SE545843C2 - Plant extracts for improving skin barrier function - Google Patents
Plant extracts for improving skin barrier functionInfo
- Publication number
- SE545843C2 SE545843C2 SE2030376A SE2030376A SE545843C2 SE 545843 C2 SE545843 C2 SE 545843C2 SE 2030376 A SE2030376 A SE 2030376A SE 2030376 A SE2030376 A SE 2030376A SE 545843 C2 SE545843 C2 SE 545843C2
- Authority
- SE
- Sweden
- Prior art keywords
- extract
- formulation
- skin
- betula alba
- glucoside
- Prior art date
Links
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- 239000000419 plant extract Substances 0.000 title abstract description 3
- 239000000284 extract Substances 0.000 claims abstract description 213
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- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
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- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
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Abstract
PLANT EXTRACTS FOR IMPROVING SKIN BARRIER FUNCTIONThe present invention provides a formulation comprising one or more of: a first extract of fruit of Empetrum nigrum,· and/or a second extract of BetulaAlba bark.
Description
The present invention provides a formulation comprising a first extract of Empetrum nigrum and/or a second extract of Betula Alba bark for use in the treatment of skin disorders associated with reduced
skin barrier function. BACKGROUND OF INVENTION
The skin is composed of several morphologically distinct layers. The protection of the skin is provided primarily by the stratum corneum. Underlying the stratum corneum is the viable epidermis (50-100 um thick), which is responsible for generation of the stratum corneum. The viable epidermis consists of various layers. From the inside to the outside, these layers of the viable epidermis are: the stratum basale, the stratum spinosum and the stratum granulosum. The epidermis is a dynamic, constantly self-renewing tissue, in which a loss of the cells from the surface of the stratum corneum (desquamation) is balanced by cell growth in the lower epidermis. Upon leaving the basal layer, the keratinocytes start to differentiate and during migration through the stratum spinosum and stratum granulosum they undergo several changes in both structure and composition. The keratinocytes synthesize and express numerous different structural proteins and lipids during their maturation. The final step in keratinocyte differentiation is associated with profound changes in their structure resulting in their transformation into corneocytes. The corneocytes are flat dead cells filled with keratin filaments and water, which are surrounded by densely crosslinked protein layers, the cell envelope. A liquid envelope is chemically linked to this densely packed cell envelope. This lipid monolayer serves as an interface between the hydrophilic corneocytes and the lipophilic extracellular non-polar lipids which are surrounding the corneocytes. Furthermore, corneodesmosomes are
interconnecting the corneocytes and are important for the stratum corneum cohesion.
The most important functions of the skin (also known as 'skin barrier function') are the protection against water loss and the prevention of substances and bacteria penetrating the body are the most important functions (known as the 'skin barrier function') of the skin. This so-called 'skin barrier function' is the natural frontier between the inner organism and the environment and is primarily
formed by the epidermis.
There is therefore a need for a cosmetic or pharmaceutical formulation for use to improve the skin barrier function of the skin of a user by one or more of: reducing water loss from the body and/or
preventing substances and bacteria penetrating the body.
ln particular, there is a need for a cosmetic or pharmaceutical formulation which is capable of
inhibiting the production of kallikrein-5 (KLK5). By inhibiting the activity of kallikrein-5, the
formulation can improve skin barrier function by reducing and/or preventing cell shedding and the degradation of proteins which form the extracellular component of cell junctions in the stratum
COfneUm. STATEl\/IENT OF INVENTION
According to a first aspect of the present invention, there is provided a formulation comprising one or
more of: a first extract of fruit of Empetrum nigrum; and/or a second extract of Betula Alba bark.
According to a second aspect of the present invention, there is provided a use of a formulation as
described herein for improving the skin barrier function of the skin of a user.
The term "improving the skin barrier function” is used herein to include: preventing or inhibiting of degradation of the stratum corneum and/or shedding; maintaining or restoring a healthy skin barrier; improving skin moisture within the skin; improving water balance, lipid composition and/or
mechanical structure of the skin.
ln one embodiment, the formulation is a cosmetic or pharmaceutical formulation, preferably a topical
cosmetic or pharmaceutical formulation. ln one embodiment, the formulation is an inhibitor of kallikrein-5 (KLK5).
ln one embodiment, the first extract of the formulation is an extract of fruit of Empetrum nigrum
obtained by cold pressing in a non-denaturing condition stabilized with organic vegetal glycerine.
ln one embodiment, the second extract of the formulation is a water /glycerine extract of Betula Alba
bark.
ln one embodiment, the first extract comprises at least one compound selected from: cyanidin-3-O- glucoside, petunidin-3-O-glucoside, peonidin-3-O-glucoside, malvidin-3-O-glucoside, delphinidin-3- arabinoside, or any combination thereof. Preferably, the first extract comprises at least one compound selected from: cyanidin-3-O-glucoside, malvidin-3-O-glucoside, delphinidin-3-arabinoside,
or any combination thereof.
ln one embodiment, the second extract comprises at least one compound selected from: catechin-7-
O-beta-D-xylopyranoside, catechin, apiosylepirhododendrin, rhododendrin, apiosylepirhododendrin,
platyphylloside, (5S)-5-hydroxy-1,7-bis-(4-hydroxyphenyl)-3-heptanone-5-O-ß-D-apiofuranosyl-(1-
>6)-ß-D-glucopyranoside, (3R)-1,7-Bis-(4-hydroxyphenyl)-3-heptanol-3-O-<2,6-bis-O-(ß-D-
apiofuranosyl)-ß-D-glucopyranoside>, aceroside VIII, 5-hydroxy-3-platyphyllone, aceroside VII,
centrolobol, acerogenin E, or any combination thereof. Preferably, the formulation comprises a first extract and a second extract.
