spacer
home > pmps > spring 2010 > in good taste
PUBLICATIONS
Pharmaceutical Manufacturing and Packing Sourcer

In Good Taste

Lyn Hughes of Dow Water and Process Solutions discusses ways to evaluate the effectiveness of taste-masking in the development of pharmaceutical products

Taste-masking can provide two product benefits to a pharmaceutical company. The first is, of course, improved patient compliance, helping to ensure that medication is taken as required for maximum therapeutic benefit and minimum risk of misuse. The second is competitive advantage, particularly for over-the-counter (OTC) products, as consumers will choose the brand that has the least objectionable taste. Both of these considerations are at their most important in paediatric and geriatric patient populations where bad taste is least tolerated. For the same reasons, there is also a major trend toward orally dissolving tablets (ODT), oral films, suspensions and chewable tablets since they are better tolerated by these populations. All of these dosage forms require taste-masking if the drug’s taste is objectionable. With these benefits and trends, it is not surprising that interest in the use of taste-masking has increased. Technologies for taste-masking have been reviewed but there has been a dearth of publications reviewing the methods used to evaluate the effectiveness of taste-masking (1).

EVALUATING TASTE-MASKING

The major problem associated with measuring the effectiveness of tastemasking is the patient – taste is a highly subjective property. Not only does taste perception vary both quantitatively and qualitatively between demographic groups (young and old, men and women), it is also highly variable within groups of the same age and gender. All of us are aware of different food preferences – some people love cabbage, some hate it; some love oysters, some feel sick at the sight of them – and these differences apply equally to taste perception of drug products. Taste perception can also be affected by food consumed prior to dosing, cigarette smoking, state of health and other drugs being taken by the patient (2-4).

The problem of assessing taste is fundamentally different from evaluating drug efficacy where the therapeutic benefit is usually directly measurable, be it a reduction in cholesterol, blood pressure, triglycerides, inflammation or any other therapeutic indicator. Measurement of efficacy is still subject to patient-to-patient variability, but the effect is quantifiable accurately; the subjectivity is all but eliminated.

There are two types of method used to evaluate taste-masking effectiveness – in vivo and in vitro. In vivo evaluation uses human taste panels to rate the taste of the product in some way. In vitro methods attempt to measure some parameter associated with the product that correlates with taste.

IN VIVO EVALUATION – TASTE PANELS

This is the most obvious choice, as it directly measures the effect one is trying to achieve, and consequently is the method most commonly used in product development. Subjects taste various drug products and rate them on a semiquantitative scale. For example, Lorentz et al used a scale where 1 = no bitterness, and 7 = strong bitterness, where any score ≥3 was considered objectionable (5). Shukla et al used a one to three scale, and Devreddy et al used -2 to +2, where +2 was best in taste (6,7). The advantages and disadvantages include:

Subjectivity

As stated above, people perceive taste in different ways and to different extents. This variability becomes part of the variability of the results and is difficult to remove by statistical analysis. The advantage is that this variability is likely to be seen in the patient population as well. The best way to handle this is to include a sufficient number of subjects in order to represent the majority of response types.

Representative Subjects

For ethical reasons, human taste panels will typically comprise healthy adults – often employees of the drug company. As stated, the major target populations for taste-masking are paediatric and geriatric who will have different taste perceptions from the panel. Consequently, the panel’s taste perception may not be highly representative of the target population.

Study Design

It is crucial that the study be designed to take into account the subjectivity of the panel members and the possible effect the product itself has on taste perception. It may be necessary to include a ‘wash-out’ period or process between samples. For example, when menthol is used in syrups, its mode of action is to partially anaesthetise the taste buds, so that the effect of one test sample may affect the perception of the next sample. Desensitisation to taste is also possible, for example, if one starts with a strongly tasting product and then tests other products.

