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Fluid Thinking


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, and provide a distinct benefit to these consumers as a result. Liquid formulations should also 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 the need to create products such as cough syrups with different colours and flavours to meet their sensitive taste and other consumer’s preferences. This should be enough to guarantee a success story.

On the other hand, liquids are not easy to handle and 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 required. Inconvenient packaging and complicated dosing procedures are all contributing factors. 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 Fluid Thinking Increasing patient compliance, while at the same time ensuring correct dosing, is an ongoing task for the OTC industry when it comes to liquid medications, so selection of a suitable system to dispense these formulations is paramount always fully compatible with the dosing system with which they are equipped. Confusing symbols and measuring units result in over or under-dosages. Apart from the limited – if not entirely absent – efficacy following under-dosing, numerous reports of accidental overdoses are of more serious concern. In a US study, 120 deaths in infants from 1969 to 2006 were attributed to the overdose of unprescribed antihistamines or decongestants (1). Consequently, in 2009 the FDA issued a draft Guidance – Dosage Delivery Devices for OTC Liquid Products – to address existing safety concerns.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 room for improvement. Just recently, Shonna Yin et al of NYU School of Medicine published a study, showing that top-selling paediatric OTC liquid medications contained highly variable and inconsistent dosing directions and measuring devices (2). Intelligent and well designed packaging can help to provide a safe, as well as cutting-edge, product to meet patients’ and consumers’ preferences. As teaspoons and tablespoons are certainly an inappropriate choice, this article tries to provide an overview on up-to-date dosing systems for multi-dose bottles.

Simple Dosing: A Major Problem

For a long time, liquid medications have been dosed by the number of drops dispensed. Alternatively, auxiliary devices such as cups or spoons are used. 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 the side effects caused by overdosing. For the drug manufacturer, easy administration is obviously an important selling point. 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.

This problem is well known and has been discussed by the industry for quite some time. Consequently, a range of more or less sophisticated solutions is available. For dosing of liquid medications, the simplest and still widely used method 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 using spoons or measuring cups are the very low costs involved, and every consumer is familiar with the method; at least people know in theory 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 challenging task. Not only will sticky medication with sometimes alarming colours 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.

Dosing syringes and sipping devices represent a step forward. An individual locking system can prevent confusion between different medications, while enabling precise dosing.These solutions also prevent hands from becoming contaminated during handling or products getting wasted.However, the use of these systems is not intuitive – it can be complex and additional information needs to be provided to the consumer. After use, and certainly if there are long intervals of non-use (such as cough and cold medication used seasonally), dosing devices must be cleaned carefully to avoid clogging or microbial growth inside.

New Technologies for Liquid Medications

A simple but efficient technology to enable precise dosing into measuring spoons or cups is a silicone valve closure system (see Figure 3). This technology was originally developed for the food and beverage sector and has been consequently adapted to the needs of pharmaceutical applications. The unique silicone valve system involved enables clean dispensing out of flexible containers. The system does not provide any metering, so dosing caps or spoons are still required, but it does facilitate convenient and precise dosing significantly.



It keeps the neck of the bottle clean of medication and will prevent clogging (see Figure 3). The valve prevents 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 their low weight and high resistance to fracture.

This type of dispensing system is today widely marketed for a broad range of products in the food and beverage industry such as honey, mustard or ketchup. Its features are also highly suitable for any liquid medications such as cough and cold syrups, decongestants or other fluids.

Multi-Dose Pumps

Another proven but more costly technology is the use of metering pumps for exact dosing and convenient handling (see Figure 4, page 95). Such pumps are available at different sizes for a wide range of dosing volumes. Packaging designers need to spend time selecting an appropriate pump because dosing volume is just one property that requires consideration. The pump must be fully compatible with the targeted formulation. Another important consideration is viscosity; not all pumps can reliably dispense highly viscous products. If the medication is of higher viscosity, the force required to deliver the dose (actuation force) may increase to an unacceptable value, in turn 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 long period of 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 (such as springs or balls) which may be incompatible with the drug. Oxidation (rusty metal parts) and discolouration 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 complicated from a manufacturing point of view. If such a change is considered, the package must explain clearly about the new dosing technology to avoid habitual use and consequent wrong dosing.

Conclusion

According to recent market research, consumers reduced their spending on OTC drugs and started to prefer private label products (3). This development of consumer behaviour within the triangle of prices, costs and perceived value will certainly continue throughout 2011 and into 2012. However, innovations in delivery mechanisms or ingredients will help manufacturers to differentiate 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 FDA can be tackled more appropriately with up-to-date technologies.

References
  1. Dart RC et al, Pediatric fatalities associated with over the counter (nonprescription) cough and cold medications, Ann Emerg Med 53(4): pp411-417, 2009
  2. Yin HS et al, Evaluation of consistency in dosing directions and measuring devices for pediatric nonprescription liquid medications, JAMA 304(23): E1-8, 2010
  3. Chmelik S, Balancing Value and Safety: Drivers for Consumer Purchasing Decisions, OTC Perspectives, May 2010, pp23-25


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Günter Nadler is Director, Business Development, at Aptar Pharma Consumer Health Care Division. He graduated in Business Administration and in Mechanical Engineering, and started his career at Aptar 11 years ago in R&D. Before joining the Business Development Team in 2010 Günter worked in different technical and commercial positions at Aptar Pharma and gained a wide range of knowledge within the pharmaceutical drug delivery industry. He was also Head of the Product Management Team for several years.

Matthias Birkhoff is Vice President, Marketing, in Aptar Pharma. He joined the former Ing Erich Pfeiffer GmbH in 1998 and was Sales Director for the Asia Pacific region before getting involved in business development and marketing. After obtaining a nursing degree he studied medicine at the University of Düsseldorf in Germany.

Degenhard Marx is Director Scientific Affairs within the Consumer Healthcare division. Following the study of veterinary medicine and the successful completion of his PhD at the University of Leipzig, Degenhard joined the Arzneimittelwerke Dresden/Asta Medica co-operate research in 1992. In 2001 he took over a senior research position at Altana Pharma/Nycomed in Constance, Germany. During this time in the pharmaceutical industry he collected ample experiences in the drug development of anti-inflammatory and cardio-vascular drugs. In 2008 he became Business Development Manager at Aptar Pharma.
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Günter Nadler
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Matthias Birkhoff
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Degenhard Marx
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