Preferably, the ratio by weight of the first extract to the second extract within the formulation is no more than 5:1, for example no more than 3:1. Preferably, the ratio by weight of the first extract to the second extract within the formulation is at least 0.5:1, for example at least 1:1. The ratio by weight of the first extract to the second extract within the formulation is preferably within the range of 0.5:1 and 5:1, preferably within the range of 0.5:1 and 3:1, preferably within the range of 1:1 and 5:1, for
example within the range of 1:1 and 3:
According to a third aspect of the present invention, there is provided the use of a formulation (for example a cosmetic or pharmaceutical formulation) as herein described in the treatment of skin disorders associated with reduced skin barrier function. The formulation is preferably topically
applied to the skin of a user.
In one embodiment, the formulation is used to improve one or more of: skin hydration, skin hydration distribution, skin anisotropy, skin barrier resilience, skin barrier quality, skin cohesiveness, skin
nourishing effect, skin barrier recovery, or any combination thereof.
Skin disorders associated with reduced skin barrier function include one or more of: atopic dermatitis,
psoriasis, impaired desquamation, sensitive skin or any combination thereof.
The formulation has been found to be able to treat skin disorders associated with reduced skin barrier
function, with improved efficacy compared to conventional medications.
The formulation of the present invention has been found to have improved anti-oxidant activity. The
formulation of the present invention may therefore be used as an anti-oxidant.
The formulation of the present invention has been found to be capable of blocking the activity or inhibiting the production of kallikrein-5 (KLK5), which consequently reduces cell shedding and the degradation of proteins which form the extracellular component of cell junctions in the stratum
COfTlelJm.
According to a further aspect of the present invention, there is provided a method for the production
of a formulation as herein described, the method comprising:
obtaining a first extract of fruit of Empetrum nigrum; and/orobtaining a second extract of Betula Alba bark; and forming a formulation with the first and/or second extract. Preferably, the method comprises combining the first and second extract to provide a formulation.
Preferably, the first and second extracts are combined such that the ratio of the first extract to the second extract in a ratio (by weight) within the formulation is no more than 5:1, for example no more
than 3:
Preferably, the first and second extracts are combined such that the ratio of the first extract to the
second extract in a ratio (by weight) within the formulation is at least 0.5:1, for example at least 1:
Preferably, the first and second extracts are combined such that the ratio by weight of the first extract to the second extract within the formulation is within the range of 0.5:1 and 5:1, preferably within the range of 0.5:1 and 3:1, preferably within the range of 1:1 and 5:1, for example within the range of 1:1 and 3:
According to a still further aspect of the present invention, there is provided a kit for the production
of a formulation as described herein, the kit comprising: a first extract of fruit of Empetrum nigrum; and a second extract of Betula Alba bark.
Embodiments of the present invention are described in detail with references to the accompanying
Figures: BRIEF DESCRIPTION OF FIGURES Figure 1 illustrates the UHPLC/Q-ToF-MS chromatogram of a water/glycerine Betula Alba bark extract;
Figure 2 illustrates the UHPLC/Q-ToF-MS chromatogram of an extract of fruit of Empetrum nigrum
obtained by cold pressing a non-denaturing condition stabilized with organic vegetal glycerine;
Figure 3 illustrates the colouration of different formulations containing an extract of fruit of Empetrum
nigrum (2%) depending on pH;
Figure 4 illustrates the anti-oxidant activity of an extract of Betula Alba (Birch 1%) and an extract of
fruit of Empetrum nigrum compared to vitamin C (VitC);
Figure 5 illustrates the percentage inhibition of the enzyme Kallikrein 5 by extracts of Betula Alba bark
and fruit of Empetrum nigrum;
Figure 6 illustrates an isobole for 50% inhibition for an extract of Betula Alba bark and an extract of
fruit of Empetrum nigrum;
Figure 7 illustrates the percentage inhibition of the enzyme Kallikrein 5 by a formulation comprising a
first extract of fruit of Empetrum nigrum and a second extract of Betula Alba;
Figure 8 illustrates the percentage inhibition of the enzyme Hyaluronidase by extracts of Betula Alba
bark and fruit of Empetrum nigrum; Figure 9 illustrates the gene expression analysis for an extract of fruit of Empetrum nigrum; Figure 10 illustrates the gene expression analysis for an extract of Betula Alba bark;
Figure 11 illustrates the gene expression of an extract of fruit of Empetrum nigrum together with an
extract of Betula Alba bark; Figure 12 illustrates the gene expression of niacinamide and retinol;
Figures 13A and 13B i||ustrate the effect of an extract of fruit of Empetrum nigrum and an extract of
Betula Alba bark on protein expression of AQP3 and OCLN;
Figures 14A and 14B i||ustrate the effects an extract of fruit of Empetrum nigrum together with an
extract of Betula Alba bark, a vehicle, and niacinamide on skin barrier;
Figures 15A and 15B i||ustrate the effects an extract of fruit of Empetrum nigrum together with an
extract of Betula Alba bark, a vehicle, and niacinamide on skin barrier resilience and recovery;
Figures 16A and 16B i||ustrate the effects an extract of fruit of Empetrum nigrum together with an
extract of Betula Alba bark, a vehicle, and niacinamide on cutaneous hydration index;
Figures 17A and 17B i||ustrate the effects an extract of fruit of Empetrum nigrum together with an
extract of Betula Alba bark, a vehicle, and niacinamide on restructuring effect;
Figures 18A and 18B i||ustrate the effects an extract of fruit of Empetrum nigrum together with an extract of Betula Alba bark, a vehicle, and niacinamide on corneocytes cohesion (Desquamation
index); and
Figures 18A and 18B i||ustrate the effects an extract of fruit of Empetrum nigrum together with an
extract of Betula Alba bark, a vehicle, and niacinamide on corneocytes cohesion (Squame surface). DETAILED DESCRIPTION
Example 1 - Method of Extraction of Betula Alba bark
Betula Alba bark is extracted with a water/glycerine solvent (10% plant extract in a mixture of water/glycerine). The solvent is removed. The extract is an amber/dark amber liquid with a pH in the
range of between 3.4 and 4.0. Example 2 - Method of Extraction of fruit of Empetrum nigrum
The Empetrum nigrum fruit extract was obtained by cold pressing a non-denaturing condition stabilized with organic vegetal glycerine. The fruit extract is a trans|ucent solution (with a slight
precipitate) which is red to brown red in colour with a pH in the range of between 4.0 and 5.4. The extracts contains anthocyans, this the formulation may change colour depending on pH.
