Issue 25 — April 2001

Issue 25
Category		Title		Author
Guest Article		Galenic principles of modern skin care products		Rolf Daniels

Contents

1.	Introduction
2.	Nanodispersed systems
2.1	Liposomes
2.2	Nanoemulsions
2.3	Lipid nanoparticles
3.	Surfactant-free emulsions
3.1	Polymer-stabilization of emulsions
3. 2	Solid particle stabilization of emulsions
4.	Conclusion
5.	References

1. Introduction

Today's skin care formulations must meet high standards of efficacy, skin compatibility and aesthetic appeal. It is commonly accepted that the performance of a cosmetic product is related to the entire formulation. Thus, an optimal galenic form is a necessary prerequisite to succeed in the market next to incorporating suitable active ingredients. The objective of topical formulations may be classified in two major areas: to modulate or assist the barrier function of the skin and to act as a delivery system for active ingredients. Moreover, the possibility to use a patented galenic form becomes progressively more important as a marketing instrument. This paper focuses on some galenically interesting formulation concepts used in contemporary skin care products.

2. Nanodispersed systems

Nanodispersed systems (Figure 1) such as liposomes, nanoemulsions and lipid nanoparticles, have become increasingly important as potential vehicles for the controlled delivery of cosmetics and for the optimized disposition of active ingredients in particular skin layers. Moreover, these systems develop their own vehicle effects, which may enhance the desired effects.

All nanodispersed systems mentioned have in common that their preparation requires refined manufacturing techniques, such as high-pressure homogenization, because the preparation of highly dispersed systems usually requires a high energy input. Furthermore, phospholipids are often used as essential excipients.

2.1 Liposomes

Liposomes are small, spherical vesicles which consist of amphiphilic lipids, enclosing an aqueous core. The lipids are predominantly phospholipids which form bilayers similar to those found in biomembranes (Figure 2). In most cases the major component is phosphatidyl choline. Depending on the processing conditions and the chemical composition, liposomes are formed with one or several concentric bilayers. Liposomes are often distinguished according to their number of lamellae and size. Small unilamellar vesicles (SUV), large unilamellar vesicles (LUV) and large multilamellar vesicles (MLV) or multivesicular vesicles (MVV) are differentiated (Figure 3). SUVs show a diameter of 20 to approximately 100 nm. LUVs, MLVs, and MVVs range in size from a few hundred nanometers to several microns. The thickness of the membrane (phospholipid bilayer) measures approximately 5 to 6 nm.

Figure 1: Structure of nanodispersed systems

1a Liposome:Lipid bilayer enclosing an aqueous core

1b Nanoemulsion: Lipid monolayer enclosing a liquid lipid core

1c Lipid nanoparticle: Lipid monolayer enclosing a solid lipid core

Figure 2: Chemical structure and schematic representation of a phospholipid (lecithin)

Large liposomes form spontaneously when phospholipids are dispersed in water above their phase transition temperature. The preparation of SUVs starts usually with MLVs, which then are transformed into small vesicles using an appropriate manufacturing technique, e.g. high-pressure homogenization (1). Niosomes and sphingosomes are vesicles with a similar structure. In contrast to liposomes, nonionic surfactants, e.g. polyglyceryl alkyl ethers, or sphingolipids make up the bilayer of niosomes and sphingosomes, respectively (Figure 4). Liposomes which are used as delivery systems, may encapsulate hydrophilic substances in their aqueous core. Amphiphilic and lipophilic substances, e.g. oil soluble UV filters, can be incorporated into the lipid bilayer. Loaded liposomes as well as non-loaded, empty liposomes are used in cosmetics. The major effect of empty liposomes is an increase in skin humidity (2).

Liposomes frequently favor the disposition of encapsulated active ingredients in the epidermis and dermis, while the permeation rate is decreased. This helps to fix active ingredients to the outermost skin layers as desired for cosmetic products. Simultaneously, the washing out may be delayed so that, for example, aqueous sun care products containing liposome-encapsulated UV filters are water-resistant (3). However, these positive effects mentioned above depend on the composition, size, and amount of liposomes (3). Therefore, general conclusions are not justified. As far as empty liposomes are concerned, it has recently been discussed that the positive effects are not strongly related to the vesicular nature. The presence of the appropriate lipids (phospholipids, sphingolipids) suffices for cosmetic efficacy.

