Development considerations with maximum effect

May 2012
In the second of a two-part article, Rick Williams outlines examples of commercial skin lightening ingredients, percutaneous absorption enhancers and product stability, which follow on from his discussion on the problems associated with getting an active ingredient into the skin via topical absorption.

Commercial ingredients

O.D.A.white – Sederma

Sederma launched a skin brightening ingredient with a new mechanism of action from the heart of the melanocyte. O.D.A.white [INCI Name: Octadecendioic Acid] was designed to treat skin pigmentation disorders such as freckles, melasma, hyperpigmentation and general dark colour of ethnic skin. The enzyme tyrosinase, is the target for this interference, as it is the limiting factor of the rate of melanogenesis. While many skin lightening ingredients inhibit tyrosinase, O.D.A.white reportedly decreases melanin synthesis via another, further upstream mechanism. The skin-lightening ingredient does not mediate melanin synthesis reduction by a direct inhibition of tyrosinase, but can inhibit the whole melanin synthesis pathway from the melanocyte nucleus by targeting the tyrosinase gene via the PPARcomplex. Testing conducted by the company showed a 50% decrease in mRNA tyrosinase and tyrosinase quantities, a decrease of the pigmentation by 44 and a 28% increase in skin clarity. According to the company, the ingredient also brightens the skin.

Lumiskin – Sederma

 Lumiskin is a solution of diaecetyl-boldine (DAB) in C8C10 triglycerides that inhibits the activity of tyrosinase, enzyme responsible for melanin synthesis. The product stabilises the tyrosinase in its inactive form via the -adrenergic antagonist receptors and calcium flow regulation. Recommended use level: 4%

Melaclear 2 – Sederma

Melaclear 2, a multi-component hydroglycolic solution, containing a keratolytic enzyme that eliminates the strongly pigmented epidermal cells. The product also contains several other components, the aim of which is to regulate tyrosinase activity, thus to diminish progressively the pigmentation located on the skin’s surface:

•  -carotene: by binding in a competitive way on cell receptors of vitamin A – which is well-known for stimulating the melanocyte activity – it acts by temporarily ‘freezing’ melanogenesis.
• Dithiaoctanediol: OH-CH2-CH2-S-CH2- CH2-S-CH2-CH2-OH – This molecule contributes to the activity of Melaclear 2 by its inhibiting effect on tyrosinase glycosylation.
• Gluconic acid: HOOC-CHO-CHOH-CHOHCHOH- CH2OH – This molecule possesses chelating properties for metals, including copper. It helps inhibit tyrosinase activity.

Melaclear 2 contributes to complexion brightening and skin lightening by accelerating cell renewal and elimination of strongly pigmented cells of the stratum corneum, through the keratolytic action of the protease and by slowing down the rhythm of melanogenesis by interfering with the activation and inherent activity of tyrosinase. Furthermore, thanks to its exfoliating action, the regular use of a cream containing the ingredient provides a smoother cutaneous surface, leading to a rejuvenated skin appearance. Recommended use level: 2% to 8%.

Etiloine – Sederma

Etioline is a concentrated, purified and standardised extract obtained from a rare African plant: mitracarpe, of the Spermacoceae genus. In Benin, the most original property attributed to mitracarpe leaves lies in the treatment of dark spots and in skin fading. In order to obtain a marked synergic effect, Sederma associated mitracarpe with bearberry (Arctostaphylos uva ursi) extract. Etioline is an active ingredient designed for the treatment of pigmentary spots and cutaneous discolouration problems. Its activity based on African ethnobotanical experience is confirmed by a strong tyrosinase inhibitory activity in vitro and ex vivo. Recommended use level: 2% to 5%.

