Oral Liquid Medications

Administration of medicines in liquid form is very common forself-medication of medical conditions in adults as well as ininfants. Preferable over tablets, liquid medications are easy toswallow, an important point for children and elderly people, andprovide a distinct benefit to these consumers as a result. Liquidformulations should also provide a more rapid onset than soliddosage forms with the same active ingredient. From a marketingperspective, liquid formulations provide a wide range of optionsto differentiate products: appealing to the senses of patients,marketing people understood the need to createproducts such as cough syrups withdifferent colours and flavours tomeet their sensitive taste andother consumer’s preferences.This should be enough toguarantee a success story.

On the other hand, liquids arenot easy to handle and dose,which often means that themedication is not taken asprescribed by the physician or asrecommended by the manufacturer.The challenging issue with all these products isthe preciseness of the dose required. Inconvenient packagingand complicated dosing procedures are all contributingfactors. As of today, liquid medications are commonly packedin conventional glass or open-mouth plastic bottlesequipped with dosing devices like measuring cups or spoons.But patients are often not able to follow the instructionsprovided by the manufacturer, and drug products are not

Fluid ThinkingIncreasing patient compliance, while at the sametime ensuring correct dosing, is an ongoing taskfor the OTC industry when it comes to liquidmedications, 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 measuringunits 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 moreserious concern. In a US study, 120 deaths in infants from 1969 to 2006 were attributed to the overdose ofunprescribed antihistamines or decongestants (1).Consequently, in 2009 the FDA issued a draft Guidance –

Günter Nadler, Matthias Birkhoff andDegenhard Marx at Aptar Pharma

Figure 1 (above): Typical in-use appearance of standard bottle: the contentmay cover the bottle and depending on the ingredients the screw may beblocked by dried medication

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Dosage Delivery Devices for OTC Liquid Products – to addressexisting 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 medicationscontained highly variable and inconsistent dosing directionsand measuring devices (2). Intelligent and well designedpackaging can help to provide a safe, as well as cutting-edge,product to meet patients’ and consumers’ preferences. Asteaspoons and tablespoons are certainly an inappropriatechoice, this article tries to provide an overview on up-to-datedosing systems for multi-dose bottles.

Simple Dosing: A Major Problem

For a long time, liquid medications have been dosed by thenumber of drops dispensed. Alternatively, auxiliary devicessuch as cups or spoons are used. Such dosing procedures ingeneral do not establish any risks for well-tolerated drugswith a high safety margin. But many drugs do require exactdosing in order to be effective and to prevent the side effectscaused by overdosing. For the drug manufacturer, easyadministration 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 negativeexperiences made with a particular drug product will

certainly influence the next purchase the consumer mayundertake when in the same or a similar condition.

This problem is well known and has been discussed by theindustry for quite some time. Consequently, a range of moreor less sophisticated solutions is available. For dosing ofliquid medications, the simplest and still widely used methodis a measuring spoon or cup with appropriate markings.Manufacturers only need to make sure that the appropriatespoon is packed with the drug product it is designed for. Theadvantages of using spoons or measuring cups are the verylow costs involved, and every consumer is familiar with themethod; at least people know in theory without consultingthe packaging information that a certain amount of liquidneeds to be poured onto the spoon or into the cup.However, the interaction between liquid properties, thebottle and the dispensing closure can sometimes turn thisinto a challenging task. Not only will sticky medication withsometimes alarming colours be found all over furniture andclothing, serious dosing issues may occur when the spoon islost or confused with one for another medication bearingdifferent markings.

Dosing syringes and sipping devices represent a step forward.An individual locking system can prevent confusion betweendifferent medications, while enabling precise dosing. Thesesolutions also prevent hands from becoming contaminated

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

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

during handling or products getting wasted. However, the use of these systems is not intuitive – it can be complex andadditional 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), dosingdevices must be cleaned carefully to avoid clogging ormicrobial growth inside.

New Technologies for Liquid Medications

A simple but efficient technology to enable precise dosing into measuring spoons or cups is a silicone valveclosure system (see Figure 3). This technology was originallydeveloped for the food and beverage sector and has beenconsequently adapted to the needs of pharmaceuticalapplications. The unique silicone valve system involvedenables clean dispensing out of flexible containers. Thesystem does not provide any metering, so dosing caps orspoons are still required, but it does facilitate convenientand precise dosing significantly.

It keeps the neck of the bottle clean of medication and willprevent clogging (see Figure 3). The valve prevents drippingand spoiling of product even if the bottle is held in topdown position. To dispense the medication, the bottle mustbe 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 protectioncap can be screwed on, using the outer thread of existingcontainers with or without child-protection features.Plenty of suitable bottles are available on the market usingpolyethylene terephthalate (PET) as preferred material. Theadvantages of such bottles are their low weight and highresistance to fracture.

