|Grade||Level of Evidence|
|A||Multiple double-blind, controlled clinical trials.|
|B||1 double-blind, controlled clinical trial.|
|C||At least 1 controlled or comparative clinical trial.|
|D||Uncontrolled, observational, animal or in-vitro studies only.|
|Grade||Effect||Size of Effect||Comments|
Repairs lines and wrinkles on the face, neck and arms, likely via influencing the synthesis and cross-linking of collagen molecules.
Improves measurements of skin roughness after as little as 2 weeks of treatment with serum of high concentration.
Synergises with vitamin E in UV protection. Attenuates the formation of sunburn cells and thymine dimers.
Makes skin more radiant and reduces the intensity of pigmented lesions such as solar lentigines and brown spots, through inhibiting melanin production.
Not as effective as hydroquinone, but almost devoid of side effects.
Enhances the moisture content of the stratum corneum and alters transepidermal water loss, possibly by increasing the formation of barrier lipids and improving barrier function.
Vitamin C is the most abundant antioxidant in the skin, and also helps to regenerate other antioxidants.
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Table of contents:
L-ascorbic acid or vitamin C is found in a wide variety of plant and animal sources, especially fruits and vegetables. It functions as a cofactor for many enzymes involved in regulating photosynthesis, hormone biosynthesis and regenerating other antioxidants, regulates cell division and growth, and is involved in signal transduction.
The Australian Kakadu plum has the highest content of vitamin C discovered so far, varying from 3.5% to 5.5% of wet weight, in comparison to orange, grapefruit and lime, which contain only approximately 0.5%. Camu-camu, acerola, chili peppers and blackcurrants are also rich sources of vitamin C.
Ascorbic acid is extremely unstable -- it is oxidised in aerobic conditions and under light exposure, resulting in irreversible degradation. It is also highly hydrophilic, contrasting with the hydrophobic nature of the stratum corneum. Methods and formulations have therefore been devised to enable the use of ascorbic acid in cosmetic products by improving its stability and penetration.
The stability of ascorbic acid in creams is also affected by light, concentration, pH and the formulation characteristics. Degradation is about 70 times slower in the dark than in light. Ascorbic acid also exhibits better stability at higher concentrations, perhaps because of the lower number of photons available for excitation per molecule. At lower pH, ascorbic acid is more stable due to its lower redox potential and the fact that its deprotonated form, which dominates at pH > 4.2, appears to be more susceptible to photo-oxidation. Palmitic acid as an emulsifier and glycerin as a humectant also impart the most stabilizing effects on ascorbic acid compared to other emulsifiers (myristic acid, stearic acid) and humectants (ethylene glycol, propylene glycol) tested.
The storage stability of ascorbic acid is also markedly increased when encapsulated in a solid-in-oil nanosuspension, owing to its low moisture content.
Ascorbic acid is water-soluble and its percutaneous absorption in aqueous solution is critically dependent on pH. Tissue levels of ascorbic acid were enhanced only at pH levels less than 3.5, in a study on porcine skin. Since the pKa of ascorbic acid is 4.2, it apparently must be un-ionized to be delivered across the stratum corneum.
Interestingly, skin resurfacing modalities have been shown to increase the topical delivery of ascorbic acid into the skin. In a study on nude mouse skin, both erbium:yttrium-aluminium-garnet (Er:YAG) and carbon dioxide lasers, as well as microdermabrasion, greatly enhanced the flux and skin deposition of ascorbic acid. Considering the hydrophilic nature of ascorbic acid, these results are not surprising as these techniques all remove layers of the stratum corneum, which is hydrophobic and hence represents the biggest barrier in the permeation of ascorbic acid into the skin.
Incorporating ascorbic acid in microemulsions, particularly gel-like microemulsions, also enhances its delivery compared to solutions. In an experiment on reconstructed human epidermis, the use of microemulsions as carriers increased the absorption of ascorbic acid and α-tocopherol in the skin layers. The increased absorption of such microemulsions is attributed to the use of penetration enhancers in the oil phase.
After reaching the dermis, ascorbic acid remains stable in the tissue for several hours before being metabolized. UV light exposure however depletes up to two-thirds of cutaneous ascorbic acid stores. In light of these findings, it has been suggested that ascorbic acid may need to be topically applied every 8 hours for optimal effect.
