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Skin Care Delivery Systems.

Various factors influence the absorption of substances through the skin. Coty researchers explain how it all works.

SKIN IS A COMPLEX entity consisting of a variety of cells and organelles, each of which has a particular function. The pathways by which the cosmetic actives are absorbed and the role of the vehicle on the skin can be better understood if one is familiar with skin structure and function. Skin protects the body's organs from external environmental threats, including ultraviolet rays, and acts as a thermostat to maintain body temperature. It consists of several different layers, each with specialized functions. The major layers include the epidermis, the dermis and hypodermis. The epidermis is a stratifying layer of epithelial cells that overlies the dermis consisting of connective tissue layer. An internal layer of adipose tissue, the hypodermis, further supports the epidermis and dermis. Various factors influence the absorption of substances through the skin. It is imperative that a cosmetic chemist be familiar with the fundamentals of the various factors that influence the absorption of substances through the skin before beginning bench work.

One of the principal functions of skin is to provide a barrier to the transportation of water and other substances. We live in a hostile environment, and the body would rapidly dehydrate without a tough, semi-impermeable skin. This barrier also helps prevent the entry of harmful substances into the body. Some materials, such as ethyl alcohol, nickel ions and poison ivy, can penetrate the barrier, but most substances cannot.

The epidermis consists of keratinocytes and is divided into several layers based on their state of differentiation. It can be further classified into the stratum corneum and the viable epidermis, which consists of the granular melphigian and basal cells. The stratum corneum is hygroscopic and requires at least 10% moisture by weight to maintain its flexibility and softness. The hygroscopicity is attributable in part to the water-holding capacity of keratin.[1] When the horny layer loses its softness and flexibility it becomes rough and brittle, resulting in dry skin. The pH of the skin is normally between 5-6. This acidity is due to the presence of amphoteric amino acids, lactic acid, and fatty acids from the secretions of the sebaceous glands. The term "acid mantle" refers to the presence of these water-soluble substances on most regions of the skin. The buffering capacity of the skin is due in part to these secretions stored in the skin's horny layer.

In the context of percutaneous absorption, the well-known principle follows that molecules in solution move in a purely random fashion without charge and move within an electrical gradient. Such random movement is called diffusion. When the molecule is uncharged, it is a nonionic diffusion. Diffusion through the stratum corneum (SC) is slow and difficult, probably because of the high keratin content and low moisture reserve. In a molecular environment, molecules move in both directions, from the region of higher to that of lower concentration. The net transfer will be proportional to the concentration differential or gradient. Nevertheless, the principal mechanisms for both water-barrier function and molecule absorption of the skin are similar. Substances that are both water- and lipid-soluble are favored by the skin. Molecules traverse membranes either by passive diffusion or active transport. A passive diffusion process implies that the solute flux is linearly dependent on the solute concentration gradient. The active transport process typically involves a saturable mechanism.[2] Simple permeation experiments using excised mammalian skin have shown that percutaneous flux is directly proportional to the concentration gradient.[3] Therefore, experiments have established that transport across the skin occurs primarily by passive diffusion which is governed by Fick's first law, which states that the rate of diffusion or transport across a membrane (dC/dt) is proportional to the difference in active concentration on both sides of the membrane ([Delta]C). Therefore:

-dC/dt = J = kp [Delta]C = kp ([C.sub.1]-[C.sub.2])

Where [C.sub.1] and [C.sub.2] refer to active concentration on each side of the membrane and kp is proportionality constant. By convention it is assumed that [C.sub.1] is greater than [C.sub.2] and, therefore, there is net transport of actives across the membrane from compartment one to compartment two. The magnitude of the proportionality constant, kp, depends on the diffusion coefficient of the active, the thickness and the area of the absorbing membrane, and the permeability of the membrane to the specific cosmetic active. The biological process of cutaneous absorption involves a system in which cosmetic active diffuses through the upper epidermis barrier from compartment one (absorption site) to the compartment two (few upper epidermis layers).

J=flux of the permeant (moles cm-2 S-1);

kp=permeability coefficient of the permeant through the membrane (cm-1); and

[Delta]C=activity gradient across the membrane (moles cm-1).

