Improving the oral bioavailability of beneficial polyphenols through designed synergies

A substantial and growing consumer demand exists for plant-based functional foods that improve general health and wellbeing. Amongst consumed phytochemicals, the polyphenolic compounds tend to be the most bioactive. Many commonly consumed polyphenols have been shown to have specific and potent health-promoting activities when assessed by high-throughput in vitro assays and when administered to experimental animals by injection. However, very few have been shown to have any beneficial effects in animals or man when orally consumed, because of the poor bioavailability exhibited by most polyphenols following the ingestion. Consumed polyphenols, like most pharmaceuticals, are regarded as xenobiotics by the body and must overcome many barriers, including extensive enzymatic and chemical modification during digestion and absorption, to reach their site(s) of action. This is especially true for polyphenols targeting the brain, which is protected by the tightly regulated blood–brain barrier. Interestingly, many polyphenols are also known to specifically modify some of the metabolic and transport processes that govern bioavailability. Therefore, the opportunity exists to increase the bioactivity of beneficial polyphenols by designing specific synergistic interactions with polyphenols that improve their oral bioavailability. This hypothesis and review paper will discuss some of the endogenous systems that limit the bioavailability of ingested polyphenols to the body and the brain, and the means by which bioavailability may be improved by specifically designing synergies between orally consumed polyphenols.     

Design and development of microemulsion drug delivery system of acyclovir for improvement of oral bioavailability

The main purpose of this work was to develop an oral microemulsion formulation for enhancing the bioavailability of acyclovir. A Labrafac-based microemulsion formulation with Labrasol as surfactant and Plurol Oleique as cosurfactant was developed for oral delivery of acyclovir. Phase behavior and solubilization capacity of the microemulsion system were characterized, and in vivo oral absorption of acyclovir from the microemulsion was investigated in rats. A single isotropic region, which was considered to be a bicontinuous microemulsion, was found in the pseudoternary phase diagrams developed at various Labrasol:Plurol Oleique:Labrafac ratios. With the increase of Labrasol concentration, the microemulsion region area and the amount of water and Labrafac solubilized into the microemulsion system increased; however, the increase of Plurol Oleique percentage produced opposite effects. The microemulsion system was also investigated in terms of other characteristics, such as interfacial tension, viscosity, pH, refractive index, diffusion, and bioavailability. Acyclovir, a poorly soluble drug, displayed high solubility in a microemulsion formulation using Labrafac (10%). Labrasol (32%), Plurol Oleique (8%), and water (50%). The in vitro intraduodenal diffusion and in vivo study revealed an increase of bioavailability (12.78 times) after oral administration of the microemulsion formulation as compared with the commercially available tablets. Published: September 15, 2006     

A cassette-dosing approach for improvement of oral bioavailability of dual TACE/MMP inhibitors

The structural features contributing to the different pharmacokinetic properties of the TACE/MMP inhibitors TNF484 and Trocade were analyzed using an in vivo cassette-dosing approach in rats. This enabled us to identify a new lead compound with excellent pharmacokinetic properties, but weaker activity on the biological targets. Directed structural modifications maintained oral bioavailability and restored biological activity, leading to a novel compound almost equipotent to TNF484 in vivo, but with a more than tenfold higher oral bioavailability.     

The rate and extent of calcium bioavailability from two oral dosage forms in rats

The purpose of the present work was to compare oral bioavailability of calcium from two calcium preparations, Calcium Sandoz forte 500 mg and Calcium Spofa effervescens. The pharmacokinetic study was carried out on rats, and plasma levels of 45Ca after administration of labelled calcium solutions were determined. Appropriate equations describing the two-compartment open model and the one-compartment model with first order absorption were fitted to the observed i.v. and oral data, respectively, using weighted nonlinear least-squares regression analysis. The extent and the time profile of the rate of 45Ca systemic bioavailability were assessed. Both parameters suggested identical bioavailability of calcium from the two dosage forms compared.     