The pH is an important factor in the colour change of anthocyans. The pH-dependent variation in the structure of anthocyan is a particular feature of these molecules. Visual inspection of an aqueous solution of anthocyan shows that the solution turns deep red at a highly acidic pH. The solution becomes paler as the pH increased towards neutrality. A neutral solution of freshly prepared anthocyan is blue but quickly changes colour. The colous changes are due to chemical balances
between the various forms of anthocyan (Brouillard and Delaporte, 1977,' Brouillard, 1982).
An Empetrum nigrum fruit extract having a pH of 4.5 is pale pink in colour (the pink colouration becomes more intensified with a more acidic pH). An Empetrum nigrum fruit extract having a pH of
beyond 6 is green in colour.
Figure 3 illustrates the colouration of formulations containing 2% Empetrum nigrum fruit extract as a
factor of pH.
Example 3 - Characterization of extracts of Betula Alba bark and Empetrum nigrum fruit using
U H PLC/Q-To F-MS
Betula Alba bark extract was diluted 10 times in 95:5 H2O:ANC and filtered through a 0.2 um syringe
filter prior to LC/MS analysis.
The Empetrum nigrum fruit extract was used without dilution and was filtered through a 0.2 um
syringe filter prior to LC/MS analysis.
The extract or extract solutions were analysed by an Agilent UHPLC/Q-ToF (1290 Infinity UHPLC and
6520 A-ToF) using the following settings.
Column: Zorbax extend C18 2.1 x 150 mm, 1.8 um
Column temp: 35°C
Flow rate: 0.25 mL/min
Injection volume: 20 uL
The UHPLC gradient results are illustrated in Table 1:
Time (min) A% (H20 + 0.1% FA) B% (ACN + 0.1% FA) 0 9810 9870 4090 295 296 98TableQ-ToF ion source: -ESI and +ES| Gas temp: 350°C
Drying gas: 8 L/min
Nebulizer: 40 psig
Vcap: 3500 V
The chromatogram of Betula Alba bark extract solution in the -ESI mode is shown in Figures 1. The chromatogram of Empetrum nigrum fruit extract Figure 9 illustrates the gene expression analysis for
an extract of Empetrum nigrum in the +ES| mode is shown in Figure
The compounds found to be present within the Betula Alba bark extract are shown in Table 2:
Compound
Catechin-7-O-beta-D-xylopyranoside
Catechin
Apiosylepirhododendrin
Rhododendnn
Apiosylepirhododendrin
Compound
(5S)-5-Hydroxy-1,7-bis-(4-hydroxyphenyl)-3-heptanone-5-
O-ß-D-apiofuranosyl-(1->6)-ß-D-glucopyranoside
Platyphylloside
(3 R)-1,7-Bis-(4-hydroxyphenyl)-3-heptanol-3-O-<2,6-bis-O-
(ß-D-apiofuranosyl)-ß-D-glucopyranoside>
Aceroside VIII
-Hydroxy-3-platyphyllone
Aceroside VII
Centrolobol
Acerogenin E
Table 2 - Compounds present within Betula Alba bark extract
The compounds found to be present within the Empetrum nigrum fruit extract are shown in Table 3:
Compound
Cynaidin-š-O-glucoside
Petunidin-3-O-glucoside
Peonidin-š-O-glucoside
Malvidin-š-O-glucoside
Delphinidin-3-O-glucoside
TableExample 4 - Preparation of oil-in-water formulations comprising an Empetrum nigrum fruit extract
and a Betula Alba bark extract
Two different oil-in-water placebo bases were evaluated to determine effects on stability of the Empetrum nigrum fruit extract and Betula Alba bark extract. The two different bases were as shown
in Tables 4 and 5:
Component Weight Share Part Long Description (%) Function 160 AQUA 70.1 SOLVENT 306 BUTYLENE GLYCOL 1 HUMECTANT CAPRYLIC/CAPRIC 404 TRIGLYCERIDE 21.5 MASKING 508 CETETH-20 0.3 SU RFACTANT 520 CETYL ALCOHOL 1.35 EMULSIFYING 712 CAPRYLYL GLYCOL 0.35 EMOLLIENT 961 CITRIC ACID 0.1 BUFFERING POLYACRYLATE EMULSION 1103 CROSSPOLYMER-6 0.75 STABILISING 1304 GLYCERYL STEARATE 1.35 EMOLLIENT 2361 SODIUM BENZOATE 0.2 PRESERVATIVE 2526 STEARETH-20 0.3 EMULSIFYING 2987 PEG-75 STEARATE 0.7 SU RFACTANT 23832 EXTRACT BIRCH BARK ORGANIC 1 23833 CAMADERM 1 Table 4 Component Weight Share Part Long Description (%) Function 160 AQUA 84.55 SOLVENT 273 ETHYLHEXYLGLYCERIN 0.5 SKIN CONDITIONING 306 BUTYLENE GLYCOL 2 HUMECTANT 344 C12-15 ALKYL BENZOATE 2 EMOLLIENT 361 PPG-3 BENZYL ETHER MYRISTATE 0.9995 PLASTICISER 404 CAPRYLIC/CAPRIC TRIGLYCERIDE 3 MASKING 520 CETYL ALCOHOL 0.5 EMULSIFYING 696 CAPRYLHYDROXAMIC ACID 0.075 CH ELATING 1052 CYCLOPENTASILOXANE 1 EMOLLIENT POLYACRYLATE CROSSPOLYMER- EMULSION 1103 6 0.9 STABILISING