The permeability coefficient kp is the inverse of the "resistance," which the membrane offers to solute transport, and is defined by kp=KD/h, where:

K=membrane-aqueous phase partition coefficient of the solute

D=diffusion coefficient of the solute in the membrane (cm2 s-1)

h=diffusion path length through the membrane. The flux is a rate process and can be described in general terms as

Rate = driving force/resistance.

The driving force for diffusion has to be the activity gradient, which, to a first approximation, can be equated to the concentration gradient across the permeability barrier. Consider a single membrane with aqueous phases on both sides--one a reservoir of solute, the other sink. Since a concentration gradient exists between the source and the sink, there is a flux of the solute molecules through the membrane. The primary function of a cosmetic active in a skin care product remains to assist or reinforce the barrier function of the skin or penetrate into the few upper epidermis layers to restore their physical appearance. This requires cosmetic active to be included in a pleasant-feeling base, reducing irritation, and it should remain in contact for an extended time period.

Cosmetic substances traverse the skin primarily either through the pores of the hair follicles, the sweat gland ducts or by passing through the protein/lipid domains of the stratum corneum. From the skin surface, the subsequent diffusion into the intra-cellular spaces and the cell takes place. In the initial transient diffusion stage, penetration occurs through the skin appendages, i.e. the hair follicles and the ducts. It then passes into the skin. The stratum corneum (SC) is a bio-membrane and distinguishes itself from the other membranes in the body in function and composition. It is made up of a matrix of protein-laden material surrounded by extracellular, multilamellar bilayers of lipid. The SC is less permeable for the lipophilic compounds compared to the water-soluble compounds. However, water-soluble molecules with low lipid solubility are usually thought to pass through the pores, whereas lipid-soluble materials pass through protein/lipid domains of the stratum corneum.

In order to facilitate the diffusion of water-insoluble actives, fatty acids having affinity for the lipid/protein domains of the stratum corneum have been used in the transportation of some pharmaceuticals. It has been established through experiments that the size of the molecule and its lipophilicity are major determinants of the penetration processes through the stratum corneum. This means the permeability of a molecule is directly related to its lipophilicity and inversely proportional to molecular size. Hence it is not surprising to find low levels of absorption for large polar molecules such as peptides. Nevertheless, even these molecules can transport measurably through the SC, albeit at extremely low rates.[4,5,6]

Percutaneous absorption involves the following sequences:

* Partitioning of the molecule into the SC from the applied vehicle phase;

* Molecular diffusion through the SC;

* Partitioning from the SC into the viable epidermis and

* Diffusion through the epidermis and upper dermis and capillary uptake.[7]

Humidity and temperature influence absorption of the substances through the skin. A 10-fold increase in the skin penetration of acetylsalicylic acid was obtained when the environment temperature was raised from 10 to 37 [degrees] C. Hydration of the skin can be improved by occluding or covering the skin with plastic sheeting to prevent moisture loss. Indeed, safety testing of most raw materials is done in this manner (patch testing). Such penetration has been demonstrated quantitatively by in vivo and in vitro experiments.

A suitable vehicle also increases skin penetration of a cosmetic active. Many substances have shown enhanced absorption through the skin when dissolved in purified water, propylene glycol, butylene glycol, polyethylene glycol, olive oil, dimethyl isosorbide and dimethylformamide. Solvolysis reactions during dissolution processing can be overcome by the inclusion of a proper buffering system. The vehicle generally does not increase the rate of penetration into the skin, but serves as a carrier. The pH of the vehicle can also influence the rate of release of the active, since the thermodynamic activity of acidic and basic substances are affected by pH. Thus, for acidic substances, the activity changes rapidly when the pH is greater than the pKa of the substance. Similarly, for basic substances the activity is influenced when the pH of the vehicle is less than the pKw - pKb of the substance.[8] The influence of the vehicle was also demonstrated with salicylic acid and its esters.[9]

Methyl salicylate is more lipophilic than the acid from which it has derived. When applied to the skin from vehicles composed of fatty or oily substances such as mineral oil, petrolatum, and silicones, the methyl salicylate has a higher penetration than salicylic acid. The amount of methyl salicylate absorbed was found to be proportional to its concentration. Insoluble cosmetic substances must be uniformly dispersed throughout the vehicle to assure homogeneity of the product. Milling to a finely divided state provides more surface area for contact with the dermal site and increases the rate of dissolution of poorly soluble substances.

