Patent Publication Number: US-2013251828-A1

Title: Lipophilic Carrier Composition for Solubilizing Lipophilic Bioactive Botanical Extracts, Methods of Solubilizing Lipophilic Bioactive Botanical Extracts, and Methods of Using Solubilized Lipophilic Bioactive Botanical Extracts

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority from U.S. Provisional Patent Application Ser. No. 61/614,838, filed Mar. 23, 2012, the disclosures of which are incorporated herein by reference in their entirety. 
    
    
     BACKGROUND 
     Skin is a complex living tissue, which is composed of two main layers: the dermis and the epidermis. The epidermis is the outer layer of the skin, and is organized in layers of cells called keratinocytes that progressively differentiate to form the outermost layer of the epidermis, known as the stratum corneum. Fully differentiated keratinocytes, known as corneocytes, are devoid of nuclei and are filled with insoluble keratin fibers. They are arranged like bricks and separated by lipid-rich layers in an array that is often referred to as the brick-and-mortar model of the stratum corneum. In addition to protecting the inner layers of the skin from deleterious chemicals and harmful radiation, the stratum corneum acts as a barrier to the passage of hydrophilic compounds. Metabolically active keratinocytes, which form the remainder of the epidermis, and cells that respond to external stimuli are located below the stratum corneum. The dermis lies below the epidermis and is constituted mainly of fibroblasts, which are metabolically active cells that can respond to signals coming from upper layers of the skin and from the external environment. 
     Bioactive botanical extracts, having beneficial effects on the skin, e.g., photoprotection, anti-aging, moisturizing, antioxidant, astringent, anti-irritant, and antimicrobial properties, are being increasingly used in the cosmetic industry and are featured in a growing variety of cosmetic formulations and products available in the marketplace. Such bioactive botanical extracts and mixtures of botanical extracts are often obtained by extracting biomasses in solvents that are compatible with cosmetic uses. For safety, environmental and economic reasons, water is generally the extraction solvent of choice and the extractions result in water soluble, or hydrophilic, biological active ingredients. Generally these extracts are formulated in a cosmetically acceptable carrier for application to the skin. Because they have been obtained through water extraction, these extracts are hydrophilic and can be easily added to hydrophilic gels and toiletries or to the water phase of an emulsion. However, because of their hydrophilic nature, the active ingredients in these extracts may have difficulty penetrating the lipophilic stratum corneum barrier of the skin. This decreased penetration generally is thought to lead to decreased efficacy. While means for facilitating the passage of hydrophilic active ingredients through the stratum corneum&#39;s lipophilic barrier exist, e.g., incorporation into liposomes or other vehicles having lipophilic characteristics, these means generally involve additional transformation of the active ingredients and may affect their efficacy. 
     The cosmetics industry is therefore becoming more interested in lipophilic bioactive botanical extracts. Due to their lipophilic nature and enhanced physiological compatibility relative to hydrophilic compounds, lipophilic bioactive extracts are thought to have enhanced ability to penetrate the skin&#39;s lipophilic stratum corneum barrier and thus improved biological efficacy resulting from a better ability to reach the metabolically active cells in the dermis and lower layers of the epidermis. 
     Lipophilic bioactive botanical extracts are known. Unfortunately, because of their physico-chemical properties, in particular their lipophilic nature, many of such lipophilic bioactive botanical extracts have the disadvantage that they do not lend themselves to easy incorporation in an effective amount into cosmetic formulations because, inter alia, they are not readily soluble in cosmetic formulation media and their solubilization requires conditions, such as excessive processing, e.g., stirring, sonication or mixing, elevated temperatures or aggressive solvents, that often result in their degradation, or conditions that are not compatible with cosmetic uses, or conditions that may be deleterious to other compounds present in the formulation. 
     Another major challenge in providing high quality cosmetic products based on “natural” ingredients such as bioactive botanical extracts is their poor stability in formulations. Many bioactive botanical extracts do not tolerate processing and storage conditions that are generally acceptable for more stable synthetic ingredients. 
     A further challenge in providing high quality cosmetic products using “natural” ingredients is the poor stability of certain vegetable oils used in cosmetic formulations. Due to their poor stability, unsaturated vegetable oils do not tolerate processing conditions, storage conditions, or the presence of other reactive ingredients in formulations that are generally acceptable for more stable synthetic ingredients. For example, some seed derived polyunsaturated oils, those containing essential fatty acids in particular, have been shown to improve the structure and function of cell membranes, improve skin barrier function and enhance skin penetration. However, because these oils contain high amounts of unsaturated fatty acids, which are in part responsible for those properties, they are also very vulnerable to oxidation. The labile olefin moiety characteristic of these oils is very easily oxidized upon exposure to oxygen, especially at elevated temperatures. As a result, it is often the case that, by the time products containing these oils reach the consumer, the benefits of such oils have been lost. Although microencapsulation technology has been proposed to protect such oils from oxidation, investment in new apparatus is generally required to utilize such technology and the process is generally time consuming and expensive. Furthermore, depending upon the microencapsulation used, the skin bioavailability of oil components may be hampered. 
     There remains a need in the cosmetics industry to provide a means of incorporating lipophilic bioactive botanical extracts into a variety of topical dermatological, pharmaceutical and cosmetic preparations that is cost-effective and compatible with standard equipment while preserving the integrity and beneficial properties of these materials, particularly the beneficial properties of the oil components of these materials. 
     The present invention provides a simple and cost-effective solution to this need by providing a lipophilic bioactive botanical extract presolubilized in an oxidation stable and cosmetically acceptable vegetable oil carrier (i.e., a lipophilic carrier composition). The inventive lipophilic carrier composition is oxidation stable and can readily be incorporated into a variety of cosmetic formulations, improving the processing time and providing a more shelf stable product. 
     SUMMARY OF THE INVENTION 
     In one embodiment, the present invention provides a lipophilic carrier composition comprising a lipophilic bioactive botanical extract, a vegetable oil, a solubilization system, and, optionally, an antioxidant, where the vegetable oil is present in a stable, relatively unoxidized state. In certain embodiments, the vegetable oil is resistant to oxidation such that the Rancimat induction time for the lipophilic carrier composition according to ISO Method no. 6886-2006 is greater than 3 hours, greater than 4 hours, greater than 5 hours, greater than 7 hours, greater than 10 hours, greater than 15 hours, or greater than 20 hours. 
     In another embodiment, the present invention provides a lipophilic carrier composition comprising a lipophilic bioactive botanical extract, a vegetable oil, a solubilization system, and, optionally, an antioxidant, where the lipophilic carrier composition is produced by a method comprising:
         (a) combining the solubilization system and the lipophilic bioactive botanical extract to form a mixture;   (b) maintaining the temperature of the mixture between 40-100° C. under a nitrogen or other inert gas atmosphere until the lipophilic bioactive botanical extract is dissolved;   (c) cooling the mixture of step (b);   (d) adding the vegetable oil; and   (e) agitating the mixture formed by the addition of the vegetable oil in step (d) until a homogeneous composition is obtained.       

     In some embodiments, the mixture of step (c) is cooled to about room temperature. 
     If the antioxidant is part of the lipophilic carrier composition, it may be added along with the vegetable oil in step (d) or it may be added after the vegetable oil but before step (e). Generally, the antioxidant is dissolved in a cosmetically acceptable alcohol before addition. 
     In another embodiment, the present invention provides a lipophilic antioxidant composition comprising an antioxidant, a vegetable oil, and a solubilization system, but not comprising a lipophilic bioactive botanical extract, where the vegetable oil is present in a stable, relatively unoxidized state. In certain embodiments, the vegetable oil is resistant to oxidation such that the Rancimat induction time for the lipophilic antioxidant composition according to ISO Method no. 6886-2006 is greater than 3 hours, greater than 4 hours, greater than 5 hours, greater than 7 hours, greater than 10 hours, greater than 15 hours, or greater than 20 hours. 
     In another embodiment, the present invention provides a lipophilic antioxidant composition comprising an antioxidant, a vegetable oil, and a solubilization system, but not comprising a lipophilic bioactive botanical extract, where the lipophilic antioxidant composition is produced by a method comprising:
         (a) combining the solubilization system and the antioxidant to form a mixture;   (b) maintaining the mixture at a temperature that is higher than room temperature under a nitrogen or other inert gas atmosphere such that the antioxidant is dissolved;   (c) reducing the temperature of the mixture of step (b) to room temperature;   (d) adding the vegetable oil to the mixture of step (c); and   (e) agitating the mixture formed by the addition of the vegetable oil in step (d) until a homogeneous composition is obtained.       

