A review on the taste masking of bitter APIs: hot-melt extrusion (HME) evaluation

The majority of active pharmaceutical ingredients (APIs) found in oral dosage forms have a bitter taste. Masking the unpleasant taste of bitter, APIs is a major challenge in the development of such oral dosage forms. Taste assessment is an important quality-control parameter for evaluating taste-masked formulations of any new molecular entity. Hot-melt extrusion (HME) techniques, have very recently, been accepted from an industrial compliance viewpoint in relation to both manufacturing operations and development of pharmaceuticals. HME achieves taste masking of bitter APIs via various mechanisms such as the formation of solid dispersions and inter-molecular interactions and this has led to its wide-spread use in pharmaceutical formulation research. In this article, the uses of various taste evaluation methods and HME as continuous processing techniques for taste masking of bitter APIs used for the oral delivery of drugs are reviewed.     

A Study of the Effects of Sucrose Concentration,Lacquer Concentration and Coating Time on the Formulation of Stable and Effective Carbenicillin Indanyl Sodium Microcapsules

Abstract

Carbenicillin indanyl sodium, commonly known as Geocillin (GC), is an orally effective derivative of carbenicillin employed in the treatment of gram negative infections of the urinary tract. GC exhibits an extremely bitter taste which affects patient compliance upon oral dosing (1). A novel coating approach allows Geocillin to be prepared as a suspension for oral administration. GC is available only as a tablet.

Eudragit E100^R [EE] is a tasteless, acid soluble cationic polymer. Encapsulation of GC with [EE] inhibited its release in the mouth, thus overcoming its bitter taste. Dissolution studies were carried out in simulated gastric fluid and simulated intestinal fluid. Three factors, viz. sucrose concentration, lacquer concentration and coating time were evaluated to arrive at an optimally acceptable formulation.

The formulation containing GC and sucrose in the ratio of 1:3, suspension coated using a 5% w/w lacquer solution for 40 mins. yielded taste free microcapsules with optimal release characteristics.     

Evaluation of taste-masking effects of pharmaceutical sweeteners with an electronic tongue system

Electronic tongue systems have been developed for taste measurement of bitter drug substances in accurate taste comparison to development palatable oral formulations. This study was to evaluate the taste masking effect of conventional pharmaceutical sweeteners such as neohesperidin dihydrochalcone, sucrose, sucralose and aspartame. The model drugs were acetaminophen, ibuprofen, tramadol hydrochloride, and sildenafil citrate (all at 20?mM). The degree of bitterness was measured by a multichannel taste sensor system (an electronic tongue). The data was collected by seven sensors and analyzed by a statistical method of principal components analysis (PCA). The effect of taste masking excipient was dependent on the type of model drug. Changing the concentration of taste masking excipients affected the sensitivity of taste masking effect according to the type of drug. As the excipient concentration increased, the effect of taste masking increased. Moreover, most of the sensors showed a concentration-dependent pattern of the taste-masking agents as higher concentration provided higher selectivity. This might indicate that the sensors can detect small concentration changes of a chemical in solution. These results suggest that the taste masking could be evaluated based on the data of the electronic tongue system and that the formulation development process could be performed in a more efficient way.     

Use of polymers for taste-masking pediatric drug products

Many drugs are bitter and overcoming this bitter taste is a major barrier in developing a successful product, especially for pediatric patients. Approaches to mask taste include changing taste perception, creating a physical barrier to separate the drug from interacting with taste buds, and changing drug solubility. This review is focused on polymers and the different ways these materials are used to achieve taste masking. Attention is given to systems that are easily swallowed, as swallowability is another concern in developing palatable products for pediatrics. Variables that should be considered when selecting a taste-masking approach are also presented.     

Formulation and development of oral dry suspension using taste masked Ornidazole particles prepared using Kollicoat® Smartseal 30 D

The purpose of this work was to taste mask highly bitter active, Ornidazole by means of particle coating. The aim of the work was further extended into formulating these coated particles into an acceptable oral dosage form such as dry suspension. Ornidazole drug particles were coated using Kollicoat^® Smartseal 30 D as a taste masking polymer. Kollicoat^® Smartseal 30 D is a methyl methacrylate – diethylaminoethyl methacrylate copolymer (6:4). Successful taste masking was achieved for Ornidazole with both top spray and bottom spray techniques using fluid bed processor. Effective taste masking was achieved at a weight gain of 50% w/w and 40% w/w for bottom and top spray techniques respectively without having a significant effect on the release pattern. A taste masked dry suspension was prepared with around 80% w/w coated Ornidazole particles and pH was maintained around 7–8. The suspension prepared with these coated Ornidazole particles, which were maintained in the alkaline pH was found to be stable for 7 days without affecting the taste. The bitter taste intensity was evaluated using volunteers by comparison of test samples with standard solutions containing Ornidazole at various concentrations. Thus, Kollicoat^® Smartseal 30 D was found to be an effective polymer for taste masking of a bitter active like Ornidazole. The formulation development of taste masked dry suspensions was only possible due to unique properties possessed by Kollicoat^® Smartseal 30 D.     

