No need to be bitter

Drug manufacturers could learn something from the food sector about making pharmaceuticals more pleasant to swallow, argues RSSL.

According to Mary Poppins, (from lyrics by Robert B. Sherman) 'Just a spoonful of sugar helps the medicine go down.' The lyrics are a clear indication of our long-held expectation that medicines always taste bad and bitter.Indeed, many of us have been brought up believing that the worse a medicine tastes, the better the consequences of taking it.

Sadly, the evidence suggests that the worse a medicine tastes, the more likely it is that it won't be taken at all. A previous article in Manufacturing Chemist1 stated that only one third of patients are compliant with their prescriptions. While there may be many reasons for such low compliance, the unpleasant taste and texture of many orally administered drugs undoubtedly contributes to a lack of uptake.

Though clearly serious for the patient, it seems it could be serious for pharmaceutical companies too. The same article suggests there is a U$30bn cost to the industry from prescriptions and repeat prescriptions that aren't taken up.

purchasing decision

In the otc sector, it is arguable that taste acceptability is even more of an issue. Where consumers know that one option tastes better than another, this is sure to influence their purchasing decision. Who wouldn't chose the medicine that tastes pleasant over one they know tastes foul?

Taste acceptability is something that the food industry has to contend with every day, and many of the techniques used by food technologists to address the negative taste characteristics associated with some ingredients are applicable also to pharmaceuticals. This is particularly the case with the taste-masking techniques that are being increasingly adopted by the food industry as its products incorporate more and more functional ingredients. Many of these ingredients, such as fish oils, soya derivatives and B vitamins, pose taste acceptability issues that need to be overcome, and the challenge of unpleasant flavour notes presented by these and many other ingredients are much the same as those presented by pharmaceutical actives.

simple mixtures

However, whereas Mary Poppins was restricted to the use of sugar to diminish the bitterness of medicines, the modern formulation laboratory has many more options to choose from.

One advantage that the pharmaceutical industry has over food is the relative simplicity of its products, and the degree of control it has over the ingredients its products contain. Whereas most foods are a highly complex mixture of hundreds of different chemicals with the potential for a wide degree of variability, the pharmaceutical product is a tightly defined mixture of a few key chemicals that are present in precisely known amounts.

It is also easier, in some ways, to define an appropriate carrier system for a pharmaceutical active than to have to take the opposite approach that is often faced by a food manufacturer. Usually, a food manufacturer will have to decide how it can incorporate a functional ingredient into an existing product without compromising any of the sensory characteristics that consumers already accept and expect. It is the complexity of this challenge that has led to the development of a variety of approaches to taste-masking that could be of equal use to pharmaceutical products, and perhaps also open the way to developing new delivery systems.

One of the most common negative taste sensations linked to pharmaceutical actives is bitterness, and a number of ingenious approaches exist to overcome this problem. Each technique has its own merits and there is no 'one cure fits all' approach. Much depends on the product into which the active is incorporated, both in terms of the concept and the specific chemical matrix. Hence, the approach used to taste mask a bitter-tasting analgesic incorporated into a chewing gum might be different from the approach used when that same analgesic is used in a soluble cold remedy.

One approach, which at first seems counter-intuitive, is to mask a bitter flavour with a small dose of a less bitter ingredient. This approach is used in otc medicines, and the idea is that the second ingredient 'competes' with the primary ingredient for a place on the tongue's bitter receptors. The human tongue has approximately 20 different types of bitterness receptor compared with only one type of sweetness receptor.

An alternative approach is the more obvious option of adding sweeteners, the modern equivalent of Mary

Poppins's sugar. Sweeteners such as thaumatin and NHDC (neo-hesperidine dihydrochalcone) can often have a bitterness masking effect at levels where sweetness is not perceptible. The more common sweeteners such as aspartame and sucralose may also be used to mask bitterness, depending on the product in question.

unpleasant aftertaste

Ironically, the aftertaste of intense sweeteners can also be unpleasant, and may be an issue in the development of syrups and soluble cold treatments.

Possible approaches for masking the sweetener aftertaste include optimising the sweetener blend ratio, adjusting flavour concentrations in order to add back some of the 'sugary' characteristics of the formulation, and perhaps adding other ingredients to modify mouthfeel or aftertaste.

Sodium, magnesium, zinc and calcium salts are frequently used as bitterness modifiers. Once again, it may not be acceptable to use these ingredients in certain pharmaceutical products. A 'heart healthy' product that was high in sodium salts would represent something of a contradiction.

Emulsifiers may be used to 'wrap up' some of the more lipophilic bitter molecules, thereby enabling them to by-pass the bitter receptors in the mouth in much the same way that encapsulation may protect other active ingredients until they reach the stomach. Encapsulation is frequently used as a way to introduce ingredients such as fish oils and starflower oil into 'dry' products, but it is more difficult to use this approach in products with a high moisture content.

A potentially exciting development in masking bitterness was recently announced in the US when the FDA indicated it was accepting the GRAS (Generally Recognised as Safe) status of adenosine monophosphate (AMP). AMP, of course, is a naturally occurring chemical involved in a wide variety of cellular processes, which also appears to inhibit the bitter taste response that would normally travel from the tongue to the brain. This effect has been identified by US company Linguagen, which also has a patent on the compound for use in bitterness blocking applications.

Sadly, nothing is guaranteed, and just because sweeteners may be used to mask the bitterness of a pharmaceutical active in one application, they may have no or negligible effect in a different product matrix.

Taste is a complicated business, and the ultimate perception of any product seems to rely on competition and synergism between the different flavour compounds it contains. In effect, the overall taste sensation cannot be predicted from the sum of the parts. Smell, colour, mouthfeel and texture also influence the perception of flavour, and different people vary in their responsiveness and preferences to different flavours.

This is true of all flavour sensations, not just bitterness. So, depending on the product to which they are to be added, it can be as much of a challenge to mask a metallic flavour or an acidic note, as it is to mask bitterness.

With otc medicines, as with foods, an important element of the taste-masking strategy is taste testing. Trained taste panellists are commissioned to taste-test the product in a controlled environment, and to identify its key sensory characteristics and flavour profile. This gives the product formulation specialist an idea of the effectiveness of the taste-masking technique adopted and a reference point against which to judge any improvements made.

Thereafter it is a case of testing various options, making subtle changes here and there until an acceptable conclusion is reached. The new product must then be proved at the production scale, rather than at the laboratory scale, since processing can also contribute its own change to flavour profiles.

ethical concerns

Clearly, there are ethical considerations to address when using volunteers to taste-test pharmaceuticals, although most otc medicines can be safely tested provided consumers are well informed, and appropriate clinical trial procedures are followed. RSSL Pharma has an independent ethics committee that oversees all such tests undertaken in its own laboratories, and has been able to work on a wide range of successful formulation projects.

Taste acceptability is one of the most important considerations for consumers in choosing and using otc medicines, and its importance in patient compliance with prescription medicines should not be underestimated.

While efficacy should always take precedence in any pharmaceutical formulation, the industry now has many techniques at its disposal for improving the sensory characteristics of existing products, and for developing new delivery systems that might improve consumer acceptance.