     In some embodiments, the temperature that is higher than room temperature of step (b) is between 40-100° C. In some embodiments, the temperature that is higher than room temperature of step (b) is between 40-50° C., between 50-60° C., between 60-70° C., between 70-80° C., between 80-90° C., or between 90-100° C. 
     In certain embodiments, the solubilization system comprises a branched, long chain alcohol such as octyldodecanol, a cosmetically acceptable alcohol such as ethanol, and one or more fatty acid esters of a branched, long chain alcohol, for example, octyldodecyl oleate and/or octyldodecyl stearoyl stearate. In certain embodiments, the branched, long chain alcohol in the fatty acid esters is the same branched, long chain alcohol as the unesterified branched, long chain alcohol. In other embodiments, the branched, long chain alcohol in the fatty acid esters is a different branched, long chain alcohol from the unesterified branched, long chain alcohol. In certain embodiments, the fatty acids of the esters are resistant to oxidation. For example, in certain embodiments, the fatty acids do not contain a double bond. In other embodiments, the fatty acids contains only one double bond. Suitable fatty acids include monounsaturated fatty acids such as myristoleic acid (14:1), palmitoleic acid (16:1), sapienic acid (16:1), oleic acid (18:1), elaidic acid (18:1), vaccenic acid (18:1), eicosenoic acid (20:1), and erucid acid (22:1). Other suitable fatty acids include saturated fatty acids such as caprylic acid (8:0), capric acid (10:0), lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), lignoceric acid (24:0), and cerotic acid (26:0). 
     The solubilization system enables the complete dissolution of lipophilic bioactive botanical extracts therein. The solubilization system thus allows for the convenient incorporation of lipophilic active ingredients such as those found in lipophilic bioactive botanical extracts into a vegetable oil, thus forming a lipophilic carrier composition comprising the solubilization system, lipophilic bioactive botanical extract, and vegetable oil, without exposing the vegetable oil to elevated temperatures or extended processing time. As is known in the art, elevated temperatures and extended processing times can lead to the undesired oxidation of vegetable oils. Thus, the lipophilic carrier composition of the present invention contains the vegetable oil in a stable, relatively unoxidized state. The ability to provide lipophilic bioactive botanical extracts in combination with a stable, relatively unoxidized vegetable oil is an advantageous feature of the present invention. 
     The lipophilic carrier composition can conveniently be used to store and distribute lipophilic active ingredients and to formulate topical cosmetic, pharmaceutical, and dermatologic formulations while maintaining the bioactivity of the lipophilic bioactive botanical extract and preventing oxidation of the vegetable oil and other oxidizable components of the formulation made from the lipophilic carrier composition. 
     A presolubilized lipophilic bioactive botanical extract for use in the present invention may be made by a method comprising combining a solubilization system with a lipophilic bioactive botanical extract and, if necessary to dissolve the lipophilic bioactive botanical extract, heating the mixture to a temperature between 40-100° C. under a nitrogen or other inert gas atmosphere. In some embodiments, the mixture is heated to a temperature between 40-50° C., between 50-60° C., between 60-70° C., between 70-80° C., between 80-90° C., or between 90-100° C. In some embodiments, the inert gas is selected from the group consisting of noble gases such as argon, xenon, neon, and helium. In some embodiments, a mixture of nitrogen and another inert gas is used. In alternative embodiments, rather than using an inert gas to prevent oxidation, a vacuum is used to prevent contact with air, and thus prevent oxidation. 
     The present invention also provides a method of making a lipophilic carrier composition comprising combining the solubilization system with the lipophilic bioactive botanical extract and, if necessary to dissolve the lipophilic bioactive botanical extract, heating the mixture to a temperature between 40-100° C. under a nitrogen or other inert gas atmosphere until the extract is dissolved, then cooling the mixture to room temperature, adding a vegetable oil, and then, optionally, adding an antioxidant extract dissolved in a cosmetically acceptable alcohol. The mixture is then agitated until a homogeneous composition is obtained. 
     The lipophilic active carrier compositions of the invention can be used to prepare cosmetics having extended shelf life, for the convenient storage and distribution of a lipophilic biological extract, for use as a base or ingredient in a variety of cosmetic compositions, and for preserving the biological activity of additional ingredients included in products produced using the inventive lipophilic active carrier composition (e.g., unsaturated fatty acids, polyphenols, additional liposoluble actives). 
     The invention also provides a method of protecting skin against erythema and/or skin barrier function loss due to exposure of the skin to radiation or chemical stress using the inventive lipophilic active carrier compositions disclosed herein. Such methods of protecting skin generally involve applying a cosmetic or pharmaceutical formulation produced by incorporating a lipophilic carrier composition of the present invention into a base cream before the insult that results in erythema and/or skin barrier function loss. Thus, included in the present invention are methods of protecting skin against erythema and/or skin barrier function loss by applying a cosmetic or pharmaceutical formulation produced by incorporating a lipophilic carrier composition of the present invention into a base cream to skin that is at risk of suffering radiation or chemical stress. Such “at risk” skin might include, e.g., the skin of a person who contemplates exposing his or her skin to a significant amount of strong sunlight, e.g., by spending a day at the beach. Other “at risk” skin might include the skin of a person who is exposed to chemical stress (e.g., by occupational exposure to chemical aggressors or by frequent use of soaps or cleansers). 
     A method of treating skin that has developed erythema and/or skin barrier function loss due to exposure of the skin to radiation or chemical stress using the lipophilic active carrier compositions disclosed herein is also provided. Such methods of treating skin generally involve applying a cosmetic or pharmaceutical formulation produced by incorporating a lipophilic carrier composition of the present invention into a base cream after the insult that results in erythema and/or skin barrier function loss. 
     Of course, cosmetic or pharmaceutical formulations produced by incorporating a lipophilic carrier composition of the present invention into a base cream may be utilized by applying such formulations to the skin both before and after an insult. 
     The invention also provides methods of treating age spots using the inventive lipophilic active carrier compositions disclosed herein. Such methods of treating age spots generally involve applying a cosmetic or pharmaceutical formulation produced by incorporating a lipophilic carrier composition of the present invention into a base cream to an area of skin containing age spots. Thus, included in the present invention are methods of treating age spots by applying a cosmetic or pharmaceutical formulation produced by incorporating a lipophilic carrier composition of the present invention into a base cream to skin containing age spots. In some embodiments, the cosmetic or pharmaceutical formulation is applied to an area of skin including the age spots and surrounding areas of skin. In some embodiments, the cosmetic or pharmaceutical formulation is applied directly to the age spots and not also to the surrounding skin areas. In some embodiments, the age spots are on the face, the upper body or chest area, the legs, the hands, or the arms. In some embodiments, the cosmetic or pharmaceutical formulation comprises an extract from  Paeonia suffruticosa  root and  Ribes nigrum  seed oil. 
     Furthermore, the clinical advantages of using cosmetic and similar formulations made from the lipophilic active carrier compositions of the present invention over formulations containing i) only a vegetable oil, ii) a vegetable oil with a solubilization system but without the lipophilic bioactive extract or iii) a simple placebo representing the formulation base are shown herein. 
     The present invention provides a lipophilic carrier composition comprising  Cnidium monnieri  fruit extract,  Echium plantagineum  seed oil, ethanol, octyldodecanol, octyldodecyl oleate, and octyldodecyl stearoyl stearate. The present invention also provides a lipophilic carrier composition comprising  Paeonia suffruticosa  root extract,  Ribes nigrum  seed oil, ethanol, octyldodecanol, octyldodecyl oleate, and octyldodecyl stearoyl stearate. 
    
    
     DETAILED DESCRIPTION 
     The term “topical” as used herein refers to the route of administration of a cosmetic composition that involves direct application to the body part being treated, e.g., the skin, hair or nails. Examples of topical application include application to the skin of creams, lotions, gels, ointments or other semisolids to rub-on, solutions to spray, or liquids to be applied by an applicator. Rinse-off applications with washes, cleansers, or shampoos are also examples of topical application. Typically, areas of the body suitable for application of the cosmetic compositions include the skin of the face, throat, neck, scalp, chest, back, ears, hands, arms, and other skin sites where dermatological conditions may occur. 
     The term “cosmetic” is intended to encompass compositions that improve the health and/or appearance of skin and hair and is used interchangeably with dermatologic and naturopathic, cosmeceutical, pharmaceutical, nutraceutical and other similar terms. 
     As used herein, “room temperature” refers to a temperature of about 18-25° C., preferably 20-22° C. 
     As used herein, “homogeneous composition” refers to a composition that is a single phase that appears clear or translucent by visual inspection. 
     In the various embodiments discussed herein the vegetable oil is preferably one with beneficial pharmacological, cosmetic or dermatological properties. Most preferably the vegetable oil has a high level of polyunsaturated fatty acids, e.g., at least about 25%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. 
     Vegetable oils which can be used in the present invention include any cosmetically compatible vegetable oil derived from a botanical source, such as a plant. Various parts of a plant may be used to obtain the vegetable oil, e.g., leaves, stems, bark, flowers, seeds, fruits, spores or roots. The vegetable oil may be obtained by conventional methods, e.g., by cold-press extraction and the like. Preferably the vegetable oil has beneficial pharmaceutical, cosmetic, or dermatological properties. Vegetable oils that include a significant proportion of polyunsaturated oils, such as the essential fatty acids omega-3 and omega-6, as well as omega-5 and omega-9 fatty acids, are particularly suitable for use in the inventive compositions and methods. In certain embodiments, the omega-3 fatty acids comprise alpha-linolenic acid (ALA) and its longer chain derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the omega-6 fatty acids comprise linoleic acid (LA) and its longer chain derivatives such as gamma-linolenic acid (GLA) and arachidonic acid (AA). Topical application of some polyunsaturated fatty acids have been shown to have bioactivity, e.g., to improve the structure and function of cell membranes and improve skin barrier function. Improving skin barrier function reduces transepidermal water loss, leaving skin more hydrated, moisturized, and protected. The amount of vegetable oil used in the inventive compositions described herein is not particularly limited. A formulations scientist will readily be able to determine the appropriate amount of vegetable oil in the composition to achieve the desired properties in the composition. Typical embodiments of the invention include lipophilic carrier compositions comprising a vegetable oil in an amount from about 10-50%. 
     Vegetable oils that are well suited for the invention include  Ribes nigrum  (black currant) seed oil,  Echium plantagineum  (purple viper&#39;s bugloss) seed oil, baobab seed oil, black cumin seed oil, borage oil, burit fruit oil, calophyllum oil, elderberry seed oil, evening primrose oil, flax seed oil, gevuina nut oil, goji seed oil, hemp seed oil, jobs tears seed oil, jojoba oil, kiwi seed oil, neem oil, olive oil, passion fruit oil, pitanga seed oil (orange, red and purple varieties), pumpkin seed oil, raspberry seed oil, rose hip oil, sacha inchi seed oil, safflower oil, sea buckthorn seed oil, sesame oil, soybean oil, sunflower seed oil and walnut oil. Vegetable oils particularly suited for use in the invention include  Ribes nigrum  (black currant) seed oil,  Echium plantagineum  (Purple Viper&#39;s Bugloss) seed oil or a combination thereof. Suitable vegetable oils for use in the present invention include those in the following table. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                   
                 Unsaturated 
                 Polyunsaturated 
                   
                   
                   
               
               
                 Name of oil 
                 FA (%) 
                 FA (%) 
                 Major constituents 
                 Color 
                 Origin 
               
               
                   
               
             
            
               
                 Apricot Kernel Oil 
                 95% 
                 29% 
                 Oleic, linoleic, 
                 clear to light 
                 Middle East 
               
               
                   
                   
                   
                 palmitic 
                 yellow 
               
               
                 Baobab Seed Oil 
                 70% 
                 35% 
                 Oleic, linoleic, 
                 golden yellow 
                 Southern 
               
               
                   
                   
                   
                 palmitic, stearic 
                   
                 Africa 
               
               
                 Blackcurrant Seed 
                 87% 
                 76% 
                 Linoleic, a-linolenic, 
                 Clear yellow 
                 Eastern 
               
               
                 Oil 
                   
                   
                 g-linolenic, oleic, 
                   
                 Europe 
               
               
                   
                   
                   
                 palmitic 
               
               
                 Black Cumin Seed 
                 78% 
                 58% 
                 Linoleic, oleic, 
                 yellow to 
                 Middle East 
               
               
                 Oil 
                   
                   
                 margaric, cis-11,14- 
                 amber 
               
               
                   
                   
                   
                 eicosadienoic acid, 
               
               
                   
                   
                   
                 stearic 
               
               
                 Borage Oil 
                 85% 
                 69% 
                 Oleic, linoleic, g- 
                 Dark green 
                 North America 
               
               
                   
                   
                   
                 linolenic, palmitic 
                   
                 and Eastern 
               
               
                   
                   
                   
                   
                   
                 Africa 
               
               
                 Burit Fruit Oil 
                 82% 
                  3% 
                 Oleic, palmitic, 
                 Red-Orange 
                 Brazil 
               
               
                   
                   
                   
                 linoleic, linolenic, 
               
               
                   
                   
                   
                 stearic, 
               
               
                 Calophyllum Oil 
                 71% 
                 31% 
                 Oleic, linoleic, 
                 clear green 
                 Pacific Islands 
               
               
                   
                   
                   
                 stearic, palmitic 
               
               
                 Elderberry Seed Oil 
                 94% 
                 80% 
                 Linoleic, a-linolenic, 
                 deep dark 
                 North America 
               
               
                   
                   
                   
                 g-linolenic oleic, 
                 green 
               
               
                   
                   
                   
                 erucic, palmitic, 
               
               
                   
                   
                   
                 stearic 
               
               
                 Evening Primrose 
                 92% 
                 81% 
                 Oleic, linoleic, g- 
                 yellow 
                 Northern Asia 
               
               
                 Oil 
                   
                   
                 linolenic, palmitic 
               
               
                 Flax Seed Oil 
                 91% 
                 72% 
                 Linoleic, a-linolenic, 
                 light yellow 
                 South America 
               
               
                   
                   
                   
                 oleic, palmitic 
               
               
                 Gevuina Nut Oil 
                 82% 
                 32% 
                 Oelic, palmitoleic, 
                 light yellow 
                 Chile 
               
               
                   
                   
                   
                 linoleic, a-linolenic 
               
               
                 Goji Seed Oil 
                 90% 
                 71% 
                 Linoleic, Oleic, 
                 Orange-yellow 
                 Asia 
               
               
                   
                   
                   
                 linolenic 
               
               
                 Hemp Seed Oil 
                 92% 
                 80% 
                 Linoleic, a-linolenic, 
                 Olive green 
                 Northern Asia 
               
               
                   
                   
                   
                 palmitic, g-linolenic, 
               
               
                   
                   
                   
                 stereadonic 
               
               
                 Jobs Tears Seed Oil 
                 86% 
                 36% 
                 Oleic, linoleic, 
                 NA 
                 Asia 
               
               
                   
                   
                   
                 palmitic 
               
               
                 Jojoba Oil 
                 90% 
                  6% 
                 Gadoleic, erucic, 
                 pale yellow 
                 Middle East &amp; 
               
               
                   
                   
                   
                 oleic, linoleic, 
                   
                 South America 
               
               
                   
                   
                   
                 lignoceric, palmitic 
               
               
                 Kiwi Seed Oil 
                 91% 
                 76% 
                 a-Linolenic, linoleic, 
                 yellow to 
                 New Zeland 
               
               
                   
                   
                   
                 oleic, stearic, 
                 amber 
               
               
                   
                   
                   
                 palmitic 
               
               
                 Neem Oil 
                 64% 
                 18% 
                 Linoleic, oleic, 
                 browny 
                 Central Asia 
               
               
                   
                   
                   
                 stearic, palmitic 
               
               
                 Olive Oil 
                 84% 
                 8% 
                 Oleic, Palmitic, 
                 Light to 
                 Western 
               
               
                   
                   
                   
                 linoleic 
                 medium green 
                 Europe and 
               
               
                   
                   
                   
                   
                   
                 Middle East 
               
               
                 Passion Fruit Oil 
                 90% 
                 78% 
                 Linoleic, oleic, 
                 Light 
                 South 
               
               
                   
                   
                   
                 palmitic, stearic, a- 
                   
                 America, 
               
               
                   
                   
                   
                 linolenic 
               
               
                 Pitanga Seeds 
                 61% 
                 47% 
                 Palmitic, linoleic, a- 
                 NA 
                 South 
               
               
                 (orange) Oil 
                   
                   
                 linoleic, oleic 
                   
                 America, 
               
               
                   
                   
                   
                   
                   
                 Southeast 
               
               
                   
                   
                   
                   
                   
                 Asia, and 
               
               
                   
                   
                   
                   
                   
                 Australia. 
               
