Considerations on skin medication dispensing

Dr Stefan Hellbardt

Skin diseases are among the most common diseases worldwide. Approximately one third of the population is affected with a pathological skin problem during lifetime. In 2010, the total dermatology drug market has been valued at $26.8 billion and is estimated to grow at a CAGR of 3.7 per cent until 2015. This growth will slow down during subsequent years with the dermatology market reaching an estimate volume of $37.8 billion in 2026[1]. In contrast to that, Asian dermatology markets have enjoyed a growth at a CAGR of around 10 per cent over the last years, which is likely to continue. This is mainly driven by the big markets China (10.7 per cent) and India (10.5 per cent)[2]. In addition to the domestic region major Indian pharmaceutical companies are increasingly looking into opportunities to supply the North American market with branded or generic drugs.

Up to 25 per cent of the worldwide total healthcare spending is for dermatology conditions. So dermatology is certainly not a niche market but a considerable part of the overall public healthcare burden.

Currently, the market is dominated by drugs which require a prescription. Within the five largest European Union countries (EU5), close to 70 per cent of skin medication are prescription-only drugs. This split is considered to reverse within the next years in favour to over-the-counter products due to the following observations:

The number of new drug molecules’ entries into the dermatology market is not projected to increase, following the general trend in new drug submission and approval[3].

Price regulation and pressure will lead to increasing numbers of switches from prescription to over-the-counter (OTC) availability of medication. The OTC market still allows for more freedom in price positioning and consequently enables pharma companies to leverage consumer benefits of their products at higher price levels.

As most skin diseases are not life threatening and often considered a ‘nuisance’ rather than a disease, many patients do not seek physician’s help. Consequently there is considerable out-of-pocket spending by affected patients. Again, these expenses are not subject to government-driven price regulations.

Besides the well documented use of medicated drugs, there is a huge market of non-medicated skin care products: emollients, skin cleansers, or hydration and protection products, among others. These do not fall under a reimbursement schedule, but contribute to the overall disease related spending by individual patients.

Current packaging for skin medication

In 2011 close to 500 million units of topical skin medication have been sold within the EU5 countries. More than 90 per cent of these products have been of semi-solid formulation such as lotions, creams, ointments, gel, paste or foams. The remaining share has been evenly split into liquids and powders[4].

What does this mean with respect to primary packaging? So far the most common packaging types for topical skin products are tubes, bottles and jars.

Tubes are well established and often the first choice for most semi-solid drugs. The simplest and cheapest version is the single layer plastic tube. But barrier function (light, evaporation) is somehow limited. Increased barrier function requirements can be satisfied by use of aluminum or multilayer tubes. The latter combine the barrier function of an aluminum layer with the look-and-feel of a plastic tube making it the most advanced product in the range of tube packaging. Tubes can be combined with a wide range of closures with different design and functionality. Independent from the tube material, once a tube is opened its content is exposed to environmental influences; drying and discoloration can occur. Also dosing and emptying is greatly dependent on tube type and user experience. Especially aluminum tubes are prone to breaking and leakage if not properly stored and handled.

Figure 1: Jar systems with means of a piston system pushed from the bottom either manually (left, Unguator) or using a turn system (right, aponorm)

The use of jars in topical dermatology is easily explained by the need for easy access to the final product. The use in pharmacy made formulations and reconstituted medications often requires a large opening. In turn this means also a large surface in contact with oxygen and allowing for evaporation. Some systems try to limit environmental influences. Additionally, attempts have been made to have better control while dispensing product (Figure 1).

Liquids and low-viscous products are often filled into bottles. While coloured glass bottles offer best barrier functions (evaporation, light protection) plastic bottles are often preferred because of the lower risk of breaking. In order to increase barrier functions, special bottles incorporate a co-blow-molded multilayer bag inside. Basic screw and flip top closures are very common in combination with bottles but bearing the risk of drying and discoloration of product around the orifice. The high-end version of a bottle closure is the pump dispenser which helps to deliver a consistent dose of product with each actuation.

