composition for in-situ training and kit

专利摘要:
These are compositions that can form a covering, a layer, a film, a device and/or a prosthetic skin that can be comfortably worn to provide skin barrier function, skin hydration and therapeutic and aesthetic benefits. The present invention provides innovative compositions that have low adhesion and quickly form, which results in a wearable, comfortable (retains temperature and humidity), breathable, thin, optically invisible, cosmetically wearable, film, film, device and/or prosthetic skin elegant, flexible, stretchable, elastic and conforms to body movement, yet durable on skin or any other body surface. The present invention provides innovative compositions that can form a covering, layer, film, device and/or prosthetic skin that works for extended periods in excess of about 24 hours, while retaining function during and after exercising, bathing and bathing (in sea water, fresh water and chlorinated water), steam room (heat in high humidity) and sauna (heat in low humidity).
公开号:BR112018009447B1
申请号:R112018009447-1
申请日:2016-11-09
公开日:2021-06-08
发明作者:Ariya Akthakul；Nithin Ramadurai；Amir Nashat；Daniela Beccati；Melaney Bouthillette
申请人:Shiseido Americas Corporation；
IPC主号:

专利说明:

CROSS REFERENCE TO RELATED ORDERS
[001] This application claims priority from Provisional Patent Application in U.S. 62/252,903, filed November 9, 2015. This provisional application is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION
[002] The skin function, eg skin barrier function, is critical to protect the body from physical injury and environmental factors, regulate skin hydration, regulate body temperature, provide protection from pathogenic invasion and appearance. When skin is damaged, its ability to serve as an effective barrier is compromised, and thus allows external irritants and potentially pathogenic organisms to enter a patient. In addition, damaged skin can allow increased transepidermal water loss when the moisture present in the body is allowed to travel directly to the skin surface where it evaporates, which leads to decreased skin hydration (eg, dry, irritated skin) and loss of skin elasticity.
[003] Skin hydration has been shown to significantly improve the skin properties and quality of life for individuals with many conditions of compromised skin barrier function such as dermatitis and psoriasis (see, for example, Guidelines of care for the management of atopic dermatitis, J. Am. Acad. Dermatol., 2014 71(1): 116 to 132; Guidelines on care for the management of psoriasis and psoriatic arthritis, J. Am. Acad. Dermatol. 2009, 60(4):643 to 659). However, individuals with such conditions still rely primarily on the use of occlusive dressings (see, eg, Hwang et al., Internat. J. Dermatol. 2001, 40(3):223 to 231), often in combination with ointments and/or topical moisturizers. For example, emollient-based moisturizers increase keratin hydration in the stratum corneum and help reduce scaling, so they are often considered an adjunctive therapy and an essential part of managing such conditions. Occlusive dressings, ointments and topical moisturizers are a valuable first-line treatment as skin hydration provides transient relief from irritation caused by transepidermal water loss. Skin hydration additionally leads to improved barrier function, as stratum corneum hydration makes the epidermis more resistant to external stressors and reduces the induction of other undesirable conditions such as the Koebner phenomenon triggered by excoriation or maceration and infectious foci due to pyogenes of Streptococcus. However, current occlusive dressings are often designed to exclude both oxygen and water and thereby cut off the skin's oxygen access while providing skin hydration.
[004] Occlusive dressings, ointments and/or topical moisturizers are often uncomfortable, making the routine activity difficult for the individual and resulting in low patient compliance with the use of such dressings, ointments and/or moisturizers. Additionally, occlusive dressings, ointments and/or topical moisturizers often require multiple applications per day to be effective as they are readily worn away. Furthermore, emollient-based moisturizers can cause side effects such as irritating dermatitis, allergic contact dermatitis, allergy to formula constituents, burning, cosmetic acne, and other unwanted effects. Therefore, it is desirable to find alternative methods of treating conditions of compromised skin barrier function that are both effective and without unwanted side effects.
[005] The design and adoption of a wearable material that conforms to the skin presents many fundamental challenges. First, the material needs to be worn securely on the skin without causing irritation and/or skin sensitization. Second, the materials need to adhere to the skin while providing a breathable yet protective interface to the environment. Third, the material must possess mechanical properties that accommodate the skin's normal mechanical responses to movement while enhancing skin traction and inherent elastic recoil. Fourth, the material should preferably mimic the appearance of normal, healthy skin, or at least not significantly interfere with it, across a wide range of individual skin types. Examples of normal, healthy skin appearances, such as lack of scaling, redness and unevenness such as bumps and/or large pores, are described in Igarashi et al, The Appearance of Human Skin: A Survey, Foundations and Trends® in Computer Graphics and Vision, 2007 3(1):1 to 95.
[006] There are commercially preformed preformed skin wound dressings available on the market today, such as silicone wound dressing (eg, Cica-Care®, Smith and Nephew, Andover, MA) and acrylic wound dressing ( for example, Tegaderm™, 3M, St. Paul, Minnesota). However, such preformed wound dressings are fixed in area and size, uncomfortable, visually perceptible, and do not provide sufficient flexibility and durability required by routine daily activities.
[007] 3M Company provides a "Liquid Bandage" product that claims to offer breathable waterproof protection to keep dirt and germs free. However, such Liquid Bandages do not provide sufficient flexibility and durability required by routine daily activities, often have glossy/glossy appearance, and suffer from very compromised mechanical integrity and adhesiveness when rubbing.
[008] Yu et al. (U.S. Patent Application 20130078209) discloses compositions for treating conditions of compromised skin barrier function such as dermatological disorders and post-laser, light or chemical treatment management. However, such compositions are still not as durable as desired and require more than one application per day.
[009] Consequently, there is a need for compositions, devices and methods to modify skin function that forms quickly and that are thin, durable, non-invasive, easy to use and with skin-like properties. SUMMARY OF THE INVENTION
[010] The present invention is based, at least in part, on the discovery of durable compositions that appear natural and non-invasive and methods for using such compositions in treating conditions of compromised skin barrier function. The present invention provides safe compositions that can form a covering, a layer, a film, a device or a prosthetic skin, which allows for enhancement and/or restoration of one or more skin barrier functions.
[011] The present compositions are distinct from previous compositions in that the layer formed by the present compositions has low adhesion and forms quickly, which results in a comfortable, wearable covering, layer, film or device (maintains temperature and humidity similar to normal, healthy skin), breathable, thin, optically invisible, cosmetically elegant, flexible, stretchable, elastic and conforms to body movement, yet durable on the outside of the body (eg on the skin or otherwise body surface). The present inventions provide innovative compositions that are durable and perform better than previous compositions, particularly during more demanding activities, for example, exercising, bathing and swimming (in seawater, fresh water or chlorinated water), steam room ( heat in high humidity) and sauna (heat in low humidity).
[012] In particular, the covering, layer, film or device formed from the compositions disclosed herein regulates transdermal skin transport properties. In one aspect, the coating, layer, film or device helps maintain skin hydration by reducing loss of water vapor from the body. In another aspect, the covering, layer, film or device helps to protect the body from external aggressions, such as environmental factors (eg, heat, cold, wind, water, moisture, bodily fluids (eg, blood, pus/puris liquor, urine, saliva, sputum, tears, semen, milk or vaginal secretion), tallow, saline solution, sea water, soapy water, detergent water or chlorinated water), pathogens, allergens and pruritogens. In another aspect, the covering, layer, film or device helps maintain conductive conditions for skin repair during new skin layer formation such as wound healing which minimizes scarring. In another aspect, the coating, layer, film or device is used to treat conditions of compromised skin barrier function, including dermatological disorders, skin conditions and wounds. In another aspect, the coating, layer, film, or device is used to treat symptoms of compromised skin barrier function conditions, such as itchy skin, dry skin, crusting, blistering, or cracked skin. , dermatitis, skin edema, skin lesion formation. In another aspect, the covering, layer, film or device is used to deliver an agent to a patient to treat a condition of compromised skin barrier function or to treat a symptom of such a condition.
[013] The coating, layer, film or device formed by the present compositions is not obstructive to the user's normal activities and is convenient (only one application is required for about 24 hours or more, up to about a week), and provides localized and prolonged skin hydration and other therapeutic, aesthetic and/or cosmetic benefits.
[014] The covering, layer, film or device formed by the present compositions has the appearance of a patient's normal and healthy skin, and thus conveys cosmetic benefits by masking, hiding, covering or reducing the appearance of compromised skin barrier function conditions, symptoms of compromised skin barrier function, and/or skin imperfections. The coating, layer, film or device formed by the present compositions may additionally comprise various colors, pearls, patterns or designs, and thus impart makeup, cosmetic, aesthetic and/or decorative benefits. BRIEF DESCRIPTION OF THE FIGURES
[015] Figure 1 is a graph illustrating the durability of formed layers of P1-016/P2-004 or a commercial product at a 24-hour time point.
[016] Figure 2 is a graph that illustrates the drying times of layers formed from P1-016/P2-004 or a commercial product.
[017] Figure 3 is a graph illustrating Drying Time and Adhesion Free Time comparing compositions P1-017/P2-004 to P1-023/P2-004, classified based on hydride/vinyl molar ratio in the first part .
[018] Figure 4 is a graph illustrating Peel Adhesion Strength per unit length comparing compositions P1-017/P2-004 to P1-023/P2-004, classified based on hydride/vinyl molar ratio in the former part.
[019] Figure 5 is a photoassembly illustrating in-vivo film resistance against rubbing of test composition P1-030/P2-021 (full coverage color film) and P1-028/P2-004 (clear color film ) in the skin.
[020] Figure 6 is a graph illustrating a clinical assessment of in-vivo durability after 6 hours and 24 hours of P1-016/P2-004 in the skin.
[021] Figure 7A is a graph illustrating in-vivo optical evaluation of L*a*b* color scales in test formulation on forearm skin, which compares invisibility of composition P1-016/P2-004 with the product Commercially available Tegaderm™ (3M).
[022] Figure 7B is a graph illustrating in-vivo optical evaluation of normalized values of L*a*b* color scales in test formulation to values on forearm skin, which compares invisibility of composition P1-016/ P2-004 with commercially available Tegaderm™ product (3M).
[023] Figure 8 is a photoset that illustrates in vivo assessment of the skin surface modulation achieved by P1-016/P2-004: (top) in both areas below the eye of a male patient, (middle) in both areas below the eye of a female patient, (bottom) in both expression line areas of a female patient.
[024] Figure 9 is a photoset that illustrates in vivo evaluation of optical skin modification achieved by P1-030/P2-021: (top) in natural hyperpigmentation coverage, (bottom) in tattoo coverage.
[025] Figure 10 is a photoset that illustrates the incorporation of stimulus-responsive components in the skin test composition. (Left) Composition P1-029/P2-004 includes graphene and (Right) composition P1-028/P2-004 includes pH sensitive dye.
[026] Figure 11 is a photoset that illustrates in-vivo barrier protection against water penetration to demonstrate the waterproof property of test composition P1-016/P2-004 on the skin.
[027] Figure 12 is a graph illustrating in-vitro barrier evaluation against nickel contact that compares the P1-016/P2-004 composition (right side) against the control (left side with no test composition). Control (left) exhibited color change to pink indicating direct contact with nickel. In contrast, the right side with test article P1-116/P2-004 exhibited no color change due to the film's barrier protection against nickel contact.
[028] Figure 13 is a graph illustrating in-vitro barrier evaluation against UV radiation comparing P1-026/P2-004 against blank control and against SPF 50 over-the-counter sprinkler (Banana Boat).
[029] Figure 14A is a graph illustrating water vapor transmission that compares P1-016/P2-004 (right side) at different thicknesses against the control (left side with no test composition).
[030] Figure 14B is a graph illustrating the water vapor transmission rate calculation based on P1-016/P2-004 (right side) at different thicknesses.
[031] Figure 15 is a graph illustrating a clinical evaluation of in-vivo Transepidermal Water Loss (TEWL) of composition P1-016/P2-004 in the skin after 2, 6 and 24 hours by Evaporimeter measurement.