               
                 Pitanga Seeds (red) 
                 52% 
                 45% 
                 Linoleic, palmitic, 
                 NA 
                 South 
               
               
                 Oil 
                   
                   
                 oleic, a-linoleic, 
                   
                 America, 
               
               
                   
                   
                   
                 palmitoleic 
                   
                 Southeast 
               
               
                   
                   
                   
                   
                   
                 Asia, and 
               
               
                   
                   
                   
                   
                   
                 Australia. 
               
               
                 Pitanga Seeds 
                 61% 
                 47% 
                 Linoleic, palmitic, 
                 NA 
                 South 
               
               
                 (purple) Oil 
                   
                   
                 oleic, a-linoleic, 
                   
                 America, 
               
               
                   
                   
                   
                 palmitoleic 
                   
                 Southeast 
               
               
                   
                   
                   
                   
                   
                 Asia, and 
               
               
                   
                   
                   
                   
                   
                 Australia. 
               
               
                 Pumpkin Seed Oil 
                 84% 
                 57% 
                 Linoleic, oleic, 
                 dark green to 
                 Syria, Austria 
               
               
                   
                   
                   
                 palmitic, stearic 
                 dark red 
                 and Slovenia 
               
               
                 Raspberry Seed Oil 
                 96% 
                 84% 
                 Linoleic, a-linolenic, 
                 gold to reddish 
                 North America 
               
               
                   
                   
                   
                 oleic 
                 color 
               
               
                 Rose Hip Oil 
                 94% 
                 79% 
                 Linolenic, linoleic, 
                 Amber 
                 South America 
               
               
                   
                   
                   
                 oleic, palmitic. 
               
               
                 Sacha inchi seed oil 
                 94% 
                 85% 
                 a-Linoleic, linoleic, 
                 intense yellow 
                 Amazon river 
               
               
                   
                   
                   
                 Oleic, palmitic, 
                 to golden 
               
               
                   
                   
                   
                 stearic 
                 amber 
               
               
                 Safflower Oil 
                 88% 
                 75% 
                 Linoleic, oleic, 
                 light yellow 
                 South Amercia 
               
               
                   
                   
                   
                 palmitic 
               
               
                 Sea buckthorn seed 
                 83% 
                 67% 
                 Linoleic, a-linolenic, 
                 golden 
                 Europe and 
               
               
                 oil 
                   
                   
                 oleic, palmitic, 
                   
                 Asia 
               
               
                   
                   
                   
                 stearic, vaccenic 
               
               
                 Sesame Oil 
                 87% 
                 45% 
                 Oleic, linoleic, 
                 Light yellow 
                 Eastern Africa 
               
               
                   
                   
                   
                 palmitic, stearic 
                   
                 &amp; Southern 
               
               
                   
                   
                   
                   
                   
                 Africa 
               
               
                 Soybean oil 
                 83% 
                 57% 
                 Linoleic, oleic, a- 
                 NA 
                 USA, Brazil, 
               
               
                   
                   
                   
                 linolenic, palmitic 
                   
                 China 
               
               
                 Sunflower Seed Oil 
                 77% 
                 66% 
                 Linoleic, oleic, 
                 slightly amber 
                 North America 
               
               
                   
                   
                   
                 palmitic, stearic 
               
               
                 Walnut Oil 
                 84% 
                 56% 
                 Linoleic, oleic, 
                 light green 
                 Eastern 
               
               
                   
                   
                   
                 palmitic 
                   
                 Europe. 
               
               
                   
               
            
           
         
       
     
     Lipophilic bioactive botanical extracts for use in the present invention are not particularly limited and include any lipophilic extract derived from a botanical source that has beneficial effects on the skin. The term botanical, as used herein, is intended to include material derived from organisms such as plants as well as fungi, algae, marine plant organisms, microorganism fermentation broths and other biological sources of cosmetic ingredients. Examples of various plant tissues include, but are not limited to whole plants, leaves, bark, roots, root bark, fruits, flowers, seeds, and pollen. The lipophilic bioactive botanical extract or compounds therefrom may be obtained by methods known in the art, e.g., by extraction with organic solvents, e.g., lipophilic organic solvents, or combinations of water and organic solvents, or by supercritical fluid carbon dioxide (SCF-CO 2 ) extraction with, or without, the addition or the presence of water. 
     Lipophilic bioactive botanical extracts include those having beneficial pharmaceutical, cosmetic, or dermatological properties. However, hydrophobic powders, waxes and other extracts having physico-chemical properties that require an inconvenient amount of cosmetically acceptable solvent, inconvenient amount of processing time, or elevated temperatures in order to incorporate the extract into a cosmetic formulation are particularly well suited for use in the inventive compositions and methods. Suitable lipophilic bioactive botanical extracts include those antioxidants listed in Table 2 that provide, in addition to antioxidant activity, a health benefit such as the health benefits listed in Table 2 under “Health Applications.” Thus, the categories of lipophilic bioactive botanical extracts and antioxidants are not intended to be mutually exclusive. Typical embodiments of the invention include lipophilic carrier compositions comprising a lipophilic bioactive botanical extract or extracts in an amount from about 0.1-5%, about 0.3-4%, about 0.5-3%, about 0.7-3%, or about 1-2% (w/w). In other embodiments, the lipophilic carrier composition comprises a lipophilic bioactive botanical extract in an amount from about 0.1-0.3%, about 0.3-0.5%, about 0.5-0.7%, about 0.7-1%, about 1.1-1.3%, about 1.3-1.5%, about 1.5-1.7%, about 1.7-2%, about 2.1-2.3%, about 2.3-2.5%, about 2.5-2.7%, about 2.7-3%, about 3.1-3.3%, about 3.3-3.5%, about 3.5-3.7%, about 3.7-4%, about 4.1-4.3%, about 4.3-4.5%, about 4.5-4.7%, or about 4.7-5% (w/w). 
     Lipophilic bioactive botanical extracts that are particularly well suited to this invention are  Cnidium monnieri  fruit extract (enriched in the compound osthol) and  Paeonia suffruticosa  root extract (enriched in the compound paeonol) or a combination thereof. Use of these extracts has been found to protect against erythema and/or skin barrier function loss due to exposure of the skin to radiation or chemical stress. 
     Suitable antioxidants for use in the present invention are not particularly limited and may be antioxidants or free radical scavengers such as vitamins, synthetic antioxidants, or plant-derived antioxidants that protect at least the vegetable oil from endogenous oxidation and/or oxidation induced or accelerated by heat, radiation or the addition of pro-oxidant compounds, thus extending shelf life and expanding compatibility of bioactive ingredients in the inventive compositions and formulations that include the inventive compositions. A list of suitable antioxidants appears in Table 2 below. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Liposoluble antioxidant actives and lipophilic bioactive botanical compounds 
               
            
           
           
               
               
               
               
               
               
            
               
                 Antioxidant/ 
                   
                   
                   
                   
                   
               
               
                 lipophilic 
               
               
                 bioactive 
               
               
                 botanical 
                   
                   
                 Health 
                 Other 
               
               
                 compound 
                 Molecular family 
                 Source(s) 
                 Applications 
                 Applications 
                 Ref. 
               
               
                   
               
               
                 Ascorbyl- 
                 Ester formed from 
                 Synthesis 
                 Immune booster; 
                 To increase the 
                 Cort, Antioxidant activity of 
               
               
                 palmitate 
                 ascorbic acid and 
                   
                 joint protection; 
                 shelf life of 
                 tocopherols, ascorbyl palmitate, 
               
               
                   
                 palmitic acid 
                   
                 promotes healing, 
                 vegetable oils and 
                 and ascorbic acid and their mode 
               
               
                   
                   
                   
                 stimulates 
                 potato chips 
                 of action. J Am Oil Chem Soc. 
               
               
                   
                   
                   
                 collagen synthesis 
                   
                 1974 Jul; 51(7): 321-5. 
               
               
                 Apigenin 
                 Biflavone 
                 
                   Ampelopsis 
                 
                 Antioxidant, 
                 Topical anti- 
                 Arsić et al, Preparation of novel 
               
               
                   
                   
                 
                   grossedentata 
                 
                 radical scavenger, 
                 inflammatory; 
                 apigenin-enriched, liposomal and 
               
               
                   
                   
                 stems;  Allium   
                 anti-inflammatory, 
                 substitute for 
                 non-liposomal, antiinflammatory 
               
               
                   
                   
                   sativum ; 
                 carbohydrate 
                 corticoid therapy 
                 topical formulations as substitutes 
               
               
                   
                   
                 Coriander fruit; 
                 metabolism 
                   
                 for corticosteroid therapy. 
               
               
                   
                   
                 Rosemary 
                 promoter, 
                   
                 Phytother Res. 2011 
               
               
                   
                   
                   
                 immunity system 
                   
                 Feb; 25(2): 228-33. 
               
               
                   
                   
                   
                 modulater. 
               
               
                   
                   
                   
                 Induces 
               
               
                   
                   
                   
                 autophagia; potent 
               
               
                   
                   
                   
                 inhibitor of 
               
               
                   
                   
                   
                 CYP2C9; 
               
               
                   
                   
                   
                 monoamine 
               
               
                   
                   
                   
                 transporter 
               
               
                   
                   
                   
                 activator 
               
               
                 Baicalein 
                 Flavone 
                 Roots of 
                 Cardiovascular 
                 Atopic dermatitis 
                 Yun et al, Therapeutic effects of 
               
               
                   
                   
                 
                   Scutellaria 
                 
                 protective; lowers 
                   
                 Baicalein on atopic dermatitis- 
               
               
                   
                   
                   baicalensis  &amp; 
                 blood pressure; 
                   
                 like skin lesions of NC/Nga mice 
               
               
                   
                   
                 
                   Oroxylum 
                 
                 anti-thrombotic, 
                   
                 induced by dermatophagoides 
               
               
                   
                   
                 
                   indicum 
                 
                 anti proliferative 
                   
                 pteronyssinus. Int 
               
               
                   
                   
                   
                 and anti- 
                   
                 Immunopharmacol. 2010 
               
               
                   
                   
                   
                 mitogenic; 
                   
                 Sep; 10(9): 1142-8 
               
               
                   
                   
                   
                 antioxidant; 
                   
                 Srinivas NR, Baicalin, an 
               
               
                   
                   
                   
                 prostaglandin 
                   
                 emerging multi-therapeutic agent: 
               
               
                   
                   
                   
                 antagonis; free 
                   
                 pharmacodynamics, 
               
               
                   
                   
                   
                 radical scavenger; 
                   
                 pharmacokinetics, and 
               
               
                   
                   
                   
                 eNOS inhibition: 
                   
                 considerations from drug 
               
               
                   
                   
                   
                 ICAM 
                   
                 development perspectives. 
               