The skin compatibility of topically applied phospholipids is very high. There are no restrictions concerning their use in foodstuff and cosmetics, neither in the EU nor for regulations of the US Food and Drug Administration; lecithins are generally accepted as safe (GRAS status). However, it is known that high doses of phospholipids which are applied topically over a longer period may lead to irritations on dry and normal skin (4). Likewise, it has been mentioned that due to a biochemical feedback mechanism a long-term application of phospholipids may have an impact on the dermal lipid metabolism.

Figure 3: Schematic illustration of liposomes of different size and number of lamellae

SUV: Small unilamellar vesicles, LUV: Large unilamellar vesicles, MLV: Multilamellar vesicles, MVV: Multivesicular vesicles

2.2 Nanoemulsions

Nanoemulsions can be defined as oil-in-water emulsions with mean droplet diameters ranging from 50 to 1000 nm. Usually, the average droplet size is between 100 and 500 nm. The terms sub-micron emulsion (SME) and mini-emulsion are used as synonyms. Emulsions which match this definition have been used in parenteral nutrition for a long time. Usually, SMEs contain 10 to 20 per cent oil stabilized with 0.5 to 2 per cent egg or soybean lecithin. A typical formulation is given in Table 1.

The preparation of nanoemulsions requires high-pressure homogenization. The particles which are formed exhibit a liquid, lipophilic core separated from the surrounding aqueous phase by a monomolecular layer of phospholipids. The structure of such lecithin stabilized oil droplets can be compared to chylomicrons. Nanoemulsions therefore differ clearly from the liposomes, where a phospholipid bilayer separates an aqueous core from a hydrophilic external phase (Figure 1). If nanoemulsions are prepared with an excess of phospholipids, liposomes may occur concurrently (1).

Due to their lipohilic interior, nanoemulsions are more suitable for the transport of lipophilic compounds than liposomes. Similar to liposomes, they support the skin penetration of active ingredients and thus increase their concentration in the skin (2,6). Furthermore, nanoemulsions gain increasing interest due to their own bioactive effects. Nanoemulsions are able favor the transport of suitable lipids into the skin. This may reduce the transepidermal water loss (TEWL), indicating that the barrier function of the skin is strengthened.

Figure 4:Chemical structure of lipids forming sphingosomes and niosomes

In addition, a special product feature is to be mentioned: nanoemulsions do not cream. This allows to formulate liquid products which are sprayable and do not show a phase separation during storage.

As an alternative to phospholipid-containing nanoemulsions, emulsifier-free o/w submicron emulsions may also be prepared as will be shown below (6).

Table 1: Example of a nanoemulsion
Ingredient	Function	Weight [% m/m]
Evening Primrose Oil	Lipid	25,0
Tocopherol	Antioxidant	5,0
Lecithin	Emulsifying Agent	4,0
Water	Diluent	ad 100,0

2.3 Lipid nanoparticles (7)

Lipid nanoparticles have a similar structure as nanoemulsions. Their size ranges typically from 50 to 1000 nm. The difference is that the lipid core is in the solid state (Figure 1). The matrix consists of solid lipids or mixtures of lipids. To stabilize the solid lipid particle against aggregation, surfactants or polymers are added, whereby natural lecithins are preferred as is the case with nanoemulsions. If lipid nanoparticles are intended to be used as a carrier, the active ingredients are dissolved or finely dispersed in the lipid matrix.

Lipid nanoparticles can be prepared by means of high-pressure homogenization, whereby a hot homogenization and a cold homogenization technique are described (Figure 5). The scaling-up to the production scale seems to be unproblematic, because high-pressure homogenization is used in large scale processing of emulsions and dispersions in several areas.