Sabiwhite – Sabinsa

SabiWhite [INCI Name: Tetrahydrodiferuloylmethane] is a colour-free natural extract derived from Curcuma longa (turmeric) roots. Laboratory studies revealed that SabiWhite is an effective skin lightening agent with multifunctional topical benefits. The extract is safe for topical use with no irritant or sensitisation side effects. The ingredient is chemically tetrahydrocurcumin, which is a major metabolite of curcumin, (the yellow pigment of turmeric), in the body. SabiWhite offers effective topical antioxidant protection. Its antioxidant action is of a comprehensive ‘bioprotectant’ nature, efficiently preventing the formation of free radicals while quenching pre-formed ones as well. This dual action protects the skin cells from damage by UV radiation and the resultant inflammation and injury with far reaching beneficial effects on overall health and well being. The free radical scavenging activity of SabiWhite was found to be superior to that of the synthetic vitamin E analogue, Trolox. Curcuminoids are reported to protect normal human keratinocytes from hypoxanthine/xanthine oxidase injury in in vitro studies. This study suggests that curcuminoids and therefore SabiWhite offer protection to the skin and could be included as functional antioxidants in topical preparations. Preliminary in vitro studies indicate that SabiWhite efficiently inhibits tyrosinase, the rate limiting enzyme in the synthesis of melanin. Sabinsa states that its efficacy is superior to that of commonly used natural skin-lightening agents such as kojic acid, and of related compounds. Laboratory studies revealed that SabiWhite offers topical protection against UVB induced inflammation and the resultant damage to the skin. These properties are particularly useful in anti-ageing, skin lightening, sun care and after sun care formulations. The powerful tyrosinase inhibitory activity of SabiWhitecould also slow down melanogenesis, thereby lightening the skin tone. Use levels range from 0.1% to 2% w/w; typically 0.25%.

Melfade-J – DSM

Melfade-J is a purified aqueous extract derived from bearberry leaves combined with magnesium ascorbyl phosphate. The product combines the topical activity of bearberry leaf extract with that of magnesium ascorbyl phosphate, for a powerful and longer lasting skin lightening. Melfade-J is a very effective inhibitor of tyrosinase activity demonstrated in in vitro studies, and is very popular in Asian countries as an effective means to depigment the skin. It reacts on the melanocytes to inhibit the tyrosinase activity by reducing melanin biosynthesis and is appropriate for use in all types of skin lightening formulations. Suggested concentration is 1.0% when combined with an exfoliant, otherwise up to 8%. [INCI Name: Water, Arctostaphylos Uva-Ursi Leaf Extract, Glycerin, Magnesium Ascorbyl Phosphate].

Symwhite 377 – Symrise

This compound [INCI: Phenylethyl resorcinol] can be used in a wide variety of cosmetics applications, such as lightening skin tone, treating for and generally reducing light-induced pigmentation of the skin and hair. Symrise says that SymWhite 377 is an excellent antioxidant that is also highly effective in influencing the formation of pigmentation. The efficacy of SymWhite 377 has been demonstrated in many studies (both in vitro and in vivo), in which researchers also observed that the compound is well tolerated. The ingredient thus succeeds where other skin-bleaching agents fail by eliminating the side-effects and disadvantages – such as skin irritation and poor performance – associated with these preparations. In a direct comparison with -arbutin, for instance, SymWhite 377 was shown to be over one hundred times as effective at lightening hair, and when tested in vivo on skin that had not been exposed to light, 0.5% SymWhite 377 proved to be more effective than 1.0% kojic acid. A concentration of between 0.1 and 0.5% is recommended. It has also been approved for use worldwide and a patent application has already been submitted.

Melanostatin-5 – Unipex

Melanostatine 5 [INCI name: Water (and) Dextran (and) Nonapeptide-1] is a biomimetic peptide antagonist specific to the -MSH (-Melanocyte-Stimulating Hormone). As an antagonist it competes against the natural ligand (-MSH) on its specific receptor (MC1-R) by preventing any further activation of the tyrosinase, and thus blocking melanin synthesis. Tyrosinase inhibition reduces the formation of unwanted pigmentation allowing for the control over skin tone and brown spots.