               
                   
                   
                   
                 expression↓ 
                   
                 Xenobiotica. 2010 
               
               
                   
                   
                   
                   
                   
                 May; 40(5): 357-67 
               
               
                 Betulinic acid 
                 Pentacyclic 
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                 Anti-retroviral, 
                 To protect foods 
                 Bracco et al, Production and use 
               
               
                   
                 triterpenoid 
                 species of plants, 
                 anti-malarial, and 
                 against oxidative 
                 of natural antioxidants. Journal of 
               
               
                   
                   
                 principally the 
                 anti-inflammatory 
                 rancidity. 
                 the American Oil Chemists&#39; 
               
               
                   
                   
                 white birch; also 
                 properties; 
                   
                 Society 1981, 58 (6): 686-690 
               
               
                   
                   
                 present in 
                 potential 
               
               
                   
                   
                 rosemary extracts 
                 anticancer agent, 
               
               
                   
                   
                   
                 by inhibition of 
               
               
                   
                   
                   
                 topoisomerase 
               
               
                 Biochanin A 
                 Phenolic 
                 
                   Ganoderma 
                 
                 Potent ligands of 
                 Skin 
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                 sprouts, peanuts, 
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                 chickpea and in 
                 CYP19 expression 
                   
                 Lin et al, Topical isoflavones 
               
               
                   
                   
                 other legumes. 
                 and aromatase 
                   
                 provide effective photoprotection 
               
               
                   
                   
                   
                 activity; anti- 
                   
                 to skin. Photodermatol 
               
               
                   
                   
                   
                 inflammatory; 
                   
                 Photoimmunol Photomed. 2008 
               
               
                   
                   
                   
                 ↓NfkB 
                   
                 Apr; 24(2): 61-6. 
               
               
                   
                   
                   
                 translocation; 
               
               
                   
                   
                   
                 chemopreventive; 
               
               
                 Bixin 
                 Carotenoid 
                 Seeds of the fruit 
                 NA 
                 To protect 
                 Castro et al, The effects of 
               
               
                   
                   
                 of Achiote ( Bixa   
                   
                 unsaturated lipids 
                 colorifico on lipid oxidation, 
               
               
                   
                   
                   orellana ) tree 
                   
                 from oxidation; 
                 colour and vitamin E in raw and 
               
               
                   
                   
                   
                   
                 also used as a 
                 grilled chicken patties during 
               
               
                   
                   
                   
                   
                 natural colorant by 
                 frozen storage. Food Chemistry 
               
               
                   
                   
                   
                   
                 the food industry 
                 2011, 124 (1): 126-131 
               
               
                 Boldine 
                 Alkaloid 
                 Boldo tree &amp; 
                 Antioxidant, cyto- 
                 Skin lightening 
                 O&#39;Brien et al, Boldine and its 
               
               
                   
                   
                 
                   Lindera aggregata 
                 
                 protective, anti- 
                 agent. 
                 antioxidant or health-promoting 
               
               
                   
                   
                   
                 tumour promoting, 
                 Improves the 
                 properties. Chem Biol Interact. 
               
               
                   
                   
                   
                 anti-inflammatory, 
                 oxidative stability 
                 2006 Jan 5; 159(1): 1-17. 
               
               
                   
                   
                   
                 anti-diabetic, anti- 
                 of bullfrog oil 
                 Méndez et al, Fatty acid 
               
               
                   
                   
                   
                 atherogenic 
                   
                 composition, extraction, 
               
               
                   
                   
                   
                 actions, 
                   
                 fractionation, and stabilization of 
               
               
                   
                   
                   
                 vasorelaxing, 
                   
                 bullfrog ( Rana catesbeiana ) oil. 
               
               
                   
                   
                   
                 immunomodulator 
                   
                 Journal of the American Oil 
               
               
                   
                   
                   
                   
                   
                 Chemists&#39; Society (1998) 75(1): 
               
               
                   
                   
                   
                   
                   
                 79-83 
               
               
                 Caffeic acid 
                 Hydroxycinnamic 
                 Burdock, 
                 Anti-inflammatory 
                 To reduce 
                 Eymard et al, Assessment of 
               
               
                   
                 acid 
                 hawthorn, 
                 and anti-cancer, 
                 oxidation of fatty 
                 washing with antioxidant on the 
               
               
                   
                   
                 artichoke, pear, 
                 UV-protection; 
                 fish (mackerel) 
                 oxidative stability of fatty fish 
               
               
                   
                   
                 basil, thyme, 
                 lipoxygenase 
                 during storage 
                 mince during processing and 
               
               
                   
                   
                 oregano, apple, 
                 inhibitor 
                   
                 storage. J Agric Food Chem. 
               
               
                   
                   
                 coffee beans 
                   
                   
                 2010, 58(10): 6182-9. 
               
               
                 Carnosic Acid &amp; 
                 Phenolic diterpene 
                 Rosemary &amp; Sage 
                 Antioxidant; 
                 Protects skin cells 
                 Reuter et al, Sage extract rich in 
               
               
                 carnosol 
                   
                 leaves 
                 inhibits lipid 
                 against UV- 
                 phenolic diterpenes inhibits 
               
               
                   
                   
                   
                 peroxidation; 
                 induced erythema 
                 ultraviolet-induced erythema in 
               
               
                   
                   
                   
                 protects from 
                 Used as a 
                 vivo. Planta Med. 2007 
               
               
                   
                   
                   
                 carcinogens 
                 preservative (anti- 
                 Sep; 73(11): 1190-1. 
               
               
                   
                   
                   
                   
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                 antioxidant in food 
                 plant extracts for antimicrobial 
               
               
                   
                   
                   
                   
                 and nonfood 
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                 products (e.g. 
                 yeasts with dermatological 
               
               
                   
                   
                   
                   
                 toothpaste, 
                 relevance. Phytomedicine. 2007 
               
               
                   
                   
                   
                   
                 mouthwash and 
                 Aug; 14(7-8): 508-16. 
               
               
                   
                   
                   
                   
                 chewing gum) 
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                 activity of Carnosol and Ursolic 
               
               
                   
                   
                   
                   
                   
                 acid. Food Microbiology (1987) 
               
               
                   
                   
                   
                   
                   
                 4(4): 311-315 
               
               
                 b-Carotene 
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                 Anti-oxidant; anti- 
                 Protection of skin 
                 Krinsky &amp; Johnson, Carotenoid 
               
               
                   
                   
                 carrots, goji, 
                 cancer; supports 
                 from ozone- 
                 actions and their relation to health 
               
               
                   
                   
                 melon 
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                 induced 
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                 (cantaloupe), 
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                 inflammation; 
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                 mangoes, apricots, 
                 protection from 
                 protection of skin 
                 Valacchi et al, Beta-carotene 
               
               
                   
                   
                 Persimmon, 
                 free radicals; 
                 from infra-red- 
                 prevents ozone-induced 
               
               
                   
                   
                 spinach, kale, and 
                 cardio protection; 
                 induced free 
                 proinflammatory markers in 
               
               
                   
                   
                 many others 
                 bone health 
                 radicals; 
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                 treatment of 
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                 melasma; 
               
               
                   
                   
                   
                   
                 food coloring 
               
               
                 Crocetin 
                 Carotenoid 
                   Crocus  flower and 
                 Improves quality 
                 To improve the 
                 Botsoglou et al, Effect of dietary 
               
               
                   
                 dicarboxylic acid 
                 
                   Gardenia 
                 
                 of sleep; energy 
                 oxidative stability 
                 saffron ( Crocus sativus  L.) on the 
               
               
                   
                   
                   jasminoides  fruits, 
                 booster; 
                 of egg yolks of 
                 oxidative stability of egg yolk. 
               
               
                   
                   
                 and pistil of 
                 neuroprotective; 
                 hens (fed with 
                 Br Poult Sci. 2005 
               
               
                   
                   
                 saffron 
                 anti-tumor 
                 saffron); also used 
                 Dec; 46(6): 701-7. 
               
               
                   
                   
                   
                   
                 as a natural 
               
               
                   
                   
                   
                   
                 colorant 
               
               
                 Cryptoxanthin 
                 Carotenoid 
                 Petals &amp; flowers 
                 Provitamin A; 
                 Associated with 
                 Namitha &amp; Negi Chemistry and 
               
               
                   
                 (xanthophyll) 
                 of plants in the 
                 Anti-oxidant; Free 
                 better skin 
                 biotechnology of carotenoids Crit 
               
               
                   
                   
                 genus  Physalis , 
                 radical scavenger; 
                 hydration (in men 
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                 papaya, egg yolk, 
                 chemopreventive; 
                   
                 Boelsma et al, Human skin 
               
               
                   
                   
                 butter, apples, 
                 anti-cancer; 
                   
                 condition and its associations 
               
               
                   
                   
                 squash, pumpkins, 
                 benefits 
                   
                 with nutrient concentrations in 
               
               
                   
                   
                 tangerine 
                 rheumatoid 
                   
                 serum and diet. Am J Clin Nutr. 
               
               
                   
                   
                   
                 arthritis 
                   
                 2003 Feb; 77(2): 348-55. 
               
               
                 Curcumin 
                 Phenolic 
                 
                   Curcuma longa 
                 
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                 To improve 
                 Rungphanichkul et al, 
               
               
                   
                   
                 (Turmeric) 
                 inflammatory &amp; 
                 transdermal 
                 Preparation of curcuminoid 
               
               
                   
                   
                   
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                 chemopreventive &amp; 
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                 chemotherapeutic; 
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                 inhibits iNOS, 
                   
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                 COX &amp; LOX, 
                   
                 heme oxygenase-1 in normal 
               
               
                   
                   
                   
                 induces HO-1; 
                   
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                 epigenetic agent 
                   
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                 antioxidant enzymes&#39; activity by 
               
               
                   
                   
                   vera  leaf,  Frangula   
                 antipsychotic, 
                   
                   Aloe vera  leaf active principles 
               
               
                   
                   
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                 inhibits NFkB 
                   
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                 activation &amp; 
                   
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                 ICAM expression; 
               
               
                   
                   
                   
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                 anti-herpes 
               
               
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                 To protect 
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                 gallate 
                   
                 tea 
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                 acid 
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                 orange; seeds and 
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                 cell walls of 
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                 commelinid plants 
               
               
                   
                   
                 (rice, wheat, oats, 
               
               
                   
                   
                 and pineapple) 
               
               
                 Honokiol &amp; 
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                 Antioxidative, 
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                 Carotenoid 
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                 Lee &amp; Mi, Effects, quenching 
               
               
                   
                   
                 greens, romaine 
                 degeneration, 
                 soybean oil from 
                 mechanisms, and kinetics of 
               
               
                   
                   
                 lettuce, eggs, red 
                 cataracts, visual 
                 photo-oxidation 
                 carotenoids in chlorophyll- 
               
               
                   
                   
                 pepper, pumpkin, 
                 performance 
                   
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                 mango, papaya, 
                   
                   
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                 oranges, kiwi, 
                   
                   
                 1990, 38 (8): 1630-1634 
               
               
                   
                   
                 peaches, squash, 
               
               
                   
                   
                 legumes, 
               
               
                   
                   
                 brassicates, 
               
               
                   
                   
                 prunes, sweet 
               
               
                   
                   
                 potatoes, 
               
               
                   
                   
                 honeydew melon, 
               
               
                   
                   
                 rhubarb, plum, 
               
               
                   
                   
                 avocado, pear 
               
               
                 Luteolin 
                 Biflavonoid 
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                 Strong antioxidant 
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                   Achillea 
                 
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                   millefolium , 
                 scavenger; anti- 
                 anti-pruritus 
                 behavior associated with allergic 
               
               
                   
                   
                 
                   Chamomillae 
                 
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                   canadensis , 
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                 inhibits lipid 
               
               
                   
                   
                   
                 peroxidation 
               
               
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                 Carotenoid 
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                 tomatoes, 
                 neuroprotective, 
                 carotenoid 
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                 Grapefruit, 
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                 quencher of 
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                 guava, apricots, 
                   
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                 933-941 
               
               
                   
                   
                 olive 
               
               
                 Moronic acid 
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                   Rhus javanica  (a 
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                 NA 
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                 sumac), mistletoe, 
                 also active against 
                   
                 69. Moronic Acid and Other 
               
               
                   
                   
                 frankincense, 
                 herpes simplex 
                   
                 Triterpene Derivatives as Novel 
               
               
                   
                   
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                 prunes 
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                 antimicrobial, and 
               
               
                   
                   
                   
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                 Vanillic acid 
                 Phenolic acid 
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                   Origanum vulgare , 
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                   Allium cepa , 
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                   Allium sativum , 
                   
                 hormone- 
                 hormone-stimulated 
               
               
                   
                   
                 
                   Armoracia 
                 
                   
                 stimulated 
                 melanogenesis of vanillin and 
               
               
                   
                   
                   rusticana , &amp; 
                   
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                   linearis 
                 
                   
                 fresh food 
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                 Verbascoside 
                 Phenylethanoid 
                 
                   Buddleja davidii 
                 
                 antioxidant, anti- 
                 Promotes skin 
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                 (acteoside) 
                 glycoside 
                 cell cultures 
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                 photoprotective 
                 ameliorates skin 
                 a novel antioxidant, in dermo- 
               
               
                   
                   
                   
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                 chelating, antiproliferative 
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                 topical formulations. Molecules. 
               