Drug Exposure

Another aspect of the study design is that multiple formulations will be evaluated for individual subjects, so the exposure of the subjects to the drug must be minimised. This is usually managed by having the subjects hold the test samples in the mouth and then spitting them out. Swallowing the products could result in over-exposure to the drug. Cost Any human trial is likely to be more expensive to set up and execute than a comparable in vitro study. It can also take longer to organise and thereby increase the time-to-market for the product under development. Any formulation changes during development will require further panel testing along with its concomitant additional costs.

Quality Control

While human trials may be suitable for product development, they are not typically acceptable for product quality control. In vitro methods, direct or indirect, must be developed at some point to support commercial production.

Technologies

One of the major advantages of human panel testing is that it applies to any and all taste-masking technologies.

IN VITRO EVALUATION

Two distinctly different approaches have been used for in vitro evaluations – methods that use dissolution rate testing and methods that use electronic sensors. Each has advantages and disadvantages.

Dissolution Methods

Dissolution methods are relatively quick and simple – they measure the amount of drug dissolved in a certain (short) time. These methods assume that the amount of drug dissolved will be an indication of the intensity of the taste perceived by the patient. This is a very sound assumption and is particularly useful for comparing different product formulations by rank order. Advantages and disadvantages include:

  • Subjectivity – the test method will give a quantitative result with no subjectivity. Note that this does not eliminate the subjectivity of human perception
  • Absolute versus relative taste – because these methods are only comparative – there is no actual measurement of taste – it is necessary to set some type of target that, if achieved, will mean an acceptable taste. This may require some minimal human testing to establish the target. If appropriate measurements are used, these methods can provide good predictability. Dissolution methods cannot characterise types of taste
  • Safety – as with all in vitro methods the risks involved with human trials are eliminated
  • Cost – dissolution methods are low cost
  • Quality control – dissolution methods for taste-masking are suitable as quality control methods. Because of the prevalence of dissolution testing in the industry, people are comfortable with them and equipment is generally already in place
  • Technologies – the major disadvantage of dissolution methods is that they cannot be applied to all types of tastemasking technologies. They cannot be applied to the use of flavours or tasteperception methods (menthol, salt form selection and so on), and are restricted to those methods that reduce the buccal exposure of the drug (for example, coating, ion exchange resins, and cyclodextrins)

Electronic Sensor Methods

Electronic sensor methods attempt to evaluate various taste characteristics by measuring an electrical effect (such as electrical potential) across different membranes. The sensors are ‘calibrated’ using a variety of substances with defined taste characteristics (bitter, salty, and so on) and the responses of the sensors are mapped in some way. This sensor map is then used to characterise the taste of other substances in product formulations. Advantages and disadvantages include:

  • Subjectivity – as with dissolution methods, subjectivity is eliminated in the measurement, but human subjectivity must still be considered
  • Absolute versus relative taste – fundamentally, this approach measures the relative taste, that is the potential across the membrane for the sample versus the reference. However, the ‘calibration’ procedure establishes an absolute correlation with standards of ‘known taste’, so that in practice this can be considered as an absolute method
  • Safety – as with all in vitro methods, the risks involved with human trials are eliminated
  • Cost – electronic methods are cheaper than human trials, but the equipment needed may be expensive and much less prevalent in laboratories than standard dissolution equipment
  • Quality control (QC) – electronic sensors certainly have the potential to be used in a QC environment – it simply involves measuring the responses from the various sensors. However, the cost of the equipment and the non-traditional technology required present some barriers to adoption in QC
  • Technologies – once the calibration is completed, the sensors can potentially be used for any taste-masking technology
  • Sample presentation – it may be difficult to take into account the transient nature of the buccal exposure so that electronic methods run the risk of underestimating taste-masking effectiveness

Table 1 summarises the suitability of the three types of test against the major taste-masking technologies and project constraints.

