Simultaneous improvement to solubility and bioavailability of active natural compound isosteviol using cyclodextrin metal-organic frameworks

Cyclodextrin metal-organic framework (CD-MOF) as a highly porous supramolecular carrier could be one of the solutions to the insolubility of isosteviol (STV). The solubility of STV was lower than 20.00 ng/mL at pH 1.0 and pH 4.5, whilst its solubility increased to 20,074.30 ng/mL at pH 6.8 and 129.58 ng/mL in water with a significant pH-dependence. The

Cubic and hexagonal liquid crystal gels for ocular delivery with enhanced effect of pilocarpine nitrate on anti-glaucoma treatment.

The objective of this work was to investigate phytantriol-based liquid crystal (LC) gels including cubic (Q2) and hexagonal (H2) phase for ocular delivery of pilocarpine nitrate (PN) to treat glaucoma. The gels were produced by a vortex method and confirmed by crossed polarized light microscopy, small-angle X-ray scattering, and rheological measurements. Moreover, the release behaviors and permeation results of PN from the gels were estimated using in vitro studies. Finally, the anti-glaucoma effect of LC gels was evaluated by in vivo animal experiments. The inner structure of the gels was Pn3m-type Q2 and H2 phase, and both of them showed pseudoplastic fluid properties based on characterization techniques. In vitro release profiles suggested that PN could be sustainably released from LC gels within 48 h. Compared with eye drops, Q2 and H2 gel produces a 5.25-fold and 6.23-fold increase in the Papp value (p < .05), respectively, leading to a significant enhancement of corneal penetration. Furthermore, a good biocompatibility and longer residence time on precorneal for LC gels confirmed by in vivo animal experiment. Pharmacokinetic studies showed that LC gels could maintain PN concentration in aqueous humor for at least 12 h after administration and remarkably improve the bioavailability of drug. Additionally, in vivo pharmacodynamics studies indicated that LC gels had a more significant intraocular pressure-lowering and miotic effect compared to eye drops. These research findings hinted that LC gels would be a promising pharmaceutical strategy for ocular application to enhance the efficacy of anti-glaucoma.

A Novel Phytantriol-Based In Situ Liquid Crystal Gel for Vaginal Delivery.

The purpose of this paper was to evaluate the potential of in situ liquid crystal (LC) gels based on phytantriol (PYT) for vaginal delivery. The PYT-based in situ liquid crystal gels (PILGs) were prepared by a vortex method using PYT, ethanol (ET), and water (in the ratio of 64:16:20, w/w). The internal structures of PILGs and cubic LC gels (formed by PILG phase conversion) were confirmed by crossed polarized light microscopy (PLM) and small-angle X-ray scattering (SAXS). And the rheological tests showed that PILGs had small viscosity and excellent fluidity. The viscosities of cubic LC gels were 4~5 orders of magnitude higher than PILGs. In vitro phase conversion experiment showed that PILGs required little vaginal fluid (64.56 µL/100 mg) and time (3.92 s) to transform to LC gels. Furthermore, cubic LC gels could reside in the vaginas for more than 12 h in vivo. The in vitro release revealed that sinomenine hydrochloride (SMH) could be sustained released from the cubic gels over a period of 144 h, which was prior to SMH solution and carbomer gels. An in vivo vaginal mucosa irritation study indicated that PILGs were nonirritant and might be suitable for various vaginal applications. In conclusion, PILGs might represent a potential vaginal delivery strategy to overcome the limitations of traditional treatments.

Preparation and evaluation of intra-articular injectable sinomenine hydrochloride-loaded in situ liquid crystals / 药学学报