[032] Figure 16A is a graph illustrating cumulative transdermal delivered dose (of recipient fluid) of triamcinolone acetonide after 1, 2, 4, 6, 8 and 24 hours of topical formulations comparing between 0.1% of lotion. triamcinolone acetonide (TA) (from Versa Pharma), P1-016/P2-004 layered on top of 0.1% TA, and P1-027/P2-004.
[033] Figure 16B is a graph illustrating cumulative delivered dose of triamcinolone acetonide on adhesive tapes after 24 hours of topical formulations comparing between 0.1% triamcinolone acetonide (TA) lotion (from Versa Pharma), P1 -016/P2-004 layered on top of 0.1% TA, and P1-027/P2-004.
[034] Figure 16C is a graph illustrating the cumulative delivered dose of triamcinolone acetonide in epidermal, dermal and recipient fluid after 24 hours of topical formulations comparing between 0.1% triamcinolone acetonide (TA) lotion (de Versa Pharma), P1-016/P2-004 layered on top of 0.1% TA, and P1-027/P2-004.
[035] Figure 17 is an exemplary form used for clinical measurement of Psoriasis Area and Severity Index (PASI) Score.
[036] Figure 18A is a graph illustrating clinical improvement in IGA eczema severity after application of composition P1-016/P2-004 for a period of 30 days.
[037] Figure 18B is a graph that illustrates improvement of clinical signs in erythema after application of composition P1-016/P2-004 for a period of 30 days.
[038] Figure 18C is a graph that illustrates improvement of clinical signs in papulation after application of composition P1-016/P2-004 for a period of 30 days.
[039] Figure 18D is a graph that illustrates improvement of clinical signs in excoriation after application of composition P1-016/P2-004 for a period of 30 days.
[040] Figure 18E is a graph that illustrates improvement of clinical signs in lichenification after application of composition P1-016/P2-004 for a period of 30 days.
[041] Figure 18F is a graph illustrating improvement of clinical signs in exudation/crust formation after application of composition P1-016/P2-004 for a period of 30 days.
[042] Figure 18G is a graph that illustrates improvement of clinical signs in pruritus after application of composition P1-016/P2-004 for a period of 30 days.
[043] Figure 18H is a graph illustrating improvement of many clinical signs of a patient's upper leg area after application of P1-016/P2-004 composition for a period of 30 days.
[044] Figure 18I is a graph illustrating improvement of many clinical signs of a patient's neck and shoulder area after application of P1-016/P2-004 composition for a period of 30 days. DETAILED DESCRIPTION OF THE INVENTION
[045] The compositions that can form a covering, layer, a film, a device and/or a prosthetic skin on the skin that have low adhesion and form quickly, which results in a covering, a layer, a film, device and/or wearable, comfortable (maintains temperature and humidity similar to normal, healthy skin), breathable, thin, optically invisible, cosmetically elegant, flexible, stretchable, elastic and conforms to body movement , yet durable, that can be comfortably worn to provide skin hydration and other therapeutic, aesthetic and/or cosmetic benefits.
[046] The present inventions provide innovative compositions that are durable and perform better than previous compositions, particularly during more demanding activities, eg exercising, bathing and swimming (in seawater, fresh water or chlorinated water), living room of steam (heat in high humidity) and sauna (heat in low humidity). An added benefit is that the wearability and/or extended durability of the layer does not require repeated applications to sustain its benefits. The formed layer can be worn for a period of about 24 hours or more without the need to reapply.
[047] In particular, the layer formed of the compositions disclosed herein regulates transdermal skin transport properties, helps maintain skin hydration by providing an additional barrier over the skin against loss of water vapor from the body to the environment, helps protect the body against external and internal aggressions such as environmental factors (eg heat, cold, wind, water, humidity), bodily fluids (eg blood, pus/puris liquor, urine, saliva, sputum, tears , semen, milk or vaginal secretion), tallow, saline, sea water, soapy water, detergent water, chlorinated water, pathogens, allergens and pruritogens, and helps to maintain conductive conditions for skin repair during skin layer formation new such as wound healing which minimizes scarring.
[048] In addition to providing increased compliance with a once-daily or less frequent application of aesthetically pleasing compositions, users of such compositions benefit from the therapeutic effects. The compositions and methods described herein provide a more attractive alternative to current treatment options for conditions of compromised skin barrier function.
[049] The present compositions are suitable for easy topical application to form a covering, a layer, a film, a device and/or an aesthetically invisible, elastic, skin-conforming prosthetic skin that can be worn securely on the skin . The materials used in the present compositions are preferably selected from the US Food and Drug Administration's list of substances generally considered to be safe (GRAS) or equivalents thereof or are otherwise safe for skin and/or body applications.
[050] As used herein, the term "skin" includes body surfaces where normal skin is intact, compromised, or partially or completely lost or removed. Skin additionally includes skin imperfections that are commonly considered to be part of “skin”. Examples of skin imperfections include wrinkles, blemishes, freckles, acne, warts, caruncles, lesions, scars, tattoos, bruises, skin disfigurements, birthmarks, sun damage, age damage, mole (eg, aging spots ), uneven skin tone, sagging skin, cellulite, stretch marks, loss of skin elasticity, skin roughness, enlarged pores, hyperpigmentation, telangiectasia, redness, shine, port wine stain (or hair malformation, for example, hair malformation of nape or midline capillary malformation) and melasma. The skin additionally includes the area of skin upon which any cosmetic, personal care, medical, ink, or other foreign material, or a combination thereof, is applied.
[051] As used herein, the term "layer" includes a covering, a film, a sheet, a barrier, a coating, a membrane, a device or a prosthetic skin formed, sprayed or spread over a surface. A layer can be, but is not necessarily, continuous. A layer may, but is not necessarily, of substantially equal and/or uniform thickness.
[052] As used herein, the terms "compromised skin barrier function", "compromised skin barrier" or "compromised skin condition" include conditions such as dermatological disorders, skin conditions and wounds.
[053] “Dermatological disorders” include disorders that cause at least one symptom on a patient's skin that may require medical treatment. Dermatological disorders can be caused, among other things, by autoimmune disorders and/or environmental factors such as allergens or chemicals. Examples of symptoms of dermatological disorders include, but are not limited to, itchy skin, dry skin, crusting, blistering, or cracked skin, dermatitis, skin edema, or skin lesion formation. Dermatological disorders include, but are not limited to, eczema, psoriasis, ichthyosis, rosacea, chronic dry skin, cutaneous lupus, chronic lichen simplex, xeroderma, acne, secondary disease-triggered dermatological disorder and ulcer.
[054] Eczema includes, for example, atopic eczema, atopic dermatitis, contact dermatitis, phototoxic dermatitis, xerotic eczema (also known as asteatotic eczema, crackle or craquelato eczema, winter itch or hyemal itching), seborrheic dermatitis (or seborrheic eczema) ), dyshidrosis (also known as dyshidrotic eczema, pompolix, palmoplantar vesicular dermatitis or housewife eczema), discoid eczema (also known as nummular eczema, exudative eczema, microbial eczema), venous eczema (also known as gravitational eczema, dermatitis of stasis, varicose eczema), dermatitis herpetiformis (also known as Duhring's Disease), neurodermatitis (also known as chronic lichen simplex, localized itching dermatitis), autoeczematization and retinoid-induced dermatitis.
[055] Psoriasis includes, for example, psoriasis vulgaris (also known as plaque psoriasis), psoriatic erythroderma, pustular psoriasis (which includes von Zumbusch, Palmoplantar, and Acropustulosis psoriasis), drug-induced psoriasis, inverse psoriasis, seboric psoriasis and guttate psoriasis.
[056] Ichthyosis includes, for example, ichthyosis vulgaris, acquired ichthyosis, X-linked ichthyosis, congenital non-bullous ichthyosiform erythroderma (nbCIE), epidermolytic hyperkeratosis (bullous ichthyosis, bCIE), Harlequin-type ichthyosis, Siemens bullous ichthyosis hystrix, Curth-Macklin type, hystrix-like ichthyosis with deafness, lamellar ichthyosis, type 1, lamellar ichthyosis, type 2, lamellar ichthyosis, type 3, lamellar ichthyosis, type 4, lamellar ichthyosis, type 5, CHILD syndrome, syndrome Conradi-Hünermann syndrome, follicular ichthyosis with photophobia and alopecia syndrome, ichthyosis deafness syndrome keratitis, Netherton syndrome, neutral lipid storage disease with ichthyosis, adult Refsum disease, ichthyosis and male hypogonadism, Sjogren-Larsson syndrome and photosensitive trichothiodystrophy (IBIDS syndrome).
[057] Rosacea includes, for example, erythematothelangiectatic rosacea, papulopustular rosacea, phimatous rosacea (eg, rhinophyma), and granulomatous rosacea.
[058] Cutaneous lupus includes, for example, acute cutaneous lupus, acute subcutaneous lupus, chronic cutaneous lupus, chilblain lupus erythematosus, discoid lupus erythematosus, lupus erythematosus-lichen planus overlap syndrome, panniculitis lupus erythematosus, lupus erythematosus, lupus erythematosus warty erythematosus.
[059] Acne includes, for example, acne vulgaris, summer acne, acne conglobata, cosmetic acne, acne fulminans, nape keloid acne, mechanical acne, drug acne (also known as drug-induced acne, e.g., steroid acne) , miliary necrotic acne, necrotic acne, acne rosacea and reverse acne.
[060] A "disease-triggered minor dermatological disorder" refers to a dermatological condition that may require treatment and was caused by or associated with a non-dermatological disorder. A "non-dermatological disorder" includes disorders not primarily associated with the skin, but which may result in, be associated with, or have a secondary manifestation of a skin condition, for example, a disorder of the patient's circulatory system or metabolism. Disease-triggered secondary dermatological disorders include, for example, an ulcer caused by diabetes mellitus (eg, diabetic foot ulcer), a bacterial, viral or fungal infection, cancer, pressure (eg, a pressure ulcer), foot disorders. blood, conditions that affect the nervous system (eg, neuropathic ulcers (also known as “mal perforans”)), conditions that affect the nervous system (eg, arterial insufficiency ulcers (also known as “ischemic ulcers”) or ulcers vascular) and/or a chronic injury.
[061] “Skin conditions” include, but are not limited to, itchy skin, raw skin, dry skin, peeling or peeling skin, skin blisters, redness, swelling or inflammation of the skin and oozing, scaly skin or crusting. Skin conditions also include compromised skin barrier conditions caused by laser treatment, light or chemical peeling.
[062] “Injuries” include lesions on the skin where the skin is torn, cut or punctured. Wounds include open wounds, for example, abrasions, lacerations, incisions, punctures, avulsions or amputations. Injuries also include burn wounds, a type of injury to the skin and/or flesh caused by heat, electricity, wind, chemicals, light, radiation, or friction.
[063] “Treat”, “treat” and “treatment” include both therapeutic and prophylactic/preventive measures. "Treat", "treat" and "treatment" additionally include both disorder modification treatment and symptomatic treatment. Treatment may ameliorate or cause a reduction in the severity and/or duration of at least one symptom of the compromised skin barrier function conditions. Treatment can also cause a complete recovery from conditions of compromised skin barrier function.
[064] "Apply", "applied" and "application" include any and all known methods of contacting or administering compositions of the invention to a patient's skin or body. Application can be by finger, hand, brush, cotton ball, cotton swab, handkerchief, pad, sponge, roll-on, spatula, dispenser, drops, spray, squirt, foam, mousse, serum, spray and other appropriate methods.
[065] "Patient" includes patients in whom the compositions disclosed herein would be suitable for use, particularly animals (eg, a human). Patients can additionally include vegetables, where skin refers to the surface over portions of the vegetable that can benefit from application of the composition, such as flowers, leaves, fruits, stems, twigs, bark and roots.
[066] “In vitro” means tested or formed not on, in or on a patient's skin or body.