Other primary packaging types used in skin medication include pouches, sachets or stick packs for single doses, airless dispensing systems, or aerosols including bag-on-valve (BOV) systems for multiple uses. Beside standard dispensing systems a range of specialised and often customised packaging solutions has been created.

Understanding trends and requirements of the future topical dermatology marketplace is key for providers of primary packaging to be able to offer specialised or customised packaging solutions.

Trends in skin medication

Some trends in the topical dermatological market start to change the way these drugs are packaged and delivered to the end consumer. Trends that drive this change and, therefore, are important to the pharma industry include:

• changes in life-style and demographics
• increased awareness of drug safety
• pressure from public healthcare systems to deliver cost efficient treatments
• drying pipelines of drug innovation and, in consequence,
• pressure to differentiate existing products from competition.

On top of these general challenges, skin medication requires a special focus on protection of mostly semi-solid drug products, convenient dosing, access to difficult-to-reach body areas and lesion-directed treatment.

Protection from environmental influences

It is likely that innovative and complex drug formulations will demand increased protection through primary packaging. Shelf-storage for up to three years is followed by an in-life period of a few weeks. After first dispensing remaining product on the dispensing system tends to dry or potentially crystallise. This is particularly observed with viscous formulations where drying product can lead to clogging and subsequent malfunction of the dispensing system.

Topical dermatology products often use fatty or oily auxiliary components to enhance the retention on and uptake of the drug substance through the skin. Such formulations are often sensitive to a variety of environmental influences. Exposure to sun light or oxygen can lead to deterioration of drug substance activity as well as development of unfavorable colour.

Intake of moisture from the environment into the formulation or evaporation of water or solvents from the package will lead to changes of the concentration of active drug and potentially to a deterioration of content. Consequently diffusion has to be eliminated by use of appropriate packaging material providing sufficient barrier function.

During the in use period, the orifice of any dispensing system is the most challenging region because here the content is in direct contact with the environment. Clogging due to drying product is actually the most often reported complaint. Standard pump systems represent a constant barrier to outside air in itself. However, at the outer part of the dispenser they will not avoid oxygen exposure or clogging due to evaporation. Modern pump dispensing systems are designed in such a way that the orifice is closed between the actuations. This prevents entry of air into and drying of the medication within the system. Different technical options are available in the market. Flexible closing lips support clean dispensing and help protecting against air intake during periods of storage. Self-closing mechanisms can be designed into pump actuators to better protect dispensing orifices (Figure 2).

Figure 2: Dispensing systems preventing air intake. From left to right: flexible lips for dispenser heads or tube closures (Aptar), self-closing mechanisms by use of elastomer (Megaplast) or mechanical elements (Aptar)

If product is dispensed from a vented system, ambient air will replace the dosed volume in the container and consequently get in contact with the remaining product. This may be critical for oxygen sensitive drug products. In situations where oxygen contact needs to be avoided so called unvented or airless packaging systems should be used. In these airless systems moving parts (tow piston) or collapsing bags compensate for the volume of the dispensed product. In such systems the wall of the container must be able to barrier against oxygen diffusion. Alternative systems use a plastic or aluminum bottle to provide the desired outer shape and use aluminum or multilayer inner bags to contain the product.

Protection from microbial contamination

To keep microorganism levels in the product low during the in use period, most often preservatives are used. But preservatives in skin medication are critically discussed by the medical community. Especially in patients with diseased skin preservatives are a potential source of additional irritation. Parabens (i.e., para-hydrobenzoic acid esters) are used for anti-microbial protection in a variety of cosmetic and pharma skin formulations. During the last years they have come under scrutiny after observation of contact sensitisation exacerbating in patients with inflamed or broken skin. Even if paraben levels nowadays are below limits where they are generally recognised as safe, they have been eliminated from most skin medications. However, the use of other preservatives that serve as replacement bears the same concerns about irritation. Therefore more and more preservative-free formulations are entering the market of skin medication.