Phytantriol (PT), ethanol (ET) and water were used to prepare in situ cubic liquid crystal (ISV2). The pseudo-ternary phase diagram of PT-ET-water was constructed and isotropic solution formulations were chosen for further optimization. The physicochemical properties of isotropic solution formulations were evaluated to optimize the composition of ISV2. In situ hexagonal liquid crystals (ISH2) were prepared based on the composition of ISV2 with the addition of vitamin E acetate (VitEA) and the amount of VitEA was optimized by in vitro release behavior. The phase structures of liquid crystalline gels formed by ISV2 and ISH2 in excess water were confirmed by crossed polarized light microscopy and small angle X-ray scattering, respectively. Rheological properties of ISV2 and ISH2 were studied by a DHR-2 rheometer. In vitro drug release studies were conducted by using a dialysis membrane diffusion method. Pharmacokinetics was investigated by determination of sinomenine hydrochloride (SMH) concentration in synovial membrane after intra-articular injection of SMH-loaded ISH2 in adjuvant-induced arthritis rats. The optimal ISV2 (PT/ET/water, 64 : 16 : 20, w/w/w) loaded with 6 mg x g(-1) of SMH showed a suitable pH, injectable and formed a cubic liquid crystalline gel in situ with minimum water absorption in the shortest time. The optimal ISV2 was able to sustain the drug release for 144 h. The optimal ISH2 system was prepared by addition of 5% VitEA into PT in the optimal ISV2 system. This ISH2 (PT/VitEA/ET/water, 60.8 : 3.2 : 16 : 20, w/w/w/w) was an injectable isotropic solution with suitable pH. The new ISH2 was able to sustain the drug release for more than 240 h. Local pharmacokinetics study indicated that the retention time and AUC(0-∞) of ISH2 group were increased significantly compared with that of SMH solution group and the AUC(0-∞) of ISH2 group was 6.01 times higher than that of SMH solution group. The developed ISH2 was suitable for intra-articular injection that may apply to patients in the treatment of rheumatoid arthritis.

Bio-mimetic drug delivery systems designed to help the senior population reconstruct melatonin plasma profiles similar to those of the healthy younger population

The secretion of melatonin (MT) is obviously different in the younger and the senior sectors of the population, and the maximum plasma concentration of seniors is only half of that in the younger population group. If exogenous MT can be supplied to senior citizens based on the secretion rate and amount of endogenous MT in the younger population by a bio-mimetic drug delivery system (DDS), an improved therapeutic effect and reduced side effects can be expected. Based upon this hypothesis, the pharmacokinetic parameters of MT, namely, the absorption rate constant (k a), the elimination rate constant (k e), and the ratio of absorption rate (F) to the apparent volume of distribution (V) were obtained by a residual method depending on the plasma concentration curve of immediate release preparations in the healthy younger population. The dose-division method was applied to calculate the cumulative release profiles of MT achieved by oral administration of a controlled release drug delivery system (DDS) to generate plasma MT profiles similar to the physiological level-time profiles. The in vivo release of MT deduced from the healthy younger population physiological MT profiles as the pharmacokinetic output of the bio-mimetic DDS showed a two-phase profile with two different zero order release rates, namely, 4.919 μg/h during 0-4 h (r=0.9992), and 11.097 μg/h during 4-12 h (r=0.9886), respectively. Since the osmotic pump type of DDS generally exhibits a good correlation between in vivo and in vitro release behaviors, an osmotic pump controlled delivery system was designed in combination with dry coating technology targeting on the cumulative release characteristics to mimic the physiological MT profiles in the healthy younger population. The high similarity between the experimental drug release profiles and the theoretical profiles (similarity factor f 2>50) and the high correlation between the predicted plasma concentration profiles and the theoretical plasma concentration profiles (r=0.9366, 0.9163, 0.9264) indicated that a prototype bio-mimetic drug delivery system of MT was established. The similarity factors between the experimental drug release profiles and the theoretical release profile were all larger than 50 both in periods of 0-4 h and 4-12 h, namely, 68.8 and 57.3 for the first batch (Batch No. 20131031), 76.7 and 50.2 for the second batch (Batch No. 20131101), and 73.7 and 51.1 for the third batch (Batch No. 20131126), respectively. The correlation coefficients between the predicted plasma concentration profiles based on the release profiles of the bio-mimetic DDS and physiological profiles were 0.9366 (Batch No. 20131031), 0.9163 (Batch No. 20131101), 0.9264 (Batch No. 20131126), respectively. Since the pharmacokinetic profile of MT in any kind of animal differs markedly from that of human beings, it is impossible to test the bio-mimetic DDS in animals directly. Therefore, the predicted pharmacokinetic profile based upon the in vitro release kinetics is an acceptable surrogate for the conventional animal test. In this research, a bio-mimetic DDS for replacement of MT was designed with in silico evaluation.

