Enhancement by sodium caprate and sodium deoxycholate of the gastrointestinal absorption of berberine chloride in rats

The aim of the investigation was to compare the effectiveness of two absorption enhancers, sodium caprate (C10) and sodium deoxycholate (SDC), in increasing the bioavailability of a poorly absorbed paracellar flux drug, berberine chloride, across the intestinal mucosae of rats in vivo, together with examination of their effects on mucosal damage. In addition, all four intestinal segments were collected after administration of the enhancers and sodium saline. The results of the bioavailability experiments showed the oral absorption of berberine chloride was poor and both C10 and SDC could significantly improve the very poor absorption of berberine chloride. After co-administration, the area under the plasma concentration–time curve of berberine chloride was increased 41.1-fold by C10 (100?mg/kg) and 35.3-fold by SDC (100?mg/kg) compared with that in the absence of C10 and SDC, respectively. Local toxicity experiment indicated that both enhancers caused no specific damage to the intact intestine. This study demonstrates that C10 and SDC could significantly promote the absorption of berberine chloride from the gastrointestinal tract with few toxic effects, which might be due mainly to relaxing the absorption limitation while inhibiting the efflux transporter of berberine chloride by the enhancers. Besides, this could lead to the development of new drug-enhancers.     

吸收式热泵中表面活性剂的强化机制研究

溴化锂水溶液中加入表面活性剂后,水蒸气吸收过程的传热与传质系数显著提高。20世纪50年代,国内外就开始对此强化过程进行研究,但目前尚未有被普遍认可的机制理论。研究人员普遍认同马拉格尼对流(marangoni convection)的强化作用,但是缺乏对其合理的解释。以往的研究大都基于静态池实验,这与实际吸收式热泵内吸收器的动态吸收过程(如液膜的形成等)相距甚远。另外,研究人员大都主要研究溴化锂水溶液与水蒸气的气液界面的强化作用,而忽视了溴化锂水溶液与铜管壁面的固液表面的强化过程。本文从微观的角度对2个强化界面进行分析,解释"马拉格尼对流"强化作用产生的原因,结论与诸多研究人员的实验结果一致。     

Rheological investigation and its correlation with permeability coefficient of drug loaded carbopol gel: influence of absorption enhancers

Context: The present study was planned to investigate the effect of absorption enhancers on the microstructure of Losartan potassium gel and hence its influence on the diffusion of Losartan potassium across nasal mucosa.

Method: Losartan potassium loaded carbopol gel (1% w/v) with and without absorption enhancers was prepared. Polyethylene glycol (PEG) 4000 and ethanol were used as absorption enhancers. Microstructural elucidation of prepared gels was done using shear rheology. Ex vivo drug release studies were performed on the prepared gels.

Results: It was observed that the absorption enhancers PEG 4000 and ethanol altered the gel microstructure. The prepared gels were viscoelastic in nature suggesting their suitability for topical application. Permeability coefficient of Losartan potassium loaded into gels was found to be inversely proportional to the storage modulus. Thus increase in storage modulus lead to slow drug diffusion.

Conclusion: The current study emphasizes on the fact that selection of polymeric carrier for nasal drug delivery and/or absorption enhancer strongly influence the microstructure of the gel and hence the pharmaceutical performance of the formulation.     

Effect of chitosan glutamate,carbomer 974P,and EDTA on the in vitro Caco-2 permeability and oral pharmacokinetic profile of acyclovir in rats

Background: Chitosan glutamate and polyacrylic acid (e.g., carbomer 974P) are known to modulate the tight junctions in the intestinal wall and increase permeability and blood exposure of drugs absorbed orally by the paracellular route. Aim: To assess the impact of chitosan glutamate and carbomer 974P on the absorption of paracellularly absorbed model drug, acyclovir, in vitro and in rat in vivo. Methods: The influence of chitosan glutamate and carbomer 974P (alone and in combination with EDTA–Na2) on the in vitro Caco-2 permeability and oral pharmacokinetic profile in the rat of acyclovir was investigated. Results: In the presence of chitosan glutamate, the apparent permeability of acyclovir across Caco2 monolayer increased 4.1 times relative to control. This increase was accompanied by a significant (～60%) decrease in transepithelial electrical resistance values indicating opening of the tight junctions in the cell monolayer. In rat, chitosan glutamate doubled oral bioavailability of acyclovir and tripled the amount of acyclovir excreted unchanged into urine. In contrast, the effect of carbomer 974P was not statistically significant at 5% level. Conclusions: In conclusion, chitosan glutamate (1–3%) and chitosan glutamate (1%)/EDTA–Na2 (0.01%) are effective excipients to increase permeability of acyclovir across Caco-2 cell monolayers and the oral absorption in the rat in vivo.     

