NIȚULESCU Georgiana1, OZON Emma Adriana1*, SEVASTRE Ani-Simona2, LUPULIASA Dumitru1
1 Pharmaceutical Technology Department, Faculty of Pharmacy, ”Carol Davila” University of Medicine and Pharmacy, 6, Traian Vuia Street, 020956, Bucharest (ROMANIA)
2 University of Medicine and Pharmacy, Faculty of Pharmacy, Craiova, (Romania)
*corresponding author, firstname.lastname@example.org
The awareness of the importance of nutrition for the general state of well-being and the growth of ”beauty from within” concept have led to an increase of the consumption of food supplements and the development of a new category: nutricosmetics. In this review clinical data regarding the effectiveness of oral collagen intake on skin were analyze. Various formulations with collagen and peptides derivates are available on the market and is anticipated these numbers to grow significantly, as there are a lot of studies that prove their efficiency.
Keywords: beauty from within; nutricosmetics, collagen
A nutrient is considered to be any ingredient that provides energy or allows growth, repairs or proper functioning of the body. Nutrients are classified in different classes such as minerals, vitamins, carbohydrates, proteins, lipids and water . The “nutricosmetics” term defines natural ingredients that increase the function and appearance of human skin, nails, and hair. The Global Nutricosmetics Market is expected to grow significantly, a compound annual growth rate (CAGR) of 8.63% is targeted in the forecast period (2020-2025) .
Methods. Articles were obtained through searches of the PubMed database (www.pubmed.gov) using several key words (collagen; oral intake; skin) and filters such as: clinical trial, meta-analysis, randomized clinical trials. Data filters were added, and from 2010 until now 43 articles were found with those key words. The articles were the tested products contain collagen or peptides derivates and have results on skin were selected.
Collagen and peptides derivates as nutricosmetic ingredients
Collagen is a fibrous protein much used in medical and dermocosmetic industries due to its effects on the skin, and its characteristics such as biocompatibility, bioactivity and weak immunogenicity . The collagen and elastin fibers are forming the main system that supports the skin’s texture, contributing to its smooth appearance. 28 collagen type were identified by now. There are 4 subfamilies based on their supramolecular structures: fibrils, beaded filaments, anchoring fibrils, and networks. Fibrillar collagens are the richest collagens in vertebrates, and they play a structural role and induce mechanical properties of tissues like the tensile strength in skin and the resistance to traction in ligaments. The most important types of collagen of the skin are I and III types, but there exist also other types of collagen like collagen VII, which is only 0.001%, but is essential for the integrity of the skin .
Skin aging is associated with an increased degradation of collagen fibers, therefore hydrolyzed collagen (HC) is very popular due to the fact it shows benefit for human skin and cartilage connective tissues . The biomolecule is obtained by extraction from different natural sources or by recombinant protein production systems like yeast, bacteria, insects or plants, mammalian cells, or artificial fibrils that have collagen characteristics such as the artificial polymer known as KOD . The main source of collagen is provided by animal products such as bovine, porcine, or poultry bones, skins or hides, tendons and cartilages, but the present focus is on more cheaper sources, having a decreased risk for bovine spongiform encephalopathy (BSE) such as fish, marine sponge and jelly fish. HC is a group of peptides with low molecular weight (3-6 kDa)  obtained by enzymatic hydrolysis in acid or alkaline media at a specific incubation temperature  or thermal hydrolysis process . The properties of HC, like solubility, molecular weight of the peptide chain and functional activity are depending on the type and source of extraction . The low molecular weight peptides are obtained by enzymatic proteolysis process which is faster and uses milder conditions . The absorption rate and bioavailability are influenced by the form of collagen that is ingested. Skov and colab. compared the postprandial absorption of enzymatically hydrolyzed collagen protein (EHC) and non-enzymatically hydrolyzed collagen protein (NC) with placebo and observed the influence of exogenous enzymatic hydrolysis on bioavailability in a randomized, blinded, cross-over study. They demonstrated that enzymatic hydrolysis enhances the absorption rate of the collagen-rich amino acids glycine (Gly), proline (Pro) and hydroxyproline (Hyp) . The composition of peptides in different types of collagen hydrolysate determines the peptide concentrations in the blood. Yazaki and colab. studied the plasma concentrations of collagen-derived peptides after the administration of high tripeptide containing collagen hydrolysate in humans and identified 17 types of collagen-derived peptides transiently, with a particular enhancement in Gly-Pro-Hyp . They proved that this type of collagen is a cheaper and effective alternative to synthesizing pure peptides that can be used as a nutricosmetic. Furthermore, hydrolyzed collagen is containing some other collagen-derived peptides with helpful effects on skin. Inoue and colab. showed in a randomized double-blind placebo-controlled clinical trial that the use of a collagen hydrolysate with a higher content of Pro-Hyp and Hyp-Gly led to more beneficial effects on the facial skin like elasticity, moisture, wrinkles and roughness  than the use of a the collagen hydrolysate with a lower content of bioactive collagen peptides. Also, the ingestion of HC offers the skin a protection against UV and melasma and an increase of fibroblast production and extracellular matrix of the derma. Regarding the collagen, the most important research interest is finding accessible sources and methods to obtain molecules with a high content of bioactive peptides, as the product efficiency is correlated with the bioactive peptides content. There are a lot of HC used in different skin and hair products due to their characteristics like low viscosity in aqueous solution, neutral odor, colorless, transparent, emulsifier and stabilizer, foam and film forming, hydrophilic character, solubility, dispersibility, powder compressibility, carrier substance and low allergenicity [12, 13]. Several studies pointed the effect on skin of different formulations (Table 1) with collagen peptides alone or with other active ingredients.