-White – Unipex

-White [INCI Name: Water (and) Butylene Glycol (and) Hydrogenated lecithin (and) Sodium Oleate (and) Oligopeptide-68 (and) Disodium EDTA] inhibits tyrosinase activity and melanin synthesis. It decreases proteins involved in the pigmentation process such as MITF, TRP1, TRP2 and tyrosinase. Inspired by TGFand MITF’s role in skin pigmentation, -White is a TGFbiomimetic peptide encapsulated in a liposome vehicle. It differentiates itself from other traditional whitening agents with its unique inhibitory action on the MITF cellular pathway to decrease constitutive and facultative pigmentation allowing optimal whitening and lightening effect with an excellent safety profile. -White decreases melanin synthesis with higher activity than arbutin and vitamin C, two well-known skin whitening agents.

Percutaneous absorption enhancers

Common percutaneous absorption enhancers are the lower organic alcohols (ethanol), humectants (such as propylene glycol) and specialties such as dimethyl sulfoxide. Organic alcohols (ethanol) are common (and low cost) penetration enhancers, also offering the added preservative (or even antiseptic) action. There are concerns regarding the use of ethanol as some believe it may remove the oils from skin. It will, if wiped off, but when used as a penetration enhancer it is left on the skin, the excess simply evaporates, without taking the precious oils with it. Propylene glycol has been recommended for many years, however recent evidence suggests that while adding small amounts of propylene glycol (and glycerine or sorbitol) does increase absorption, high levels may in fact decrease absorption. The optimum level must be determined for each drug/carrier combinations. Essential oils (particularly those high in terpenes) have also been shown to aid the penetration of drugs. As an example, piperine has been shown to be effective in this area. Other means are by patches or ‘plastic wraps’, where the ingredient is kept (in a very humid environment) for a longer time than usual thereby increasing the chance of absorption. For those that doubt its relevance to the topic or that it is a ‘cosmetic approach’ should see customers in beauty salons sitting there swathed in ‘Glad-Wrap’. In a more refined form of this treatment, film-forming agents are used, such as the carbomers, PVP and some polyquaterniums that assist penetration by trapping the drug into the film matrix and holding it onto the skin, thereby increasing the time a drug is in contact with the skin, thereby enhancing its penetration. Liposomes and other percutaneous absorption enhancers assist with this transfer, some having more luck than others. Liposomes act by dissolving the active ingredient within its unique structure then, because of its lipophilic nature, will pass into the skin where the active is released. Other ways ingredients can penetrate through the skin is through the hair follicles, sebaceous (oil) glands or eccrine (sweat) glands, where the ingredient, once in the follicle or gland has passed the horny layer, can be more easily absorbed – still the assistance from the above aids will apply. I will leave this discussion to the experts and will refer anyone interested to the work done by Professor Michael Roberts and Dr Sheree Cross at the University of Queensland. Liposomes are unique forms of triglycerides and phospholipids in that they form a special structure in solutions. If this structure becomes large (and this can be created by special formulations) then liposomes are formed. Where the triglycerides and phospholipids form a spherical structure of a bi-layer of triglycerides and phospholipids molecules. Each side of the bi-layer has the ionic part of the molecule point outwards from the bi-layer and the hydrophobic ‘tails’ point in towards each other. This forms a very stable structure with unique properties:

•  Water soluble components that are susceptible to degradation by other required additives can be formulated inside the liposome and hence be made more ‘stable’, e.g. vitamin C.
•  Oil soluble components that are susceptible to degradation by other required additives can be formulated inside the liposome shell (between the bi-layers) and hence be made more ‘stable’, e.g. vitamin A.
•  Water soluble components that are not susceptible to degradation by other required additives or those in large abundance can be formulated outside the liposome.

