Evaluation of the effect of carrier material on modification of release characteristics of poor water soluble drug from liquisolid compacts.

Liquisolid compact is a novel dosage form in which a liquid medication (liquid drug, drug solution/dispersion in non-volatile solvent/solvent system) is converted to a dry, free flowing powder and compressed. Objective of the study was to elucidate the effect of carrier material on release characteristics of clopidogrel from liquisolid compacts. Different formulations of liquisolid compacts were developed using microcrystalline cellulose, starch maize, polyvinyl pyrollidone and hydroxypropyl methylcellulose as carrier material in three concentrations (40, 30 and 20%, w/w). Liquid vehicle was selected on the basis of solubility of clopidogrel. Colloidal silicondioxide was used as coating material and ratio of carrier to coating material was kept 10. A control formulation comprised of microcrystalline cellulose (diluents), tabletose-80 (diluents), primojel (disintegrant) and magnesium stearate (lubricant) was prepared by direct compression technique and was used for comparison. All the formulations were evaluated at pre and post compression level. Acid solubility profile showed higher solubility in HCl buffer pH2 (296.89±3.49 µg/mL). Mixture of propylene glycol and water (2:1, v/v) was selected as liquid vehicle. Drug content was in the range of 99-101% of the claimed quantity. All the formulations showed better mechanical strength and their friability was within the official limits (<1%). Microcrystalline cellulose and starch maize resulted in faster drug release while polyvinyl pyrollidone and HPMC resulted in sustaining drug release by gel formation. It is concluded from results that both fast release and sustained release of clopidogrel can be achieved by proper selection of carrier material.

Proanthocyanidins from Chinese berry leaves modified the physicochemical properties and digestive characteristic of rice starch.

Proanthocyanidins extracted from Chinese berry leaves (CBLPs) were heated with rice starch in aqueous solution to prepare polyphenols-starch complexes. The physicochemical properties of the complexes were characterized with XRD, DSC, RVA and FT-IR and starch constituents were also analyzed with an enzyme method. Results indicated that the addition of CBLPs destroyed the long ordered structure of rice starch rather than the short ordered structure, since the crystallinity decreased from 21.96% to 18.90% and the ratio of 1047 cm-1/1022 cm-1 showed little difference, consistent with the lower ΔH of complexes with higher CBLPs content. Additionally, the CBLPs-rice starch complexes showed a significantly lower content of rapidly digested starch (RDS, 45.64 ± 3.25%) than that of the native rice starch (67.76 ± 2.15%). These results indicated that CBLPs complexes with rice starch might be a novel way to prepare functional starch with slower digestion.

Inhibitory effect of chestnut (Castanea mollissima Blume) inner skin extract on the activity of α-amylase, α-glucosidase, dipeptidyl peptidase IV and in vitro digestibility of starches.

This study aimed to investigate the inhibitory effect of chestnut inner skin extract (CISE) on the activity of postprandial blood sugar-related enzymes. In total, 12 flavonoids were identified by HPLC-TOF-MS. CISE showed strong and weak inhibition on α-amylase and α-glucosidase, with the IC50 of 27.2 and 2.3 µg/mL, respectively. The inhibition modes of CISE against α-amylase and α-glucosidase were mixed-type and non-competitive type, respectively. Epicatechin gallate noncompetitively inhibited α-amylase, α-glucosidase and dipeptidyl peptidase IV (DPP-IV). Analysis by ultraviolet-visible spectroscopy, fluorescence spectroscopy and circular dichroism suggested that flavonoids altered the hydrophobicity and microenvironment of these enzymes. CISE decreased the starch bioavailability by reducing the enzymatic hydrolysis rate and increasing the fraction of undigested starch. The extract reduced the rapidly digestible starch and increased the resistant starch after incorporation into A-, B- or C- crystallinity starch. Thus, the chestnut inner skin is a useful resource for regulating postprandial blood sugar level.

The influence of starch structure and anthocyanin content on the digestibility of Thai pigmented rice.