[067] "Routine daily activities" include instrumental activities of daily living, such as feeding (e.g., eating, drinking, taking medication), continence (e.g., urination and defecation), help with going to the bathroom, dressing, bathing (eg, shower, bath), sanitizing, physical ambulation (eg, walking, using transport), talking (eg, using the phone), preparing food, housekeeping, washing clothes, shopping, and handling finances. Examples of such daily activities are described in Lawton and Brody, Assessment of older people: self-maintaining and instrumental activities of daily living, Gerontologist 1969 autumn;9(3):179 to 186 and Katz et al., Studies of Illness in the Aged. The ADL Index: A Standardized Measure of Biological and Psychosocial Function, JAMA 1963 September 21;185:914 to 919.
[068] “Demanding activities” include activities that create a high level of tension and/or stress on a patient's skin compared to the tension or stress generated by routine daily activities. Examples of such demanding activities include exercising, swimming (in seawater, fresh water, or chlorinated water), steam room (heat in high humidity), sauna (heat in low humidity), and other similar activities.
[069] Unless otherwise stated, descriptions of any material used as part of any composition disclosed herein are of such material as an ingredient of the composition prior to mixing, combining and/or reacting such material with another ingredient (or other ingredients) of the composition.
[070] One aspect of the invention is directed to a composition comprising at least one crosslinkable polymer. A "crosslinkable polymer" refers to a polymer that can interact physically or chemically, or interact both physically and chemically, with itself or with other polymers to form a layer on a surface (eg, skin, leather, glass, plastic, metal) on which it is applied. “Physically interacting” refers to the formation of non-covalent interactions (eg, hydrogen bonds or electrostatic, polar, ionic, van der Waals or London forces) between two or more polymer chains. "Interacting chemically" refers to the formation of covalent bonds between two or more polymer chains. Covalent bonds can be formed through chemical reactions that occur spontaneously or are initiated, for example, by catalyst, humidification, heat, pressure, change in pH or radiation. The crosslinkable polymer (or the crosslinkable polymers) can (or can) be homopolymer or copolymer, for example random copolymer, alternating copolymer, periodic copolymer, statistical copolymer, block copolymer, graft or graft copolymer or a combination thereof.
[071] In certain embodiments, the composition comprises one or more physically crosslinkable polymers such as semi-crystalline polymers, charged polymers, polymers with bonds capable of hydrogen bonds, or polymers capable of forming phase separation networks (e.g., poly(styrene) - butadiene), poly(dimethylsiloxane-ethyleneoxide)). In preferred embodiments, the composition comprises one or more physically crosslinkable polymers that can form hydrogen bond crosslinking networks and/or ionic crosslinking networks, non-limiting examples of which include copolymers between two or more of the following: caprolactone, lactide, glycolide, sebaceous, adipic and trimethylene carbonate. In further preferred embodiments, the composition comprises one or more crosslinkable biological polymers, non-limiting examples of which include one or more of the following: protein-based polymers such as keratin, elastin, collagen; or sugar based polymers such as chitin, chitosan, cellulose, starch; or lipid-based polymers such as ceramide, triglyceride, sphingosine or a combination thereof.
[072] In certain embodiments, the composition comprises one or more chemically crosslinkable polymers such as polymers containing functional groups capable of addition polymerization, chain growth polymerization, step-growth polymerization, ring opening polymerization, radical polymerization , anionic polymerization, cationic polymerization, condensation polymerization, live polymerization, photopolymerization, radiation polymerization, or other chemical reactions that form one or more chemical bonds. In preferred embodiments, the composition comprises one or more chemically cross-linkable polymers that can form covalent cross-link networks. In further preferred embodiments, the composition comprises one or more chemically crosslinkable polymers selected from polysiloxane, polyethylene oxide, polypropylene oxide, polyurea, polycarbonate, polyglycerol, polyurethane, polyester (including, but not limited to, polylactic-co-glycolic acid, polycaprolactone , polylactic acid, polyglycolic acid, and polyhydroxybutyrate, polyamide), polysulfone, polyphosphate, polyamine, polyimine, polythiol, polyboron or a combination thereof.
[073] In certain embodiments, the composition comprises one or more physically and chemically crosslinkable polymers. In preferred embodiments, the composition comprises one or more physically and chemically crosslinkable polymers such as keratin, elastin, collagen or a combination thereof.
[074] In preferred embodiments, the composition comprises one or more crosslinkable organopolymers. An "organopolymer" refers to a polymer that includes carbon.
[075] In certain embodiments, the composition comprises: Polymer A) one or more organopolymers having on average at least two carbon double bonds (i.e., alkenyl-functional group) or at least one carbon triple bond (i.e., alkynyl-functional group) on each molecule; and Polymer B) one or more organopolysiloxanes having on average at least two Si-hydrogen containing monomer units (SiH units) in each molecule.
[076] In preferred embodiments, the organopolymer comprises organopolysiloxanes, which are polymers based on the following monomer units:
and terminal units:
wherein each R1, R2 and Rt1 to Rt6 is independently selected from hydrogen, C1 to C25 alkyl, C2 to C25 alkenyl, C2 to C25 alkynyl, C5 to C10 aryl, halogen, amino and hydroxy, where C1 to C25 alkyl, C2 to C25 alkenyl, C2 to C25 alkynyl and C5 to C10 aryl may be optionally substituted by 1 to 3 substituents selected from C1 to C25 alkyl, halogen, C1 to C25 haloalkyl, amino and hydroxy and where n is an integer between 10 and 3,000. R1 and R2 of each monomer unit may be, but not necessarily, the same.
[077] As used herein, "alkyl", "alkenyl" and "alkynyl" include both straight and branched chain hydrocarbon groups. As used herein, "amino" includes both primary amines such as -NH2 and secondary or tertiary amines in which one or both of the hydrogen atoms have been replaced by an alkyl group. Repeating units other than siloxane may be present in the organopolysiloxane polymer structure.
[078] In preferred embodiments, Rt1 and Rt4 are alkenyl or alkynyl and each R1, R2, Rt2 Rt3, Rt5 and Rt6 is independently selected from C1 to C25 alkyl, C5 to C10 aryl, halogen, amino and hydroxy, where the alkyl C1 to C25, C2 to C25 alkenyl and C5 to C10 aryl may be optionally substituted by 1 to 3 substituents selected from C1 to C25 alkyl, halogen, C1 to C25 haloalkyl, amino and hydroxy. In further preferred embodiments, Rt1 and Rt4 are alkenyl or alkynyl and each R1, R2, Rt2 Rt3, Rt5 and Rt6 is independently C1 to C25 alkyl optionally substituted by 1 to 3 substituents selected from halogen or C1 to C25 haloalkyl.
[079] In certain embodiments, Rt1 and Rt4 are hydrogen and each R1, R2, Rt2 Rt3, Rt5 and Rt6 is independently selected from C1 to C25 alkyl, C5 to C10 aryl, halogen, amino and hydroxy, where C1 to alkyl C25 and C5 to C10 aryl may be optionally substituted by 1 to 3 substituents selected from C1 to C25 alkyl, halogen, C1 to C25 haloalkyl, amino and hydroxy. In preferred embodiments, each R1, R2 and Rt1 to Rt6 is independently selected from hydrogen, C1 to C25 alkyl, C5 to C10 aryl, halogen, amino and hydroxy, wherein the C1 to C25 alkyl and C5 to C10 aryl may be optionally substituted by 1 to 3 substituents selected from C1 to C25 alkyl, halogen, C1 to C25 haloalkyl, amino and hydroxyl. In a preferred embodiment, the Si-H units in the organopolysiloxane are spaced on average by at least about 1 monomer units, about 2 monomer units, about 5 monomer units, about 10 monomer units, about 20 monomer units, about 40 monomer units, about 200 monomer units, about 400 monomer units, about 1,000 monomer units, or about 2,000 monomer units.
[080] In certain embodiments, the organopolysiloxane is primarily comprised of siloxane monomer units, i.e. substantially all of the repeating units along the polymer structure are siloxane units. In preferred embodiments, the organopolysiloxane comprises greater than 90%, greater than 95%, greater than 98% or greater than 99% siloxane repeating units throughout the polymer structure.
[081] In certain embodiments, the molar ratio of Si-H to alkenyl (eg, vinyl) or Si-H to alkynyl of the polymers in the composition is about 1:5 to about 60:1; about 10:1 to about 30:1; or about 20:1 to about 25:1.
[082] In preferred embodiments, the composition comprises: Polymer A) one or more organopolysiloxanes having on average at least two carbon double bonds or at least one carbon triple bond in each molecule; and Polymer B) one or more organopolysiloxanes having on average at least two Si-H units in each molecule.
[083] In preferred embodiments, the composition additionally comprises one or more reinforcing components. In certain embodiments, the reinforcing component is selected from surface treated carbon, silver, mica, zinc sulfide, zinc oxide, titanium dioxide, aluminum oxide, clay (eg, Al2O3, SiO2), chalk, talc, calcite (eg CaCO3), barium sulfate, zirconium dioxide, polymer spheres and silica (eg silica aluminates, calcium silicates or surface treated silica (eg fumed silica, hydrated silica or anhydrous silica) ) or a combination thereof. Such reinforcement components enhance the physical properties of the layer as discussed herein. In preferred embodiments, the reinforcing component is surface treated silica, for example, silica treated with hexamethyldisilazane, polydimethylsiloxane, hexadecylsilane or methacrylsilane. In further preferred embodiments, the reinforcing component is fumed silica, including fumed silica that has been surface treated with hexamethyldisilazane.
[084] In certain embodiments, the reinforcement component particles have an average surface area of between about 50 and about 500 m2/g. In preferred embodiments, the reinforcement component particles have an average surface area of between about 100 and about 350 m2 /g. In further preferred embodiments, the reinforcement component particles have an average surface area of between about 135 and about 250 m2 /g. In certain embodiments, the reinforcement component has an average particle diameter of between about 1 nm and about 20 µm. In preferred embodiments, the reinforcement component has an average particle diameter of between about 2 nm and about 1 µm, and more preferably between about 5 nm and about 50 nm.
[085] In preferred embodiments, the composition comprises about 5 to about 90% by weight of Polymer A; about 5 to about 75% by weight of Polymer B; and about 0 to about 25% by weight of reinforcing component. In further preferred embodiments, the composition comprises from about 50 to about 90% by weight of Polymer A; about 5 to about 30% by weight of Polymer B; and about 5 to about 15% by weight of reinforcing component.
[086] In certain embodiments, organopolysiloxane having carbon double or triple bonds includes such carbon double or triple bonds in terminal polymer units, non-terminal polymer monomer units, or a combination thereof. In preferred embodiments, the organopolysiloxane having carbon double or triple bonds includes such carbon double or triple bonds in non-terminal monomer units of the polymer. In preferred embodiments, the carbon double bond-containing monomer units in the organopolysiloxane are spaced apart on average by at least about 40 monomer units, about 200 monomer units, about 400 monomer units, about 1,000 monomer units or about 2,000 monomer units.
[087] In certain embodiments, the organopolysiloxane having carbon double or triple bonds has a weight percentage of carbon double/triple bond containing monomer units of between about 0.01 and about 2%, and preferably, between about 0.03 and about 0.6%. In certain embodiments, the organopolysiloxane having carbon double or triple bonds has a vinyl equivalent per kilogram of between about 0.005 and about 0.5, and preferably, between about 0.01 and about 0.25. An approximate molar amount of carbon double/triple bonds in the organopolysiloxane can be calculated based on the average molecular weight of the organopolysiloxane.
[088] In certain embodiments, the organopolysiloxane having Si-H units includes such Si-H units in polymer terminal units, non-terminal polymer monomer units, or a combination thereof. In preferred embodiments, the organopolysiloxane having Si-H units includes such Si-H units in non-terminal monomer units of the polymer. In preferred embodiments, the Si-H containing monomer units in the organopolysiloxane are spaced on average by at least about 1 monomer units, about 2 monomer units, about 5 monomer units, about 10 monomer units, about 20 monomer units, about 40 monomer units, about 200 monomer units, about 400 monomer units, about 1,000 monomer units, or about 2,000 monomer units.
