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.     

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.     

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.     

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.     

Nanosponge-based pediatric-controlled release dry suspension of Gabapentin for reconstitution

Abstract

Context: Gabapentin was selected to formulate oral controlled release dry suspension because of short biological half life of 5–7?h and low bioavailability (60%). Gabapentin is a bitter drug so an attempt was made to mask its taste.

Objective: To formulate and evaluate controlled release dry suspension for reconstitution to increase the bioavailability and to control bitter taste of drug.

Materials and methods: Cyclodextrin based nanosponges were synthesized by previously reported melt method. The nanosponge–drug complexes were characterized by FTIR, DSC and PXRD as well as evaluated for taste and saturation solubility. The complexes were coated on Espheres by a suspension layering technique followed by coating with ethyl cellulose and Eudragit RS-100. A dry powder suspension for reconstitution of the microspheres was formulated and evaluated for taste, redispersibility, in vitro dissolution, sedimentation volume, leaching and pharmacokinetics.

Results and discussion: The complexes showed partial entrapment of drug nanocavities. Significant decrease in solubility (25%) was observed in the complexes than pure drug in different media. The microspheres of nanosponge complexes showed desired controlled release profile for 12?h. Insignificant drug leaching was observed in reconstituted suspension during storage for 7 days at 45?°C/75% RH. Nanosponges effectively masked the taste of Gabapentin and the coating polymers provided controlled release of the drug and enhanced taste masking. The results of in vivo studies showed increase in bioavailability of controlled release suspension by 24.09% as compared to pure drug.

Conclusion: The dry powder suspension loaded with microspheres of nanosponges complexes can be proposed as a suitable controlled release drug delivery for Gabapentin.     

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.     

In vitro and in vivo investigation of taste-masking effectiveness of Eudragit E PO as drug particle coating agent in orally disintegrating tablets

Abstract

Context: Considering that bitter taste of drugs incorporated in orally disintegrating tablets (ODTs) can be the main reason for avoiding drug therapy, it is of the utmost importance to achieve successful taste-masking. The evaluation of taste-masking effectiveness is still a major challenge.

Objective: The objective of this study was to mask bitter taste of the selected model drugs by drug particle coating with Eudragit^® E PO, as well as to evaluate taste-masking effectiveness of prepared ODTs using compendial dissolution testing, dissolution in the small-volume shake-flask assembly and trained human taste panel.

Materials and methods: Model drugs were coated in fluidized bed. Disintequik? ODT was used as a novel co-processed excipient for ODT preparation. Selected formulations were investigated in vitro and in vivo using techniques for taste-masking assessment.

Results and discussion: Significantly slower drug dissolution was observed from tablets with coated drug particles during the first 3?min of investigation. Results of in vivo taste-masking assessment demonstrated significant improvement in drug bitterness suppression in formulations with coated drug. Strong correlation between the results of drug dissolution in the small-volume shake-flask assembly and in vivo evaluation data was established (R?≥?0.970).

Conclusion: Drug particle coating with Eudragit^® E PO can be a suitable approach for bitter taste-masking. Strong correlation between in vivo and in vitro results implicate that small-volume dissolution method may be used as surrogate for human panel taste-masking assessment, in the case of physical taste-masking approach application.     

Enhancing the solubility and masking the bitter taste of propiverine using crystalline complex formation

Context: Patient compliance can be reduced when bitter-tasting compounds, such as propiverine hydrochloride, are administered orally. Propiverine hydrochloride is an example of a drug with a bitter taste, used for the treatment of overactive bladders.

Objective: This study tested whether propiverine free base palatability and aqueous solubility could be improved by crystalline complex formation.

Materials and methods: We used 42 compounds, and found 9 new propiverine crystalline complexes. The properties and solubility of these complexes were studied using a range of techniques. A taste perception study was carried out using a taste sensor to evaluate the taste masking ability of the crystalline complex formation.

Results: The melting points of the crystalline complexes were higher than that of propiverine. The dissolution rates of the crystalline complexes in aqueous buffer solution (pH 6.8) and in purified water were much faster than that of propiverine. Propiverine salicylic acid crystalline complex had substantially less bitterness than propiverine hydrochloride, which was extremely bitter.

