May 23, 2017 MCM-M05-NI-001
The improved safety profile and patient compliance of topical delivery compared with traditional oral and parenteral administration are appealing features for drug developers. Renewed interest in dermatology has been observed; major pharmaceutical companies have re-entered this sector mainly by extending the indications of existing products into dermatology.2 Meanwhile, the cost of skin medications is rising. An average five-fold price increase of 19 brand-name dermatology prescription drugs has been observed between 2009 and 2015.3
Skin diseases are one of the most common health problems, affecting approximately one third of the global population. Each year, about 60.5 billion units of topical skin medication are sold worldwide.4 The global dermatology market is projected to grow at a moderate 5-year compound annual growth rate (CAGR) of 3.6% and reach $20.4 billion in 2020 (from $17.1 billion in 2015). The United States represents the largest dermatology market (valued at $7.5 billion in 2015; 44% of market share). Its dominance will continue during the next 5 years while the BRIC (Brazil, Russia, India, China) countries are expected to experience the fastest growth rate at a CAGR of 6%, taking 23% of market share by 2020.2 Patent cliffs, the increased incidence of chronic skin conditions, the need to improve patient compliance and innovations in topical drug formulation and delivery are the main driving forces for the growth.
Topical dermatology drugs can be formulated into liquid, solid and semisolid dosage forms. Semisolids are the most common topical formulations and constitute 80% of the global topical dermatology market.4 A wide range of dosage forms belong to this category, including creams, emulsions, ointments, pastes and gels.5 Their ability to adhere to the application surface for a reasonable period of time enables them to achieve extended release to a targeted area in a controlled manner.6 Semisolid formulations are primarily intended for surface action on the skin. They may also be used to transdermally deliver drugs into the systemic circulation, bypassing first-pass hepatic metabolism and gastrointestinal degradation. In addition to the skin, semisolid drugs can also be applied to the surface of other epithelial and mucosal membranes, such as the cornea, nasal mucosa, rectal tissue, vaginal tissue and the external lining of the ear.
Along with the expansion of the topical dermatology market, interest in formulations for skin conditions, especially semisolid products, is increasing. According to the 2017 Nice Insight Pharmaceutical Equipment Survey, more respondents reported that their companies manufacture semisolid dosage forms in 2017 (50%) than in 2016 (45%). In both surveys, semisolid dosage forms were the third most common dosage forms manufactured after liquid and oral solid dosage forms, but the difference between the rankings (semisolid versus oral and liquid) is getting smaller. 7,8 With respect to the purchasing need for processing equipment of semisolid dosages, stronger demand is observed in mixers/stirrers/blenders (45%), heating/cooling equipment (43%) and homogenising equipment (41%) than form-fill-seal equipment (37%), milling equipment (34%) and size reduction equipment (32%).7
A simple scheme for a topical formulation is an active pharmaceutical ingredient dissolved or dispersed into a carrier base with selected excipients to achieve the desired stability and functionality. However, developing an appropriate topical formulation is a complex and challenging process. Many factors need to be taken into consideration, ranging from the intended use and the site of action to the properties of active ingredients and the choice of excipients.
Semisolid drugs are generally developed from four major formulation bases: oleaginous or hydrocarbon bases (ointments), anhydrous or absorption bases, emulsion bases (including water in-oil or oil-in-water bases) and water-soluble bases (gels). Oleaginous, anhydrous and water-in oil bases are lipophilic, emollient and occlusive (prevent water loss from the skin) with a prolonged contact on the application area while oil-in-water and water-soluble bases are hydrophilic, non-greasy, non-occlusive and water washable. Some common excipients used in semisolid formulations include buffers, humectants, permeation enhancers, antioxidants, preservatives, thickeners and chelating agents.9
The ultimate goal of any topical formulation is to allow active ingredients to be absorbed into the desired skin layers at sufficient amounts for therapeutic effects. For most skin diseases, the target site lies in the viable epidermis or upper dermis, which is beneath the stratum corneum, the outermost layer of skin made up of non-viable cells. The stratum corneum is considered to be the major barrier for drug penetration, which is impermeable to almost all compounds and molecules with a molecular weight greater than 500 Daltons.10 Adjusting the carrier base, the incorporation of permeation enhancers into the formulation (such as ethanol, propylene glycol), and increasing skin hydration are commonly used strategies to enhance skin absorption.11 Topical drugs can also be absorbed through hair follicles and sweat glands, but their role is almost negligible in most cases.