               
                   
                   
                   
                   
                   
                 2011 Aug 18; 16(8): 7068-80 
               
               
                 Vitexin 
                 Biflavonoid 
                 
                   Ampelopsis 
                 
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                 Inhibition of 
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                   grossedentata 
                 
                 anti-tumor, anti- 
                 adipogenesis; 
                 other flavonoids from  Spirodela   
               
               
                   
                   
                 stems;  Jatropha   
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                   curcas  leaves; 
                 hypotensive, 
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                 hawthorn herb; 
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                 2010 Oct; 24(10): 1543-8. 
               
               
                   
                   
                 
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                 investigations on vitexin. Planta 
               
               
                   
                   
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                 Med. 1981 Dec; 43(4): 396-403. 
               
               
                   
                   
                 
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                   longifolius ;  Acer   
                   
                   
                 mung bean extract and its 
               
               
                   
                   
                 
                   palmatum 
                 
                   
                   
                 constituents vitexin and 
               
               
                   
                   
                   
                   
                   
                 isovitexin on the formation of 
               
               
                   
                   
                   
                   
                   
                 advanced glycation endproducts. 
               
               
                   
                   
                   
                   
                   
                 Food Chemistry (2008) 106 (2): 
               
               
                   
                   
                   
                   
                   
                 475-481 
               
               
                 Vitamin E 
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                 Thiele &amp; Ekanayake- 
               
               
                   
                   
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                 and skin barrier 
                 Vitamin E in human skin: organ- 
               
               
                   
                   
                 vegetables, 
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                 specific physiology and 
               
               
                   
                   
                 avocado, 
                   
                 properties 
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                 To increase oil 
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                 2007 28(5-6): 646-67. 
               
               
                   
                   
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                 Kiokias et al, In Vitro Activity of 
               
               
                   
                   
                 potatoes, papayas 
                   
                   
                 Vitamins, Flavonoids, and 
               
               
                   
                   
                   
                   
                   
                 Natural Phenolic Antioxidants 
               
               
                   
                   
                   
                   
                   
                 Against the Oxidative 
               
               
                   
                   
                   
                   
                   
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                 Zeaxanthin (lutein 
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     When present, antioxidants may be present in an amount that increases the Rancimat induction time (according to the ISO Method no. 6886-2006) to greater than 3 hours, greater than 4 hours, or greater than 5 hours, or more. Natural antioxidants may be selected from botanical extracts known to have antioxidant activity. Typically, amounts from about 0.1-2% (w/w) of such extracts are sufficient to impart the desired stability to a lipophilic carrier composition. Preferably, amounts from 0.2% to 2.0% or from 0.5% to 1.5% (w/w) are present in the inventive lipophilic carrier compositions. Suitable antioxidants for use with the present invention include natural or synthetic caffeic acid and carnosic acid and mixtures thereof. Preferably, the antioxidants are  Rosmarinus officinalis  (rosemary) leaf extract and/or  Solidago virgaurea  (goldenrod) extract. Most preferable is a combination of  Rosmarinus officinalis  extract and  Solidago virgaurea  extract. When used in normal daily conditions, oils or any compounds used in formulations may be exposed to light (UV) or a combination of light, heat, and air. Furthermore, they may also be in contact with other compounds having pro-oxidative properties. In such conditions, various types of reactive oxygen species or free radicals may be generated. Antioxidants usually target specific types of reactive oxygen species or free radicals. To ensure broader protection (especially of the vegetable oil), rosemary and goldenrod extracts together may be suitable. 
     Nevertheless, rosemary extract and goldenrod extract may also be used separately. For example, either only 0.1% of rosemary extract (and no solidago extract) or only 0.1% of solidago extract (and no rosemary extract) in the lipophilic carrier composition may be used. 
     The solubilizing system of the present invention preferably includes a cosmetically acceptable alcohol such as ethanol, and preferably also octyldodecanol and a fatty acid ester of octyldodecanol, e.g., octyldodecyl oleate and/or octyldodecyl stearoyl stearate. In some embodiments, the solubilization system comprises ethanol at 2-20% (w/w) of the total solubilization system, octyldodecanol at 20-40% (w/w) of the total solubilization system, a first fatty acid ester of octyldodecanol at 20-55% (w/w) of the total solubilization system, and, optionally, a second fatty acid ester of octyldodecanol at 20-55% (w/w) of the total solubilization system. 
     Preferably, the amounts of the components of the solubilization system are chosen such that, when the solubilization system is used to prepare a lipophilic carrier composition, the ethanol is present in an amount from 2-15%, 2-10%, 2-7%, 3-10%, or 4-8% (w/w) of the lipophilic carrier composition. Preferably, the octyldodecanol is present in the lipophilic carrier composition in an amount from 15-35%, 15-30%, 20-30%, or 25-30% (w/w) of the lipophilic carrier composition. Preferably, octyldodecyl oleate is present in an amount from 15-25%, 15-20%, or 20-25% (w/w) of the lipophilic carrier composition. Preferably, octyldodecyl stearoyl stearate is present in an amount from 5-15%, 5-10%, or 10-15% (w/w) of the lipophilic carrier composition. 
     In certain embodiments, the solubilization system may contain different components from those described above. In such embodiments, the solubilization system is such that the lipophilic bioactive botanical extract may be dissolved therein, if necessary by the use of elevated temperatures (e.g., 40-100° C.), and remain dissolved as the temperature is lowered to about room temperature, at which point the vegetable oil is added. The solubilization system allows for the combining of bioactive botanical extract and vegetable oil in one composition, without unacceptable oxidation of the fatty acids in the vegetable oil. 
     Lipophilic bioactive botanical extracts can be solubilized in a lipophilic carrier composition comprising a vegetable oil using a solubilizing system as described above. In one embodiment, a first phase is prepared by combining the lipophilic bioactive botanical extract and the solubilizing system to form a mixture. The mixture is then heated to between 40° C. and 100° C. under a nitrogen atmosphere until complete solubilization of the extract, as judged by visual inspection. The solution is then cooled, preferably to a temperature of about 35-40° C., about 30-35° C., about 25-30° C., about 20-25° C., or about 15-20° C., the vegetable oil is added, and the mixture is cooled to room temperature, if not already at room temperature. A second phase is prepared separately by dissolving the antioxidant extracts in a cosmetically compatible alcohol, e.g., ethanol, and the resulting mixture is then agitated at room temperature until the extracts are dissolved. The first and second phases are then combined together under agitation until a homogenous mixture is obtained. 
     In certain embodiments, the lipophilic carrier composition of the present invention comprises more than one lipophilic bioactive botanical extract, more than one vegetable oil, or more than one antioxidant. In certain embodiments, the lipophilic carrier composition comprises two lipophilic bioactive botanical extracts, two vegetable oils, or two antioxidants. 
     
       
         
           
               
             
               
                 TABLE 3 
               
               
                   
               
               
                 Representative ranges of ingredients suitable for certain embodiments 
               
               
                 of lipophilic bioactive botanical extracts solubilized with vegetable oils 
               
               
                 (lipophilic carrier compositions). 
               
               
                 Percentages represent w/w of the total lipophilic carrier composition. 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Vegetable Oil 
                 20-40% 
               
               
                   
                 Octyldodecanol 
                 15-35% 
               
               
                   
                 Octyldodecyl Oleate, 
                 15-25% 
               
               
                   
                 Octyldodecyl Stearoyl Stearate 
                  5-15% 
               
               
                   
                 Lipophilic bioactive botanical extract 
                 0.1-5.0%  
               
               
                   
                 Ethanol 
                  2-15% 
               
               
                   
                 Antioxidant 
                 0.01-2.0%  
               
               
                   
                   
               
            
           
         
       
     
     In certain embodiments, the vegetable oil is present at 20-25%, 25-30%, 30-35%, or 35-40% (w/w). In certain embodiments, the octyldodecanol is present at 15-20%, 20-25%, 25-30%, or 30-35% (w/w). In certain embodiments, the octyldodecyl oleate is present at 15-20% or 20-25% (w/w). In certain embodiments, the octyldodecyl stearoyl stearate is present at 5-10% or 10-15% (w/w). In certain embodiments, the lipophilic bioactive botanical extract is present at 0.1-0.5%, 0.5-1%, 1-2%, 2-3%, 3-4%, or 4-5% (w/w). 
     The presolubilized extracts in lipophilic carrier compositions are easily incorporated into a wide variety of product types that include but are not limited to solid and liquid compositions intended for topical use such as lotions, creams, gels, sticks, sprays, shaving creams, ointments, cleansing liquid washes and solid bars, pastes, powders, mousses, masks, peels, makeup, and wipes. The compositions may be used in conjunction with other devices such as skin abrading, skin massaging, or electro-stimulation devices, light-therapy devices, ultrasound devices, radio frequency devices, thermal/cooling devices, iontophoresis devices, and micro-penetration devices. 
     EXAMPLES 
     To assess the efficacy of skin protective, soothing and repairing effects as well as the oxidation stability of a cosmetic topical product incorporating the inventive lipophilic carrier compositions, the following generic formulations were prepared. In a first embodiment, a lipophilic bioactive botanical extract of  Cnidium monnieri  fruit in a lipophilic carrier composition that included  Echium plantaginium  seed oil was used to prepare a cosmetic formulation that was evaluated for skin protective, soothing and repairing effect upon exposure to a chemical agent. 
     In a second embodiment, a lipophilic bioactive botanical extract of  Cnidium monnieri  fruit in a lipophilic carrier composition that included  Echium plantaginium  seed oil was used to prepare a cosmetic formulation that was evaluated for skin protective, soothing and repairing effect upon exposure to ultraviolet radiation. 
     The following general formulations were prepared in order to assess the stability and efficacy of the inventive compositions: 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Formulations 
               
            
           
           
               
               
               
               
               
            
               
                 Ingredients 
                 Formula 1 
                 Formula 2 
                 Formula 3 
                 Formula 4 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Total 
                 100.00 
                 100.00 
                 100.00 
                 100.00 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Trade 
                   
                   
                   
                   
               
               
                 INCI Name 
                 Name 
               
               
                   
               
               
                 Water Phase (Phase A): 
               
               
                 Water 
                   
                 96 
                 95.3 
                 95.3 
                 95.3 
               
               
                 Sodium Polyacrylate 
                 Cosmedia 
                 0.6 
                 0.6 
                 0.6 
                 0.6 
               
               
                   
                 SP 
               
               
                 Preservative 
                 Euxil K300 
                 0.4 
                 0.4 
                 0.4 
                 0.4 
               
               
                 Oil Phase (Phase B): 
               
               
                 Cetearyl Alcohol 
                 Hydrenol D 
                 2 
                 2 
                 2 
                 2 
               
               
                 Ceteareth-20 
                 Eumulgin 
                 1 
                 1 
                 1 
                 1 
               
               
                   
                 B2 
               
               
                 Active (Part C): 
               
               
                 Part C1 
               
               
                 Lipophilic bioactive extract‡ 
                   
                 0 
                 0 
                 0 
                 0.01 
               
               
                 Octyldodecanol 
                   
                 0 
                 0 
                 0.63 
                 0.62 
               
               
                 Octyldodecyl Oleate 
                   
                 0 
                 0 
                 0.39 
                 0.39 
               
               
                 Octyldodecyl Stearoyl 
                   
                 0 
                 0 
                 0.18 
                 0.18 
               
               
                 Stearate 
               
               
                 Part C2 
               
               
                 Vegetable Oil† 
                   
                 0 
                 0.7 
                 0.7 
                 0.7 
               
               
                 Rosemary leaf extract 
                   
                 0 
                 0 
                 0.002 
                 0.002 
               
               
                 Goldenrod Extract 
                   
                 0 
                 0 
                 0.002 
                 0.002 
               
               
                 Ethanol 
                   
                 0 
                 0 
                 0.096 
                 0.096 
               
               
                 Total Oil Loading: 
                   
                 3.00 
                 3.70 
                 3.70 
                 3.70 
               
               
                 Total Water Loading: 
                   
                 97.00 
                 96.30 
                 96.30 
                 96.30 
               
               
                   
               
               
                 Exemplified lipophilic bioactive botanical extract: Example 6:  Cnidium monnieri  Fruit Extract; Example 7:  Paeonia suffruticosa  Root extract. 
               
