Retinyl Palmitate

Retinyl palmitate is a fat-soluble form of vitamin A that is commonly used in cosmetic products because it is more stable to heat than retinol.

Effects


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

C

Photoprotection

Moderate

Acts as a UV filter by absorbing UV radiation in the range between 300-350 nm. 2% retinyl palmitate is as effective as an SPF 20 sunscreen in inhibiting sunburn erythema and thymine dimer formation.

C

Wrinkle treatment

Mild

Improves wrinkles around the eyes and possibly on the face and neck.

D

Increased skin thickness

Mild

Increases the thickness of the epidermis in mouse and guinea pig skin.

D

Antioxidant

Mild

Prevents the reduction in superoxide dismutase activity by UV light.

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Scientific Research


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Table of contents:

1. Sources

1.1 In the skin

Retinyl esters are the major storage forms of vitamin A in animal tissues, including those of humans.[1][2][3] In human skin, retinyl esters account for >70% of the endogenous vitamin A.[4] Of these retinyl palmitate, an ester of retinol and palmitic acid, is the predominant component.[5]

The epidermis contains approximately 3.5 times more retinyl esters (including retinyl palmitate) than the dermis, but sunlight induces a rapid degradation of epidermal retinyl esters without significantly reducing dermal retinyl esters. In an experiment on cultured keratinocytes, 80% of retinyl esters disappeared upon irradiation.[6]

The amount of retinyl palmitate in the skin may decline with age. In an experiment on female mice, age-related effects were observed in the stratum corneum, epidermis and dermis, with the level of retinyl palmitate being the highest in the epidermis of 20-week-old mice, and decreasing by about 4-fold at 60-68-weeks of age.[5]

1.2 In cosmetic products

Retinyl palmitate is widely used in cosmetics. In 2008, there were 1778 cosmetic products containing retinyl palmitate in the US FDA's Voluntary Cosmetic Registration Program, compared to 160 products containing retinol, 28 products containing retinyl acetate and 3 products containing retinoic acid.[7] The concentration of retinyl palmitate in cosmetic products ranges from 0.1% to 10%, but is generally less than or equal to 1%.[7][8]

2. Bioavailability

2.1 Topical administration

Retinyl palmitate is more thermally stable than retinol, and is therefore frequently used as a retinoid in cosmetic products.[9] It is however more photochemically labile than retinol, which is problematic.[10] The addition of sunscreens such as butyl methoxy dibenzoylmethane and antioxidants such as vitamin C, vitamin E and butyl hydroxytoluene (BHT) helps increase the stability of retinyl palmitate in cosmetic formulations.[7][11][12][13] Other details of the formulation also matter -- one formulation containing combinations of retinyl palmitate, tocopherol acetate and α-tocopherol had a shelf life of just 77 days,[14] but a different formulation containing retinyl palmitate, ascorbyl tetraisopalmitate and tocopheryl acetate had a much better shelf life of 120 days.[15] The difference was thought to be due to the high levels of water in the first formulation, which enhances hydrolysis reactions, versus the second formulation that contains ethylhexyl ethylhexanoate, a high molecular weight emollient that reduces the electrical conductivity of the medium and consequently the hydrolysis of retinyl palmitate.[15]

The percutaneous absorption of retinyl palmitate is well-established; it diffuses rapidly into the stratum corneum and epidermis after application.[4][16][17] In one study, 18% of topically applied retinyl palmitate was absorbed into human skin from an acetone vehicle.[18] Interestingly, the permeation and deposition of retinyl palmitate can be enhanced by the combined use of pectin and ascorbyl palmitate, which increases the amount of retinyl palmitate deposited in the epidermis substantially, presumably through their antioxidative effect.[19] The addition of glycolic acid on the other hand may not increase the total amount of retinyl palmitate that penetrates into the skin, although it seems to promote a faster permeation.[20]

