Preparation and evaluation of an orally fast disintegrating tablet formulation containing a hydrophobic drug

Abstract

Orally fast disintegrating tablets (FDTs or ODTs) have received ever-increasing demand during the last decade, and the field has become a rapidly growing area in the pharmaceutical industry. Upon introduction into the mouth, these tablets dissolve or disintegrate in the mouth in the absence of additional water for easy administration of active pharmaceutical ingredients. Although the FDT area has passed its infancy, as shown by a large number of commercial products on the market, there are still many aspects to improve in the FDT formulations. Despite advances in the FDT technologies, formulation of hydrophobic drugs 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 hydrophobic drug; meloxicam, without affecting the fast disintegrating properties of the formulation. In order to enhance the solubilization of meloxicam in FDT formulations, β cyclodextrin inclusion complex of the drug is prepared and FDTs containing meloxicam--β cyclodextrin inclusion complex (F1 A and F2 A) were compared and evaluated with the FDTs containing pure meloxicam (F1 and F2) by means of in vitro quality control tests.     

Orally fast disintegrating tablets: developments, technologies, taste-masking and clinical studies

Fast disintegrating tablets (FDTs) have received ever-increasing demand during the last decade, and the field has become a rapidly growing area in the pharmaceutical industry. Upon introduction into the mouth, these tablets dissolve or disintegrate in the mouth in the absence of additional water for easy administration of active pharmaceutical ingredients. The popularity and usefulness of the formulation resulted in development of several FDT technologies. This review describes various formulations and technologies developed to achieve fast dissolution/dispersion of tablets in the oral cavity. In particular, this review describes in detail FDT technologies based on lyophilization, molding, sublimation, and compaction, as well as approaches to enhancing the FDT properties, such as spray-drying, moisture treatment, sintering, and use of sugar-based disintegrants. In addition, taste-masking technologies, experimental measurements of disintegration times, and clinical studies are also discussed.     

Evaluation of a taste sensor instrument (electronic tongue) for use in formulation development

A taste sensor instrument (electronic tongue) was evaluated to determine its utility in developing a taste-enhanced liquid formulation. To train the electronic tongue, human sensory panel data were collected for two prototype formulations, a solution of the drug in water and several marketed products. Studies using the electronic tongue were conducted to determine taste-masking effectiveness of formulations compared to a matching placebo, to establish correlation with human sensory data, and to evaluate unknown formulations and predict their bitterness scores. In the first experiment, the effectiveness of a proposed taste-masking strategy was determined by comparing formulation prototypes containing a bitter active pharmaceutical ingredient (API) against corresponding placebos (i.e. formulations without an active ingredient) using electronic tongue data. The analysis of the electronic tongue data was based on the assumption that the drug was well taste masked if the placebo matched the formulation with API. In a second set of experiments, electronic tongue data were compared to existing data from a human taste panel for several marketed products and prototype formulations. A good correlation (r(2)=0.99) was achieved from this comparison, and the relative taste of prototype formulations not tasted by humans was predicted.     

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.     

Formulation and development of taste masked fast-disintegrating tablets (FDTs) of Chlorpheniramine maleate using ion-exchange resins

Context: Masking of bitter taste of drug for better patient compliance.

Objective: The objective of this research was to mask the bitter taste of Chlorpheniramine maleate using cation exchange resins.

Materials and methods: Different cation exchange resins were used for taste masking. The drug resin complexes (DRC) were prepared by batch process. Complexes of ion-exchange resin and Chlorpheniramine maleate were prepared by taking drug: resin ratios 1:1, 1:2, 1: 3 and 1:4 (w/w). The optimum drug: resin ratio and the time required for maximum complexation was determined. The drug resinates were evaluated for the drug content, taste, drug release, FTIR, DSC and X-ray diffraction (PXRD).

Results and discussion: The X-ray diffraction study confirmed the monomolecularity of entrapped drug in the resin beads. The taste evaluation depicted the successful taste masking of Chlorpheniramine maleate with DRCs. Fast disintegrating tablets (FDTs) were developed depending upon percent complexation, release study at salivary and gastric pH, taste evaluation; Chlorpheniramine maleate: Indion-234 complex of ratio 1:2 was used to develop and formulate FDTs. The drug release of 94.77% in 30?min was observed from FDTs.

Conclusion: The Effective taste masking can be obtained from DRC that can be formulated as FDTs for better patient compliance.     

Utility of Mannitol and Citric Acid for Enhancing the Solubilizing and Taste Masking Properties of β-Cyclodextrin: Development of Fast-Dissolving Tablets Containing Extremely Bitter Drug

Introduction

Development of Fast dissolved tablets (FDTs) in which taste is masked, and drug dissolution is improved, is a major challenge especially in case of extremely bitter drug with poor water solubility such as aceclofenac.