Formulation and evaluation of meloxicam oral disintegrating tablet with dissolution enhanced by combination of cyclodextrin and ion exchange resins

Context: The bitter taste of drug is masked by the exchange of ionized drugs with counter ions of ion exchange resin, forming “resinate”. Cyclodextrin reduces the unpleasant taste and enhances the drug solubility by encapsulating drug molecules into its central cavity.

Objective: Oral disintegrating tablets (ODTs) using the combination of ion exchange resin and cyclodextrin was developed, to mask the bitter taste and enhance drug dissolution.

Methods: Meloxicam (MX) was selected as a model drug. Formulations containing various forms of MX (free drug, MX-loaded resin or resinate, complexes of MX and 2-hydroxypropyl-β-cyclodextrin (HPβCD) or MX/HPβCD complexes, and a mixture of resinate and MX/HPβCD complexes) were made by direct compression. The ODTs were evaluated for weight variation, thickness, diameter, hardness, friability, disintegration time, wetting time, MX content, MX release, degree of bitter taste and stability.

Results and discussion: The tablet hardness was ～3?kg/in², and the friability was <1%. Tablets formulated with resinate and the mixture of resinate and MX/HPβCD complexes disintegrated rapidly within 60?s, which is the acceptable limit for ODTs. These results were corresponded to the in vivo disintegration and wetting times. However, only tablets containing the mixture of resinate and MX/HPβCD complexes provided complete MX dissolution and successfully masked the bitter taste. In addition, this tablet was stable at least 6 months.

Conclusions: The combination of ion exchange resin and cyclodextrin could be used in ODTs to mask the bitter taste and enhance the dissolution of drugs that are weakly soluble in water.     

Taste Masking Technologies in Oral Pharmaceuticals: Recent Developments and Approaches

Taste is one of the most important parameters governing patient compliance. Undesirable taste is one of several important formulation problems that are encountered with certain drugs. Oral administration of bitter drugs with an acceptable degree of palatability is a key issue for health care providers, especially for pediatric patients. Several oral pharmaceuticals, numerous food and beverage products, and bulking agents have unpleasant, bitter‐tasting components. So, any pharmaceutical formulation with a pleasing taste would definitely be preferred over a competitor's product and would translate into better compliance and therapeutic value for the patient and more business and profits for the company. The desire of improved palatability in these products has prompted the development of numerous formulations with improved performance and acceptability. This article reviews the earlier applications and methodologies of taste masking and discusses the most recent developments and approaches of bitterness reduction and inhibition for oral pharmaceuticals.     

Mathematical Model of Magnetic Aftereffect in Hydrogenated Ferromagnets

We consider a mathematical model of magnetic aftereffect in ferromagnets saturated with hydrogen. The influence of the concentration of hydrogen on the magnetic aftereffect is taken into account by the dependence of the coefficient of relaxation of magnetization on the level of strains, which, in turn, depends on the concentration of hydrogen. The time dependence of the electromotive force in a contour enclosing a long cylinder is established for various values of the rate of magnetic relaxation. The obtained dependences can be used for the interpretation of the results of measurements aimed at the evaluation of the concentration of hydrogen.     

Micropellets coated with Kollicoat® Smartseal 30D for taste masking in liquid oral dosage forms

The objective of this study was to develop delivery systems for taste masking based on multiparticulates coated with Kollicoat^® Smartseal 30D formulated as liquid oral suspensions. Coating of particles containing bitter drugs with Kollicoat^® Smartseal reduced drug leaching into aqueous medium, especially when increasing pH, therefore can be used for the formulation of liquid dosage forms. Application of an intermediate layer of ion exchange resins between drug layer and coating can further decrease drug leaching into aqueous vehicle that is beneficial in terms of taste masking. Using optimized compositions of liquid vehicles such as addition of sugar alcohols and ion exchange resin, reconstitutable or ready-to-use liquid dosage forms with micropellets can be developed with bitter taste protection after redispersion lasting longer than 3?weeks, which exceeds the usual period of application.     