Table 1: Comparison of test types    
  Human panel  Dissolution  Electronic 
Flavours  ++  ++ 
Coating  ++  ++ 
Cyclodextrins  ++  ++ 
Ion exchanging resins  ++  ++ 
Changing taste perception  ++  -/+ 
Cost  ++  -/+ 
Speed  --  ++  -/+ 
Quality control  --  ++  -/+ 

MEDIA

An important consideration for in vitro testing is the choice of fluid to be used. This is true even for electronic methods because the medium will affect the dissolution of the product and only dissolved components can be evaluated. In many cases reported in the literature, a simple phosphate buffer at pH 6.8 has been used (an obvious carry-over from traditional dissolution testing). However this is not a good representation of saliva in chemical composition, pH, or buffer capacity. There is considerable variability in the composition of natural saliva, but a number of groups have developed reasonable versions of simulated saliva based on published ranges of composition. An example of one such composition which is cheap and easy to make is shown in Table 2.

Table 2: Composition of a simulated saliva   
  mmol/L  g/L 
KH2PO4  12  1.632 
NaCl  40  2.34 
CaCl2  1.13  0.1257 
0.2M NaOH to pH 6.2   
Source: Composition based on ranges by Ritschel and Tompson (8)   

EXAMPLES OF IN VITRO METHODS

Dissolution Methods

In many cases, dissolution methods are developed in-house and, like traditional dissolution test methods, tend to vary depending on the specific needs of the product or project. A generally applicable method is described here (9). The sample to be tested is introduced into a stirred vessel through which simulated saliva is pumped. The cell is plumbed in such a way that small particulates are flushed out of the cell. The average residence time in the cell is very short (one to two minutes) and the fluid volume is small (around 6ml). The result of this arrangement is that a transient dissolution curve is generated whereby the peak concentration of the curve correlates with the taste intensity. The advantage of this method over more traditional dissolution testing approaches is that the removal of solids represents the swallowing effect. Because of its simplicity, this method is very rapid (around one day for method development and testing of several samples), low cost, and requires very little in the way of calibration beyond that required for analysing the drug concentration. This approach works for ODTs and suspensions, where taste-masking is a crucial requirement. As with all dissolution methods, the results are in rank order, but with minimal human evaluation can be made predictive.

An example of the more traditional dissolution approach was published by Shukla et al (6). This study focused on risperidone orally dissolving tablets and developed a method comprising a short residence time (a few minutes) and small volume (5ml).

Electronic Methods

Probably the best known electronic method is the ‘e-Tongue’, developed and marketed by Alpha-MOS. The version of this equipment recommended for pharmaceutical use has seven different sensors which are chemically modified field-effect transistors, where the difference between them is the proprietary coating applied to each. The various responses from the sensors can be mapped using multivariate techniques such as principle component analysis and discriminator function analysis. A recent article by Lorentz et al describes the use of this technique in the development of a taste-enhanced formulation and includes a description of the e-Tongue ‘training’ procedure (that is, calibration) using a human panel as the reference (5). Hashimoto et al describes similar work using a taste sensor, and Akiyoshi describes both a taste sensor approach and the use of cultured neuronal cells as a predictive indicator for bitterness (10,11).

CONCLUSION

Because of the subjective nature of taste, it is highly unlikely that human evaluation will be eliminated completely anytime soon. The best that is achievable at this time is to minimise the use of human testing by limiting it to establishing acceptable correlation with in vitro measurement. Which in vitro method is selected will depend on the specific tastemasking technology used, and the time and cost constraints imposed on the product development team.