In vitro assessment of acyclovir permeation across cell monolayers in the presence of absorption enhancers

The aim of the investigation was to establish transepithelial permeation of acyclovir across Caco-2 and Madin-Darby canine kidney (MDCK) cell monolayers and attempt to improve its permeation by employing absorption enhancers (dimethyl β cyclodextrin, chitosan hydrochloride and sodium lauryl sulfate) and combinations thereof. Caco-2 and MDCK cell monolayers have been widely employed in studying drug transport, mechanisms of drug transport, and screening of absorption enhancers and excipients. Transepithelial electrical resistance and permeation of ^99mTc-mannitol were employed as control parameters to assess the tight junction and paracellular integrity. Permeation of acyclovir in the presence of absorption enhancers was found to be significantly higher compared with drug permeation in their absence when assessed as apparent permeability coefficients (P_app). Synergistic improvements in P_app values of acyclovir were obtained in case-selected combinations of absorption enhancers; dimethyl β cyclodextrin-chitosan hydrochloride, chitosan hydrochloride-sodium lauryl sulfate, and dimethyl β cyclodextrin-sodium lauryl sulfate, were used. Recovery and viability assessment studies of both cell monolayers suggested reestablishment of paracellular integrity and no damage to cell membranes. Significantly improved permeation of acyclovir in the presence of selected combinations of absorption enhancers may be used as a viable approach in overcoming the problem of limited oral bioavailability of acyclovir.     

Gas absorption with interfacial resistance in the case of temperature‐dependent physical,transport and reaction properties

Abstract

This work analyzes the problem of interfacial resistance to heat and mass transfer for a gas absorption system with first order reaction when the solubility, the diffusivity, and the reaction rate constant are dependent upon temperature. A film theory model is applied. Two different types of temperature‐dependent solubility relationships, the linear and the exponential approximations, are employed. The temperature‐dependent diffusivity and reaction rate constant are expressed in exponential form. Three cases of different solute concentrations are compared to study the influence of solubility on the system performance. One of these cases with the exponential temperature‐dependent solubility is further examined for the effects of diffusivity coefficient and of surface resistance on the enhancement factor, the temperature rise, and the solubility. The results indicate that the form of the temperature‐dependent solubility relationship plays an important role in the estimation of the surface temperature rise and hence the enhancement factor. The linear approximation predicts slightly higher values in the intermediate region of √M_o , while the exponential approximation results in dramatically higher values at very large √M_o. The surface resistance significantly affects the absorption rate, the interfacial temperature rise, and the solubility at small values of √M_o. The effect of the variation of diffusivity on the system performance is of secondary importance, especially when the values of √M_o are not large.     

国内外吸收式热泵强化传热传质研究综述

综述国内外对吸收式热泵强化传热传质研究的现状。目前主要的研究方向为新型强化管的开发、新型表面活性剂及强化吸收机制的研究,主要研究目的是如何增大传热面积与加强界面马拉格尼对流,以此提高传热传质系数。     