Discussion: The present findings indicated that crystalline complex formation provided an effective approach to enhancing propiverine solubility, and to masking its bitter taste.

Conclusion: Crystalline complex formation represents a useful and valuable technique for the preparation of orally disintegrating tablets and improving patient compliance, even for substances with bitter tastes.     

Quantitative estimation of the bitter taste intensity of oxyphenonium bromide reduced by cyclodextrins from electromotive force measurements

The bitter taste of oxyphenonium bromide, an antiacetylcholine drug, is suppressed by cyclodextrins. The extent of the suppression can be predicted from the electromotive force measurements with an oxyphenonium bromide-selective electrode. The relationship between the bitter taste intensity and the electromotive force holds true, regardless of the kind and concentration of natural and modified cyclodextrins. This result is explicable on the basis of the observation that both the bitter taste and the electric potential are determined by the concentration of free oxyphenonium bromide. Some implications and limitations of the present approach are discussed.     

Preparation and evaluation of orally disintegrating tablets of taste masked phencynonate HCl using ion-exchange resin

This study was intended to design an orally disintegrating tablet (ODT) formulation that can mask the extremely bitter and metallic taste of phencynonate HCl by novel ion-exchange resins. The drug–resin complexes (DRCs) were prepared and characterized by scanning electron microscopy, X-ray powder diffraction and differential scanning calorimetry. In vitro properties (dissolution, wetting time and disintegration time) and in vivo behavior (disintegration time and taste-masking effect) in healthy volunteers of the prepared ODTs were also investigated. The drug was changed from the crystal structure to the amorphous form in the DRC. Compared with commercial tablets, the in vitro and in vivo disintegration of optimized DRC-loaded ODTs with a drug-resin ratio of 1:1 was greatly improved and better palatability with a low bitterness index (0.33) was obtained. The current DRC-loaded ODT could promise a good way to mask the unpleasant taste of certain drugs and accordingly improve the patient compliance.     

Preparation of polymer-blended quinine nanocomposite particles by spray drying and assessment of their instrumental bitterness-masking effect using a taste sensor

Abstract

Context: The development of taste-masking technologies for foods and drugs is essential because it would enable people to consume and receive healthy and therapeutic effect without distress.

Objective: In the current study, in order to develop a novel method to prepare nanocomposite particles (microparticles containing bitter nanoparticles) in only one step, by using spray drying, a two-solution mixing nozzle-equipped spray dryer that we previously reported was used. The nanocomposite particles with or without poorly water-soluble polymers prepared using our spray-drying technique were characterized.

Methods: (1) The organic solution containing quinine, a model of bitter compound and poorly water-soluble polymers and (2) sugar alcohol (mannitol) aqueous solution were separately flown in tubes and two solutions were spray dried through two-solution type spray nozzle to prepare polymer-blended quinine nanocomposite particles. Mean diameters of nanoparticles, taste-masking effect and dissolution rate of quinine were evaluated.

Results: The results of taste masking by taste sensor suggested that the polymer (Eudragit EPO, Eudragit S100 or Ethyl cellulose)-blended quinine nanocomposite particles exhibited marked masking of instrumental quinine bitterness compared with the quinine nanocomposite particles alone. Quinine nanocomposite formulations altered the quinine dissolution rate, indicating that they can control intestinal absorption of quinine.

Conclusion: These results suggest that polymer-blended quinine composite particles prepared using our spray-drying technique are useful for masking bitter tastes in the field of food and pharmaceutical industry.     

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.     

Pharmaceutical and pharmacokinetic characterization of a novel sublingual buprenorphine/naloxone tablet formulation in healthy volunteers

Context: Bitter taste, as well as dissolve time, presents a significant challenge for the acceptability of formulations for oral transmucosal drug delivery.

Objective: To characterize a novel sublingual tablet formulation of buprenorphine/naloxone with regards to pharmacokinetics, dissolve time and formulation acceptability.

