Selection of Vehicle Type

The type of vehicle may already be determined by the product target profile. If various types are possible, the most suitable should be selected. The following selection criteria are important: function or desired effect of the vehicle on the skin, ease of formulation feasibility, and physical and chemical stability. Furthermore, solubility, polarity, saturation solubility, vehicle interactions, and formation of mesophases are subjects to be considered when dealing with development and selection of vehicles. These topics are discussed later.

True Solution Versus Disperse System

Whenever the target of an active substance lies in deeper regions of the skin or even in skin cells, the substance must be present in molecular form for successful and efficient delivery, i.e., it must be dissolved in the vehicle or it must be able to dissolve, at least, after application. In other words, dissolution of a substance is a prerequisite for its delivery to a biological viable target (e.g., cell, enzyme). It is only in the dissolved state that fast and efficient penetration and transport into the deeper skin layers and cells is possible.

Thus, the first goal in formulation development is to dissolve the active substance in the vehicle. Therefore, the vehicle should be an ideal solvent for the active substance. If a substance cannot be dissolved in the vehicle—this may happen because of low solubility properties or stability reasons—then the substance has to be incorporated in particulate form; the smaller the size, the better. Fine particles in the order of 1 |m can be delivered onto or even into the uppermost layers of the skin, as close as possible to the target site. There they may dissolve, faster or slower, depending on their solubility in the skin. In vehicle systems containing particulate matter, homogeneous distribution of the undis-solved substances must be guaranteed.

In summary, if the first goal—dissolution of active substance in the vehicle—is not achieved, the first alternative in formulation development must be targeted: the substance to be delivered must occur in particulate form as fine as possible. This is the prerequisite for fast and efficient delivery of unsoluble matter into the skin close to the target site.

Polarity

In order to achieve dissolution of a substance (solute), the adequate vehicle (solvent) has to be selected. The solubility of a substance is attributable in large measure to the polarity of the solvent, and it generally depends on chemical, electrical, and structural effects that lead to mutual interactions between the solute and solvent [29]. Polar solvents dissolve ionic solutes and other polar substances, whereas nonpolar substances are dissolved in nonpolar, lipophilic solvents. Solubility properties determine the selection of the appropriate vehicle for both, for solid as well as for liquid substances. Only nonpolar liquids are mutually completely miscible and thus can be used to make a nonpolar liquid vehicle. Accordingly, the same is true for polar liquids (e.g., water and alcohol).

Solubility characteristics of a compound used in formulation is one of the most important factors to be considered. Solubility data can be found in the literature; very often they are delivered by suppliers of the substances or they must be determined experimentally. In formulation the solubility parameter 5, according to Hildebrand and Scott [30], is a useful tool for selection of appropriate solvents. The more alike the 5-values of the compounds, the greater is their mutual solubility. A list of solubility parameters of cosmetic ingredients is given in Ref. 31. Very apolar substances have a low 5-value, and water has the highest value [23]. A rule of thumb states that mutual solubility is given if the difference between the two specific 5-values is at maximum 2 units (cal/cm3)-2.

Particularly in cosmetic formulation, where oils and lipids play a dominating role, polarity of oils is a factor to be considered. According to ICI Surfactants [16], the polarity may also be expressed by the polarity index based on the surface tension between the oil and water. Another interesting and simple characterization method is based on the bathochromic effect of a suitable dye dissolved in oils. The absorption maximum in the visible light—and therefore the color—of a nil-red-oil solution depends on the polarity of the oil; the higher the absorption maximum, the more polar is the oil or oil mixture [32].

In conclusion, if a monophasic system has to be formulated, only substances with mutual solubility can be combined. In contrast, if multiphasic systems such as emulsions and suspensions are made, the phase-forming components must be mutually insoluble. Nevertheless, preparation and solubilization of multiphasic systems require the addition of amphiphilic substances (emulsifiers in emulsions, surfactants for wetting and repulsing the particles in suspensions). In emulsions, polar as well as nonpolar substances can be dissolved in the hydrophilic or lipophilic phase, respectively. This is one reason for the popularity of emulsions.

