Boswellic acids: a review on its pharmacological properties, molecular mechanism and bioavailability

Boswellic acids is a general term for a series of pentacyclic triterpenoid compounds that are isolated from the oleogin resin of the Boswellia genus and serve as the main active ingredient.It exhibits a wide range of biological activities,such as anti-inflammatory,anti-cancer,antibacterial,antiviral,hepatoprotective,neuroprotective,anti-diabetic,and anti-thrombotic properties.As a result,it has gained significant recognition among practitioners of traditional Chinese and Indian medicine.These biological effects may be associated with multiple molecular targets and signal transduction pathways.However,the poor pharmacokinetic properties of the substance lead to lower bioavailability,which affects its effectiveness.To address this issue,scientists have proposed a number of strategies,such as solid dispersions,phytosome®technologies,and novel drug delivery systems.This article aims to provide a comprehensive overview for boswellic acids on the phytochemistry,molecular mechanisms,potential therapeutic applications,and strategies to improve bioavailability.

Enhancement in Bioavailability of CurCousin®, A Minor Metabolite from Curcuma longa by Addition of BioPerine® —A Pharmacokinetic Study

In recent years, metabolic syndrome has been a growing health concern across the world. The role of nutraceuticals and functional foods in this area has a significant place due to the adverse effects of contemporary modes of treatment. CurCousin® is a nutritional ingredient containing bioactive Calebin A, (analog of Curcumin) with self-affirmed GRAS status. CurCousin® has been a clinically studied dietary supplement ingredient with a positive impact on body weight, lipid levels and metabolic health. Bioenhancers play an important role in increasing the bioavailability of the active in turn enhancing efficacy as well as reducing the dosage required to achieve the therapeutic effect. This study investigated the possible pharmacokinetic interaction between CurCousin® at two different doses (2.25 and 4.5 mg/kg) in the presence and absence of BioPerine® (0.27 mg/kg), a natural bioenhancer in Sprague-Dawley rats. The results revealed that the addition of BioPerine® into CurCousin® (2.25 mg/kg) half the dose when administered enhances the bioavailability and was equipotent to CurCousin® (4.5 mg/kg) double the dose without BioPerine®. Thus, leading to future clinical studies to evaluate its improved pharmacological efficacy as well as reduced therapeutic dosage.

Fabrication of taxifolin loaded zein-caseinate nanoparticles and its bioavailability in rats

Taxifolin loaded zein-caseinate nanoparticles(TZP)were fabricated by the anti-solvent method and were used as an oral delivery vehicle to improve their bioavailability in the rat.The formulations of TZP were optimized.With mass ratio of 1:1:2 between taxifolin,zein and sodium caseinate,the particle size andζpotential of TZP were(168.74±0.35)nm and−(57.67±0.25)mV,while the encapsulation and loading efficiency of taxifolin were(85.83±0.89)%and(17.11±0.88)%,respectively.After freeze-drying,TZP exhibited excellent redispersibility in water without aggregation.Physicochemical characterization showed that taxifolin existed in amorphous form in TZP and its interaction with the protein was observed.After encapsulating in TZP,the excellent dispersion of taxifolin in water signifi cantly improve its diffusion velocity through a semipermeable membrane.After oral administration,taxifolin and its 5 metabolites were identifi ed in rat plasma by ultra high performance liquid chromatography(UPLC)with quadrupole time-of-flight mass spectrometry(UPLC-QTOF-MS).The dynamic variation of taxifolin and its metabolites in plasma were then quantifi ed by UPLC with a triple-quadrupole typemass spectroscopy(UPLC-QqQ-MS/MS).A pharmacokinetic study showed that the bioavailability of taxifolin increased from 0.35%to 0.52%through TZP fabrication.The plasma concentration of taxifolin glucuronide and methylated taxifolin glucuronide was much higher than taxifolin.Glucuronidation was the dominating metabolism pathway of taxifolin in vivo.

