Development of oral acetaminophen chewable tablets with inhibited bitter taste

Various formulations with some matrix bases and corrigents were examined for development of oral chewable tablets which suppressed the bitter taste of acetaminophen, often used as an antipyretic for infants. Corn starch/lactose, cacao butter and hard fat (Witepsol H-15) were used for matrix bases, and sucrose, cocoa powder and commercial bitter-masking powder mixture made from lecithin (Benecoat BMI-40) were used for corrigents against bitter taste. The bitter taste intensity was evaluated using volunteers by comparison of test samples with standard solutions containing quinine at various concentrations. For the tablets made of matrix base and drug, Witepsol H-15 best inhibited the bitter taste of the drug, and the bitter strength tended to be suppressed with increase in the Witepsol H-15 amount. When the inhibitory effect on the bitter taste of acetaminophen solution was compared among the corrigents, each tended to suppress the bitter taste; especially, Benecoat BMI-40 exhibited a more inhibitory effect. Further, chewable tablets were made of one matrix base and one corrigent, and of one matrix base and two kinds of corrigents, their bitter taste intensities after chewing were compared. As a result, the tablets made of Witepsol H-15/Benecoat BMI-40/sucrose, of Witepsol H-15/cocoa powder/sucrose and of Witepsol H-15/sucrose best masked the bitter taste so that they were tolerable enough to chew and swallow. The dosage forms best masking bitter taste showed good release of the drug, indicating little change in bioavailability by masking.     

Elimination of bitter, disgusting tastes of drugs and foods by cyclodextrins.

The bitter taste of drugs, food components, and any other substances which get in the mouth as dissolved in an aqueous solution, or in the saliva, can be strongly reduced or fully eliminated, if the bitter component forms an inclusion complex with an appropriate cyclodextrin (CD). The value of the complex association constant (determined by the structure of the bitter 'guest' molecule and the size and eventual substitution of the 'host' CD molecule), the temperature and the host/guest ratio determine the extent of complexation of the guest molecule (percentage of complexation) at the equilibrium. The K(ass) for most drug/CD complexes at 36 degrees C buccal cavity temperature is between 10(2) and 10(4) mol-1. If the unit dose (of a sublingual or chewing tablet, chewing gum) with a bitter drug (molecular weight of about 150, forming a 1:1 complex with betaCD) is approximately 10mg then the betaCD can be taken in a 5- or even 10-fold molar excess. Under such conditions more than 99% of the bitter drug is complexed, and because complexed molecules cannot react with the taste buds in the buccal cavity no bitter taste is perceived. Frequently, preparation of the drug/CD complex is not necessary, because the betaCD is present in a large excess, dissolved very quickly in the saliva and results in a saturated CD solution. Therefore, the complexation of the bitter drug is completed very rapidly. Only dissolved substances have taste and only CD complexable drug molecules can become debittered by CDs. Bitter, astringent components of foods (e.g. soya), beverages (e.g. naringin in citrus fruit juice, or chlorogenic acid and polyphenols in coffee) cigarette smoke (nicotine) also can be complexed and their taste reduced or fully eliminated.     

Formulation and in vitro evaluation of ketoprofen fast-dissolving tablets

Drugs exhibiting satisfactory absorption from the oral mucosa or intended for immediate pharmacological action can be advantageously formulated as orally fast-disintegrating tablets (FDTs or ODTs). Therefore, taste masking of active ingredients becomes essential in these systems because the drug is entirely released in the mouth. Despite advances in the FDT technologies, formulation of drugs with a bitter taste is still a challenge, especially when the amount of drug is high. In this study, a new solution is being developed to incorporate higher doses of a model bitter taste drug; ketoprofen, without affecting the fast-disintegrating properties of the formulation. The unpleasant taste of the active drug usually masked by adding flavoring ingredients and sweeteners to improve taste and palatability but in this study a novel approach of using a polymer; Eudragit EPO and a granulation procedure of this polymer with the active drug was applied to mask the bitter taste of ketoprofen. In order to produce ketoprofen FDT formulations, a two-stepped procedure was followed; granulation process with the taste-masking agent (Eudragit EPO) and then direct compression (F3 and F4). In F1 and F2 formulations, granulation process was not implemented in order to observe the effect of application method of Eudragit EPO. As well as observing the effect of taste-masking agent, crospovidone and sodium starch glycolate were used in different concentrations (2, 4 and 8wt%) to examine the influence of superdisintegrants on FDT properties. All the FDTs containing 30?mg ketoprofen (F1, F2, F3 and F4) were evaluated by means of in vitro quality control tests.     

