Taste Masking

Reducing the Bitterness of Drugs

Taste, smell, texture and aftertaste are important factors in the development of solid dosage forms and establishment of parameters for governing patient compliance

© PHOTOGRAPHY: CHRISTOPHER TESTI, JAN KALICIAK, TOMASZ SOWINSKI, BRETT RABIDEAU, JAIMIE DUPLASS | AGENCY:

UNDESIRABLE TASTE is one of several important formulation problems that are encountered with certain drugs. Several oral pharmaceuticals, numerous food and beverage products, and bulking agents have unpleasant, bitter-tasting components. The desire of improved palatability in these products, especially for pediatric patients, has prompted the development of numerous formulations with improved performance and acceptability.�

Fig. 1: Generation of micro-pellets.

The methods most commonly involved for achieving taste masking include various chemical and physical methods, which prevent the drug substance from interacting with taste buds. The simplest method involves use of flavor enhancers. Where these methods fail, more complex methodologies are adopted. Various techniques have been identified for taste-masking, including polymer coating, inclusion complex formation with cyclodextrin, use of ion exchange resins, solubility limiting methods, liposome, multiple emulsions, use of anesthetic agents, etc.

DIFFERENT TECHNIQUES EMPLOYED FOR TASTE MASKING

Taste masking technologies for bitterness reduction and inhibition for oral pharmaceuticals offer a great scope for innovations. The following methods commonly employed for achieving effective taste-masking include various physical and chemical methods:

Use of Flavor Enhancers

Flavoring and perfuming agents can be obtained from either natural or synthetic sources. Natural products include fruit juices, aromatic oils such as peppermint and lemon oils, herbs, spices and distilled fractions of these. They are available as concentrated extracts, alcoholic or aqueous solutions, syrups or spirit.

Use of flavor enhancers are limited only to unpleasant tasting substances, and is not applicable to oral administration of extremely bitter tasting drugs like various antibiotics.

Applying Polymer Coatings on APIs

Micro-encapsulation, or API particle coating, uses polymers or lipids to taste-mask bitter APIs. The coated composition may be incorporated into a great number of pharmaceutical formulations, including chewable tablets, effervescent tablets, powder and liquid dispersions.

Prepared micro-capsules of APIs with various cellulosic polymers have a pH-dependent solubility with the aim to mask its taste while assuring its release in the intestinal cavity. The drug release studies and the stability assay of the encapsulated moiety demonstrated micros-pheres represent a useful approach to achieve the proposed objectives. Low melting point substances, like lipophilic waxes, are also used for masking the bitter taste of the drugs. Such substances also have a deteriorating effect on the dissolution kinetics and, therefore, are not applicable to fast-disintegrating and fast-dissolving compositions.

The most widely used synthetic materials for coating are polymers such as polyacrylates referred to as Eudragit-types. Polymer coatings make it possible to formulate functional coatings, and thus to design solid pharmaceutical dosage forms with specific release profiles. Coating of small API particles has the disadvantage that due to the huge surface area of fine API particles, large quantities of polymeric coating material must be used. Typically, coating of very fine API crystals is associated with particle agglomeration. Breaking of these agglomerates could unleash the bitter taste again. Table 1 summarizes some challenges of taste-masking coating of API powders and pellets a micro-pellitzation technology.

Fig. 2: Process equipment in a fluid bed with WSA module.

Table 1: Comparison of API coating with micro-pelletization and micro-encapsulution.

Fig. 3: Cross-section of the formulation principle for taste-masked pellets process.

Fig. 4: Two-layer Coated Pellets (SEM Cross-section and Detail).

Other Techniques

Cyclodextrins are used for inclusion complex formation, which is capable of masking the bitter taste of drugs either by decreasing its solubility on digestion or decreasing the amount of drug particles exposed to taste buds thereby reducing its perception of bitter taste. The use of cyclodextrins for taste-masking is limited because of very high concentrations necessary for taste masking.

TASTE MASKING OF AN ANTIBIOTIC

Multiparticulate dosage forms are widely used in pharmaceutical formulations. They are considered to provide pharmacokinetic advantages compared with monolithic dosage forms. Pellets of different formulation types are filled into capsules or processed tablets. Moreover, the formulation of oral liquids in which the drug substance is contained in a taste masked or modified release form is of broad interest. For this purpose, micro-pellets smaller than 400 �m are generated by the micro-pelletization technology, providing ideal cores for application of functional coatings and to mask inconvenient taste.

The development of such small particles with smooth and uniform surface allows application of different kinds of polymers onto these particles. To achieve a uniform film thickness on the micro-pellets containing the API, a narrow particle size distribution is needed. These requirements are fulfilled by pellets in a pharmaceutical dosage form:

• Spherical particles with smooth and uniform surface;

• Mean particle size of taste-masked pellets should be in the range of 50 to 500 microns (�m);

• Narrow particle size distribution;

• Containing active pharmaceutical ingredients and (functional) excipients;

• Coating of pellets in order to achieve;

• Gastro-resistence (enteric coating) and/or;

• Modified release functions (delayed release, controlled release) and/or;

• Pulsatile release and/or taste masking.