Purpose

The purpose of this study was to enhance the taste masking and solubilizing properties of β-cyclodextrin using citric acid and mannitol through preparation of acid soluble taste masked granules of aceclofenac (ASTMGA).

Methods

General factorial design was applied to optimize FDTs containing ASTMGA so to have short disintegration time (<30 sec.), acceptable taste and enhanced drug dissolution in gastric fluid. Three formulation variables; the type of sugar / cellulose based diluents, X₁ (Galen IQ® and Prosolv®), superdisintegrant type, X₂ (Crospovidone®, Glycolys® and Ac-Di-Sol®) and superdisintegrant concentration, X₃ (10 % and 20 %) were included in the design. The systems were assessed for hardness, friability, in vitro disintegration, wetting time, in vitro dissolution and in vivo oral study.

Results

The combination of Prosolv® and Crospovidone® in the formulation of FDT gave optimum disintegration time. The stability of the optimized FDT in different package materials was retained after storage at 40 ?C/75 % RH for six months. Contrary to FDT containing conventional aceclofenac β-cyclodextrin inclusion complex, FDT containing ASTMGA showed highest dissolution rate in both simulated salivary and gastric fluids and excellent ability to mask the bitterness of drug.

Conclusions

Our results propose that the combination of citric acid, mannitol and β-cyclodextrin could be promising to improve taste masking and solubilizing properties of β-cyclodextrin.     

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.     

我国儿童药物发展环境与市场分析

儿童偏好甜味,药物的苦味常常导致患儿服药顺应性降低,苦味药物的掩味是儿童口服制剂研发过程中面临的一大难题。简介苦味产生机制,传统和新型掩味方法和技术,各制药公司提出的掩味专利以及掩味效果的评价方法等,为掩味制剂的进一步开发提供参考。

     

精制的聚丙烯酸树脂Ⅳ号用于盐酸小檗碱掩味微丸的制备及评价

目的 本文以盐酸小檗碱为模型药物,研究精制后聚丙烯酸树脂IV号作为包衣材料的掩味能力。方法 建立了盐酸小襞碱紫外分光光度法含量测定方法学,并以蔗糖微丸为丸心,采用流化床沸腾上药制备了盐酸小襞碱微丸。分别采用精制前的聚丙烯酸树脂IV号、精制后的聚丙烯酸树脂IV号,以及市售尤特奇? EPO作为包衣材料,制备了不同包衣增重的盐酸小襞碱掩味微丸,并对其口感和水中释放度进行测定。结果 成功建立盐酸小襞碱紫外分光光度法含量测定方法学;制备了盐酸小襞碱普通微丸,含量均一度和上药量符合要求。不同包衣材料制备了不同包衣增重的盐酸小襞碱掩味微丸,经聚丙烯酸树脂IV号包衣后,微丸的苦味被显著掩盖,同时对微丸在水中溶出度的测定结果显示,随着包衣增重的不断变大,微丸的溶出量显著下降;对于精制后的聚丙烯酸树脂Ⅳ,包衣增重达到4.0%时才能充分起到掩盖苦味的作用;而对于尤特奇?EPO,3.0%的包衣增重即可达到相同要求。结论 在相同的包衣增重下,尤特奇?EPO的掩味能力明显优于精制前后的聚丙烯酸树脂Ⅳ,而精制后的聚丙烯酸树脂Ⅳ的掩味能力较精制前有所提高。     

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.     

Design of taste masked enteric orodispersible tablets of diclofenac sodium by applying fluid bed coating technology

Diclofenac sodium (DS) a non-steroidal anti-inflammatory drug has a bitter taste and is a local stomach irritant. The aim of this study was to formulate taste masked DS orally dispersible tablets (ODTs) with targeted drug release in the intestine. Pellets of DS were designed using sugar sphere cores layered with DS followed by an enteric coat of Eudragit L100 and a second coat of Eudragit E100 for taste masking. The produced pellets had a high loading efficiency of 99.52% with diameters ranging from 493.7 to 638.9?µm. The prepared pellets were spherical with smooth surfaces on scanning electron microscopy examination. Pellets with the 12% enteric coat Eudragit L100 followed by 5% Eudragit E 100 resulted in 1.4?±?0.5% DS release in simulated gastric fluid (SGF) and complete dissolution in simulated intestinal fluid (SIF). The pellets were then used to formulate ODTs. In vitro disintegration time of ODTs ranged from 20?±?0.26 to 46?±?0.27?s in simulated saliva fluid (SSF). Dissolution was less than 10% in SGF while complete drug release occurred in SIF. The release rate was higher for the optimized formulation (F12) in SIF than for the marketed product Voltaren® 25?mg tablets. The optimized ODTs formulation had a palatable highly acceptable taste.     