Enhancing effect of Labrasol on the intestinal absorption of ganciclovir in rats

Ganciclovir (GCV), like other nucleoside analogs such as trifluridine and acyclovir (ACV), is hydrophilic, poorly permeable across membranes and orally low-bioavailable. In the present studies, Labrasol was evaluated for improving intestinal absorption of GCV through in vitro and in vivo experiments. The effect of Labrasol on absorption of GCV in rat small intestine was investigated using an in situ single-pass perfusion technique. The apparent absorptive clearance (PeA) of GCV with Labrasol in the duodenum, jejunum and ileum was 1.01, 1.28, and 1.49?mL/min/cm (n?=?6), respectively, and significant regional differences of GCV absorption among the three segments were observed (p jejunum (p duodenum (p?>?0.05). The effects of EDTA, verapamil on the permeability of GCV were conducted. The permeability of GCV was increased by EDTA, verapamil, respectively. The results indicated that paracellular absorption and efflux played important roles in GCV absorption. In vivo absorption GCV in rats was conducted. When GCV at 1?mg/kg dose was administered with Labrasol (10%, v/v), the mean AUC of was determined as 14.45?±?3.88 μg*h/mL, compared to 8.05?±?1.52 µg*h/mL without Labrasol. Based on the results, we could conclude that the absorption of GCV through GI lumen would be enhanced by Labrasol. The effect of Labrasol maybe ascribed to both (i) inhibit efflux of GCV from the enterocytes to the GI lumen; and (ii) enhance GCV absorption from the GI lumen through paracellular pathway.     

聚丙烯酰胺及其多孔材料吸湿性功能研究

以丙烯酰胺(AM)为单体,N,N’-亚甲基双丙烯酰胺为交联剂,亚硫酸钠-过硫酸铵为引发剂,采用水溶液聚合法制备聚丙烯酰胺(PAM)吸湿材料。系统研究了单体浓度、交联剂用量和水解度等聚合条件对其吸湿性能的影响。吸湿实验表明,PAM的吸湿性能优于传统的无机吸湿材料硅胶和分子筛。采用聚乙二醇(PEG)、碳酸钙(CaCO3)两种致孔剂合成多孔PAM,并与PAM的吸湿性能进行对比。实验结果知PAM/PEG的吸湿速率比PAM提高50%以上,吸湿容量也显著提高;而PAM/CaCO3的吸湿效果并不理想。热失重分析TGA得出PAM/PEG比PAM的热稳定性稍稍降低,而PAM/CaCO3的热稳定性则稍稍提高。     

Ni/Zr-Co-Re堆栈层薄膜吸气剂的吸气性能及Ni作用机理研究

采用磁控溅射的方法制备了带有Ni保护层和Zr-Co-Re(Re代表稀土元素)主体层的堆栈层薄膜吸气剂。通过X射线光电子能谱仪(XPS)分析了薄膜吸气剂内部O元素的含量分布,研究了薄膜吸气剂中Ni层的防氧化作用和机理。研究表明:(1)Ni/Zr-CoRe堆栈层薄膜吸气剂在160℃保温3h的条件下可以有效激活,并具有高于Zr-Co-Ni单层薄膜吸气剂的吸气性能;(2)Ni保护层降低了吸气剂的被氧化程度,促进了表面吸附的H2分子的解离和扩散。     

石墨炉原子吸收法测定头发中硒

利用优级纯硝酸浸润,放置过夜,适当水浴加热的方法,将头发样品制备成溶液,用石墨炉原子吸收法测定头发中硒,在选定的测定条件下检出限0．004mg／l,精密度3．7％,回收率在91．1％-98．2％之间。     

Interaction of tenoxicam with cyclodextrins and its influence on the in vitro percutaneous penetration of the drug

Solid complexes of tenoxicam (TEN) with cyclodextrins (CDs), in a 1:1 molar ratio, were obtained by the coprecipitation method and characterized by x-ray diffractometry, infrared spectroscopy, and differential scanning calorimetry. The binding capacity of the CDs with TEN was also demonstrated in aqueous solution and in water-propylene glycol mixtures. The purpose of this study was to determine the effect of CDs on the in vitro percutaneous penetration of TEN from carbopol gels, taking into account the role of the CD cavity size and the nature of the substituents. The effect of pretreatment was studied too. In vitro permeation experiments were carried out on Franz diffusion cells using cellulose nitrate membranes and abdominal rat skin. In these results, the release rates of the drug scarcely decreased when the CDs were added, probably because of a lower concentration of the free drug and an increased gel viscosity. However, it was also found that CDs, particularly γ-CD and M-β-CD, can improve slightly TEN absorption through the skin. Pretreatment studies with CDs, however, provided no effects on TEN permeation, but lag time was markedly reduced, suggesting a faster partitioning of TEN into the skin. Therefore, the use of pretreatment with CDs would be interesting when a quick action of the drug is desired.     

