© Mibelle Biochemistry, Switzerland 2009 MAXnolia H-instant Protects skin against inflammatory aging

© Mibelle Biochemistry, Switzerland 2009 Inflammation First response to infection or irritation Increase in local blood flow Migration and activation of the immune cells in the affected area Release of large amounts of free radicals Destruction of normal tissue

© Mibelle Biochemistry, Switzerland 2009 Chronic Inflammation & Aging Ideally, inflammation should clear out the infection and then subside to allow normal tissue to be rebuilt. But inflammation may become chronic (in case of a remaining infection, or an inflammation response that has become too sensitive or because of autoimmune reactions) Besides, as we age, we tend to develop chronic inflammation Chronic inflammation contributes to the aging process notably because of free radicals.

© Mibelle Biochemistry, Switzerland 2009 Chronic Inflammation in the Skin leads to premature Aging Chronic inflammation  fine lines and wrinkles enlarged pores puffiness, sagging reddening of the skin Age-related increased level of chronic inflammation enhances adds to inflammation-triggering factors such as -the sun‘s ultraviolet radiation -radicals coming from environmental pollution -chemical irritants for people with sensitive skin

© Mibelle Biochemistry, Switzerland 2009 Inflammation is now recognized as one of the key risk factors for heart disease and stroke, an even bigger risk factor than high cholesterol or homocysteine, according to some estimates. Inflammation is also viewed as a contributor to common age-related neurodegenerative diseases, such as Alzheimer's and Parkinson's. While keeping inflammation under control should

© Mibelle Biochemistry, Switzerland 2009 Inflammation is now recognized as one of the key risk factors for age related deseases such as heart disease and stroke. Inflammation is also viewed as a contributor to common age-related neurodegenerative diseases, such as Alzheimer's and Parkinson's. In people in a weakened condition, usually an excess level of one or more of the inflammatory cytokines, e.g., TNF-a, IL-6, IL-1(b), or IL-8 is found An other process that contributes to this chronic inflammation is the formation of AGEs (advanced glycation endproducts). As these degraded proteins accumulate, they cause cells to emit signals that induce the production of inflammatory cytokines.

© Mibelle Biochemistry, Switzerland 2009 Inflammation in Skin Cells: Biochemical Pathways Triggers UV Bacterial Infection Chemical Irritant Pollution Radical Autoimmune Reaction ROS NF-kB COX Prostaglandins IL-1, IL-8 TNF-  iNOS Inflammation Matrix Metallo proteinases IkB kinase enzyme Collagen Destruction NuclearFactor-kappaB: Transkriptionsfaktor involved in the control of a large number of processes, such as immune and inflammatory responses, developmental processes, cellular growth, and apoptosis IkB family of inhibitor proteins NFκB is a transcription factor that is a major regulator of immune responses stimulated by pro-inflammatory agents such as tumor necrosis factor, viruses, interleukin-1, and bacteria. NFκB normally resides in the cytoplasm bound by an inhibitory protein known as IκB. Phosphorylation of IκB by IκB kinase-β (IKK-β) releases NFκB, which then moves into the nucleus where it acts in the induction of numerous regulatory genes of the immune system. The products of these genes are pro-inflammatory factors. nucleus fibroblast

© Mibelle Biochemistry, Switzerland 2009

Nf kappa B von Cytosol in kern UV Chemical Irritant Pollution Radical Bacterial Infection Autoimmune Reaction ROS NF-kB Genes COX Prostaglandins IL-1, IL-8 TNF-  iNOS Inflammation Triggers Matrix Metalloproteinases Collagen Destruction IkB kinase enzyme

© Mibelle Biochemistry, Switzerland 2009 MAXnolia H-instant as Natural NF-kB Inhibitor Magnolia bark is a traditional Chinese medicine to treat cough, anxiety and allergic diseases. The pharmacologically active substance magnolol is a low molecular weight lignan. Magnolol has a broad spectrum anti-inflammatory effect. It suppresses the expression of the inducible nitric oxide synthase (iNOS) and the production of the inflammatory cytokines IL-8 and TNF- .

© Mibelle Biochemistry, Switzerland 2009 Inhibition of NF-kB by Magnolol: Mechanism In non-stimulated cells, NF-kB is sequestered in the cytoplasm by binding to the inhibitory protein IkB. When cells are activated, the enzyme IkB kinase (IKK) phosphorylates the IkB protein. Once phosphorylated, IkB is quickly degraded by the proteasomal pathway. Free NF-kB translocates into the nucleus where it induces the expression of inflammatory mediators and matrix degrading enzymes. Magnolol was shown to suppress NF-kB activation through inhibition of the IKK enzyme (Anfernee Kai-Wing Tse et al., Molecular Immunology 44, , 2007). Magnolol

© Mibelle Biochemistry, Switzerland 2009 Inhibition of NF-kB by Magnolol: Mechanism In non-stimulated cells, NF-kB is sequestered in the cytoplasm by binding to the inhibitory protein IkB. When cells are activated, the enzyme IkB kinase (IKK) phosphorylates the IkB protein. Once phosphorylated, IkB is quickly degraded by the proteasomal pathway. Free NF-kB translocates into the nucleus where it induces the expression of inflammatory mediators and matrix degrading enzymes. Magnolol was shown to suppress NF-kB activation through inhibition of the IKK enzyme (Anfernee Kai-Wing Tse et al., Molecular Immunology 44, , 2007). Magnolol

© Mibelle Biochemistry, Switzerland 2009 MAXnolia H-instant INCI Magnolia Officinalis Bark Extract Lecithin Vitis Vinifera Grape Seed Extract Maltodextrin

© Mibelle Biochemistry, Switzerland 2009 Highly Optimized Powder Form MAXnolia H-instant Spray dried extract of magnolia bark on a carrier Carrier is a mixture of lecithin and maltodextrin Powder can be dispersed directly in the water phase Liposomes are formed immediately Active components are integrated in the liposomes and are thus solubilized

© Mibelle Biochemistry, Switzerland 2009 Inhibition of Cyclooxigenase II (COX II) Enzymatic Assay COX II = enzyme which produces mediators of inflammation S-208

© Mibelle Biochemistry, Switzerland 2009 Anti-Irritation Effect Use of occlusive patch with 2% SDS for 48 hours to produce a local erythemal irritation on forearm of 15 subjects. Application twice daily of a cream with 0.5% MAXnolia H-instant during 7 days. Analysis of skin redness with Chromameter CR 300 (Konica Minolta) S-227

© Mibelle Biochemistry, Switzerland 2009 Anti-Aging Effect Study with 22 subjects over 56 days. Application twice daily of a cream with 0.5% MAXnolia H- instant in the crow’s feet area and on the forearm. Analysis of skin elasticity with cutometer

© Mibelle Biochemistry, Switzerland 2009 Claims and Market Positioning Antifungal, antibacterial → to treat impure skin Anti-inflammatory → Anti-Aging

© Mibelle Biochemistry, Switzerland 2009 Advanced anti-aging skin care regime Products with anti-inflammatory activity Combination with antioxidant compounds Optimize the stratum corneum permeability barrier

© Mibelle Biochemistry, Switzerland 2009 Advantages of the new Preliposomes (instantly formed) -> optimal solubilisation and delivery of actives into deeper skin layers High concentration of Lecithin -> stregthen the skin barrier High content of lipophilic plant metabolites thanks to EtOH extraction No preservatives -> no restrictions for formulators And: no alcohol in the formulation