrointestinal absorption of insulin. METHODS: Insulin-loaded PLGA multiple emulsions were prepared by a double-emulsion method. Using chitosan as a stabilizer, chitosan-coated PLGA-NPs was prepared. The changes of the morphology, size distribution and Zeta potential of the NPs were examined. The encapsulation efficiency was determined by HPLC. The release behaviors in vitro were assessed, and the hypoglycemic effects were evaluated by monitoring the glucose levels in diabetic rats. RESULTS: Chitosan-coated PLGA-NPs showed a narrow size of distribution and regular surface with layer structure and their Zeta potential can be changed by chitosan. Chitosan-coating increased the encapsulation efficiency of insulin, reduced the initial burst and improved the release behavior of the NPs. About 14-16 h after intragastric administration of chitosan-coated INS-PLGA-NPs, the plasma glucose level decreased significantly compared with intragastric administration of same dose of non-coated NPs (P < or = 0.05), and the relative pharmacological availability was increased up to (15.4 +/- 1.2)%. CONCLUSION: Chitosan-coated PLGA-NPs could enhance gastrointestinal absorption of insulin.

Thermosetting gels with modulated gelation temperature for ophthalmic use: the rheological and gamma scintigraphic studies.

For ophthalmic drug delivery, Pluronic F127 solutions have a phase transition temperature too low for them to be instilled into the eye at room temperature. Refrigerator storage is usually required to make administration easier, whereas the potential irritation of cold to the sensitive ocular tissues may result in poor topical bioavailability. The purpose of this study is to develop a thermosetting gel with a suitable phase transition temperature by combining Pluronic analogs and to examine the influence of incorporating mucoadhesive polysaccharide, sodium hyaluronate (HA-Na), on the ocular retention of the gel. Dynamic rheological method and single photon emission computing tomography (SPECT) technique were used to ex/in vivo evaluate the thermosetting gels, respectively. An optimized formulation containing 21% F127 and 10% F68 increased the phase transition temperature by 9 degrees C as evaluated by elasticity modulus compared to that of individual 21% F127 solution. Rheological behaviors of the Pluronic solutions showed that the combined Pluronic formulation was free flowing liquid below 25 degrees C and converted to a firm gel under the physiological condition. Furthermore, this formulation possessed the highest viscosity both before and after tear dilution at 35 degrees C. Gamma scintigraphic data demonstrated that the clearance of the thermosetting gel labeled with 99mTc-DTPA was significantly delayed with respect to the phosphate buffered solution, and at least a threefold increase of the corneal residence time was achieved. However, no further improvement in the ocular retention was observed when adding HA-Na into the thermosetting gel due to the substantially decreased gel strength.

[Effect of solution viscosity on polymer precorneal residence time evaluated by in vitro method].

AIM: To evaluate how solution viscosity affects the precorneal residence of five water-soluble polymers with different properties. METHODS: Captive bubble technique was used, with the consecutive change of contact angle interpreted as an indication of desorption process, to study the residence of those polymers in vitro on freshly enucleated rabbit eyes under physiological conditions. RESULTS: Carbopol and sodium hyaluronate (HA), which adsorbed to isolated ocular surface more than 15 min, showed the optimum precorneal retentive capabilities. When the solution viscosity increased from 12 mPa.s to 50 mPa.s, the residence time of carbopol and HA were prolonged 10 min and 7 min, respectively, but that of sodium carboxymethylcellulose was not affected. CONCLUSION: The result suggested that higher viscosity is beneficial to improve the ocular residence time of bio-adhesive polymers.