Enhancing effects of chitosan and chitosan hydrochloride on intestinal absorption of berberine in rats

Berberine chloride (BBR) is a plant alkaloid that has been used for centuries for treatment of inflammation, dysentery, and liver diseases. It is poorly absorbed from the gastrointestinal (GI) tract and its various clinical uses are limited because of its poor bioavailability. The object of the present study was to investigate the absorption enhancing effect of chitosan on BBR. Mixtures of BBR and chitosan were prepared and the absorption enhancement was investigated in rats. The results showed a dose-dependent absorption enhancement produced by chitosan. Formulations containing 0.5%, 1.5%, and 3.0% chitosan resulted in improvement of AUC_{0–36 h} values by 1.9, 2.2, 2.5 times. The absorption enhancing ability of chitosan may be due to its ability to improve the BBR paracellular pathway in the intestinal tract. Chitosan hydrochloride, a salt of chitosan, was also investigated in this study. However, the addition of 2.0% and 3.3% chitosan hydrochloride to BBR solution did not produce any increase in either C_max or AUC_{0–36 h} of BBR. Subsequent solubility studies suggested that the reduced berberine chloride solubility in chitosan hydrochloride may limit the enhancement ability. This study showed that the optimum formulation producing the highest BBR absorption is the BBR solution containing 3.0% chitosan.     

Moisture absorption and its effect on the electrical properties of high silica fabric

High silica fabric with a silica content >98% can be prepared by removing the non-siliceous ions from the E-glass fabric using HCl as the leachant. The presence of Si-OH groups makes the material hydrophilic. The extent of moisture absorption depends on the extent of leaching. The moisture present in the leached fabric decreases the volume and surface resistivity values.     

In vitro–in vivo extrapolation (IVIVE) for predicting human intestinal absorption and first-pass elimination of drugs: principles and applications

Oral administration remains the preferred dosing method in clinical practice and drug development. Oral bioavailability (F) is a function of the fraction absorbed (F_abs), gastrointestinal or gut wall availability (F_G), and hepatic availability (F_H). Therefore, predicting intestinal absorption (F_abs) and first-pass elimination (F_G and F_H) from in vitro data may facilitate the selection of more orally bioavailable drug candidates in earlier stages of drug discovery and development. This review provides an overview of the determinants of intestinal absorption and first-pass elimination of drugs and focuses on the principles and applications of conventional in vitro--in vivo extrapolation (IVIVE) methods to predict F_abs, F_G, and F_H in humans.     

Transdermal absorption of L-dopa from a new system composed of two separate layers of L-dopa and hydrogel in rats

To maintain the stability of L-dopa in hydrogel, a new system composed of two separate layers of L-dopa and hydrogel was developed. L-Dopa sheets were made by immersing L-dopa solution into wiper sheets and by lyophilizing them. Examination for stability of L-dopa in the L-dopa sheet revealed that its stability was maintained for at least 12 weeks, providing the sheet was kept at room temperature in a dark box. In a cutaneous absorption study of L-dopa in rats, an L-dopa sheet was attached to the shaved abdominal skin. A hydrogel composed of cutaneous absorption enhancers, water and ethanol, was spread on vinyl tape (hydrogel sheet), and this sheet was placed over the L-dopa sheet. L-Dopa that was administered transdermally effectively penetrated through the skin: The plasma level of L-dopa peaked at 30 min and remained high between 60 and 180 min after the cutaneous application. Our system, composed of two separated layers of L-dopa and hydrogel, enabled the stability of L-dopa to be maintained without losing transdermal absorption of L-dopa.     

In vivo absorption study of ritodrine hydrochloride in the buccal administration to rats

Background: Although ritodrine (RD)-hydrochloride (HCl), named RD-HCl, is widely used in the treatment of premature labor by intravenous prolonged infusion or frequent oral dosing of tablets, those administrations often lower patients’ quality of life (QOL) or cause undesirable side effects, such as tachycardia; therefore, in this study, the potential usefulness of buccal administration as a novel administration method was examined in vivo.