Many drug delivery systems have been developed to further improve the dermal and transdermal release of retinyl palmitate, including hydrogels,[21] micelles,[22] microcapsules,[21] liposomes[21] liquid crystalline systems[23][24] and nanoparticles.[25][26][27] Retinyl palmitate can also be used as the core of polymeric nanocapsules to deliver retinyl palmitate and other actives into deep layers of the skin.[28][29]

To be pharmalogically active, retinyl palmitate must be enzymatically converted in the skin to retinol by cleavage of the ester linkage and subsequently converted to tretinoin via oxidative processes.[24] There is evidence that this does happen; in an experiment on human skin, 44% of absorbed retinyl palmitate was hydrolyzed by esterases in the skin to retinol.[18] Although no other metabolites were detected, retinol is known to be metabolized to tretinoin in small amounts in the epidermis and dermis.[30] Some of the absorbed retinyl palmitate is likely stored in the skin, as topical application of retinyl palmitate has been shown to alter the physiological levels of retinoids in mice skin and human skin explants.[4][16][17] In fact, cultured human fibroblasts have demonstrated a remarkable uptake and storage of retinyl palmitate in vitro.[31]

Because of the multiple conversion steps, higher concentrations of retinyl palmitate as compared to retinol or retinal are required in cosmetic formulations to produce similar cellular and molecular changes in the skin.[32]

2.2 Oral administration

Oral supplementation with retinyl palmitate raises the circulating serum levels of retinoic acid and retinol.[33][34] On average, for every 10,000 IU of retinyl palmitate/day, the serum retinol concentration increases by 13 µg/l after 3 months and 12 µg/l after 6 months of supplementation (a 2% increase).[34] However, the concentrations of retinol and retinyl palmitate in the skin does not change significantly compared to controls even after long periods of supplementation.[35]

3. Effects on the skin

3.1 Photoprotection

Retinyl esters strongly absorb UV radiation between 300-350 nm, a wavelength range received from the sun at earth level. In vitro, retinyl palmitate displayed a UV filtering capacity similar to that of the sunscreen octylmethoxycinnamate. In vivo, 2% retinyl palmitate prevented the formation of thymine dimers in hairless mice, and was as effective as an SPF 20 commercial sunscreen in inhibiting sunburn erythema and thymine dimer formation in human buttock skin.[36]

Although the natural concentrations of epidermal retinyl esters are too low to exert a measurable sunscreen effect, retinyl esters can be easily loaded to the skin by topical application.[37] Hence, retinyl palmitate can be used as a supplement in cosmetic formulations containing UV filters.[38] It does not protect the skin when applied after UV exposure, however.[39]

Topical retinyl palmitate alters skin composition, morphometry and histology. In mouse skin 0.1-5% retinyl palmitate increased the thickness of the epidermis and caused an accumulation of collagen within the dermis.[40] In guinea pig skin 0.5% retinyl palmitate also led to a thickening of the epidermis and improved skin hydration when combined with 4.2% glycolic acid.[41]

Retinyl palmitate is also known to ease wrinkles. 30 days of treatment with 1% retinyl palmitate in lamellar liquid crystalline systems significantly reduced the percentage areas with wrinkle traces of the eyes of 30 volunteers.[23] 2 studies have also shown that nanoparticles loaded with retinyl palmitate have an anti-wrinkle effect.[26][27] Because retinyl palmitate-loaded nanoparticles prevented the degradation of elastic fibres and the reduction in superoxide dismutase activity by UV irradiation, it has been hypothesized that retinyl palmitate exerts an antioxidative effect by protecting superoxide dismutase from UV irradiation, preventing the loss of elastin and ultimately resulting in its anti-wrinkle effect.[27]