Primary packaging and dispensing systems that are able to handle non-preserved drug products need to prevent bacterial ingress into the drug product. These dispensing systems build a physical barrier to microbes at the interface to the outside. Sealing needs to be sufficiently strong to break product micro-films.

Recently systems with self-sealing dispensing orifices have reached the market. These systems make use of elastomer elements or spring-loaded tips sealing the dispensing orifice. They can effectively protect non-preserved formulations or allow for lower concentrations thereof.

Figure 3: Microbial-tight dispensing systems. Aptar APFPLUS spray pump with spring controlled tip-seal mechanism and bacteria-blocking filter for venting air

Another source of microbes is venting air. Whereas non-vented packaging prevents contamination by avoiding incoming air, sophisticated systems allow incoming air to pass through layers of filtering micro-membranes (Figure 3). All dispensing systems supporting preservative-free drug formulations have to prove the ability to resist microbial challenge testing simulating storage and use conditions.

Consumer convenience

A substantial number of dermatological diseases require daily use of skin medication over a prolonged time. Dispensing systems for skin medication should be convenient supporting patients’ adherence to long-time treatment.

Smooth actuation and good control of product flow can be obtained from non-metered systems (e.g., BOV, tube). Obtaining a consistent amount of medication as appropriate for the diseased skin area is very much user dependent. For non-metered dispensing systems concerns of under- or overdosing can only be minimised by dosing recommendations from drug manufacturers. Commonly these are either describing the thickness of product layer onto the affected area (e.g., ‘Cover … with a thin film of…’), make use of comparisons to phalanges, or provide card box rulers together with the medication package.

Metered dispensing systems for lotions or creams are available using precision pumps. Delivering a consistent dose per stroke from a metered pump system enables the patient to have the same amount of product used each day even over long time. Thereby the prescribed dose is ensured and safety concerns regarding overdosing are minimised.

Product dispensing and application

In dermatological disease the skin is often inflamed or broken, and therefore sensitive to direct contact. Formulations that can be applied easily and homogenously are preferred. Target lesions might be anywhere on the body or even be very small. Therefore, packaging that supports dispensing to difficult-to-reach body areas is appreciated.

Liquids can be applied by continuous valve or metered pump dispensers creating a soft spray without any need to touch skin areas that are sensitive or inflamed. Likewise skin medication formulated as foam or mousse ensures smooth spread across the area to treat. Aerosol foams are commonly created by use of pressurised packages in combination with specialised foam actuators. More recently innovative mixing and filling techniques in connection with BOV systems allowing the generation of mousse from a semi-solid preparation has raised the interest of drug manufacturers. BOV technology does not require the use of a propellant as part of the drug formulation. Instead pressurised air in the outer container is used to deliver the bulk from a separated inner pouch. Pump foamers are non-pressurised systems that are mainly used in skin cleansing and care.

Reach to body areas is greatly supported by dispensing systems that enable use at different device orientations. Not all delivery systems can be used upside-down. All so called Airless Systems can be used at any direction thereby providing maximum flexibility during drug application.

By using specialised applicators in combination with small volume pumps skin medication can be directly applied to a tiny target lesion. These applicators can be designed for dispensing medication on-the-spot avoiding the need for additionally use of finger tips (Figure 4). In situations where other persons give care to a relative or child this might be appreciated.

Figure 4: Applicator systems to help with lesion directed dispensing. Digital Airless with finger-like applicator head. SofTips tube closure with soft touch silicone lips. (Aptar)

Life-style

Stigmatisation of patients in need for medical treatment should be avoided. Especially for certain patient groups like teenagers with acne, peer group pressure can lead to treatment discontinuation and non-adherence.

Ideally treatment regimen and dispensing should match a patient’s daily schedule, activity and capability. In consequence dispensing systems might be targeted to different user groups. Mobile and active life style or an increasingly aging population with e.g. limited dexterity, are two examples of related mega trends in the western population.