Method: First, the HPLC method was assessed for the determination of plasma RD concentration. Then, after RD-HCl solution in saline was administered intravenously (1?mg/kg), intragastrically (10?mg/kg) or buccally (10?mg/kg) in rats, the plasma concentration–time profiles were investigated, and the absorption extent and rate compared.

Results: The present modified determination method by HPLC with fluorescence detection (Ex. 278?nm, Em. 306?nm) was suitable to analyze the plasma level at 8–200?ng/mL. Buccal administration gave the best plasma concentration–time profile for maintenance of an effective plasma level and fewer side effects. Absorption rates calculated by deconvolution also supported better sustained absorption in buccal dosing.

Conclusion: Buccal application of RD-HCl was demonstrated to be a potentially useful dosing method in the treatment of premature labor with RD-HCl.     

Capsaicin pretreatment enhanced the bioavailability of fexofenadine in rats by P-glycoprotein modulation: in vitro,in situ and in vivo evaluation

Background and objective: Capsaicin is the main pungent principle present in chili peppers has been found to possess P-glycoprotein (P-gp) inhibition activity in vitro, which may have the potential to modulate bioavailability of P-gp substrates. Therefore, purpose of this study was to evaluate the effect of capsaicin on intestinal absorption and bioavailability of fexofenadine, a P-gp substrate in rats.

Methods: The mechanistic evaluation was determined by non-everted sac and intestinal perfusion studies to explore the intestinal absorption of fexofenadine. These results were confirmed by an in vivo pharmacokinetic study of oral administered fexofenadine in rats.

Results: The intestinal transport and apparent permeability (P_app) of fexofenadine were increased significantly by 2.8 and 2.6 fold, respectively, in ileum of capsaicin treated rats when compared to control group. Similarly, absorption rate constant (K_a), fraction absorbed (F_ab) and effective permeability (P_eff) of fexofenadine were increased significantly by 2.8, 2.9 and 3.4 fold, respectively, in ileum of rats pretreated with capsaicin when compared to control group. In addition, maximum plasma concentration (C_max) and area under the concentration-time curve (AUC) were increased significantly by 2.3 and 2.4 fold, respectively, in rats pretreated with capsaicin as compared to control group. Furthermore, obtained results in rats pretreated with capsaicin were comparable to verapamil (positive control) treated rats.

Conclusions: Capsaicin pretreatment significantly enhanced the intestinal absorption and bioavailability of fexofenadine in rats likely by inhibition of P-gp mediated cellular efflux, suggesting that the combined use of capsaicin with P-gp substrates may require close monitoring for potential drug interactions.     

Chitosan nanoparticles for the oral delivery of tenofovir disoproxil fumarate: formulation optimization,characterization and ex vivo and in vivo evaluation for uptake mechanism in rats

Objective: Design chitosan based nanoparticles for tenofovir disoproxil fumarate (TDF) with the purpose of enhancing its oral absorption.

Significance: TDF is a prodrug that has limited intestinal absorption because of its susceptibility to gut wall esterases. Hence, design of chitosan based polymeric novel nanocarrier systems can protect TDF from getting metabolized and also enhance the oral absorption.

Methods: The nanoparticles were prepared using the ionic gelation technique. The factors impacting the particle size and entrapment efficiency of the nanoparticles were evaluated using design of experiments approach. The optimized nanoparticles were characterized and evaluated for their ability to protect TDF from esterase metabolism. The nanoparticles were then studied for the involvement of active transport in their uptake during the oral absorption process. Further, in vivo pharmacokinetic studies were carried out for the designed nanoparticles.

Results: The application of design of experiments in the optimization process was useful to determine the critical parameters and evaluate their interaction effects. The optimized nanoparticles had a particle size of 156?±?5?nm with an entrapment efficiency of 48.2?±?1%. The nanoparticles were well characterized and provided metabolic protection for TDF in the presence of intestinal esterases. The nanoparticles were able to increase the AUC of tenofovir by 380%. The active uptake mechanisms mainly involving clathrin-mediated uptake played a key role in increasing the oral absorption of tenofovir.

Conclusions: These results show the ability of the designed chitosan based nanoparticles in enhancing the oral absorption of TDF along the oral route by utilizing the active endocytic uptake pathways.