A few commercially available products containing retinyl palmitate have demonstrated their efficacy in treating aged skin. In a randomized, controlled and single-blinded clinical study, an oil-based moisturizer containing retinyl palmitate and antioxidants (Bio-Oil) was tested for its effects on improving photoaged skin on the face, neck, décolletage, arms and lower legs. 73 women with mild-to-moderate photodamage were randomly assigned to the treatment or no-treatment group, with those in the treatment group instructed to use the moisturizer twice daily on the facial and body skin sites. After 12 weeks, clinical grading revealed significant improvements in overall appearance, fine lines, coarse wrinkles, mottled pigmentation, uneven skin tone, visual and tactile roughness, firm appearance and clarity of the face and neck in women who had used the moisturizer compared to those who had not. There were also significant improvements in overall appearance, crepey texture, dryness/scaling, visual roughness/smoothness, and tactile roughness/smoothness on the décolletage, arms and lower legs of women in the treatment group versus those in the no-treatment group.[42]

In addition, an antiaging product by The Boots Company (possibly the forerunner of the Boots No7 Protect & Perfect Intense Beauty Serum) induced partial repair of photoaged human skin in a 12-day patch test of the forearm, increasing the deposition of fibrillin-1 and procollagen I in the papillary dermis. Retinyl palmitate was present only at a low concentration (0.2%) in the formulation however, and may not have contributed to these positive changes.[43]

3.3 Other effects and uses

Alterations of the extracellular matrix is thought to be one factor involved in the etiology of cellulite.[44] Hence, retinyl palmitate should aid in the treatment of cellulite in theory, but a study on the use of intense pulsed light (IPL) therapy with a retinyl palmitate cream did not find conclusive evidence that retinyl palmitate augments the cosmetic improvement of cellulite.[45]

In another study, retinyl palmitate was included in an ointment used to re-epithelialize the skin following fractional skin resurfacing with a carbon dioxide laser, though its effect in this respect was not measured.[46]

4. Side Effects

4.1 Low risk of systemic toxicity

Although the application of retinyl palmitate to the relatively permeable skin of newborn rats led to significantly higher concentrations of retinyl palmitate and retinol in the lungs and liver,[47] retinyl palmitate does not appear to penetrate well through the skin of adult rats, guinea pigs or humans, indicating only a small risk of systemic exposure.[18][19] For instance, repeated topical treatment with 0.55% retinyl palmitate on large swathes of the body for 21 days did not alter plasma concentrations of retinol, retinyl esters or retinoic acids in a study on 14 women of child-bearing age.[48]

Retinyl palmitate is included in the US FDA's list of nutrients or dietary supplements that are Generally Recognized as Safe (GRAS). Although chronic retinyl palmitate supplementation induced oxidative stress, mitochondrial impairment and altered behaviour in rats[49][50][51] as well as osteotoxicity in mice,[52] oral doses of retinyl palmitate up to 75,000 IU/day for a year has been proven to be safe and efficacious in humans.[53] Single oral doses of up to 30,000 IU/day did not result in any systemic adverse events in adult women either.[48][54]

4.2 Adverse skin reactions

Topical retinyl palmitate amounting to a total of approximately 30,000 IU/day for 21 days followed by single oral doses of 10,000 IU or 30,000 IU retinyl palmitate has been observed to lead to transient, mild local irritation reactions on the treatment sites in adult women.[48]

Oral administration of 300,000 IU retinyl palmitate daily for 12 months or more as an adjuvant treatment for resected stage I lung cancer also frequently resulted in skin dryness and desquamation in many patients (60% of those treated), with other rarer symptoms such as dyspepsia, headache, nosebleeds and mild hair loss occurring in less than 10% of patients. Fortunately, most of the latter were self-terminating, and overall high-dose retinyl palmitate was considered a safe and well-tolerated treatment in this patient group.[55]

A moisturizer containing 0.1% retinyl palmitate applied to the shaved backs of albino rabbits daily for 4 days led to only slight dermal irritation, but a body lotion containing 0.1% retinyl palmitate applied in the same way caused the development of erythema and edema within 48 hours. These persisted for at least 7 days, resulting in skin dehydration and desquamation.[56]

Dermal irritation and sensitization studies on humans using patch tests concluded that a 1% retinyl palmitate-containing moisturizer was most likely not a primary skin irritant, but may be a sensitizing agent, and that a body lotion containing 0.1% retinyl palmitate was neither a strong irritant nor a strong contact sensitizer.[56]