When the liposome is applied to the skin three possible mechanisms allow the actives to be delivered from the liposome:

•  The liposome is broken by the action of rubbing and the actives released to the skin surface.
•  The liposome does not break up and the actives slowly diffuse through the bi-layer onto the skin.
•  The liposome is absorbed into the skin and the actives slowly diffuse through the intercellular channel into the skin.

Liposomes act to alter the molecules ‘external’ polarity. The benefits of liposomes are that their outer surface has essentially low polarity with the polar drug encapsulated. Hence the liposomes can pass through the intercellular channels, releasing the drug in lower layers of the skin where it is more easily absorbed. New technology now available utilises an active drug, completely encased in a capsule usually comprised of an agarchitin film. This film is insoluble in the water phase of an emulsion but biodegradable, and when applied to the skin is either broken by the mechanical action of spreading over the skin or broken down by the skin’s microflora releasing the active onto the skin. This technology, while not strictly a liposome, is used to protect active ingredients that have known instability in cosmetic formulations such as retinol. The bioavailability of retinol in this case would be increased from a typical value of about 15% to a minimum of 85%, mainly due to the increased shelf life or stability in the formulation before use. An extension of the use of film-formers is used in sunscreens and wear-resistant lipsticks, where the film-former is chosen from a group that have very high water resistance, and these are combined with emollients that are also water resistant, or have low penetration ability. This combination forms a matrix with the active ingredients, preventing them from entering the skin. This is particularly important in sunscreens, as you do not want the sunscreen active to penetrate skin, but to reside on the surface to protect the skin. These film-formers also have the ability to form a uniform topical layer which gives a consistent uniform layer of sunscreen that will also provide better protection. This is a case where the target of active delivery is not in the skin but on the skin.

Product stability

A new theory on another factor that may affect the rate of drug penetration is that relating to the emulsion stability. That is, when a water based solution or an oil based solution is applied to skin the active ingredient (and solvent) seems to penetrate fairly rapidly. However, when a cream is applied to the skin it requires the emulsion to break down (the less stable emulsions breaking down quicker) into the original component parts, of the water phase and oil phase. The rate of this breakdown determines the rate of absorption. When the emulsion does not break down readily into its oil and water phases it is prevented from absorption. This is because the emulsion particles are usually spherical in nature while the interfacial layers, between skin cells, are separate lamellar phases of oil and water (see the earlier description of these layers). It requires energy to convert the spherical particles into lamellar particles for absorption and this is only achieved by persistent rubbing. When there are these discreet phases of oil and water on the skin, because the emulsion has broken down readily, absorption appears to be enhanced. That is, if the emulsion readily splits into the component phases this energy required to allow oil and water components to enter the skin’s lamellar interfacial phases, is not required and the product seems to absorb readily. An example of this is a cream, when rubbed onto skin, appears to form a creamy/milky layer that is hard to absorb. This occurs because the emulsion has not broken down and hence does not absorb. Two things achieve absorption in this case:

•  Continual rubbing, applying energy to the system, will cause absorption. That is, it requires energy to convert the spherical particles into lamellar particles for absorption and this is only achieved by persistent rubbing.
•  If you allow the creamy/milky layer to sit for a few seconds then rub again it seems to absorb more readily. This occurs when the waiting period allows some solvent (usually water) to evaporate and the emulsion, having changed its oil:water ratio, will become less stable. When it is less stable the emulsion breaks more readily, into its basic components, and the cream seems to absorb more rapidly.

The theory why nonionic creams are better penetration enhancers than anionic creams is that the nonionic creams are generally less stable. This is not to say that we should produce unstable emulsions as we still need a certain shelf life for commercial viability. However we should be producing emulsions that have the ability to break down readily, and by producing a slightly less stable emulsion than one with complete physical stability, this assists in the rate of skin penetration. As was stated previously, we are still learning more about this area of absorption every day and despite major advances still have a long way to go before total understanding, however from these thoughts we can formulate for any degree of stability on application hence regulate percutaneous absorption.


 


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