VERISOL® (GELITA AG, Eberbach, Germany) is a specific bioactive collagen peptide (BCP) studied in three [14–16] placebo-controlled trials for its effects on the skin. It consists of different specific collagen peptides of an average molecular weight of 2.0 kDa with a high safety profile derived from a complex multistep procedure by degradation of porcine type I collagen. It diminished the wrinkles with benefic effects on skin matrix synthesis, enhanced the skin elasticity and density, and decreased the degree of cellulite. An open-label, single-center trial proved that the daily intake of BCP increased nail growth and improved brittle nails associated with a significant decrease in the recurrence of broken nails .
ELASTEN®, QUIRIS Healthcare, Gütersloh, Germany, containing a specially developed mixture of collagen peptides, acerola fruit extract, vitamin C, zinc, vitamin E and biotin, together with sorbate, sodium benzoate, carboxymethylcellulose, citric acid, natural aroma, and water was studied in two placebo-controlled trials [18, 19]. The specific collagen peptides were produced following GMP (good manufacturing practice) guidelines in an IFS (international featured standards)—and ISO (International Organization for Standardization)—certified plant by water extraction of the endogenous collagen from bovine skin, and subsequent enzymatic hydrolysis and sterilization. It was observed a cosmetically significant improvement of the facial skin after 12 weeks of ingestion of the supplement.
BioCell Collagen® (BioCell Technology, LLC), which contains a hydrolyzed chicken sternal cartilage extract composed of a naturally occurring matrix of hydrolyzed collagen type II (molecular weight range of 1–2.5 kDa), low molecular weight hyaluronic acid, and chondroitin sulfate was first studied in a pilot open-label study on 26 healthy females who showed deep signs of natural and photoaging on the face. It was observed that daily intake of 1 g of BCC for 12 weeks generate a notable diminish of skin dryness/scaling (76%) and global lines/wrinkle (13.2%) and also, a remarkable enhance in the content of hemoglobin and collagen (6.3%) in the skin was noticed after 6 weeks of use . The results were confirmed with a 12-week, double-blind, placebo-controlled trial . Another double-blind, randomized, placebo controlled clinical trial conducted on healthy post-menopausal women shows that the oral intake of hydrolyzed collagen, hyaluronic acid and vitamins and minerals, produces a notable change of wrinkle depth. It is also capable to lead to a significant enhance in elasticity and hydration of the skin . In comparison with collagen peptide obtained from land animals, collagen peptides extracted from aquatic sources have particular molecular and biological characteristics regarding the amino acid composition, the antioxidant effect, the neuroprotective action and the antiage activity, due to the low temperature and/or high salt contain of their environment . Two liquid nutraceuticals manufactured by MINERVA Research Labs (London, UK) containing hydrolyzed collagen type I with a molecular weight of 0.3–8 kDa, were observed in double-blind, randomized, placebo-controlled clinical trials. Their complete formula can be seen in Table 1. Subjects consuming GOLD COLLAGEN® ACTIVE (4000 mg HC) had an comprehensive notable improve in skin elasticity (+40%; P < .0001) in comparison with placebo. Histological analysis of skin biopsies revealed benefic effects on the skin architecture, with a decrease of solar elastosis and an increase of collagen fiber arrangement in the test product group. Daily oral intake of the nutricosmeceutical GOLD COLLAGEN® FORTE (5000 mg HC) produced a significant improvement of skin elasticity (+7.5%), p ≤ 0.001 and an enhancement in skin consistency.
