Browning white adipose tissue using adipose stromal cell-targeted resveratrol-loaded nanoparticles for combating obesity.

Enhancing thermogenic energy expenditure via promoting the browning of white adipose tissue (WAT) is a potential therapeutic strategy to manage energy imbalance and the consequent comorbidities associated with excess body weight. Adverse effects and toxicities of currently available methods to induce browning of WAT have retarded exploration of this promising therapeutic approach. Targeted delivery of browning agents to adipose stromal cells (ASCs) in subcutaneous WAT to induce differentiation into beige adipocytes may overcome these barriers. Herein, we report for the first time, ASC-targeted delivery of trans-resveratrol (R), a representative agent, using ligand-coated R-encapsulated nanoparticles (L-Rnano) that selectively bind to glycanation site-deficient decorin receptors on ASCs. After biweekly intravenous administration of L-Rnano to obese C57BL/6 J mice for 5 weeks targeted R delivery significantly induced ASCs differentiation into beige adipocytes, which subsequently resulted in 40% decrease in fat mass, accompanied by improved glucose homeostasis and decreased inflammation. Our results suggest that the ASC-targeted nanoparticle delivery of browning agents could be a transformative technology in combating obesity and its comorbidities with high efficacy and low toxicity.

Nanoparticles target intimal macrophages in atherosclerotic lesions.

Oxidized phosphatidylcholines (oxPCs) enriched on the oxidized LDL (oxLDL) surface are responsible ligands for binding oxLDL to the CD36 receptor of intimal macrophages in atherosclerotic lesions. We synthesized liposome-like nanoparticles (NPs) using soy phosphatidylcholine and incorporated 1-palmitoyl-2-(4-keto-dodec-3-enedioyl) phosphatidylcholine, a type of oxPCs, on their surface to make ligand-NP (L-NPs). The objectives of this study were to measure and compare their binding affinity to and uptake by primary mouse and THP-1 derived macrophages, and to determine their target specificity to intimal macrophages in aortic lesions in LDL receptor null (LDLr-/-) mice. All in vitro data demonstrate that L-NPs had a high binding affinity to macrophage CD36 receptor. L-NPs had 1.4-fold higher accumulation in aortic lesion areas than NPs. L-NPs co-localized with intimal macrophages and CD36 receptors in the aortic lesions. This target delivery approach may portend a breakthrough in molecular imaging and targeted treatment of atherosclerosis.

Anti-atherogenic effects of CD36-targeted epigallocatechin gallate-loaded nanoparticles.

Intimal macrophages play a critical role in atherosclerotic lesion initiation and progression by taking up oxidized low-density lipoprotein (oxLDL) and promoting inflammatory process. 1-(Palmitoyl)-2-(5-keto-6-octene-dioyl) phosphatidylcholine (KOdiA-PC), a major type of oxidized phosphatidylcholines (PC) found on oxLDL, has a high binding affinity to the macrophage scavenger receptor CD36 and participates in CD36-mediated recognition and uptake of oxLDL by intimal macrophages. We successfully synthesized epigallocatechin gallate (EGCG)-loaded nanoparticles (Enano), which were composed of EGCG, PC, (+) alpha-tocopherol acetate, and surfactant. We also incorporated KOdiA-PC on the surface of Enano to make ligand-coated Enano (L-Enano) to target intimal macrophages. The objectives of this study were to determine the anti-atherogenic effects of Enano and L-Enano in LDL receptor null (LDLr-/-) mice. Our in vitro data demonstrated that L-Enano had a higher binding affinity to mouse peritoneal macrophages than Enano. This high binding affinity was diminished by CD36 antibodies or knockdown of the CD36 receptor in mouse peritoneal macrophages, confirming the specific binding of L-Enano to the macrophage CD36 receptor. LDLr-/- mice were randomly divided to six groups and received weekly tail vein injection with PBS, EGCG, void nanoparticles (Vnano), Enano, ligand-coated Vnano (L-Vnano), or L-Enano once per week for 22 weeks. The dose of EGCG was 25 mg per kg body weight. L-Enano at 20 µg/mL significantly decreased production of monocyte chemoattractant protein-1, tumor necrosis factor alpha, and interleukin-6 from mouse macrophages, while having no effect on their plasma levels compared to the PBS control. There were no significant differences in blood lipid profiles among six treatment groups. Mice treated with L-Enano also had significantly smaller lesion surface areas on aortic arches compared to the PBS control. Liver EGCG content was decreased by treatments in the order of EGCG>Enano>L-Enano. Native EGCG had inhibitory effects on liver and body fat accumulation. This molecular target approach signals an important step towards inhibiting atherosclerosis development via targeted delivery of bioactive compounds to intimal macrophages.

