Unpalatability of pharmaceutical products, particularly paediatric medicines, can adversely affect patient compliance. Ideally a taste-masking technology should not add to manufacturing time or cost and should not affect bioavailability of the active ingredient. OXP zero is a novel salt system that allows anionic drugs to be administered orally without bad taste or irritation. The API is surrounded in a protective, layered structure that is insoluble in the mouth but it readily releases the API in the stomach.
Taste is a major issue for a number of classes of pharmaceutical products and often leads to a lack of patient compliance, especially with paediatric medicines. Claire Thompson, Director of Pharmaceutical Development, Oxford Pharmascience, looks at how new technology could open up dosage formats and dosage regimes previously precluded by taste.
It is estimated that there are about 10,000 taste buds on the tongue, roof of the mouth, cheeks and throat, and each bud has around 100 receptor cells. These cells interact with molecules dissolved in the saliva and produce a positive or negative taste sensation. Many drugs are unpalatable and unattractive in their natural state, including those with the following therapeutic indications: cardiac, analgesic, antibacterial, anticoagulant, antiepileptic, antimalarial, diuretic, histamine receptor antagonists and vaccines.
Physiological and physicochemical approaches have been used to prevent drugs from interacting with taste buds, and thus to eliminate or reduce negative sensory response.1
Conventional taste masking methods focus on three main approaches:
An ideal taste masking technology should have the properties listed in Table 1.
|Table 1: Ideal properties of taste masking technologies|
|Minimal additional manufacturing and/or processing steps|
|Minimal additional excipients, which should also be safe, inexpensive and readily available|
|No adverse affect on drug bioavailability|
|Low cost of manufacture|
Commonly used taste masking approaches include:
The addition of flavours/sweeteners – Sugar-based or sugar-like excipients dissolve quickly in saliva, and can provide a pleasing mouth feel and good taste masking to the final product.2 For non-tablet products, such as syrups, suspensions, liquids and orally disintegrating granules, flavourings are often added to the formulation to mask taste. For example, WOWTAB, Zydis and DuraSolv formulations use sweeteners and flavours to mask an unpleasant taste.3,4
Although the excipients used to flavour formulations are inexpensive, they cannot be applied to all problematic drug molecules and are limited by dose.
Coating or encapsulation of unpleasant drugs – In some instances, sweeteners and flavours may not be sufficient to mask bitter drugs, so alternative methods of taste masking are required. Frequently, the bitter-tasting drug powder is coated to inhibit or retard dissolution and solubilisation of the drug.5 This allows time for the dosage format to be swallowed before the taste is perceived in the mouth.
When using coating or encapsulation for taste masking, complete coating is necessary to prevent exposure of the taste buds to a bitter-tasting drug. It is important that the coating remains intact while the dosage form is in the mouth. Coating technologies utilise polymeric hydrophilic or lipophilic materials such as starch, gelatine, lecithin, methylcellulose or ethylcellulose to coat the drug formulation.6-9
Encapsulation is the process of applying a relatively thin coating to small particles of solid, droplets of liquid and dispersion. Encapsulation agents include gelatin, povidone HPMC, ethylcellulose, carnauba wax, acrylics and shellac.10
In this process, drug particles are first encapsulated to give free-flowing microcapsules and are then blended with further excipients and formulated into the final product. The encapsulation process itself can be multi-step, as demonstrated by enteric coated micro-granules of Lansoprazole, which have seven layers.11,12
Crystals, granules and pellets of drugs have been coated with aqueous dispersions of Eudragit polymers for taste masking purposes and formulated as fast disintegrating tablets (FDTs).13,14 Microcaps and Flashtab technologies also utilise encapsulated multi-particles of active ingredients for effective taste masking.15,16
An undesirable aspect of coating or encapsulation processes is that they add to the manufacturing cost and time
An undesirable aspect of coating or encapsulation processes is that they add to the manufacturing cost and time. In addition, coating can affect the dissolution profile of a drug. Encapsulation of particles or granules is technically very difficult, even when a large dose of the drug is required. Furthermore, encapsulated particles can be unstable and may rupture in liquid systems.
Taste masking by complexation – Taste masking via complexation involves the drug forming a complex at a molecular level. Cyclodextrins and ion exchange resins are the most commonly used complexing agents.17,18 They weakly bind the drug molecule using Van der Waals forces and reduce the degree to which the drug molecule structure is exposed to the taste buds.
The suppression of bitter taste by cyclodextrins has been shown to increase in the order of alpha, gamma, beta-cyclodextrin. Thus, beta-cyclodextrin is most widely used complexing agent for inclusion type complexes.
Cyclodextrin is a naturally sweet, nontoxic, cyclic oligosaccharide obtained from starch. The bitter taste of carbapentane citrate syrup was reduced to approximately 50% by preparing a 1:1 complex with cyclodextrin.19
The methods used to make drug cyclodextrin complexes are often complex themselves. These include grinding, solid dispersion, precipitation, freeze-drying and melting.23 Many of these processes are difficult to perform at scale.