Effect of Glycosylation on the Physicochemical Properties,Structure and Iron Bioavailability of Ferritin Extracted from Tegillarca granosa

Iron deficiency anemia(IDA)is a major global health problem.Tegillarca granosa has been considered as an excellent source of iron given its high content of iron-binding protein,ferritin.The aim of the present study was to determine the physicochemical properties,protein structures,and iron uptake of ferritin extracted from T.granosa,and to evaluate the potential impacts of chitosan glycosylation on these characteristics.Based on Box-Behnken design and response surface methodology,the optimal conditions for glycosylation included a ferritin/chitosan mass ratio of 4:1,a pH of 5.5,a reaction time of 10 min,and a reaction temperature of 50℃.Glycosylation caused decreased surface hydrophobicity and elevated water-holding capacity of ferritin due to the introduction of hydrophilic groups.Additionally,glycosylation improved antioxidant capacity of ferritin by 20.69%–189.66%,likely owing to the protons donated by saccharide moiety to terminate free radical chain reaction.The in vitro digestibility of ferritin was elevated by 22.56%–104.85%after glycosylation,which could be associated with lessβ-sheet content in secondary structure that made the glycosylated protein less resistant to enzymatic digestion.The results of the iron bioavailability in Caco-2 cells revealed that ferritin(78.85–231.77 ngmg^(−1))exhibited better iron bioavailability than FeSO4(51.48–114.37 ngmg^(−1))and the values were further elevated by glycosylation with chitosan(296.23–358.20 ngmg^(−1)),which may be related to the physicochemical properties of ferritin via glycosylation modification.These results provide a basis for the development of T.granosa derived ferritin and its glycosylated products,and can promote the utilization of aquatic resources.

Optimized solubility and bioavailability of genistein based on cocrystal engineering

With various potential health-promoting bioactivities,genistein has great prospects in treatment of a series of complex diseases and metabolic syndromes such as cancer,diabetes,cardiovascular diseases,menopausal symptoms and so on.However,poor solubility and unsatisfactory bioavailability seriously limits its clinical application and market development.To optimize the solubility and bioavailability of genistein,the cocrystal of genistein and piperazine was prepared by grinding assisted with solvent based on the concept of cocrystal engineering.Using a series of analytical techniques including single-crystal X-ray diffraction,powder X-ray diffraction,Fourier transform infrared spectroscopy,differential scanning calorimetry and thermogravimetric analysis,the cocrystal was characterized and confirmed.Then,structure analysis on the basis of theoretical calculation and a series of evaluation on the stability,dissolution and bioavailability were carried out.The results indicated that the cocrystal of genistein and piperazine improved the solubility and bioavailability of genistein.Compared with the previous studies on the cocrystal of genistein,this is a systematic and comprehensive investigation from the aspects of preparation,characterization,structural analysis,stability,solubility and bioavailability evaluation.As a simple,efficient and green approach,cocrystal engineering can pave a new path to optimize the pharmaceutical properties of natural products for successful drug formulation and delivery.

Determination of Loratadine in Human Plasma by High Performance Liquid Chromatography-Electrospray Mass Spectrometry and Studies on Its Pharmacokinetics and Relative Bioavailability

A new HPLC MS method to determine loratadine in human plasma was established. The method involved extracting drug with organic solvent under basic conditions. The samples were seperated by ODS column and determined by mass detector. The calibration curve of loratadine was linear within the range of 0.4～100 ng·mL -1 with r=0.9995 . The recovery of this method was within 95%～104%, within day and between day RSD were less than 12%. To study the pharmacokinetics and relative bioavailability of loratadine tablets, two formulations of loratadine tablets were given to 18 healthy male volunteers according to a randomized 2 way cross over design. The C max , AUC 0 t and T max values of the two formulations were 51.89±20.18 ng·mL -1 and 52.48±22.35 ng·mL -1 ; 140.75±88.42 ng·h·mL -1 and 147.24±92.33 ng·h·mL -1 ; 0.81±0.35 h and 0.81±0.27 h respectively. Results from statistic analysis showed that there were no significant difference between the C max , AUC 0-t and T max values of the two formulations. The relative bioavailability of tablets I with respect to tablets II was 97%±13% from the AUC 0 t measurement. Bioequivalance was observed between the two tablets.