Hologram QSAR model for the prediction of human oral bioavailability

A drug intended for use in humans should have an ideal balance of pharmacokinetics and safety, as well as potency and selectivity. Unfavorable pharmacokinetics can negatively affect the clinical development of many otherwise promising drug candidates. A variety of in silico ADME (absorption, distribution, metabolism, and excretion) models are receiving increased attention due to a better appreciation that pharmacokinetic properties should be considered in early phases of the drug discovery process. Human oral bioavailability is an important pharmacokinetic property, which is directly related to the amount of drug available in the systemic circulation to exert pharmacological and therapeutic effects. In the present work, hologram quantitative structure–activity relationships (HQSAR) were performed on a training set of 250 structurally diverse molecules with known human oral bioavailability. The most significant HQSAR model (q² = 0.70, r² = 0.93) was obtained using atoms, bond, connection, and chirality as fragment distinction. The predictive ability of the model was evaluated by an external test set containing 52 molecules not included in the training set, and the predicted values were in good agreement with the experimental values. The HQSAR model should be useful for the design of new drug candidates having increased bioavailability as well as in the process of chemical library design, virtual screening, and high-throughput screening.     

Bioavailability of oral drugs and the methods for its improvement

Recent studies in nanotechnology resulted in the development of novel formulations with improved bioavailability. This is especially important for oral administered drugs as the most convenient formulations for administration to patients. The review considers processes occurring in the gastro-intestinal (GI) tract during oral administration of drugs. The increase of bioavailability of the drug may be achieved through designing novel formulations according to the specific drug properties. These include capsules that release pharmaceutical agents at various parts of the GI tract, floating systems that prolong the presence of the drug in stomach, maximally dispersed forms containing surface-active soluble polymers or micelles that carry poor-soluble drugs inside their non-polar core, agents that facilitate tight junction opening, such as caprate and chitosan, and lipid-based formulations. The own data show the stimulating influence of phospholipid nanoparticles on peroral absorption of the drug, indomethacin, in rats and on passage of transport marker and drugs through Caco-2 cell monolayer in vitro. The review summarizes current understanding of factors that influence the bioavailability of the oral drug formulations, currently used models for pharmacokinetic studies, and various approaches to developing novel pharmaceutical formulations that increase the bioavailability of the drugs.     

Formulation and development of novel control release transdermal patches of carvedilol to improve bioavailability for the treatment of heart failure

The main aim of this study is to optimize and evaluate transdermal patch of Carvedilol by the use of different polymer and different permeation enhancers which help to release drug in controlled action and thereby increase the bioavailability of the drug. Main objective was to avoid first pass metabolism of Carvedilol. Transdermal patches were developed by solvent evaporation method. The combination of Eudragit RS-100 as rate controlling polymer and Span 80 as a permeation enhancer was found to be ideal formulation (Formulation F7) with maximum drug release i.e. 100.29 ± 0.44 % within 12 h. Formulation F7 showed maximum bioavailability and showed maximum drop of BP at 6 h. From this study the conclusion was, transdermal patch of Carvedilol which contains Eudragit RS-100 polymer and Span 80 as penetration enhancer produced sustained and continued drug release.     

Fluoride reduces the rate of dissolution of bone

Recently, fluoride has been used in the treatment of osteoporosis in an attempt to rebuild bone lost due to this disease. Fluoride has been shown to have a profound effect on osteoblasts and bone formation. Studies have shown that synthetic fluorapatite is more stable and less soluble than hydroxyapatite. This study was designed to determine the dissolution properties of bones from rats fed a normal diet versus rats fed a high fluoride diet. Intact and deproteinized bones were dissolved in buffered solutions, containing physiological amounts of inorganic Ca and P, at pH 3.4, 4.4 and 5.4 The data demonstrate that fluoridated bones dissolve slower than normal bones, deproteinized bones dissolve faster than intact bones and that the initial rate of dissolution of fluoridated bone is always significantly lower than that of normal bone. This may help to explain the reduced rate of osteoclastic resorption in patients undergoing fluoride therapy.     