参比氢分压对固体电解质浓差电池氢传感器测试准确性的影响

采用固相反应法合成了CaZr_0.9In_0.1O_3-α高温质子导体材料并制备了固体电解质管。通过组装两类浓差电池氢传感器研究了不同参比氢分压对电动势测量误差和待测端氢分压计算误差的影响。结果表明, 在873~1073 K, 且待测端氢分压在0.005~0.1 atm (1 atm=1.013×10⁵ Pa)范围内, 参比端氢分压与测试端氢分压相差越大, 所测电动势相对误差越大, 尤其在873 K低温下更明显。根据Nernst定律计算待测端氢分压的计算误差极大依赖于参比端与待测端氢分压的比值。该误差可通过用电动势为零时的参比氢分压代替测试端氢分压的方法加以消除。利用该方法测定出在873~1073 K, 氢化锆在β-ZrH_x和δ-ZrH_x两相共存区的平台氢分压以及两相转变过程中的生成焓和生成熵。     

Alternating-Current Solenoid of Finite Length in a Medium with Hall Conductivity

The electric field of an alternating-current solenoid of finite length in conducting media is investigated. The first-order (Hall) effect of an externally applied, constant, axial magnetic field on the electric field is considered. The coil impedance and the electromotive force induced in a certain closed path are calculated numerically for small frequencies.     

Influence of hydrogen on the thermoelectric voltage signal in a Pt/WO<Subscript><Emphasis Type="Italic">x</Emphasis></Subscript>/6<Emphasis Type="Italic">H</Emphasis>-SiC/Ni/Pt layered structure

The possibility of detecting H₂ by registering the thermal electromotive force signal, which arises between the surfaces of 6H-SiC plates with a thickness of 400 μm, is established. The working surface of the plates is modified by deposition of a WO _x film and catalytic Pt. An ohmic contact (Ni/Pt) is created on the rear surface of the plate, and this surface is maintained at a stabilized temperature of 350°C. The temperature gradient through the plate thickness arises due to the cooling of the working surface with the air medium. The delivery of H₂ into this medium up to a concentration of 2% gives rise to a 15-fold increase in the electric signal, which considerably exceeds the Pt/WO _x /SiC/Ni/Pt system’s response registered in the usual way by measuring the current–voltage dependence. In this case, an additional power source for the registration of the thermal electromotive force is not required.     

基于霍耳效应的气敏传感器的研制

利用霍耳效应成功地研制了WO3半导体气敏传感器.这种新型传感器不仅可以根据需要输出几毫伏至几十毫伏甚至几百毫伏的直流电压,而且具有其它半导体传感器所没有的优点--无需另外加热.在实验中对NO2气体进行检测,结果表明:传感器的输出霍耳电动势在几毫伏到几百毫伏之间,且随待测气体浓度变化而变化.因此,利用霍耳效应制作气敏传感器是一条完全可行的新思路.     

强振动下比例电磁铁输出力特性研究

为研究强振动对比例电磁铁输出力特性的影响,应用电磁场理论和强迫振动理论建立了强振动环境下比例电磁铁的动态数学模型和仿真模型,仿真分析了不同振动参数下比例电磁铁的气隙磁阻、动生感应电动势及输出力的变化规律,讨论了强振动对电磁铁输出力的影响原理。同时分析了衔铁质量、阻尼系数、弹簧刚度对比例电磁铁输出力波动的影响规律。结果表明:强振动幅值和频率与电磁铁的动生感应电动势的波动幅值正相关;比例电磁铁的气隙磁阻和输出力的波动幅值与强振动幅值呈线性正相关;随阻尼系数的增加,比例电磁铁输出力的波动幅值近似线性减小;弹簧刚度小于20 000N/m时比例电磁铁的输出力波动幅值随刚度增加而快速减小。研究结果为提高振动环境下比例元件的工作性能提供了理论参考。     

Microaggregated Egg Albumin Particles Containing Paraoetamol Tableting Processes

Microaggregated egg albumin particles containing paracetamol were prepared by a new microencapsulation method. Thus, paracetamol was suspended into an ovalbumin solution and then heated to coagulate the protein. The paracetamol crystals were entrapped into the new protein structure and as a consequence microaggregated egg albumin particles were obtained. This novel microencapsulation method improved the flow properties of paracetamol powder that are normally poor. The flow characteristics of the microaggregated particles depended on the paracetamol concentration and the particle size. Furthermore, the bitter taste of paracetamol was masked by this microencapsulation method and the microaggregated particles were used to produce chewable and non chewable paracetamol tablets. The “in vivo” oral relative bioavailability of these two kinds of tablets oF microencapsulated paracetamol in six volunteers were 99.5 and 92.5%, respectively, as determined from the urinary accumulative excretion.     