The cosmetic property is a unique feature to be addressed during topical formulation development. An aesthetically pleasant product is more likely to gain patient acceptance and thus improve compliance. It can also help products to differentiate themselves in a crowded marketplace. For example, water-soluble based topical products (oil-in-water creams) are often more popular than ointments because they don’t appear greasy, spread easily and leave minimal residue on the skin. This improved cosmetic property is especially important in treating skin conditions such as acne as most of the patients are teenagers and young adults who are extremely self-image conscious.
Like all other pharmaceuticals, there are regulations set forth for topical drugs to ensure drug efficacy and safety both at release and during their shelf-life. The International Conference on Harmonization (ICH) Guidance Q6A recommends four universal tests that are applicable to all topically applied drug products: description, identification, assay (a specific and stability indicating test to determine product strength) and impurities. The United States Pharmacopeia Convention (USP) requires two categories of tests for topical drugs — product quality tests and product performance tests. Specific product quality tests include uniformity of dosage units, water content, microbial limits, antimicrobial preservative content, antioxidant content, sterility, pH and particle size. Apparent viscosity and uniformity in containers are specific tests for topically applied semisolid drugs. Drug release testing is a required drug performance test. The USP recommends the vertical diffusion cell (VDC) method for in vitro drug release testing.1,5
A suitable packaging and dispensing system is a critical component of a finished topical dosage form. The primary role of a packaging system is to protect the product from environmental influences (sunlight, oxygen, moisture, evaporation) and maintain the formulation’s integrity for up to 3 years during shelf storage or a few weeks after first usage.12 Supporting easy, smooth and homogenous dispensing is another important aspect of the packaging. A well-designed dispensing system should also match up with a patient’s lifestyle, capability and cosmetic concerns.
Tubes, jars and bottles are the most common containers used for topical medications. Tubes often serve as the first choice for most semisolid products because of their simplicity and low cost, but they offer only limited barrier protection.Novel drug formulations usually require better barrier protection and the use of advanced dispensing systems to minimise product oxidation, degradation, microbial contamination, drying and clogging.
An airless dispensing system represents an example of a modern dispensing technology. Instead of the traditional pump and straw design, this system applies the concept of vacuum and piston, which completely avoids the contact between the content and the air.4 The airless system can be further optimised by adding features such as a metered system for precise dispensing, a child-resistant, senior-friendly cap for improved safety and convenience, and/or a specialised (digital) applicator for difficult-to-reach body areas.4
An innovative patient-centric packaging system can lead to an attractive brand image, better compliance and, consequently, enhanced customer loyalty. For this purpose, collaborations between drug developers and specialty companies holding advanced dispensing technologies are more likely to increase in the future. In addition, the trend of increased outsourcing activities for pharmaceutical packaging supports this prediction. In the 2017 Nice Insight Pharmaceutical Equipment Survey, the proportion of respondents whose companies have in-house packaging capabilities for both clinical- and commercial-scale manufacturing fell to 49% in 2017 from 68% in 2016. Also, 4% have no in-house packaging line at all in contrast to 0% in 2016.7,8 These observations are clear indications that more pharmaceutical companies are moving toward outsourcing their packaging needs.
Innovation in the field of dermatology occurs at a slower pace than in other therapeutic areas. Moreover, the US FDA approved fewer innovative topical drugs in recent years (2010–2014) than in the 2000–2009 period (4.8 approvals/year versus 8.8 approvals/year). Anti-infective agents and corticosteroids are the two most commonly approved drug types. The most common indications are for acne, tinea infections, psoriasis and atopic dermatitis. Only one eighth of the total approvals (112, 2000–2014) were for new molecular entities (NMEs). Most approvals were for dosage changes, new combinations and new formulations.13 Developing novel topical products based on existing drug substances represents an important strategy for topical drug innovation.
Mr. Walker is the founder and managing director of That’s Nice LLC, a research-driven marketing agency with 20 years dedicated to life sciences. Nigel harnesses the strategic capabilities of Nice Insight, the research arm of That’s Nice, to help companies communicate science-based visions to grow their businesses. Mr. Walker earned a bachelor’s degree in graphic design with honors from London College of Communication, University of the Arts London, England.