Major aspects why lipid nanoparticles appear interesting for cosmetic use are:

	Improved stability of chemically unstable active ingredients
	Controlled release of active ingredients
	Pigment effect
	Improved skin hydration and protection through film formation on the skin

In contrast to liposomes and nanoemulsions, it is not necessary to develop completely new products if one intends to use lipid nanoparticles. Due to their good physical stability and compatibility with other ingredients they can often be added to existing formulations without any problems.

As lipid nanoparticles are patent protected worldwide as Lipopearls® or Nanopearls®, a product exclusivity can be guaranteed when they are used in new products.

3. Surfactant-free emulsions
Since most skin care products represent a mixture of two or more materials that are not miscible in each other, they are, according to the second law of thermodynamics, inherently unstable. They require the addition of suitable stabilizers to guarantee an appropriate shelf life. Traditionally, ionic or non-ionic surfactants are used as emulsifiers. However, such low molecular weight, amphiphiles are known to cause incompatibilities of cosmetics with the skin. Consequently, the cosmetic industry has been seeking for surfactant-free emulsions as alternatives to the conventional formulations. The most promising alternatives use polymeric emulsifiers or solid particles as stabilizers in order to yield sufficiently stable products with a pleasant appearance.

Figure 5: Scheme for the production of lipid nanoparticles by the hot or cold homogenization technique (from(7))
1	Melt lipid; dissolve or solubilize active ingredient in the lipid
.	Hot homogenization technique	Cold homogenization technique
2	Disperse melted lipid in hot aqueous surfactant solution	Cooling and recrystallization of active lipid mixture using liquid nitrogen or dry ice
3	Preparation of a pre-emulsion by means of a rotor-stator homogenizer	Milling of the active lipid mixture by means of a ball mill or a jet mill
4	High-pressure homogenization above the melting point of the lipid	Disperse lipid microparticles in cold aqueous surfactant solution
5	Cooling and recrystallization	High-pressur homogenization at or below room temperature

3.1 Polymer-stabilization of emulsions

In contrast to the traditional formulation concept, emulsions can be stabilized also by appropriate macromolecules without using any low molecular weight surfactant (Figure 6). Polymers are frequently added to increase the stability of an emulsion by thickening and adding yield value to the continuous phase. But it is, however, much more effective to use surface-active polymers, e.g. carbomer 1342 or hydroxypropyl methylcellulose (8), as primary emulsifiers. Such polymers form structured interfacial films, which effectively prevent the coalescence of oil drops. In this case, the increase of the viscosity of the external phase plays only a minor role for the stabilizing action.

Such a formulation concept - often named hydrolipid dispersion or hydro dispersion gel - is preferably used for sun care products which are consequently called "emulsifier-free" formulations. This is not correct from a physicochemical point of view. (The IUPAC defines the properties of an emulsifier as follows (9): An emulsifier is a surface-active substance. It lowers the interfacial tension of the medium in which it is dissolved and, accordingly is positively adsorbed at interfaces. Small amounts of emulsifiers facilitate the formation of an emulsion or enhances its colloidal stability by decreasing either or both of the rates of aggregation and coalescence.)

However, such formulations can be distinguished from emulsions stabilized with "traditional" emulsifiers concerning their irritative potential: Due to their high molecular weight polymeric emulsifiers are not able to penetrate the stratum corneum. Thus, unwanted interactions, such as Mallorca acne, have not to be expected. Therefore, the term "emulsifier-free" is used.

Table 2 shows some typical examples.

Formulation A uses acrylate/C10-30 alkylacrylate crosspolymer as a polmeric emulsifier. Polyacrylic acid and Hydroxypropyl methylcellulose are used as co-stabilizers.

Figure 6:Schematic representation of the structure of different interfacial films

(A) Liquid crystalline surfactant film (B) Mono molecular surfactant film (C) Polymeric film according to the tail-loop-train model

Carbomer 1342 polymeric emulsifiers are copolymer of acrylic acid, modified by C10-30-alkyl acrylates, and crosslinked with allylpentaerithrol. The hydrophilic acrylic acids portion dominates the lipophilic alkyl acrylate portion. The molecular weight of the resulting giant molecule is 4 x 10 exp. 9. The substance swells 1000-fold after neutralization with an appropriate base but it does not dissolve.

