Development and Evaluation of Artemether Taste Masked Rapid Disintegrating Tablets with Improved Dissolution Using Solid Dispersion Technique

The purpose of this research was to mask the intensely bitter taste of artemether (ARM) and to formulate a rapid-disintegrating tablet (RDT) of the taste-masked drug. Taste masking was done by solid dispersion with mono amino glycyrrhyzinate pentahydrate (GLY) by solvent evaporation method. To characterize and formulate taste masked rapid disintegrating tablets (RDTs) of ARM, the 1:1M solid dispersion was selected based on bitterness score. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD) were performed to identify the physicochemical interaction between drug and carrier, hence its effect on dissolution. RDTs were evaluated for weight variation, disintegration time, hardness and friability. In vitro drug release studies were performed for RDTs at pH 1.2 and 6.8. Bitterness score was evaluated using mini-column method and compared with gustatory sensation test. FTIR spectroscopy and DSC showed no interaction while XRPD showed amorphization of ARM in GLY solid dispersion. RDTs prepared using solid dispersion, (RDT3), showed faster disintegration (within 28 s) and complete bitter taste masking of ARM. In addition, RDT3 exhibited better dissolution profile at both pH 1.2 and 6.8, than RDTs prepared from pure ARM (RDT5). Taste evaluation of RDTs in human volunteers rated tasteless with a score of 0 to RDT3 and 3 to RDT5. Mini-column revealed that RDT5 showed increase in number of persons who sensed bitterness with increased amount of ARM release while RDT3 sensed no bitterness. Thus, results conclusively demonstrated successful masking of taste and rapid disintegration of the formulated tablets in the oral cavity with improved dissolution.     

Formulation and Evaluation of Taste Masked Oral Reconstitutable Suspension of Primaquine Phosphate

The purpose of this research was to mask the intensely bitter taste of primaquine phosphate (PRM) and to formulate suspension powder (cachets) of the taste masked drug. Taste masking was done using beta-cyclodextrin. To characterize and formulate taste masked cachets of PRM, the 1:25 M physical mixture was selected based on bitterness score. Phase solubility studies, fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD) were performed to identify the physicochemical interaction between drug and carrier, hence its effect on dissolution. Cachets were evaluated for angle of repose, sedimentation characterization and pH. In vitro drug release studies for physical mixture and kneaded system were performed at pH, 1.2 and 6.8. Bitterness score was evaluated using gustatory sensation test. Phase solubility studies showed weak interaction between PRM and CD. The FTIR, DSC and XRPD studies indicated inclusion complexation in physical mixture and kneaded system. In addition, kneaded system and physical mixture exhibited better drug release at pH 1.2 and negligible effect at pH 6.8. Cachets prepared using physical mixture, (DS24), showed complete bitter taste masking and easy redispersibility. Taste evaluation of cachets in human volunteers rated tasteless with a score of 0 to DS24 and 3 to DS25. Thus, results conclusively demonstrated successful taste masking and formulation of cachets with taste masked drug.     

Formulation Design and Optimization of Novel Taste Masked Mouth-Dissolving Tablets of Tramadol Having Adequate Mechanical Strength

The purpose of this work was to develop novel taste masked mouth-dissolving tablets of tramadol that overcomes principle drawback of such formulation which is inadequate mechanical strength. Tramadol is an opioid analgesic used for the treatment of moderate to severe pain. Mouth-dissolving tablets offer substantial advantages like rapid onset of action, beneficial for patients having difficulties in swallowing and in conditions where access to water is difficult. The crucial aspect in the formulation of mouth-dissolving tablets is to mask the bitter taste and to minimize the disintegration time while maintaining a good mechanical strength of the tablet. Mouth-dissolving tablets of tramadol are not yet reported in the literature because of its extreme bitter taste. In this work, the bitter taste of Tramadol HCl was masked by forming a complex with an ion exchange resin Tulsion335. The novel combination of a superdisintegrant and a binder that melts near the body temperature was used to formulate mechanically strong tablets that showed fast disintegration. A 3² full factorial design and statistical models were applied to optimize the effect of two factors, i.e., superdisintegrant (crospovidone) and a mouth-melting binder (Gelucire 39/01). It was observed that the responses, i.e., disintegration time and percent friability were affected by both the factors. The statistical models were validated and can be successfully used to prepare optimized taste masked mouth-dissolving tablets of Tramadol HCl with adequate mechanical strength and rapid disintegration.     