Methods: Dry mixing techniques were employed to produce a small and fast dissolving buprenorphine/naloxone sublingual tablet formulation, OX219 (Zubsolv®), using sucralose and menthol as sweetener and flavor to mask the bitter taste of the active ingredients. Two cross-over studies were performed in healthy volunteers to evaluate pharmacokinetics, dissolve time and acceptability of OX219 5.7/1.4?mg tablets compared to the commercially available buprenorphine/naloxone formulations Suboxone® tablets and films (8/2?mg).

Results: Buprenorphine exposure was equivalent in OX219 and Suboxone tablets. Sublingual dissolve times were significantly shorter for OX219 than for Suboxone tablets and were similar to Suboxone films. The OX219 formulation received significantly higher subjective ratings for taste and overall acceptability than both Suboxone formulations. OX219 was preferred over Suboxone tablet and film formulations by 77.4% and 88.9% of subjects, respectively.

Conclusions: A sublingual tablet formulation with an improved acceptability has been successfully developed.     

Polyvinyl alcohol-cellulose composite: a taste sensing material

There are reports of fabrication of taste sensor by adsorbing lipids into Millipore filter paper. With this lipid based sensor, it has been found that the taste sensing efficiency of membrane can be remarkably improved. We have made an attempt to prepare taste sensor material by using functionalized polymer without any lipid. PVA-cellulose composite has been modified to use as the sensor material. The research work covers polymer membrane preparation, morphology study and structural characterization of the membrane and study of the taste sensing characteristics of this membrane for five different taste substances. PVA-cellulose composite membrane was modified by phosphorylation with POCl₃. FTIR spectroscopic analysis, XRD analysis and SEM were done to get an idea about the structure and morphology of the prepared phosphorylated PVA-cellulose composite membrane. The sensor characteristics like temporal stability, response stability, response to different taste substances, and reproducibility of sensing performance were studied using phosphorylated PVA-cellulose composite membrane. Sensor device prepared with this membrane has shown distinct response patterns for different taste substances in terms of membrane potential. Threshold concentrations of phosphorylated PVA-cellulose composite membrane for HCl, NaCl, Q-HCl, sucrose and MSG are 0001 mM, 0.001 mM, 0.001 mM, 0.001 mM and 0.009 mM, respectively. The threshold concentrations are below human threshold concentrations. Membranes also showed characteristic response patterns for organic acids like acetic acid, citric acid, formic acid etc, mineral acids like HCl, H₂SO₄ and HNO₃ salts, bitter substances, sweet substances and umami substances. Sensor device prepared with this membrane has excellent shelf life.     

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.     

Formulation studies for mirtazapine orally disintegrating tablets

Abstract

Objective: Orally disintegrating tablets (ODTs) recently have gained much attention to fulfill the needs for pediatric, geriatric, and psychiatric patients with dysphagia. Aim of this study was to develop new ODT formulations containing mirtazapine, an antidepressant drug molecule having bitter taste, by using simple and inexpensive preparation methods such as coacervation, direct compression and to compare their characteristics with those of reference product (Remereon SolTab).

Materials and methods: Coacervation method was chosen for taste masking of mirtazapine. In vitro characterization studies such as diameter and thickness, weight variation, tablet hardness, tablet friability and disintegration time were performed on tablet formulations. Wetting time and in vitro dissolution tests of developed ODTs also studied using 900?mL 0.1?N HCl medium, 900?mL pH 6.8 phosphate buffer or 900?mL pH 4.5 acetate buffer at 37?±?0.2?°C as dissolution medium.

Results: Ratio of Eudragit® E-100 was chosen as 6% (w/w) since the dissolution profile of A1 (6% Eudragit® E-100) was found closer to the reference product than A2 (4% Eudragit® E-100) and A3 (8% Eudragit® E-100). Group D, E and F formulations were presented better results in terms of disintegration time. Dissolution results indicated that Group E and F formulations showed optimum properties in all three dissolution media.

Discussion: Formulations D1, D4, D5, E3, E4, F1 and F5 found suitable as ODT formulations due to their favorable disintegration times and dissolution profiles.

Conclusion: Developed mirtazapine ODTs were found promising in terms of showing the similar characteristics to the original formulation.     

