Lonza

Metabiotics® Resveratrol

Lonza Personal Care initiated development to examine the effects of Fusion Technologies anticipating that treatment of yeast with a small molecule might create a synergistic benefit; a potential overlapping of the individual physiological pathways of the yeast and phytonutrient benefits from the active; potentially creating a subset of attributes that exceed the initial benefits or are not observed by the two individually. This was the objective behind Metabiotics® Resveratrol whereby the yeast, Pichia pastoris, utilized a positive nutrient supplement, resveratrol, and completely metabolized it by fermentation. This fermentation of the small molecule, resveratrol, is an application of Fusion Technologies.

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Properties

Features And Benefits
Ingredient Claims
Natural or derived natural ingredient (ISO 16128)
End Use Claims
Anti-aging
Toning
Firming
Anti-irritant
Whitening
Product Characteristics
Origin
Plant Origin
Formulation Conditions
Use Level
1.0–5.0%

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Technical product information

Key Attributes
  • Anti-aging
  • Anti-irritation
  • Promotes Collagen IV synthesis In Vitro
  • Enhances skin tone
  • Skin brightening
  • Non-animal derived
Introduction

Recent developments for cosmetic and personal care have imitated ideas from the food, nutritional and pharmaceutical industries for crossover applications. Until recently, skin care and skin health was restricted to mainly cosmetic applications such as topical creams rather than internal nutrition. However, with increasing consumer awareness and education, the perception has been altered to confirm that the skin is a reflection of internal health and well-being. The marketplace has evolved from traditional cosmetic topical applications to advanced nutritional regimens for anti-aging purposes. One only needs to look at the recent trend in probiotics to observe the potential crossover success or overlap that can occur between the Nutritional, Pharmaceutical and Cosmetic Industries.

Background Information

Lonza Personal Care, is a pioneer in the development of cosmetic ingredients based on biofermentation, and has been actively selling these unique products to the personal care industry for nearly twenty years. The biofermentation platform is a core competency for Lonza Personal Care and significant efforts are devoted to the development of value-added products for topical application. Most recently, research efforts at Lonza Personal Care have created a novel  biofermentation product line, which we are calling Metabiotics®. We believe in the potential of crossover technologies and have developed ‘Fusion Technologies’ combining insights from these industries. Our goal is to develop unique bio-processed ingredients for topical applications. 

Lonza Personal Care initiated development to examine the effects of Fusion Technologies anticipating that treatment of yeast with a small molecule might create a synergistic benefit; a potential overlapping of the individual physiological pathways of the yeast and phyto-nutrient benefits from the active; potentially creating a subset of attributes that exceed the initial benefits or are not observed by the two individually. This was the objective behind Metabiotics® Resveratrol whereby the yeast, Pichia pastoris, utilized a positive nutrient supplement, resveratrol, and completely metabolized it by fermentation. This fermentation of the small molecule, resveratrol, is an application of Fusion Technologies.

A key reason why Pichia pastoris was used as the microorganism in the Metabiotics® platform was due to it having a long history of use in the pharmaceutical industry, considered GRAS or generally recognized as safe by the FDA, and only recently being explored for personal care applications. Pichia pastoris belongs to the genus Saccharomycetase and is closely related to Saccharomyces cerevisiae. Like Saccharomyces, the microorganism has distinctive abilities to express bio-actives that are capable of unique benefits, without application of human cell lines. From a formulating point of view, Pichia pastoris also affords the unique affinity for lipid based compounds, and therefore acts as a model organism for biofermentation of oil soluble or insoluble actives, and an ideal choice to advance the natural discovery of skin care actives

Product Information

Resveratrol is an ideal small molecule for fermentation for several reasons, particularly because of theories such as the “French Paradox”. This theory is focused on wine and its bio-actives for increasing cellular longevity predominantly through the ‘sirtuin’ protein influences. It is also widely known that resveratrol offers anti-inflammatory benefits. Inflammation has been identified as one of the main causes of cellular aging throughout the body, and current research in this area focuses on anti-aging from a nutritional, pharmaceutical and cosmetic point of view. Antioxidant activity is another key benefit of resveratrol. Resveratrol has been used in personal care products, but it has some formulating challenges due to its water solubility and stability limitations. The resveratrol is derived from the root of the Japanese Knotweed plant. Japanese Knotweed is a traditional medicine in several Asian countries and is one of the best known plants for resveratrol extraction.