Figure 5: Convenient dispensing systems for everyday use. Aptar Bag-on-valve and small piston system for carry-on

Medication that is handy at the time the patient needs to use it is more likely to be taken. Therefore dispensing systems need to be limited in size and robust enough to be carried around in a sports bag or purse. Small airless pump systems and bag-on-valves offer a convenient size, protect the medication from influence of air, leakage or damaging impact, and provide good control of dispensing (Figure 5). Dispensing systems that appear pleasant, trendy or look like ‘just another cosmetic’, are likely to enhance acceptance.

Safety

There is an ever increasing amount of information delivered together with pharma products. Despite efforts to improve readability and comprehension of printed patient information [5] it is common belief that most patients do not properly read this. Self-explanatory and convenient dispensing systems can support correct and safe use. Key instructions repeated on the dispensing system, symbols to guide the patient, and finger flanges providing tactile feedback during dispensing are only some examples that, if properly designed, help intuitive use. On the other hand such intuitive guidance should be introduced cautiously. Symbols may be interpreted differently in different regions of the world. Understanding of design features might not be the same with every cultural background. Consequently regional consumer input into innovation is key to develop successful dispensing systems that add value to the drug product.

More recently products that are exceptionally potent or cause serious side effects have come under observation. To prevent contact with potentially harmful medication (e.g., hormones, minoxidil) by unattended children, special primary packaging incorporating child resistant features may become mandatory[6]. Push-and-turn solutions that are used for tablet containers are already implemented as bottle or tube closure. Over-cap solutions that are known from e.g. household chemicals can be implemented in packaging for pharma. Locking mechanisms integrated into the dispenser head offer the benefit of not being accidentally separated from the medication package during use.

Introducing safety features into pharma packaging always has to be balanced with accessibility. The megatrend of demographic shift will lead to increasing numbers of elderly consumers. Patients with limited dexterity or poor eyesight might have problems to access the drug product at all. Innovative packaging solutions can help to improve accessibility to medication and compliance to treatment schedules (e.g. triangle-shaped closures or bottle shapes)[7].

Product differentiation

The growing number of drugs that are put on the market has led to increased competition within every single treatment regimen. Presently several pharma companies are developing drugs using the same active molecule and wish to differentiate their product from competition. Brand recognition plays a major role in a situation where patients are well educated, have access to multiple sources of information and are faced with increasing out-of-pocket expenses when buying their medicine.

Next to efficacy and safety of a drug attractiveness of the package, convenience and differentiation together help to generate consumer loyalty.

Currently, the dominant packaging forms are tubes, bottles with basic closure, and jars. Due to the number of medication on the market using similar packaging types there is little opportunity to differentiate a product beyond printed design or secondary packaging.

Figure 6: Aptar creative design for differentiated products. Innovative packaging for modern consumers: pen dispenser study, bottle design

Dispensing systems that offer additional characteristics will provide potential to stick out from the crowd. Innovative design in bottle or container shape will offer product recognition (Figure 6). The use of custom made applicator systems will not only enhance convenience but also help to create a dispensing experience that will last in the mind of the patient.

Life cycle management of a drug changing from a more common to innovative packaging systems bears the opportunity to create a new brand image, to retain existing or attract new consumers, and to differentiate from competition.

Summary

Traditional packaging of topical medication appears to be almost boring, but new delivery devices are on the horizon. Primary packaging systems for topical dermatological products face different challenges but at the same time are offering great opportunities. Depending on the needs, the content will be protected from environmental influences, like oxygen, light or drying and clogging. New systems are able to block microbial contamination and will help to reduce or even avoid the need for potentially harmful preservatives. Ideally innovative dispensing systems support long-term treatment schedules through attractiveness, convenience, intuitive design, and a match with the daily activity of the patient.

Metered pump systems or continuous valves provide good control of product dispensing. Airless systems as well as BOV technology ensure all angle use enabling good reachability of body locations. Specialised actuators help in treating small lesions or avoiding finger contact with aggressive formulations. Early life cycle management by introducing innovative dispensing systems can help to differentiate drug products from competition, attract consumers and secure brand recognition.