The Pragmatic Approach to Masking

This paper advocates the use of a pragmatic approach to the problem of masking in real-life situations involving an abrupt change in the timing of sleep, i.e. shiftwork and “jet-lag” situations. Although “pure” chronobiological research has pointed to the importance of taking masking effects into account, the techniques that it has provided for doing so are extremely difficult to apply in real-life situations. The approach advocated here is based on Wever's pioneering work, and involves estimating the normative endogenous and exogenous components of the circadian rhythm in body temperature. These estimates are then used to: (a) simulate the results of shiftwork studies; and (b) to “remove” the exogenous component in “jet-lag” studies to allow analysis of the estimated endogenous component. The simulated curves obtained cross-correlated extremely highly with published night-shift temperature curves, while the “removal” of the exogenous component resulted in very similar findings to those obtained in temporal isolation studies. It is concluded that this pragmatic approach to masking may prove extremely useful in interpreting the results of field studies of shiftwork and “jet-lag”.     

Indinavir-Loaded pH-Sensitive Microparticles for Taste Masking: Toward Extemporaneous Pediatric Anti-HIV/AIDS Liquid Formulations with Improved Patient Compliance

The aim of this work was to develop indinavir pediatric anti-HIV/AIDS formulations enabling convenient dose adjustment, ease of oral administration, and improved organoleptic properties by means of the generation of drug-loaded microparticles made of a polymer that is insoluble under intake conditions and dissolves fast in the stomach in order to completely release the active agent. Indinavir-loaded microparticles made of a pH-dependent polymeric excipient soluble at pH < 5, Eudragit E100, were prepared using a double emulsion solvent diffusion technique and the in vitro release profiles characterized. Finally, taste masking properties were evaluated in blind randomized sensory experiments by ten healthy human volunteers. The use of a w/o/o emulsion system resulted in indinavir loads around 90%. Thermal analysis of the microparticles by differential scanning calorimetry revealed that indinavir appeared mainly dispersed at the molecular level. Concentrations of residual organic solvents as determined by gas chromatography were below the upper limits specified by the European Pharmacopeia for pharmaceutical oral formulations. Then, the behavior of drug-containing microparticles in aqueous media at different pH values was assessed. While they selectively dissolved in gastric-like medium, in tap water (intake conditions), the matrix remained almost unchanged and efficiently prevented drug dissolution. Finally, sensoring taste tests performed by volunteers indicated that systems with indinavir loads ∼15% displayed acceptable taste. This work explored the production of indinavir-containing microparticles based on a common pharmaceutical excipient as a means for the improvement of medicines of drugs involved in the treatment of HIV/AIDS. For systems containing about 15% drug, taste studies confirmed the acceptability of the formulation. In pediatric regimes, this composition would require an acceptable amount of formulation (0.7–1.5 g). Diego A. Chiappetta and ángel M. Carcaboso contributed equally to this work.     

Masking of antigenic epitopes by antibodies shapes the humoral immune response to influenza

The immune responses to influenza, a virus that exhibits strain variation, show complex dynamics where prior immunity shapes the response to the subsequent infecting strains. Original antigenic sin (OAS) describes the observation that antibodies to the first encountered influenza strain, specifically antibodies to the epitopes on the head of influenza''s main surface glycoprotein, haemagglutinin (HA), dominate following infection with new drifted strains. OAS suggests that responses to the original strain are preferentially boosted. Recent studies also show limited boosting of the antibodies to conserved epitopes on the stem of HA, which are attractive targets for a ‘universal vaccine’. We develop multi-epitope models to explore how pre-existing immunity modulates the immune response to new strains following immunization. Our models suggest that the masking of antigenic epitopes by antibodies may play an important role in describing the complex dynamics of OAS and limited boosting of antibodies to the stem of HA. Analysis of recently published data confirms model predictions for how pre-existing antibodies to an epitope on HA decrease the magnitude of boosting of the antibody response to this epitope following immunization. We explore strategies for boosting of antibodies to conserved epitopes and generating broadly protective immunity to multiple strains.     