Formulation, characteristics and antiatherogenic bioactivities of CD36-targeted epigallocatechin gallate (EGCG)-loaded nanoparticles.

Intimal macrophages are determinant cells for atherosclerotic lesion formation by releasing inflammatory factors and taking up oxidized low-density lipoprotein (oxLDL) via scavenger receptors, primarily the CD36 receptor. (-)-Epigallocatechin-3-gallate (EGCG) has a potential to decrease cholesterol accumulation and inflammatory responses in macrophages. We made EGCG-loaded nanoparticles (Enano) using phosphatidylcholine, kolliphor HS15, alpha-tocopherol acetate and EGCG. 1-(Palmitoyl)-2-(5-keto-6-octene-dioyl) phosphatidylcholine (KOdiA-PC), a CD36-targeted ligand found on oxLDL, was incorporated on the surface of Enano to make ligand-Enano (L-Enano). The objectives of this study are to deliver EGCG to macrophages via CD36-targeted L-Enano and to determine its antiatherogenic bioactivities. The optimized nanoparticles obtained in our study were spherical and around 108 nm in diameter, and had about 10% of EGCG loading capacity and 96% of EGCG encapsulation efficiency. Compared to Enano, CD36-targeted L-Enano had significantly higher binding affinity to and uptake by macrophages at the same pattern as oxLDL. CD36-targeted L-Enano dramatically improved EGCG stability, increased macrophage EGCG content, delivered EGCG to macrophage cytosol and avoided lysosomes. L-Enano significantly decreased macrophage mRNA levels and protein secretion of monocyte chemoattractant protein 1, but did not significantly change macrophage cholesterol content. The innovative CD36-targeted nanoparticles may facilitate targeted delivery of diagnostic, preventive and therapeutic compounds to intimal macrophages for the diagnosis, prevention and treatment of atherosclerosis with enhanced efficacy and decreased side effects.

Detection of atherosclerotic lesions and intimal macrophages using CD36-targeted nanovesicles.

Current approaches to the diagnosis and therapy of atherosclerosis cannot target lesion-determinant cells in the artery wall. Intimal macrophage infiltration promotes atherosclerotic lesion development by facilitating the accumulation of oxidized low-density lipoproteins (oxLDL) and increasing inflammatory responses. The presence of these cells is positively associated with lesion progression, severity and destabilization. Hence, they are an important diagnostic and therapeutic target. The objective of this study was to noninvasively assess the distribution and accumulation of intimal macrophages using CD36-targeted nanovesicles. Soy phosphatidylcholine was used to synthesize liposome-like nanovesicles. 1-(Palmitoyl)-2-(5-keto-6-octene-dioyl) phosphatidylcholine was incorporated on their surface to target the CD36 receptor. All in vitro data demonstrate that these targeted nanovesicles had a high binding affinity for the oxLDL binding site of the CD36 receptor and participated in CD36-mediated recognition and uptake of nanovesicles by macrophages. Intravenous administration into LDL receptor null mice of targeted compared to non-targeted nanovesicles resulted in higher uptake in aortic lesions. The nanovesicles co-localized with macrophages and their CD36 receptors in aortic lesions. This molecular target approach may facilitate the in vivo noninvasive imaging of atherosclerotic lesions in terms of intimal macrophage accumulation and distribution and disclose lesion features related to inflammation and possibly vulnerability thereby facilitate early lesion detection and targeted delivery of therapeutic compounds to intimal macrophages.

Biocompatible and biodegradable nanoparticles for enhancement of anti-cancer activities of phytochemicals.

