Other chapters have discussed the biology and medical consequences of acne, and with it the types of actives required to be delivered to resolve them. This chapter focuses on the actives and the delivery vehicle used, and considers the myriad types of formulation available.
This is not intended to be a truly comprehensive and in-depth study, since space does not permit it. Rather, it is designed to inform and, hopefully, excite inter- est and provide a starting platform for further investigation and experimentation. Some guideline formulations will be given, but there are other sources that offer these in greater number. Suppliers of raw materials are always valuable sources of starting formulary, some of which may already have undergone some perform- ance testing. As with all published formulae, the principle of caveat emptor applies, and the formulator should always confirm that the product performs to the required standards.
The sections within this chapter are intended to form the basis of the infor- mation that needs to be generated in developing the product. Although this may not seem relevant in this context, the risks associated with the formulation are such that a wide range of proof should be established. Some of this is prescribed in legislation, and the requirements this imposes on formulations will be discussed.
Formulations are much more than a simple mix of chemicals with long and often incomprehensible names. The formulation is the long-term success story of a product in that:
B It carries the active and ultimately determines whether or not the active delivers the desired benefits.
B It can influence a user ’s desire to continue using the product to obtain the full benefit of the active.
B For commercial products, persuading consumers to make an initial purchase requires good marketing; getting them to purchase it a second time (and hope- fully more) requires a good formulation.
It is important to note that the majority of topical acne treatment products are commercial in nature, purchased directly from a store shelf or pharmacy counter. Consumer promotion and advertising are an integral part of this market place, and the formulator of such products must be aware of and take into account the demands of these consumers.
Before a product can be considered fit for release to the consumer, consider- ation must be given to the following points:
B Does the product meet the brief set by the marketing team and will it satisfy the end consumer ’s needs?
B Does it conform to the product description, advertising, and any claims that may be made?
B Is it economically viable?
B Does it infringe others’ intellectual property rights?
B Is it safe for its intended purpose?
B Is it stable and will it remain fit for the purpose for a reasonable length of time?
B Can it be manufactured reproducibly and in reasonable quantities to satisfy consumer demand?
Failure to satisfy these principles increases the risk of issues arising in the market place and, with it, potential harm to the user and commercial damage to the produ- cer. As with many things, preparation is the key and a clear strategy of how these points will be addressed should be in place before the formulation is considered. Careful planning, sound scientific skills, and a robust process will ensure the ulti- mate end point—a successful product.
In treating acne, we are attempting to:
B Clear existing lesions and prevent the formation of new ones.
B Relieve the discomfort from the biophysical process of acne formation and therapy.
B Reduce inflammation.
B Minimize the negative psychological effects.
The physical/chemical activities that the product will be attempting to deal with are:
B Reducing excess oil.
B Controlling the bacteria associated with acne.
B Reducing the effects of hyperkeratinization.
B Unclogging pores.
The extent of the condition will dictate the type of active required:
B Moderate-to-severe drug products, some requiring a physician’s prescription.
B Mild-to-moderate mixture of drug products that do not require a physician’s prescription and more cosmetic products from a range of producers, for example, Clearasilw (Reckitt Benckiser Inc., New Jersey, U.S.A.), Clean & Clearw (Johnson & Johnson Corporation, New Jersey, U.S.A.), and Neutrogenaw (Neutrogena Corporation, California, U.S.A.).
The formulator must consider the technical characteristics of maintaining and delivering the drug active alongside the need for an elegant product that the user will enjoy using. Although this may sound incongruous, a product that is enjoyable to use is more likely to be used as required and, therefore, deliver the full benefit of the active.
Formulating the product, that is, putting a mixture of ingredients together, is only the first stage and in doing so the formulator must always bear in mind the basic principles outlined earlier. In order to do that, a clear understanding of what is required allows a robust strategy to be developed, reducing time wasted on unnecessary formulation.
A clear brief or desired end point is essential for an effective strategy. Once obtained, there are three routes the formulator can take:
B Modify an existing product with a known history.
B Use or modify a formulation obtained from the literature.
B Devise an entirely new formulation.