[089] In certain embodiments, the organopolysiloxane having Si-H units has a weight percentage of Si-H containing monomer units of between about 0.003 and about 50%, and preferably, between about 0.01 and about 25%. In certain embodiments, organopolysiloxane having Si-H units has an Si-H content of between about 0.1 mmol/g and about 20 mmol/g, about 0.5 mmol/g and about 10 mmol/ g, and preferably, between about 1 mmol/g and about 5 mmol/g. An approximate molar amount of the Si-H units in the organopolysiloxane can be calculated based on the average molecular weight of the organopolysiloxane. The average molecular weight, or molar mass, of the ingredients disclosed herein are commonly provided by the ingredient manufacturer, expressed in Dalton units (Da) or their equivalent g/mol.
[090] The term “viscosity” refers to the measure of the strength of a fluid that is deformed by shear stress or tensile stress. The viscosity of the composition affects the thickness, dispersibility and flatness and/or uniformity of the layer formed on a substrate. Viscosity can be reported as dynamic viscosity (also known as absolute viscosity, typical units Pa-s, Poise, P, cP) or kinematic viscosity (typical units cm2/s, Stokes, St, cSt), which is the dynamic divided viscosity by density of the measured fluid. Viscosity ranges of ingredients disclosed herein are commonly provided by the ingredient manufacturer in kinematic viscosity units (eg, cSt) as measured using a Rheometer or Cannon-Fenske Tube Viscometer.
[091] The viscosity of a fluid can be measured in vitro, for example, with the use of a rheometer (eg, linear shear rheometer or dynamic shear rheometer) or a viscometer (also called a viscometer, e.g., viscometer capillary or rotary viscometer) at a specific instrument voltage. For example, Thomas G. Mezger, The Rheology Handbook: For Users of Rotational and Oscillatory Rheometers (2nd Edition), Vincentz Network, 2006, and American Society for Testing and Materials (ASTM) standards such as ASTM D3835-08, ASTM D2857- 95, ASTM D2196-10 and ASTM D2983-09 provide instructions on how to measure the viscosity of a fluid. The viscosity of a fluid is preferably measured in vitro using the Rheometer Viscosity Measurement Test described herein. Fluid density can vary with temperature or pressure. Unless otherwise specified, all properties of compositions, layers and/or devices disclosed herein, including viscosity, are measured at room temperature (about 25°C) and about 1 atmospheric pressure.
[092] In certain embodiments, the composition has a viscosity above about 100 cP and below about 1,000,000 cP at about 25°C. In certain embodiments, the composition has a viscosity below about 750,000 cP, below about 500,000 cP, or below about 250,000 cP at about 25°C. In preferred embodiments, the composition has a viscosity below about 200,000 cP, below about 175,000 cP, below about 150,000 cP, below about 125,000 cP, below about 100,000 cP, or below about 80,000 cP at about 25°C. In certain embodiments, the composition has a viscosity above about 100 cP, above about 500 cP, or above about 1000 cP at about 25°C. In preferred embodiments, the composition has a viscosity above about 2,000 cP, above about 5,000 cP, above about 7,500 cP, or above about 10,000 cP at about 25°C. In further preferred embodiments, the composition has a viscosity above about 15,000 cP at about 25°C.
[093] In preferred embodiments, the composition comprises: Polymer A) one or more organopolysiloxanes having on average at least two alkenyl-functional groups and having a viscosity of about 10,000 to about 2,000,000 cSt at about 25° Ç; Polymer B) one or more organopolysiloxanes having on average at least two Si-H units and having a viscosity of about 2 to about 100,000 cSt at about 25°C; and, optionally, Polymer C) one or more organopolysiloxanes having on average at least one alkenyl-functional group and having a viscosity of about 0.7 to about 10,000 cSt at about 25°C.
[094] In certain embodiments, the molar ratio of Si-H functional group of Polymer B to alkenyl-functional group of Polymer A is from about 60:1 to about 1:5. In preferred embodiments, the molar ratio of Si-H functional group of Polymer B to alkenyl-functional group of Polymer A is about 45:1 to about 15:1. In certain embodiments, the molar ratio of Si-H functional group of Polymer B to alkenyl-functional group of Polymer C is from about 60:1 to about 1:5. In preferred embodiments, the molar ratio of Si-H functional group of Polymer B to alkenyl-functional group of Polymer C is about 45:1 to about 15:1. In certain embodiments, the molar ratio of Polymer A's alkenyl-functional group to Polymer C's alkenyl-functional group is about 100:1 to about 1:100. In preferred embodiments, the molar ratio of Polymer A's alkenyl-functional group to Polymer C's alkenyl-functional group is about 10:1 to about 1:10.
[095] In certain embodiments, Polymer A has a viscosity between about 10,000 and about 2,000,000 cSt at about 25 °C. In preferred embodiments, Polymer A has a viscosity above about 20,000, above about 40,000, above about 60,000, above about 80,000, or above about 100,000 cSt at about 25°C. In further preferred embodiments, Polymer A has a viscosity above about 125,000 or above about 150,000 cSt at about 25°C. In preferred embodiments, Polymer A has a viscosity below about 1,000,000 cSt, below about 500,000 cSt, below about 450,000, below about 400,000, below about 350,000, below about 300,000 or below of about 250,000 cSt at about 25 °C. In further preferred embodiments, Polymer A has a viscosity below about 200,000 or below about 180,000 cSt at about 25°C. In further preferred embodiments, Polymer A has a viscosity of about 165,000 cSt at about 25°C.
[096] In certain embodiments, Polymer A has an average molecular weight between about 60,000 Da and about 500,000 Da. In preferred embodiments, Polymer A has an average molecular weight above about 72,000 Da, about 84,000 Da, about 96,000 Da or about 100,000 Da. In further preferred embodiments, Polymer A has an average molecular weight above about 140,000 Da or about 150,000 Da. In preferred embodiments, Polymer A has an average molecular weight below about 200,000 Da. below about 190,000 Da, about 180,000 Da, or about 170,000 Da. In further preferred embodiments, Polymer A has an average molecular weight below about 160,000 Da. In further preferred embodiments, Polymer A has an average molecular weight of about about of 155,000 Da.
[097] In certain embodiments, Polymer B has a viscosity between about 2 to about 500,000 cSt at about 25 °C. In preferred embodiments, Polymer B has a viscosity above about 3 cSt, above about 4 cSt, or above about 12 cSt at about 25°C. In further preferred embodiments, Polymer B has a viscosity above about 40 cSt at about 25°C. In preferred embodiments, Polymer B has a viscosity below about 200,000, below about 100,000, below about 50,000, below about 20,000, below about 10,000, below about 5,000, below about 2,000 or below about 1000 cSt at about 25 °C. In further preferred embodiments, Polymer B has a viscosity below about 500 cSt at about 25°C. In further preferred embodiments, Polymer B has a viscosity between about 45 to about 100 cSt at about 25°C.
[098] In certain embodiments, Polymer B has an average molecular weight between about 400 and about 500,000 Da. In preferred embodiments, Polymer B has an average molecular weight above about 500 Da, about 800 Da, about 1,200 Da or about 1,800 Da. In further preferred embodiments, Polymer B has an average molecular weight above about 2,000 Da. In preferred embodiments, Polymer B has an average molecular weight below about 250,000 Da, below about 140,000 Da , below about 100,000 Da, below about 72,000 Da, below about 62,700 Da, below about 49,500 Da, below about 36,000 Da or below about 28,000 Da. In additionally preferred embodiments, Polymer B it has an average molecular weight below about 17,200 Da. In further preferred embodiments, Polymer B has an average molecular weight between about 2,200 Da and 6,000 Da.
[099] In certain embodiments, Polymer C has a viscosity of between about 0.7 cSt to about 10,000 cSt at about 25 °C. In preferred embodiments, Polymer C has a viscosity of above about 1 cSt, above about 6 cSt, above about 10 cSt, above about 20 cSt, above about 50 cSt, or above about 100 cSt at about 25°C. In further preferred embodiments, Polymer C has a viscosity of above about 200 cSt at about 25°C. In preferred embodiments, Polymer C has a viscosity of below about 5,000 cSt, about 4,000 cSt, below about 2,000 cSt, or below about 1,000 cSt at about 25°C. In further preferred embodiments, Polymer C has a viscosity of below about 500 cSt at about 25°C. In further preferred embodiments, Polymer C has a viscosity of about 250 cSt at about 25°C.
[100] In certain embodiments, Polymer C has an average molecular weight between about 180 Da and about 65,000 Da. In preferred embodiments, Polymer C has an average molecular weight above about 500 Da, about 800 Da, about 1,500 Da, about 3,000 Da, or about 6,000 Da. In further preferred embodiments, Polymer C has an average molecular weight above about 9,400 Da. In preferred embodiments, Polymer C has an average molecular weight below about 50,000 Da. about 45,000 Da or about 30,000 Da. In further preferred embodiments, Polymer C has an average molecular weight below about 17,500 Da. In further preferred embodiments, Polymer C has an average molecular weight of about 10,000 Da.
[101] In preferred embodiments, Polymers A and C are each independently selected from vinyl-terminated polydimethylsiloxane, vinyl-terminated diphenylsiloxane-dimethylsiloxane copolymers, vinyl-terminated polyphenylmethylsiloxane, vinyl-terminated polyphenylsiloxane-phenylmethylsiloxane, vinyl-terminated trifluoromethylsiloxane, vinyl-terminated trifluoromethylsiloxane copolymer, vinyl-terminated dimethylsiloxane, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer, triethylsiloxy-terminated vinylmethylsiloxane-dimethylsiloxane copolymer, silanol-terminated vinylmethylsiloxane-dimethylsiloxanes copolymer, dimethyl vinyloxane vinyloxane homopolymers vinylmethylsiloxane, vinyl T-structure polymers, vinyl Q-structure polymers, unsaturated organopolymers (non-limiting examples of which include one or more of unsaturated fatty alcohols, unsaturated fatty acids, this unsaturated fatty resins, unsaturated grease amide, unsaturated fatty urethane, unsaturated grease urea, ceramide, cocetin, lecithin and spinosine), vinyl-terminated monopolydimethylsiloxanes, vinylmethylsiloxane terpolymers, vinylmethoxysilane homopolymers, polyalkylsilox-terminated vinyloxysiloxane polymers vinyl and combinations thereof. In further preferred embodiments, Polymers A and C are each vinyl dimethicone.
[102] In preferred embodiments, Polymer B is selected from hydride-terminated polydimethylsiloxane, polyphenyl-(dimethylhydrosiloxy)siloxane, hydride-terminated methylhydrosilane-phenylmethylsiloxane copolymer, triethylsiloxane-dimethylsiloxane-terminated triethylsiloxy, polymethanesyloxy, polymethanesyloxy-terminated copolymers triethylsiloxane, methylhydrosiloxane-phenyloctylmethylsiloxane copolymer, methylhydrosiloxane-phenyloctylmethylsiloxane terpolymer and combinations thereof. In further preferred embodiments, Polymer B is hydrogen dimethicone.
[103] In certain embodiments, the composition is a two-part composition comprising a first part and a second part. In preferred embodiments, the first part comprises Polymers A and B. In preferred embodiments, the first part further comprises one or more reinforcing components. In preferred embodiments, the second part comprises Polymer C.
[104] In certain embodiments, the weight ratio of polymer to reinforcement component is from about 100:1 to about 1:1. In preferred embodiments, the weight ratio of polymer to reinforcement component is about 50:1 to about 2:1. In further preferred embodiments, the weight ratio of polymer to reinforcement component is about 15:1 to about 3:1. In more preferred embodiments, the weight ratio of polymer to reinforcement component is about 10:1 to about 4:1. In even more preferred embodiments, the weight ratio of polymer to reinforcement component is about 7:1 to about 8:1.
[105] In preferred embodiments, the first portion comprises about 5 to about 90% by weight of Polymer A; about 5 to about 75% by weight of Polymer B; and about 0 to about 25% by weight of reinforcing component. In further preferred embodiments, the first portion comprises from about 50 to about 90% by weight of Polymer A; about 5 to about 30% by weight of Polymer B; and about 5 to about 15% by weight of reinforcing component.