Skin care products, especially products designed for the face, have evolved into a technological spearhead for cosmetic sciences during the past 20 years. Anti-aging concepts remain the hottest area of research. The type of vehicle selected to deliver cosmetic actives must be non-irritating and safe. It depends on whether penetration or protection is desired. A cosmetic formula should alleviate immediate dryness and restore innate moisture contents along with other replenishers at the epidermis/dermis level of the skin.

In cosmetics, molecule penetration is limited to the epidermis and, to some extent, to the dermis. Skin care preparations include emulsions (hydrous creams and lotions), pastes and jellies, anhydrous cream and lotion, ointments, hydro/alcoholic solution or gel, sprays and sticks. Among these, emulsions (oil in water and water in oil) have generally been the most desirable vehicles for the delivery of cosmetic actives to the desired site. An emulsion is perceived to be emollient, with moisturizing benefits, and can include UV-filtering effects, vitamins, antioxidants, plant-derived proteins or amino acids/peptides, plant-derived flavonoids, AHAs and other skin beneficial agents. The selection of a well-balanced emulsifier system is also essential for effective delivery of emollients and humectants. Mixtures of emulsifiers must be selected intelligently to maximize the benefits of the rest of the formulation.

How to Ensure a Long Shelf Life

The cosmetic chemist must make sure that the pH, viscosity and preservative systems will remain stable for two years under variable storage conditions. If there is any doubt regarding the instability of a cosmetic active in the main vehicle, the chemist should look for other delivery means such as chemical or polymeric modifications (magnesium ascorbyl phosphate) of an individual cosmetic ingredient or through other means such as encapsulation with liposomes, nanoparticles, microspheres (microencapsulations), multiple emulsions, microemulsions or by preloading spherical beads and sponges. The formulator should also be well aware of the safety and irritation prognosis. Duration of actions such as time release, sustained release or continuous release and delayed release are other important parameters which should be another criterion for the selection of the special delivery mechanism. The main vehicle in which the cosmetic carrier is to be incorporated requires very careful selection of raw materials that do not harm it on account of any physio-chemical instability. The final product must be elegant with an acceptable and pleasant skin feel.

Among the most popular cosmetic active delivery systems, liposomes have been successfully employed as carriers in skin care products for several years. Developed nearly 40 years ago, liposomes were initially developed as models of biological membranes. However, in recent years, chemists have discovered their potential as a drug/cosmetic delivery system. The lipid bilayer structures of liposomes mimic the barrier properties of biomembranes, and therefore they offer the potential of examining the behavior of membranes of a known composition. Thus, by altering the lipid composition of the bilayer or the material incorporated, it is possible to establish differences in membrane properties.

Model membranes have facilitated the study of the lipidprotein interactions occurring in biological membranes and have been used in a multitude of research projects concerning membrane structure and function. Liposomes are microscopic lipid vesicles that are formed when thin phospholipid films or lipid cakes are hydrated and stacks of liquid crystalline bilayers become fluid and swell. The hydrated lipid sheets detach during agitation and self-close to form large multilamellar vesicles (LMV) which prevent interaction of water with the hydrocarbon core of the bilayer at the edges. Larger multilamellar vesicles are reduced to liposome size by application sonication or mechanical energy (extrusion) used. Numerous techniques for liposome preparation result in either large or small vesicles that are either unilamellar or multilamellar.

Multilamellar vesicles (MLV), composed of numerous concentric baitlayers, are produced from mechanical agitation of a dispersion of dried lipid with an aqueous phase. Mechanical agitation is the simplest method for producing MLV. The technique produces a suspension of large liposomes, which are very heterogeneous in size and exhibit a relatively low level of aqueous encapsulation. However, homogeneous liposome formulations that exhibit reduced vesicle diameters are advantageous with respect to extended circulation half-life, and consequently, enhanced uptake by tissues and organs. Large unilamellar vesicles (LUV), prepared from MLV, exhibit the characteristics that are beneficial for enhanced delivery of the incorporated material. The most common method for LUV preparation is extrusion of MLV under pressure through membranes of known pore sizes. These LUVs are used to optimize the incorporation of a desired compound within liposomes, to limit the permeability of the membrane to the entrapped substance and to alter half-life.

