From Collagen Production to 190-nm Emulsions: Literature Findings

Apr 1, 2008 | Contact Author | By: Charles Fox, Independent Consultant
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Title: From Collagen Production to 190-nm Emulsions: Literature Findings
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Skin and Skin Care
Effects of alpha-ketoglutarate: Son et al. report on alpha-ketoglutarate as a key intermediate in the Krebs cycle and as a rate-limiting cofactor of prolyl-4-hydroxylase.1 Alpha-ketoglutarate also has been shown to have a potent effect on increasing the proline pool during collagen production; however, the details underlying its boosting effect on collagen remain unreported.

To investigate the effects of alpha-ketoglutarate on procollagen production and wrinkle formation, Son et al. conducted experiments in cultured human dermal fibroblasts and UVB-irradiated hairless mice. Based on enzyme-linked immunosorbent assay (ELISA) measurements, 10 mm of alpha-ketoglutarate stimulated procollagen production in fibroblasts by 25.6% ± 4.6%, compared to a control vehicle.

In addition, the researchers demonstrated that alpha-ketoglutarate increased activities of prolidase, which is known to play an important role in collagen metabolism. In fibroblasts and N-benzyloxycarbonyl-l-proline, a prolidase inhibitor, alpha-ketoglutarate inhibited procollagen synthesis by alpha-ketoglutarate in fibroblasts. 

To determine the effect of topically applied alpha-ketoglutarate on wrinkle formation, alpha-ketoglutarate at 1% and a vehicle consisting of 70% propylene glycol and 30% ethanol were applied on the dorsal skin of UVB-induced hairless mice for 12 weeks. The researchers found that alpha-ketoglutarate decreased wrinkle formation after long-term topical application. These results suggest that alpha-ketoglutarate diminishes UVB-induced wrinkle formation by increasing collagen production through a pathway that involves prolidase activation. Therefore, application of alpha-ketoglutarate may represent an effective anti-wrinkle agent for the cosmetic field. 

Lithospermum erythrorhizon in skin protection: Ishida et al. have published on the protection of human keratinocytes from UVB-induced inflammation using root extract of Lithospermum erythrorhizon.2 UVB irradiation is an important inducer of biological changes in skin and can activate inflammatory reactions and apoptotic pathways, leading to skin damage. 

According to the authors, the described root extract has naphthoquinone pigments in it that contain shikonin and shikonin derivatives; it is known for its anti-inflammatory, antibacterial and antitumor activity as well as for scavenging reactive oxygen species. However, the effect of the extract against UV damage is not clear. 

The aim of the presented study was to evaluate the efficacy of the extract against UVB-induced damage in normal human epidermal keratinocytes (NHEK). UVB-irradiated NHEK showed decreased cell viability, increased production of interleukin (IL)-1alpha, IL-6, IL-8 and tumor necrosis factor-alpha, and induced apoptosis. In an apoptosis pathway assay, UVB-irradiated NHEK showed increased caspase-3 activity and its phosphorylation at serine 15 compared with nonirradiated cells. 

All these effects induced by UVB irradiation were inhibited by treatment with the extract before and after the irradiation for 24 hr. The researchers suggest that it can protect epidermal cells against the harmful effects of UVB irradiation and that the material probably is beneficial for photoprotection of the skin. 

Hyaluronic acid, soybean protein and glycine for antiaging: L’Oréal discloses antiaging cosmetic compositions containing hyaluronic acid and/or one of its salts, one or more soybean protein extracts, and at least one glycine derivative.3 This composition is useful for preventing and decreasing the signs of skin aging, in particular the loss of firmness and elasticity of the skin. 

The antiaging effects of a complex containing the three actives: acetyl trifluoromethylphenyl valylglycine at 0.10%, hydrolyzed soybean extract at 2.00%, and sodium hyaluronate at 0.02%, on human skin were shown to be effective. The formulation of an o/w emulsion containing these three compounds is also disclosed. 

Sunscreen nanoparticles and skin penetration: Cross et al. have published an in vitro assessment of a novel micronized zinc oxide formulation and the penetration of such sunscreen nanoparticles into human skin.4 

The extent to which topically applied solid nanoparticles can penetrate the stratum corneum (SC) and access the underlying viable epidermis, as well as the rest of the body, is a great safety concern. Therefore, human epidermal penetration of a novel, transparent, nanoparticulate zinc oxide sunscreen formulation was determined using Franz-type diffusion cells. After 24 hr of exposure, electron microscopy verified the location of nanoparticles in exposed membranes, revealing that less than 0.03% of the applied zinc content penetrated the epidermis—not significantly more than the zinc detected in receptor phases following application of a placebo formulation. No particles could be detected in the lower SC or viable epidermis by electron microscopy, suggesting that minimal nanoparticle penetration occurs through the human epidermis. 