Manufacturing Process

Metabiotics® Resveratrol is manufactured using fermentation with Pichia pastoris. The proprietary growth conditions allow the yeast to utilize the small molecule, resveratrol, during growth. During feeding, the cells are actively replicating, allowing utilization of the small molecule. Several growth and fermentation parameters are monitored during the growth phase of the yeast to ensure the viability of the cells and complete utilization of resveratrol. Pichia pastoris utilizes resveratrol as a nutrient and by metabolization, the yeast convert the resveratrol into more bioavailable intermediates. Upon completion of the fermentation process, the composition is filtered and the extract is isolated.

Manufacturing Process

Fate of Resveratrol Determined by LC-MS

The objective of this analysis was to determine levels of resveratrol during fermentation by LC-MS, liquid chromotagraphy-mass spectroscopy. Samples were taken during various stages of fermentation and analyzed to determine the level of resveratrol. Initially, 1000μg/ml, or 0.01% of resveratrol was added in the nutrient media. The tests indicate that the resveratrol is metabolized by Pichia pastoris during the fermentation process as there is no resveratrol found in the 24 hour harvest sample of the fermentation extract.

Fate of Resveratrol measured by LC-MS analysis. The results indicate that there is no resveratrol left in the medium, as it has been completely metabolized by the microbe during the fermentation process. LOD refers to the Limit of Detection on the instrument.

2-D Electrophoresis Analysis

2-Dimensional gel electrophoresis was conducted to examine protein expression in the resveratrol treated yeast. The resveratrol treatment of Pichia pastoris resulted in a 6-fold increase in total protein expression as measured by BCA assay. There are changes in the peptide chemistry of the ferment due to the resveratrol treatment. The resveratrol also resulted in the increased expression of 96 unique proteins not seen in the untreated yeast. This demonstrates that Pichia pastoris has metabolized new proteins due to the treatment with resveratrol.

In Vitro Studies

1. Anti-Inflammation Study (Cyclooxygenase 1)

COX1 is an enzyme that is involved in the conversion of Arachidonic acid to prostanoids (PGH 2). The conversion via a two-step enzymatic process involving the cyclooxygenation and peroxidation of Arachidonic acid is shown in figure below. The action of COX1 is a rate-limiting step that triggers the inflammatory pathway via the expression of prostanoids. This enzyme, constitutive to most cells, incites the pro-inflammatory response, which is believed to contribute to cellular aging. Skin studies demonstrate that topical application of resveratrol can significantly reduce the expression of the COX1 enzyme.

In Vitro test results from Metabiotics® Resveratrol on MatTek® full thickness tissue against resveratrol are shown in figure below. A statistically significant reduction in COX1 activity was observed with both a 1% and 2% treatment. The results suggest that Metabiotics® Resveratrol has anti-inflammatory activity which is more pronounced than the resveratrol treatment by itself.

In vitro results indicate that Metabiotics® Resveratrol strongly inhibits COX1 activity at 1% and 2% treatment.

2. Collagen Study — Type IV Collagen (COL4A1)

Type IV Collagen is an essential matrix protein that is necessary for maintaining the structural integrity of the skin cells, by forming sheet-like structures found in the dermal-epidermal junction, DEJ.15 It is an integral part of the basal membrane capable of binding molecules that maintain the extracellular matrix. Recent literature suggests that Type IV Collagen might play an important role in binding keratinocyte skin stem cells at the DEJ.

In Vitro testing with Metabiotics® Resveratrol on MatTek® full thickness tissue against resveratrol is shown in Figure below. Statistically significant increases in Type IV Collagen expression was observed at 1% and 2% levels. In addition, the results from the In Vitro study indicate that the Type IV Collagen cannot be stimulated by the topical application of resveratrol by itself. Metabiotics® Resveratrol is significantly impacting the structural matrix of skin cells, possibly by improving the scaffold of skin cells, thereby promoting the synthesis of Type IV Collagen.

In vitro results indicate that Metabiotics® Resveratrol strongly increases Type IV Collagen expression at 1% and 2% treatment.

3. Brightening Study on Tanned Epidermis

In Vitro testing with Metabiotics® Resveratrol on Skin Ethic Tanned Epidermis model against ascorbic acid is shown in figure below. At 1.0% Metabiotics® Resveratrol appears to offer skin brightening benefits comparable to 1.0% Ascorbic Acid. The decrease in melanin production is statistically significant compared to the treatment of the Pichia pastoris on the tissue. At 1.0% Metabiotics® Resveratrol has a statistically significant decrease in melanin compared to the untreated tissues.