Ultradian Rhythms in Arousal-The Problem of Masking

Studies utilizing widely different experimental techniques provided evidence that there are spontaneous ultradian cycles in arousal during the waking state. These comprised of cyclic fluctuations between increased and decreased sleep propensity with a periodicity of about 1.5 hr. Being of relatively low amplitude, these cycles are vulnerable to masking effects by a variety of experimental conditions. Masking can be exerted by varying the tonic level of arousal, by coexisting slow ultradian components which are particularly prominent during the second half of the day, or by some specific experimental conditions. Furthermore, increased sleepiness was shown to enhance the slow ultradian components and suppress the 1.5-hr cycles in EEG indices of arousal on the one hand, and to emphasize the 1.5-hr cycles in motor activity and reaction time performance on the other hand. Much more attention should be paid to the problem of masking of ultradian cycles in arousal. Recognizing the sources and reasons for masking will ad vance our knowledge of the characteristics of these cycles and their function.     

Adaptation to Shift Work-Experimental Approaches with Reduced Masking Effects

Chronobiological characteristics of night and shift work, features of the adaptive process to be expected are briefly considered in the first part of the paper. Demands for experimental routines to imitate these situations and the need for routines reducing masking effects are discussed. Experiments meeting these demands are reviewed. Practical considerations are derived. Interindividual differences of the circadian system are taken into account.     

哺乳动物舌面味蕾的发育

根据近年来有关大鼠、小鼠味觉发育方面的大量研究,对哺乳动物味蕾(taste buds)发育的情况进行了综述和讨论.哺乳动物舌面上的味蕾分布在菌状乳头(fungiform papillae,FF)、叶状乳头(foliate papillae,FL)、轮廓状乳头(circumvallate papillae,CV)之中,味蕾细胞(taste bud cells)不断地进行着周期性的更新,味蕾的形态、数量和功能随动物随年龄而变化.有关味孔头的研究表明,味乳头(gustatory papillae)在味蕾形成和维持味蕾存在及正常发育方面有着独特的功能.味乳头和味蕾的发育过程与细胞信号分子(signaling molecules)、味觉神经(gustatory nerve fibers)等许多因素有着密切的关系,其中有些作用机理至今尚无定论.     

Regression Models for the Estimation of Orcadian Rhythms in the Presence of Effects Due to Masking

The estimation of human circadian rhythms from experimental data is complicated by the presence of “masking” effects associated with the sleep-wake cycle. The observed rhythm may include a component due to masking, as well as the endogenous component linked to a circadian pacemaker. In situations where the relationship between the sleep-wake cycle and the circadian rhythm is not constant, it may be possible to obtain individual estimates of these two components, but methods commonly used for the estimation of circadian rhythms, such as the cosinor analysis, spectral analysis, average waveforms and complex demodulation, have not generally been adapted to identify the modulations that arise from masking. The estimates relate to the observed rhythms, and the amplitudes and acrophases do not necessarily refer to the endogenous rhythm.

In this paper methods are discussed for the separation of circadian and masking effects using regression models that incorporate a sinusoidal circadian variation together with functions of time since sleep and time during sleep. The basic model can be extended to include a time-varying circadian rhythm and estimates are available for the amplitude and phase at a given time, together with their joint confidence intervals and tests for changes in amplitude and acrophase between any two selected times. Modifications of these procedures are discussed to allow for non-sinusoidal circadian rhythms, non-additivity of the circadian and time-since-sleep effects and the breakdown of the usual assumptions concerning the residual errors.

This approach enables systematic masking effects associated with the sleep-wake cycle to be separated from the circadian rhythm, and it has applications to the analysis of data from experiments where the sleep-wake cycle is not synchronized with the circadian rhythm, for example after time-zone transitions or during irregular schedules of work and rest.     