Many phytochemicals show promise in cancer prevention and treatment, but their low aqueous solubility, poor stability, unfavorable bioavailability, and low target specificity make administering them at therapeutic doses unrealistic. This is particularly true for (-)-epigallocatechin gallate, curcumin, quercetin, resveratrol, and genistein. There is an increasing interest in developing novel delivery strategies for these natural products. Liposomes, micelles, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers and poly (lactide-co-glycolide) nanoparticles are biocompatible and biodegradable nanoparticles. Those nanoparticles can increase the stability and solubility of phytochemicals, exhibit a sustained release property, enhance their absorption and bioavailability, protect them from premature enzymatic degradation or metabolism, prolong their circulation time, improve their target specificity to cancer cells or tumors via passive or targeted delivery, lower toxicity or side-effects to normal cells or tissues through preventing them from prematurely interacting with the biological environment, and enhance anti-cancer activities. Nanotechnology opens a door for developing phytochemical-loaded nanoparticles for prevention and treatment of cancer.

Application of nanotechnology in improving bioavailability and bioactivity of diet-derived phytochemicals.

Nanotechnology is an innovative approach that has potential applications in nutraceutical research. Phytochemicals have promising potential for maintaining and promoting health, as well as preventing and potentially treating some diseases. However, the generally low solubility, stability, bioavailability and target specificity, together with the side effects seen when used at high levels, have limited their application. Indeed, nanoparticles can increase solubility and stability of phytochemicals, enhance their absorption, protect them from premature degradation in the body and prolong their circulation time. Moreover, these nanoparticles exhibit high differential uptake efficiency in the target cells (or tissue) over normal cells (or tissue) through preventing them from prematurely interacting with the biological environment, enhanced permeation and retention effect in disease tissues and improving their cellular uptake, resulting in decreased toxicity, In this review, we outline the commonly used biocompatible and biodegradable nanoparticles including liposomes, emulsions, solid lipid nanoparticles, nanostructured lipid carriers, micelles and poly(lactic-co-glycolic acid) nanoparticles. We then summarize studies that have used these nanoparticles as carriers for epigallocatechin gallate, quercetin, resveratrol and curcumin administration to enhance their aqueous solubility, stability, bioavailability, target specificity and bioactivities.

Quercetin-nanostructured lipid carriers: characteristics and anti-breast cancer activities in vitro.

Quercetin (Q), a common dietary flavonoid, has gained research attention in cancer chemo-prevention, but its low level of aqueous solubility, stability, cellular bioavailability has limited its application. We have synthesized biocompatible and biodegradable Q-nanostructured lipid carriers (Q-NLC) using a novel phase inversion-based process method. The average size of Q-NLC was 32 nm in diameter. Q-NLC had good chemical and physical stability, and showed a sustained release pattern. The encapsulation efficiency and loading capacity of Q-NLC were 95% and 11%, respectively. The aqueous solubility of Q was dramatically improved by at least 1000 folds. The results from Raman spectroscopy, powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) demonstrated that Q presented in NLC as an encapsulated molecule form. As compared to native Q, Q-NLC dramatically increased cytotoxicity in a dose-dependent manner (1-50 µM) and induced apoptosis at 20 µM in MCF-7 and MDA-MB-231 breast cancer cells. The enhanced cytotoxicity and apoptosis were parallel to increased Q uptake by those cancer cells. Void NLC did not change the viability and apoptosis of those cancer cells as compared to phosphate buffered saline. In conclusion, Q-NLC dramatically enhanced the anti-cancer activities of Q, which were associated with enhanced Q solubility and stability, and increased Q content in those cancer cells. Q-NLC have a potential for chemo-preventive use in breast cancer.

Nanoencapsulation enhances epigallocatechin-3-gallate stability and its antiatherogenic bioactivities in macrophages.

We have successfully synthesized (-)-epigallocatechin-3-gallate (EGCG) encapsulated nanostructured lipid carriers (NLCE) and chitosan-coated NLCE (CSNLCE) using natural lipids, surfactant, chitosan, and EGCG. Nanoencapsulation dramatically improved EGCG stability. CSNLCE significantly increased EGCG content in THP-1-derived macrophages compared with nonencapsulated EGCG. As compared to 10 µM nonencapsulated EGCG, both NLCE and CSNLCE at the same concentration significantly decreased macrophage cholesteryl ester content. NLCE and CSNLCE significantly decreased mRNA levels and protein secretion of monocyte chemoattractant protein-1 (MCP-1) levels in macrophages, respectively. These data suggest that nanoencapsulated EGCG may have a potential to inhibit atherosclerotic lesion development through decreasing macrophage cholesterol content and MCP-1 expression.