In vitro results indicate that Metabiotics® Resveratrol decreases melanin production at 0.5% and 1% treatment. At 1% treatment, the decrease in melanin is comparable to 1% Ascorbic Acid.

In Vivo Studies

Test Procedure

In order to evaluate the impact of Metabiotics® Resveratrol on human skin, a 22 person, double-blind, placebo controlled, half face in vivo study was initiated.

The participants were broken down into two groups of 11 panelists each. Each person acted as their own control group with a ½ face application of a placebo lotion, Product 1. 11 of the panelists, the Treatment group, applied Product 2, an SPF 8 lotion containing 5% Metabiotics® Resveratrol to half of their face; while the remaining 11 panelists, acting as the control group, applied a lotion containing 5% Pichia Ferment Extract (without Resveratrol treatment), Product 3, to half of their face. The participants were instructed to apply the products twice a day, for 28 days.

On Days 14 and 28, the participants were tested in the following ways: Corneometric readings were taken to determine skin hydration and pictures were taken using the Canfield Visia CR system. The study was monitored by a skilled dermatologist who examined the participants throughout the course of the evaluation for changes in the appearance of fine lines and wrinkles and overall skin appearance.

Moisturization Results

The corneometric data for this study is outlined below in the figure. A 5% treatment of Metabiotics® Resveratrol resulted in a statistically significant 36% increase in hydration over the Control, 5% Pichia Ferment lotion.

In Vivo Corneometric Evaluation Results indicate that Metabiotics® Resveratrol offers a superior moisturizing effect over the control, Pichia Ferment. All data is shown as an improvement over the placebo lotion.

Visia CR Photograph Results

 The photographs taken from the Visia CR camera, indicated that the treatment with Metabiotics® Resveratrol showed significant improvement in the overall appearance of the skin. Dramatic lifting was noted in the perioral area including smoothing of expression lines and ameliorating wrinkles. 

Shown above, In vivo lateral results on panelist following Metabiotics® Resveratrol treatment. Left—Baseline; Right—28 days. Significant wrinkle reduction in the perioral, periocular and nasolabial region was observed. Significant changes in the chin area are clearly visible.

Shown above, In vivo lateral results of panelist following Metabiotics® Resveratrol treatment. Left—Baseline; Right—28 days. Significant wrinkle improvement in overall skin tone and diminishing of age-spot was observed.

Dermatological Evaluation from Clinical Photography

A professional grading evaluation for each panelist was conducted by evaluating fine wrinkles, coarse wrinkles, skin tone and radiance on a descriptive basis according to the R.W. Johnson Pharmaceutical Research Scale. Based on this scale, a 5% treatment of Metabiotics® Resveratrol was found to be significantly more effective than the control treatment of 5% Pichia Ferment in improving skin tone at Day 14 and fine lines at Day 28.

Summary of expert grading evaluation from Visia CR photographs. Data as shown above indicates the percentage of panelists showing improvements over placebo lotion in each category.

Conclusions

The concept of Fusion Technologies paired with technological innovations offers tremendous potential for cosmetic applications. Our research demonstrates that the potential anti-aging actives obtained from Metabiotics® Resveratrol offers unique benefits obtained from the yeast and the small molecule. Metabiotics® Resveratrol offers a multi-dimensional approach to cellular modulation, thereby creating potent anti-aging bio-actives. The response of the microbe and resveratrol appears to be superior to the application of individual components alone.

In Vitro studies confirm that Metabiotics® Resveratrol inhibits the activity of COX1, cyclooxygenase 1, a key pro-inflammatory mediator, and also promotes the synthesis of Type IV Collagen, COL4AI, superior to a resveratrol control. In addition, Metabiotics® Resveratrol also has enhanced skin lightening benefits by controlling melanin expression as demonstrated in the skin lightening study on tanned epidermis tissues. The in vivo study demonstrates that treatment of the Pichia pastoris with the small molecule, resveratrol, provides a consumer appreciable benefit in regards to reducing the signs of aging.

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Branded product

Metabiotics® Resveratrol ECT GEO

INCIs: Pichia/Resveratrol Ferment Extract

Categories: Sensorial Modifiers

412 Mt. Kemble Avenue
Morristown, NJ 07960
United States