Effects and mechanisms of Shaoqiduogan on immunological hepatic fibrosis / 中国药理学通报

Aim To investigate the effects of Shaoqiduogan(SQDG)on immunological hepatic fibrosis induced by human albumin in rats as well as its possible mechanisms.Methods The model of immunological hepatic fibrosis induced by human albumin was prepared.The rats were randomly divided into 6 groups,namely normal control group,liver fibrosis model group,SQDG(42.5,85,170 mg·kg~(-1))treated groups and colchicine(0.1 mg·kg~(-1)) treated group.HE staining was used to examine the histopathological change.The activities of transaminase in serum,malondiadehyde(MDA)content,superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px)activities,hydroxyproline(Hyp)content in liver homogenate were assayed byspectrophotometry.The levels of hyaluronic acid(HA)and procollagen Ⅲ (PCⅢ)in serum were determined by radioimmunoassay.In vitro,the collagen production of hepatic stellate cell(HSC)-T6 stimulated with transforming growth factor beta1(TGF-β1)was measured with 3H-Proline uptake.Results SQDG had obvious protective effects on human albumin induced hepatic fibrosis in rats.The results showed that the serum ALT and AST decreased by SQDG treatment,but had no significant difference compared with model group.Pathological examination showed that SQDG could remarkably alleviate the hepatic fibrosis.SQDG not only decreased the Hyp content in liver homogenates,but also the elevated level of HA,PCⅢ in serum.SQDG also ameliorated the oxidative stress state of hepatic fibrosis rats,decreased the production of MDA and enhanced the activities of antioxidative enzyme including SOD and GSH-Px.Furthermore,SQDG(20～160 mg·L~(-1))inhibited the collagen production of HSC stimulated with TGF-β1 in vitro.Conclusion sSQDG has protective effect on liver fibrosis rats induced by human albumin.The mechanisms of its anti-fibrotic effects may be associated with its action of ameliorating the oxidative stress in liver,and inhibiting the production of collagen in HSC.

Effects of Shaoqiduogan on MMP-13, TIMP-1 expression in liver and hepatic stellate cells of hepatic fibrosis rats / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate the effects of Shaoqiduogan (SQDG) on the expression of matrix metalloproteinase 13 (MMP-13) and tissue inhibitor of metalloproteinase 1 (TIMP-1) in carbon tetrachloride (CCl4) induced hepatic fibrosis rats and transforming growth factor beta1 (TGF-beta1) irritated hepatic stellate cells (HSC), and to explore its possible mechanisms.</p><p><b>METHOD</b>The model of chemical hepatic fibrosis induced by CCl4 was prepared. The rats were randomly divided into 5 groups, including normal control group, liver fibrosis model group and SQDG (42. 5, 85, 170 mg x kg(-1)) treated groups. The level of collagen type 1 (C-1) in serum was determined by radioimmunoassay. Masson stain was used to examine the histopathological change. MMP-13 and TIMP-1 ex-pression in liver tissues were assayed by immunohistochemistry. In vitro, effects of SQDG on the expression of MMP-13, TIMP-1 and C-1 in HSC-T6 stimulated by TGF-beta were measured by Western-blot.</p><p><b>RESULT</b>The results showed that SQDG significantly decreased the elevated level of C-1 in serum of hepatic fibrosis rats induced by CCl4. Pathological examination showed that SQDG could remarkably alleviate the degree of liver fibrogenesis and formation of pseudolobulus. The results of immunohistochemistry demonstrated that SQDG significantly increased MMP-13 expression and decreased TIMP-1 expression in liver tissues. Furthermore, SQDG (20-160 mg x L(-1)) could facilitate MMP-13 expression, inhibit TIMP-1 expression and significantly inhibit the C-I production of HSC stimulated with TGF-beta1 in vitro.</p><p><b>CONCLUSION</b>The anti-fibrotic effects of SQDG may be associated with its action of promoting collagen degradation via controlling the levels of MMP-13 and TIMP-1 in liver.</p>

Absorption transport mechanism of puerarin oil-in-oil nanoemulsion / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate the mechanisms of the oil-in-oil nanoemulsions transport through the gastrointestinal tract and the transport efficiency changed with its different particle size in the lymphatic channels.</p><p><b>METHOD</b>The behavior of nanoemulsions in vivo and their absorption via lymph after oral administration was investigated, with the transport efficiency and absorption pathway of nanoemulsions clarified by lymph duct cannulation in rats.</p><p><b>RESULT</b>It suggested about 36.8% of puerarin nanoemulsions was transported into systematic circulation via lymph. Nanoparticles with different size absorbed by the lymphatic channels varied as the degree of transportion.</p><p><b>CONCLUSION</b>The degree of absorption and particle transport is inversely proportional to the size.</p>

Study on preparation of berberine microemulsion and its absorption in intestine / 中国中药杂志

