Calculation of the intake of three intense sweeteners in young insulin-dependent diabetics.

In 1994, European Directive 94/35/CE authorised the use as food additives of five intense sweeteners for which Acceptable Daily Intakes (ADI) were established. The same directive stipulated that member states should organise a monitoring system to determine the consumption of these substances. Diabetic children are normally considered to constitute a group with a high consumption of sweeteners (European Commission, 1998. Report on Methodology for the Monitoring of Food Additives Intake across the European Union. Report of the Scientific Cooperation, Task 4.2 SCOOP/INT/REPORT/2. European Commission Directorate General III, Brussels.). A stepwise approach to the food additive intake in the general population had shown that three of the five authorised intense sweeteners (aspartame, saccharin and acesulfame K) are used at particularly high levels in sugar-free foods and are also very commonly utilised as table-top sweeteners. This paper presents the results of a food intake survey conducted in a group of French, insulin-dependent children in 1997, aimed at estimating the Theoretical Maximum Daily Intake (TMDI) for these three sweeteners and comparing this with the relevant ADI values. A 5-day diary questionnaire was used to estimate the intake of sugar-free, artificially sweetened foods and table-top sweeteners. When assessing the intake of each additive, all sugar-free products were assumed to be sweetened using a single sweetener at its maximum authorised level. This study was performed in five age groups, and based on the mean and 97.5th percentile of the distribution of consumption, demonstrated that it was unlikely that total exposure could rise above the ADI.     

Improving the prediction of exceptionally poor tableting performance: an investigation into Hiestand's "special case"

The mechanical and flow properties of selected pharmaceutical powdered excipients and drug substances were evaluated to investigate their behavior as extremely poor tableting, or "special case," materials. The compaction stress, dynamic indentation hardness, and tensile strength of compacts compressed to 15% porosity and their powder's effective angle of internal friction were measured using the tableting indices technology and a simple shear cell, respectively. It has been previously demonstrated that compacts of special case materials exhibit a dynamic indentation hardness greater than the stress required to form the compact under slow compression conditions. In addition, new data suggest that special case materials also exhibit low compact dynamic indentation hardness, low compact tensile strength, and low powder effective angle of internal friction. These findings support the theory that the particles of such materials preferentially rearrange rather than deform under compressive conditions because bonding between them is weak. The added special case indicator measurements can be used to clearly identify exceptionally poor tableting powders during the selection of components for solid dosage formulations. Careful consideration of the data will provide guidance to the proper use of the bonding indices equations.     

Taste masking analysis in pharmaceutical formulation development using an electronic tongue

The purpose of this study is to assess the feasibility for taste masking and comparison of taste intensity during formulation development using a multichannel taste sensor system (e-Tongue). Seven taste sensors used in the e-Tongue were cross-selective for five basic tastes while having different sensitivity or responsibility for different tastes. Each of the individual sensors concurrently contributes to the detection of most substances in a complicated sample through the different electronic output. Taste-masking efficiency was evaluated using quinine as a bitter model compound and a sweetener, acesulfame K, as a bitterness inhibitor. In a 0.2 mM quinine solution, the group distance obtained from e-Tongue analysis was reduced with increasing concentration of acesulfame K. This result suggests that the sensors could detect the inhibition of bitterness by a sweetener and could be used for optimization of the sweetener level in a liquid formulation. In addition, the bitterness inhibition of quinine by using other known taste-masking excipients including sodium acetate, NaCl, Prosweet^® flavor, and Debittering^® powder or soft drinks could be detected by the e-Tongue. These results further suggest that the e-Tongue should be useful in a taste-masking evaluation study on selecting appropriate taste-masking excipients for a solution formulation or a reconstitution vehicle for a drug-in-bottle formulation. In another study, the intensity of the taste for several drug substances known to be bitter was compared using the e-Tongue. It was found that the group distance was 695 for prednisolone and 686 for quinine, which is much higher than that of caffeine (102). These results indicate that the taste of prednisolone and quinine is stronger or more bitter than that of caffeine as expected. Based on the group distance, the relative intensity of bitterness for these compounds could be ranked in the following order: ranitidine HCl > prednisolone Na > quinine HClphenylthiourea > paracetamol  sucrose octaacetate > caffeine. In conclusion, the multichannel taste sensor or e-Tongue may be a useful tool to evaluate taste-masking efficiency for solution formulations and to compare bitterness intensity of formulations and drug substances during pharmaceutical product development.     