Anticancer activities of (-)-epigallocatechin-3-gallate encapsulated nanoliposomes in MCF7 breast cancer cells.

The chemopreventive actions exerted by green tea are thought to be due to its major polyphenol, (-)-epigallocatechin-3-gallate (EGCG). However, the low level of stability and bioavailability in the body makes administering EGCG at chemopreventive doses unrealistic. We synthesized EGCG encapsulated chitosan-coated nanoliposomes (CSLIPO-EGCG), and observed their antiproliferative and proapoptotic effect in MCF7 breast cancer cells. CSLIPO-EGCG significantly enhanced EGCG stability, improved sustained release, increased intracellular EGCG content in MCF7 cells, induced apoptosis of MCF7 cells, and inhibited MCF7 cell proliferation compared to native EGCG and void CSLIPO. The CSLIPO-EGCG retained its antiproliferative and proapoptotic effectiveness at 10 µM or lower, at which native EGCG does not have any beneficial effects. This study portends a potential breakthrough in the prevention or even treatment of breast cancer by using biocompatible and biodegradable CSLIPO-EGCG with enhanced chemopreventive efficacy and minimized immunogenicity and side-effects.

Novel ophthalmic timolol meleate liposomal-hydrogel and its improved local glaucomatous therapeutic effect in vivo.

To overcome the limitations of common eye drops, the study developed a novel timolol mealate (TM) liposomal-hydrogel to enhance drug permeability and prolong residence time in the precorneal region, which achieved more effective local glaucomatous therapeutic effect. Firstly, TM liposome was prepared by an ammonium sulfate gradient-pH regulation method, which its entrapment efficiency reached up to 94% and its averaged particle size is 187 nm with narrow distribution. The corneal permeability through isolated rabbit cornea was measured by modified Franz-type diffusion cells. The results of trans-corneal penetration exhibited that the apparent permeability coefficients (P(app)) and the flow rates of steady state (J(ss)) of TM liposome was 1.50-fold higher than that of the commercialized eye drop, while TM liposome with 0.02% transcutol P was 2.19 times. In order to increase the retention time and improve the stability of liposome, we further developed a TM liposomal-hydrogel formulation by adding 1.0% HPMC K4M in TM liposome. The results showed an stability during a 120 days storage period than TM liposome. Precorneal retention study in vivo indicated that the optimal liposomal-hydrogel formulation had improved bioavailability and its retention time on rabbit corneal surface were significantly longer than that of pure liposomes or eye-drops. No obvious irritations to rabbit eyes were observed by histopathology microscopy after 7 days exposure.. Comparing to the eye drops, the TM liposomal-gel displayed prolonged therapeutic effect in cornea and greatly lowered the intraocular pressure IOP on the eyes of normal and glaucomatous pigmented rabbits.

[Comparison of the characteristics of several polymer materials used in hydrophilic matrix tablets].

Pure and drug hydrophilic matrix tablets were prepared by direct compression method with theophylline as a model drug. The characteristics of four hydrophilic matrix polymers, hydroxypropylmethylcellulose (HPMC), polyethylene oxide (PEO), sodium alginate (NaAlg) and xanthan gum (XG), were compared by investigating the water absorption, swelling, erosion and gel layer strength. The sequence of water absorption rate was XG >> NaAlg (H) > PEO > NaAlg (L) >> HPMC; The sequence of swelling index was XG >> PEO >> HPMC >> NaAlg; The sequence of erosion rate was NaAlg (L) > NaAlg (H) >> PEO80 > PEO200 > PEO300 > XG approximately PEO400 approximately K4M > K15M > PEO600 approximately K100M; The sequence of the gel layer strength was PEO > HPMC > XG >> NaAlg. For the PEO and HPMC matrix tablets, with the polymer molecular weight increased, the drug release mechanism was gradually transferred from mainly depending on the erosion to the diffusion; for SAL matrix tablets, the drug release mainly depends on erosion mechanism; and for XG matrix tablets, the drug release mainly depends on non-Fick diffusion mechanism. Comparison of the performance difference between the polymer materials will contribute to rational design and prediction of drug release behaviors from matrix tables and ultimately to achieve clinical needs.

