Shufang Nie

Liposome coated with low molecular weight chitosan and its potential use in ocular drug delivery

In this study liposome coated with low molecular weight chitosan (LCH) was proposed and investigated its in vitro and in vivo properties, and its potential use in ocular drug delivery was evaluated. LCH with a molecular weight of 8kDa was prepared and coated on liposome loaded with diclofenac sodium. The LCH coating changed the liposome surface charge and slightly increased its particle size, while the drug encapsulation was not affected. After coating, the liposome displayed a prolonged in vitro drug release profile. LCH coated liposome also demonstrated an improved physicochemical stability at 25 degrees C in a 30-day storage period. The ocular bioadhesion property was evaluated by rabbit in vivo precorneal retention, and LCH coated liposome achieved a significantly prolonged retention compared with non-coated liposome or drug solution. The LCH coating also displayed a potential penetration enhancing effect for transcorneal delivery of the drug. In the ocular tolerance study, no irritation or toxicity was caused by continual administration of LCH coated liposome in a total period of 7 days. In conclusion, the LCH coating significantly modified the properties of liposome and brought a series of notable advantages for ocular drug delivery.

Preparation and Evaluation of SEDDS and SMEDDS Containing Carvedilol

ABSTRACT A new self-emulsifying drug delivery system (SEDDS) and self-microemulsifying drug delivery system (SMEDDS) have been developed to increase the solubility, dissolution rate, and, ultimately, oral bioavailability of a poorly water soluble drug, carvedilol. Ternary phase diagrams were used to evaluate the self-emulsification and self-microemulsfication domains. The self-emulsification time following introduction into an aqueous medium under gentle agitation was evaluated. The minimum self-emulsification time was found at a Tween 80 content of 40%. The particle size distribution and ζ-potential were determined. Benzoic acid had a dual function, it improved the self-emulsification performance of SEDDS and SMEDDS in 0.1 N HCl and lead to a positively charged emulsion. The in vitro dissolution rate of carvedilol from SEDDS and SMEDDS was more than two-fold faster compared with that from tablets. The developed SEDDS formulations significantly improved the oral bioavailability of carvedilol significantly, and the relative oral bioavailability of SEDDS compared with commercially available tablets was 413%.

A controlled-release ocular delivery system for ibuprofen based on nanostructured lipid carriers.

The objective of this study was to develop an ocular drug delivery system based on nanostructured lipid carrier and investigate its in vitro and in vivo characteristics. Ibuprofen was chosen as the model drug. Four different formulations of ibuprofen nanostructured lipid carriers were prepared by melted-ultrasonic methods; gelucire 44/14 was screened as one of the solid lipid matrix materials due to the good particle size dispersion and excellent contribution to the corneal permeability of the model drug. The modified Franz-type diffusion cells and isolated corneas were used in the test of drug corneal permeability and the in vivo releasing tests were carried out using microdialysis method. gelucire 44/14 and transcutol P could enhance the corneal permeability by different mechanisms. The corresponding apparent permeability coefficients (P(app)) were 1.28 and 1.36 times more than that of the control preparation. Stearylamine could prolong the pre-cornea retention time of the model drug to some extent. Ibuprofen nanostructured lipid carriers displayed controlled-release property. The AUC of the optimized formulation of ibuprofen nanostuctured lipid carriers was 3.99 times more than that of ibuprofen eye drops).

Preparation and Evaluation of Self-Microemulsifying Drug Delivery System Containing Vinpocetine

The main purpose of current investigation is to prepare a self-microemulsifying drug delivery system (SMEDDS) to enhance the oral bioavailability of vinpocetine, a poorly water-soluble drug. Suitable vehicles were screened by determining the solubility of vinpocetine in them. Certain surfactants were selected according to their emulsifying ability with different oils. Ternary phase diagrams were used to identify the efficient self-microemulsifying region and to screen the effect of surfactant/cosurfactant ratio (Km). The optimized formulation for in vitro dissolution and bioavailability assessment was oil (ethyl oleate, 15%), surfactant (Solutol HS 15, 50%), and cosurfactant (Transcutol® P, 35%). The release rate of vinpocetine from SMEDDS was significantly higher than that of the commercial tablet. Pharmacokinetics and bioavailability of SMEDDS were evaluated. It was found that the oral bioavailability of vinpocetine of SMEDDS was 1.72-fold higher as compared with that of the commercial tablet. These results obtained demonstrated that vinpocetine absorption was enhanced significantly by employing SMEDDS. Therefore, SMEDDS might provide an efficient way of improving oral bioavailability of poorly water-soluble drugs.

