Pharmaceutical uses of sucrose
The unique, multi-functional properties of sugar find many applications in the drugs sector. Julian Cooper, of British Sugar, highlights some of its uses, and shows how companies have developed the market
The unique, multi-functional properties of sugar find many applications in the drugs sector. Julian Cooper, of British Sugar, highlights some of its uses, and shows how companies have developed the market
Sugar is combined with other ingredients to provide palatable dosage forms of many drugs, thus aiding compliance.The techniques to produce the dosage forms (e.g. medicated confectionery and tablets) are similar to those employed in the confectionery industry, with companies developing specific sugar-based products - Directly Compressible (DC) sugars and sugar spheres - to meet the needs of the pharmaceutical formulator.
In addition to sweetness, sugar also provides desirable functional properties. The low toxicity, high purity and diverse physicochemical properties of sugar account for its popularity in pharmaceutical applications.
Sugar and other ingredients used in the food industry (e.g. starches, bulk sweeteners, thickeners, flavours etc) are used in the pharmaceutical and nutraceutical industries as excipients in dosage forms.
masking taste
The primary function of formulation is to ensure that the api is delivered to its site of action at an appropriate concentration. An important aspect of this is to ensure patient compliance. For example, many drugs have a bitter taste, so sugar provides the taste-masking sweetness that is an important aid to patient compliance. In addition to the sweetness, sucrose performs many functions and these are summarised in Table 1.
Excipients have been found to perform other functions in addition to the traditional ones, and the correct formulation of excipient and active can provide accurate delivery of the required dose with a reduction in side-effects and targeted/controlled release to the site of therapeutic need.
The development of particular sugar-based products meeting these specific requirements has expanded the application of these products in the sector.
The volume of sugar used is not great when compared with routinely used binders and fillers,1 but sugar does have some properties, including sweetness and preservative properties, that are hard to replicate with other products. Thus there will always be opportunities for sugar-based products in this sector.
Medicated confectionery is an area where confectionery crosses over into the pharmaceutical sector. The production techniques employed are essentially the same in both applications.2
In medicated confectionery the main objective is to produce pleasant-tasting confectionery that delivers specific actives targeted at alleviation of symptoms. Products are typically high boil sweets, but could also be lozenges and more recently liquid-filled high boils.
The key targets are the symptoms associated with coughs and colds and the flavours used with these products are generally those associated with cold remedies, e.g. honey and lemon. The main actives typically employed are menthol and oil of eucalyptus to provide the desired therapeutic action.
Due to their volatile nature these ingredients are usually added at the end of processing to ensure the requisite amount is present in the final product. These actives can be declared as flavours, however if a therapeutic action or relief of symptoms are claimed the products must be licensed with the relevant authority.
tabletting process
Blended powders are dry mixes which contain actives such as paracetamol, phenylephedrine and vitamins, which are self-administered to alleviate the symptoms of colds and flu.
Sucrose typically powdered or milled sugars, with other flavours and sweeteners, are added to provide a pleasant tasting remedy. In these applications the sugar performs a taste-masking role to hide the bitterness of the actives and improve the dispersability and resultant solubility of the ingredients.
Sugar has been used to sweeten liquid medicines to ensure compliance. In these applications sucrose is considered to be more acceptable than some artificial sweeteners that have a bitter after-taste that can affect patient compliance.3
Sucrose also controls Ostwald Ripening and thus prevents the crystallisation of actives in suspension. Paracetamol suspensions are particularly prone to this.4
The use of artificial sweeteners and polyols is increasing due to concerns about 'medication caries', particularly in the treatment of chronically sick children. These products are usually launched as line extensions rather than direct replacements and the sugar variants are seen as the 'gold standard' for taste and functionality against which the sugar-free alternatives have to compete.4
The techniques used in the pharmaceutical industry to make tablets and lozenges are essentially the same (see Figure 1) as those used in the confectionery industry.5
Sugar and sugar- based products, e.g. liquid sugar and inverts, can be used to provide different functions in the tabletting process.
