Enhancing compliance for oral liquid medications

To increase patient compliance while at the same time ensuring correct dosing is an ongoing task for the OTC industry when it comes to liquid medications. Administration of medicines in liquid form is very common for self medication of medical conditions in adults, as well as in infants. Preferable over tablets, liquid medications are easy to swallow, an important point for children and elderly people. They provide a distinct benefit to these consumers. Liquid formulations should provide a more rapid onset than solid dosage forms with the same active ingredient. From a marketing perspective, liquid formulations provide a wide range of options to differentiate products: appealing to the senses of patients, marketing people understood to create products e.g. cough syrups with different colours and flavours to meet their sensitive taste and other consumer’s preferences. This should be enough for a story of success.

Figure 1: Typical in-use appearance of standard bottle: the content may cover the bottle and depending on the ingredients the screw may be blocked by dried medication

On the other hand, liquids are not easy to handle and to dose, which often means that the medication is not taken as prescribed by the physician or as recommended by the manufacturer. The challenging issue with all these products is the preciseness of the dose. Inconvenient packaging and complicated dosing procedures contribute here. As of today, liquid medications are commonly packed in conventional glass or open-mouth plastic bottles equipped with dosing devices like measuring cups or spoons. But patients are often not able to follow the instructions provided by the manufacturer, and drug products are not always fully compatible with the dosing system they are equipped with. Confusing symbols and measuring units result in over or under- dosages. Apart from the limited if not erased efficacy following under dosing, numerous reports of accidental overdoses are of more serious concern. In an US study, 120 deaths in infants from 1969 to 2006 were attributed to the overdose of unprescribed antihistamines or decongestants1. Consequently, in 2009 the FDA issued a draft guidance “Dosage Delivery Devices for OTC Liquid Products” to address existing safety concerns.

However, there is still space for improvements. Shonna Yin et al of NYU School of Medicine published a study2, showing that top-selling paediatric OTC liquid medications in the US contained highly variable and inconsistent dosing directions and measuring devices. Intelligent and well designed packaging can help to provide a save product as well as a cutting edge to meet patients’ and consumers’ preferences. As tee- and tablespoons are certainly an inappropriate choice, this article tries to provide an overview on up to date dosing systems for multi-dose bottles.

Major problem is simple dosing

Since ages, liquid medications are dosed by numbers of drops dispensed. Alternatively, auxiliary devices such as cups or spoons are utilised. Such dosing procedures in general do not establish any risks for well tolerated drugs with a high safety margin. But many drugs do require exact dosing in order to be effective and to prevent side effects caused by overdosing. For the drug manufacturer easy administration is obviously an important selling argument. Under dosing will result in poor and slow symptom relief, overdosing in more or less severe side effects. Such negative experiences made with a particular drug product will certainly influence the next purchase the consumer may undertake when in the same or a similar condition.

Figure 2: When using a measuring cup with a standard bottle it is hard to hit the mark

The problem is well known and in discussion for quite some time. Consequently, a range of more or less sophisticated solutions is available. The simplest solution and still widely used for dosing of liquid medications is a measuring spoon or cup with appropriate markings. Manufacturers only need to make sure that the appropriate spoon is packed with the drug product it is designed for. The advantages of such spoons or measuring cups are obviously very low costs, and any consumer knows how to deal with it. At least in theory it can be concluded that people know even without consulting the packaging information that a certain amount of liquid needs to be poured onto the spoon or into the cup. However, the interaction between liquid properties, the bottle and the dispensing closure can sometimes turn this into a very challenging task. Not only that sticky medication with sometimes alarming colours will be found all over furniture and clothing, serious dosing issues may occur when the spoon is lost or confused with one for another medication bearing different markings. (See Figure 2)

A step forward is also provided by dosing syringes and recently developed sipping devices. An individual locking system can prevent confusion between different medications while enabling precise dosing. These solutions also prevent contamination of hands or waste of product during handling. However, the use of these systems is not intuitive, comparably complex and requires additional information provided to the consumer. After use and certainly if there are longer intervals of non-use (e.g. cough and cold medication used seasonally), these dosing devices must be cleaned carefully to avoid clogging or microbial growth inside.