Starch digestibility and polyphenol content were investigated in six (white, red and purple) Thai rice varieties. Total phenolic content (TPC), total anthocyanin content (TAC), amylose content, gelatinization parameters and in vitro digestibility were determined. Purple and red rice varieties were found to have the highest levels of TPC, TAC and amylose content. TAC was not detected in white rice, while purple rice had the highest values. Gelatinization parameters were determined using differential scanning calorimetry. Red rice (Sung Yod) showed the highest gelatinization enthalpy. Non-pigmented rice (Hom Mali) in both purified starch and flour showed the highest starch digestibility, with a total starch digestibility of 76.85% and a digestion rate of 0.25 min-1. In contrast pigmented rice varieties showed lower starch digestibility. These results suggest that pigmented rice varieties are a source of phenolics and anthocyanin and also a possible good source of low digestible starch to develop as functional food products.

The hepatic-targeted, resveratrol loaded nanoparticles for relief of high fat diet-induced nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the early stage of many metabolic syndromes. The intervention of NAFLD can prevent its further development into severe metabolic syndromes. Given the inefficiency and side effects of chemical drugs for treating NAFLD, the hepatic-targeted nanocarriers loaded with bioactive compounds may offer a more effective and acceptable strategy for eliminating NAFLD. Here we developed hepatic-targeted oxidized starch-lysozyme (OSL) nanocarriers to specifically deliver resveratrol (Res) to liver tissue in order to maximize its therapeutic efficiency. The hepatic targeting was achieved using covalently conjugated galactose (Gal), which is recognized by the asialoglycoprotein receptors specifically expressed in hepatocytes. In steatotic HepG2 cell model, treatment with hepatic-targeted Gal-OSL/Res nanocarriers enhanced the cellular Res uptake and anti-lipogenesis capabilities, and effectively decreased triglyceride accumulation by modulating AMP-activated protein kinase (AMPK)/silent information regulation 2 homolog 1(SIRT1)/fatty acid synthase (FAS)/sterol regulatory element-binding protein-1c (SREBP1c) signaling pathway. In mice, Gal-OSL increased Res delivery into liver tissues and increased their hepatic effective concentration in liver. Most importantly, Gal-OSL/Res nanocarriers effectively reversed NAFLD and recovered hepatic insulin sensitivity of NAFLD mice to the healthy state. Furthermore, Gal-OSL/Res efficiently ameliorated lipid deposition and insulin resistance by modulating AMPK/SIRT1/FAS/SREBP1c signaling pathway and downregulated insulin receptor substrate-1 (IRS-1) phosphorylation at serine 307 in liver. These findings suggested that the hepatic-targeted Gal-OSL nanocarriers delivering Res could potentially serve as a safe and promising platform for NAFLD and other liver related diseases.

Structural, physicochemical, and digestibility properties of starch-soybean peptide complex subjected to heat moisture treatment.

Interactions among food components during food processing play important role in starch digestibility. The objective of this study was to investigate the effects of heat moisture treatment on the structural, physicochemical, and digestibility properties of starch-soybean peptide complexes. Corn and potato starch mixed with different amounts of soybean peptide were subjected to heat moisture treatment. The addition of soybean peptide increased pasting temperature, while decreased peak viscosity and swelling power in both starch samples under heat moisture treatment. Thermal analysis showed that soybean peptide retarded starch gelatinization, and heat moisture treatment contributed to a more stable crystalline structure. Lower RDS contents and higher RS contents were associated with higher soybean peptide amounts. Potato starch was more sensitive to heat moisture treatment than corn starch. The results will enrich the interaction theory between starch and protein, and will be important for the development of carbohydrate-restricted diet and protein-based functional foods.

Effect of iron and folic acid fortification on in vitro bioavailability and starch hydrolysis in ready-to-eat parboiled rice.

Iron (Fe) and folic acid (FA) fortified parboiled rice was produced by applying 'brown rice parboiling' method. The effect of milling and the effectiveness of fortification were tested in relation to the amount of bioaccessible and bioavailable form of Fe and FA. An in vitro starch hydrolysis assay was employed to assess the effect on simulated glycaemic index (GI). The % bioaccessiblity of Fe and FA in the unmilled fortified rice were in the range of 57.6-65.8%, and 55.1-91.9%, respectively. The % bioavailability in the unfortified parboiled rice was negligible as compared to Fe (14.7-32.1%) and FA (13.5-27.5%) fortified rice. The GI of unfortified and fortified parboiled rice samples was in the range of 56-69, which was lower than the raw rice. The results demonstrated that this approach can be a novel and rapid method to produce micronutrient enhanced ready-to-eat rice.