Stability, Dose Uniformity, and Palatability of Three Counterterrorism Drugs—Human Subject and Electronic Tongue Studies

Purpose These studies evaluated the ability of common household food and drink products to mask the bitter taste of three selected anti-terrorism drugs. Methods Three anti-terrorism drugs (doxycycline, ciprofloxacin hydrochloride, and potassium iodide) were mixed with a variety of common household food and drinks, and healthy adult volunteers evaluated the resulting taste and aftertaste. In parallel, the ASTREE Electronic Tongue was used to evaluate taste combinations. Stability of the mixtures over time was monitored, as was the dosage uniformity across preparations. Results Foods and drinks were identified that satisfactorily masked the bitter flavor of each drug. Dose uniformity and stability were also acceptable over the range studied, although some combinations were significantly less stable than others. The electronic tongue was able to differentiate between tastes, but ranked masking agents in a different order than human volunteers. Conclusions Doxycycline, potassium iodide, and ciprofloxacin, which are stockpiled in solid tablet form, can conveniently be prepared into more palatable formulations, using common household foods and drinks. The electronic tongue can be used to perform an initial screening for palatability.     

Fast dissolving films: a review

Fast-dissolving drug delivery systems have been developed as an alternative to conventional dosage form as an oral means of drug delivery in case of chronic conditions. Now a day's fast dissolving films are preferred over conventional tablets and capsules for masking the taste of bitter drugs to increase the patient compliance. Fast dissolving films consist of a very thin oral strip which dissolves in less than one minute when placed on the tongue. Dissolvable oral thin films are in the market since past few years in the form of breath strips and are widely accepted by consumers for delivering vitamins, vaccines and other drug products. The various manufacturing techniques for the preparation of films have also been detailed in the review. The present review details most of the patents on such fast dissolving films in recent years. A brief study has been made on various parameters which are used to evaluate such films. In case of chronic disorders these fast dissolving films are better for delivering drugs and obtaining faster therapeutic blood levels and superior in comparison to other oral conventional dosage forms.     

Elimination of bitter,disgusting tastes of drugs and foods by cyclodextrins

The bitter taste of drugs, food components, and any other substances which get in the mouth as dissolved in an aqueous solution, or in the saliva, can be strongly reduced or fully eliminated, if the bitter component forms an inclusion complex with an appropriate cyclodextrin (CD). The value of the complex association constant (determined by the structure of the bitter ‘guest’ molecule and the size and eventual substitution of the ‘host' CD molecule), the temperature and the host/guest ratio determine the extent of complexation of the guest molecule (percentage of complexation) at the equilibrium. The K_ass for most drug/CD complexes at 36 °C buccal cavity temperature is between 10² and 10⁴ mol⁻¹. If the unit dose (of a sublingual or chewing tablet, chewing gum) with a bitter drug (molecular weight of about 150, forming a 1:1 complex with βCD) is approximately 10 mg then the βCD can be taken in a 5- or even 10-fold molar excess. Under such conditions more than 99% of the bitter drug is complexed, and because complexed molecules cannot react with the taste buds in the buccal cavity no bitter taste is perceived. Frequently, preparation of the drug/CD complex is not necessary, because the βCD is present in a large excess, dissolved very quickly in the saliva and results in a saturated CD solution. Therefore, the complexation of the bitter drug is completed very rapidly. Only dissolved substances have taste and only CD complexable drug molecules can become debittered by CDs. Bitter, astringent components of foods (e.g. soya), beverages (e.g. naringin in citrus fruit juice, or chlorogenic acid and polyphenols in coffee) cigarette smoke (nicotine) also can be complexed and their taste reduced or fully eliminated.     