1143 DISODIUM EDTA 0.1 CHELATING 1281 GLYCERIN 0.105 HUMECTANT 1287 GLYCERYL CAPRYLATE 0.57 EMOLLIENT 1304 GLYCERYL STEARATE 0.5 EMOLLIENT 1911 PEG-100 STEARATE 0.5 SURFACTANT 2533 STEARYL ALCOHOL 0.5 EMOLLIENT 2395 SODIUM HYDROXIDE 0.0058 pH ADJUSTMENT PENTAERYTHRITYL TETRA-Dl-T- BUTYL 116 HYDROXYHYDROCINNAMATE 0.0005 ANTIOXIDANT VISCOSITY 2700 XANTHAN GUM 0.2 CONTROLLING EXTRACT BIRCH BARK ORGANIC HYDROGLYCERINED EXTRACT (SB) 23832 410017 1 23833 CAMADERMTableNo difficulties in terms of incorporation or incompatibility of the extracts within the formulations were determined. lt was found that the extracts can both be added towards the end of the manufacturing process, after emulsification in terms of emulsions. Preferably, the extracts are
incorporated into the formulation during cooling from 45 °C. Example 5 - Anti-Oxidant activity testing
2,2-Diphenyl-1-picrylhydrazy radica| (DPPH.) is a stable free radica| which can be used to assess the radica| scavenging activity of plant materials. At radica| state, the methanolic solution of this compound is purple (absorbs light at a wavelength of516 nm) which when reacted with an antioxidant
is reduced to the molecular form (DPPHH) which is yellow with no absorbance at 516 nm.
DPPH assay principle
The primary screening assays for anti-oxidant activity are performed according to the validated
standard protocols (i.e. SP-SR-107-v4) for DPPH Assay.
The results of anti-oxidant activity screening for Betula Alba bark extract and Empetrum nigrum fruit
extract are shown in Figure
lt can be seen that the extracts of Betula Alba bark and Empetrum nigrum fruit both display good antioxidant activity. The Betula Alba bark extract was found to have a 57.5% radical inhibition and the
Empetrum nigrum fruit extract was found to have a 693% radical inhibition.
ICSO Betula alba bark extract = 0,60 % i 0,02 % (n=3) ICSO Empetrum nigrum fruit extract = 0,42 % i 0,03 % (n=3) The anti-oxidant activity of the Betula alba bark extract and Empetrum nigrum extract are compara ble
to that of Vitamin C. lt is known that anti-oxidants support physiological mechanisms to maintain or
restore a healthy skin barrier. Example 6 - Kallikrein 5 |nhibition Assay
Human tissue Kallikrein 5 (KLK5 or KK5), also known as stratum corneum tryptic enzyme) is a serine protease expressed in the epidermis. KLK5 regulate cell shedding (desquamation) in conjunction with KLK7 and KLK14 given its ability to degrade proteins which form the extracellular component of cell
junctions in the stratum corneum.
The activity of the enzyme KLK5 is measured by its ability to cleave the fluorogenic peptide substrate Boc-VPR-AMC. The assay measures the formation of AMC that is a highly fluorescent group (Ä exc =
380nm; Ä em = 460nm)The primary screening assays are performed according to the validated standard protocol i.e. SP-SR- 201-v3 for KLK5 enzyme inhibition Assay. The activity of the combinations of active components within a formulation is performed according to the validated standard protocol i.e. SP-SR-234 for
lsobologram Analysis.
Figure 5 i||ustrates the % inhibition of Kallikrein 5 for extracts of Betula Alba bark and Empetrum nigrum fruit. The ICSO of each of these active components and extracts were determined and the
results are shown in Table
Extract |CBetula Alba 0.06 %
Empetrum nigrum 0.51%
Tablelt can be seen from Figure 5 and from Table 6 that the extracts of Betula Alba bark and Empetrum nigrum fruit show good KLK-5 inhibition activity. By inhibiting the production of or activity of KLK-5, the extracts of the present invention prevent or inhibit the degradation of proteins which form the extracellular component of cell junctions in the stratum corneum. As a result, the extracts of Betula Alba bark and Empetrum nigrum fruit (and the formulations of the present invention containing these extracts) can improve skin barrier function of the skin of a user by preventing or inhibiting the
degradation of the stratum corneum and/or cell shedding.
ln order to determine if the combination a synergistic effect of the two active components within formulations of the present invention, isobolograms analysis is performed according to the validated
standard protocol i.e. SP-SR-234 for lsobologram Analysis.
The first step is to determine the |C50s of each of the individual active components (i.e. active component A and active component B) within the formulation of the present invention, Table 6. The
additive isobole for 50% inhibition is then traced on Graph Pad Prism (Figure 6).