Saturation, Supersaturation

Theoretically, a solute can be dissolved in a solvent up to the saturation solubility. Beyond this concentration, precipitation of the solute or phase separation usually occurs. Some substances are able to remain transiently in solution above saturation solubility. This phenomenon is known as supersaturation, a metastable condition. Supersaturated solutions can be caused to return to saturation equilibrium by triggers such as agitation, scratching the wall of containers, or addition of seeding crystals.

The driving force for delivery of substances, i.e., release from vehicle and penetration into skin, is thermodynamic activity, which is maximal at saturation concentration [33]. Consequently, in order to achieve maximal penetration rate into the skin, a substance must be dissolved in a vehicle at saturation concentration. Moreover, saturated or supersaturated systems are necessary, but not the only prerequisites for optimal topical delivery. For example, the skin—vehicle partition coefficient of the solute also plays a role. The partition coefficient may be raised because of the vehicle—skin interaction yielding in increased skin penetration. In conclusion, achieving the highest possible concentration in the dissolved state is the second goal to be aimed for in formulation development if delivery into the skin is targeted.

Vehicle Interactions

Sun-protection products are a good example of showing interactions between vehicle, active substance, and the skin. The absorption of UV radiation not only depends on the molecular structure and concentration of the protecting agent, but on the solvent as well. Also, water resistancy may be influenced by selection and composition of the vehicle.

Vehicle components may penetrate into the stratum corneum and interact with the stratum corneum lipids. This may result in disturbance of their lamellar structures and increased and faster penetration of compounds in the stratum corneum. Alternatively, presence of vehicle components in the stratum corneum may cause a depot effect for certain compounds.

Substantivity

The term substantivity describes adherence properties of materials to keratinous substrates in the upper skin layers, in particular regarding deposition and retention capacity when in contact with water, which could deplete the material [34]. High substantivity is especially important for sun protection products. It is primarily a function of the physicochemical properties of the active molecules but may also be influenced by the vehicle. For example, addition of film-forming, skin-adherent polymeric substances to the vehicle may increase retention of sunscreens in the skin and thus result in an improved water-resistant product. Another means is creating formulations that contain phospholipids, enabling the formation of vesicular, liposomal structures in the vehicle or in the upper layers of stratum corneum and thus yielding in a depot effect.

An interesting model to assess substantivity has been presented by Ref. 34. The investigators used human callus to simulate and quantify solute sorption to human skin, which was found to be more suitable than octanol or animal keratin. However, water resistancy still has to be determined in vivo to know the true quality of the product.

Mesophases

Not only the type of vehicle, e.g., solution or o/w emulsion, but also occurrence and type of mesophases (liquid crystal structures) determine the properties and behavior of a vehicle. At certain concentrations and combinations of specific emulsifying agents in liquids, associations may be formed, resulting in liquid crystal structures, also called mesomorphic state or mesophase. The mesophase shows anisotropy and is thermodynamically stable. Different types of mesophases have been described: middle phase (hexagonal), cubic phase, and neat phase (lamellar).

Fatty amphiphiles (e.g., long chain alcohols, acids, monoglycerides) that are dispersed in water in the presence of a high hydrophilic-lipophilic balance (HLB) surfactant form lamellar phases. They are able to swell at an elevated temperature close to the melting point of the hydrocarbon chain. These swollen lamellar liquid crystalline phases can incorporate significant quantities of water. The hydrocarbon chains are liquid-like, i.e., disordered. If the temperature decreases, the lamellar liquid crystalline phases of fatty amphi-philes are transformed to so-called lamellar crystalline gel network phases, which build complex gel networks. Such networks not only stabilize creams and lotions, but also control their consistency because of their viscoelastic properties. Such mesophases provide the following advantages to emulsions:

1. Increased stability

2. Prolonged hydration properties

3. Controlled release of active ingredient

4. Easy to formulate

5. Well-liked skin feel [35]

Metamorphosis of Vehicles

Most vehicles undergo considerable changes during and after application to the skin because of mechanical stress when spread over the surface and/or evaporation of volatile ingredients. Mechanical stress and skin temperature may influence the viscosity of the vehicle and consequently the release rate of active ingredients. Uptake of water from the skin may alter the composition of the vehicle. All these factors may also cause phase inversion or phase separation. And last but not least, as a consequence of these alterations the thermodynamic activity of an active ingredient within its vehicle will change as well. Thus, by controlling or changing the thermodynamic activity, release of a substance from the vehicle and penetration into the skin can be modulated. For example, if after application the volatile component of the vehicle, being an excellent solvent of the active substance, evaporates, saturation concentration of the active in the remaining vehicle or even supersaturation may be achieved. This results either in improved release and delivery as previously mentioned (see Section 5.2.3) or in precipitation and deposition of the active substance. Another interesting example is given by an optimally composed sun-protecting o/w-emulsion; after application the emulsion has transformed to the w/o type because of water evaporation and the mechanical stress caused by spreading. The remaining lipophilic protective film yields in improved water resistancy.