Resistant starch formation through intrahelical V-complexes between polymeric proanthocyanidins and amylose.

Reducing starch digestibility can significantly benefit efforts to combat obesity and associated chronic diseases. Polymeric proanthocyanidins (PA) form complexes with starch via unknown mechanisms, resulting in dramatically decreased starch digestibility. We hypothesized that V-type complexes are involved in these interactions. Sorghum derived PA was complexed with amylose, amylopectin, and granular maize starches in regular and deuterated solvents, and structural properties and in vitro digestibility of the complexes investigated. Based on iodine binding, X-ray diffraction patterns, crystallinity, and thermal properties, we demonstrated, for the first time, that type II semi-crystalline V-complexes are formed between amylose and PA. Furthermore, suppression of H-bonding led to amorphous complexes, suggesting extensive H-bonding facilitate and/or stabilize the V-complexes. We speculate that the complexation involves inclusion of B-rings of the PA units into the amylose helical cavity. The V-complex formation significantly increased resistant starch in gelatinized normal starch and pure amylose (by 35-45%), indicating likely physiological benefits.

Starch-based dual amphiphilic graft copolymer as a new pH-sensitive maltidrug co-delivery system.

Amphiphilic dual graft copolymer composed of starch (St) as main chain, poly caprolactone (PCL) and poly (2-ethyl 2-oxazoline) (POX) as hydrophobic and hydrophilic side chains were synthesized and characterized successfully. Firstly, polycaprolactone with propargyl end group prepared and attached to the surface of azido starch (St-N3) which was prepared through incomplete azidation of starch tosylate, by click chemistry reaction. Thereafter, the polymerization of 2-ethyl-2-oxazoline initiated from the remaining tosyl groups of PCL-starch. Finally, polymerization of POX quenched by doxorubicin (DOX) as anticancer drug as well as terminator and curcumin (Cur) physically loaded in to the obtained copolymer. Dual graft copolymer (PCL-St-POX) as the co-delivery system containing covalently conjugated doxorubicin and non-covalently loaded curcumin could be promising biocompatible system to achieve combination therapy. The SEM images showed that resulting copolymer exhibited sphere-shaped particles ranging from 50 to 100 nm which is completely different from ungrafted starch. The release studies also revealed that obtained copolymer is pH-sensitive and the release rate was more favorable at acidic pH (tumor cells) than neutral pH (normal cells) for both drugs.

Starch and antioxidant compound release during in vitro gastrointestinal digestion of gluten-free pasta.

The microstructure of cooked gluten-free pasta depends on the ingredients used, and this microstructure affects the starch hydrolysis (SH), the release of phenolic compounds (PC) and their antioxidant capacity (AC). The aim of this study was to evaluate the SD and bioaccessibility of PC during in vitro gastrointestinal digestion of gluten-free pasta and its relationship with the microstructure. The highest SH was during the intestinal phase (≈60%), but pasta with the highest content of unripe plantain and chickpea presented the lowest release of PC (≈60%). The insoluble dietary fibre could be responsible (≈12.5%) for these effects. The cooked pasta showed high AC in the intestinal phase. Regions with gelatinized starch granules in a less dense protein network and other regions with intact or swollen granules surrounded by a protein network were observed. The starch digestion and bioaccessibility of PC were related to the structure of the matrix.

Modulation of Starch Digestibility in Breakfast Cereals Consumed by Subjects with Metabolic Risk: Impact on Markers of Oxidative Stress and Inflammation during Fasting and the Postprandial Period.