Preparation and evaluation of taste-masked dextromethorphan oral disintegrating tablet

This study was aimed at preparing and evaluating oral disintegrating tablets (ODTs) using a strongly cationic resin, Amberlite(?) IRP-69, to mask the bitter taste of a delivered drug, i..e. dextromethorphan hydrobromide. The drug was loaded into the resin (referred to as resinate) or physically mixed with the resin (referred to as physical mixture), and was then incorporated into ODTs by direct compression. A variety of formulae was developed to acquire the optimal formulations of taste-masked ODTs that had acceptable hardness and mouth feel (grittiness). The optimized ODTs were further evaluated for thickness, diameter, weight, friability, disintegration time, wetting time, wetting rate, drug content, drug release and degree of bitter taste, respectively. The thickness, diameter, weight and friability of the tablet with resinate were slightly higher than those with physical mixture. The tablet with resinate had a longer disintegration time, corresponding with its slower wetting time and rate. Both tablets with resinate and physical mixture provided a sustained pattern of drug release. However, only tablets with resinate successfully masked the bitter taste of the drug. In conclusion, the combination of drug and ion exchange resin as resinate could increase the palatability and acceptability of ODTs containing bitter drugs.     

Development and characterization of mouth dissolving tablets of prednisolone

Prednisolone is a glucocorticoid with the general properties of the corticosteroids. It is used as anti-inflammatory or immunosuppressive agent in asthmatic condition mostly in pediatric and geriatric population. So the present investigation was conducted with an aim of to formulate a taste masked patient friendly dosage form i.e. mouth dissolving tablets of prednisolone. In this study, taste masking of drug was critical parameter for this study. Masking of bitter taste of prednisolone was carried out using techniques like preparation of solid dispersion with PEG 6000, complex formation with Indion-204 resin and β-cyclodextrin. Among them complex prepared from β-cyclodextrin in weight ratio 1:4 was optimized basis on taste panel evaluation and drug release from complex. A successful taste masking of complex was confirmed by time intensity method and also by taking drug release in simulated gastric fluid and in simulated salivary fluid. The values of pre-compression parameters evaluated, were within prescribed limits and indicated good free flowing properties. Tablets optimization was carried out through 3² full factorial designs, concentration of superdisintegrants like croscarmellose sodium and sodium starch glycolate as independent variable. Whereas wetting time, disintegrating time and cumulative percentage of drug release as dependent variable. The data obtained of post-compression parameters such as weight variation, hardness, friability, wetting time, water absorption ratio, content uniformity, disintegration time and dissolution was found within specified limit. Prepared check point batch having disintegrating time 16.12 s and drug release 98.34 after 30 min was selected as optimized formula. This formula was compared with marketed formulation and was found better disintegration and drug release property. Optimized formulation was subjected for accelerated stability study as per ICH guideline.     

Orally disintegrating dosage forms and taste-masking technologies; 2010

INTRODUCTION: In the last decade the development of orally disintegrating tablets (ODTs) and thin-film platforms has grown enormously in the field of pharmaceutical industry. A wide variety of new masking technologies combined with the aforementioned platforms have been developed in order to mask the taste of bitter active substances and achieve patient compliance. The commercial success and viability of such products requires the development of robust formulations with excellent palatability, disintegration times, physicochemical stability and pharmacokinetic profiles. AREAS COVERED: In this review, emerging taste-masking technologies applied to solid dosage form manufacturing are summarized. The unique features and principles of taste-masking approaches used with ODT platforms are discussed, including the advantages and limitations of each technology. A brief discussion is also included on the taste masking of thin-film technologies, owing to their similar applications and requirements. EXPERT OPINION: This review elucidates the unique features of current commercially available or highly promising ODT and thin-film technologies, along with taste-masking approaches used in the manufacturing of oral solid dosage forms. A better understanding of these drug delivery approaches will help researchers to select the appropriate platform, or to develop innovative products with improved safety, compliance and clinical value.     