Pharmacokinetics and Absolute Bioavailability of the Sublingual Naloxone Hydrochloride Tablet in Dogs

The pharmacokinetics and absolute bioavailability of the sublingual naloxone tablet were studied with HPLC-electrochemical detection. Eight male dogs received single 5 mg dose of naloxone intravenously, the plasma concentration-time curves could be fitted to two-compartment open model, with 12.0 min of t1/2( , 143.4 min of t1/2( and 7.92 mg(min/L of AUC. The same eight dogs received 5 mg dose of the sublingual naloxone tablet after an interval of a week. The main pharmacokinetic parameters were: t1/2ka = 11.0 min, t1/2( = 15.4 min, t1/2( = 164.1 min, Tmax = 27.7 min, Cmax = 34.2 ng / ml, and AUC = 6.79 mg(min / L, respectively. The plasma concentration-time curves were fitted to the first order absorption two-compartment open model also. The mean absolute bioavailability of the sublingual naloxone tablet was 86.8 ( 10.9%. No statistically significant differences were found with t1/2(, t1/2(, ( and ( between the two routes of administration. These results indicated that the course of disposition for naloxone in dogs was similar for the two routes of administration, and the absolute bioavailability of the sublingual naloxone tablet was high. Thus satisfactory clinical effects could be expected.

Preparation and bioavailability in healthy volunteers of cefaclor modified-release capsules

Aim To investigate whether modified-release cefaclor capsules could lead to a more suitable pharmacokinetic profile in the plasma. Methods Cefaclor pellets were prepared by extrusion/spheronization and coated by Eudragit L30D-55 or Eudragit NE30D, then the two sorts of pellets were filled to capsules in a 35：65 ratio to made a modified-release （MR） capsules. The bioavailability of the MR capsules was studied in 24 healthy volunteers after oral administration in a fast state using a commercially available immediate release （IR） capsule as a reference. Results The results showed that the MR formulation had a relatively good bioavailability compared with the commercial capsules, as well as a longer time keeping drug level above MIC than immediate release capsule. The relative bioavailability of the MR capsules was 97.4- 12.1%. Conclusion The data of the present study indicate that time of cefaclor plasma concentration above MIC can be substantially prolonged if cefaclor is administered as a modified- release product.

HPLC Determination of Captopril in Human Plasma with Pre-column Derivation and Solid-phase Extraction and Studies on Its Pharmacokinetic and Relative Bioavailability

A new pre-column derivation HPLC method with solid-phase extraction to determine captopril in human plasma was established. Derivation products were extracted by a solid-phase extraction method after the reagent, p-a-dibromoacetophenone(p-BPB), was added in the plasma samples. The samples were analyzed in a VP-ODS column with UV-detector. The calibration curve of captopril was linear within the range of 5~1000 ngmL-1 with r=0.9987, the recovery of this method was 98.652.04%, within day and between day RSD were no more than 3.4% and 8.4% respectively. To study the pharmacokinetics and the relative bioavailability of captopril tablets, two formulations of captopril tablets were given to 18 healthy male volunteers according to a randomized 2-way cross-over design with a 1-week washout period. The respective AUC0~6 , Cmax and Tmax values of the two formulations were 424.5125.7 and 439.4113.3 mghL-1; 505.9244.6 and 504.8172.2 mgL-1; 0.6620.181 and 0.5280.176 h. Results from statistics analysis showed that there were no significant difference between the AUC0~6 , Cmax and Tmax values of the two formulations, The relative bioavailability of tablets I with respect to II was 96.114.6% from AUC0~6 measurement. Bioequivalance was observed between the two tablets.

Determination of Lovastatin Level in Human Plasma and Lovastatin Capsules Bioavailability in Healthy Volunteers Using HPLC-MS

Aim To establish a sensitive and specific liquid chromatography-mass spectrometry (HPLC-MS) method for measuring lovastatin level in human plasma and the relative bioavailability. Methods Lovastatin in the plasma was extracted with acetoacetate. Simvastatin was added as internal standard (IS). Samples were separated on a C_ 18 column with a mobile phase consisting of methanol and 50 mmol·L~ -1 sodium acetate (88 ∶ 12). The flow rate was 1 mL·min~ -1 . Sample was detected using an electrospray ionization (ES...