Utilization of date syrup as a tablet binder,comparative study

The aim of this study was to investigate the possibility of using dates syrup as a tablet binder. Dates syrup (40%, 50%, 60% w/w dates syrup:water) was utilized for the granulation of sodium bicarbonate and calcium carbonate as examples for water-soluble and water-insoluble materials; correspondingly. Those two materials represent examples of bulky drugs as well. Starch paste (10% w/w starch in water) and sucrose syrup (50% w/w sucrose in water), the well-known tablet binders, were used in the granulation of the same materials for the sake of comparison. The granulations were evaluated with regard to particle size and particle size distribution, granule strength, bulk density, flowability, moisture content and compression behavior. In addition, tablets prepared and evaluated from these granules. Taste and flavor of the prepared tablet have been tested by seven healthy volunteers. Within the scope of this work, dates syrup showed excellent properties as a tablet binder in comparison to starch paste or sucrose syrup for the granulation of both water-soluble and water-insoluble materials. Also, better flavoring and masking taste have been noticed from an evaluation by human volunteers demonstrating the usefulness of the date syrup as sweetener and flavoring the tablets in addition to its use as binder.     

Use of aspartame by apparently healthy children and adolescents.

This study was conducted to determine the effects and the differences, if any, resulting from the ingestion of aspartame (sweetener) versus sucrose. A 13-wk, double-blind study was conducted using 126 apparently healthy children and adolescents as panelists. Individuals were randomly assigned in a double-blind design to aspartame or sucrose in each of five age groups; dosage levels were assigned according to age and weight groups. Physical examinations and special eye examinations were performed at the beginning and end of the study. Other parameters determined including laboratory tests of liver and renal function, hematologic status, and plasma levels of phenylalanine and tyrosine. Clinically significant differences in laboratory parameters measured could not be demonstrated; all mean values were within normal limits. No unusual findings were observed in phenylalanine or tyrosine levels. All phenylpyruvic acid and methanol determinations were negative. No important physical changes occurred, and no product-related side effects were reported.     

Commercial pregelatinized starches: ability to settle and rheological evaluation

The ability to settle and the tribological properties of three samples of pregelatinized starch widely available commercially were investigated with reference to their technological implications. In particular, we evaluated the influence of storage conditions, storage time, moisture content, equipment, handling, and mechanical treatment on the apparent volume, poured density and tapped density, as well as on tests of flow parameters such as basic flowability energy. The results obtained highlight the fact that the technologically relevant behaviour of pregelatinized starches in terms of apparent volume and tribological properties may be influenced not only by relative humidity (RH%) conditions, but also by common pharmaceutical operating practices. In particular, previous mechanical treatment can lead to statistically different behaviour in tests of ability to settle according to pharmacopoeial specifications, depending on both RH% conditioning and the amount of powder, although the materials under investigation all conform to the respective monograph in the Pharmacopoeia. All these aspects are of special interest with regard to the various pharmaceutical formulations which include pregelatinized starch, both on an industrial scale and in small-scale production.     

Caffeine intensifies taste of certain sweeteners: role of adenosine receptor

Caffeine, a potent antagonist of adenosine receptors, potentiates the taste of some but not all sweeteners. It significantly enhances the taste of acesulfam-K, neohesperidin dihydrochalcone, d-tryptophan, thaumatin, stevioside, and sodium saccharin. Adenosine reverses the enhancement. Caffeine has no effect on aspartame, sucrose, fructose, and calcium cyclamate. These results suggest that the inhibitory A1 adenosine receptor plays an important local role in modulating the taste intensity of certain sweeteners and that several transduction mechanisms mediate sweet taste.     