In aqueous media with low electrolyte concentration carbomer 1342 polymeric emulsifiers form thick protective gel layers around each oil droplet with the hydrophobic alkyl chains anchored in the oil phase. This allows to emulsify up to 20 per cent oil with typical usage levels of only 0.1 to 0.3 per cent of the polymeric emulsifier.

Upon contact with the electrolyte containing surface of the skin such emulsions become unstable because the protective gel layer deswells instantly. The oil phase is released and a thin oil film deposits on the skin. This mechanism allows an easy formulation of sun care products which are waterproof despite their hydrophilic properties during application.

Emulsions which have been stabilized with acrylate/C10-30 alkylacrylate crosspolymer may be prepared using the direct method or the indirect method (Figure 7).

High performance homogenizers should be used carefully to avoid mechanical degradation of the high molecular weight polymeric emulsifiers which would then decrease emulsion stability. Such preparations often exhibit a mean droplet diameter between 20 and 50 µm. However, this has no negative impact on the physical stability. If for aesthetic reasons a finely dispersed system (1 - 5 µm) is desired, the addition of an amphiphilic co-emulsifier, e.g. sorbitan monooleate, is recommended. However, such a formulation could no longer be claimed as "emulsifier-free".

Formulation B (Table 2) is also of the hydrolipid dispersion type but uses solely hydroxypropyl methylcellulose (HPMC) as polymeric emulsifier.

Contrary to those hydrolipid dispersions with carbomer 1342 polymeric emulsifiers, preparations with HPMC as polymeric emulsifier are less sensitive to electrolytes. Therefore o/w emulsions with a normal saline solution as the external phase are still stable on storage. When applied on the skin, the mechanical stress may cause a partial breakdown of these emulsions and a thin oil film spreads on the skin, thus reducing the wettability of the skin. After the water evaporates, the emulsion remains partially on the skin and forms a flexible film where oil droplets are embedded into a polymer matrix.

The preparation of HPMC stabilized emulsion can be performed using a rotor stator homogenizer, e.g. Ultra Turrax®, yielding a mean droplet size between 2 and 5 µm (8). Nanoemulsions with a mean diameter between 100 and 500 nm can be achieved by using high energy input from ultra sound or high-pressure homogenization.

Table 2: Examples of polymer-stabilized emulsions
	Ingredient (INCI-Name)	Weight (% m/m)	Function
Formulation A
Water phase	Aqua	73,37	Diluent
	Glycerine	2,50	Humectant
	Disodium EDTA	0,03	Chelating agent, Stabilizer
Lipid phase	Octyl Methoxycinnamate	7,50	UV B-filter
	Octyl Salicylate	5,00	UV B-filter
	Benzophenone-3	5,00	Broad spectrum UV-filter
	C12-C15 Alkyl Benzoate	4,00	Emollient
	Sorbitan Oleate	0,30	W/O-Emulsifier
	Acrylates/C10-30 Alkyl Acrylate Crosspolymer	0,30	Polymeric emulsifier
	Carbomer	0,30	Thickener
Additives, hydrophilic	Propylenglycol	0,80	Humectant
	Diazolidinyl Urea Parabene	0,80	Preservative
	Triethanolamine	0,70	Neutralizer
Formulation B
Water phase	Aqua	78,0	Diluent
	Hydroxypropyl Methylcellulose	2,0	Polymeric emulsifier
Lipidphase	Caprylic/Capric Triglyceride	15,0	Emollient
	Triticum Vulgare	5,0	Emollient

HPMC-stabilized nanoemulsions from liquid lipid phases can be processed cold (6): The aqueous polymer solution and the liquid oil phase are mixed at room-temperature to yield a crude pre-emulsion. The final nanoemulsion is obtained by passing the pre-emulsion several times through a high-pressure homogenizer at pressures between 20 and 90 MPa. Further increasing the pressure above this optimal range, although technically feasible without further problems, does often end up with an increase in droplet size and not as expected in the desired higher degree of dispersion (Figure 8). This phenomenon is called over-processing and is a common feature of polymer-stabilized emulsions.