Formulation and evaluation of microsphere based oro dispersible tablets of itopride hcl

Background

The purpose of the present work is to mask the intensely bitter taste of Itopride HCl and to formulate an Oro dispersible tablet (ODT) of the taste-masked drug by incorporation of microspheres in the tablets for use in specific populations viz. pediatrics, geriatrics and patients experiencing difficulty in swallowing.

Methods

With this objective in mind, microspheres loaded with Itopride HCl were prepared by solvent evaporation method using acetone as solvent for pH-sensitive polymer, Eudragit EPO and light liquid paraffin as the encapsulating medium. The prepared microspheres were characterized with regard to yield, drug content, flow properties, particle size and size distribution, surface features, in vitro drug release and taste. The ODTs so prepared from these microspheres were evaluated for hardness, thickness, weight variation, friability, disintegration time, drug content, wetting time, water absorption ratio, moisture uptake, in vitro dispersion, in vitro disintegration, in vitro drug release and stability.

Results

The average size of microspheres was found to be satisfactory in terms of the size and size distribution. Microspheres prepared were of a regular spherical shape. Comparison of the dissolution profiles of microspheres in different pH media showed that microspheres having drug: polymer ratio of 1:2 produced a retarding effect in simulated salivary fluid (pH 6.8) and were further used for formulation into ODTs after addition of suitable amounts of excipients such as superdisintegrant, diluent, sweetener and flavor of directly compressible grade.

Conclusions

Effective taste-masking was achieved for Itopride HCl by way of preparation of microspheres and ODTs of acceptable characteristics.     

Phospholipids and Lipid-Based Formulations in Oral Drug Delivery

Phospholipids become increasingly important as formulation excipients and as active ingredients per se. The present article summarizes particular features of commonly used phospholipids and their application spectrum within oral drug formulation and elucidates current strategies to improve bioavailability and disposition of orally administered drugs. Advantages of phospholipids formulations not only comprise enhanced bioavailability of drugs with low aqueous solubility or low membrane penetration potential, but also improvement or alteration of uptake and release of drugs, protection of sensitive active agents from degradation in the gastrointestinal tract, reduction of gastrointestinal side effects of non-steroidal anti-inflammatory drugs and even masking of bitter taste of orally applied drugs. Technological strategies to achieve these effects are highly diverse and offer various possibilities of liquid, semi-liquid and solid lipid-based formulations for drug delivery optimization.     

Application of poly(acrylic acid) superporous hydrogel microparticles as a super-disintegrant in fast-disintegrating tablets

Poly(acrylic acid) superporous hydrogel (SPH) microparticles possessing a unique porous structure were used as a wicking agent to decrease disintegration time of fast-disintegrating tablets (FDTs). The compression behaviour of poly(acrylic acid) SPH microparticles was evaluated using the Kawakita equation. Effects of various SPH microparticle sizes and a 19-run fractional factorial design were evaluated. The factorial design was based on four factors consisting of ketoprofen, SPH microparticle, filler, and tableting pressure, and each factor contained three levels on the disintegration time and tensile strength of the prepared FDTs. The poly(acrylic acid) SPH microparticles existed in an amorphous state and swelled approximately 80-times in distilled water and 50-times in pH 6.8 0.2 M phosphate buffer. The compressibility of SPH microparticles increased significantly as the microparticle size increased. The FDTs made of SPH microparticles in the range of 75-106 microm showed the fastest disintegration time and higher tensile strength. SPH microparticle, tableting pressure and ketoprofen had significant effects on disintegration time and tensile strength of ketoprofen FDTs. The FDTs that were prepared with 2.5% w/w SPH microparticles of 75-106 microm at 63 MPa pressure possessed a tensile strength of 84.4 +/- 4.1 N cm(-2) and disintegrated in 15.0 +/- 2.0 s. It was concluded that the poly(acrylic acid) SPH microparticles could serve as a good super-disintegrant decreasing the disintegration time of FDTs.     

Improvement of the bitter taste of drugs by complexation with cyclodextrins: applications, evaluations and mechanisms

Drugs having bitter tastes cause low patient compliance. Many taste-masking techniques such as physical barrier coatings, chemical modification and sensory masking have been developed. Among chemical modification, the inclusion complexation of drugs with cyclodextrins (CyDs) can provide the effective bitter taste-masking effects without complicated formulation and/or delayed dissolution of drugs. Herein, we describe some quantitative methods to evaluate the taste-masking effects of CyD complexes with drugs in solution and the solid state. In addition, we introduce the recent applications of CyDs to excipients for taste masking against various bitter-taste drugs, as well as discuss the possible mechanisms for the taste-masking effect of CyD complexation.     