In vitro and in vivo studies on the complexes of glipizide with water-soluble ß-cyclodextrin-epichlorohydrin polymers.

The purpose of this study was to evaluate the potential of a newly modified cyclodextrin derivative, water-soluble ß-cyclodextrin-epichlorohydrin polymer (ß-CDP), as an effective drug carrier to enhance the dissolution rate and oral bioavailability of glipizide as a poorly water-soluble model drug. Inclusion complexes of glipizide with ß-CDP were prepared by the co-evaporation method and characterized by phase solubility, dissolution, and differential scanning calorimetry. The solubility curve was classified as type A(L), which indicated the formation of 1:1 complex between glipizide and ß-CDP. ß-CDP had better properties of increasing the aqueous solubility of glipizide compared with HP-ß-CD. The dissolution rate of drug from the ß-CDP complexes was significantly greater than that of the corresponding physical mixtures indicating that the formation of amorphous complex increased the solubility of glipizide. Moreover, the increment in drug dissolution rate from the glipizide/ß-CDP systems was higher than that from the corresponding ones with HP-ß-CD, which indicated that ß-CDP could provide greater capability of solubilization for poorly soluble drugs. Furthermore, in vivo study revealed that the bioavailability of glipizide was significantly improved by glipizide /ß-CDP inclusion complex after oral administration to beagle dogs.

Thermoreversible Pluronic F127-based hydrogel containing liposomes for the controlled delivery of paclitaxel: in vitro drug release, cell cytotoxicity, and uptake studies.

PURPOSE: To develop an in situ gel system comprising liposome-containing paclitaxel (PTX) dispersed within the thermoreversible gel (Pluronic® F127 gel) for controlled release and improved antitumor drug efficiency. METHODS: The dialysis membrane and membrane-less diffusion method were used to investigate the in vitro drug release behavior. Differential scanning calorimetry (DSC) thermal analysis was used to investigate the "micellization" and "sol/gel transition" process of in situ gel systems. In vitro cytotoxicity and drug uptake in KB cancer cells were determined by MTT, intercellular drug concentration, and fluorescence intensity assay. RESULTS: The in vitro release experiment performed with a dialysis membrane model showed that the liposomal gel exhibited the longest drug-release period compared with liposome, general gel, and commercial formulation Taxol(®). This effect is presumably due to the increased viscosity of liposomal gel, which has the effect of creating a drug reservoir. Both drug and gel release from the in situ gel system operated under zero-order kinetics and showed a correlation of release of PTX with gel, indicating a predominating release mechanism of the erosion type. Dispersing liposomes into the gel replaced larger gel itself for achieving the same gel dissolution rate. Both the critical micelle temperature and the sol/gel temperature, detected by DSC thermal analysis, were shifted to lower temperatures by adding liposomes. The extent of the shifts depended on the amount of embedded liposomes. MTT assay and drug uptake studies showed that the treatment with PTX-loaded liposomal 18% Pluronic F127 yielded cytotoxicities, intercellular fluorescence intensity, and drug concentration in KB cells much higher than that of conventional liposome, while blank liposomal 18% Pluronic F127 gel was far less than the Cremophor EL® vehicle and empty liposomes. CONCLUSIONS: A thermosensitive hydrogel with embedded liposome is a promising carrier for hydrophobic anticancer agents, to be used in parenteral formulations for treating local cancers.

Influence of admixed citric acid and physiological variables on the vinpocetine release from sodium alginate compressed matrix tablets.

In this study, the controlled release matrix tablets of vinpocetine were prepared by direct compression using sodium alginate (SAL) as hydrophilic polymer and different amounts of citric acid as hydrosoluble acidic excipient to set up a system bringing about zero-order release of this drug in distilled water containing 0.5% sodium dodecyl sulfate. At the critical content of admixed citric acid (60 mg/tab.), the lowest drug-release rate was observed. In order to explain the effect of this critical content on drug-release rate from SAL matrices, investigation of the possibility of interaction of citric acid with SAL was performed using differential scanning calorimetric analysis and infrared analysis, which confirmed the existence of direct citric acid-SAL interaction when these two excipients came in contact with water. A zero-order drug-release system could be obtained by regulating the ratio of citric acid-to-SAL and the capacity of this system in controlling drug-release rate depended on the extent of interaction between citric acid and SAL. It is worth noticing that pH and the ionic strength of the dissolution medium were found to exert an influence on the drug-release performance of SAL tablets.