Another special feature of HPMC-stabilized emulsions is that they may be sterilized in an autoclave without substantial impact on their quality (8). This is due to the fact that they show a thermally reversible sol-gel transition. Above 60° C, the external phase gels and immobilizes the dispersed oil drops. The droplets cannot collide and the rate of coalescence is almost negligible. Thus, formulators have the opportunity to formulate a preservative-free o/w emulsion, presumed that a recontamination proof packaging is used.

As mentioned earlier, emulsions might also be stabilized solely by the viscosity enhancing effect of the added polymer, e.g. carbomer (polyacrylic acid). Such preparations where no interfacial activity is involved in the stabilizing action of the polymer are termed "quasi"-emulsions. Appropriate products on the market, often named "balm", usually consist of considerably small amount of lipids dispersed in a hydrogel.

Figure 7: Scheme for the preparation of hydro dispersion gels with a polymeric emulsifier by the indirect or direct method
Step	Indirect Method	Direct Method
1	Mix homogeneously all ingredients of the oil phase	Mix homogeneously all ingredients of the oil phase
2	Combine the ingredients of the water phase (including neutralizing alkali) to yield a clear solution	Combine the ingredients of the water phase (without neutralizing alkali) to yield a clear solution
3	Disperse polymeric emulsifier 1 in the homogeneous oil phase	Disperse polymeric emulsifier 1 by sifting slowly into rapidly agitating water phase
4	Add the oil phase (containing polymeric emulsifier 1) to the water phase (containing neutralizing alkali) under vigorous agitation (15-30 min)	Disperse oil phase homogeneously in water phase (containing polymeric emulsifier 1) under vigorous agitation (15-30 min)
5	Add remaining ingredients (preservatives, fragrance) and disperse homogeneously	Neutralize with a suitable base and mix until smooth and uniform. Add remaining ingredients (preservatives, fragrance) under moderate stirring
Polymeric emulsifier 1 = INCI-Name: Acrylates/C10-30 Alkyl Acrylate Crosspolymer

The physical stability and an adequate shelf life are obtained through finely dispersing the lipids. This measure and the yield value of the external phase reduce droplet mobility and thus effectively prevent creaming and coalescence of the oil droplets.

Figure 8: Influence of homogenizing pressure on the particle size of HPMC stabilized emulsions (from (6))

3. 2 Solid particle stabilization of emulsions

Alternatively, surfactant-free emulsions might be formulated as so called Pickering emulsions. In this case, a stable interfacial film with good protection against coalescence can be achieved by densely packed solid particles in the o/w interface. The key factor for the use of particles as a stabilizing agent is their wetting by the two phases, the oil and the aqueous phase. However, the affinity to each of the two phases should be different. This is expressed by the contact angle (Figure 9).

Pickering emulsions require sufficiently small particles which arrange in the o/w interface. This means that the solid particles usually are at least 10-fold smaller in size than the dispersed droplets of the emulsion. Capillary forces can support the formation a particulate network in the interface (Figure 10). This serves as a mechanical barrier to prevent the coalescence of the droplets. The protection against coalescence is based on the energy to expel the particles from the interface into the dispersed droplets. This energy depends on the contact angle, which ideally should be close to 90°.

Figure 9: Influence of the contact angle on the stabilizing action of solid particles

Figure 10: Solid particles stabilizing an emulsion

Table 3 shows some examples of particulate emulsifiers.

The following factors mainly influence the stability of Pickering emulsions (10):

	Contact angle
	Particle size
	Solid concentration
	Interparticulate interaction

Further critical parameters are the nature of the oil, the phase volume fraction and last not least the order of addition during processing.

So far hints for the preparation of particle stabilized emulsions have been scant and only few formulations are available in literature and patents.

Table 4 lists a suitable base for the formulation of an o/w emulsion.

For the preparation, both phases are mixed and homogenized for 2 minutes. After the pH has been adjusted to approximately 6 the emulsion is again homogenized for 10 minutes.

Although very interesting not only from theory but also from an application point of view, Pickering emulsions are not en vogue as a research topic and cosmetic products only make rare use of this principle.