Design and Optimization of Mefloquine Hydrochloride Microparticles for Bitter Taste Masking

The objective of the present investigation was to reduce the bitterness with improved dissolution, in acidic medium (pH 1.2), of mefloquine hydrochloride (MFL). Microparticles were prepared by coacervation method using Eudragit E (EE) as polymer and sodium hydroxide as precipitant. A 3² full factorial design was used for optimization wherein the drug concentration (A) and polymer concentration (B) were selected as independent variables and the bitterness score, particle size and dissolution at various pH were selected as the dependent variables. The desirability function approach has been employed in order to find the best compromise between the different experimental responses. The model is further cross validated for bias. The optimized microparticles were characterized by FT-IR, DSC, XRPD and SEM. Bitterness score was evaluated by human gustatory sensation test. Multiple linear regression analysis revealed that the reduced bitterness of MFL can be obtained by controlling the dissolution of microparticles at pH 6.8 and increasing the EE concentration. The increase in polymer concentration leads to reduction in dissolution of microparticles at pH > 5 due to its insolubility. However the dissolution studies at pH 1.2 demonstrated enhanced dissolution of MFL from microparticles might be due to the high porosity of the microparticles, hydrophilic nature of the EE, and improved wettability, provided by the dissolved EE. The bitterness score of microparticles was decreased to zero compared to 3+ of pure ARM. In conclusion the bitterness of MFL was reduced with improved dissolution at acidic pH.     

Taste masking of ondansetron hydrochloride by polymer carrier system and formulation of rapid-disintegrating tablets

The purpose of this research was to mask the intensely bitter taste of ondansetron HCl and to formulate a rapiddisintegrating tablet (RDT) of the taste-maske drug. Taste masking was done by complexing ondansetron HCl with aminoalkyl methacrylate copolymer (Eudragit EPO) in different ratios by the precipitation method. Drug-polymer complexes (DPCs) were tested for drug content, in vitro taste in simulated salivary fluid (SSF) of pH 6.2, and molecular property. Complex that did not release drug in SSF was considered taste-masked and selected for formulation RDTs. The complex with drug-polymer ratio of 8∶2 did not show drug release in SSF; therefore, it was selected. The properties of tablets such as tensile strength, wetting time, water absorption ratio, in vitro disintegration time, and disintegration in the oral cavity were investigated to elucidate the wetting and disintegration characteristics of tablets. Polyplasdone XL-10 7% wt/wt gave the minimum disintegration time. Tablets of batch F4 containing spray-dried mannitol and microcrystalline cellulose in the ratio 1∶1 and 7% wt/wt Polyplasdone XL-10 showed faster disintegration, within 12.5 seconds, than the marketed tablet (112 seconds). Good correlation between in vitro disintegration behavior and in the oral cavity was recognized. Taste evaluation of RDT in human volunteers revealed considerable taste masking with the degree of bitterness below threshold value (0.5) ultimately reaching to 0 within 15 minutes, whereas ondansetron HCl was rated intensely bitter with a score of 3 for 10 minutes. Tablets of batch F4 also revealed rapid drug release (t₉₀, 60 seconds) in SGF compared with marketed formulation (t₉₀, 240 seconds;P<.01). Thus, results conclusively demonstrated successful masking of taste and rapid disintegration of the formulated tablets in the oral cavity. Published: June 22, 2007     

Taste preferences and feeding behaviour in the facultative herbivorous fish,Nile tilapia Oreochromis niloticus