<p><b>OBJECTIVE</b>To prepare berberine microemulsion, and to investigate its properities and the absorption character in rat intestine in situ.</p><p><b>METHOD</b>The optimum formulation of the blank microemulsion selected by pseudo tertiary phase diagrams and the berberine microemulsion was prepared based on the blank microemulsion. The viscosity, conductance, refraction rate and particle size of berberine microemulsion were surveyed. An in situ rat perfusion method was used to investigate the intestinal absorption of berberine microemulsion. A UV method for determination of berberine in the intestinal flux was established.</p><p><b>RESULT</b>The viscosity, conductance, refraction rate and particle size of berberine microemulsion were 2.11 cPas, 125.5 microomega, 1.363 and 24.0 nm, respectively. The absorption rate of berberine at the ileum was the best. The absorption of berberine microemulsion at the ileum was significantly higher than that of raw medicine (P < 0.01).</p><p><b>CONCLUSION</b>The microemulsion system might improve the absorption of berberine in the intestinal tract.</p>

Study on Extraction Process of Total Flavonoids of Hypericum perforatum L. by Orthogonal Test / 中国中医药信息杂志

Objective To optimize the extraction process of total flavonoids in Hypericum perforatum L.. Methods The concentration and volume of alcohol, extraction time and frequency were systematically studied by the total flavonoids as the marker. Results The more effective way to extract total flavones was extraction with 8 times amount of 70% alcohol under reflux for 3 times and 2 h for each time. Conclusion This method obtains more effective components. It is stable and reliable.

A study on the collagen metabolism and therapy of hepatic fibrosis / 中国药理学通报

Hepatic fibrosis is the hallmark of most chronic liver diseases. Its essense is excessive deposition of extracellular matrix components(ECM) in liver, which occurs due to an imbalance between the production and degradation of matrix. Collagen is the most important part of ECM. Therefore,one important antifibrotic pathway is to effectively inhibit the synthesis of collagen or increase its degradation. The review describes the current progress in collagen metabolism and antifibrotic therapy related to hepatic fibrosis.

Determination of Secnidazole in Secnidazole Tablets by RP-HPLC / 中国药房

OBJECTIVE:To determine the contents of secnidazole in secnidazol e tablets by RP-HPLC.METHODS:The chromatographic column was VP-ODS C 18 with acetonirile-0.05mol/L potassium dihydrogen phosphate-triethylamine(15∶85∶0.4)as the mobile phase,the detection wavelength was311nm and the flow rate was0.8ml/min.RESULTS:There was a good linear relationship when the sample size was within the range of0.166?g～0.832?g(r=0.9999),the average re?covery was99.84%(RSD=1.05%,n=15).CONCLUSION:The method is simple and accurate,sensible and reproducible,which can be used for the assaying of both the raw materials and preparations and the quality control of secnidazole tablets.

Studies on anti-proliferation and inducing apoptosis effects of paeonol on human esophageal cancer cell line Eca-109 in vitro and in vivo / 中国药理学通报

Aim To investigate the inhibitory effect of paeonol (Pae) on the human esophageal cancer cell line Eca-109 in vitro and in vivo and its effect on apoptosis.Methods Cytotoxic effect of Pae on Eca-109 cells cultured in vitro was measured by MTT assay.Anti-tumor activity was performed on BALB/c nude mice xenografts model.The morphologic changes of tumor tissue were observed under light microscope and transmission electron microscope.The apoptosis index was assessed by TUNEL.Results Pae had significant in- hibitory effect on the proliferation of Eca-109 cells,and the IC50 value was 0.342 mmol?L-1.In the model of human esophageal cancer xenografts in BALB/c nude mice,the inhibitory rates of Pae group (25、50、100、200 mg?kg-1) were 10.67%、23.54%、27.91% and 34.46% respectively.In vivo administration of Pae 100 mg?kg-1 combined with cisplatin 5 mg?kg-1 resulted in a significant inhibition of Eca-109 tumor growth with the inhibitory rate of 77.91%,compared with cisplatin used alone (58.71%).The more apoptotic tumor cells could be seen under light microscope in every theraperutic groups than those in control.Changes of ultrastructure of tumor cells including concentration and side accumulation of the nuclear chromatin,and the fragmentation of the nuclear was observed under transmission electronic microscope.Apoptosis body was also found.The apoptosis indexes of every theraperutic groups were significantly different from the control.Conclusion Pae can inhibit the cell growth and induce apoptosis in human esophageal cancer cell line Eca-109 in vitro and in vivo.