SCOPE: Decreasing postprandial glycaemic excursions may have a beneficial effect on inflammatory and oxidative stress profiles. In this study, we investigated the impact of carbohydrate digestibility modulation per se, as a means of reducing the glycaemic response, on metabolic and inflammatory responses in subjects with metabolic risk factors. METHODS AND RESULTS: Twenty healthy subjects with metabolic risk consumed a cereal product either high in Slowly Digestible Starch (HSDS) or low in SDS (LSDS) at breakfast daily for 3 weeks, in a cross-over design. Following each 3-week session, postprandial glycaemia, insulinaemia, the lipid profile, inflammation and oxidative stress markers were assessed and compared to those induced by ingestion of a glucose solution (as a reference). The 2-h glycaemic and insulinaemic responses were significantly lower following the HSDS breakfast compared with the LSDS breakfast or glucose. No significant differences between the products were observed in terms of the lipid profile, C-reactive protein, IL-6 and tumour necrosis factor alpha. We observed a slight increase in fasting lipid peroxidation markers, including an increase in plasma malondialdehyde (MDA) and a decrease in whole blood glutathione (GSH), without significant alteration of urinary F2-isoprostanes or plasma glutathione peroxidase (GPx) activity. CONCLUSION: Consumption of HSDS products for 3 weeks significantly altered both postprandial glycaemia and insulinaemia, but was not sufficient to modify the inflammatory profile. Consumption of both cereal products was associated with a slightly higher fasting oxidative stress profile.

The nutritional property of endosperm starch and its contribution to the health benefits of whole grain foods.

Purported health benefits of whole grain foods in lowering risk of obesity, type 2 diabetes, cardiovascular disease, and cancer are supported by epidemiological studies and scientific researches. Bioactive components including dietary fibers, phytochemicals, and various micronutrients present in the bran and germ are commonly considered as the basis for such benefits. Endosperm starch, as the major constituent of whole grains providing glucose to the body, has been less investigated regarding its nutritional property and contribution to the value of whole grain foods. Nutritional quality of starch is associated with its rate of digestion and glucose absorption. In whole grain foods, starch digestion and glucose delivery may vary depending on the form in which the food is delivered, some with starch being rapidly and others slowly digested. Furthermore, there are other inherent factors in whole grain products, such as phenolic compounds and dietary fibers, that may moderate glycemic profiles. A good understanding of the nutritional properties of whole grain starch is important to the development of food processing technologies to maximize their health benefits.

Experimental Design for Determination of Effects of Superdisintegrant Combinations on Liquisolid System Properties.

The preparation of liquisolid systems presents a promising and innovative possibility for enhancing dissolution profiles and improving the bioavailability of poorly soluble drugs. This study aims to evaluate the differences in the properties of liquisolid systems containing combinations of 3 commercially used superdisintegrants (sodium starch glycolate, crospovidone, and croscarmellose sodium). Multiple regression models and contour plots were used to study how the amount and the type of superdisintegrant used affected the quality parameters of liquisolid tablets. The results revealed that an increased amount of crospovidone in the mixture improves disintegration and wetting time and enhances drug release from the prepared liquisolid tablets. Moreover, it was observed that a binary blend of crospovidone and sodium starch glycolate improved tablet disintegration. Considering the obtained results, it could be stated that crospovidone showed the best properties to be used as superdisintegrant for the preparation of liquisolid systems containing rosuvastatin.

Presence of starch enhances in vitro biodegradation and biocompatibility of a gentamicin delivery formulation.

The effect of α-amylase degradation on the release of gentamicin from starch-conjugated chitosan microparticles was investigated up to 60 days. Scanning electron microscopic observations showed an increase in the porosity and surface roughness of the microparticles as well as reduced diameters. This was confirmed by 67% weight loss of the microparticles in the presence of α-amylase. Over time, a highly porous matrix was obtained leading to increased permeability and increased water uptake with possible diffusion of gentamicin. Indeed, a faster release of gentamicin was observed with α-amylase. Starch-conjugated chitosan particles are non-toxic and highly biocompatible for an osteoblast (SaOs-2) and fibroblast (L929) cell line as well as adipose-derived stem cells. When differently produced starch-conjugated chitosan particles were tested, their cytotoxic effect on SaOs-2 cells was found to be dependent on the crosslinking agent and on the amount of starch used.

Iron uptake and ferrokinetics in healthy male subjects of an iron-based oral phosphate binder (SBR759) labeled with the stable isotope (58)Fe.