Aminoethanesulfonates for antiwrinkle cosmetics: Shiseido Company Ltd. discloses antiwrinkle cosmetics containing aminoethanesulfonates.5 This approach addresses lowered skin barrier function and simultaneously attains prevention and the remedy of wrinkles formed by aging and photo-aging. The described remedy comprises, as an active ingredient, at least one compound selected from a group of specified aminosulfonic acid compounds and their salts. An example of an antiwrinkle cream is shown in Formula 1.

Hydroxyl acid-containing o/w emulsions: L’Oréal discloses hydroxyl acid-containing cosmetic o/w emulsions.6 An o/w skin cleansing composition is described, comprising at least one hydroxy acid such as an alpha- or beta-hydroxy acid, and at least one fatty alcohol selected from fatty alcohols comprising 12 to 30 carbon atoms and having a melting point equal to or higher than 45°C. An example of such an emulsion is shown in Formula 2.

Hair and Hair Care

Nitrones for hair growth: The Procter and Gamble Co. discloses personal care compositions comprising nitrones and methods for regulating mammalian hair growth.7 Personal care compositions comprising: a) an ingredient selected from the group consisting of: alpha-phenylbutylnitrone (PBN); PBN doxylcyclohexane radicals; 5,5-dimethylpyrroline-N-oxide (DMPO); alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN); 2,2,6,6-tetramethylpiperidine-1-oxide; 4-hydroxytetramethyl piperidine-1-oxide;  and the salts of: N-(1-oxido-2,2,6,6-tetramethyl-4-piperidyl)-N,N-dimethyl-N-hydroxyethylammonium; 3,5-dibromo-4-nitrosobenzenesulfonic acid; 2-methyl-2-nitrosopropane; nitrosodi-sulfonic acid; alpha-(4-pyridyl-1-oxide)-N-t-butylnitrone; 3,3,5, 5-tetra-methylpyrroline-N-oxide; and 2,4,6-tri-t-butylnitrosobenzene and spin-trapping derivatives thereof; and mixtures thereof; b) an ingredient selected from the group consisting of particulate materials, panthenol, pantothenic acid derivatives, tanning actives, and mixtures thereof; and c) a dermatological acceptable carrier. 

Hydroxy acid, mono/disaccharide, ceramide for hair: L’Oréal, in a recent patent, discusses a composition containing at least one hydroxy acid, one or more mono- or disaccharides, and at least one ceramide, as well as methods of use.8 This invention relates to a composition that contains, in a preferred embodiment and a cosmetically acceptable medium, at least one monosaccharide or disaccharide, at least one alpha hydroxy acid, and at least one ceramide compound for use in a topical application for the treatment of keratinous substances, particularly keratinous fibers such as hair. An example of such a shampoo composition is shown in Formula 3.


W/O emulsion: Shiseido Co. discloses a w/o emulsified sunscreen cosmetic composition.9 The disclosed  composition exhibits UV-shielding effects while also preventing and suppressing skin discoloration. Specifically disclosed is a composition containing: a) 0.2–15% w/w octocrylene; b) 0.2–30% w/w zinc oxide subjected to a hydrophobilizing treatment such as a silane coupling agent; c) a cationic surface active agent such as distearyldimethylammonium chloride; and d) silica. 


Vicinal diol, isothiazolinone antimicrobials: Inolex Investment Corp. discloses antimicrobial cosmetic compositions comprising a blend of vicinal diol and isothiazolinone that are liquid at room temperature and that offer antifungal properties.10 Thus, skin care emulsions were developed containing 0.5% of a preservative blend comprising: 36% of 1,2-hexanediol; 4% of a methylisothiazolinone solution, 50% in water; and 60% of ethylhexylgycerin. The product containing the preservative blend meets the Personal Care Products Council’s (PCPC, formerly the CTFA) acceptance criteria of a greater than 90% reduction in fungus (mold) in 7 days, with no increase in mold thereafter up to 28 days. 


Zeolite, powders in ap/deo: Shiseido Co., Ltd., discloses deodorant compositions containing antibacterial zeolite and specified powders.11 The invention was designed to provide a suitable antiperspirant that also helps to remove sweat stains from clothing during laundering. Disclosed is a deodorant composition containing an antibacterial zeolite and a powder with a specific surface area > 150 m2/g, and an oil absorption > 100 mL/100 g. A deodorant composition further containing zinc oxide is also disclosed and an example of an antiperspirant stick composition is shown in Formula 4.

Skin Pigmentation

Glycyrrhetic acid, glycyrrhizin in skin tanning: Beiersdorf reports on the use of glycyrrhetic acid and glycyrrhizin in cosmetic and dermatological compositions to increase the effect of natural skin tanning.12 An example is shown in Formula 5.