This type of dispensing system is today widely marketed for abroad range of products in the food and beverage industrysuch as honey, mustard or ketchup. Its features are also highly

Figure 4: Examples of marketed products featuring metering dispenserssuitable for any liquid medications such as cough and coldsyrups, decongestants or other fluids.

Multi-Dose Pumps

Another proven but more costly technology is the use of metering pumps for exact dosing and convenienthandling (see Figure 4, page 95). Such pumps are availableat different sizes for a wide range of dosing volumes.Packaging designers need to spend time selecting anappropriate pump because dosing volume is just oneproperty that requires consideration. The pump must befully compatible with the targeted formulation. Anotherimportant consideration is viscosity; not all pumps canreliably dispense highly viscous products. If the medicationis of higher viscosity, the force required to deliver the dose(actuation force) may increase to an unacceptable value, inturn decreasing consumer compliance. Dosing problemsmay occur because of trapped air bubbles, especially whenthe bottle is shaken before use. If the pump is not used for a long period of time, the outlet channels in the actuatormay be subject to clogging as a result of crystallisation – in particular if a medication contains a lot of sugar. Toovercome such hurdles, some pumps incorporate sealingfeatures at the orifice. Alternatively, flexible caps which haveto be reattached after use are available. Another importantpoint to consider is that some pumps have metal parts in the fluid path (such as springs or balls) which may beincompatible with the drug. Oxidation (rusty metal parts)and discolouration of the drug product are problemsreported in such cases. New pump generations with metalfree fluid paths and special design for high viscous productscan help addressing such issues. Metering pumps willnormally fit standard glass bottles with screw or snap onclosures, so the switch from a simple cap to a meteringpump is not complicated from a manufacturing point ofview. If such a change is considered, the package mustexplain clearly about the new dosing technology to avoidhabitual use and consequent wrong dosing.

Conclusion

According to recent market research, consumers reducedtheir spending on OTC drugs and started to prefer privatelabel products (3). This development of consumer behaviourwithin the triangle of prices, costs and perceived value willcertainly continue throughout 2011 and into 2012. However,innovations in delivery mechanisms or ingredients will helpmanufacturers to differentiate their products and defendhigher price positions. In order to maintain margins andcompetitive advantages, companies must think about novelproducts or features appreciated by consumers. If consumersdo not perceive value, they will maintain a level of loyalty toa product which is mandatory to keep them fromconsidering private label alternatives.

Packaging suppliers can contribute substantially here tobalance convenient handling and patients expectations with

manufacturing costs. Last but not least, recent findings andconsequent expectations concerning dosing accuracy raisedby agencies such as the US FDA can be tackled moreappropriately with up-to-date technologies.

References1. 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 directionsand measuring devices for pediatric nonprescription liquidmedications, JAMA 304(23): E1-8, 2010

3. Chmelik S, Balancing Value and Safety: Drivers for Consumer Purchasing Decisions, OTC Perspectives, May 2010, pp23-25

About the Authors

Günter Nadler is Director, BusinessDevelopment, at Aptar Pharma ConsumerHealth Care Division. He graduated inBusiness Administration and in MechanicalEngineering, and started his career at Aptar11 years ago in R&D. Before joining theBusiness Development Team in 2010 Günter

worked in different technical and commercial positions atAptar Pharma and gained a wide range of knowledge withinthe pharmaceutical drug delivery industry. He was also Headof the Product Management Team for several years. Email: guenter.nadler@aptar.com

Matthias Birkhoff is Vice President, Marketing,in Aptar Pharma. He joined the former IngErich Pfeiffer GmbH in 1998 and was SalesDirector for the Asia Pacific region beforegetting involved in business development andmarketing. After obtaining a nursing degree he studied medicine at the University of

Düsseldorf in Germany. Email: matthias.birkhoff@aptar.com

Degenhard Marx is Director ScientificAffairs within the Consumer Healthcaredivision. Following the study of veterinarymedicine and the successful completion of his PhD at the University of Leipzig,Degenhard joined the ArzneimittelwerkeDresden/Asta Medica co-operate research

in 1992. In 2001 he took over a senior research position atAltana Pharma/Nycomed in Constance, Germany. Duringthis time in the pharmaceutical industry he collected ampleexperiences in the drug development of anti-inflammatoryand cardio-vascular drugs. In 2008 he became BusinessDevelopment Manager at Aptar Pharma. Email: degenhard.marx@aptar.com