Pharmacokinetics and Relative Bioavailability ofsustained-release Tablets of Diclofenac Sodiumin Male Volunteers

The pharmacokinetics of a sustained- release formulation and an enteric- coated tablet of diclofenac sodium were studied on 8 healthy male volunteers in an open,randomized crossover study.Drug level in serum was assayed by HPLC method.The changes in serum concentration were conformed to a l-compartment open model.The t_1/2 (Ke)averaged 2.15±0.17 and ll.60 ± l.95 h,and the areas under the drug concentration curves were 5.87 ± 0.67 and 5.55 ± 0.57μgh/ml for enteric-coated and sustained-release tablet of diclofenac sodium,respectively. The mean relative bioavailability of sustained-release tablet was 0.95 to that of enteric-coated tablet.

Study on Relative Bioavailability of Famotidine Sustained-release Tablets in Healthy Volunteers

The relative bioavailability of famotidine sustained release (SR) tablets was studied in 16 healthy male volunteers. Famotidine plasma concentration was determined by HPLC method, and the plasma concentration time data were processed with the method provided by USP XXIII. For single dose administration the peak plasma concentration occurring at 8 13±0 34 h was 69 52±3 00 ng/ml and the relative bioavailability was 112 4±8 6%. For multiple dose administration the peak plasma concentration of SR tablet was 86 14±2 95 ng/ml and the degree of fluctuation (DF) was 140 6±13 5% at steady state. Two one sided tests were performed in bioequivalence assessment. The results showed that the sustained release tablets were basically bioequivalent to the immediate release (IR) tablets on sale.

A nano-cocrystal strategy to improve the dissolution rate and oral bioavailability of baicalein

Baicalein(BE) is one of the main active flavonoids representing the variety of pharmacological effects including anticancer, anti-inflammatory and cardiovascular protective activities, but it's very low solubility, dissolution rate and poor oral absorption limit the therapeutic applications. In this work, a nano-cocrystal strategy was successfully applied to improve the dissolution rate and bioavailability of BE. Baicalein-nicotinamide(BE-NCT) nanococrystals were prepared by high pressure homogenization and evaluated both in vitro and in vivo. Physical characterization results including scanning electron microscopy, dynamic light scattering, powder X-ray diffraction and differential scanning calorimetry demonstrated that BE-NCT nano-cocrystals were changed into amorphous state with mean particle size of 251.53 nm. In the dissolution test, the BE-NCT nano-cocrystals performed 2.17-fold and 2.54-fold enhancement than BE coarse powder in FaSSIF-V2 and FaSSGF. Upon oral administration, the integrated AUC0-t of BE-NCT nano-cocrystals(6.02-fold) was significantly higher than BE coarse powder(1-fold), BE-NCT cocrystals(2.87-fold) and BE nanocrystals(3.32-fold). Compared with BE coarse powder, BE-NCT cocrystals and BE nanocrystals, BENCT nano-cocrystals possessed excellent performance both in vitro and in vivo evaluations.Thus, it can be seen that nano-cocrystal is an appropriate novel strategy for improving dissolution rate and bioavailability of poor soluble natural products such as BE.

Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs

Nanocrystals,a carrier-free colloidal delivery system in nano-sized range,is an interesting approach for poorly soluble drugs.Nanocrystals provide special features including enhancement of saturation solubility,dissolution velocity and adhesiveness to surface/cell membranes.Several strategies are applied for nanocrystals production including precipitation,milling,high pressure homogenization and combination methods such as Nano-Edge^(TM),SmartCrystal and Precipitation-lyophilization-homogenization(PLH)technology.For oral administration,many publications reported useful advantages of nanocrystals to improve in vivo performances i.e.pharmacokinetics,pharmacodynamics,safety and targeted delivery which were discussed in this review.Additionally,transformation of nanocrystals to final formulations and future trends of nanocrystals were also described.