In another patent assigned to Beiersdorf, the use of cosmetic or dermatological preparations containing glycyrrhetin, glycyrrhizin and 2,4-bis-{[4-(2-ethyl-hexyloxy)-2-hydroxy]-phenyl}-6-(4-methoxyphenyl)-1,3,5-triazine to increase pigmentation of human skin is disclosed.13 An example of such a cream is shown in Formula 6.

Interesting Vehicles

Humectant powder compositions: Shiseido Co. discloses powder cosmetic compositions containing humectants in high concentration.14 The described powder is characterized by containing 5–70% of a calcined clay mineral and 3–20% of a humectant exhibiting a moisture absorption as specified below, and by having a content of powder, inclusive of the mineral, of 60–95% based on the whole cosmetic. 

The moisture absorption in a weight change of 0.2–30% is determined by accurately weighing 5 g of the humectant into a 20 mL screw tube and allowing it to stand for a whole day and night under the conditions of 37°C and 98% relative humidity. The invention aims at providing a high-quality and stable powder cosmetic that has excellent moisturizing effect. An example is shown in Formula 7.

Wax crystal emulsions and gels: An anonymous author has published on novel wax crystal emulsions and gels.15 One of the primary tools used to adjust leave-on formulations to the desired skin feel is through the use of emollients. To achieve a light skin feel in a given formulation, emollients of higher spreadability should be used; for a rich skin feel, emollients of medium and lower spreadability should be used. Use of the spreading cascade principle is always recommended for an optimal balance of a formulation’s sensorial characteristics, such as smoothness. 

To obtain a waxier, drier and often quicker-absorbing or softer skin feel, solid emollients often are the ingredients of choice and a mix of solid emollients with different melting points can optimize the skin feel. Special crystals of a diameter size larger than 50 mm offer a massaging, scrubbing-like sensorial feel. Depending on crystal size, shape and chemical composition, this scrubbing effect can be more or less intense. Gel creams in particular allow larger crystal size development for such scrub-type applications. 

Low viscosity, w/o emulsions: Shiseido discloses low-viscosity, w/o emulsions containing water-soluble, UV-absorbing sulfonic acids, titanium dioxide or zinc oxide, and silicone oils.16 The described cosmetics show good storage stability, no stickiness and smooth spreading properties. They are stirred with a steel ball just before use. 

The disclosed emulsions contain: a) water-soluble UV absorbers having a sulfo group; b) TiO2 and/or ZnO;c) > 10% silicone oils; d) water, and e) optionally, > 1% of an ingredient selected from: NaCl, MgCl2, Na2SO4 and MgSO4 to improve emulsification stability. Thus, a w/o sunscreen emulsion was formulated containing decamethylcyclopentasiloxane, dimethicone, dimethicone-treated ZnO, water, Na phenylbenzimidazole-5-sulfonate, and NaCl. 

The emulsion, housed in a container with a stainless steel ball, was stored at 50°C for one month, then removed and shaken 10 times to uniformly disperse the formula. The final formula showed no changes in the appearance, odor or feel upon application to skin.

Alkylresorcinol and N-acyl glutamate esters to stabilize viscosity: Kuraray Co., Ltd., and Pola Chemical Industries Inc. disclose viscosity stabilizers containing alkylresorcinol and N-acyl glutamate esters, and skin compositions containing the same.17 The invention relates to a viscosity-stabilizing agent suitable for use in a skin composition with a viscosifier, a salt, and/or an electrolyte, wherein the viscosity-stabilizing agent is characterized by containing 4-alkylresorcinol or its salt and N-acylglutamic acid dialkyl ester. An example is shown in Formula 8.

Phospholipids, surfactants, glycols in o/w emulsions: Shiseido Co. discloses the manufacture of milky o/w emulsions containing hydrogenated phospholipids, nonionic surfactants and glycols.18 The cosmetic emulsion described exhibited an average droplet particle size between 100–500 nm and contained: a) oils, liquid at an ambient temperature, with a viscosity at 25°C < 100 mPa-s; b) hydrogenated phospholipids; c) nonionic surfactants with an HLB between 9–16, selected from those having sterol, alkyl ether or sorbitan fatty acid ester groups; d) glycols; and e) water. 

The emulsions are manufactured by adding an aqueous phase containing 3:7–7:3 w/w mixtures of glycols and water to an oily phase, stirred at 50–80°C, containing a), b) and c) at a ratio between 1:2 w/w oily phase and 1:5 w/w aqueous phase for forming emulsion drops with an average particle size of between 100–500 nm, adding a uniform aqueous phase containing other aqueous ingredients and water, and cooling the emulsions to an ambient temperature. 