However, particle-stabilized emulsions seems to be of great value in the formulation of sun care products. If such products use physical sun screen substances, e.g. TiO2 or ZnO, these physical filters can be distributed uniformly and they can act concurrently as emulsion stabilizers.

Table 3: Examples of particulate emulsifiers
Compound		Emulsion Type Stabilized
Alumina		W/O
Betonite		O/W
Magnesium Aluminum Silicate		O/W
Fat Crystals		W/O
Magnesium Oxide		W/O
Magnesium Trisilicate		W/O
Titanium Dioxide (coated)		O/W, W/O
Silica		O/W
Tin Oxide		O/W

Table 4: Emulsion stabilized by flocculated solid particles (from (11))
	Ingredient (INCI name)		Amount
Water phase	Hydroxypropylcellulose		0,1 g
(50 ml)	Silica		1,13 g
	Aqua		49,5 g
Lipid phase	Paraffinum Liquidum		150 ml

4. Conclusion

In recent years, much progress has been made to improve the performance of skin care products. New excipients, refined processing techniques and a better knowledge of the physicochemical properties have led to the development of new concepts. Some of them such as liposomes are well established in the market. Lipid nanoparticles are currently introduced and particle stabilized emulsion are on the way to be implemented in new products.

However, a lot of good new ideas - coming from specialists from different fields - will be required in order to succeed in this growing market in future.

5. References

(1) Gareiß, J., Hoff, E. und Ghyczy, M., Phospholipide - Liposomen - Nanoemulsionen, Parfümerie und Kosmetik 10 (1994) 652 - 659.

(2) Gareiß, J., Hoff, E. und Ghyczy, M., Phospholipide - Liposomen - Nanoemulsionen. II. Effekte auf der Haut, Parfümerie und Kosmetik 11 (1995) 152 - 155.

(3) Huber, P.A. und Gabard, B., Liposomen in der Dermokosmetik, Hautnah Dermatologie 3/1997, 128 - 131.

(4) Produktinformation Natipide II, Nattermann Phospholipid GmbH, April 1996.

(5) Driller, H., Verbesserte Wirkung durch Nanoemulsionen, In: Ziolkowsky, B., Kosmetikjahrbuch 1996, Verlag für chemische Industrie, Augsburg 1996.

(6) Schulz, M.B., und Daniels, R., Hydroxypropylmethylcellulose (HPMC) as emulsifier for submicron emulsions: influence of molecular weight and substitution type on the droplet size after high-pressure homogenization. Eur. J. Pharm. Biopharm. 49 (2000) 231-236.

(7) Müller, R.H., und Dingler, A., The next generation after the liposomes: solid lipid nano particles (SLN®, LipopearlsTM) as dermal carrier in cosmetics. Eurocosmetics 7/8 (1998) 19-26.

(8) Rimpler, S., Pharmazeutisch-technologische Charakterisierung von O/W-Emulsionen mit Methylhydroxypropylcellulose als Polymeremulgator, Dissertation Universität Regensburg, 1996

(9) IUPAC (International Union of Pure and Applied Chemistry), Division of Physical Chemistry, Manual of Symbols and Terminology for Physicochemical Quantities and Units, Appendix II part I, Butterworths London, 1972, S. 611

(10) Mennon, V.B., Wasan, D.T., A review of the factors affecting the stability of solids-stabilized emulsions. Separation Science and Technology 23 (1988) 2131 - 2142.

(11) Midmore, B., Herrington, T., Using silica flocs to stabilize o/w emulsions. Proc. 2nd World Congress in Emulsion, Vol. 1, 1-1-124.

Author

Prof. Dr. Rolf Daniels



Prof. Dr. Rolf Daniels has a Ph.D. degree in Pharmaceutics. Before continuing his academic career, he worked for Pfizer in the department of pharmaceutical development for 2 years. In 1995 he became Professor of Pharmaceutics in the Institute of Pharmaceutical Technology at the Technical University of Braunschweig. His main interests are in the field of surfactant-free emulsions, stability assessment of semi-solids, and controlled delivery of insect repellents. Since 1997 he has been head of the department Dermocosmetics of the Society of Dermopharmacy (GD).