The effects of a low-molecular-weight collagen peptide (LMWCP), obtained from the sutchi catfish’s skin (Pangasius hypophthalmus) were proved in a randomized, double-blind, placebo-controlled clinical trial. LMWCP is a fish-derived type I collagen hydrolysate that is prepared by enzymatic hydrolysis and has a >15% content of tripeptides (Gly-X-Y, where X and Y are different amino acid residues that are often proline, hydroxyproline, or alanine) including 3% Gly-Pro-Hyp. The results demonstrated that oral supplementation with 1 g of LMWCP once daily for 12 weeks remarkably enhanced skin hydration, wrinkling and elasticity for most of the people . Asserin and colab. developed two double-blind, randomized, placebo controlled clinical trials to determine the effect of a daily oral intake of collagen peptides on skin hydration, collagen density and collagen fragmentation. The products provided by Rousselot are containing specific collagen peptides of fish origin (Peptan® F) and porcine origin (Peptan® P) with an average molecular weight of 2000–5000 Da. They give clinical test for the potency of specific collagen peptide to increase skin moisture, related to improvement of collagen and glycosaminoglycan synthesis in the same skin layers and to prevent and decrease the fragmentation of the skin collagen matrix . The clinical effects after oral collagen peptides supplementation on skin different properties such as hydration, elasticity, erythema, and pigmentation were noticed in a randomized controlled study. The CP was a 15% tripeptide form, highly advanced-collagen tripeptide developed by Jellice Co., Ltd (Sendai, Japan). It contains 3% Gly – Pro – Hyp. Average molecular weight is 1500Da. A subsidiary aim of the study was to examine the effects of concomitant administration of vitamin C. The results showed that oral CP supplementation may increase skin hydration and elasticity with no action of CP on skin erythema and pigmentation and the concomitant ingestion of vitamin C did not improve the efficacy of CP on hydration and elasticity . The effects on skin characteristics, plasma growth hormone and IGF-1 levels of a fish-derived collagen peptide obtained from Tilapia were analyzed in a randomized, double-blind, placebo-controlled, parallel-group comparison trial. The liquid product contained 10 g of fish-derived collagen peptide (FUJIFILM, Tokyo, Japan), ornithine and other substances like vitamin C, acidifier and sweetener. The average molecular weight of the collagen peptide was 2000 to 3000 Da and the total amount of hydroxyproline was 1100 mg in one dose. The obtained results proved increased plasma IGF-1 levels after 8 weeks of intake in the test group, and the skin elasticity and transepidermal water loss (TEWL) were remarkably enhanced, facts which offer the innovative idea that the use of collagen peptides are improving skin properties by increasing plasma IGF-1 levels .
CELERGEN are soft gelatin capsules that contain marine collagen peptides obtained from skin of deep-sea fish (MCPs), grape-skin extract, coenzyme Q10 of plant origin, luteolin, and selenium of vegetal origin. In the clinical-laboratory study the product was administrated to 41 volunteers for 8 weeks and at the end some skin properties such as moisture, elasticity, sebum production and biological age were tested. The results proved that the intake improved significantly the skin elasticity, sebum production and dermal ultrasonic markers. Metabolic data presented a remarkable enhance of plasma hydroxyproline and ATP storage in erythrocytes. Redox parameters, GSH/coenzyme Q10 content, and GPx/GST activities remained unaffected, while NO and malondialdehyde were moderately increased, but still on a regular range of values .
Table 1. Clinical trials of collagen-based products
|Type of study||No. Subjects/
|Verisol®: specific collagen peptides derived from a complex multistep procedure by degradation of porcine type I collagen||double-blind, placebo-controlled||114 / 8 weeks||significant decrease of eye wrinkle volume (p < 0.05); significantly higher content of procollagen type I (65%), elastin (18%) and a 6% increase for fibrillin.|||
|double-blind, placebo-controlled||69 / 8 weeks||statistically remarkably better skin elasticity was demonstrated in elderly women and a good effect on skin moisture and skin evaporation but without a statistical significance|||
|double-blind, placebo-controlled||105 / 6 months||improvement of the skin texture in women suffering from moderate cellulite and has a positive influence on skin health|||
|open-label, single-center trial||25 / 24 weeks||increased nail growth and improved brittle nails in association with a significant decrease in the frequency of broken nails.|||
2.5 g collagen peptides, 666 mg acerola fruit extract, 80 mg vitamin C, 3 mg zinc, 2.3 mg vitamin E, and 50 μg biotin.