In conclusion, the optimally designed and developed vehicle not only demonstrates excellent properties after manufacturing and storage, but also after application and metamorphosis at the application site.

Rheology

The term rheology describes the flow characteristics of liquids and the deformation of solids. Viscosity is an expression of the resistance of a fluid to flow. Rheological properties are crucial for liquid and semiliquid cosmetic formulations because they determine the product's properties meaningful in mixing and flow when produced, filled into containers and removed before use, as well as sensory properties when applied, such as consistency, spreadability, and smoothness. Furthermore, the rheology of a product may also affect the physical stability and the biological availability of the product [36].

Regarding rheological characteristics, there are two main types of systems: Newtonian and non-Newtonian. The former show constant viscosity when stressed, i.e., the rate of shear (flow velocity) is directly proportional to the shearing stress, e.g., water, mineral oil, etc. In non-Newtonian systems (most cosmetic products), however, viscosity changes with varying stress, i.e., viscosity depends on the degree of shearing stress, resulting either in plastic, pseudoplastic, or dilatant flow or in thixothropy, characteristics that are not discussed in depth here although they are of practical significance. An ideal topical product, e.g., shows optimal thixotropic properties; it does not flow out of a tube's orifice unless slightly pressed, and when on the skin it does not immediately flow and drop off unless easily spread over the application area, where under a certain stress it becomes more fluid because of the thixotropy. The rheological properties of semisolid products are determined first for general characterization in the development phase and second for quality-control reasons after manufacturing. There are various instrumental methods used to measure rheology or viscosity. Today, apparatus based on rotation or oscillation are commonly used for non-Newtonian systems.

In order to adjust the rheology of products, various means and excipients are available. If the viscosity has to be increased, addition of viscosity increasing agents is needed. Addition or increase in concentration of electrolytes may influence viscosity. Many systems, e.g., polyacrylates, are sensitive to the presence of ions and the viscosity is reduced.

In particular, emulsions are susceptible to rheological issues. Various factors determine the rheological properties of emulsions, such as viscosity of internal and external phases, phase volume ratio, particle size distribution, type and concentration of emulsifying system, and viscosity-modifying agents. However, this topic is too complex to be treated comprehensively in this context. It is further discussed in a review by Sherman [37]. It is important to realize that small changes in concentrations or ratio of certain ingredients may result in drastic changes of the rheological characteristics. Emulsified products may undergo a wide variety of shear stresses during either preparation or use. Thus, an emulsion formulation should be robust enough to resist external factors that could modify its rheological properties or the product should be designed so that change in rheology results in a desired effect.

Preservation

Antimicrobials

Most cosmetic care products must be protected against microbial growth. Not only for the protection of consumers against infection but also for stability reasons. Growth of microorganisms might result in degradation of ingredients and consequently in deterioration of physical and chemical stability. In general, presence of water in the vehicle as well as other ingredients susceptible to microbial metabolism require adequate preservation.

There are various ways to protect a product against microbial growth:

1. Addition of an antimicrobial agent, which is common practice

2. Sterile or aseptic production and filling into packaging material, preventing mi-crobial contamination during storage and usage

3. Reduced water activity, i.e., controlling growth of spoilage microorganisms by reducing the available amount of water in cosmetic preparations [38]

It is not only mandatory to add antimicrobials but also to test their efficacy after manufacturing and after storage until the expiration date. Nowadays performance of the preservative efficacy test (PET), also known as the challenge test, is state of the art [39]. Today more and more in-use tests are performed to simulate the usage by the consumer and to show efficacious protection against microbial growth after contamination.