The route taken will clearly be dictated by a number of factors, but will include such things as the degree of risk the formulator is able to take and the timescales in which the product has to be delivered. The first route is clearly the lowest risk, as there will be information on many of the key factors required for a successful development. The second route provides for somewhat higher risk in that the product may not have undergone a complete evaluation.
The final route clearly has the highest risk but offers the greatest flexibility for incorporation of actives, and allows for significant innovation. A clear view of the intended application and all claims that will be made about the product are essen- tial. The starting point will be the active, or actives, and the formulation should be built with the view to maximizing performance, safety, and stability. It is important to remember that this must include end-user compliance; petrolatum may be the best carrier for a topical active, but it would not be the most likely base to ensure continued use. The complexity of factors in producing novel formulations is shown in Figure 1 (1).
FIGURE 1 There are clearly inter-related events that must be taken into account when formulating new products. They are not mutually exclusive and it is important to consider all possibilities during the whole process of development. Source: From Ref. 1.
Acne treatments fall within three major regulatory areas:
B Licensed prescription or licensed over-the-counter (OTC) medicines.
B Monographed OTC medicines.
Regulations exist in all countries concerning most, if not all, of these three areas. Although somewhat easier in the European Union (EU), where there is harmoniza- tion of regulations, formulators should confirm that the ingredients used and pro- ducts produced comply with local regulations, especially where they are likely to be sold in different countries. While the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has attempted to introduce a degree of harmonization in certain areas, it should be remembered that products considered drugs in one country are cosmetics in another.
Even with increasing harmonization, formulators should be aware of the local regulatory status of their product as this may affect:
B The type of claims that can be made.
B The status of certain ingredients such as sunscreens, colors, preservatives, and herbal extracts in terms of ability to use and level.
B The statutory warnings that require displaying for the product, actives, and excipients.
B The quality standards of the actives and excipients used in the formulation.
B The type and extent of the testing required to bring the product to market.
Regulations constantly change and formulators require up-to-date knowledge on the legal requirements and the implications that these may have on the formulation of topical acne products.
In the next section, the range of technologies available for use will be discussed.
There are six major technology areas that formulators may wish to utilize, as shown in Table 1.
An emulsion is a dispersion of two immiscible liquids in the form of droplets. The majority of emulsions fall into one of two types, as shown in Figure 2.
The following general characteristics of emulsions are displayed in Table 2. Emulsions are thermodynamically unstable, which means they are always attempt- ing to return to their natural, single-phase states. This is overcome through the addition of energy in two forms:
B Mechanical energy through the use of high shear mixers.
B Chemical energy through the use of emulsifiers.
In practice, both forms of energy would be used to deliver a longer-term stable product.
Note: The range of products available for use is wide, and careful consideration should be given to the best type to achieve maximum active delivery and good patient compliance.
Emulsifiers are materials that have an affinity for both the oil and water phases, and as such, sit at the interface of the two phases. There are a number of types, as shown in Table 3.
Anionic emulsifiers have increasingly become replaced by nonionic systems, as they offer the formulator much greater flexibility in terms of range, end product characteristics, mildness, and compatibility with actives. Cationic emulsifiers are only rarely used.
With the myriad of emulsifiers that are available for the formulator, the choice is not an easy one. Considerations such as compatibility with actives and excipients and finished product stability are clear priorities, but significant thought should be given to ease of use (both in terms of laboratory and large scale), safety profile, supply chain and, of course, price.
For systems in which the formulator has decided to use nonionic emulsifiers, help is available in deciding the type of emulsifier. Known as the Hydrophilic – Lipophilic Balance (HLB) system, it gives the formulator an indication (within a
given molecule) of the balance between affinity for oil and water. HLB uses a simple numbering system to indicate the relative balance. In the system, 1 represents highly lipophilic (oil-loving) and 20 represents highly hydrophilic (water-loving). Figure 3 illustrates how this is achieved in practice.
The HLB number is determined experimentally by producing emulsions with oils of known HLB, or by theoretical calculation based on the chemistry of the molecule. A blend of high and low HLB emulsifiers will generally be more effective than a single emulsifier that yields an equivalent HLB, as illustrated in Figure 4.