The aforementioned technology describes how to make micro-pellets with high drug loadings smaller than 400 �m. Conventional pellet manufacturing techniques are frequently based upon extrusion of pre-wetted masses or on fluid bed layering and coating processes. Obtained pellet sizes are typically in a range between 500 to 1500 �m. The fluid bed technology allows numerous and different formulation approaches, extending the scope and applicability of traditional pelletizing techniques. It produces homogeneous particle sizes of 100 to 400 �m that are not achievable with conventional pelletizing technologies. It is based on a continuous fluid bed process. In the process the API is sprayed as a liquid (solution, suspension, emulsion etc.) into the processing unit. Generated micro-pellets are classified by applying a vertical online air sifting system. The entire process constitutes of a well balanced system of spray drying and ongoing micro-particle growth. A scheme about the principle of pellet formation is depicted in Figure 1.

Properties of micro-pellets:

• High drug load (typically: less than 95 percent);

• Homogenous and uniform pellet matrix;

• Micro pellets: mean particle size of 100 �m up to 500 �m;

• Narrow particle size distribution (e.g. less than 90 percent between 200 to 400 �m);

• Spherical pellets with smooth surface;

• Mechanically very stable;

• Ideal core pellets for coating applications.

Both in pilot and in commercial scales, the technology process takes place in a rectangular shaped fluid bed processing chamber. A directed fluid bed air stream provides specific circulation of coated products. Micropellets matured to the desired particle size distribution are discharged through a hooked-up multiple chamber classifier. In this device, particles of varying sizes, are separated and immature pellets are led back to the ongoing pelletization process by air pressure. In Figure 2, a schematic drawing of the equipment as used in the pelletization process is shown.

Fig. 5: Release of Taste-masked API.

Fig. 6: Dissolution Profile in Phosphate Buffer pH 6.8.

As an example to depict the performance of the process, taste masking of bitter tasting APIs is given. Applying Wurster fluid bed technology, micro-pellets with a particle size distribution between 200 to 400 �m were coated with two functional coatings. Manufactured core pellets proved to be extremely mechanically stable, a prerequisite for application of subsequent functional coatings like taste masking, enteric coatings, modified release coating and similar processes. The core pellets manufacturing process was developed at a laboratory standard and then up-scaled to commercial scale and validated.

Drug product specification:

• Drinkable oral suspension including taste-masked micro-pellets;

• To be prepared before use / to be stable up to 14 days as aqueous suspension;

• Immediate release of API in the intestine.

Formulation concept:

• Drug substance = extremely bitter ? taste masking required;

• Drug substance = insoluble in water and poorly wettable ? specific requirements on formulation and drug quality;

• Dosage strength = high (250 mg API / dose) ? high drug load for core micro-pellets required;

• Particle size of coated taste-masked pellets: to be less than 500 �m ? extrusion / spheronisation technology: Not applicable ? Wurster drug layering technology: Particle size <>in-vitro dissolution profile: fast dissolution in pH 6.8 (80 percent after 30 min) ? feasible coating material to be developed.

The developed formulation consists of a pellet core with highly concentrated drug and excipients. Effective taste masking would be achieved by applying two coating layers; a seal or protection layer and a functional taste-masking coating (see Figures 3 and 4).

As a requirement for stability, the taste masking layer must last at least one week in an aqueous suspension at room temperature. Further, in vitro dissolution of active ingredients from coated micro-pellets must be more than 80 percent after 30 minutes. Figure 5 reveals the amount of drug release at storage times of up to three days in an aqueous suspension as detected by HPLC. Two different levels of acceptable drug release into the suspension had been defined. The drug content in the final suspension to be applied to the patient after a storage time of one week at room temperature was far below the specified limit of 0.2 mg/ml (Figure 6). As specified, the release in phosphate buffer pH 6.8 was less than 80 percent after 30 minutes.

ADVANTAGES

• Small particle sizes that cannot be reached by applying conventional pelletizing technologies;

• Spherical pellet shape;

• Very homogeneous and narrow particle size distribution;

• Drug loads achievable of up to 95 percent available in;

• Laboratory, pilot and industrial production scales;

• Small taste-masked micro-pellets can be suspended in oral liquid without providing an inconvenient "sandy" mouth feeling.

CONCLUSION

Micro-pelletization technology together with a Wurster coating process offers a solution for effectual taste-masking of very bitter drug substances. High drug load, small particle size and narrow particle size distribution might lead to the development of several multi-particulate dosage forms like oral suspension, sachets, multi-particulate tablets and fast disintegrating and chewable tablets or capsules. Small particle sizes of less than 500 �m allows swallowing of suspended pellets without exhibiting a sand-like mouth feeling. Coating with Wurster technology lead to functional polymer films being able to provide perfect taste-masking in combination with appropriate in vitro dissolution kinetics and in vivo properties