Fast dispersible/slow releasing ibuprofen tablets

Eight formulations were developed containing ibuprofen in the form of orally disintegrating tablets. To prevent bitter taste and side effects of the drug, the drug was associated with Phospholipon 80H, a saturated lecithin, by wet granulation. The granules were then coated using different film forming agents (Kollicoat SR 30, Amprac 01, Kollidon 90F, Eudragit RD 100) obtaining four lots 1–4. Coated granules were then formulated with a sweetener (Aspartame), a mannitol-based diluent (Pearlitol SD 200) and Kollidon CL (1-4K) or Explotab (1-4E) were added as superdisintegrants and compacted under low compression force. The eight lots of tablets, 1-4K and 1-4E, were assessed if suitable as oral disintegrating tablets by determination of a range of technological parameters. Wetting and disintegregation time matched with the requirements of EP IV Ed., for almost all these formulations. Dissolution profiles suggested that the combined action of the hydrophobic lecithin and the coating delay the release of the drug from tablets with respect to when it is free or in the form of simple granules. By an appropriate combination of excipients it was thus possible to obtain orally disintegrating tablets and a delayed release of ibuprofen using simple and conventional techniques.     

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 <Emphasis Type="Italic">in vivo</Emphasis> evaluation of ondansetron orally disintegrating tablets using different superdisintegrants

The aim of this study was to formulate cost effective taste-masked orally disintegrating tablets of ondansetron, a bitter drug using different superdisintegrants by a wet granulation technique. Microcrystalline cellulose (Avicel) as a diluent and disintegrant in addition to aspartame as a sweetener were used in all formulations. The prepared tablets were evaluated for weight variation, thickness, hardness, friability, drug content, water content, in vitro disintegration time and in vitro drug release. The tablets’ hardness was maintained in the range of 2–3 kg and friability was <1% for all batches. All tablet formulations disintegrated rapidly in vitro within 5.83 to 33.0 sec. The optimized formulation containing 15% Polyplasdone XL-10 released more than 90% of drug within 5 min and the release was comparable to that of a commercial product. In human volunteers, optimized formulation was found to have a pleasant taste and mouth feel and they disintegrated in the oral cavity within 12 sec. The stability results were also satisfactory. A pharmacokinetic study with the optimized formulation was performed in comparison with a reference (Zofer MD 8®) and they were found to be bioequivalent. In conclusion, a cost effective ondansetron orally disintegrating tablet was successfully prepared with acceptable hardness, desirable taste and rapid disintegration in the oral cavity.     

Preparation and in vitro evaluation of slow release ketoprofen microcapsules formulated into tablets and capsules

Abstract

Ketoprofen powder was encapsulated with Eudragit RL/RS polymer solutions in isopropanol-acetone 1:1, using a simple and rapid method. Microcapsules were prepared using Eudragit solutions with different RL/RS ratios. The encapsulation process produces free-flowing microcapsules with good drug content and marked decrease in dissolution rate. The retardation in release profile of ketoprofen from microcapsules was a function of the polymer ratio employed in the encapsulation process. In vitro release of ketoprofen from microcapsules either filled in gelatin capsules or compressed into tablets, using calcium sulphate as diluent, confirmed the efficiency of the encapsulation process for preparing prolonged release medication. A capsule formulation with optimum sustained-release profile was suggested.     

Formulation development and rheological studies of palatable cefetamet pivoxil hydrochloride dry powder suspension

Background and the purpose of the study

Because of its intense bitter taste and susceptibility to moisture Cefetamet Pivoxil (CPH) is presently available only in the form of tablet. The aim of this study was to develop taste masked CPH dry powder suspension.

Methods

Methods employed for formulations were: a) Film coating of CPH using Eudragit E100 and subsequent adsorption on different carriers such as spray-dried lactose, sodium starch glycolate and spray-dried mannitol and b) Complexation of CPH with three different ion exchange resins indion 234 amberlite IRP64 and amberlite IRP69.

Results

Taste viz evaluation as recognized by volunteers revealed that coating with Eudragit E100 and subsequent adsorption on different carriers do not mask the bitter taste of the drug. Suspensions prepared using amberlite IRP64 and amberlite IRP69 were extremely palatable with no bitter after taste. They showed pseudoplastic flow behavior and were too viscous even after shearing for sufficient duration of time and exhibited poor pourability. The suspension made with indion 234 was palatable with slight or no bitter after taste. It demonstrated plastic flow with negligible thixotropy. It had moderate viscosity at rest and could be poured after a reasonable amount of shaking. CPH dry powder suspensions were very unstable under different conditions except under refrigeration. A 5% degradation of drug was occurred in reconstituted suspension in 4 days period when stored at room temperature.

Conclusion

Dry powder suspension prepared with indion 234 having 5% overages was stable even after 4th day of reconstitution and palatable with slight or no bitter after taste.