The concentration of active component B that will give 50% inhibition is interpolated with a chosen concentration of active component A. The combination of the two active components A and B at
these concentrations needs to then be screened.
°|f the results show 50 % inhibition, it means that there is an additive effect between the two active
components of the formulation at those concentration; or°|f the results show <50% inhibition, it means that the formulation needs more concentrated active components to be present in order to achieve 50 % inhibition, i.e. that the combination of the active
components has an antagonist effect; or
°|f the results >50% inhibition, it means that the formulation needs less concentrated active components to be present within the formulation to achieve 50 % inhibition, i.e. that the combination
of the active components has a synergistic effect.
Example 7- Formulation comprising a first extract of fruit of Empetrum nigrum and a second extract
of Betula Alba bark.
A formulation was prepared comprising a first extract of fruit of Empetrum nigrum and a second
extract of Betula Alba bark.
The first extract was present within the formulation in an amount of 0.073 % by weight. The second extract was present within the formulation in an amount of 0.025% by weight. The results of the KLK5 enzyme inhibition assay for this formulation are shown in Figure 7. The percentage (%) inhibition for the formulation is greater than the additive percentage (%) inhibition for each of the extracts. The formulation comprising the first and second extracts demonstrates a synergistic effect on the resultant
KLK5 enzyme inhibition.
lt can therefore be seen that a formulation comprising a combination of the extracts of Betula Alba bark and Empetrum nigrum fruit can have a synergistic effect on the skin barrier function of the skin
of a user by preventing or inhibiting the degradation of the stratum corneum and/or cell shedding. Example 8 - Hyaluronidase |nhibition Assay
A key molecule involved in skin moisture is hyaluronic acid (HA). Hyaluronic acid is a nonsulfated glycosaminoglycan composed of alternating residues of the monosaccharide's glucuronic acid and glucosamine. Hyaluronic acid is a natural compound found in the human body and is degraded and synthesized every day. Hyaluronic acid is degraded into fragments of varying sizes by hyaluronidase
(HYAL) by hydrolysis.
The principle of the hyaluronidase inhibition assay is to measure the turbidity at 600 nm based on the
following reaction:
ššà -------- ------- a» íïfš» :så ïë-*š§xt:a:§;§§r§f§;a_§ïš:les + stzmišeët* 'Efšßå širzägfiïisfaiïis
The addition of acidic albumin solution makes the remaining hyaluronic acid within the solution
precipitate. Therefore, the absorbance of the control (hyaluronic acid with no enzyme is equivalentto 100% inhibition) results in the maximum absorbance. The maximum activity (i.e. hyaluronic acid plus hyaluronidase is equivalent to 0% inhibition) results in the minimum absorbance. The presence
of a hyaluronidase inhibitor results in a greater inhibition resulting in a higher absorbance.
The primary screening assays are performed according to the validated standard protocols (i.e. SP-SR- 197-v2) for Hyaluronidase lnhibition Assay. The results are shown in Figure 8. lt can be seen that the extract of Empetrum nigrum fruit is a medium hyaluronidase inhibitor and the extract of Betula Alba
bark is a good hyaluronidase inhibitor.
The extracts and formulations of the present invention (comprising one or more of extracts of Empetrum nigrum fruit and Betula Alba bark)) shows good inhibition of hyaluronidase and as such can reduce the degradation of hyaluronic acid. The extracts and formulation of the present invention can
therefore improve skin barrier function by improving the skin moisture within the skin. Example 9 - Gene expression analysis of barrier genes in keratinocytes
The effects of an extract of fruit of Empetrum nigrum and an extract of Betula Alba bark on 10 selected skin barrier genes of interest were analysed. The ten selected skin barrier genes were OCLN, AQP3,
cLDN1, ivL, cAsP14, kRT1, kRT1o, FLG, PNPLA and TJP
AQP3; Aquaporin 3 A membrane transporter of water and glycerol expressed in the basal layer keratinocytes of
epidermis in normal skin. Important for water content and elasticity of the skin
OCLN, Occludin
Together with Claudin and TJP1, the main component of the tight junctions.
TJP1, Tight junction proteinTogether with Claudin and OCLN, the main component of the tight junctions.
CLDN1, ClaudinTogether with TJP1 and OCLN, the main component of the tightjunctions.
FLG, Filaggrin
Filaggrin is essential for the regulation of epidermal homeostasis. Filaggrin monomers can become
incorporated into the lipid envelope, which is responsible for the skin barrier function.CASP14, Caspase 14 Caspase-14 is required for the degradation of Filaggrin into natural moisturizing factors (NMFs) in
the skin. Blocking the filaggrin processing done by Caspase-14, results in defects in water retention.
KRT1 and KRT10, Keratin 1 and 10 Differentiation of keratinocytes from the basal to the spinous layer is characterized by a shift to Keratins 1 and 10. The primary function of the keratin intermediate filament cytoskeleton is to
provide cells with structural resilience against mechanical trauma
IVL, lnvolucrine Cornified envelope protein, together with keratins responsible for the mechanical stability of the corneocytes. lnvolucrine binds covalently to ceramides, forming a backbone for the subsequent
attachment of free ceramides.
PNPLA1, Patatin-like phospholipase domain-containing 1 PNPLA1, an enzyme expressed in differentiated keratinocytes, plays a crucial role in the biosynthesis
of w-O-acylceramide, a lipid component essential for skin barrier.
qPCR was used to analyze the gene expression of barrier genes. Human epidermal keratinocytes (KC) were cultured in 48-well plates and treated for 24h with actives before RNA extraction followed by
cDNA synthesis and then qPCR was performed for the selected genes.