Optimized preparation of vinpocetine proliposomes by a novel method and in vivo evaluation of its pharmacokinetics in New Zealand rabbits.

Free-flowing proliposomes which contained vinpocetine were prepared successfully to increase the oral bioavailability of vinpocetine. In this study the proliposomes were prepared by a novel method which was reported for the first time and the formulation was optimized using the centre composite design (CCD). The optimized formulation was Soybean phosphatidylcholine: 860 mg; cholesterol: 95 mg and sorbitol: 8000 mg. After the proliposomes were contacted with water, the suspension of vinpocetine liposomes formed automatically and the entrapment efficiency was approximately 86.3% with an average particle size of about 300 nm. The physicochemical properties of the proliposomes including SEM, TEM, XRD and FTIR were also detected. HPLC system was applied to study the concentration of vinpocetine in the plasma of the New Zealand rabbits after oral administration of vinpocetine proliposomes and vinpocetine suspension. The pharmacokinetic parameters were calculated by the software program DAS2.0. The concentration-time curves of vinpocetine suspension and vinpocetine proliposomes were much more different. There were two absorption peaks on the concentration-time curves of the vinpocetine proliposomes. The pharmacokinetic parameters of vinpocetine and vinpocetine proliposomes in New Zealand rabbits were T(max) 1 h and 3 h (there was also an absorption peak at 1 h); C(max) 163.82+/-12.28 ng/ml and 166.43+/-21.04 ng/ml; AUC(0-infinity) 1479.70+/-68.51 ng/ml h and 420.70+/-35.86 ng/ml h, respectively. The bioavailability of vinpocetine in proliposomes was more than 3.5 times higher than the vinpocetine suspension. The optimized vinpocetine proliposomes did improve the oral bioavailability of vinpocetine in New Zealand rabbits and offer a new approach to enhance the gastrointestinal absorption of poorly water soluble drugs.

Investigations of a Novel Self-Emulsifying Osmotic Pump Tablet Containing Carvedilol

Carvedilol has been made into a novel osmotic pump tablet which includes Gelucire 44/14, Lutrol F68, Transcutol P, silicon dioxide, mannitol, citric acid, and sodium hydrogen carbonate. The Self-emulsifying osmotic pump tablet (SEOPT) has two outstanding features. It could improve the bioavailability of carvedilol by self-emulsifying drug delivery system (SEDDS), control the release rate and make the plasma concentrations more stable by elementary osmotic pump tablet. The results of transmission electron microscope (TEM) and particle size assessment showed that the shape of the resultant emulsion was round and regular, the average diameter of the particles was 246 nm. Since the solubility of carvedilol was improved by the emulsion, the elementary SEOPT could guarantee a complete release of carvedilol under the osmotic pressure of mannitol. The cumulative release at 12 hr was 85.18%. Therefore the disadvantage that lipophilic drugs can not be released completely when prepared into elementary osmotic pump tablet was resolved. The results of Differential scanning calorimetry (DSC), Infrared spectroscopy (IR) and X-ray diffraction diffraction (XRD) proved that carvedilol was amorphous in the preparation. The relative bioavailability of carvedilol in beagle dogs was 156.78%. The plasma concentrations were more stable compared with that of commercially available tablet (Luode®). And the in vitro and in vivo correlation was good (r = 0.9725). Therefore, the elementary SEOPT developed in this paper might provide a new idea for preparing lipophilic drugs into osmotic pump tablet conveniently.

Effects of Transcutol P on the corneal permeability of drugs and evaluation of its ocular irritation of rabbit eyes

Our purpose was to explore the use of Transcutol P (Trans) in an ocular drug delivery system. The effect of Trans on the corneal permeability of drugs was investigated in‐vitro, using isolated rabbit corneas. The ocular irritation of Trans was also tested in rabbits in‐vivo. In the presence of Trans, at a concentration of 0.005–0.03%, the maximum increase in the apparent permeability coefficient (Papp) was 1.5, 1.5, 3.0 and 3.3 fold for ribavirin, gatifloxacin, levofloxacin hydrochloride and enoxacin, respectively. However, the Papp value of oxaprozin was reduced in the presence of Trans. The maximum reduction was found to be 2.8 fold at a concentration of 0.03% Trans. The results of the ocular irritation studies showed that Trans was non‐irritant at the concentrations studied (0.005–0.03%), while it produced slight irritation at a concentration of 0.05%. It was also found that Trans did not cause any visible ocular damage or abnormal clinical signs involving the cornea, iris or conjunctivae at all concentrations. We concluded that Trans may have potential clinical benefits in improving the ocular drug delivery of hydrophilic compounds.