Tannate complexes of antihistaminic drug: sustained release and taste masking approaches

The aim of this investigation was to evaluate the complexation potential of brompheniramine maleate (BPM) and tannic acid (TA) for sustained release and taste masking effects. The complexes (1:1-1:7 TA to BPM ratio) were prepared by the solvent evaporation method using methanol, phosphate buffer pH 6.8 or 0.1N HCl as common solvents. The complexes were characterized microscopically by scanning electron microscopy (SEM), chemically by Fourier transform infrared (FTIR) and solid-state NMR (SSNMR), thermally by differential scanning calorimetry (DSC), for crystallinity by powder X-ray powder diffraction (PXRD), for organoleptic evaluation by electronic tongue (e-tongue), and for solubility in 0.1N HCl and phosphate buffer pH 6.8. The dissolution studies were carried out using the USP II method at 50 rpm in 500 ml of dissolution media (0.1N HCl or phosphate buffer pH 6.8). SEM images revealed that the morphology of complexes were completely different from the individual components, and all complexes had the same morphological characteristics, irrespective of the solvent used for their preparation, pH or ratio of BPM and TA. The FTIR spectra showed the presence of chemical interactions between the TA and BPM. DSC, PXRD and SSNMR indicated that the drug lost its crystalline nature by formation of the complex. Complexation has significantly reduced the solubility of BPM and sustained the drug release up to 24h in phosphate buffer pH 6.8 media. The bitter taste of the BPM was completely masked which was indicated by Euclidean distance values which was far from the drug but near to its placebo in the complexes in all ratios studied. The taste masked complexes can be potentially developed as suitable dosage forms for pediatric use. In summary, complexation of BPM and TA effectively sustained the dissolution and masked the bitter taste of drug for the development of suitable dosage forms for pediatric use.     

Practical approaches of taste masking technologies in oral solid forms

In the pharmaceutical industry, taste masking techniques are applied to prevent active pharmaceutical ingredients exhibiting a bitter and unpleasant taste. The oral administration of bitter drugs through solid dosage forms requires an acceptable degree of palatability, patient tolerance and significant therapeutic value. In the recent years, enormous progress in taste masking technologies has given rise to novel strategies such as fast dissolving dosage forms, chewable tablets and coating of molten materials. Similarly, common technologies applying double coating layers, microencapsulation or even chemical modification have been employed to improve patient compliance. This review endeavours to present the practical technologies and platforms applied for taste masking and indicate the most interesting features of each approach.     

Ultraviolet spectroscopic estimation of microenvironments and bitter tastes of oxyphenonium bromide in cyclodextrin solutions.

The UV absorbance and bitter taste of oxyphenonium bromide (OB), an antiacetylcholine drug, in cyclodextrin (CD) solutions are measured, and the local environment of the binding site and the reduction of the bitter taste intensity are quantitatively estimated from the UV data. The UV spectrum of OB is changed with the addition of alpha-, beta-, and gamma-CD, because the phenyl group of OB is included into the CD cavity. The maximum wavelength, lambda(max), senses environmental changes of OB best among several spectral characteristics. From comparison of lambda(max) between a CD solution and the reference ethanol-water and dioxane-water systems, the dielectric constant of the binding site is evaluated. This value leads us to estimate the microenvironment and structure of the binding site. The suppression of the bitter taste of 4 mM OB by CDs is in the increasing order alpha-CD < gamma-CD < beta-CD. The extent of this suppression can be quantitatively predicted from the UV absorbance by assuming that the free OB molecule alone exhibits the bitter taste, regardless of the kind and concentration of CD. Some implications and limitations of the present approach are discussed.     