|double-blind, placebo-controlled||75 / 12 weeks||remarkably improved skin hydration, elasticity, roughness, and density|||
|triple-blind, placebo-controlled||60 / 12 weeks||a cosmetically relevant improvement of the facial skin was demonstrated|||
|BioCell Collagen® 500 mg:
hydrolyzed collagen type-II (≥300 mg), chondroitin sulfate (≥100 mg), hyaluronic acid (≥50 mg)
|a pilot open-label study||26 / 12 weeks||notable decrease of skin dryness/scaling and global lines/wrinkle|||
|double-blind, placebo-controlled||128 / 12 weeks||significantly reduced facial and crow’s feet lines and wrinkles; increased skin elasticity and collagen content by 12%; decreased skin dryness and erythema.|||
|GOLD COLLAGEN® ACTIVE:
Hydrolysed Collagen, Glucosamine Hydrochloride, Chondroitin Sulphate, L-Carnitine, Dried Maca (Lepidium Meyenii), Hyaluronic Acid, Zinc, Black Pepper Extract (Piper Nigrum), Copper, Biotin, Vitamins (C, B6, B12, D) 
|double-blind, placebo-controlled||120 / 90 days||overall significant increase in skin elasticity (+40%), positive changes in the skin structure, with a diminish in solar elastosis and improvement in collagen fiber organization|||
|GOLD COLLAGEN® FORTE:
Hydrolysed collagen L-Carnosine, Hyaluronic Acid, Acai Berry, CoEnzyme Q10; Evening Primrose Oil (Oenothera biennis), Borage Seed Oil (Borago Officinalis) Zinc, Piper Nigrum (Bioperine®), Copper, β-carotene, Lycopene, Biotin, Vitamins (C, B6, D, E) 
|double-blind, placebo-controlled||120 / 90 days||Notable enhance in skin elasticity (+7.5%) and improvement in skin texture|||
|Wellnex Collagen peptides:
L-CP: collagen hydrolysate with low ratio of dipeptide (0.1g /kg of product)
H-CP: collagen hydrolysate with high ratio of dipeptide (2 g /kg of product)
|double-blind placebo-controlled||85 /8 weeks||facial skin moisture, elasticity, wrinkles and roughness|||
|Low-molecular-weight collagen peptide (LMWCP) 1000 mg
and Vitamin C
|double-blind placebo-controlled||64 / 12 weeks||skin-hydration values were significantly higher in the LMWCP group; three parameters of skin wrinkling and one of skin elasticity were remarkably improved|||
|Specific collagen peptides of fish origin (Peptan® F) and porcine origin (Peptan® P)||double-blind placebo-controlled||106 / 84 days||improved skin moisture associated with an increase of collagen and glycosaminoglycan synthesis in the respective skin layers|||
|Oral nutritional supplement drink containing: hydrolyzed collagen, hyaluronic acid, Borage oil emulsion (borage oil 20%), Zinc gluconate, Pyridoxine Hydrochloride, Piper Nigrum extract, Copper, D-Biotin, Vit D3||double-blind placebo-controlled||18 / 12 weeks||noticeable enhancement in wrinkle depth and significant improvement in elasticity and hydration of the skin|||
|Collagen peptide with 15% tripeptide form||prospective, controlled, open, with blinded assessment||32 / 12 weeks||enhance skin hydration and elasticity with no efficacy of CP on skin erythema and pigmentation|||
|10 g of fish-derived collagen peptide, 400 mg of ornithine, vitamin C||double-blind placebo-controlled||22 / 8 weeks||improvement of skin elasticity, TEWL and increase of IGF-1 levels by CPO|||
|CELERGEN: marine collagen peptides derived from skin of deep-sea fish (MCPs, 570 mg), 10 mg grape-skin extract, 10 mg coenzyme Q10, 10 mg luteolin and 0.05 mg selenium||clinical-laboratory study||41 / 8 weeks||increased skin elasticity, sebum production, and dermal ultrasonic markers.|||
The discovery of new sources for collagen such as marine-derived compounds represent an important advantage for manufacturers due to their accessibility and production costs. From the available data, supplementation with collagen may improve the skin aspect and properties, but more research is needed in order to obtain strong results regarding its effectiveness.
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