SBR759 is a novel polynuclear iron(III) oxide-hydroxide starch·sucrose·carbonate complex being developed for oral use in chronic kidney disease (CKD) patients with hyperphosphatemia on hemodialysis. SBR759 binds inorganic phosphate released by food uptake and digestion in the gastro-intestinal tract increasing the fecal excretion of phosphate with concomitant reduction of serum phosphate concentrations. Considering the high content of ∼20% w/w covalently bound iron in SBR759 and expected chronic administration to patients, absorption of small amounts of iron released from the drug substance could result in potential iron overload and toxicity. In a mechanistic iron uptake study, 12 healthy male subjects (receiving comparable low phosphorus-containing meal typical for CKD patients: ≤1000 mg phosphate per day) were treated with 12 g (divided in 3 × 4 g) of stable (58)Fe isotope-labeled SBR759. The ferrokinetics of [(58)Fe]SBR759-related total iron was followed in blood (over 3 weeks) and in plasma (over 26 hours) by analyzing with high precision the isotope ratios of the natural iron isotopes (58)Fe, (57)Fe, (56)Fe and (54)Fe by multi-collector inductively coupled mass spectrometry (MC-ICP-MS). Three weeks following dosing, the subjects cumulatively absorbed on average 7.8 ± 3.2 mg (3.8-13.9 mg) iron corresponding to 0.30 ± 0.12% (0.15-0.54%) SBR759-related iron which amounts to approx. 5-fold the basal daily iron absorption of 1-2 mg in humans. SBR759 was well-tolerated and there was no serious adverse event and no clinically significant changes in the iron indices hemoglobin, hematocrit, ferritin concentration and transferrin saturation.

Inhibition of starch digestion by the green tea polyphenol, (-)-epigallocatechin-3-gallate.

SCOPE: Green tea has been shown to ameliorate symptoms of metabolic syndrome in vivo. The effects could be due, in part, to modulation of postprandial blood glucose levels. METHODS AND RESULTS: We examined the effect of coadministration of (-)-epigallocatechin-3-gallate (EGCG, 100 mg/kg, i.g.) on blood glucose levels following oral administration of common corn starch (CCS), maltose, sucrose, or glucose to fasted CF-1 mice. We found that cotreatment with EGCG significantly reduced postprandial blood glucose levels after administration of CCS compared to control mice (50 and 20% reduction in peak blood glucose levels and blood glucose area under the curve, respectively). EGCG had no effect on postprandial blood glucose following administration of maltose or glucose, suggesting that EGCG may modulate amylase-mediated starch digestion. In vitro, EGCG noncompetitively inhibited pancreatic amylase activity by 34% at 20 µM. No significant change was induced in the expression of two small intestinal glucose transporters (GLUT2 and SGLT1). CONCLUSIONS: Our results suggest that EGCG acutely reduces postprandial blood glucose levels in mice when coadministered with CCS and this may be due in part to inhibition of α-amylase. The relatively low effective dose of EGCG makes a compelling case for studies in human subjects.

Assam Bora rice starch based biocompatible mucoadhesive microsphere for targeted delivery of 5-fluorouracil in colorectal cancer.

The aim of this study was to develop novel colon targeted mucoadhesive microspheres (MAMs) for site specific delivery of 5-fluorouracil (5-FU) to colon without the drug being released in the stomach or small intestine. MAMs were prepared using Assam Bora rice starch, a natural mucoadhesive polymer, by a double emulsion solvent evaporation method. The microspheres were characterized for their shape, size, surface morphology, size distribution, incorporation efficiency, and in vitro and in vivo drug release studies. The release study confirmed the insignificant release of 5-FU in physiological condition of stomach and small intestine and major drug release in the cecal content. In vivo release study of the optimized MAMs was compared with immediate release (IR) 5-FU. 5-FU was distributed predominantly in the upper GI tract from the IR, whereas 5-FU was distributed primarily to the lower part of the GI tract from the MAM formulation. Enhanced levels of liver enzymes were found in animals given IR 5-FU as well as augmented levels of serum albumin, creatinine, leucocytopenia and thrombocytopenia was also observed. Thus to sum up, it can be appropriately established that the 5-FU release pattern from MAMs exhibits slow and extended release over longer periods of time with reduced systemic side effects.

Slowly and rapidly digestible starchy foods can elicit a similar glycemic response because of differential tissue glucose uptake in healthy men.