Quantification of suppression of bitterness using an electronic tongue.

Phospholipids, such as phosphatidic acid, suppress bitter taste without affecting other taste qualities. In the present study, we detected and quantified this suppression effect with an electronic tongue whose transducer is composed of several kinds of lipid/polymer membranes with different characteristics. We measured a phospholipid cocktail and various kinds of taste substances with five basic taste qualities. The responses to quinine hydrochloride and L-tryptophan, which have a bitter taste, were reduced as the phospholipid concentration was increased, and the responses to the other taste substances were not affected by the phospholipids, as with the human sensation test. Furthermore, the change of bitter intensity caused by phospholipid was quantified by principal component analysis and the tau scale, which expresses the relationship between taste intensity and taste substance concentration. The results are compared with those of the human sensory test and discussed.     

Validation of a rat behavioral avoidance model from a drug delivery perspective

Conventional taste-masking strategies are used to overcome the bitter taste perception of pharmaceuticals by coating the drug particles and/or adding flavoring agents. However, for certain product categories such as rapid dissolve sublingual tablets, taste-masking is challenging. Programs exploring such formulation strategies in the LO-CS phase or post CS phase possess very little toxicological information available in order to conduct human taste panel studies. The potential of a bitter taste perception can present a significant business risk. The objective of the study was to validate a rat behavioral avoidance model that identifies bitter-tasting compounds. Most classic bitter substances elicit a response in the micromolar concentration range while most drugs elicit a response in the millimolar range, hence a validation exercise was conducted to examine if the existing biological model was sensitive enough to identify known bitter tasting drugs as such. Five compounds: ergotamine tartrate, fluoxetine, sucrose, sumatriptan and povidone were chosen to represent a spectrum of compounds. The bitter tasting compounds were identified as such in the model. Based on these results, the assay may serve as a useful surrogate test to identify compounds that may have bitter taste issues.     

药物制剂中苦味掩盖方法的研究进展

药物具有较好的口感是提高患者服药顺应性的重要参数。为了使终产品具有较好的市场前景,应该将掩盖药物的不良气味(通常是苦味)作为处方设计时考虑的重要因素之一。现综述近年来有关文献资料中掩盖药物苦味的各种方法以及这些方法的掩味机制,从而为掩味技术的发展提供参考。     

Enhancement of the Aqueous Solubility and Masking the Bitter Taste of Famotidine Using Drug/SBE-β-CyD/Povidone K30 Complexation Approach

The objective of the present study was to evaluate the potential of ternary system (comprised of famotidine, β-cyclodextrin (β-CyD) or its derivatives and a hydrophilic polymer) as an approach for enhancing the aqueous solubility and masking the bitter taste of famotidine. The aqueous solubility of famotidine increased in the presence of β-CyDs, particularly sulfobutyl ether β-CyD (SBE-β-CyD), and it was further enhanced by the combination of SBE-β-CyD and polyvinyl pyrrolidone (Povidone) K30. The solid binary (drug-β-CyDs) and ternary (drug-β-CyDs-Povidone K30) systems were prepared by the kneading and freeze-drying methods. The dissolution rates of these solid systems were much faster than that of the drug alone. A taste perception study was carried out, initially using a taste sensory machine and subsequently on human volunteers to evaluate the taste masking ability of the ternary complexation. Our results indicated that the combination of SBE-b-CyD and Povidone K30 is effective not only in the enhancement of the solubility and dissolution rate of famotidine, but also in masking of the bitter taste of the drug. This technique may be of value for the pharmaceutical industries, especially in preparation of rapidly disintegrating tablets dealing with bitter drugs to improve patient compliance and thus effective pharmacotherapy.     