Optionally, the emulsions also contain ethyl alcohol and/or phosphate-containing anionic surfactants. An example is shown in Formula 9. The resulting product showed an average particle size of 190 nm, good emulsion stability and no separation or precipitation after storage for one month at 0°C, 25°C or 50°C, as well as no sticky feeling and good skin-moisturizing, refreshing and emollient effects. 


1.  ED Son et al, Alpha-ketoglutarate increased activities of prolidase, which is known to play an important role in collagen metabolism, Biol & Pharma Bulletin 30(8) 1395–1399 (2007) (in English)

2. T Ishida et al, Protection of human keratinocytes from UVB-induced inflammation using root extract of Lithospermum erythrorhizon, Biol & Pharma Bulletin 30(5) 928–934 (2007) (in English)

3. US 2007 202,203, Anti-aging cosmetic composition containing hyaluronic acid, extract of soybean proteins and a glycine derivative, L’Oréal, France (Aug 30, 2007)

4. SE Cross et al, Human skin penetration of sunscreen nanoparticles: In-vitro assessment of a novel micronized zinc oxide formulation, Skin Pharmay and Physiol 20(3) 148–154 (2007)

5. WO 2007 100,006, Antiwrinkle cosmetics containing aminoethanesulfonates, Shiseido Co., Ltd., Japan (Sep 7, 2007)

6. FR 2,898,046, Hydroxyacid-containing cosmetic oil-in-water emulsions, L’Oréal, France (Sep 7, 2007)

7. US 2007 203,240, Personal care compositions comprising nitrones and methods for regulating mammalian hair growth, The Procter & Gamble Co., USA (Aug 30, 2007)

8. US 2007 226,916, Composition containing at least one hydroxy acid, at least one mono- or disaccharide and at least one ceramide, and methods, L’Oréal, France (Oct 4, 2007)

9. WO 2007 97,304, Water-in-oil emulsified sunscreen cosmetic composition, Shiseido Co., Ltd., Japan (Aug 30, 2007)

10. WO 2007 98,135, Antimicrobial cosmetic compositions comprising a blend of vicinal diol and isothiazolinone, Inolex Investment Corp., USA (Aug 30, 2007)

11. JP 2007 223,994, Deodorant compositions containing antibacterial zeolite and specified powders, Shiseido Co., Ltd., Japan (Sep 6, 2007)

12. DE 102,006,009,850, Use of glycyrrhetic acid and/or glycyrrhizin in cosmetic preparations for tanning skin, Beiersdorf A-G, Germany (Sep 6, 2007)

13. DE 102,006,009,783, Use of cosmetic or dermatological preparations containing glycyrrhetin and/or glycyrrhizin and 2,4-bis-{[4-(2-ethyl-hexyloxy)-2-hydroxy]-phenyl}-6-(4-methoxyphenyl)-1,3,5-triazine (Aniso Triazine) for increase of pigmentation of human skin, Beiersdorf A-G, Germany (Sep 6, 2007)

14. WO 2007 97,128, Powder cosmetic composition containing humectant in high concentration, Shiseido Co., Ltd., Japan (Aug 30, 2007)

15. Anon, (UK) Novel wax crystal emulsions and gels, Research Disclosure 511(Nov), P1516, No. 511076 (2006) (in English)

16. JP 2007 217,393, Low-viscosity water-in-oil cosmetic emulsions containing water-soluble UV-absorbing sulfonic acids, titania or zinc oxide, and silicone oils, Shiseido Co., Ltd., Japan (Aug 30, 2007)

17. JP 2007 223,991, Viscosity stabilizers containing alkylresorcinol and N-acyl glutamate esters, and skin composition containing the same, Kuraray Co., Ltd. and Pola Chemical Industries, Inc., Japan (Sep 6, 2007)

18. JP 2007 254,405, Manufacture of milky oil-in-water emulsion cosmetics containing hydrogenated phospholipids, nonionic surfactants and glycols, Shiseido Co., Ltd., Japan (Oct 4, 2007)                



Formula 1. Antiwrinkle cream

 Formula 1. Antiwrinkle cream5

Formula 2. Skin cleanser

 Formula 2. Skin cleanser6

Formula 3. Shampoo

 Formula 3. Shampoo8

Formula 4. Antiperspirant with zeolite

 Formula 4. Antiperspirant with zeolite11

Formula 5. Skin tanning lotion

 Formula 5. Skin tanning lotion12

Formula 6. Skin pigmentation cream

 Formula 6. Skin pigmentation cream13

Formula 7. Powders with high humectant concentrations

 Formula 7. Powders with high humectant concentrations14

Formula 8. Emulsion with viscosity stabilizer

 Formula 8. Emulsion with viscosity stabilizer17

Formula 9. O/W emulsions with hydrogenated phospholipids

 Formula 9. O/W emulsions with hydrogenated phospholipids18

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