Microaggregated Egg Albumin Particles Containing Paraoetamol Tableting Processes

Abstract

Microaggregated egg albumin particles containing paracetamol were prepared by a new microencapsulation method. Thus, paracetamol was suspended into an ovalbumin solution and then heated to coagulate the protein. The paracetamol crystals were entrapped into the new protein structure and as a consequence microaggregated egg albumin particles were obtained. This novel microencapsulation method improved the flow properties of paracetamol powder that are normally poor. The flow characteristics of the microaggregated particles depended on the paracetamol concentration and the particle size. Furthermore, the bitter taste of paracetamol was masked by this microencapsulation method and the microaggregated particles were used to produce chewable and non chewable paracetamol tablets. The “in vivo” oral relative bioavailability of these two kinds of tablets oF microencapsulated paracetamol in six volunteers were 99.5 and 92.5%, respectively, as determined from the urinary accumulative excretion.     

Synthesis and in‐vivo taste assessment of meloxicam pivalate

Abstract

Meloxicam (MX), a nonsteroidal anti-inflammatory drug, widely used to treat arthritis, has a very bitter taste. Chemical modification of the bitter functionality was achieved by synthesis of a prodrug, meloxicam pivalate (MXP). Taste improvement was evaluated using single bottle-test rat model. It was found that palatability of MXP solution improved significantly as compared to MX.     

Taste masking technologies in oral pharmaceuticals: recent developments and approaches

Taste is one of the most important parameters governing patient compliance. Undesirable taste is one of several important formulation problems that are encountered with certain drugs. Oral administration of bitter drugs with an acceptable degree of palatability is a key issue for health care providers, especially for pediatric patients. Several oral pharmaceuticals, numerous food and beverage products, and bulking agents have unpleasant, bitter-tasting components. So, any pharmaceutical formulation with a pleasing taste would definitely be preferred over a competitor's product and would translate into better compliance and therapeutic value for the patient and more business and profits for the company. The desire of improved palatability in these products has prompted the development of numerous formulations with improved performance and acceptability. This article reviews the earlier applications and methodologies of taste masking and discusses the most recent developments and approaches of bitterness reduction and inhibition for oral pharmaceuticals.     

Application of a sensorial response model to the design of an oral liquid pharmaceutical dosage form

In this paper, we discuss the application of a compartmental model to study the sensorial response, in terms of taste intensity versus time, in an oral solution for pharmaceutical use. The numerical model was developed from sensorial response curves obtained by a panel of three trained individuals. Parameter identification was carried out by means of a least-squares procedure that obtained the linear coefficients in the model by solving an exact linear least-squares problem conditional on the values of the nonlinear parameters for each iteration. Thus, nonlinear estimation was done in terms of the first-order kinetic parameters only, and ill-conditioning of the Hessian matrix present in these models was solved. Results of modeling for a set of formulations were used to determine the effects of various ingredients (sweeteners and an essence) on a baseline unflavored formulation of acetaminophen in a mixture of cosolvents. The first moment of the area under the curve of taste intensity versus time was found to be the best global indicator of taste for the purpose of product design. It was found that a mixture of sweeteners and an essence was the most efficient way of masking the bitter taste of this active ingredient.     

Application of a Sensorial Response Model to the Design of an Oral Liquid Pharmaceutical Dosage Form

In this paper, we discuss the application of a compartmental model to study the sensorial response, in terms of taste intensity versus time, in an oral solution for pharmaceutical use. The numerical model was developed from sensorial response curves obtained by a panel of three trained individuals. Parameter identification was carried out by means of a least-squares procedure that obtained the linear coefficients in the model by solving an exact linear least-squares problem conditional on the values of the nonlinear parameters for each iteration. Thus, nonlinear estimation was done in terms of the first-order kinetic parameters only, and ill-conditioning of the Hessian matrix present in these models was solved. Results of modeling for a set of formulations were used to determine the effects of various ingredients (sweeteners and an essence) on a baseline unflavored formulation of acetaminophen in a mixture of cosolvents. The first moment of the area under the curve of taste intensity versus time was found to be the best global indicator of taste for the purpose of product design. It was found that a mixture of sweeteners and an essence was the most efficient way of masking the bitter taste of this active ingredient.