Aspartame: Scientific Evaluation in the Postmarketing Period

Prior to marketing, the safety of the high-intensity sweetener aspartame for its intended uses as a sweetener and flavor enhancer was demonstrated by the results of over 100 scientific studies in animals and humans. In the postmarketing period, the safety of aspartame was further evaluated through extensive monitoring of intake, postmarketing surveillance of anecdotal reports of alleged health effects, and additional research to evaluate these anecdotal reports and other scientific issues. The results of the extensive intake evaluation in the United States, which was done over an 8-year period, and the results of studies done in other countries demonstrated intakes which were well below the acceptable daily intakes set by the FDA and regulatory bodies in other countries, as well as the Joint FAO/WHO Expert Committee on Food Additives. Evaluation of the anecdotal reports of adverse health effects, the first such system for a food additive, revealed that the reported effects were generally mild and also common in the general population and that there was no consistent or unique pattern of symptoms that could be causally linked to consumption of aspartame. Finally, the results of the extensive scientific research done to evaluate these allegations did not show a causal relationship between aspartame and adverse effects. Thus, the weight of scientific evidence confirms that, even in amounts many times what people typically consume, aspartame is safe for its intended uses as a sweetener and flavor enhancer.     

Mechanical property anisotropy of pharmaceutical excipient compacts

The mechanical property anisotropy of compacts made from six commercially available pharmaceutical excipient powders was evaluated. Uni-axially compressed cubic compacts of each excipient were subjected to pendulum impact testing and transverse tensile testing in several orientations. The pendulum impact test was used to measure the dynamic indentation hardness of each compact face (side, top, and bottom). Transverse tensile testing was utilized to determine the compact axial and radial tensile strength values. The indentation hardness (top>bottom>side) and tensile strength tests (radial>axial) revealed mechanical property anisotropy in all the compacts. The extent of mechanical property anisotropy was quantified by using dimensionless ratios and was found to be significantly different for each material. In general, compacts with a higher degree of compact mechanical anisotropy also exhibited a higher brittle fracture index (BFI). This suggests that the macroscopic flaws intentionally made in the compact for the BFI measurement were similar to the flaws induced in highly anisotropic materials during uni-axial compaction. These results are consistent with the practical observation that brittle materials are more likely to exhibit failure in a plane normal to the compaction axis, i.e. experience tablet capping and lamination phenomena.     

First European conference on aspartame: putting safety and benefits into perspective. Synopsis of presentations and conclusions.

A Conference was held in Paris in 2006 to review the safety and benefits arising from the replacement of sucrose with the intense sweetener aspartame. The intakes of aspartame are only about 10% of the acceptable daily intake, even by high consumers, so that the safety margin is about 3 orders of magnitude. The safety of aspartame was confirmed in the EFSA Opinion of a recent controversial rodent cancer bioassay. There is increasing evidence that even modest reductions in the intake of calories can reduce the risk factors associated with a number of diseases, such as diabetes and cardiovascular disease. A key issue addressed at the conference was whether the replacement of sucrose with aspartame could result in a prolonged decrease in calorie intake that was of similar magnitude to that necessary to produce a health benefit. A recent meta-analysis of published data showed that an adequate, prolonged weight reduction could be achieved with aspartame. It was recognised that risk assessment alone gave an unbalanced impression to regulators and consumers, and that in the future quantitative risk-benefit analyses should be able to provide more comprehensive advice.     

Dietary estimated intake of intense sweeteners by Italian teenagers. Present levels and projections derived from the INRAN-RM-2001 food survey.

In a previous study, Italian female teenagers regular consumers of sugar free soft drinks and table-top sweeteners were suggested to have a higher intake of intense sweeteners than other teenagers. A food frequency questionnaire designed to identify adolescents who were high consumers of these food products was filled in by a randomly extracted sample of teenagers (n=3982) living in the District of Rome (Italy) in year 2000. A consumer survey was then carried out in a randomly extracted sub-sample of males and females and in all females who reported high consumption of sugar-free soft drinks and/or table-top sweeteners. A total of 362 subjects participated in a detailed food survey by recording, at brand level, all foods and beverages ingested over 12 days. For each sugar-free product, producers provided the concentration of intense sweeteners (saccharin, aspartame, acesulfame K and cyclamate). No intake in excess of the Acceptable Daily Intake (ADI) was observed. Also medicines and supplements were taken into account and these did not result in a large impact on chronic exposure to intense sweeteners. The intake levels did not exceed the ADI even under a worst case scenario which was performed to take into consideration a hypothetical future substitution of all regular food products with their sugar-free version. It can be concluded that, with the observed current consumption patterns and occurrence levels, the risk of an excessive intake of intense sweeteners by Italian teenagers is extremely low.     