3. Effects on the skin
Topical ascorbic acid is the most plentiful antioxidant in human skin and has been shown to protect against UV radiation-induced injury in vitro. When the skin is exposed to UV light, reactive oxygen species (ROS) are generated. Ascorbic acid protects the skin from oxidative stress by donating electrons to neutralize these free radicals.
The skin uses both ascorbic acid and α-tocopherol (vitamin E) to protect itself from the damaging effects of sunlight. Ascorbic acid, being water-soluble, protects the aqueous environment, while vitamin E protects lipid structures, including membranes.
It is also known that ascorbic acid and α-tocopherol work synergistically in biological systems; when vitamin E is oxidized by free radicals, it is regenerated in the membrane by ascorbic acid. As expected, the combination of both vitamins has been demonstrated to achieve greater UV protection than equivalent concentrations of topical ascorbic acid or α-tocopherol alone.
The addition of other antioxidants also appear to augment the protective effects of vitamins C. Ferulic acid, another potent plant-derived antioxidant, improves the chemical stability and photoprotective effects of ascorbic acid and α-tocopherol. Topical formulations of 15% ascorbic acid, 1% α-tocopherol and 0.5% ferulic acid have been shown to meaningfully increase photoprotection of solar-irradiated human skin, decreasing erythema, sunburn cells, thymine dimers, p53 expression and cytokine formation. Another study on 10 human subjects discovered that a topical antioxidant mixture consisting of ascorbic acid, ferulic acid and phloretin attenuated sunburn cell formation, thymine dimer formation, matrix metalloproteinase expression, p53 protein expression and immunosuppression following UV irradiation.
Ascorbic acid also seems to significantly increase the skin deposition of physical sun blocking agents used in sunscreens, such as titanium oxide and zinc oxide, without increasing their permeation through the skin. This is important as these UV-absorbing agents need to accumulate within the upper skin layers in order to provide a dense light-absorbing layer and guarantee water resistance.
3.2 Anti-wrinkle effect
Multiple studies have determined the efficacy of topical ascorbic acid application in improving the appearance of wrinkles. In one such study, a 3-month, double-blind, vehicle-controlled trial, 19 volunteers applied a serum containing topical ascorbic acid (Cellex-C High Potency Serum) and a control serum to randomly assigned sides of their faces for 3 months. Both computer-assisted image analysis of skin surface topography and clinical assessment demonstrated improvement in wrinkling. Another randomized, double-blind, placebo-controlled study had volunteers apply a cream containing 5% ascorbic acid to the lower neck and arms. After 6 months, skin relief parameters showed a decrease of deep furrows and ultrastructural evidence of elastic tissue repair was obtained, corroborating with the favorable results of clinical skin surface examinations. In addition, a vitamin C complex containing 10% ascorbic acid and 7% tetrahexyldecyl ascorbate in an anhydrous polysilicone gel base led to clinically visible and statistically significant improvements in wrinkling when used topically for 12 weeks.
Ascorbic acid also works on normal to oily facial skin, as evidenced by a study in which 30 patients with normal to oily skin and mild photodamage applied a treatment system containing 4% hydroquinone and 10% ascorbic acid (Obagi-C Rx System) for 12 weeks. The treatment system was found to improve fine lines and wrinkles significantly. As the active ingredient with the highest concentration, this result strongly suggested that ascorbic acid can help ameliorate wrinkles.
Ascorbic acid has been shown to have a role in collagen stimulation. It is thought to directly and specifically activate collagen gene regulation, both by increasing the transcription rate and by stabilizing procollagen mRNA. Ascorbic acid is also necessary for the formation of prolyl hydroxylase and lysyl hydroxylase, which are required for the production of collagen and for cross-linking collagen molecules, respectively. It is likely that the anti-wrinkle effects of ascorbic acid results at least in part from its influence on collagen synthesis and on stimulating qualitative changes to collagen molecules.
3.3 Smoothing effect
Many of the same studies that found improvements in fine lines and wrinkles after topical application of ascorbic acid also noted an improvement in skin roughness.