Addition of preservatives to complex, multiphasic systems, in particular, is a critical formulation issue for the following reasons:

1. Many preservatives interact with other components of the vehicle, e.g., with emulsifyers, resulting in change of viscosity or in phase separation in the worst case.

2. Depending on the physicochemical characteristics, preservatives are distributed between the different phases which might result in too-low effective concentration in the aqueous phase.

3. Adsorption of the preservatives to polymers in the formulation and/or packaging material; complexation or micellization might also result in too-low antimicrobial activity.

In conclusion, it is not sufficient to add a preservative at recommended concentration. To protect the vehicle sufficiently, a properly designed preservative system is required that must be tested in the formulation regarding efficacy and safety. It is a great formulation challenge to achieve sufficient protection against microbial growth in the product, especially as many antimicrobials are discredited because of their irritation and sensitization potential.

Antioxidants

Protection against oxidation may also be a formulation issue although not so relevant as antimicrobial efficacy. It is achieved by addition of antioxidants or by manufacturing and storing in an inert atmosphere. In particular, modern formulations containing oxidationsensitive compounds, such as certain vitamins and vegetable oils with unsaturated fatty acid derivatives, must be sufficiently protected against oxygen.

Development Strategy and Rationale |

Having considered the aforementioned issues, formulation development is preferably conducted according to a suitable, rational procedure. The complex formulation development process may be represented symbolically by the ''magic formulation triangle'' (Fig. 1), s showing the mutual interaction and dependency of the following:

is Q

1. Feasibility of preparation or formulation of the active substance(s) in the vehicle

2. Stability (chemical and physical) of the product, and

3. Effectivity or activity of the product when applied.

Feasibility

, iation

Feasibility

, iation

Activity

Stability

- preparation of the active substance in the vehicle

— availability of required equipment and materials

♦ Activity (effectivity)

- after application at the target Stability (storage)

— physical chemical

Figure 1 Magic triangle of formulation: mutual interaction and dependency.

First, the feasibility of preparation and formulation has to be checked. For example, if a low-water-soluble compound should be dissolved in an aqueous vehicle, solubility-enhancing studies are performed. Or if an emulsion is desired, it has to be checked whether the phases can be emulsified with the selected emulsifying system.

After having prepared the desired formulation, both stability and effect must be assessed, preferably more or less in parallel. It does not make any sense to have a stable but ineffective product, or to develop a very effective system that remains stable for a few days or that contains an ingredient that is irritating or sensitizing. Such a product cannot be marketed. For example, if a relatively unstable active substance (e.g., ascorbic acid) must be delivered in dissolved form to be effective or bioavailable at the target site, then a suitable vehicle with good solvent properties must be used. However, the chemical stability of compounds is generally lower when in solution. Therefore, not every suitable solvent can be used as a vehicle, but an optimum has to be found, a vehicle enabling both, keeping the active to remain dissolved and in a chemically stable state.

Having in mind those three cornerstones of the formulation triangle, formulation development to find the right vehicle is performed stepwise, addressing the following issues:

1. Objective, definition of target profile (See p. 158.)

2. Preformulation investigation: determination of physicochemical properties of (active) substances to be formulated, such as solubility data, partition coefficient, dissociation constant, pH, crystal morphology, particle size distribution, and assessment of their stability and incompatibility

3. Selection of appropriate excipients to be used for formulation

4. Based on the outcome of these three working steps the feasibility of preparation is checked and modifications are made if necessary, all of these together to prepare the next step

5. Formulation screening on a small-scale basis with as many as possible and feasible variations in composition, excipients, preparation methods, and so on

6. Selection of the best formulations and preparation methods from the screening program for technical scaling-up as well as for confirmation and validation of the results obtained with the formulations. The selection of the formulations is based on criteria such as physical stability or absence of precipitation in solu

tion, no sedimentation or phase separation or recrystallization in multiphasic systems; chemical stability or degradation, respectively; preservative efficacy test (PET); biological assessment, e.g., skin-hydration effect, sun-protecting effect, and antioxidant or radical scavenger effect in cells; and 7. Safety evaluation in human beings with formulation chosen for introduction into market.

Beauty for Newbies

Beauty for Newbies

Do you feel like an ugly duckling sometimes? Doesn't it seem like everyone else seems to know the best ways to present themselves, from their hair, to their skin, to their makeup?

Get My Free Ebook


Post a comment