Accordingly, with an efficient and robust system, a homogenous unilamellar liposome can exhibit diameters ranging from 100-200nm. Liposomes store water-soluble substances in their interiors like biological cells. The phospholipids forming these liposomes enhance the penetration of the encapsulated active agents into the stratum corneum. They are biodegradable and non-toxic in nature. Due to the higher fatty acids characteristic of the phospholipids molecule, they also provide the skin with high quality plant fats. Today's liposomes are available with variable lipid contents, size, lamellarity and surface charge. Liposomes enable water-soluble and water-insoluble materials to be used together in a formulation without the use of surfactants or emulsifiers. It is also possible to entrap oils or oil-soluble materials in the liposome wall. Liposomes are regarded as suitable carriers because they can serve as a depot system for the sustained release of an entrapped compound. The best demonstrable feature of liposomes is that cosmetic ingredients exhibit better stability, penetration and efficacy at lower use levels.

With the many potential uses presented by these liposomes, beneficial application depends on the physical integrity and stability of the lipid bi- or multi-layer structure incorporated in an emulsion base. The best bet would be to select a base that comprises not only nonionic but non-reacting materials. Other precautions include keeping ethyl alcohol concentration below 5% and solvent concentration below 10%. In addition, high levels of salts ([is greater than] 0.5%) should be avoided. An appropriate preservative system and the addition of liposomes in the final formula at 25 [degrees] C or below are desirable.

Lipid nanoparticles are vesicles formed by lecithin encapsulated in an oil core and are thus ideal carriers for lipophilic substances. They enhance the bioavailability of the encapsulated material to the skin. High-pressure homogenization results in a 100% encapsulation of the oily phase. With positively charged nanoparticles, lipophilic UV filters and other active materials are efficiently targeted to hair or skin. In the nanoparticle dispersions, a particle size less than 60 nm can be obtained. The composition of nanoparticles is detailed below and shown at lower left.[10]

1. Membrane: 1-15% (5%), lecithin (phospholipids)

2. Oil: 1-40% (15%), triglycerides

3. Active Ingredients: 1-40% (5%), any substance soluble in the oil phase

4. Water: 25-95% (70%), alcohols: 0-20% (10%), ethanol.

There is no proof that liposomes penetrate intact into the stratum corneum. However, it is believed that they can deliver the cosmetic active by adhering to the corneocyte through diffusion as a result of fusion of bilayers of liposomes with the proteins and lipids of the stratum corneum. Continuing with the delivery system, there are three additional systems which are as important as liposomes, though their particle sizes are very small and do not penetrate as such into the skin. However, they facilitate the absorption of the cosmetic active efficiently in the few upper layers of the stratum corneum. Under emulsions there are three kinds of technologies available: multiple emulsions, nanoemulsions and microemulsions.

Multiple emulsions are ideal three-compartment systems; i.e., an emulsion dispersed in a third phase. There are two types, O/W/O = O/W emulsion in oil phase and W/O/W = W/O emulsion in water phase. They have many distinctive attributes, especially the compartmentalization of actives in the three phases, controlled and sustained release of actives and W/O hydrating performance with O/W skin feel. They also provide longer lasting moisturizing effects comparable to a conventional emulsion. Additionally, they can enclose dissolved materials of diverse nature. These technologies have been widely used as a means to deliver several soluble cosmetic actives in internal aqueous droplets and the external continuous phase.

However, compartmentalization of such components with an oil layer can prevent the chemical interaction between them. The enzymes, vitamins, amino acids/proteins, radical scavenging materials and oil soluble compounds can be contained within the emulsion individually without chemical instability. The time release action can also be sustained by control of the breakdown process that occurs on application. In an emulsion liquid, droplets and/or liquid crystals are dispersed in a liquid. Most common emulsions differ in respect to droplet size range--from 5 to 50nm.