               
                   † Exemplified Vegetable Oil Example 6:  Echium plantagineum  seed oil; Example 7:  Ribes nigrum  (black currant) seed oil. 
               
            
           
         
       
     
     Comparative Example 1 
     Method of Preparing Base Cream Formula 1 
     Phase A and Phase B (see Table 4) were prepared separately by weighing their ingredients at room temperature, warming the ingredients to 75° C., and then combining the respective ingredients of the two phases with stirring. The phases were then warmed to about 75° C. and combined with agitation until homogenous. 
     Comparative Example 2 
     Method of Preparing Formula 2, Base Cream Plus Vegetable Oil 
     Phase A and Phase B were prepared separately by weighing their ingredients at room temperature, warming the ingredients to 75° C., and then combing the respective ingredients of the two phases with stirring. The phases were then warmed to about 75° C. and combined with homogenization until homogenous. Vegetable oil was then added at 75° C. with agitation until homogenous. 
     Comparative Example 3 
     Method of Preparing Formula 3, Base Cream, Vegetable Oil Plus Solubilization System and Antioxidants 
     Phase A and Phase B were prepared separately by weighing their ingredients at room temperature, warming the ingredients to 75° C., and then combing the respective ingredients of the two phases with stirring. The phases were then warmed to about 75° C. and combined with agitation until homogenous. Part C was prepared by separately combining the respective ingredients of Parts C1 (lipophilic bioactive extract is not included) and C2 with stirring and then combining Parts C1 and C2 at room temperature. Part C was then added to the mixture of Phase A and Phase B and homogenized. 
     Example 4 
     Method of Preparing Formula 4, Active Cream Incorporating Inventive Presolubilized Lipophilic Bioactive Botanical Extract in a Lipophilic Carrier Composition 
     A presolubilized lipophilic bioactive botanical extract was prepared as follows: Part C was prepared by first combining the lipophilic bioactive botanical extract in a mixture of octyldodecanol, octyldodecyl oleate, and octyldodecyl stearoyl stearate while heating to between 65-70° C. under a nitrogen atmosphere until complete solubilization of the extract resulting in a clear or translucent solution. The solution was then cooled to 45° C., the vegetable oil was added, and the mixture was cooled to room temperature. A mixture of the antioxidants dissolved in ethanol was then added to the cooled solution with agitation. This presolubilized lipophilic bioactive botanical extract in a lipophilic carrier composition (Part C) was then combined with a base cream of Formula 1 (comparative example 1) and homogenized. 
     Example 5 
     Protective Effect of Antioxidants 
     Experiments were performed using the Rancimat method (Method: ISO 6886-2006) to assess the efficacy of a lipophilic carrier composition comprising  Rosmarinus officinalis  leaf extract and  Solidago virgaurea  (Goldenrod) extract to protect oil derived from  Echium plantagineum  seeds or from  Ribes nigrum  seeds from oxidation when the oil and the antioxidants are present in the lipophilic carrier composition. In the Rancimat method, a sample of oil is heated under atmospheric pressure, and air is allowed to bubble through the oil at a selected temperature. Under these conditions, a lipoperoxidative reaction occurs and the short-chain volatile acids produced thereby are recovered and measured conductometrically in distilled water. The time required to produce a sudden increase in conductivity, due to the formation of volatile acids, determines an induction time which can be defined as a measure of the oxidative stability of the oil. A Metrohm Rancimat model 743® (Herisau, Switzerland) was used. Results obtained showed that the presence of  Rosmarinus officinalis  leaf extract and  Solidago virgaurea  extract protected the oil derived from  Echium plantagineum  seeds (Table 5) or from  Ribes nigrum  seed extract (Table 6) from degradation induced by heat and air contact. Furthermore, it was demonstrated that the addition of other ingredients of the lipophilic carrier composition, e.g., a  Cnidium monnieri  fruit extract or a  Paeonia suffruticosa  root extract, does not negatively affect the stability of  Echium plantagineum  oil or  Ribes nigrum  oil towards oxidation. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Effect of various components of the  Echium plantagineum  seed oil-based compositions on Rancimat time. 
               
            
           
           
               
               
               
            
               
                   
                 octyldodecyl 
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 
                   Echium 
                 
                   
                 oleate, 
                   
                 
                   Rosmarinus 
                 
                 
                   Solidago 
                 
                 
                   Cnidium 
                 
                   
               
               
                 
                   plantagineum 
                 
                   
                 octyldodecyl 
                   
                 
                   officinalis 
                 
                 
                   virgaurea 
                 
                 
                   monnieri 
                 
               
               
                 seed oil (%) 
                 Octyldodecanol 
                 stearoyl 
                 Ethanol 
                 (Rosemary) leaf 
                 (Goldenrod) 
                 Fruit 
                 Rancimat 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Source 1 
                 Source 2 
                 (%) 
                 stearate (%) 
                 (%) 
                 extract (%) 
                 extract (%) 
                 Extract (%) 
                 time (hr) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 100  
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 0.3 
               
               
                 — 
                 100 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 0.1 
               
               
                 35 
                 — 
                 29.5 
                 30 
                 4.8 
                 — 
                 — 
                 — 
                 3.3 
               
               
                 35 
                 — 
                 29.5 
                 30 
                 4.8 
                 0.1 
                 0.1 
                 — 
                 19.6 
               
               
                 35 
                 — 
                 29.5 
                 30 
                 4.8 
                 0.1 
                 0.1 
                 0.5 
                 20.4 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Effect of various components of the  Ribes nigrum  (black currant) seed oil-based compositions on Rancimat time. 
               
            
           
           
               
               
               
            
               
                   
                 octyldodecyl 
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 
                   Ribes nigrum 
                 
                   
                 oleate, 
                   
                 
                   Rosmarinus 
                 
                 
                   Solidago 
                 
                 
                   Paeonia 
                 
                   
               
               
                 (Black Currant) 
                   
                 octyldodecyl 
                   
                 
                   officinalis 
                 
                 
                   virgaurea 
                 
                 
                   suffruticosa 
                 
               
               
                 seed oil (%) 
                 Octyldodecanol 
                 stearoyl 
                 Ethanol 
                 (Rosemary) leaf 
                 (Goldenrod) 
                 Root 
                 Rancimat 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Source 1 
                 Source 2 
                 (%) 
                 stearate (%) 
                 (%) 
                 extract (%) 
                 extract (%) 
                 extract (%) 
                 time (hr) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 100  
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 0.2 
               
               
                 — 
                 100 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 0.1 
               
               
                 35 
                 — 
                 29 
                 30 
                 4.8 
                 — 
                 — 
                 — 
                 7.4 
               
               
                 35 
                 — 
                 29 
                 30 
                 4.8 
                 0.1 
                 0.1 
                 — 
                 30.7 
               
               
                 35 
                 — 
                 29 
                 30 
                 4.8 
                 0.1 
                 0.1 
                 1.0 
                 33.4 
               
               
                   
               
            
           
         
       
     
     Summary of Clinical Trials 
     Several lipophilic bioactive botanical extracts solubilized using the solubilization system described herein and present in a lipophilic carrier composition comprising vegetable oil were tested in human clinical trials for efficacy. These tests showed safety and efficacy in preventing and treating skin erythema and lessening the reduction of the skin barrier function after exposure to radiation and chemical stress. 
     Example 6 
     Echium Plantaginium-Based Active Cream with Cnidium Monnieri Fruit Extract 
     Formulas 1-4 as described above were prepared, wherein the lipophilic bioactive botanical extract was  Cnidium monnieri  fruit extract and the vegetable oil was  Echium plantaginium  seed oil. 
     The skin protective, soothing and repairing effect of a cosmetic topical product incorporating the presolubilized  Cnidium monnieri  fruit extract in a lipophilic carrier composition comprising  Echium plantaginium  seed oil upon exposure of the skin to a chemical agent was evaluated by applying topical treatments (2 mg/cm 2 ) of each of Formulas 1 through 4. 
     Example 6 
     A Skin Protective Effect Upon Exposure to Chemical Agent 
     The test was carried out on a panel of 10 healthy volunteers. Selected skin areas were kept untreated and unexposed to the chemical agent as controls. Other skin areas were treated with the relevant formulation for a period of 10 days (from Day 1 to Day 10) preceding exposure to the chemical agent. 
     On Day 11, a solution of sodium lauryl sulfate (SLS) was applied to the skin using Finn chambers to chemically aggress the skin. Finn chambers were kept in contact with the skin for 20±4 hours. On Day 12, the Finn chambers were removed and skin erythema and the skin barrier function were assessed to measure the protective effect of the treatment with the formulations. The skin barrier function was assessed by the measurement of trans-epidermal water loss (TEWL) using the TEWAMETER 300® (Courage+Khazaka, electronic GmbH) apparatus and skin erythema was measured using the MEXAMETER® MX 18 (Courage+Khazaka, electronic GmbH) apparatus. Results are shown in Tables 7 and 8. 
     Application of the  Echium Plantaginium  Active Cream with  Cnidium Monnieri  Fruit Extract prior to the application of the SLS-containing Finn chambers resulted in a reduction of the SLS-induced increase in TEWL (Table 7). This demonstrated that the  Echium Plantaginium  Active Cream with  Cnidium Monnieri  Fruit Extract (made with a lipophilic carrier composition of the present invention) can protect the skin barrier function from a chemical aggression. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Effect of a topical composition incorporating a presolubilized 
               
               
                   Cnidium monnieri  fruit extract in a lipophilic carrier composition 
               
               
                 comprising  Echium plantagineum  seed oil on the prevention of 
               
               
                 chemically-induced skin barrier damage - reduction of TEWL increase 
               
               
                 when cream formulations produced with the lipophilic carrier 
               
               
                 composition are applied as a preventive treatment. 
               