BACKGROUND: Previously we observed that the consumption of pasta and bread resulted in a similar glycemic response, despite a slower intestinal influx rate of glucose from the pasta. Underlying mechanisms of this effect were not clear. OBJECTIVE: The objective was to investigate the differences in glucose kinetics and hormonal response after consumption of products with slow and rapid in vivo starch digestibility but with a similar glycemic response. DESIGN: Ten healthy male volunteers participated in a crossover study and consumed (13)C-enriched wheat bread or pasta while receiving a primed-continuous D-[6,6-(2)H(2)]glucose infusion. The dual-isotope technique enabled calculation of the following glucose kinetics: rate of appearance of exogenous glucose (RaE), endogenous glucose production, and glucose clearance rate (GCR). In addition, postprandial plasma concentrations of glucose, insulin, glucagon, and glucose-dependent insulinotropic polypeptide (GIP) were analyzed. RESULTS: GIP concentrations after pasta consumption were lower than after bread consumption and strongly correlated with the RaE (r = 0.82, P < 0.01). The insulin response was also lower after pasta consumption (P < 0.01). In accordance with the low insulin response, the GCR was lower after pasta consumption, which explained the high glycemic response despite a low RaE. CONCLUSIONS: Slower intestinal uptake of glucose from a starchy food product can result in lower postprandial insulin and GIP concentrations, but not necessarily in a lower glycemic response, because of a slower GCR. Even without being able to reduce postprandial glycemia, products with slowly digestible starch can have beneficial long-term effects. These types of starchy products cannot be identified by using the glycemic index and therefore another classification system may be necessary. This trial was registered at controlled-trials.com as ISRCTN42106325.

Feasibility of Assam Bora rice starch as a compression coat of 5-fluorouracil core tablet for colorectal cancer.

The colon and rectum are the parts of digestive system of human beings. Cancer affecting either of these organs may be called colorectal cancers. Conventional cancer chemotherapy is not very effective for treatment of colorectal cancer, as the drug molecule does not reach the target site at therapeutic concentration, on the other side they produces sever systemic toxic effect. Aim of this study was to develop a novel colon targeted Assam Bora rice starch compression coated tablet for site specific delivery of 5-FU to the colon without the drug being released in stomach or small intestine. Core tablet of 5-FU was prepared using microcrystalline cellulose (MCC) and spray dried lactose by direct compression method. The in vitro drug release study in different physiological environment confirmed insignificant release of 5-FU in physiological condition of stomach and small intestine further fast and major drug release in caecal content. In vivo drug absorption of optimized formulation was performed in order to establish its targeting potential in colon. It is concluded from the present study that Assam Bora rice starch can be used as a drug carrier for an effective colon targeted delivery system for drugs effective against the large intestine resident disease condition.

Influence of resistant starch alone or combined with wheat bran on gastric emptying and protein digestion in healthy volunteers.

OBJECTIVE: Resistant starch (RS) is not absorbed in the small intestine, but is partly fermented in the colon and may positively influence putative risk factors for colon cancer. The purpose of the study was to investigate the influence of RS type 3 (retrograded amylose) alone or combined with wheat bran on gastric emptying (GE) and protein assimilation. MATERIAL AND METHODS: GE and protein assimilation were investigated by means of breath-test technology in 20 healthy volunteers who were randomly divided into two groups, each subject performing two tests. In each test, the volunteers received a labelled test meal either as such or in combination with, respectively, 15 g RS3 or 15 g RS3 combined with 6 g wheat bran (WB). Breath samples were collected during the 6 h after administration of a test meal containing egg proteins, intrinsically labelled with (13)C-leucine, to measure protein digestion and sodium-(14)C-octanoate for measurement of GE. RESULTS: Intake of RS3 +WB did not influence GE time compared to baseline values, whereas intake of RS3 seemed to hasten GE: from 93 +/- 32 min to 55 +/- 15 min (p = 0.012). The overall protein assimilation parameters at baseline were not significantly different from those obtained after simultaneous intake of RS3 +WB, whereas RS3 significantly shortened the time of maximum excretion compared to baseline, but the extent of protein digestion after RS3 intake was not affected (12.54 +/- 3.60% versus 13.43 +/- 3.40%). CONCLUSIONS: The presence of RS3 alone or in combination with wheat bran demonstrates that there are no adverse effects on protein digestion and no influence on the nitrogen supply to the colon.