Serum methanol concentrations in rats and in men after a single dose of aspartame

Serum methanol concentrations were measured in rats and in humans given oral aspartame. The dose given to rats was the FDA's projected 99th percentile daily intake for humans, assuming aspartame were to replace all sucrose sweeteners in the diet (34 mg/kg). Four male adult volunteers each received 500 mg, equivalent to 6-8.7 mg/kg, which is approximately the FDA's estimate of mean daily human consumption. Both treatments caused a rise in serum methanol. In rats the mean peak value was 3.1 mg/litre 1 hr after administration; serum methanol returned to endogenous values 4 hr after treatment. In the men, the mean rise over endogenous values was 1.06 mg/litre after 45 min. Two hours after treatment, serum methanol had returned to basal levels. The temporary serum methanol increase showed peak values within the range of individual basal levels.     

Indentation Test for Free-Flowable Powder Excipients

Indentation of a sphere into nonconsolidated powder excipients is a suitable complementary method for the evaluation of flow properties of the free-flowable noncohesive powders. To use the standard penetrometry method to indentation of nonconsolidated powder layer by a glass sphere of 16 mm in diameter, the suitable geometry of the measurement container is required to prevent undesirable moving in a direction opposite to that in which the indenting sphere moves. Thus, the powder indentation by a sphere seems to be similar to indentation by the Brinell hardness tester. In this work, the depth of indentation was measured for five pharmaceutical powder excipients: sodium chloride, sodium citrate, potassium citrate, sorbitol, and boric acid with the three size fractions in the range of 0.315–0.630 mm. To express powder flowability, the uniform mass and/or volume flow rate from the 10-mm cylindrical outlet of the cylindrical testing hopper was used. The relationships between the powder flow rate and its bulk density and/or the different characteristics of indentation were modeled by using linear regression. Out of the indentation characteristics, the mass of indentation calculated as the multiple of the volume of indentation and the powder bulk density could be recommended to estimate the powder mass flow rate due to the linear regression with the coefficient of determination equal to 0.973 and the accuracy of 4.3%. In conclusion, the indentation by the sphere could be recommended as a quick simple method for the comparison of flow properties of the nonconsolidated, noncohesive powder excipients.     

Indentation test for free-flowable powder excipients

Indentation of a sphere into nonconsolidated powder excipients is a suitable complementary method for the evaluation of flow properties of the free-flowable noncohesive powders. To use the standard penetrometry method to indentation of nonconsolidated powder layer by a glass sphere of 16 mm in diameter, the suitable geometry of the measurement container is required to prevent undesirable moving in a direction opposite to that in which the indenting sphere moves. Thus, the powder indentation by a sphere seems to be similar to indentation by the Brinell hardness tester. In this work, the depth of indentation was measured for five pharmaceutical powder excipients: sodium chloride, sodium citrate, potassium citrate, sorbitol, and boric acid with the three size fractions in the range of 0.315-0.630 mm. To express powder flowability, the uniform mass and/or volume flow rate from the 10-mm cylindrical outlet of the cylindrical testing hopper was used. The relationships between the powder flow rate and its bulk density and/or the different characteristics of indentation were modeled by using linear regression. Out of the indentation characteristics, the mass of indentation calculated as the multiple of the volume of indentation and the powder bulk density could be recommended to estimate the powder mass flow rate due to the linear regression with the coefficient of determination equal to 0.973 and the accuracy of 4.3%. In conclusion, the indentation by the sphere could be recommended as a quick simple method for the comparison of flow properties of the nonconsolidated, noncohesive powder excipients.     