It was found that an extract of fruit of Empetrum nigrum significantly upregulated seven out of the
ten genes (ACP3, OCLN, KRT1, KRT10, PNPLA1, IVL and Casp 14) as shown in Figure
It was also found that the extract of Betula Alba bark significantly upregulated six out of the ten genes
(OCLN, KRT1, KRT10, PNPLA1, IVL and Casp 14) as shown in Figure
A combination of 0.5% of an extract of fruit of Empetrum nigrum together with 0.5% of an extract of Betula Alba bark was found to significantly upregulate eight of the ten genes (IVL, AQP3, OCLN, FLG, Kl, K10, CASP14, CLDN1) as shown in Figure 11. It was found that the upregulation provided by the combination of 0.5% of an extract of fruit of Empetrum nigrum together with 0.5% of an extract of
Betula Alba bark was greater than the upregulation provided by each extract alone.
Known agents for improving skin barrier function are niacinamide and retinol. The gene expression of barrier genes, as a result of being treated with niacinamide or retinol, was analyzed, and the results
are shown in Figure
From Figure 12, it can be seen that niacinamide and retinol did not show significant upregulation of the genes. Retinol was found to increase the gene expression of AQP3 while it downloaded most
other genes.
The extracts of fruit of Empetrum nigrum and Betula Alba bark were found to provide good upregulation of several skin-barrier genes in vitro. These genes are involved in different aspects of skin barrier function such as water balance, lipid composition and mechanical structure. The extracts and formulations of the present invention can therefore be used to improve skin barrier function, and
in particular to improve water balance, lipid composition and mechanical structure of the skin barrier. Example 10 - Detection of proteins using flow cytometry in vitro
The effect of the extracts of fruit of Empetrum nigrum and Betula Alba bark on protein expression of
AQP3 and OCLN were investigated.
Human epidermal keratinocytes were treated with an extract of fruit of Empetrum nigrum, an extract of Betula Alba bark, an extract of fruit of Empetrum nigrum together with an extract of
Betula Alba bark, or niacinamide (control).
Cells were treated with the actives for 48h before they were stained with antibodies for AQP3 and OCLN conjugated to Alexa fluor 488 and Alexa fluor 647 respectively. The stained cells were run
through the flow cytometer where the intensity of fluorescent was analysed.
The highest concentration of the extracts used was 0.25% of both extracts of fruit of Empetrum
nigrum and Betula Alba bark.
lt was found that 0.25% an extract of fruit of Empetrum nigrum did not show any upregulation of AQP3 and OCLN proteins after 48 hours. ln contrast, 0.25% of an extract of Betula Alba bark showed significant upregulation of both AQP3 and OCLN proteins as shown in Figures 13A and 13B. Furthermore, 0.25% of an extract of fruit of Empetrum nigrum together with an extract of Betula Alba bark showed significant upregulation of both AQP3 and OCLN proteins. ln comparison,
niacinamide did not show any significant upregulation of AQP3 or OCLN proteins. Example 11 - Consumer/Clinical Testing
A clinical study was carried out in September/October 2020 in France, on two groups of female
volunteers.
ln the first group, each of the volunteers used both the vehicle and the vehicle containing an extract
of fruit of Empetrum nigrum together with an extract of Betula Alba bark at a concentration of 1%.ln the second group, each of the volunteers used both the vehicle containing an extract of fruit of
Empetrum nigrum together with an extract of Betula Alba bark at a concentration of 1% and the
vehicle containing Niacinamide at a concentration of 3%.
The study has been conducted using with a double-blinded set up with a CRO, meaning that none of
the volunteers, investigators, local project manager and statisticians were aware of the nature of the
products applied.
The Study population information is shown in Table 7:
Number of volunteers
Volunteers age
Study location
Investigation site
Product application
Wash out
Timepoints
(group 1) and 36 (group 2) female volunteers
18 to 65 years
(Mean age group 1 = 47 years, Mean age group 2 = 49 years) Lyon, France Face (Temple & Forehead)
Split face: group 1 with one side for the vehicle, opposite side with vehicle + extracts of fruit of Empetrum nigrum together with an extract of Betula Alba bark. Group 2 with one side for the vehicle + Empetrum nigrum together with an extract of Betula Alba bark at 1 %, opposite side with vehicle + Niacinamide at 3 %.
Double-blinded
Randomised
Application twice daily: morning & evening 2 weeks with the use of 30558 alt 78 only as Moisturiser
Baseline, 1 month
TableThe parameters measured during the study are shown in Table 8:Skin barrier (TEWL) Aquaflux
Skin barrier resilience Aquaflux and tape stripping (TEWL)
Skin barrier resilience Aquaflux and tape stripping (TEWL)
Cutaneous hydration MoistureMap MM
index Restructuring effect SquameScan
(protein content removed)
Corneocytes cohesion S|A & Quantiscam
(Desquamation index)
Corneocytes cohesion
(Squame surface)
TableSkin barrier (TE WL)
The results of the treatments on the skin barrier for each group are shown in Figures 14A and 14B. lt can be seen that there was no significant changes observed (versus baseline) as a result of being treated by the vehicle formulation or by the extract of fruit of Empetrum nigrum together with an
extract of Betula Alba bark (Figure 14A).