References

  1. Hughes L, Making Medicines Taste Better, PMPS: pp44-47, Spring 2004
  2. Sanders OG, Ayers JV and Oakes S, Taste acuity in the elderly: the impact of threshold, age, gender, medication, health and dental problems, Journal of Sensory Studies 17(1): pp89-104, 2007
  3. Wardwell L, Chapman-Novakofski K and Brewer MS, Effects of age, gender and chronic obstructive pulmonary disease on taste acuity, International Journal of Food Sciences and Nutrition, March 2009
  4. Doty RL and Bromley SM, Effects of drugs on olfaction and taste, Otolaryngologic Clinics of North America 37(6): pp1,229-1,254, 2004
  5. Lorentz JK, Reo JP, Hendl O, Worthington JH and Petrossian VD, Evaluation of a taste sensor instrument (electronic tongue) for use in formulation development, Int J Pharmaceutics 367: pp65-72, 2009
  6. Shukla D, Chakraborty S, Singh S and Mishra B, Mouth dissolving tablets II: an overview of evaluation techniques, SciPharm 77: pp327- 341, 2009
  7. Devreddy SD, Gonugunta CSR and Veeradreddy PR, Formulation of Evaluation of Taste-masked Levocetirizine Dihydrochloride Orally Dissolving Tablets, J Phar SCi Technol 63(6): pp521-526, 2009
  8. Ritschel WA and Tompson GA, Methods and Findings in Experimental and Clinical Pharmacology 5(8): pp511-525, 1983
  9. Hughes L, Buccal dissolution of active substances, US Patent 7, 470, 545
  10. Hashimoto Y, Tsuji YE, Miyanaga Y, Uchida T and Okada H, J Drug Delivery Sci Technol 16(3): pp235- 240, 2006
  11. Akiyoshi T, Development of Novel Evaluation System for Bitter-Taste using Cultured Neuronal Cells, Fukuoka Daigaku Yakugaku Shuho 9: pp95-106, 2009

Read full article from PDF >>

Rate this article You must be a member of the site to make a vote.  
Average rating:
0
     

There are no comments in regards to this article.

 You must be a member of the site to make a comment.
spacer
Lyn Hughes is the Global Application Development Specialist for Dow Water & Process Solutions’ pharmaceutical applications. A 32-year employee of Rohm and Haas, now Dow Water & Process Solutions, Lyn spent the first part of his career providing technical support for monomer manufacturing in both the UK and Texas. Since 1989, he has been at the Spring House, Pennsylvania site working in the ion exchange resins business in several different technical roles including research, applications development and technical/sales service, with an everincreasing focus on the pharmaceutical applications of ion exchange resins.
spacer
Lyn Hughes
spacer
spacer
Print this page
Send to a friend
Privacy statement
News and Press Releases

A new market reference added to Safe’n’Sound®, our passive safety device platform

Safe’n’Sound® is on the market in Europe with a newly registered injectable medication. The commercial launch of HULIO™ (Adalimumab Biosimilar) was initiated in selected European markets on October 19,2018. Hulio™, developed by Fujifilm Kyowa Kirin Biologics Co., Ltd. and marketed in the European Union by Mylan N.V. is approved as a biosimilar for the same indications as the reference product, Humira®.
More info >>

White Papers

7 Common Myths about QP Training Debunked: A Guide for Senior Managers

RSSL

The role of the Qualified Person (QP) in the pharmaceutical industry is mandated by law (Directive 2001/83/EC, Directive 2001/20/EC, UK SI 2012/1916, UK SI 2004/103). Every holder of a relevant Manufacturers Authorisation (human and veterinary) must have at least one QP; without one, no batch of medicinal product can be certified for release for sale.
More info >>

 
Industry Events

CPhI & P-MEC India

26-28 November 2019, India Expo Centre, Greater Noida, Delhi NCR, India

As the pharma industry looks increasingly towards India forhigh quality, low   cost pharma solutions, CPhI & P-MEC Indiais the ideal event for companies wanting to pick up on the latest trends and innovations the market has to offer. At CPhI & P-MEC India, you will meet the movers and shakers from India’s pharma machinery, technology and ingredients industries, giving you a competitive advantage that will help grow your business.
More info >>

 

 

©2000-2011 Samedan Ltd.
Add to favourites

Print this page

Send to a friend
Privacy statement