4.3 Reproductive and developmental toxicity

Excessive intake of retinyl palmitate during pregnancy may lead to maternal toxicity and adverse effects for the developing offspring. The feeding of 2,500-25,000 IU/kg of retinyl palmitate to female rats during gestation and lactation has been shown to induce oxidative stress and redox modulation in both the mothers and their pups,[57][58] and mice administered 10,000-15,000 IU/kg retinyl palmitate on different days of pregnancy led to malformations in the forelimbs and hindlimbs of the offspring.[59] There have not yet been any studies conducted on the effects of retinyl palmitate supplementation in pregnant women however.

4.4 Possible tumour promotion

The photocarcinogenicity of retinyl palmitate is controversial. There is some indication that retinyl palmitate may potentiate the damaging effects of UVA exposure, as treating mouse lymphoma cells with 1 to 25 µg/ml retinyl palmitate or its photodecomposition products in the presence of UVA light has been shown to induce mutations via a clastogenic mode of action.[60][61] Photoirradiation of retinyl palmitate and anhydroretinol, one of its major photodecomposition products, is also known to generate reactive oxygen species that can mediate the induction of lipid peroxidation.[62][63][64][65] Similarly, in human skin Jurkat T-cells illumination with UVA + visible light in the presence of retinyl palmitate or its photodecomposition products at concentrations of 100 µM and greater resulted in DNA fragmentation and increased cell death.[66] Retinyl palmitate also appears to have a synergistic effect on the phototoxicity of cosmetic formulations containing avobenzone, a commonly used sunscreen ingredient.[67] However, no overt cytotoxicity was seen in another study where Chinese hamster ovary cells were treated with retinyl palmitate under pre-irradiation or simultaneous irradiation conditions, raising the question of whether the previously reported photogenotoxic effects are due to the different test conditions used.[68][69] It has also been noted that caution should be exercised in extrapolating the relevance of the findings of such in vitro studies to humans, since these studies do not take into account the complex antioxidant network in human skin.[70]

A few studies have also investigated the photocarcinogenicity of retinyl palmitate in vivo. One revealed that when 0.05% retinyl palmitate in an oil-in-water cream was applied to the backs of hairless mice, it significantly decreased the the number of apoptotic cells as well as the formation of thymine dimers in the epidermis following acute UVB exposure.[71] The National Toxicology Program has also conducted a 1-year study was to investigate the effects of topically applied skin cream containing retinyl palmitate on the photocarcinogenicity of simulated solar light or UV light in hairless mice. Although this study concluded that retinyl palmitate enhanced the photocarcinogenicity activity of SSL and UVB in hairless mice, its findings are considered to be seriously compromised by the effects of the control cream used as the vehicle. This is because the control cream alone caused substantial adverse effects in the control mice exposed to simulated sunlight, UVA, or UVB, as indicated by markedly reduced survivability and in-life skin lesion onset and elevated in-life skin lesion incidence and multiplicity, and is therefore a major confounding factor.[8]

On the other hand, ingestion of retinyl palmitate may lower cancer risk. Female rats on a retinyl palmitate-enriched diet had reduced mammary cancer multiplicity induced by 1-methyl-1-nitrosourea, an animal carcinogen.[72] 2 studies on mice likewise demonstrated that dietary supplementation with retinyl palmitate or retinyl palmitate + the carotenoid canthaxanthin led to decreases in the tumour burden induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) and UV irradiation, respectively.[73][74] This effect may be due to a heightened tumoricidal capacity of macrophages in mice administered dietary retinyl palmitate.[75]

In humans, daliy oral administration of retinyl palmitate was effective in reducing the number of new primary tumours in the lungs of patients patients cured of early-stage lung cancer,[76] but oral retinyl palmitate alone or plus β-carotene was not effective in reducing the long-term risk of oral cancer.[77]

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