[106] In certain embodiments, the composition additionally comprises a catalyst that facilitates crosslinking of the one or more crosslinkable polymers. In the case of a two-part composition, in certain embodiments, the second part further comprises one or more catalysts which facilitate crosslinking of the one or more crosslinkable polymers. “Catalyst” includes any substance that causes, facilitates or initiates a physical and/or chemical crosslinking reaction. The catalyst may or may not undergo permanent physical and/or chemical changes during or at the end of the process. In preferred embodiments, the catalyst is a metal catalyst capable of initiating and/or facilitating crosslinking at or below body temperature, for example, Group VIII metal catalysts such as platinum, rhodium, palladium, cobalt, catalysts, nickel, ruthenium, osmium and iridium, and group IVA metal catalysts such as germanium and tin. In further preferred embodiments, the catalyst is a platinum catalyst, a rhodium catalyst or a tin catalyst. Examples of platinum catalysts include, for example, platinum carbonyl cyclovinylmethylsiloxane complexes, platinum divinyltetramethyldisiloxane complexes, platinum cyclovinylmethylsiloxane complexes, platinum octanaldehyde/octanol complexes and other Pt(0) catalysts such as Karstedt's catalyst, platinum-alcohol complexes , platinum-alkoxide complexes, platinum-ether complexes, platinum-aldehyde complexes, platinum-ketone complexes, platinum-halogen complexes, platinum-sulfur complexes, platinum-nitrogen complexes, platinum-phosphorus complexes, complexes platinum-carbon double bond complexes, platinum-carbon triple bond complexes, platinum-imide complexes, platinum-amide complexes, platinum-ester complexes, platinum-phosphate ester complexes, platinum-thiol ester complexes, platinum-electron solitary complexes, platinum-aromatic complexes, platinum electron complexes and combinations thereof. Examples of rhodium catalyst include rhodium tris(dibutylsulfide) trichloride and rhodium trichloride hydrate. Examples of tin catalysts include tin II octoate, tin II neodecanoate, dibutyltin diisooctylmaleate, Di-n-butylbis(2,4-pentanedionate)tin, di-n-butylbutoxychlorotin, dibutyltin dilaurate, dimethyltin dyneodecanoate, dimethylhydroxy(oleate )tin and tin oleate II. In preferred embodiments, the catalyst is a platinum catalyst. In further preferred embodiments, the catalyst is platinum divinyltetramethyldisiloxane complexes.
[107] In preferred embodiments, the composition comprises about 0.001 to about 1% by weight of (i.e., about 10 ppm to about 1,000 ppm), preferably about 0.005 to about 0.05% by weight of (i.e., about 50 ppm to about 500 ppm) catalyst. In further preferred embodiments, the composition comprises from about 0.01 to about 0.03% by weight of catalyst.
[108] In certain embodiments, the composition is a two-part composition comprising a first part comprising polymer (or polymers) A and Polymer B; and a second part comprising polymer (or polymers) C and one or more catalysts.
[109] In certain embodiments, the composition is a two-part composition comprising a first part comprising polymer (or polymers) A and polymer (or polymers) C and one or more catalysts; and a second part comprising Polymer B.
[110] In certain embodiments, the composition is a two-part composition comprising a first part comprising polymer (or polymers) A and one or more catalysts; and a second part comprising Polymer B and polymer (or polymers) C.
[111] In certain embodiments, the composition is a two-part composition comprising a first part comprising Polymer B and polymer (or polymers) C; and a second part comprising polymer (or polymers) A and one or more catalysts.
[112] In preferred embodiments, the second portion comprises from about 0.005 to about 0.05% by weight of catalyst. In further preferred embodiments, the second portion comprises from about 0.01 to about 20% by weight of Polymer C; and about 0.005 to about 0.05% by weight catalyst. In further preferred embodiments, the second portion comprises from about 0.5 to about 10% by weight of Polymer C; and about 0.01 to about 0.03% by weight of catalyst.
[113] In certain embodiments, the first part is applied to the skin before the second part is applied, and a layer is formed after the second part is applied over the first part. In certain embodiments, the second part is applied to the skin before the first part is applied and a layer is formed after the first part is applied over the second part. In certain embodiments, the first part is applied to the skin along with the second part and a layer is formed after both compositions are applied. In certain embodiments, the first part and the second part are mixed together and then applied to the skin, and a layer is formed after the mixture is applied. In preferred modalities, the first part is gently spread over an area of the patient's skin, the second part is gently spread over the first part so as to cover the entire area of the first part.
[114] In certain embodiments, the ratio of weight or amount to volume of the first part to the second part is from about 5:1 to about 1:20. In preferred embodiments, the weight ratio or volume amount of the first part to the second part is about 2:1 to about 1:2. In further preferred embodiments, the weight ratio or volume amount of the first part to the second part is about 1:1.
[115] Anhydrous compositions generally have a longer shelf life than emulsions with similar ingredients, without the need for preservatives against bacteria or mold. "Anhydrous" as used herein refers to containing an ingredient less than about 10%, less than about 5%, less than about 2%, less than about 1% or less than about 0.1% water. In some embodiments, the composition is anhydrous. In some embodiments, the composition is an emulsion. In some embodiments, the composition is a dispersion. In some embodiments, the composition is a suspension. In some embodiments, the composition is a paste. In some embodiments, the composition is a semi-solid. In some modalities, the composition is an ointment. In some embodiments, the composition is a cream. In some embodiments, the composition is a serum. In some modalities, the makeup is a lotion. In some embodiments, the composition is a plaster. In certain embodiments, the composition can be spread, sprayed, stencilled, patterned, plastered, transferred, layered, covered or sprayed onto the skin.
[116] In certain modalities, the first part is anhydrous. Alternatively, the first part is an emulsion. In certain embodiments, the first part can be spread, sprayed or sprayed onto the skin.
[117] In certain modalities, the second part is anhydrous. Alternatively, the second part is an emulsion. In certain embodiments, the second part can be spread, sprayed or sprayed onto the skin.
[118] In certain embodiments, the first part has a viscosity above about 100 cP, above about 500 cP, or above about 1000 cP at about 25°C. In preferred embodiments, the first part has a viscosity above about 2,000 cP, above about 5,000 cP, above about 7,500 cP, or above about 10,000 cP at about 25°C. In further preferred embodiments, the first part has a viscosity above about 15,000 cP at about 25°C. In certain embodiments, the first part has a viscosity below about 1,000,000 cP, below about 750,000 cP, below about 500,000 cP, or below about 250,000 cP at about 25°C. In preferred embodiments, the first part has a viscosity below about 200,000 cP, below about 175,000 cP, below about 150,000 cP, below about 125,000 cP, below about 100,000 cP, or below about 80,000 cP cP at about 25°C.
[119] In certain embodiments, the second part has a viscosity above about 100 cP, above about 500 cP, or above about 1000 cP at about 25°C. In preferred embodiments, the second part has a viscosity above about 2,000 cP, above about 5,000 cP, above about 7,500 cP, or above about 10,000 cP at about 25°C. In further preferred embodiments, the second part has a viscosity above about 15,000 cP at about 25°C. In certain embodiments, the second part has a viscosity below about 1,000,000 cP, below about 750,000 cP, below about 500,000 cP, below about 250,000 cP, below about 200,000 cP, or below about about 200,000 cP of 175,000 cP at about 25°C. In preferred embodiments, the second part has a viscosity below about 150,000 cP, below about 125,000 cP, or below about 100,000 cP at about 25°C. In further preferred embodiments, the second part has a viscosity below about 80,000 cP at about 25°C.
[120] In certain embodiments, the composition additionally comprises one or more additives. In certain embodiments, the first part and/or the second part further independently comprise (or comprise) one or more additives. Suitable additives include, but are not limited to, feel modifiers, tack modifiers, dispersibility enhancers, diluents, adhesion modifiers, volatile siloxanes, emulsifiers, emollients, surfactants, thickeners, solvents, film formers, wetting agents, preservatives, pigments, improvers permeation agents, optical modifiers, gas transport modifiers, liquid transport modifiers, pH modifiers, sensitization modifiers, aesthetic modifiers and a combination thereof. Additional suitable additives are disclosed in the International Dictionary of Cosmetic Ingredient Nomenclature (INCI), which is incorporated herein by reference in its entirety. In preferred embodiments, the emulsifiers are alkoxydimethicone, alkyldimethicone, amodimethicone, sulfodimethicone, phosphodimethicone, borodimethicone, halodimethicone, fluorodimethicone, chlorodimethicone, bromodimethicone, loaded dimethicone, and a combination thereof.
[121] In certain embodiments, the composition additionally comprises one or more additional agents. In certain embodiments, the first part and/or the second part further independently comprise (or comprise) one or more additional agents, including cosmetic agents, therapeutic agents, stimulus responsive agents, uptake agents, drug delivery agents, optical agents, coloring agents, pigments, spreading agents, sorption agents, temperature active agents, heat active agents, UV active agents, light active agents, sound active agents, pressure active agents, active agents in motion , radioactive agents, electrical agents, magnetic agents and other beneficial agents.
[122] Suitable cosmetic agents include, but are not limited to, moisturizers, sunscreens, UV protecting agents, skin protecting agents, skin softening agents, skin lightening agents, skin lightening agents, skin softening agents skin, skin softening agents, skin bleaching agents, skin exfoliating agents, skin tightening agents, cosmeceutical agents, vitamins, antioxidants, cell signaling agents, cell modulating agents, cell interacting agents, skin tanning agents, anti-aging agents, anti-wrinkle agents, signal reducers, alpha-hydroxy acids, beta-hydroxy acids, ceramides and a combination thereof.
[123] Suitable therapeutic agents include, but are not limited to, pain relievers, analgesics, anti-itch agents, anti-acne agents (beta-hydroxy acids, salicylic acid, benzoyl peroxide), anti-inflammatory agents, antihistamines, corticosteroids, NSAIDs ( Non-Steroidal Anti-Inflammatory Drugs), antiseptic agents, antibiotics, antibacterial agents, antifungal agents, antiviral agents, antiallergenic agents, anti-irritants, insect repellent agents, phototherapy agents, blood clotting agents, antineoplastics, blood-enhancing agents immune system, immune system suppressing agents, coal tar, anthralin, fluocinonide, methotrexate, cyclosporine, pimecrolimus, tacrolimus, azathioprine, fluorouracil, ceramides, counterirritants, skin cooling compounds and a combination thereof.
[124] Suitable beneficial agents include, but are not limited to, antioxidants, vitamins, vitamin D3 analogues, retinoids, minerals, mineral oil, petroleum jelly, fatty acids, plant extracts, polypeptides, antibodies, proteins, sugars, humectants, emollients, a combination thereof, and other similar beneficial agents for topical application known in the art.
[125] Another aspect of the present invention is directed to a composition that forms a layer on the skin, wherein the composition has a glass transition temperature near or below body temperature. The term “glass transition temperature” refers to the temperature at which a transition from solid to liquid state occurs. The glass transition temperature can be reported as a temperature (°C, °F or K). Glass transition temperature can be measured in vitro, for example, using thermal analysis instruments such as a Differential Scanning Calorimeter (DSC) or a Thermogravimetric Analysis (TGA). In certain embodiments, the layer-forming composition has a glass transition temperature below about 37°C. In preferred embodiments, the layer-forming composition has a glass transition temperature below about 25°C. In further preferred embodiments, the layer-forming composition has a glass transition temperature below about 0°C. In certain embodiments, the first portion of the composition that forms the layer has a glass transition temperature below about 37°C. In preferred embodiments, the first portion of the composition that forms the layer has a glass transition temperature below about 25°C. In further preferred embodiments, the first portion of the composition that forms the layer has a glass transition temperature below about 0°C. In certain embodiments, the second portion of the composition that forms the layer has a glass transition temperature below about 37°C. In preferred embodiments, the second portion of the composition that forms the layer has a glass transition temperature below about 25°C. In further preferred embodiments, the second portion of the composition that forms the layer has a glass transition temperature below about 0°C.