New technologies for liquid medications

Figure 3: SimpliSqueeze® is a unique silicone valve system enabling clean dispensing out of flexible bottles and precise dosing into dosing caps or spoons

A very simple but highly efficient technology to enable precise dosing into measuring spoons or cups was recently introduced: Aptar Pharma’s SimpliSqueeze closure system. This is a successful technology, originally developed for the food and beverage sector and consequently adapted to the needs of pharma applications. SimpliSqueeze is a unique silicone valve system enabling clean dispensing out of flexible containers. The system does not provide any metering, so dosing caps or spoons are still required. But SimpliSqueeze facilitates convenient and precise dosing significantly. It keeps the neck of the bottle clean of medication and will prevent clogging (see picture). The valve will prevent dripping and spoiling of product even if the bottle is held in top down position. To dispense the medication, the bottle must be squeezed; the applied pressure controls the product flow. The viscosity of the product may range from water to syrup. As the system is plugged into the bottleneck, the protection cap can be screwed on, using the outer thread of existing containers with or without child-protection features. Plenty of suitable bottles are available on the market using polyethylene terephthalate (PET) as preferred material. The advantages of such bottles are a low weight and high resistance to fracture. (See Figure 3)

SimplySqueeze is, as of today, widely marketed for a broad range of products in the food & beverage (F&B) industry for e.g. honey, mustard or ketchup. Its features make the patented SimpliSqueeze technology the choice for any liquid medications such as cough and cold syrups, decongestants or other liquid medications.

Multi-dose pumps

Figure 4: Examples of vitamin supplements using metering dispensers which ensure easy handling and precise dosing

Another proven but more costly technology is the use of metering pumps for exact dosing and convenient handling (see picture: example Simetocin (Lefax). Such pumps are available at different sizes for a wide range of dosing volumes. Packaging designers need to spend some time to select an appropriate pump, because dosing volume is just one property that requires consideration. The pump must be fully compatible with the targeted formulation. An important consideration is viscosity. Not all pumps can reliably dispense high viscous products. If the medication is of higher viscosity, the force required to deliver the dose (actuation force) may increase to an unacceptable value, certainly decreasing consumer compliance. Dosing problems may occur because of trapped air bubbles, especially when the bottle is shaken before use. If the pump is not used for a longer time, the outlet channels in the actuator may be subject to clogging as a result of crystallisation, in particular if a medication contains a lot of sugar. To overcome such hurdles, some pumps incorporate sealing features at the orifice. Alternatively, flexible caps which have to be reattached after use are available. Another important point to consider is that some pumps have metal parts in the fluid path (e.g. springs or balls) which may be incompatible with the drug. Oxidation (rusty metal parts) and discoloration of the drug product are problems reported in such cases. New pump generations with metal free fluid paths and special design for high viscous products can help addressing such issues. Metering pumps will normally fit standard glass bottles with screw or snap on closures, so the switch from a simple cap to a metering pump is not that complicated from a manufacturing point of view. If such a change is considered, the package must clearly inform about the new dosing technology to avoid habitual use and consequent wrong dosing. (See Figure 4)

Summary

According to a recent market research, consumers reduced their spending on OTC drugs and start to prefer private label products3. This development of consumer behaviour within the triangle of prices, costs, and perceived value will certainly continue throughout the next future. However, innovations in delivery mechanisms or ingredients will help manufacturers in differentiating their products and defend higher price positions. In order to maintain margins and competitive advantages, companies must think about novel products or features appreciated by consumers. If consumers do not perceive value, they will maintain a level of loyalty to a product which is mandatory to keep them from considering private label alternatives.

Packaging suppliers can contribute substantially here to balance convenient handling and patients expectations with manufacturing costs. Last but not least, recent findings and consequent expectations concerning dosing accuracy raised by agencies such as the US Food and Drug Administration (FDA) can be tackled more appropriately with up-to-date technologies.

References:

1. Dart RC et al. Paediatric fatalities associated with over the counter (non-prescription) cough and cold medications. Ann Emerg Med. 2009; 53(4):411-7
2. Yin HS et al. Evaluation of consistency in dosing directions and measuring devices for paediatric non-prescription liquid medications. JAMA. 2010;304(23); E1-8
3. Chmelik S. Balancing Value and Safety: Drivers for Consumer Purchasing Decisions. OTC Perspectives, May 2010, 23-5