The types of oils used in the formulation will determine the required HLB number. Formulators need to consider the type of emulsion they are intending to make as this can affect the choice of emulsifier system required. For example, to emulsify Paraffinium Liquidium (2):
Required HLB for oil in water: 10 12
Required HLB for water in oil: 4 5
The choice of oils will be determined by the desired texture of the finished product. Such blends are determined by trial and error until optimum product per- formance is achieved. Other ingredients that might form part of the emulsion system include humectants, water phase thickeners, such as carbomer and xanthan gum, preservatives, and fragrance.
An important part of acne treatment is ensuring that the affected area is kept clean. This product category is clearly important in achieving this objective. Although the emulsifiers, described in the previous section, are surfactant in nature, their concen- tration is significantly lower than that found in many washing products such as shampoos and shower gels.
FIGURE 3 Nonionic emulsifier, Cetearyl Glucoside [Tegow Care CG90 (Goldschmidt GmbH, Essen, Germany)], illustrating the balance between hydrophilic and lipophilic entities. The Hydrophilic – Lipophilic Balance of this molecule is 11+1 and by manipulating the number of units on either side, changes the balance and with it the likelihood of being able to produce different emulsion types. Source: Diagram courtesy Degussa Goldschmidt Personal Care.
The classification given in Table 3 remains applicable here, although Table 4 indicates the relative merits of these materials for this application.
The primary purpose of surfactant products in acne applications is the removal of surface oils. While it is possible to add active ingredients to such systems, formulators must remember that they are wash-off products and the degree of deposition of active can vary.
Formulating surfactant products is not simply a matter of maximizing the level of surfactant. Even in oily skin, excessive defatting remains a problem, and the balance between cleanliness and drying/irritation should be taken into account. Due to their nature, surfactants tend to form the micellular structure shown in Figure 5.
This is an important property as it helps to explain the mechanism by which the products remove oil and prevent re-deposition. The surfactant reduces the surface tension of the oil on the skin, allowing dispersion of the unwanted oil in the surfactant system. The lipophilic core of the micelle is where the oil is held.
Formulators must also be aware of the reverse happening with a detrimental effect on product performance. Such situations may occur where actives have signifi- cant affinity for the surfactant micelle, and the active ingredient becomes effectively trapped and is removed on rinsing. This is most likely to occur with lipophilic actives, or in anionic systems with small cationic materials due to charge coupling.
There is a range of anionic surfactants that the formulator may consider. The most popular is based on alkyl ether sulfates, such as sodium or ammonium lauryl ether sulfate. The extent of ethylene oxide addition determines the overall proper- ties of the surfactant. Two or three units are the most common format combining good surfactancy; ammonium salts produce richer creamy foam than the more open but equally copious sodium version. For the equivalent degree of ethoxyla- tion, magnesium salts show more mildness than their sodium counterpart and increasing the number of ethoxylated units also increases mildness (3). Alkyl ether sulfates provide the backbone to many wash products, given their ease of handling, wide range of stability, and cost.
Other commonly used primary surfactants include those from groups such as sarcosinates and sulfosuccinates. These ingredients offer greater mildness (3) and con- ditioning than alkyl ether sulfates, but their cost-performance ratio has not led to their
extensive use. In normal circumstances, product viscosity can be raised through the controlled addition of a compatible electrolyte. This group of surfactants does not easily lend itself to this method and alternative means of thickening, for instance, the use of materials such as PEG-55 propylene glycol oleate need to be considered.
A further way to enhance the characteristics of the primary surfactant is through the use of secondary surfactants such as amphoteric betaines and amine oxides. The most common of this class used is cocamidopropyl betaine, which enhances foam quality and provides some form of skin conditioning.
Although many nonionic surfactants are equally effective at removing excess oils, they are not widely used as primary materials in this medium. The reason is their poor foam production that most consumers associate with an effective product. More commonly found playing a secondary role, many nonionic products can enhance foam stability, leave a good skin feel, and may also have a thickening effect for the products. Among commonly used nonionics are sugar-based gluco- sides such as Decyl Glucoside, alkoxylated amides such as PEG 5 Cocamide, and alkanolamides such as Cocamide DEA.
If using diethanolamines such as Cocamide DEA, the formulator must use high- purity material and avoid using nitrating agents to prevent formation of nitrosamines.
A wide range of additional materials are found in surfactant systems, as shown in Table 5.