A microemulsion is a thermodynamically stable dispersion of one liquid phase into another, stabilized by an interfacial film of surfactant. The interfacial tension between the two phases is extremely low. This dispersion may be either oil-in-water or water-in-oil. A microemulsion consists of swollen micelles and may appear transparent in solutions/gel or milky. In the case of transparency, the particle size is less than 0.5nm and it appears that light passes right through the transparent emulsion. The clear gel or liquid system provides an elegant feel and lays down a smooth film on the skin. The thickness of the film can vary with the amount of the microemulsion applied. In the ringing microemulsion gel, the micelles are so densely packed that they enable the gel to ring.

Recently another emulsion class--nanoemulsions--has been distinguished from a microemulsion based on smaller droplet size in the submicron range (typically 100-200 nm). The nanoemulsion system has also been categorized as transparent or translucent depending on the droplet size and the difference in refractive index between the oil and continuous phase. Both microemulsions and nanoemulsions are acceptable in cosmetics because there is no inherent creaming, sedimentation, flocculation or coalescence observed within macroemulsions. Another advantage is the small-sized droplet with its high surface area allowing effective transport of the active to the skin. The incorporation of potentially irritating surfactants can often be avoided by using high-energy equipment during manufacturing.

So far, the response from the cosmetic houses to adopt these systems into their products has been very slow due to the manufacturing complexities and the non-availability of highly trained personnel in this area. From the research point of view, there have been further advances in product understanding and evolution. A brilliant research paper presented by Th. F. Tadros at 21st IFSCC Congress 2000, Berlin, described a current breakthrough in this field.

Another very sophisticated technology, microencapsulation, has been available for many years, but it has recently been improved and the technology expanded. Microencapsulation (functionalized vectors) are micron-sized capsules that can also encapsulate cosmetic active compounds in a matrix of membrane-like liposomes. The capsules are made up of naturally -derived materials from animal, fish or plant origin. These constructing materials may be collagen, glycosaminoglycans such as chondroitin sulfate or polysaccharides of plant (soy and wheat) or marine origin (shells of crustaceans). In general, their dimensions vary from 200nm to several hundred nanometers. The active compound is wrapped in a thin, natural, tough membrane. The membrane will be broken under the enzymatic action of amylases or proteases, slowly releasing the contents of the nanocapsule.

In the same category, there is another class in the form of a sphere. In the sphere, a tough protein polysaccharide matrix encircles and traps an active ingredient. This spherical matrix is more resistant than the membrane wrapping the capsule, but is just as biodegradable and biocompatible. The diameter of spheres ranges from 0.2 mm to 900 mm, which is similar to the nanocapsules. These vectors, capsules and spheres can enclose active compounds having lipid solubility, hydrosoluble or insoluble pigments and micronized extracts. Like liposomes, the above mentioned spheres can be modified with a positive charge on their outer covering which can target keratin of the hair and skin.[11]

As a means of delivering pharmaceuticals, transdermal drug delivery (TDD) through patches has been in practice for more than two decades. This technology was successfully tapped by cosmetic companies in the 1990s with the introduction of anti-acne, anti-wrinkle, moisturizing, anti-blemish and pore-cleansing patches. There are many advantages that include the creation of a cosmetic reservoir that provides a continuously-controlled delivery profile. Other benefits include reduced frequency and longer duration of action. It also protects the cosmetic active from deterioration and washing off.

Oil Bodies, A New Delivery System

The newest dimension in the cosmetic active delivery system has been the introduction of oil body/oleosin technology. It was suggested as a potential delivery system for topical and oral active ingredients.[12] This involves oil body forms derived from oilseeds. Oil bodies are discrete organelles found in oil seeds, pollen and some fruit, where they serve as the site for triacylglyceride storage. They are comprised of a triacylglyceride core (TAG) surrounded by a half-unit phospholipid membrane and an outer shell of specialized proteins known as oleosin. Oil bodies can be formulated into a variety of cosmetic and personal care products. According to the inventors, preliminary in vivo (tape stripping) and in vitro (Franz assay) dermal penetration studies demonstrated that oil bodies facilitate the delivery of certain small molecule actives (e.g. salicylic acid and retinyl palmitate) and large protein molecules, respectively, through the stratum corneum.