Improving Powder Flow Properties of a Cohesive Lactose Monohydrate Powder by Intensive Mechanical Dry Coating

The objective of this study was to improve the cohesive lactose powder flowability. A cohesive lactose monohydrate powder was processed in either a tumbling blender or an intensive mechanical processor with either magnesium stearate or fumed silica. No substantial changes in particle size were detected by laser diffraction following either treatment. The untreated lactose sample exhibited very poor powder flow. Only limited improvements in powder flowability were indicated after the tumbling blending, intensive mechanical processing with the fumed silica or without additives. However, the intensive mechanical processing of the lactose sample with magnesium stearate demonstrated exceptionally large increases in both poured and tapped density as well as notable improvements in all powder flowability indicators examined. Our findings support the use of intensive mechanical processing technique as an effective method to coat cohesive pharmaceutical powders with selected additives, modify the surface nature of the particles, reduce the interparticle cohesive forces and hence improve powder flowability. The subtle differences in powder flow behaviour of lactose samples between the untreated and tumbling blended powders with magnesium stearate were only detected by the powder rheometer using its dynamic mode, indicating its potential advantages over traditional powder flow characterisation approaches. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:969–981, 2010     

Detection of 10 sweeteners in various foods by liquid chromatography/tandem mass spectrometry

The analytical method for sweeteners in various food matrixes is very important for food quality control and regulation enforcement. A simple and rapid method for the simultaneous determination of 10 sweeteners [acesulfame potassium (ACS-K), aspartame (ASP), cyclamate (CYC), dulcin (DUL), glycyrrhizic acid (GA), neotame (NEO), neohesperidin dihydrochalcone (NHDC), saccharin (SAC), sucralose (SCL), and stevioside (STV)] in various foods by liquid chromatography/tandem mass chromatography (LC–MS/MS) was developed. The chromatographic separation was performed on a Phenomenex Luna Phenyl-Hexyl (5 μm, 4.6 mm × 150 mm) column with gradient elution of 10 mM ammonium acetate in water and 10 mM ammonium acetate in methanol. The recoveries of the 10 sweeteners were between 75% and 120%, and the coefficients of variation were less than 20%. The limits of quantification were 0.5 μg/kg for NHDC and SCL. For the other sweeteners, the limits of quantification were 0.1 μg/kg. Compared to the traditional high-performance liquid chromatography method, the LC–MS/MS method could provide better sensitivity, higher throughput, enhanced specificity, and more sweeteners analyzed in a single run. The samples included 27 beverages (16 alcoholic and 11 nonalcoholic beverages) and 15 pickled foods (1 pickled pepper, 3 candies, and 11 candied fruits). Two remanufactured wines were found to contain 7.2, 8.5 μg/g SAC and 126.5, 123 μg/g CYC, respectively. ACS-K, ASP, SCL, and NEO were detected in five beverages and drinks. The pickled peppers and candied fruits were found to contain SAC, GA, CYC, ASP, STV, NEO, and ACS-K. The wine with sweeteners detected was remanufactured wine, not naturally fermented wine. Therefore, the ingredient label for the sweeteners of remanufactured wine should be regulated by the proper authority for inspection of sweeteners.     

The metabolism of intense sweeteners

Three organic acids (saccharin, acesulfame-K and cyclamate) are used or have been used extensively as intense sweeteners. Once absorbed from the gut they are eliminated, largely in the urine, without undergoing metabolism. Early studies using radiolabelled saccharin indicated the existence of limited metabolism, but this was not confirmed by later more extensive studies using highly purified compound. Metabolism could not be induced by a variety of pretreatments. Following an initial report of the presence of traces of cyclohexylamine in the urines of subjects given cyclamate, it was shown that chronic administration of the sweetener caused the induction of extensive metabolism. The metabolism, which showed wide inter- and intra-individual variability was performed the gut microflora. The peptide sweeteners (aspartame and thaumatin) are metabolized to their constituent amino acids in the gastro intestinal tract, prior to absorption. As such they are incorporated into normal intermediary metabolism and their low-calorie applications derive from their intense sweetness.