Orally disintegrating dosage forms and taste-masking technologies; 2010

Introduction: In the last decade the development of orally disintegrating tablets (ODTs) and thin-film platforms has grown enormously in the field of pharmaceutical industry. A wide variety of new masking technologies combined with the aforementioned platforms have been developed in order to mask the taste of bitter active substances and achieve patient compliance. The commercial success and viability of such products requires the development of robust formulations with excellent palatability, disintegration times, physicochemical stability and pharmacokinetic profiles.

Areas covered: In this review, emerging taste-masking technologies applied to solid dosage form manufacturing are summarized. The unique features and principles of taste-masking approaches used with ODT platforms are discussed, including the advantages and limitations of each technology. A brief discussion is also included on the taste masking of thin-film technologies, owing to their similar applications and requirements.

Expert opinion: This review elucidates the unique features of current commercially available or highly promising ODT and thin-film technologies, along with taste-masking approaches used in the manufacturing of oral solid dosage forms. A better understanding of these drug delivery approaches will help researchers to select the appropriate platform, or to develop innovative products with improved safety, compliance and clinical value.     

Formulation and In vitro Evaluation of Sustained Release Dosage Form with Taste Masking of Metformin Hydrochloride

An attempt was made to sustain the release of metformin HCl as well as to mask the bitter taste by complexation technique using strong cation-exchange resins, indion 244 and indion 264. The drug loading onto ion-exchange resin was optimized for mixing time, activation, effect of pH, mode of mixing, ratio of drug:resin and temperature. The resinate was evaluated for micromeritic properties, taste masking and characterized using XRPD and IR. Using resinate sustained release tablets were formulated using hydoxypropylmethylcellulose K100M.The tablets were evaluated for hardness, thickness, friability, drug content, weight variation and in vitro drug release. Tablets thus formulated (Batch B-6) provided sustained release of drug over a period of 10 h with first order kinetics. The release of metformin HCl from resinate controls the diffusion of drug molecules through the polymeric material into aqueous medium. Results showed that metformin HCl was successfully taste masked and formulated into a sustained dosage form as an alternative to the conventional tablet.     

Playing hide and seek with poorly tasting paediatric medicines: Do not forget the excipients

The development of paediatric medicines can be challenging since this is a diverse patient population with specific needs. For example, the toxicity of excipients may differ in children compared to adults and children have different taste preferences. Acceptable palatability of oral paediatric medicinal products is of great importance to facilitate patient adherence. This has been recognised by regulatory authorities and so is becoming a key aspect of paediatric pharmaceutical development studies. Many active pharmaceutical ingredients (APIs) have aversive taste characteristics and so it is necessary to utilise taste masking techniques to improve the palatability of paediatric oral formulations. The aim of this review is to provide an overview of different approaches to taste masking APIs in paediatric oral dosage forms, with a focus on the tolerability of excipients used. In addition, where possible, the provision of examples of some marketed products is made.     

Improved Buccal Delivery of Opioid Analgesics and Antagonists with Bitterless Prodrugs

Buccal delivery of opioid analgesics and antagonists is a useful way of improving bioavailability relative to the oral route. These compounds taste bitter, however. Various prodrugs of nalbuphine, naloxone, naltrexone, oxymorphone, butorphanol, and levallorphan, in which the 3-phenolic hydroxyl group was esterified, lacked a bitter taste. This taste difference was not due to differences in water solubility, suggesting that for these compounds the phenolic functional group is important for interaction with the taste receptor. In rats, nalbuphine, naloxone, and naltrexone administered buccally as prodrugs exhibited up to 90% bioavailability. In dogs, the bitter taste of buccally administered nalbuphine and naloxone caused salivation and swallowing, and bioavailability was low. Buccal dosing of the prodrugs of these compounds caused no adverse effects and the bioavailability ranged from 35 to 50%, a significant improvement relative to the oral bioavailability, which is 5% or less. The feasibility of buccal prodrug delivery using an adhesive patch formulation was demonstrated.