There was however a significant difference between the formulation containing an extract of fruit of Empetrum nigrum together with an extract of Betula Alba bark and the formulation containing Niacinamide (Figure 14B). lt can be seen that there was significant skin barrier improvement when treated with an extract of fruit of Empetrum nigrum together with an extract of Betula Alba bark in comparison to the niacinamide treated side.Skin barrier resilience and recovery (TE WL)
The results of the treatments on the skin barrier resilience and recovery for each group are shown in Figures 15A and 15B. lt can be seen that there was no significant changes or differences observed as a result of being treated by the vehicle formulation or the extract of fruit of Empetrum nigrum together with an extract of Betula Alba bark. Furthermore, it can be seen that there was no significant changes or differences observed as a result of being treated by niacinamide or the extract of fruit of Empetrum nigrum together with an extract of Betula Alba bark. Skin barrier recovery data
remains inconclusive, irrespective of the group.
Cutaneous hydration index
The results of the treatments on the cutaneous hydration index for each group are shown in Figures 16A and 16B. lt can be seen that there was a near significant improvement (versus baseline) observed for those treated with an extract of fruit of Empetrum nigrum together with an extract of Betula Alba bark in the first group (p = 0.06). Furthermore, a significant improvement was seen for those treated with an extract of fruit of Empetrum nigrum together with an extract of Betula Alba
bark in the second group.
The improvement achieved by being treated with an extract of fruit of Empetrum nigrum together with an extract of Betula Alba bark outperformed the improvement achieved by being treated with
niacinamide following a month of use.
Restructuring effect
The results of the treatments on the restructuring effect are shown in Figures 17A and 17B. lt can be seen that there was a significant improvement observed for those treated with an extract of fruit of Empetrum nigrum together with an extract of Betula Alba bark when compared to those treated with the vehicle. Furthermore, there was a tendancy of a better restructuring effect observed for those treated with an extract of fruit of Empetrum nigrum together with an extract of Betula Alba
bark compared to those treated with niacinamide (p=0.10).
Corneocytes cohesion (Desquamation index & Squame surface)
The results of the treatments on the corneocytes cohesion are shown in Figures 18A and 18B (Desquamation index) and in Figures 19A and 19B (Squame surface). lt can be seen that a significant worsening (versus baseline) was observed for those treated with the vehicle formulation aftermonth. lt can however also be seen that there was an improvement observed for those treated withan extract of fruit of Empetrum nigrum together with an extract of Betula Alba bark after 1 month of
use (Figures 18A and 19A), to a significant extent when compared to the vehicle treated side.
ln the second group, a worsening versus baseline was observed for those treated with an extract of fruit of Empetrum nigrum together with an extract of Betula Alba bark and for those treated with
niacinamide (Figures 18B and 19B).
The results show that the extracts of the present invention demonstrate efficacy in several parameters which relate to skin barrier function and hydration. ln particular, the extracts of the present invention have been found to improve decrease protein content removed by tape stripping (restructuring effect), the desquamation index and squame surface (corneocytes cohesiveness). The extracts of the present invention have also been shown to significantly improve the cutaneous hydration index (compared to the baseline). The extracts of the present invention have also been shown to produce a significantly higher hydrating effect than that producing by the use of a niacinamide formulation. Differences in transepidermal water loss were observed after 4 weeks, with an observed decrease for those treated with extracts of the present invention compared to an
increase in water loss for those treated with niacinamide.
Claims (15)
1. A formulation comprising: a first extract of Empetrum nigrum; and a second extract of Betula Alba bark, in which the second extract is a water /glycerine extract of Betula Alba bark, for use in the treatment of skin disorders associated with reduced skin barrier function selected from one or more of: atopic dermatitis, psoriasis, impaired desquamation, or any combination thereof.
2 A formulation as c|aimed in c|aim 1, in which the first extract comprises at least one compound selected from: cyanidin-3-O-glucoside, petunidin-3-O-glucoside, peonidin-3-O-glucoside, malvidin-3- O-glucoside, delphinidin-3-arabinoside, or any combination thereof.
3. A formulation as c|aimed in either of claims 1 and 2, in which the second extract comprises at least one compound selected from: catechin-7-O-beta-D-xylopyranoside, catechin, apiosylepirhododendrin, rhododendrin, apiosylepirhododendrin, platyphylloside, (5S)-5-hydroxy-1,7- bis-(4-hydroxyphenyl)-3-heptanone-5-O-ß-D-apiofuranosyl-(1->6)-ß-D-glucopyranoside, (3R)-1,7-Bis- (4-hydroxyphenyl)-3-heptanol-3-O-<2,ö-bis-O-(ß-D-apiofuranosyl)-ß-D-glucopyranoside>, aceroside Vlll, 5-hydroxy-3-platyphyllone, aceroside Vll, centrolobol, acerogenin E, or any combination thereof.
4. A formulation as c|aimed in any one of claims 1 to 3, in which the ratio by weight of the first extract to the second extract within the formulation is no more than 5:
5. A formulation as c|aimed in any one of claims 1 to 3, in which ratio by weight of the first extract to the second extract within the formulation is no more than 3:
6. A formulation as c|aimed in any preceding c|aim, in which the ratio by weight of the first extract to the second extract within the formulation is at least 0.5:
7. A formulation as c|aimed in any preceding c|aim, in which the ratio by weight of the first extract to the second extract within the formulation is at least 1:1.
8. Use of a cosmetic formulation comprising: a first extract of Empetrum nigrum; and a second extract of Betula Alba bark, in which the second extract is a water /glycerine extract of Betula Alba bark, in the cosmetic treatment of sensitive skin associated with reduced skin barrier function.
9. Use as claimed in claim 8, in which the first extract comprises at least one compound selected from: cyanidin-3-O-glucoside, petunidin-3-O-glucoside, peonidin-3-O-glucoside, malvidin-3-O- glucoside, delphinidin-3-arabinoside, or any combination thereof.