A treatment system (Obagi-C Rx System) containing 10% ascorbic acid and 4% hydroquinone, among other ingredients, led to at least 1-grade improvements in tactile roughness in 90% of patients after 12 weeks, according to investigator evaluations. The results from other studies substantiate this benefit. Optical profilometry image analysis has demonstrated a 73.7% improvement over control in arithmetic average roughness and a 68.4% improvement over control in roughness in the periorbital region following daily application of 0.5ml of an ascorbic acid-containing serum (Cellex-C High Potency Serum). Likewise, 3D microtopography analysis showed statistically significant improvements in overall skin roughness after just 2 weeks of daily treatment with a system consisting of 23.8% ascorbic acid serum and penetration enhancers with iontophoresis.
3.4 Increased moisture
Ascorbic acid appears to enhance the moisture content of the stratum corneum, according to the results of one study. After daily applications of topical formulations containing either ascorbic acid or one of its derivatives for 4 weeks, only the formulation with ascorbic acid both increased the moisture content and altered transepidermal water loss.
The mechanisms by which this happens may be 2-fold. In vitro experiments have shown that ascorbic acid not only plays a key role in the formation of stratum corneum barrier lipids by increasing the synthesis of ceramides, but also improves endothelial barrier function via an increase in collagen synthesis.
3.5 Lightening effect
Apart from its well-documented efficacy in treating melasma, ascorbic acid is also able to whiten the skin and lighten hyperpigmented spots. One study evaluating the skin whitening ability of lactic acid and ascorbic acid found that treatment with 8.8% lactic acid did not significantly affect skin pigmentation, but that the supplementation of 1% ascorbic acid produced a whitening effect after 3 months.
A separate study investigated the effect of ascorbic acid in improving the appearance of solar lentigines, hyperpigmented lesions associated with aging and accumulated sun exposure. 30 subjects applied a product containing 10% vitamin C + 2% phytic acid to one side of the face and vehicle to the other twice daily for 3 months, after which pigmentation of product-treated lentigines was found to be reduced, while that for vehicle-treated lesions remained stable.
The lightening effect of ascorbic acid is due to its inhibition of melanogenesis through the inhibition of tyrosinase, the rate-limiting enzyme in melanin production. It has also been hypothesized that UVA radiation may play a role in melanogenesis through promoting oxidative stress, which results in the increased formation of reactive oxygen and nitrogen species. Hence, it is possible that ascorbic acid also reduces melanogenesis through the improvement of antioxidant defense capacity and inhibition of nitric oxide production.
3.6 Melasma treatment
Melasma is a common, acquired hypermelanosis seen in women, that is often recalcitrant to treatment with depigmentation agents. Several studies have assessed the effectiveness of varying concentrations of topical ascorbic acid in treating melasma. In one, 5% ascorbic acid cream was as effective as 4% hydroquinone in improving melasma over 16 weeks based on colorimetric analysis, and had the advantage of being nearly devoid of side effects compared to to the hydroquinone cream. One open-label trial utilizing a formulation of 25% ascorbic acid (C'ensil) on 40 subjects also concluded it was an effective treatment modality for melasma, as it significantly decreased the degree of pigmentation.
Ascorbic acid also seems to be able to exert its effects when incorporated into chemical peels or as a separate, additional treatment. A superficial chemical peel containing α-hydroxy acid, ascorbic acid and oxygen (Theraderm Melasma peel) successfully improved hyperpigmentation in 25 Korean patients with moderate to severe melasma following 4 treatments over 8 weeks. Further, a 6-week treatment regimen consisting of 20% trichloroacetic peel on a weekly basis and daily application of topical 5% ascorbic acid, showed greater decreases in melasma area and severity compared to treatment with the peel alone, indicating that the addition of ascorbic acid helped improve the results and response to therapy.
4. Side Effects
Topical ascorbic acid is more effective when formulated at a pH of 3.5 or less, but the more acidic the formulation, the more irritation it can cause to the skin. Nevertheless, a cream with 5% ascorbic acid did not induce dermal sensitization in 103 human subjects, a product containing 10% ascorbic acid was non-irritant in a 4-day patch assay on human skin and a facial treatment with 10% ascorbic acid was not a contact sensitizer in a maximization assay on 26 humans. Based on these clinical results, the Cosmetic Ingredient Review Expert Panel has concluded that ascorbic acid is a safe cosmetic ingredient. The very few reports in the clinical literature of ascorbic acid sensitization, irritation or other adverse events, support this conclusion. Very high (>20%) concentrations of ascorbic acid have led to stinging, burning sensations, itching and erythema, however, as expected.
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