PEGylated nanostructured lipid carriers loaded with 10‐hydroxycamptothecin: an efficient carrier with enhanced anti‐tumour effects against lung cancer

Most drugs do not have the pharmacokinetic features required for optimal pulmonary delivery. In this study, we developed PEGylated nanostructured lipid carriers (PEG‐NLCs) to improve the delivery of anti‐tumour agents to lung tumours. PEG‐40 NLCs modified with PEG‐40 stearate (molecular weight 2000 Da), PEG‐100 NLCs modified with PEG‐100 stearate (molecular weight 5000 Da) and NLCs without PEG modification were prepared by melt‐emulsification and homogenization, and were loaded with 10‐hydroxycamptothecin (HCPT). They were investigated in terms of physiological characteristics, biodistribution, cellular uptake, and anti‐tumour effect in‐vivo. PEG‐NLCs exhibited regular morphology, with a spherical shape. The particle size (measured by laser diffraction) was approximately 100 nm. Encapsulation in PEG‐NLCs protected the active lactone form of HCPT compared with HCPT solution after incubation with plasma. In biodistribution studies, PEG‐NLCs, especially PEG‐40 NLCs, had longer circulation time and decreased uptake by the reticuloendothelial system (RES) compared with unmodified NLCs. PEG‐NLCs accumulated in the lungs after i.v. injection in mice. PEG‐NLCs showed enhanced cellular uptake by human lung adenocarcinoma epithelial A549 cells. In‐vivo experiments indicated that PEG‐NLCs loaded with HCPT have superior efficacy against A549 lung cancer compared with HCPT solution and NLCs. These results suggest that PEG‐NLCs is a promising delivery system for HCPT in the treatment of lung cancer.

A novel gastric-resident osmotic pump tablet: In vitro and in vivo evaluation

A novel famotidine gastric-resident osmotic pump tablet was developed. Pharmaceutical iron powder was used as a gas-formation and density-increasing agent. Central composite design-response surface methodology was used to investigate the influence of factors, i.e., polyethylene oxide (Mw 1,000,000) content, NaCl content, iron powder content and weight gain, on the responses including ultimate cumulative release and correlation coefficient of drug release profile. A second-order polynomial equation was fitted to the data and actual response values are in good accordance with the predicted ones. The optimized formulation displays a complete drug delivery and zero-order release rate. Gamma scintigraphy was selected as the method to monitor in vivo gastric residence time of the (99m)Tc-labeled system in Beagle dogs. It was observed that the system can retain in stomach for an extended period of 7h after administration compared with conventional tablets. The present investigation suggests that water-insoluble drug can be delivered from single-layer osmotic pump tablets completely due to the push power of the hydrogen gas generated by the reaction of the iron and gastric fluid. And iron powder can increase the system density which is over 2.5 g cm(-3), making the system resident in stomach to prolong the drug delivery time in absorption zone.

Optimization of tocol emulsions for the intravenous delivery of clarithromycin

In the present study, novel less-painful tocol emulsions for the intravenous delivery of clarithromycin were prepared and optimized. The therapeutically effective concentration of clarithromycin, 5mg/ml, was achieved using tocopherol succinate (TS) combined with oleic acid as lipophilic counterions. The possibility of employing the microdialysis technique to investigate the distribution of the drug in emulsions was explored. A three-level three-factorial Box-Behnken experimental design was utilized to conduct the experiments. The effects of selected variables, tocopherol succinate/oleic acid relation, poloxamer 188 content and 0.1M NaOH amount, on three considered responses were investigated. The particle size, zeta potential and the oil phase distribution of clarithromycin for the optimized formulation were observed to be 138.5 nm, -32.16 mV and 97.28%, respectively. The emulsions prepared with the optimized formula demonstrated good physical stability during storage at 4 degrees C and room temperature. The histopathological examination for rabbit ear vein irritation test indicated that the irritation of clarithromycin could be eliminated by formulating the drug in a tocol emulsion.