Estimation of rate constant for dissolution of radioactive fuel particles

Some theoretical of the experimental investigation of solubility of radioactive aerosols were examined. Filters, which were exposed during October-November 1987 in Pripyat town, were studied. Measurements on 22 November 1987 showed that an activity in the air was 12.1-20.8 mBq/m3 for 137Cs, 34.9-89.3 mBq/m-3 for 144Ce, 24.3-30.5 mBq/m-3 for 106Ru. Disperse structure of aerosol hot particles and the number of hot particles on each filter fragment was estimated by radiography. To determine a dissolution rate constant a static system with two 0.14 micron pore size membrane MFE filters (Dubna, Russia) enclosing fragments of Petryanov filters was selected. The composition was held in Gamble's solution lung fluid anf then in 0.1 mol/l HCl as dastic juice simulation. The activity of 90Sr, 238Pu, 239 + 240Pu, 241Am and 244Cm in aerosol filters and solutions was measured by radiochemical methods. It was shown that leaching of radionuclides from aerosol hot particles in lung fluid simulation decreases in line 137Cs > 90Sr > 239 + 240Pu > or = 241Am, depending om particle diameter and time. Dissolution constants were presented. Dissolution of aerosol particles in 0.1 mol/l HCl is also shown (dissolution time was 3 days). A radionuclide transition to HCl solution decreases in line 90Am 241Am > 137Cs > 239 + 240Pu. A transition degree reached 21% for 90Sr and extraction of 241Am was 3-17%.     

Study of prolactin permeation through the pericardium and its bioavailability

The prolactin (PRL) permeation through the pericardium depending on the species of origin (porcine, bovine and ovine) was studied, and the parameters of its bioavailability were calculated. An in vitro model using pericardium as a natural membrane and Frantz cell method was applied. Significant differences in permeation were observed depending on the species of origin. Within 5 h, 17.5% of bovine PRL, 27.2% of porcine PRL and 90.3% of ovine PRL permeated the pericardium. The amount of permeated ovine PRL was 3.3-fold higher than porcine PRL and 5.2-fold higher than bovine PRL. The maximum concentration of permeated PRL was reached in the thirtieth minute of the experiment and was the highest for ovine PRL (C(max) = 677.21 μg/cm2) and the lowest for bovine PRL (C(max) = 259.97 μg/cm2). Bioavailability of PRL through the pericardium is 3.3-fold greater for ovine PRL in comparison to porcine or bovine PRL. The relative extent of bioavailability for bovine and ovine prolactin versus the porcine PRL standard was 85.6% and 229.3%, respectively.     

Gas chromatograph-mass spectrometric method for the determination of carvedilol and its metabolites in human urine

A sensitive and efficient method was developed for the determination of carvedilol and its metabolites in human urine by gas chromatography-mass spectrometry (GC-MS). Urine samples were hydrolyzed with beta-glucuronidase/arylsulfatase (from Helix pomatia) and the target compounds were extracted with liquid-liquid extraction. The extracts were completely derivatized with MSTFA and MBTFA and analyzed by GC-MS using an Ultra-2 column. The linearity of the assay ranges were 0.75-75 ngmL(-1) for carvedilol and o-desmethyl carvedilol (o-DMC), and 3.0-75 ngmL(-1) for 4-hydroxyphenyl carvedilol (4-HPC) and 5-hydroxyphenyl carvedilol (5-HPC). The absolute recovery of carvedilol and its metabolites added to a blank urine sample was 80.1-97.8%. The limits of detection (LOD) and quantitation (LOQ) of carvedilol and o-DMC were 0.30 and 0.75 ngmL(-1), and its of 4-HPC and 5-HPC were 0.75 and 3.0 ngmL(-1), respectively. The reproducibilities were 1.86-11.5% for the intra-day assay, and 0.70-1.71% for the inter-day assay precision and the degree of inaccuracy was -3.0 to 3.9% at the concentration of 75 ngmL(-1). The proposed GC-MS method was effective for the determination of carvedilol and its three metabolites in human urine.     