Synthetic ion exchange resins have been used in pharmacy and medicine for taste masking or controlled release of drugs as early as 1950.20,21 These are high molecular weight, water insoluble polymers that are not absorbed by the body.
The long-term safety of ion exchange resins has been established, even when ingested in relatively large doses, as demonstrated by the use of the ion exchange resin cholestyramine for the reduction of cholesterol.21 Ion exchange resins possess charged functional groups, attached to a water insoluble polymer backbone, to which drug molecules adhere.
The adsorption of bitter drugs onto synthetic ion exchange resins to achieve taste coverage has been well documented. Amberlite CG 50, an ion exchange resin, was used for taste masking of pseudoephedrine in the chewable Rondec decongestant tablet.21 The taste profiles of antibacterials such as ciprofloxacin and norfloxacin have been improved through use of ion exchange resins.22
The drawbacks of complexation technologies are that they too add to the cost and time of the manufacturing process and are suitable only for low dose drugs.23 In addition, complexation does not encapsulate the entire structure of the drug molecule, leaving parts of the structure free to interact with cell receptors in the mouth, buccal cavity and larynx. Hence taste, bitterness, burn or irritation may not be completely negated using this method.
Complexation does not encapsulate the entire drug molecule, leaving parts of the structure free to interact with cell receptors in the mouth, buccal cavity and larynx
Complexing agents can also affect the release profile of drugs. For example, ion exchange resin complexes release the drug by exchanging with appropriately charged ions within the gastrointestinal tract, followed by diffusion of the free drug from the resin.24 This exchange and release may not provide immediate release of the drug from the formulation and thus hamper the dissolution profile.
Other less common methods applied to delivery of poor tasting drugs include:
Prodrugs: These are chemically modified forms of an active drug, which transform to give the active parent drug in vivo; for example, the diacetate ester of triamcinolone and the palmitate ester of clindamycin or chloramphenicols.25
Multiple emulsions preparation: Prepared by dissolving the drug in the inner aqueous phase of water/oil/water emulsion, this process is difficult to scale.
Adjustment of pH values: Many drugs are less soluble at pHs different from the pH value of the mouth, which is around 5-6. Solubilisation inhibitors, such as sodium carbonate, sodium bicarbonate, sodium hydroxide and calcium carbonate, have been shown to increase locally the pH in the mouth. When used in combination with a sweetener, these pH modifiers masked the taste of sildenafil.26
OXP zero is a novel technology that allows anionic drugs to be administered orally without bad taste or irritation. OXP zero is a novel salt system where the API is surrounded in a layered structure, which protects it. The salt is insoluble in the mouth but it readily releases the API in the stomach. Thus, it releases the API in the anionic form without affecting the release profile.
OXP zero can open up formulation opportunities which, to date, have been precluded by taste, dose or stability. For example, it can be incorporated into tablet or non-tablet formats, such as suspensions, syrups, liquids and orally disintegrating granules.
The characteristics of OXP zero in comparison with the properties of an ideal taste masking system are illustrated in Table 2.
|Table 2: Comparison of OXP zero characteristics with ideal taste masking criteria|
|Ideal properties of taste masking technologies||OXP zero characteristics|
|Minimal additional manufacturing and/or processing steps||Process is a simple, one step crystallisation followed by particle annealing, isolation and drying|
|Minimal additional excipients that should also be safe, inexpensive and readily available||The salt consists of aluminium magnesium hydroxide. These starting materials are inexpensive and readily available and safe|
|No adverse effect on drug bioavailability||OXP zero has no effect on bioavailability. Fig. 2 shows the in vitro release profile of OXP zero ibuprofen|
|Low cost of manufacture||This is a high yield and low cost manufacturing process|
|Rapid process||The OXP zero manufacturing process can be bolted onto the current API synthetic route or can be applied as a standalone process to a purchased API|
|Scalable process||The manufacturing process is proven to operate at scale|
Proof of concept has been established for OXP zero ibuprofen, which has totally removed the typical burning sensation on the throat of this active. Examples of formats that are made possible through the application of OXP zero technology to ibuprofen products are shown in Figure 1.
Figure 1: Examples of formats that are made possible through the application of OXP zero technology: ibuprofen products
In summary, for this ibuprofen alone OXP zero would enable:
This could also enable a switch of medication for arthritis patients, especially those who have problems with swallowing (dysphagia).
In addition, OXP zero ibuprofen has shown in vitro bioequivalent release profiles to those of standard ibuprofen tablets, surpassing the USP monograph requirements, which state that 80% of the drug must be released within 60 mins (Figure 2).
Figure 2: In vitro dissolution profile of OXP zero ibuprofen. The graph shows that the in vitro dissolution profile of OXP zero ibuprofen surpasses the requirements of the USP monograph
The need for taste masking of pharmaceuticals is evident, but the complexity and costs must be kept to a minimum. OXP zero can be applied as a cost efficient means not only to mask taste, but also to enable medicines to be easier to take.
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