10. Use as claimed in either of c|aims 8 and 9, in which the second extract comprises at least one compound selected from: catechin-7-O-beta-D-xylopyranoside, catechin, apiosylepirhododendrin, rhododendrin, apiosylepirhododendrin, platyphylloside, (5S)-5-hydroxy-1,7-bis-(4-hydroxyphenyl)-3- heptanone-5-O-ß-D-apiofuranosyl-(1->6)-ß-D-glucopyranoside, (3R)-1,7-Bis-(4-hydroxyphenyl)-3- heptanol-3-O-<2,6-bis-O-(ß-D-apiofuranosyl)-ß-D-glucopyranoside>, aceroside VIII, 5-hydroxy-3- platyphyllone, aceroside VII, centrolobol, acerogenin E, or any combination thereof.
11. Use as claimed in any one of c|aims 8 to 10, in which the ratio by weight of the first extract to the second extract within the cosmetic formulation is no more than 5:
12. Use as claimed in any one of c|aims 8 to 11, in which ratio by weight of the first extract to the second extract within the cosmetic formulation is no more than 3:
13. Use as claimed in any one of c|aims 8 to 12, in which the ratio by weight of the first extract to the second extract within the cosmetic formulation is at least 0.5:
14. Use as claimed in any one of c|aims 8 to 13, in which the ratio by weight of the first extract to the second extract within the cosmetic formulation is at least 1:1.
15. Use of a cosmetic formulation comprising: a first extract of Empetrum nigrum; and a second extract of Betula Alba bark, in which the second extract is a water /glycerine extract of Betula Alba bark, for cosmetically improving one or more of: skin hydration, skin hydration distribution, skin barrier resilience, skin barrier quality, skin cohesiveness, skin nourishing effect, skin barrier recovery, or any combination thereof, of the skin of a user.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE2030376A SE545843C2 (en) | 2020-12-23 | 2020-12-23 | Plant extracts for improving skin barrier function |
| CN202180086919.5A CN116685341A (en) | 2020-12-23 | 2021-11-25 | Plant extracts for improving skin barrier function |
| EP21820219.0A EP4267103A1 (en) | 2020-12-23 | 2021-11-25 | Plant extracts for improving skin barrier function |
| PCT/EP2021/083045 WO2022135827A1 (en) | 2020-12-23 | 2021-11-25 | Plant extracts for improving skin barrier function |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE2030376A SE545843C2 (en) | 2020-12-23 | 2020-12-23 | Plant extracts for improving skin barrier function |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| SE2030376A1 SE2030376A1 (en) | 2022-06-24 |
| SE545843C2 true SE545843C2 (en) | 2024-02-20 |
Family
ID=78822514
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE2030376A SE545843C2 (en) | 2020-12-23 | 2020-12-23 | Plant extracts for improving skin barrier function |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP4267103A1 (en) |
| CN (1) | CN116685341A (en) |
| SE (1) | SE545843C2 (en) |
| WO (1) | WO2022135827A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2028150C1 (en) * | 1990-02-20 | 1995-02-09 | Краснов Ефим Авраамович | Agent for atopic dermatitis treatment |
| US20070231418A1 (en) * | 2000-03-28 | 2007-10-04 | Birken Gmbh | Emulsion containing a plant extract, method for producing said emulsion and for obtaining said plant extract |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20090089982A (en) * | 2008-02-20 | 2009-08-25 | 코스맥스 주식회사 | Cosmetic compositions containing extract of empetrum nigrum var. japonicum used for antiwrinkle |
| BR112020000123A2 (en) * | 2017-07-04 | 2020-07-07 | Lubrizol Advanced Materials, Inc. | compound, use of a compound, cosmetic composition, and, method for non-therapeutic cosmetic care and / or treatment of skin, hair, nails and / or mucous membranes |
-
2020
- 2020-12-23 SE SE2030376A patent/SE545843C2/en unknown
-
2021
- 2021-11-25 CN CN202180086919.5A patent/CN116685341A/en active Pending
- 2021-11-25 WO PCT/EP2021/083045 patent/WO2022135827A1/en active Application Filing
- 2021-11-25 EP EP21820219.0A patent/EP4267103A1/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2028150C1 (en) * | 1990-02-20 | 1995-02-09 | Краснов Ефим Авраамович | Agent for atopic dermatitis treatment |
| US20070231418A1 (en) * | 2000-03-28 | 2007-10-04 | Birken Gmbh | Emulsion containing a plant extract, method for producing said emulsion and for obtaining said plant extract |
Non-Patent Citations (3)
| Title |
|---|
| Rastogi, S. et al. "Medicinal plants of the genus Betula - Traditional uses and a phytochemical-pharmacological review" In: J. Ethnopharmcol., 2015, Jan., Vol. 159, pp. 62-83. * |
| Revivekliniken - Biologique Recherche Creme Anti-C ; Retrieved from the Internet: 2021-07-09 from <URL: https://www.revivekliniken.com/products/creme-anti-c> [Internet archive from 2020-09-22 URL: https://web.archive.org/web/20200922002604/https://www.revivekliniken.com/products/creme-anti-c] * |
| Topestetic - Biologique Recherche Paris - Creme Anti - C; Retrieved from the Internet: 2021-07-08 from <URL: https://www.topestetic.pl/biologique-recherche/creme-anti-c-wyszczuplajacy-krem-antycellulitowy-200-ml> * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2022135827A1 (en) | 2022-06-30 |
| EP4267103A1 (en) | 2023-11-01 |
| CN116685341A (en) | 2023-09-01 |
| SE2030376A1 (en) | 2022-06-24 |
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