Fractions and Bioavailability of Soil Inorganic Phosphorus in the Loess Plateau of China under Different Vegetations

Plants play an important role in soil phosphorus nutrition. However, the effect of plants on phosphorus nutrition in soils of the Loess Plateau of China is not well understood. This study was conducted to reveal the relationships between plants and phosphorus＇ fractions and availability in the Loess Plateau of China. Twenty-two plant communities were surveyed and soil samples under different plant canopies were collected for the determination of soil properties and inorganic phosphorus fractionation. The results showed that Leguminosae and Lilaceae reduced pH and increased organic matter, cation exchange capacity, total and Olsen phosphorus in soils under their canopies, while Labiatae and Rosaceae increased pH and decreased organic matter, cation exchange capacity, total and Olsen phosphorus in soils under their canopies. The contents of Ca2P, CasP, AI-P and Fe-P were highly related with soil Oisen phosphorus. They were all higher in soils under Leguminosae and Lilaceae and lower in softs under Labiatae and Rosaceae. The results of this study indicate that Leguminosae and Lilaceae improved phosphorus nutrition in soils, yet Labiatae and Rosaceae impeded the improvement of phosphorus nutrition in soils under their canopies, which will be of more help to instruct vegetation restoration in the region and provide information for soil development.

Andrographolide Loaded in Micro-and Nano-Formulations: Improved Bioavailability, Target-Tissue Distribution, and Efficacy of the “King of Bitters”

Andrographolide (AG) is the characteristic constituent of Andrographis paniculata, of the Acanthaceae family. This plant is a well-known Asian medicinal plant that is widely used in India, China, and Thailand. A monograph of Herba Andrographidis (Chuanxinlian) is included in the Chinese Pharmacopoeia, which reports that this decoction can “remove heat, counteract toxicity, and reduce swellings.” The numerous potential activities of AG range from anti-inflammatory to anti-diabetic action, from neuroprotection to antitumor activity, and from hepatoprotective to anti-obesity properties. However, AG has low bioavailability and poor water solubility, which can limit its distribution and accumulation in the body after administration. In addition, AG is not stable in gastrointestinal alkaline and acidic environments, and has been reported to have a very short half-life. Among the diverse strategies that have been adopted to increase AG water solubility and permeability, the technological approach is the most useful way to develop appropriate delivery systems. This review reports on published studies related to microparticles (MPs) and nanoparticles (NPs) loaded with AG. MPs based on polylactic-glycolic acid (PLGA), alginic acid, and glucan derivatives have been developed for parenteral oral and pulmonary administration, respectively. NPs include vesicles (both liposomes and niosomes);polymeric NPs (based on polyvinyl alcohol, polymerized phenylboronic acid, PLGA, human serum albumin, poly ethylcyanoacrylate, and polymeric micelles);solid lipid NPs;microemulsions and nanoemulsions;gold NPs;nanocrystals;and nanosuspensions. Improved bioavailability, target-tissue distribution, and efficacy of AG loaded in the described drug delivery systems have been reported.

Phyto-phospholipid complexes(phytosomes): A novel strategy to improve the bioavailability of active constituents

Although active constituents extracted from plants show robust in vitro pharmacological effects, low in vivo absorption greatly limits the widespread application of these compounds. A strategy of using phyto-phospholipid complexes represents a promising approach to increase the oral bioavailability of active constituents, which is consist of ‘‘label-friendly'phospholipids and active constituents. Hydrogen bond interactions between active constituents and phospholipids enable phospholipid complexes as an integral part. This review provides an update on four important issues related to phyto-phospholipid complexes: active constituents, phospholipids, solvents, and stoichiometric ratios. We also discuss recent progress in research on the preparation, characterization, structural verification, and increased bioavailability of phyto-phospholipid complexes.

Optimal dietary copper requirements and relative bioavailability for weanling pigs fed either copper proteinate or tribasic copper chloride