A novel paclitaxel microemulsion containing a reduced amount of Cremophor EL: pharmacokinetics, biodistribution, and in vivo antitumor efficacy and safety.

The purpose of this study was to prepare a novel paclitaxel (PTX) microemulsion containing a reduced amount of Cremophor EL (CrEL) which had similar pharmacokinetics and antitumor efficacy as the commercially available PTX injection, but a significantly reduced allergic effect due to the CrEL. The pharmacokinetics, biodistribution, in vivo antitumor activity and safety of PTX microemulsion was evaluated. The results of pharmacokinetic and distribution properties of PTX in the microemulsion were similar to those of the PTX injection. The antitumor efficacy of the PTX microemulsion in OVCRA-3 and A 549 tumor-bearing animals was similar to that of PTX injection. The PTX microemulsion did not cause haemolysis, erythrocyte agglutination or simulative reaction. The incidence and degree of allergic reactions exhibited by the PTX microemulsion group, with or without premedication, were significantly lower than those in the PTX injection group (P < .01). In conclusion, the PTX microemulsion had similar pharmacokinetics and anti-tumor efficacy to the PTX injection, but a significantly reduced allergic effect due to CrEL, indicating that the PTX microemulsion overcomes the disadvantages of the conventional PTX injection and is one way of avoiding the limitations of current injection product while providing suitable therapeutic efficacy.

Characterization and in vivo evaluation of novel lipid-chlorambucil nanospheres prepared using a mixture of emulsifiers for parenteral administration.

PURPOSE: The purpose of the study was to develop and evaluate different lipid-based formulations for parenteral administration, as potential novel carrier systems for lipophilic drugs, and to turn an unstable drug such as chlorambucil into a useful one. METHODS: A two-stage, high-pressure homogenizer was used to yield a very fine monodispersed lipid nanosphere. The strategy of combining egg yolk phospholipid and nonionic emulsifier (Lutrol F 68 and Tween 80) as an emulsifier mixture was adopted to increase safety and tolerance. The final lipid nanospheres, in a lipophilic mixture consisting of three components, monostearin, medium-chain triglycerides and soya oil, were evaluated for physicochemical properties, such as particle size, surface morphology, drug-entrapment efficiency, drug-loading capacity, lyophilization and in vivo drug-release behavior. RESULTS: A monodispersed lipid nanosphere with a mean particle size ranging from 90 to 150 nm was achieved. The optimized injectable cryoprotectants for lipid nanosphere were sucrose (7.5%) and mannitol (7.5%), which can stabilize the particle size (LD50) at approximately 129 nm after reconstitution. The results show that the formulation can effectively administer anticancer drugs and thus improve patient quality of life. CONCLUSIONS: The novel lipid nanosphere complex developed is a useful anticancer drug delivery vehicle for parenteral administration. The formulation strategy has the potential for the development of further methods of drug delivery for a wide variety of anticancer drugs.

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.

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.

Evaluation of Pharmasolve corneal permeability enhancement and its irritation on rabbit eyes.

The aim of this study was to explore the use of Pharmasolve as a new kind of permeability enhancer in ophthalmic drug delivery systems. The ocular irritation of different concentrations of Pharmasolve on rabbit eyes was evaluated in detail. Four drugs ranging from hydrophilic to lipophilic, namely ribavirin, puerarin, enoxacin, and ibuprofen, were used as model compounds to investigate the effects of different concentrations of Pharmasolve on the corneal permeability. The mechanism of ocular permeation enhancement of drugs by Pharmasolve was also discussed. The results showed that Pharmasolve presented no irritation when the concentration used was lower than 10%. Pharmasolve could enhance the ocular permeability of the four test drugs; the maximum enhancement in P(app) was 4.04, 2.76, and 2.67-fold for ribavirin, enoxacin, and puerarin, respectively; 2.5% (v/v) Pharmasovle increased the P(app) by about 1.47-fold for ibuprofen; which suggested that it would have a great potential to be used as a safe and effective penetration enhancer in ocular drug delivery systems in the future.