Scale-up effects on dissolution and bioavailability of propranolol hydrochloride and metoprolol tartrate tablet formulations

This study evaluated the effects of batch size on the in vitro dissolution and the in vivo bioavailability of immediate release formulations of propranolol hydrochloride and metoprolol tartrate. The formulations were manufactured as small and large batches (6 kg and 60 kg for propranolol; 14 kg and 66 kg for metoprolol), and dissolution was performed using USP Apparatus I at 100 rpm and pH 1.2. Two panels of 14 subjects each were randomly assigned to receive the small and large batches of either propranolol or metoprolol in an open randomized single-dose study. Blood samples were collected over a 24-hour (propranolol) or 18-hour (metoprolol) period and analyzed by validated methods. As determined by thef ₂ metric (similarity factor), the dissolution of the small and large batches of propranolol and metoprolol was similar. The mean C_max and AUC_inf for the small batch of propranolol were 79.0 μ g/L and 536 μ g/L/hr and for the large batch they were 83.5 μ g/L and 575 μ g/L/hr. C_max and AUC_inf for the small batch of metoprolol were found to be 95.5 μ g/L and 507 μ g/L/hr and for the large batch, 95.1 μ g/L and 495 μ g/L/hr. The 90% confidence intervals for the small and large batches were within the 80% to 120% range for InC_max, and InAUC_inf for both the propranolol and metoprolol formulations. These results suggest that the scale-up process does not significantly affect the bioavailability of highly soluble, highly permeable drugs and in vitro dissolution tests may be useful in predicting in vivo behavior.     

Potential for the improvement of Salicornia bigelovii through selective breeding

Salicornia bigelovii Torr. is an annual salt marsh plant that produces seed oils, protein meal, fresh salad greens and forage on seawater irrigation. We compared S. bigelovii lines produced in two breeding programs with wild germplasm in greenhouse trials on brackish water (10 ppt NaCl) irrigation. S. bigelovii is an out-crossing species that is also capable of selfing, and the breeding programs showed it is possible to use both hybridization and pedigree breeding to improve the germplasm. Lines selected in a breeding program carried out in Eritrea, Africa, had smaller plant size and lower biomass yields than the starting germplasm, due to the need to compress the growth cycle within the cool months of the year in that hot climate, but seed yields and harvest index were improved. Lines produced from wild germplasm by mass selection and hybridization in Tucson, Arizona had higher biomass yield than starting germplasm. We conclude that S. bigelovii has sufficient genetic diversity among wild accessions and cultivars to support a crop improvement program.     

Preparation and characterization of Eudragit Retard nanosuspensions for the ocular delivery of cloricromene

The purpose of this study was to improve the stability of cloricromene (AD6) in ophthalmic formulations and its drug availability at the ocular level. To this end, AD6-loaded polymeric nanoparticle suspensions were made using inert polymer resins (Eudragit RS100 and RL100). We modified the quasi-emulsion solvent diffusion technique by varying some formulation parameters (the drug-to-polymer ratio, the total drug and polymer amount, and the stirring speed). The chemical stability of AD6 in the nanosuspensions was assessed by preparing some formulations using (unbuffered) isotonic saline or a pH 7 phosphate buffer solution as the dispersing medium. The formulations were stored at 4°C, and the rate of degradation of AD6 was followed by high performance liquid chromatography (HPLC). The obtained nanosuspensions showed mean sizes and a positive surface charge (ζ-potential) that make them suitable for an ophthalmic application; these properties were maintained upon storage at 4°C for several months. In vitro dissolution tests confirmed a modified release of the drug from the polymer matrixes. Nanosuspensions prepared with saline solution and no or lower amounts of surfactant (Tween 80) showed an enhanced stability of the ester drug for several months, with respect to an AD6 aqueous solution. Based on the tecnological results, AD6-loaded Eudragit Retard nanoparticle suspensions appear to, offer promise as a means to improving the shelf life and bioavailability of this drug after ophthalmic application. Published: March 24, 2006     