Taste preferences in fishes are known mainly for carnivorous species, whereas herbivorous consumers were rarely used in such studies. The main goal of the present study was to evaluate the taste preferences in the herbivorous African cichlid fish, Nile tilapia Oreochromis niloticus. In laboratory settings, the palatability of widely used taste substances (four taste substances that are considered to be sweet, sour, bitter and salty for humans – sucrose, citric acid, calcium chloride and sodium chloride; 21 free L -amino acids; 12 sugars and artificial sweetener Na-saccharin; 0.1–0.0001 M) was evaluated. In each trial, a standard agar pellet flavoured with a substance was offered for fish individually. The consumption of pellet, the number of grasps and the retention time before the pellet was finally ingested or rejected were registered. Overall, 21 of 38 substances were palatable, whereas other substances did not shift consumption of pellets in relation to blank pellets. Pellets containing citric acid, L -cysteine, L -norvaline, L -isoleucine, L -valine, Na-saccharin and D -sorbitol were consumed in >85% of trials. Taste attractiveness of amino acids was highly species-specific and was not associated with the trophic category of the 19 species compared. Moreover, it did not correlate with dietary quantitative requirements of Nile tilapia (r_s = 0.27; P > 0.05). Palatability of sugars for O. niloticus and their sweetness for humans did not correlate as well (r_s = 0.21; P > 0.05); nonetheless, Na-saccharin has the most attractive taste for both O. niloticus and humans. The most palatable amino acids lost their effect if the concentration was lowered to 0.01 M for L -cysteine and 0.001 M for L -norvaline (lower than 242.3 μg and 23.4 μg per a pellet, respectively). Single pellet grasp was characteristic of O. niloticus feeding behaviour (>95% of trials), and this pattern may be related to the social lifestyle of this species. Fish spent 4–8 s on average for orosensory evaluation of pellet edibility. The retention time correlated with the palatability of substances and was significantly longer in trials that ended up with pellet swallowing. It is suggested that prolonged orosensory evaluation of food before swallowing provides a reliable and accurate sensory evaluation, which, in turn, can reduce the probability that inadequate food will be consumed.     

Spatial Features of Vibrotactile Masking Effects on Airpuff-Elicited Sensations in the Human Hand

It was recently shown that the cutaneous sensitivity to airpuffs is decreased by a low-frequency vibrotactile masker in the hairy skin, and by a low-frequency but especially by a high-frequency masker in the glabrous skin. In the current study, the spatial features of this masking effect were determined in four healthy human subjects, using a reaction time paradigm. The masking effect decreased monotonically with increasing interstimulus distance, and identically in longitudinal and transverse (i.e., lateral) directions in the palm or dorsal surface of the hand. The masking effect was stronger in the glabrous than in the hairy skin, especially in the fingers. In the glabrous skin, the spread of masking effect produced by a high-frequency masker was more extensive than that produced by a low-frequency masker. The mechanical spread of high-frequency vibration was less extensive than that of low-frequency vibration in the skin. In the glabrous skin, a masker applied to the tip of the finger produced a stronger masking effect on sensations in the base of the finger than when the masker was located at the base and the test stimulus was located at the tip. It is concluded that mechanical spread of vibration in the skin is of minor importance in explaining the masking effects. Different peripheral neural mechanisms underlie the airpuff-elicited sensations in the hairy and glabrous skin. The afferent inhibitory mechanisms are stronger for signals coming from the glabrous skin of the fingers than for signals coming from the hairy skin. Furthermore, the peripheral innervation density and size of the cortical representational areas may be of importance in determining the magnitude of the masking effect.     

Taste evaluation of potato glycoalkaloids by the Aymara: A case study in human chemical ecology

A chemical ecological model can be the basis for defining testable hypotheses concerning human interactions with plants. Selection by Aymara subsistence cultivators against toxic glycoalkaloids in the ongoing domestication of the Bolivian potato cultigen Solanum X ajanhuiriwas used as a specific case study of human interactions with phytochemicals. In taste perception tests, Aymara subjects were able to discriminate between concentrations of pure glycoalkaloids in solution only above 20 mg/100 ml. Taste panel tests of potato clones indicated that glycoalkaloid levels are important to the Aymara in determining quality only as part of a decision-making process involving two character states: too high or acceptable. Glycoalkaloids in potatoes are regarded as toxic to humans above 20 mg/100 g fresh weight. Among the Aymara, a breakpoint in the curve for glycoalkaloid preference appears to occur between 20–38 mg/100 g. This distinction is evident in the Aymara potato taxonomy which distinguishes bitter (luq'i ch'oke) from nonbitter (ch'oke) potatoes.