            
           
           
               
               
            
               
                   
                 Chemically-induced 
               
               
                   
                 increase in TEWL (%) 1   
               
               
                   
                   
               
            
           
           
               
               
            
               
                 Control (untreated skin) 
                 400.5 
               
               
                 Formula 1: base cream 
                 350.6 
               
               
                 Formula 2: Formula 1 with 
                 319.3 (p = 0.020) vs Placebo 5   
               
               
                   Echium plantagineum  seed oil 
                 (p = 0.011) vs Active cream 6   
               
               
                 Formula 3: Formula 2 with  
                 331.3 (p = 0.028) vs Placebo 3   
               
               
                 antioxidants and solubilization system 
                 (p = 0.016) vs Active cream 4   
               
               
                 Active Cream Formula 4: Formula 3 with 
                 289.9 (p &lt; 0.002) vs Placebo 2   
               
               
                 presolubilized  Cnidium monnieri   
               
               
                 fruit extract 
               
               
                   
               
               
                   1 Compared to non-chemically stressed skin (baseline) 
               
               
                   2 Statistically significant when compared to Placebo cream 
               
               
                   3 Statistically significant when compared to Placebo cream 
               
               
                   4 Statistically significant when compared to Active cream 
               
               
                   5 Statistically significant when compared to Placebo cream 
               
               
                   6 Statistically significant when compared to Active cream 
               
            
           
         
       
     
     The measurement of skin erythema (Table 8) also demonstrated that the application of the  Echium plantaginium  Active Cream with  Cnidium monnieri  Fruit Extract can protect from chemically-induced skin erythema. 
     The above results demonstrate that a topical composition comprising a lipophilic carrier composition of the present invention that was produced using a presolubilized  Cnidium monnieri  fruit extract provided better protection against an increase in TEWL than the same composition lacking certain ingredients present in the inventive composition. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Effect of a topical composition incorporating a presolubilized 
               
               
                   Cnidium monnieri  fruit extract in a lipophilic carrier composition 
               
               
                 comprising  Echium plantagineum  seed oil on chemical agent-induced 
               
               
                 skin erythema when applied as a cream formulation produced with 
               
               
                 the lipophilic carrier composition as a preventive treatment 
               
            
           
           
               
               
            
               
                   
                 Chemically-induced increase 
               
               
                   
                 in skin erythema (%) 1   
               
               
                   
                   
               
            
           
           
               
               
            
               
                 Control (untreated skin) 
                 59.0 
               
               
                 Formula 1: base cream 
                 51.2 
               
               
                 Formula 2: Formula 1 with 
                 43.8 (p = 0.030) vs Placebo 5   
               
               
                   Echium plantagineum  seed oil 
                 (p = 0.004) vs Active cream 6   
               
               
                 Formula 3: Formula 2 with 
                 41.3 (p = 0.002) vs Placebo 3   
               
               
                 antioxidants and solubilization system 
                 (p = 0.033) vs Active cream 4   
               
               
                 Active Cream Formula 4: Formula 3 with 
                 36.8 (p &lt; 0.001) vs Placebo 2   
               
               
                 presolubilized  Cnidium monnieri  fruit 
               
               
                 extract 
               
               
                   
               
               
                   1 Compared to non-chemically stressed skin (baseline) 
               
               
                   2 Statistically significant when compared to Placebo cream 
               
               
                   3 Statistically significant when compared to Placebo cream 
               
               
                   4 Statistically significant when compared to Active cream 
               
               
                   5 Statistically significant when compared to Placebo cream 
               
               
                   6 Statistically significant when compared to Active cream 
               
            
           
         
       
     
     The above results demonstrate that a topical composition comprising a lipophilic carrier composition of the present invention that was produced using a presolubilized  Cnidium monnieri  fruit extract provided better protection against chemically-induced skin erythema than the same composition lacking certain ingredients present in the inventive composition. 
     Example 6B 
     Skin Soothing and Repairing Effect after Exposure to Chemical Agent 
     In another experiment, some skin areas were treated only upon removal of the SLS-containing Finn chambers (Day 12). In this case, skin was post-treated with one application (2 mg/cm 2 ) of the Placebo cream prepared according to Formula 1 or the  Echium Plantaginium  Active Cream with  Cnidium Monnieri  Fruit Extract prepared according to Formula 4. The repairing effect of the treatments was assessed for skin barrier function and for skin erythema at time 30 minutes, 1 hour, 2 hours and 24 hours after the topical application of the cream formulations. The skin barrier function and erythema were assessed as described in Example 6A above. Results are shown in Tables 9 and 10 and reveal that applying the active cream formulation after the chemical stress with SLS significantly reduces the extent of skin barrier damage. This demonstrates the therapeutic action of the active cream formulation in promoting skin barrier function. The data on skin erythema in Table 10 also demonstrate that the therapeutic application of the active cream formulation can help repair chemically-induced skin erythema. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Effect of a topical composition incorporating a presolubilized 
               
               
                   Cnidium monnieri  fruit extract in a lipophilic carrier composition 
               
               
                 comprising  Echium plantagineum  seed oil on chemically-induced 
               
               
                 skin barrier damage when cream formulations are applied after 
               
               
                 chemical damage. The therapeutic effect was measured at various 
               
               
                 time periods after the cream formulation application. 
               
            
           
           
               
               
            
               
                   
                 Reduction of chemically-induced skin increase in 
               
               
                   
                 TEWL upon product application (%) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 After 
               
               
                   
                 After 30 min 
                 After 1 hour 
                 After 2 hour 
                 24 hour 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                 Control 
                 −1.3 
                 −6.4 
                 −11.2 
                 −23.2 
               
               
                 (untreated 
               
               
                 skin) 
               
               
                 Base cream: 
                 −8.1 
                 −8.4 
                 −13.2 
                 −20.6 
               
               
                 Formula 1 
               
               
                 Active cream: 
                 −18.5 
                 −24.4 
                 −24.5 
                 −28.8 
               
               
                 Formula 4 
                 (p = 0.005) 1   
                 (p = 0.007) 1   
                 (p = 0.006) 1   
                 (p = 0.009) 1   
               
               
                   
               
               
                   1 Statistically significant when compared to Placebo cream 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Effect of a topical composition incorporating a presolubilized 
               
               
                   Cnidium monnieri  fruit extract in a lipophilic carrier composition 
               
               
                 comprising  Echium plantagineum  seed oil on chemically-induced 
               
               
                 skin erythema when cream formulations are applied after chemical 
               
               
                 damage. The therapeutic effect was measured at various time 
               
               
                 periods after the cream formulation application 
               
            
           
           
               
               
            
               
                   
                 Reduction of chemically-induced skin 
               
               
                   
                 erythema upon product application (%) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 After 
               
               
                   
                 After 30 min 
                 After 1 hour 
                 After 2 hour 
                 24 hour 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                 Control 
                 3.7 
                 4.1 
                 4.4 
                 2.4 
               
               
                 (untreated 
               
               
                 skin) 
               
               
                 Base cream: 
                 −4.3 
                 −5.5 
                 −5.6 
                 −6.1 
               
               
                 Formula 1 
               
               
                 Active cream: 
                 −5.2 
                 −6.7 
                 −7.0 
                 −9.2 
               
               
                 Formula 4 
                 (p = 0.463) 2   
                 (p = 0.510) 2   
                 (p = 0.394) 2   
                 (p = 0.032) 1   
               
               
                   
               
               
                   1 Statistically significant when compared to Placebo cream 
               
               
                   2 Not statistically significant when compared to Placebo cream 
               
            
           
         
       
     
     The data shown in Tables 9 and 10 demonstrate that a topical composition comprising a lipophilic carrier composition of the present invention that was produced using a presolubilized  Cnidium monnieri  fruit extract provided better protection against an increase in TEWL as well as better protection against chemically-induced skin erythema than the same composition lacking certain ingredients present in the inventive composition. 
     Example 7 
     Ribes Nigrum-Based Active Cream with Paeonia Suffruticosa Root Extract 
     Formulas 1-4 as described above were prepared wherein the lipophilic bioactive botanical extract was  Paeonia suffruticosa  root extract and the vegetable oil was  Ribes nigrum  seed oil. 
     Example 7A 
     Skin Protective, Soothing Effect Upon UV Exposure 
     The skin protective, soothing and repairing effect of a cosmetic topical product incorporating the presolubilized  Paeonia suffruticosa  root extract in a lipophilic carrier composition comprising  Ribes nigrum  seed oil upon UV exposure (UVA+B using a solar simulator) was evaluated by applying topical treatments (2 mg/cm 2 ) of each of Formulas 1 through 4. 
     The UV exposure intensity was calibrated to induce 1.5 MED. 1 MED, or Minimal Erythema Dose, corresponds to the minimum amount of UVB radiation required to produce redness 24 hours after skin exposure. The test was carried out on a panel of 10 healthy volunteers. Selected skin areas were kept untreated and unexposed to UV as controls. Other skin areas were treated with the relevant formulation for a period of 10 days (from Day 1 to Day 10) preceding UV exposure. 
     On Day 11, specific skin sites were exposed to UV. On Day 12, 20±4 hours after UV exposure, skin erythema and the skin barrier function were assessed to measure the protective effect of the treatments. The skin barrier function was assessed by the measurement of trans-epidermal water loss (TEWL) using the TEWAMETER 300® apparatus (Courage+Khazaka, electronic GmbH) and skin erythema was measured using the MEXAMETER® MX 18 apparatus (Courage+Khazaka, electronic GmbH). The results are reported in Tables 11 and 12. 
     The application of the cosmetic topical product incorporating the presolubilized  Paeonia suffruticosa  root extract in a  Ribes nigrum  seed oil prior to the application of UV light resulted in a reduction of the UV-induced increase in TEWL (Table 11). The most favorable results were observed for the active cream formulation, which was produced by using the solubilization system of the present invention to presolubilize the  Paeonia suffruticosa  root extract, followed by addition of the  Ribes nigrum  seed oil to form a lipophilic carrier composition comprising both the  Paeonia suffruticosa  root extract and the  Ribes nigrum  seed oil. This lipophilic carrier composition was incorporated into the base formulation to give the active cream. These results demonstrate that the active cream formulation can protect against UV-induced skin barrier function loss. 
     The measurement of skin erythema (Table 12) demonstrated that the application of the active cream formulation can protect from UV-induced skin erythema. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Effect of a topical composition incorporating a presolubilized 
               
               
                   Paeonia suffruticosa  root extract in a lipophilic carrier 
               
               
                 composition comprising  Ribes nigrum  (black currant) seed oil 
               
               
                 on the prevention of UV-induced skin barrier damage - reduction 
               
               
                 of TEWL increase when cream formulations are applied as a 
               
               
                 preventive treatment. 
               
            
           
           
               
               
            
               
                   
                 UV-induced increase 
               
               
                   
                 in TEWL (%) 1   
               
               
                   
                   
               
            
           
           
               
               
            
               
                 Control (untreated skin) 
                 79.5 
               
               
                 Formula 1: placebo base cream 
                 81.2 
               
               
                 Formula 2: Formula 1 with  Ribes   
                 51.9 (p = 0.001) vs Placebo 5   
               
               
                   nigrum  (black currant) seed carrier oil 
                 (p = 0.612) vs Active cream 6   
               
               
                 Formula 3: Formula 2 with 
                 50.7 (p = 0.002) vs Placebo 3   
               
               
                 antioxidants and solubilization system 
                 (p = 0.705) vs Active cream 4   
               
               
                 Active Cream Formula 4: Formula 3 
                 48.0 (p &lt; 0.002) 2   
               
               
                 with presolubilized  Paeonia   
               
               
                   suffruticosa  root extract 
               
               
                   
               
               
                   1 Compared to non-irradiated skin (baseline) 
               
               
                   2 Statistically significant when compared to Placebo cream 
               
               
                   3 Statistically significant when compared to Placebo cream 
               
               
                   4 Non-statistically significant when compared to Active cream 
               
               
                   5 Statistically significant when compared to Placebo cream 
               
               
                   6 Non-statistically significant when compared to Active cream 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Effect of a topical composition incorporating a presolubilized 
               
               
                   Paeonia suffruticosa  root extract in a lipophilic carrier composition 
               
               
                 comprising  Ribes nigrum  (black currant) seed oil on UV-induced 
               
               
                 skin erythema when applied as a cream formulation 
               
               
                 as a preventive treatment. 
               