[126] One aspect of the invention is directed to compositions that form a layer on a surface such as leather, glass, plastic, metal, ceramic, semiconductor, insulator, conductor, or the skin, mucous membrane, lip, hair or the nail in-situ, that is, at the location where the compositions disclosed herein are applied. The layer is preferably formed without the need for exposure to heat, UV, light, electrical, magnetic, pressure or sound. The layer can be further formed with exposure to one or more of heat, UV, light, electricity, magnetism, pressure and sound. Another aspect of the invention is directed to compositions that form a layer on a surface such as leather, glass, plastic, ceramic, semiconductor, insulator, conductor or metal, which is then applied to the skin, mucous membrane, lip, hair or a patient's nail.
[127] Another aspect of the present invention is directed to a composition that forms a layer that has low adhesion and forms quickly. The term “drying time” refers to the time when the layer has solidified sufficiently so that it no longer flows and transfers to a finger or an artificial substrate that lightly touches it under a normal force of less than 50 Newtons. When the layer is “ready to play”, it becomes substantially resistant to environmental factors, and thus allows the user to resume the intended activities. The term "tack free time" refers to the time when the layer has solidified sufficiently so that it no longer sticks to a finger or a substrate that lightly touches it under normal force less than 0.15 Newtons, and it incurs tackiness. to the movie. When the layer is “adhesion free”, it becomes substantially resistant to surface friction and abrasion from environmental factors, and thus allows the user to additionally resume the intended activities. Consequently, proper drying time and tack-free time for the layer is important: a longer drying time and tack-free time would require the user to wait a longer time before resuming activities, which affects consumer compliance; while a shorter drying time and tack-free time would require faster handling, application and/or spreading of the composition, which is not achievable by all users, or may otherwise negatively affect continuity, leveling, uniformity and/or the physical properties of the layer. It has been found that increasing the molar ratio of the low viscosity crosslinkable polymer (or crosslinkable polymers), particularly low viscosity alkenyl or alkynyl organopolymer in the composition (even more particularly in the second part in case of a two part composition), Reduced drying and tack-free time of the formed layer. Thus, it is critical to have an appropriate amount of low viscosity crosslinkable polymer (or crosslinkable polymers), particularly low viscosity alkenyl or alkynyl organopolymer in the composition to achieve a desirable drying time and tack free time.
[128] In certain embodiments, the composition additionally comprises between 0.05% and 30% by weight of one or more polymers and/or non-polymers which affects the drying time of the composition. Such polymers can be, but not necessarily, any of polymers A, B or C. Other suitable polymers include, but are not limited to, polytetrafluoroethylene (PTFE), poly(methyl methacrylate) (PMMA), polyethylene (PE or polyethene), polypropylene (PP or polypropene), polyvinylidene fluoride (PVDF), polyurethane, acrylate, polyester such as nylons, polyether, polycarbonate, polysulfone, polyphosphate or a combination thereof. Non-suitable polymers include, but are not limited to, particles such as carbon, silica, boron nitride, metal oxides (eg, zinc oxide, titanium dioxide) and salts such as carbonate salts (eg, calcium, magnesium, sodium salts), sulfates, phosphates, borates, halogenated salts or a combination thereof.
[129] Drying time can be measured on test patients, for example, using the Drying Time and Film Adhesion Free Time Test described herein, as modified from ASTM D5895-03. Drying time can also be measured in vitro, for example using the Dry Time Film Test described herein, using suitable substrates, eg polyurethane, polypropylene and/or leather from tooling tools. bovine skin. In certain embodiments, the composition has a drying time of greater than about 1 second and less than about 10 minutes. In preferred embodiments, the composition has a drying time of greater than about 30 seconds and less than about 4 minutes. In further preferred embodiments, the composition has a drying time of greater than about 30 seconds and less than about 2 minutes. In further preferred embodiments, the composition has a drying time of greater than about 1 minute and less than about 2 minutes. In other preferred embodiments, the composition has a drying time of about 2 minutes. Polyurethane and polypropylene have surface conditions preferentially used for drying time measurement due to their smoothness, low aspect ratio and in-vitro cure characters that are similar to in-vivo skin cure characters.
[130] Adhesion free time is measured in test patients using the Drying Time and Film Adhesion Free Time Test described herein, as modified from ASTM D5895-03. Tack free time can also be measured in vitro using the Dry Time Test and Film Tack Free Time described herein on suitable substrates, eg polyurethane, polypropylene and leather from bovine hide tools . In certain embodiments, the composition has a tack-free time of greater than about 1 second and less than about 10 minutes. In preferred embodiments, the composition has a tack-free time of greater than about 30 seconds and less than about 4 minutes. In further preferred embodiments, the composition has a tack-free time of greater than about 30 seconds and less than about 2 minutes. In further preferred embodiments, the composition has a tack-free time of greater than about 1 minute and less than about 2 minutes. In other preferred embodiments, the composition has a tack-free time of about 2 minutes. Polyurethane and polypropylene have surface conditions preferentially used for tack free time measurement due to their smooth surface with low aspect ratio and in-vitro cure characters that are similar to the in-vivo skin cure characters.
[131] Another aspect of the invention is directed to a composition that forms a thin layer on the skin. The thickness of the layer affects both its breathability, invisibility, compressibility, and its occlusive skin effects. “Thickness” refers to the average thickness of the layer applied to a surface. The thickness of the formed layer can be measured in vitro, for example, in a cross-section of a layer using a microscope that has a stage or ocular micrometer. Layer thickness is measured on a formed specimen of the composition in vitro using the ASTM D3767 Rubber Size Measurement using the Mitutoyo Thickness Gauge test, modified to be used in free film or in a layer on a substrate such as polyurethane, polypropylene and cowhide tool leather at room temperature and about 50% relative humidity. Polyurethane and polypropylene have surface conditions that are preferentially used for thickness measurement due to their smooth surface with low aspect ratio, which allows the layer to be easily removed as a free layer. Bovine Skin Tool Leather has the necessary water absorption and bead surface conditions for thickness measurement. Bovine hide tool leather is commonly vegetable tanned and readily absorbs water and dries quickly because the fiber structure is less compact than that of chrome tanned leather. Leather from bovine hide tools is “full bead”, which means that the hair has been removed and the original bead remains. Layer thickness can also be measured on a formed specimen of the composition in vitro, for example using the ASTM D-6132 Applied Organic Coatings Dry Film Thickness Non-Destructive Measurement test using the Coating Thickness Gauges test PosiTector Ultrasonic, modified to use polyurethane as substrate at room temperature and about 50% relative humidity.
[132] The measurement of substrate thickness is made before and after applying the makeup, the difference in thickness before and after applying the makeup indicates the layer thickness. In certain embodiments, the average layer thickness is less than about 0.1 mm (100 microns). In preferred embodiments, the average layer thickness is about 0.5 to about 100 microns, about 1 to about 90 microns, about 10 to about 80 microns, about 30 to about 70 microns, about 40 to about 60 microns. In further preferred embodiments, the average layer thickness is about 50 microns.
[133] Another aspect of the invention is directed to a composition that forms a durable layer on the skin. The durability of the layer on skin can be determined, for example, using the Film on Skin Durability test described herein. Increasing the molar ratio and/or viscosity/molecular weight of the high viscosity crosslinkable polymer, particularly high viscosity alkenyl or alkynyl organopolymer in the composition (even more particularly in the first part in case of a two-part composition) has been found to improve durability, including both physical and adhesion integrity, of the formed layer. It has been found that there is a range of the relative molar ratio between the unsaturated carbon groups in the alkenyl or alkynyl organopolymer (or polymers) and the hydride groups in the organopolymer (or polymers) in the composition (even more particularly in the first part in the case of a composition part), which additionally improves durability, including both physical and adhesion integrity, of the formed layer. It has further been found that although preforming the layer provides a cohesive layer with good adhesion to the substrate, in-situ formation of the layer promotes better adhesion to the surface and provides further improved layer durability. Crosslink density gradients created by catalyst migration in a two-part composition can further improve adhesion to the substrate and, consequently, further improved layer durability. The balance of different viscosities and different types of crosslinkable polymers in the compositions affects the balance between drying time, tack-free time and durability of the formed layer.
[134] In certain modalities, the layer remains substantially intact on the skin for about 24 hours or more with routine daily routine activities and/or demanding activities. In preferred embodiments, the layer remains substantially intact on the skin for at least about 30 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, or about 96 hours with activities daily routine and/or demanding activities. In other preferred embodiments, the layer remains substantially intact on the skin for at least about 120 hours, about 144 hours, or about 168 hours with routine daily routine activities and/or demanding activities. "Remains substantially intact" means the layer remains at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95% of the area of skin to which it was originally applied, or at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95% by weight of it remains on the skin.
[135] In certain modalities, the layer remains at least about 50% intact, at least about 60% intact, at least about 70% intact by area or weight on the skin for about 24 hours or more with common activities daily routine and/or demanding activities. In preferred embodiments, the layer remains at least about 80% intact by area or by weight on the skin for about 24 hours or more with common daily routine activities and/or demanding activities. In other preferred embodiments, the layer remains at least about 90% intact, or at least about 95% intact by area or by weight on the skin for about 24 hours or more with common daily routine activities and/or demanding activities . In certain embodiments, the layer remains at least about 50% intact, at least about 60% intact, at least about 70% intact by area or by weight on the skin for at least about 30 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, about 96 hours, at least about 120 hours, about 144 hours or about 168 hours with common daily routine activities and/or with demanding activities. In preferred embodiments, the layer remains at least about 80% intact by area or weight on the skin for at least about 30 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, about 96 hours, at least about 120 hours, about 144 hours, or about 168 hours with common daily routine activities and/or demanding activities. In other preferred embodiments, the layer remains at least about 90% intact, or at least about 95% intact by area or weight on the skin for at least about 30 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, about 96 hours, at least about 120 hours, about 144 hours, or about 168 hours with common daily routine activities and/or demanding activities.
[136] Another aspect of the invention is directed to a composition that forms a layer on the skin that resists peeling. Peel strength is determined by measuring adhesive strength using the Peel Adhesion test described in this document. The term “adhesive strength” refers to the force per unit length required to separate materials adhered to a standard substrate such as leather or polypropylene or polyurethane. In certain embodiments, the adhesive strength of the layer on the polypropylene substrate is greater than about 2 N/m. In a preferred embodiment, the adhesive strength of the layer on the polypropylene substrate is greater than about 5 N/m. In further preferred embodiments, the adhesive strength of the layer on the polypropylene substrate is greater than about 20 N/m, 40 N/m, 60 N/m, 80 N/m, greater than about 100 N/m or greater than about 200 N/m.
[137] Another aspect of the invention is directed to a composition that forms a layer that is resistant to environmental factors such as exposure to heat, cold, wind, water, moisture, bodily fluids (e.g., blood, pus/puris liquor, urine, saliva, sputum, tears, semen, milk or vaginal secretion), tallow, saline, sea water, soapy water, detergent water or chlorinated water. Such resistance to environmental factors is represented by the minimum weight gain upon exposure to these environmental factors. The change in layer weight is determined using the ASTM D2765-95 Crosslinked Ethylene Plastics Gel Content and Swelling Ratio Determination test using a weight scale. In certain embodiments, the layer weight increases by less than about 10% upon exposure to such environmental factors at about 1 hour time point (i.e., 1 hour after application of the composition disclosed herein), time point time about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 30 hours, about 36 hours, about 48 hours, or between 48 hours and a week. In preferred embodiments, the layer weight increases by less than about 5% or less than about 1% upon exposure to such environmental factors at a time point of about 1 hour, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 30 hours, about 36 hours, about 48 hours, or between 48 hours and a week. In further preferred embodiments, the layer weight increases by less than about 0.5% upon exposure to such environmental factors at a time point of about 1 hour, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 30 hours, about 36 hours, about 48 hours, or between 48 hours and a week.
[138] In certain embodiments, layer weight increases by less than about 50% upon exposure to such environmental factors at a time point of about 1 hour (ie, 1 hour after application of the composition disclosed herein) , a time point of about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 30 hours, about 36 hours, about 48 hours, or between 48 hours and a week. In preferred embodiments, the layer weight increases by less than about 5% or less than about 1% upon exposure to such environmental factors at a time point of about 1 hour, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 30 hours, about 36 hours, about 48 hours, or between 48 hours and a week. In further preferred embodiments, the layer weight increases by less than about 0.5% upon exposure to such environmental factors in about 1 hour, a time point of about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 30 hours, about 36 hours, about 48 hours, or between 48 hours and a week.