Retinol Molecular Film Fluid is also a relatively new entry in this arena. It was developed as a compound which, on application, forms a thin uniform monolayer film that facilitates the transfer of actives to the stratum corneum. Retinol (vitamin A) is a highly unstable compound and requires special skills and techniques to be included in cosmetic products. Retinol molecular film is a specially designed delivery system for retinol. It is a very thin monolayer functional film which was developed by incorporating cyclomethicone, dimethiconol, soybean oil, octyl cocoate, sphingolipids and retinol obtained at 12,000 p.s.i, under microfluidizing conditions. This oil-soluble molecular film is very occlusive and also shows a significant moisturizing profile under TEWL techniques.[13]

The poly acrylo nitrile polymers controlled release system is a new skin care concept that synchronizes the release of an active ingredient along with a fragrance as a sensory marker. This sensory marker conveys the efficacy of the product. It is a controlled release mechanism obtained through the polymerized Poly Acrylo Nitrile (PAN) systems. Initial studies indicate that this can function as an "invisible patch" ensuring a longer duration of skin assimilation, while the continued release of a "marker," in this case fragrance, assists in consumer perception of an actively working material.[14,15]


There are many ways to deliver cosmetic actives to the skin. Some of the techniques are worth mentioning and some are trade secrets. Most of the techniques have come from pharmaceutics and have been successfully adapted as is or with some modifications. Cosmetic chemists should do their homework before selecting a particular cosmetic active delivery system. They should have in-depth knowledge about the physico-chemical parameters of the cosmetic active that are compatible with raw materials selected to construct the final formula. Cosmetic chemists should be able to select an appropriate preservative system and perfume. The process requires the careful selection of nonreacting emulsifiers, as well as stabilized, mild, and superb feeling emollient esters that may also help to improve the shelf life. The final product should be elegant feeling, free of oiliness and long-lasting. The product as a whole should be result-oriented.


[1.] Blank, I.H., Factors which influence the water content of the stratum corneum, J. Inves. Dermatol., 18, 433, 1952.

[2.] Friedman, M.H., Principles and Models of Biological Transport, Springer Verlag, Berlin, 1986, 74.

[3.] Blank, I. H. and Scheuplein, R.J., Transport into and within the skin, Br. J. Dermatol. 81,4., 1969.

[4.] Bodde, H. E., Verhoef, J. C., and Ponec, M., Transdermal peptide delivery, Biochem. Soc. Trans., 17, 943, 1989.

[5.] Burnette, R.R. and Marrero, D., Comparison between the ionophoric and passive transport of thyrotropin releasing hormone across nude mouse skin, J. Pharm. Sci., 75, 738, 1986.

[6.] Chien, Y.W., Siddiqui, O., Shi, W., Lelawongs, P., and Liu, J., Direct current ionophoric transdermal delivery of peptide and protein drugs, J. Pharm. Sci., 78, 376, 1989.

[7.] Albery, W.J. and Hadgraft, J. Percutaneous absorption theoretical description, J. Pharm. Pharmacol., 31, 129, 1979.

[8.] Scheuplein, R.J., Mechanism of percutaneous absorption. J. Invest. Dermatol, 45, 334, 1965.

[9.] Higuchi, T., J. Soc. Cosm., Chem., 11: 85, 1960.


[11.] Bioetica Inc., Portland, ME.

[12.] Markly, Nancy, Oil body/Oleosin Technology: Novel raw material and delivery system for the cosmetic industry, SemBiosSys Genetics Inc., 29th St., NE, Calgary, Alberta Canada.

[13.] Lipotech, S.A. C/O Centerchem Inc., Glover Av., Norwalk, CT.

[14.] Sam Shefer, Adi Shefer, Controlled Release Technologies, PO Box 6233, East Brunswick, NJ 08816.

[15.] Charles Kliment, Hymedix International, Inc.,
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Author:Mufti, Jabbar; Cernasov, Domnica; Macchio, Ralph
Publication:Household & Personal Products Industry
Date:Mar 1, 2001
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