            
           
           
               
               
            
               
                   
                 UV-induced increase in 
               
               
                   
                 skin erythema (%) 1   
               
               
                   
                   
               
            
           
           
               
               
            
               
                 Control (untreated skin) 
                 62.1 
               
               
                 Formula 1: base cream 
                 57.3 
               
               
                 Formula 2: Formula 1 with  Ribes nigrum   
                 44.4 (p = 0.012) vs Placebo 5   
               
               
                 (Black Currant) seed carrier oil 
                 (p = 0.127) vs Active cream 6   
               
               
                 Formula 3: Formula 2 with antioxidants 
                 36.5 (p = 0.014) vs Placebo 3   
               
               
                 and solubilization system 
                 (p = 0.470) vs Active cream 4   
               
               
                 Active Cream Formula 4: Formula 3 with 
                 33.0 (p &lt; 0.002) 2   
               
               
                 presolubilized  Paeonia suffruticosa  root 
               
               
                 extract 
               
               
                   
               
               
                   1 Compared to non-irradiated skin (baseline) 
               
               
                   2 Statistically significant when compared to Placebo cream 
               
               
                   3 Statistically significant when compared to Placebo cream 
               
               
                   4 Non-statistically significant when compared to Active cream 
               
               
                   5 Statistically significant when compared to Placebo cream 
               
               
                   6 Non-statistically significant when compared to Active cream 
               
            
           
         
       
     
     Example 7B 
     Skin Soothing and Repairing Effect after Uv Exposure 
     In another experiment, some skin areas were treated only after exposure of the skin to UV (Day 12). In this case, skin was post-treated with one application (2 mg/cm 2 ) of the Placebo cream prepared according to Formula 1 or the Active Cream prepared according to Formula 4. The repairing effect of the treatments was assessed for skin barrier function and for skin erythema at time 30 minutes, 1 hour, 2 hours and 24 hours upon the topical application of the cream formulations. The skin barrier function and erythema were assessed as described above. Results are reported in Tables 13 and 14 and show that applying the active cream formulation after UV exposure significantly reduces the extent of skin barrier damage (Table 13). This provides evidence for the therapeutic action of the active cream formulation in promoting skin barrier function. The measurement of skin erythema (Table 14) also demonstrated that the therapeutic application of the active cream formulation can help repair damage from UV-induced skin erythema. 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Effect of a topical composition incorporating a presolubilized 
               
               
                   Paeonia suffruticosa  root extract in a lipophilic carrier composition 
               
               
                 comprising  Ribes nigrum  (black currant) seed oil on UV-induced skin 
               
               
                 barrier damage when cream formulations were applied after UV - 
               
               
                 therapeutic effect measured at various time periods after the cream 
               
               
                 formulation application. 
               
            
           
           
               
               
            
               
                   
                 Reduction of UV-induced skin increase in 
               
               
                   
                 TEWL upon product application (%) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 After 
               
               
                   
                 After 30 min 
                 After 1 hour 
                 After 2 hour 
                 24 hour 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                 Control 
                 −0.6 
                 1.2 
                 −0.8 
                 −6.2 
               
               
                 (untreated 
               
               
                 skin) 
               
               
                 Placebo Base 
                 −10.1 
                 −9.8 
                 −12.3 
                 −10.2 
               
               
                 cream: 
               
               
                 Formula 1 
               
               
                 Active cream: 
                 −16.7 
                 −18.2 
                 −19.7 
                 −28.7 
               
               
                 Formula 4 
                 (p = 0.003) 1   
                 (p = 0.001) 1   
                 (p = 0.003) 1   
                 (p &lt; 0.001) 1   
               
               
                   
               
               
                   1 Statistically significant when compared to Placebo cream 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 Effect of a topical composition incorporating a presolubilized 
               
               
                   Paeonia suffruticosa  root extract in a lipophilic carrier composition 
               
               
                 comprising  Ribes nigrum  seed oil on UV-induced skin erythema 
               
               
                 when cream formulations are applied after UV - therapeutic effect 
               
               
                 measured at various time periods after the cream formulation application. 
               
            
           
           
               
               
            
               
                   
                 Reduction of UV-induced skin erythema 
               
               
                   
                 upon product application (%) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 After 
               
               
                   
                 After 30 min 
                 After 1 hour 
                 After 2 hour 
                 24 hour 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                 Control 
                 0.7 
                 −1.1 
                 −3.3 
                 −11.0 
               
               
                 (untreated 
               
               
                 skin) 
               
               
                 Placebo base 
                 −6.2 
                 −9.1 
                 −10.3 
                 −11.7 
               
               
                 cream: 
               
               
                 Formula 1 
               
               
                 Active cream: 
                 −8.7 
                 −12.1 
                 −16.3 
                 −19.5 
               
               
                 Formula 4 
                 (p = 0.046) 1   
                 (p = 0.010) 1   
                 (p = 0.008) 1   
                 (p = 0.007) 1   
               
               
                   
               
               
                   1 Statistically significant when compared to Placebo cream 
               
            
           
         
       
     
     Example 7C 
     Reduction of the Appearance of Age Spots (Melasma) 
     Another experiment demonstrated the efficacy of a cosmetic topical product incorporating the presolubilized  Paeonia suffruticosa  root extract in a lipophilic carrier composition comprising  Ribes nigrum  seed oil in reducing the appearance of age spots (also known as brown spots, liver spots, melasma, solar lentigo, freckles, senile freckles, lengitines or chloasma “mask of pregnancy”). Age spots are hyperpigmented skin areas that may arise from over UV-exposure, in pregnant women, or in subjects undergoing hormonal replacement therapies. Their visual appearance is due to an accumulation of melanocytes and/or an excessive production of melanin pigments and this phenomenon becomes more apparent with increasing age. The efficacy of the cosmetic topical products disclosed herein for the treatment of age spots was evaluated by applying topical treatments (2 mg/cm 2 ) of each of Formula 1 (Placebo cream) and Formula 4 (Active cream). 
     The test was carried out on a panel of 15 healthy volunteers with visible age spots. Formulas 1 and 4 were tested as a split-face clinical protocol where each Formula was applied on separate sides of the face down up to the upper chest area, twice daily. Evaluation of age spot appearance was measured at Day 0 (baseline) and after 30 (Day 30) and 60 days (Day 60) of product applications. The MEXAMETER® MX 18 apparatus (Courage+Khazaka, electronic GmbH) was used to measure the age spot color based on specific light wave-length absorption by melanin-related chromophores. Results are expressed as variation of the melanin index. The Spectrophotometer CM-700d (Konica Minolta Optics, Inc) was chosen to measure the age spot color intensity by computing specific light wave-length reflection of L* parameter (skin brightness) and b* parameter (variation from blue to yellow color) as the Individual Typology Angle)(ITA°). An increase in ITA° is indicative of a color intensity reduction. A separate individual measurement of the L* parameter was also performed to assess variations in general skin color lightness. 
     As a more visual assessment of the effect the treatments, a skilled dermatologist evaluated, in a blind fashion, the visual reduction of age spot appearance and the increase in skin complexion (color homogeneity). The evaluation criteria were as follows: 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 15 
               
               
                   
                   
               
               
                   
                 Dermatologist clinical evaluation at Day 30 and 
                   
               
               
                   
                 Day 60 in comparison to baseline 
                 Score 
               
               
                   
                   
               
             
            
               
                   
                 No variation 
                 1 
               
               
                   
                 Slight improvement 
                 2 
               
               
                   
                 Moderate improvement 
                 3 
               
               
                   
                 Remarkable improvement 
                 4 
               
               
                   
                   
               
            
           
         
       
     
     Topical applications of the Active cream statistically reduced the melanin index (age spot pigment density) and increased the lightening of age spots present in the face, neck, and upper chest areas (Table 16 and 17, respectively). Furthermore, treatment with the Active cream statistically improved the general skin lightness (Table 18). Dermatologist assessments have shown that a reduction of age spot color appearance (Table 19) and an improvement in skin complexion (Table 20) can be visually observed already after 30 days of treatment. Those results demonstrate that topical applications of a cosmetic product incorporating the presolubilized  Paeonia suffruticosa  root extract in a lipophilic carrier composition comprising  Ribes nigrum  seed oil reduces the color pigmentation and the visual appearance of age spots. Furthermore, a general improvement in skin complexion could be observed. 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 Effect of a topical composition incorporating a presolubilized 
               
               
                   Paeonia suffruticosa  root extract in a lipophilic carrier composition 
               
               
                 comprising  Ribes nigrum  seed oil on age spot melanin index - 
               
               
                 MEXAMETER ® MX 18. 
               
            
           
           
               
               
            
               
                   
                 Variation in melanin index upon product 
               
               
                   
                 application in comparison to baseline (%) 
               
            
           
           
               
               
               
            
               
                   
                 Day 30 
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Placebo 
                   
                 Day 60 
               
            
           
           
               
               
               
               
               
            
               
                 Treatment 
                 cream 
                 Active cream 
                 Placebo cream 
                 Active cream 
               
               
                   
               
               
                 Melanin index 
                 −2.5 
                 −14.4 
                 −1.5 
                 −18.1 
               
               
                 variation (%) 
               
               
                 p value 
                 N/A 
                 p = 0.025 1   
                 N/A 
                 p = 0.004 1   
               
               
                   
               
               
                   1 Statistically significant when compared to Placebo cream 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Effect of a topical composition incorporating a presolubilized 
               
               
                   Paeonia suffruticosa  root extract in a lipophilic carrier composition 
               
               
                 comprising  Ribes nigrum  seed oil on age spot color intensity 
               
               
                 reduction (ITA °) - Spectrophotometer CM-700d. 
               
            
           
           
               
               
            
               
                   
                 ITA ° variation upon product application 
               
               
                   
                 in comparison to baseline (%) 
               
            
           
           
               
               
               
            
               
                   
                 Day 30 
                 Day 60 
               
            
           
           
               
               
               
               
               
            
               
                 Treatment 
                 Placebo cream 
                 Active cream 
                 Placebo cream 
                 Active cream 
               
               
                   
               
               
                 ITA ° 
                 −2.6 
                 +12.4 
                 −3.7 
                 +20.1 
               
               
                 variation 
               
               
                 (%) 
               
               
                 p value 
                 N/A 
                 p = 0.019 1   
                 N/A 
                 p = 0.002 1   
               
               
                   
               
               
                   1 Statistically significant when compared to Placebo cream 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 Effect of a topical composition incorporating a presolubilized 
               
               
                   Paeonia suffruticosa  root extract in a lipophilic carrier composition 
               
               
                 comprising  Ribes nigrum  seed oil on face, neck and upper chest 
               
               
                 skin area color brightness (L*) - Spectrophotometer CM-700d. 
               
            
           
           
               
               
            
               
                   
                 L* variation upon product application 
               
               
                   
                 in comparison to baseline (%) 
               
            
           
           
               
               
            
               
                   
                 Day 60 
               
            
           
           
               
               
               
               
            
               
                   
                 Day 30 
                   
                 Active 
               
            
           
           
               
               
               
               
               
            
               
                 Treatment 
                 Placebo cream 
                 Active cream 
                 Placebo cream 
                 cream 
               
               
                   
               
               
                 L* parameter 
                 −0.7 
                 +2.5 
                 −0.5 
                 +4.2 
               
               
                 variation (%) 
               
               
                 p value 
                 N/A 
                 p = 0.003 1   
                 N/A 
                 p &lt; 0.001 1   
               
               
                   
               
               
                   1 Statistically significant when compared to Placebo cream 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 Effect of a topical composition incorporating a presolubilized 
               
               
                   Paeonia suffruticosa  root extract in a lipophilic carrier composition 
               
               
                 comprising  Ribes nigrum  seed oil on age spot visual appearance - 
               
               
                 dermatologist evaluation. 
               
            
           
           
               
               
            
               
                   
                 Proportion of subjects for which a 
               
               
                   
                 reduction in the visual appearance 
               
               
                   
                 of age spots was observed (%) 
               
            
           
           
               
               
            
               
                   
                 Day 60 
               
            
           
           
               
               
               
               
            
               
                   
                 Day 30 
                   
                 Active 
               
            
           
           
               
               
               
               
               
            
               
                 Treatment 
                 Placebo cream 
                 Active cream 
                 Placebo cream 
                 cream 
               
               
                   
               
               
                 Proportion of 
                 0.0 
                 26.7 
                 6.7 
                 53.3 
               
               
                 subjects (%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 Effect of a topical composition incorporating a presolubilized 
               
               
                   Paeonia suffruticosa  root extract in a lipophilic carrier composition 
               
               
                 comprising  Ribes nigrum  seed oil on the visual assessment of skin 
               
               
                 complexion - dermatologist evaluation. 
               
            
           
           
               
               
            
               
                   
                 Proportion of subjects for which an 
               
               
                   
                 improvement of skin complexion was 
               
               
                   
                 visually observed (%) 
               
            
           
           
               
               
            
               
                   
                 Day 60 
               
            
           
           
               
               
               
               
            
               
                   
                 Day 30 
                   
                 Active 
               
            
           
           
               
               
               
               
               
            
               
                 Treatment 
                 Placebo cream 
                 Active cream 
                 Placebo cream 
                 cream 
               
               
                   
               
               
                 Proportion of 
                 0.0 
                 13.3 
                 6.7 
                 33.3 
               
               
                 subjects (%)