[139] Another aspect of the invention is directed to a composition that forms a layer that is flexible, stretchable, elastic and conforms to body movement. Such flexible, stretchable, elastic properties that conform to the body movement of the layer are represented by measurements of tensile modulus, shear modulus, residual cyclic tensile stress, cyclic tensile hysteresis lost energy, fracture stress, fracture stress and fracture toughness, which can be tested in vitro on a formed specimen of the composition using the methods described herein. In order for a layer to have the appearance and durability of normal, healthy skin, these physical properties of the layer are preferably covered by specific bands so that the layer will not break when deformed by bodily movement and will return to essentially the same state when the body returns to the original state.
[140] The terms "tensile strength", "final tensile strength", "fracture stress", "breaking stress", "maximum tensile stress", "final tensile stress", "fracture strength" or “break strength” refers to stress at which a specimen fails through fracture. Tensile strength can be measured on a specimen formed of the composition in vitro, for example, using the Cyclic Pull and Extension Test as described herein. In certain embodiments, the layer tensile strength is greater than about 0.05 MPa or greater than 0.10 MPa or greater than 0.20 MPa or greater than about 0.5 MPa. In preferred embodiments, the tensile strength of the layer is greater than about 1.0 MPa or greater than about 2.0 MPa. In preferred embodiments, the tensile strength of the layer is less than about 5 MPa. In further preferred embodiments, the tensile strength of the layer is about 3.0 MPa.
[141] The terms "fracture stress", "breaking elongation", "breaking stretch", "breaking stress", "maximum elongation", "maximum stress", "maximum stretch", "breaking extension" or “maximum extent” refers to the tension at which a specimen fails through fracture. Fracture stress can be measured on a formed specimen of the composition in vitro, for example, using the Cyclic Pull and Extend Test as described herein. In certain embodiments, layer fracture stress is greater than about 25%, greater than 50%, greater than about 100%, greater than about 200%, or greater than about 400%. In additionally preferred embodiments, the layer fracture stress is greater than about 600%, greater than about 800%, greater than about 1,000%, greater than about 1200%, or greater than about 1,500 %.
[142] The terms "tensile modulus", "Young's modulus", "elasticity modulus", "stiffness", "tensile stiffness" or "elastic modulus" refer to the force per unit area that is required to stretch and deform a material beyond its initial length. The tensile modulus is an inverse of compliance, it refers to the flexibility or deformability of a material beyond its initial length. The tensile modulus can be measured on a formed specimen of the composition in vitro, for example, using the Cyclic Pull and Extension Test as described herein. The tensile modulus can also be measured using the standard Tensile Properties of Thermoset Plastics Reinforced test using ASTM D5083 Straight Side Specimens. In certain embodiments, the layer's tensile modulus is from about 0.01 to about 40 MPa. In preferred embodiments, the layer tensile modulus is about 0.05 to about 20 MPa or about 0.1 to about 10 MPa, about 0.1 to about 5 MPa, about 0.1 to about 1 MPa. In further preferred embodiments, the layer's tensile modulus is about 0.25 to about 0.75 MPa. In further preferred embodiments, the layer's tensile modulus is about 0.5 MPa.
[143] The terms "modulus of shear" or "modulus of stiffness" or "shear stiffness" refer to the force per unit area that is required to shear and deform a material beyond its initial length. Shear modulus shall be measured on a formed specimen of the in vitro composition using the Asphalt Binder Determine Rheological Properties test using an ASTM D7175 Dynamic Shear Rheometer. In certain embodiments, the layer's shear modulus is about 0.005 to about 10 MPa. In preferred embodiments, the shear modulus of the layer is about 0.05 to about 5 MPa or about 0.1 to about 1 MPa. In further preferred embodiments, the layer's shear modulus is about 0.25 to about 0.75 MPa. In further preferred embodiments, the shear modulus of the layer is about 0.5 MPa.
[144] The term “cyclical tensile residual stress” refers to a residual tensile stress after cyclical tensile deformation. The term "residual stress" refers to a stress that remains in a material after the original cause of stress is removed. Residual stress can be reported as plastic stress, inelastic stress, inelastic stress, or viscoelastic stress. Cyclic residual tensile stress can be measured on a formed specimen of the composition in vitro, for example, using the Cyclic Pull and Extend Test as described herein. In certain embodiments, the residual cyclic tensile stress of the layer is less than about 10%. In preferred embodiments, the residual cyclic tensile stress of the layer is less than about 5% or less than about 2.5%. In further preferred embodiments, the residual cyclic tensile stress of the layer is less than about 1%. In other preferred embodiments, the residual cyclic tensile stress of the layer is less than about 0.5%, less than about 0.25%, or less than about 0.1%.
[145] The terms “cyclical tensile hysteresis lost energy” or “cyclical hysteresis stress energy” refer to the excess energy that is dissipated as heat when the specimen is subjected to cyclical tensile strain. The energy lost from Cyclic Traction Hysteresis can be measured on a formed specimen of the composition in vitro, for example, using the Cyclic Pull and Extend Test as described herein. In certain embodiments, the lost cyclic tensile hysteresis energy of the layer is less than about 1 kJ/m3. In preferred embodiments, the lost cyclic tensile hysteresis energy of the layer is less than about 0.5 kJ/m3. In further preferred embodiments, the lost cyclic tensile hysteresis energy of the layer is less than about 0.2 kJ/m3.
[146] The terms "fracture toughness", "toughness", "tensile toughness", "deformation energy", "failure energy" or "fracture energy" refer to the ability to absorb mechanical deformation energy per unit volume to the point of failure. Fracture toughness can be measured on a formed specimen of the composition in vitro, for example, using the Cyclic Pull and Extension Test as described herein. In certain modalities, the fracture toughness of the layer is greater than about 500 kJ/m3. In preferred modalities, the fracture toughness of the layer is greater than about 5,000 kJ/m3. In further preferred embodiments, the fracture toughness of the layer is greater than about 10,000 kJ/m3 or greater than about 50,000 kJ/m3.
[147] Another aspect of the invention is directed to a composition that forms a layer that is permeable to oxygen and water vapor, as represented by water permeability coefficient, water vapor permeability coefficient, oxygen transmission rate, rate of water vapor transmission, oxygen permeation and/or water vapor permeance, which are tested in vitro using the methods described in this document.
[148] The term “rate of oxygen transmission” or OTR refers to the flow of oxygen permeation through a membrane of a certain thickness. The oxygen transmission rate can be measured on a formed specimen of the composition in vitro, for example, using the ASTM F2622 Plastic Film Oxygen Gas Transmission Rate test and Lamination Using Multiple Sensors. In certain embodiments, the oxygen transmission rate of the layer is greater than about 5x10-9 cm3/(cm2^s). In preferred embodiments, the oxygen transmission rate of the layer is greater than about 5x10-7 cm3/(cm2-s). In additionally preferred embodiments, the oxygen transmission rate of the layer is greater than about 5x10-5 cm3/(cm2-s). In other preferred embodiments, the layer oxygen transmission rate is greater than about 5x10-4 cm3/(cm2^s), greater than about 5x10-3 cm3/(cm2-s), greater than about of 5x10-2 cm3/(cm2-s), greater than about 0.5 cm3/(cm2-s). In preferred embodiments, the layer's oxygen transmission rate is less than about 5 cm3/(cm2-s).
[149] The term “oxygen permeance” refers to the flux of oxygen permeation through a membrane of a certain thickness, per unit difference in oxygen vapor pressure between the membrane (typically in cmHg). Oxygen permeance can be measured on a specimen formed from the composition in vitro, for example, using the Oxygen Gas Transmission Rate Test through Plastic Film and Lamination Using Multiple Sensors ASTM F2622. In certain modalities, the oxygen permeance of the layer is greater than about 5x10-11 cm3/(cm2-s-cm Hg). In preferred embodiments, the oxygen permeance of the layer is greater than about 5x10—9 cm3/(cm2-s-cm Hg) or greater than about 5x10—7 cm3/(cm2-s-cm Hg). In additionally preferred embodiments, the oxygen permeance of the layer is greater than about 5x10-6 cm3/(cm2-s-cm Hg). In other preferred embodiments, the oxygen permeance of the layer is greater than about 5x10—5 cm3/(cm2-s-cm Hg), greater than about 5x10—4 cm3/(cm2-s-cm Hg), larger than about 5x10—3 cm3/(cm2-s-cm Hg) or larger than about 5x10—2 cm3/(cm2-s-cm Hg). In preferred embodiments, the oxygen permeance of the layer is less than about 0.5 cm3/ (cm2-s-cm Hg).
[150] The terms "oxygen permeability coefficient" or "intrinsic oxygen permeability" refer to a measurement of how fast oxygen can move across a membrane, which involves a successive process of sorption of oxygen on a membrane then followed by oxygen diffusion across the membrane. The oxygen permeability coefficient can be measured on a formed specimen of the composition in vitro, for example, using the Oxygen Gas Transmission Rate through Plastic Film and Lamination Using Multiple Sensors ASTM F2622 test. In certain embodiments, the layer's oxygen permeability coefficient is greater than about 5x10-4 Barrer. In preferred embodiments, the oxygen permeability coefficient of the layer is greater than about 5x10-2 Barrer, greater than about 5 Barrer, or greater than about 50 Barrer. In further preferred embodiments, the oxygen permeability coefficient of the layer is greater than about 500 Barrer. In other preferred embodiments, the layer's oxygen permeability coefficient is greater than about 5,000 Barrer. In preferred embodiments, the oxygen permeability coefficient of the layer is less than about 20,000 Barrer.
[151] The term “water vapor transmission rate” or WVTR refers to the flow of water vapor permeation through a membrane with a certain thickness. The water vapor transmission rate can be measured on a formed specimen of the composition in vitro, for example, using the Water Vapor Transmission Rate Through Plastic Film test and Lamination Using a Sensor Modulated Infrared ASTM F1249. In certain embodiments, the water vapor transmission rate of the layer is greater than about 1x10-9 cm3/(cm2-s) and less than about 1.5x10-1 cm3/(cm2-s). In preferred embodiments, the water vapor transmission rate of the layer is greater than about 1x10-8 cm3/(cm2-s). In further preferred embodiments, the water vapor transmission rate of the layer is greater than about 1x10-7 cm3/(cm2-s). In other preferred embodiments, the water vapor transmission rate of the layer is greater than about 1x10-6 cm3/(cm2-s), greater than about 1x10-5 cm3/(cm2-s) or greater than that about 1x10-4 cm3/(cm2-s). In preferred embodiments, the water vapor transmission rate of the layer is less than about 1.5x10-2 cm3/(cm2-s).
[152] The term "water vapor permeance" refers to the flow of water vapor permeation through a barrier of a certain thickness, per unit water vapor pressure difference between one side and the other side of the barrier (typically in cmHg). Water vapor permeance can be measured on a formed specimen of the composition in vitro, for example, using the Water Vapor Transmission Rate Through Plastic Film test and Lamination Using a Modulated Infrared Sensor ASTM F1249. In certain modalities, the water vapor permeance of the layer is greater than about 1x10-11 cm3/(cm2-s-cm Hg) and less than about 2x10-3 cm3/(cm2-s-cm Hg ). In preferred embodiments, the water vapor permeance of the layer is greater than about 1x10-10 cm3/(cm2-s-cm Hg) or greater than about 1x10-9 cm3/(cm2-s-cm Hg ). In further preferred embodiments, the water vapor permeance of the layer is greater than about 1x10-8 cm3/(cm2-s-cm Hg). In other preferred embodiments, the water vapor permeance of the layer is greater than 1x10-7 cm3/(cm2-s-cm Hg) or greater than 1x10-6 cm3/(cm2-s-cm Hg). In preferred embodiments, the water vapor permeance of the layer is less than about 2x10-2 cm3/(cm2-s-cm Hg).