While solutions are the simplest and easiest to produce formulation, consideration must be given to the way in which the end user will use the product and, therefore, whether this is the most effective format for delivering actives and benefits.
The major advantage of using solutions is the range of individual and mix- tures of polar and nonpolar solvents that are available to the formulator from water through to oils. Due to the simplicity of many solutions, formulation inter- actions can be more carefully managed than in more complex systems such as emulsions.
There has been an increasing trend toward the use of wipe products that con- sists of a fibrous cloth soaked in a suitable solution. The formulator preparing sol- utions for this type of application must bear in mind the possible interactions with the cloth and the way in which the wipes will be used. This is important for packs offering multiple wipes that allow the user to reseal the pack after each removal. When choosing the solvent, the formulator should consider whether the volatility of their chosen solvent might cause unacceptable changes in the level and
availability of the active. This may manifest itself in two ways. First, the loss of solvent may increase the concentration of active above the legally allowed level, or above the level at which it remains safe. Second, for crystalline solutes (which may or may not include the active), loss of solvent increases the risk of precipi- tation. This may result in injury to the end user, particularly if the product is intended for use around the eye area.
Gel formulations are particularly useful in acne treatments as they offer the possi- bility of delivering active ingredients in a totally oil-free manner. The majority of formulations will be water, alcohol, or mixtures of these materials, but formulators need to be aware that it is possible to gel oils, although this is unlikely to be used in this application. The exception to this is ointments, which it could be argued, are thickened oils, but the formulation of ointments is more complex and is dealt with in a later section.
In its simplest terms, a gel is a thickened solution, although the differing rheo- logical qualities of gels from solutions offer formulators the possibility of improving application and ensuring better control of coverage than for solutions.
Carbomers are acrylic acid polymers available in a variety of grades, offering formulators a range of viscosities and textures with defined yield points that allow excellent spreading and rapid absorption during use. Standard grade carbomers lose viscosity in the presence of electrolyte, although hydrophobically modified grades with improved electrolyte tolerance are available. Due to the need to neu- tralize carbomers to achieve the gel structure, the range of actives that can be used is reduced compared with other gellants.
Xanthan gums are polysaccharides with high molecular weight that show much greater stability toward electrolytes. They have excellent suspending proper- ties due to their pseudoplastic rheology. They will not produce clear gels easily and they are not as rapidly adsorbed onto the skin as carbomers.
Modified cellulose gums are similar in their chemistry to xanthan gums, but clear gels can be produced with certain grades. With a more lubricious feel than car- bomers, they can be used on their own or in combination with carbomers to extend rub-in time.
Silicate systems are available from both natural and synthetic sources. The synthetic material produces clear water white gels that can be stabilized to produce products over a very wide pH range. Due to their anionic nature, they are incompatible with cationic materials.
Although consumers may classify these products and creams as the same for the purpose of this section, an ointment is considered to be an oil base only with no water present. While this may seem unusual for a condition where excess oil is a major cause of the problem, as will be seen later, water-free conditions may be required to provide the best environment for the active.
Ointments, due to their oily nature, can be difficult to remove and leave the skin feeling greasy. For this application, formulators may consider the ointment to be the oil phase of an as yet unfinished emulsion, where the water used to wash the product off forms the final piece. Careful choice of ingredients will improve the rate of removal and with it the after use-skin feel. As always, there
is a balance, in this case, between the desire for effective removal and the risk of irri- tation from the emulsifiers. There are a number of emulsifiers that offer a low irritation potential and their ability to form emulsions at low temperatures, includ- ing the polysorbate group.
Soap remains one of the most widely used personal washing products, and formu- lators should not discount this fact when considering topical treatments. Soap, while it has excellent cleansing properties, does not lend itself to efficient active delivery. The two major drawbacks with soap are that it is washed off and so the active concentration deposited may be small and its high pH can degrade certain actives, and cause a lower tolerability on more sensitive skin.
Alternatives to soap are Combi bars (combinations of soap and synthetic detergents) or Syndet bars, based wholly on synthetic detergents. Syndet bars offer the formulator more flexibility in that their pH is lower and can be modified by allowing a wider range of actives to be used. Soap, Combi, and Syndet formu- lations require specialist knowledge and equipment, and a number of companies offer contracted services in this area.