suitable diluent
Many potent drugs have doses of only a few milligrams or less. Since tablets weighing less than 50mg are difficult for patients to handle, tablets containing potent actives need a suitable diluent to make up the bulk. Lubricants and glidants are added to improve the tabletting efficiency - a lubricant, typically magnesium stearate, is added to tabletting mixtures to aid removal/ejection from the tabletting die. Other ingredients are added to aid dispersion and dissolution of the tablet once it is inside the body. For example, disintegrants such as carboxymethyl cellulose are added to increase the rate at which a tablet breaks up on contact with water or other fluids.6
Granulated sugar alone does not tablet effectively so manufacturers use powdered sugars like icing or confectioners grades in wet granulation processes. Sugar companies around the world have developed a range of directly compressible (DC) sugars that can be used in the two-stage process outlined in Figure1.
viable delivery
Compressible sugars contain not less than 95% and not more than 98% sugar. They may also contain starch, maltodextrin, glucose syrup or invert sugar and can contain a suitable lubricant (e.g. magnesium stearate) and colours (United States Pharmacopoeia (USP) & British Pharmacopoeia (BP)).
Tablets and other solid dosage forms can be panned or spray coated to provide a uniform surface, protection to the main core and a pleasant tasting sugar coat. Once again confectionery techniques5 can be used to provide an attractive, functional finish to pharmaceutical dosage forms.
Recent developments in technology have been applied to provide viable delivery systems for people who may have difficulty in swallowing tablets or liquids. Several companies have designed fast dissolving tablets. These are rapidly dissolved in the mouth in several seconds thus delivering the active into the oral cavity. In these instances taste-masking becomes vital to achieve compliance. This type of system has been reviewed.7
drug actives
The Flashdose products from Fuisz Technologies are based on sugar which is melted/spun like candy floss to deliver a rapidly dissolving or compressible sugar which is formulated into oral delivery systems.
The ability to deliver drug actives in a controlled manner is a main objective for the pharmaceutical industry. Precise delivery of an accurate dose to the designated target area in the body at the correct time is highly desirable. It reduces side-effects, minimises drug overload and ensures effective 'cost in use' for expensive actives.
Sugar spheres are solid dosage forms for sustained and controlled release pharmaceutical products, and they have been developed in connection with hard gelatine capsules.
Sugar spheres are defined particle sizes and are essentially spherical. They can be coated with drug actives at precise levels, and can be coated again with materials that change the solubility of the sphere and thus provide control/delay of the release of the active from the matrix. Several different 'time-release' spheres can be combined to give a capsule that delivers the api in a predetermined manner with respect to time or conditions prevailing at the desired site of action.
Sugar spheres are produced by traditional panning/coating techniques found in the confectionery industry.5 The sugar granules are coated in a mixture of sugar and starch to give a uniform sphere. These are screened to give the required particle size.
Sugars are typically not produced under specific process conditions (unless they are for use in injectables or parenteral nutrition), however they are subject to detailed analytical requirements. These are detailed in the phamacopoeial monographs.
Attempts to harmonise excipient standards on a global basis are now well advanced. The International Pharmaceutical Excipients Council (IPEC) has been set up and worldwide specifications for excipients and their test methods have been proposed.8,9
The analytical specifications and test methods (including standards and reagents) for Sugar (Sucrose (JP, USP); Sucrose, Saccharum (PhEur)) are detailed in monographs in the pharmacopoeias; a comparison of the specific requirements is summarised in Table 2.
Included in the Table are the current PhEur details and proposed amendments pending ratification (Pharm-europa, 2001).
Other sugar products that are routinely used in pharmaceutical applications, which have monographs in the pharmacopoeias, are compressible sugar (USP/NF, BP), Sugar Spheres (USP/NF, PhEur) and confectioners sugar (USP/NF).
Conformance to pharmacopoeial specification is not essential for all pharmaceutical products. However, if a product is to be licensed the clearance procedures are simpler if all the components conform to the specification.
Acknowledgements
The author would like to thank the many people who contributed to the information in the article, in particular to Dr Anthony Armstrong at Cardiff University for information on the pharmaceutical industry and proof reading the manuscript, Janice Cacace at Pformulate (www.pformulate.com) for providing information on the US excipient market, Geoff Parkin, and Dr Malcolm Burge for advice on the intricacies of the pharmacopoeial systems and finally to colleagues in Associated British Foods and British Sugar who have assisted in the collection of information. This article was first published in the International Sugar Journal. Vol 104, July 2002.