Background: The objective of this study was to determine the effects of supplementing Cu on growth performance, Cu metabolism and Cu-related enzyme activities of weanling pigs fed diets with two different Cu sources, and to estimate optimal Cu requirements and relative bioavailability from these two sources for pigs.Methods: Weanling pigs were allocated to 14 treatments arranged factorially, including 6 added Cu levels(5, 10,20, 40, 80, 160 mg/kg), and 2 mineral sources(tribasic Cu chloride, TBCC and copper proteinate, Cu Pro), as well as one negative control(0 mg/kg added Cu level) and one maximum allowed level treatment(200 mg/kg TBCC) for the entire 38-d experiment. Growth performance, mineral status and enzyme activities were measured at the end of this study.Results: Increasing levels of Cu showed linear and quadratic responses(P < 0.01) for final BW, ADG and FCR regardless of the sources. Supplementation with TBCC(> 80 mg/kg) and Cu Pro(> 20 mg/kg) significantly decreased(P < 0.05) diarrhea incidence of weanling pigs. There were linear and quadratic increases(P < 0.01) in bile, hepatic,and intestinal Cu concentrations, fecal Cu contents, and plasma enzyme activities(alkaline phosphatase,ceruloplasmin, Cu, Zn-Superoxide dismutase(Cu/Zn SOD), and glutathione peroxidase), whereas plasma malondialdehyde decreased(P < 0.01) linearly and quadratically as dietary Cu level increased. Similarly, pigs fed Cu Pro absorbed and retained more Cu and excreted less Cu than those fed TBCC when supplemented 80 mg/kg and above. Optimal dietary Cu requirements for pigs from 28 to 66 d of age estimated based on fitted broken-line models(P < 0.05) of bile Cu, plasma Cu/Zn SOD and growth performance were 93–140 mg/kg from TBCC, and 63–98 mg/kg from Cu Pro accordingly. According to slope ratios from multiple linear regression, the bioavailability value of Cu Pro relative to TBCC(100%) was 156–263%(P < 0.01).Conclusion: The findings indicated that Cu recommendation from current NRC(5–6 mg/kg) was not sufficient to meet the high requirement of weanling pigs. Cu from Cu Pro was significantly more bioavailable to weanling pigs than TBCC in stimulating growth and enzyme activities, decreasing diarrhea frequency and fecal Cu contents to the environment.

Improved dissolution and bioavailability of silymarin delivered by a solid dispersion prepared using supercritical fluids

The objective of this study was to improve the dissolution and bioavailability of silymarin(SM).Solid dispersions(SDs)were prepared using solution-enhanced dispersion by supercritical fluids(SEDS)and evaluated in vitro and in vivo,compared with pure SM powder.The particle sizes,stability,and contents of residual solvent of the prepared SM-SDs with SEDS and solvent evaporation(SE)were investigated.Four polymer matrix materials were evaluated for the preparation of SM-SD-SEDS,and the hydrophilic polymer,polyvinyl pyrrolidone K17,was selected with a ratio of 1:5 between SM and the polymer.Physicochemical analyses using X-ray diffraction and differential scanning calorimetry indicated that SM was dispersed in SD in an amorphous state.The optimized SM-SD-SEDS showed no loss of SM after storage for 6 months and negligible residual solvent(ethanol)was detected using gas chromatography.In vitro drug release was increased from the SM-SDSEDS,as compared with pure SM powder or SM-SD-SE.In vivo,the area under the rat plasma SM concentration-time curve and the maximum plasma SM concentration were 2.4-fold and 1.9-fold higher,respectively,after oral administration of SM-SD-SEDS as compared with an aqueous SM suspension.These results illustrated the potential of using SEDS to prepare SM-SD,further improving the biopharmaceutical properties of this compound.

Application of hot melt extrusion to enhance the dissolution and oral bioavailability of oleanolic acid

The aim of this study was to improve the in vitro dissolution rate and oral bioavailability of oleanolic acid(OA), a water insoluble drug belonging to BCS class IV. Hot melt extrusion(HME) was applied to develop OA amorphous solid dispersions. The characterizations of the optimal formulation were performed by differential scanning calorimetry, X-ray powder diffraction, Fourier transform infrared spectroscopy and in vitro dissolution test.The in vivo pharmacokinetic study was conducted in rats. As a result, OA solid dispersion based on PVP VA 64(OA-PVP) was successfully prepared. In the dissolution medium containing 0.3% SDS, OA-PVP dramatically increased the releasing rate of OA compared with the physical mixture(PM-PVP) and commercial tablet. Furthermore, OA-PVP exhibited higher AUC(P < 0.05) and Cmax(P < 0.05) than PM-PVP and commercial tablet. The superior dissolution property and bioavailability of OA-PVP mainly attributed to the amorphous state of OA in PVP VA64 and the well dispersion caused by thermal melting and shearing. Overall, hot melt extrusion was an efficient strategy to enhance the dissolution rate and oral bioavailability of OA.