A method for the improvement of threading-based protein models

A new method for the homology-based modeling of protein three-dimensional structures is proposed and evaluated. The alignment of a query sequence to a structural template produced by threading algorithms usually produces low-resolution molecular models. The proposed method attempts to improve these models. In the first stage, a high-coordination lattice approximation of the query protein fold is built by suitable tracking of the incomplete alignment of the structural template and connection of the alignment gaps. These initial lattice folds are very similar to the structures resulting from standard molecular modeling protocols. Then, a Monte Carlo simulated annealing procedure is used to refine the initial structure. The process is controlled by the model's internal force field and a set of loosely defined restraints that keep the lattice chain in the vicinity of the template conformation. The internal force field consists of several knowledge-based statistical potentials that are enhanced by a proper analysis of multiple sequence alignments. The template restraints are implemented such that the model chain can slide along the template structure or even ignore a substantial fraction of the initial alignment. The resulting lattice models are, in most cases, closer (sometimes much closer) to the target structure than the initial threading-based models. All atom models could easily be built from the lattice chains. The method is illustrated on 12 examples of target/template pairs whose initial threading alignments are of varying quality. Possible applications of the proposed method for use in protein function annotation are briefly discussed.     

Optimizing bioavailability of oral administration of small peptides through pharmacokinetic and pharmacodynamic parameters: The effect of water and timing of meal intake on oral delivery of Salmon Calcitonin

Background

To investigate the influence of water intake and dose timing on the pharmacokinetic and pharmacodynamic parameters of an oral formulation of salmon calcitonin (sCT).

Methods

The study was a randomized, partially-blind, placebo-controlled, single dose, exploratory crossover phase I study. 56 healthy postmenopausal women were randomly assigned to receive five treatments. The treatments comprised a combination of study medication (SMC021 (0.8 mg sCT + 200 mg 5-CNAC), SMC021 placebo, or 200 IU Miacalcic^® NS nasal spray), water volume given with the tablet (50 or 200 ml water), and time between dosing and meal (10, 30, or 60 minutes pre-meal). Plasma sCT levels and changes in the bone resorption (C-terminal telopeptide of collagen type I) was investigated. Trial regristration

Results

Oral delivery of 0.8 mg of sCT with 50 ml of water compared to that with 200 ml water resulted in a two-fold increase in maximum concentration (C_max and AUC_0–4) of plasma sCT but comparable time to reach maximum concentration (T_max). The sCT AUC_0–4 with 50 ml of water was 4-fold higher than that obtained with nasal calcitonin. The increased absorption of sCT resulted in increased efficacy demonstrated by AUC of the relative change of serum CTX-I measured in the 6 hours post dosing.

Conclusion

0.8 mg sCT with 50 ml of water taken 30 and 60 minutes prior to meal time resulted in optimal pharmacodynamic and pharmacokinetic parameters. The data suggest that this novel oral formulation may have improved absorption and reduction of bone resorption compared to that of the nasal form.     

Role of dissolution rate and solubility in biodegradation of aromatic compounds

[This corrects the article on p. 294 in vol. 53.].     

Role of dissolution rate and solubility in biodegradation of aromatic compounds

Strains of Moraxella sp., Pseudomonas sp., and Flavobacterium sp. able to grow on biphenyl were isolated from sewage. The bacteria produced 2.3 to 4.5 g of protein per mol of biphenyl carbon, and similar protein yields were obtained when the isolates were grown on succinate. Mineralization of biphenyl was exponential during the phase of exponential growth of Moraxella sp. and Pseudomonas sp. In biphenyl-supplemented media, Flavobacterium sp. had one exponential phase of growth apparently at the expense of contaminating dissolved carbon in the solution and a second exponential phase during which it mineralized the hydrocarbon. Phase-contrast microscopy did not show significant numbers of cells of these three species on the surface of the solid substrate as it underwent decomposition. Pseudomonas sp. did not form products that affected the solubility of biphenyl, although its excretions did increase the dissolution rate. It was calculated that Pseudomonas sp. consumed 29 nmol of biphenyl per ml in the 1 h after the end of the exponential phase of growth, but 32 nmol of substrate per ml went into solution in that period when the growth rate had declined. In a medium with anthracene as the sole added carbon source, Flavobacterium sp. converted 90% of the substrate to water-soluble products, and a slow mineralization was detected when the cell numbers were not increasing. Flavobacterium sp. and Beijerinckia sp. initially grew exponentially and then arithmetically in media with phenanthrene as the sole carbon source. Calculations based on the growth rates of these bacteria and the rates of dissolution of phenanthrene suggest that the dissolution rate of the hydrocarbon may limit the rate of its biodegradation.