Egg Albumin Microaggregates Containing Colistin for Oral Administration: Organoleptic Characteristics

In order to mask the bitter taste of drug, a microencapsulation method for the production of egg albumin microaggregates was employed. As model bitter-tasting drug, colistin sulfonate was used. The heat denaturation technique for egg albumin microaggregates (coagulation temperature: 60°C) is different from that for human serum albumin (coagulation temperature: l00°C), which is quite important for high temperature unstable drugs. This method was subsequently used to produce microaggregates with a size range of 108.76 ± 32 μm. The egg albumin microaggregates were able to improve the organoleptic characteristics of colistin sulfonate. Drug release from these microaggregates was confirmed by jitting the dissolution data to the equation of Peppas; this resulted in an n value of 0.9791, signifying zero-order kinetics.     

浅析饮用水嗅味评价标准化问题

本文总结和分析了国内外饮用水嗅味评价的标准化现状,指出了饮用水嗅味评价标准化工作中存在的主要问题在于嗅味标准物质数据库、嗅味评价标准、公众满意度测评方法等方面的缺失或不完善,并建议加强研究形成感官与量化指标相结合的饮用水嗅味评价标准,构建和完善饮用水嗅味评价标准体系.     

A new reconstitutable oral paediatric hydrocortisone solution containing hydroxypropyl-β-cyclodextrin

Hydrocortisone (HC) despite a low aqueous solubility and a very poor palatability is frequently used unlicensed in paediatric practice. Hence a reconstitutable taste masked hydrocortisone solution with the potential to be easily produced extemporaneously was developed. Excipients for the reconstitutable dry powder mix were selected based on their aqueous solubility, compatibility, safety profile in children and stability at the optimum pH for HC. Formulations were visually inspected and pH was checked. The chemical and microbiological stability was assessed by a validated HPLC method and the European Pharmacopeia tests. A taste assessment study was performed on 20 young healthy adults to determine the optimum sweetener. HC was flavored (orange tangerine), preserved (methyl paraben sodium salt/potassium sorbate), adjusted to pH 4.2 (citric acid buffer) and included in a 1:6 hydroxypropyl-β-cyclodextrin (HP-β-CyD) complex which allowed complete solubilization of the drug following reconstitution within 1?min of handshake. Neotame 0.075% was found to be the sweetener of choice to mask the unpalatable taste and aftertaste of HC. All formulations tested at different storage conditions were found to be chemically stable after reconstitution with a HC recovery of >95% for 1 month. Microbiological assessment showed that the selected preservative combination was efficient and the presence of preservative ensured the recommended acceptance criteria for microbiological quality after reconstitution with repetitive sampling. The successfully developed 5?mg/mL reconstituted oral palatable paediatric HC solution was stable for 1 month after reconstitution and has the potential to facilitate dosing, acceptability, availability and affordability.     

Taste masking of azithromycin by resin complex and sustained release through interpenetrating polymer network with functionalized biopolymers

Abstract

Objective: The objective was to evaluate taste masking of azithromycin (AZI) by ion exchange resins (IERs) and the formation of covalent semi interpenetrating polymer network (IPN) beads using chitosan (CS) and sodium carboxylated agarose (SCAG) for sustained release of drug.

Methods: Methacrylic acid (MAA)-based IERs were prepared by suspension polymerization method. Drug release complexes (DRCs) were prepared by different drug:resin ratios i.e. 1:1, 1:2 and 1:4. The resultant DRCs were characterized using DSC, FTIR, PXRD, in vivo and in vitro taste masking, and in vitro drug release at gastric pH. IPN beads were prepared by entrapping DRCs with bio polymers and cross linked with trisodium citrate (NaCIT), and further cross-linked with glutaraldehyde (GA) for sustained release of AZI.

Results: In vitro and in vivo taste masking studies showed that MD1:4 DRC formulation was optimal. The release of AZI from DRC was found to be very fast at gastric pH i.e. 97.37?±?1.02% within 45?min. The formation of IPN beads was confirmed by FTIR. The release of drug from IPN beads at gastric and intestinal pH was found to be “<28% and <60%”, respectively. The release kinetics showed Fickian diffusion profile for ionically cross-linked beads and zero-order release mechanism for GA cross-linking beads.

Conclusions: DRCs can be effectively used for taste masking and newly formulated IPN beads demonstrated sustained release of AZI.