[153] The terms "water vapor permeability coefficient" or "intrinsic water vapor permeability" refer to a measurement of how fast water vapor can move through a barrier, which involves a process successive sorption of water vapor in a barrier, followed by diffusion of water vapor through the barrier. The water vapor permeability coefficient can be measured on a formed specimen of the composition in vitro, for example, using the Water Vapor Transmission Rate Through Plastic Film test and Lamination Using a Sensor Modulated Infrared ASTM F1249. In certain embodiments, the water vapor permeability coefficient of the layer is greater than about 1x10-3 Barrer and less than about 1x106 Barrer. In preferred embodiments, the water vapor permeability coefficient of the layer is greater than about 0.01 Barrer, greater than about 0.1 Barrer, greater than about 1 Barrer, greater than about 10 Barrer , larger than about 100 Barrer or larger than about 1x103 Barrer. In further preferred embodiments, the water vapor permeability coefficient of the layer is greater than about 1x104 Barrer and less than about 1x105 Barrer.
[154] Another aspect of the invention is directed to a composition that forms a layer over the skin such that transepidermal water loss from the area treated with the composition is reduced or comparable to untreated skin. The term “transepidermal water loss” refers to measuring the amount of water that passes from within a body through the epidermal layer to the surrounding atmosphere through processes of diffusion and evaporation. Transepidermal water loss is measured using the Transepidermal Water Loss (TEWL) measurement test as described in this document. Differences in TEWL measurements caused by the age, race, gender and/or skin area of the tested patient are generally less than the standard error in the TEWL measurements. TEWL measurements can be taken at any time at or after a time point of about 30 minutes, for example, at a time point of about 1 hour, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 30 hours, about 36 hours, about 48 hours, or between 48 hours and a week. In certain embodiments, the transepidermal water loss after application of the composition is less than about 40 g/(m2 -h). In preferred embodiments, the transepidermal water loss after application of the composition is less than about 20 g/(m2 •h). In further preferred embodiments, the transepidermal water loss after application of the composition is less than about 10 g/(m2 •h). In other preferred embodiments, the transepidermal water loss after application of the composition is less than about 5 g/(m2 •h) or less than about 1 g/(m2 •h).
[155] Another aspect of the invention is directed to a composition that forms a layer over the skin such that skin hydration of the area treated with the composition is enhanced or comparable to untreated skin. The term “skin hydration” refers to the measurement of the skin's water content, typically through a corneometer that is based on measuring the capacitance of a dielectric medium near the surface of the skin. Skin hydration measurements can be taken at any time at a time point of about 30 minutes or thereafter, such as at a time point of about 1 hour, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 30 hours, about 36 hours, about 48 hours, or between 48 hours and a week. Skin hydration can be measured, for example, using a corneometer under the procedure as described in H. Dobrev, “Use of Cutometer to assess epidermal hydration”, Skin Research and Technology 2000, 6(4):239 to 244. In certain embodiments, skin hydration after application of the composition is greater than about 20 arbitrary Corneometer units (normalized hydration value). In preferred modalities, skin hydration after application of the composition is greater than about 40 arbitrary corneometer units. In other preferred embodiments, skin hydration after application of the composition is greater than about 60 arbitrary corneometer units or greater than about 80 arbitrary corneometer units.
[156] Skin hydration can also be measured, for example, using the procedure as described in Clarys et al., Hydration measurements of the stratum corneum: comparison between the capacitance method (digital version of the corneometer CM 825 (R) ) and the impedance method (Skicon-200EX (R)), Skin Research and Technology 2011, 18(3):316 to 323. In certain modalities, skin hydration after application of the composition is greater than about 20 microSiemens. In preferred embodiments, skin hydration after application of the composition is greater than about 50 microSiemens. In other preferred embodiments, skin hydration after application of the composition is greater than about 100 microSiemens or greater than about 200 microSiemens or about 400 microSiemens.
[157] Another aspect of the invention is directed to a composition that forms a layer on the skin that hardens the skin. The firming effect that is caused by increasing skin traction is quantified from a specimen formed of the composition in vitro using the in-vitro dimple test as described herein. In certain embodiments, traction is increased by more than 0.1 N/m. In preferred embodiments, traction is increased by more than 0.2 N/m. In preferred embodiments, traction is increased by more than 0.5 N/m, by more than 1.0 N/m, by more than 2.0 N/m, by more than 5.0 N/m m, for more than 10 N/m, for more than 20 N/m, for more than 50 N/m, for more than 100 N/m, for more than 500 N/m or for more than than 1,000 N/m.
[158] Another aspect of the invention is directed to a composition that forms a layer on the skin so that the surface contour of the skin can be modulated. The “skin surface contour” is observed with Canfield 3-D Imaging System or visually with comparative photos before and after application of the test composition.
[159] In preferred embodiments, the composition forms a layer that is cosmetically elegant and has the appearance of normal, healthy, youthful skin on the patient to which the composition or layer is applied. Consequently, the layer can carry cosmetic and therapeutic benefits that reduce the appearance of any signs of aging that include under-eye bags, smile lines, crow's feet, forehead lines and wrinkles.
[160] Another aspect of the invention is directed to a composition that forms a layer on the skin such that the retraction time of the area treated with the composition is decreased compared to untreated skin. The term “retraction time” refers to the time it takes the skin to return to its original state after initial deformation by the Suction Cup device. Skin retraction time can be measured, for example, with the use of a cutometer/suction cup under the procedure as described in H. Dobrev, “Use of Cutometer to assess epidermal hydration”, Skin Research and Technology 2000, 6(4):239 to 244. Skin retraction time measurements can be taken at any time at a time point of about 30 minutes or thereafter, such as at a time point of about 1 hour , about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 30 hours, about 36 hours, about 48 hours, or between 48 hours and a week. In certain embodiments, the skin's retraction time after application of the composition is decreased by about 5% to about 75%. In preferred embodiments, the skin's retraction time after application of the composition is decreased by more than about 10%. In other preferred embodiments, the skin's retraction time after application of the composition is decreased by more than about 25% or more than about 50%.
[161] Another aspect of the invention is directed to a composition that forms a layer that is cosmetically elegant and has the appearance of normal, healthy skin of the patient to which the composition or layer is applied. Consequently, the layer can convey cosmetic and therapeutic benefits by masking, hiding, covering or lessening the appearance of skin conditions, eg, compromised skin barrier function conditions, symptoms of skin conditions, for example, conditions of compromised skin barrier function and/or skin imperfections such as hyperpigmentation, melisma and vitiligo.
[162] Another aspect of the invention is directed to a composition that forms a layer that is cosmetically elegant and has the novel appearance of the patient's skin to which the composition or layer is applied. Consequently, the layer can carry cosmetic and therapeutic benefits by improving the appearance of skin that includes tattooing and makeup.
[163] In preferred embodiments, the composition additionally comprises one or more optical modifiers. In other preferred embodiments, the first part and/or the second part further independently comprise one or more optical modifiers or particles. Optical modifiers or particles introduce surfaces responsive to optical or photonic interaction, for example, roughness for light scattering, and thereby impart a glossy, lustrous, glowing, matte appearance beyond normal healthy skin or comparable thereto, preferably avoid a significantly brighter and/or lustrous appearance than normal skin. Suitable optical modifiers or particles include, for example, pigments, dyes, polymers such as nylon (eg, nylon-6, nylon-10, nylon-12), silicone, acrylic, acrylates/carbamate, or polymer spheres or particles or copolymer, polyethylene spheres, polymethmethacrylate spheres, polystyrene spheres, polyurethane spheres; inorganics such as silica (eg silica and DMPA/isophthalic acid/SMDI copolymer, available as ChronoSphere® Opticals from Lonza Group), boron nitride, talc, mica, alumina, titania; metal such as silver nanoparticles; and silicone, acrylic, acrylates/carbamate or other polymer or copolymer spheres or particles. In certain embodiments, the modifiers or optical particles have an average particle diameter between about 1 µm and about 20 µm. In a preferred embodiment, the modifiers or optical particles have an average particle diameter between about 0.1 µm and about 20 µm. In preferred embodiments, the modifiers or optical particles have an average particle diameter of 2 µm to 15 µm and more preferably 5 to 10 µm.
[164] Another aspect of the invention is directed to a composition that forms a layer that does not significantly change the gloss and/or luster of the area over which the composition is applied. Gloss and/or luster can be measured on a formed specimen of the composition in vitro, for example, using a Luster Meter under the ASTM D523 Specular Luster test, at measuring angles of 20°, 60° and /or 85°. Light angle and measurement can be selected based on anticipated luster range. For example, if the measurement taken at 60° is greater than about 70 luster units (GU), the measurement angle should be changed to 20° in order to optimize measurement accuracy. Conversely, if the measurement taken at 60° is less than about 10 GU, the measurement angle should be changed to 85° in order to optimize measurement accuracy. A measuring angle of 45° or 75° can also be used depending on the luster of the substrate used for the test. Various materials can be used as substrate to mimic normal, healthy skin for testing, eg natural colored bovine hide tool leather. Gloss and/or luster change is indicated by the percentage increase or decrease in luster units in a measurement area after treatment compared to before treatment. In certain embodiments, the change in brightness and/or luster of the area treated with the composition is less than about 20%. In preferred embodiments, the change in brightness and/or luster of the area treated with the composition is less than about 10%. In further preferred embodiments, the change in brightness and/or lustre of the area treated with the composition is less than about 5%.
[165] Another aspect of the invention is directed to a composition that forms a layer that is clear, transparent and/or optically invisible. Another aspect of the invention is directed to a composition that forms a layer such that the area with the composition applied has minimal color shift before and after application, such as L* scale shift of color, a* scale shift of color and/or b* scale change of color. The L* color scale, a* color scale, and b* color scale are the three L*a*b* color spaces specified by the International Commission on Illumination. L* color scale, a* color scale, and b* color scale changes can be measured on a formed specimen of the composition in vitro, for example, using a Minolta Color Meter in terms of the Calculate test Yellow and White Indices of Color Coordinates Instrumentally measured ASTM E313. Various materials can be used as substrate to mimic normal, healthy skin for testing, eg natural colored bovine hide tool leather.
[166] In certain embodiments, the L* scale change of color of the area treated with the composition is less than about 2. In preferred embodiments, the L* scale change of color of the area treated with the composition is less than about 2. that about 1.5. In other preferred embodiments, the color scale change L* of the area treated with the composition is less than about 1 or less than about 0.5. In certain embodiments, the a* color scale change of the composition treated area is less than about 2. In preferred embodiments, the a* color scale change of the composition treated area is less than about 1.5. In other preferred embodiments, the color scale a* of the area treated with the composition is less than about 1 or less than about 0.5. In certain embodiments, the color scale b* of the composition treated area is less than about 2. In preferred embodiments, the color scale b* of the composition treated area is less than about 166.5. In other preferred embodiments, the color scale change b* of the area treated with the composition is less than about 1 or less than about 0.5.
[167] Another aspect of the invention is directed to a composition that forms a layer that is translucent or opaque. In certain embodiments, the composition additionally comprises one or more dyes, including, but not limited to, pigments, dyes (including fluorescent dyes), FD&C colors, D&C colors, lake colors, other color imparting compounds, and a combination thereof. Other suitable colorants are disclosed, for example, in the CTFA Cosmetic Ingredient Handbook, 2nd Edition, 1992. In preferred embodiments, the layer color is substantially contiguous with the patient's normal, healthy skin color. In other preferred embodiments, the layer further comprises various colorants, pearls, patterns, designs or a combination thereof, and thus imparts makeup, cosmetic, aesthetic and/or decorative benefits.
[168] In certain embodiments, a finish formulation may be applied with or over the layer during or after formation to provide a desired tactile or aesthetic visual feel. For example, the finish formulation can provide a silky, smooth and/or smooth tactile feel or a dewy, cool, matte, glossy or luminescent aesthetic look. In certain embodiments, the finish formulation comprises one or more of oils, esters or ethers, feel modifiers, tack modifiers, dispersibility improvers, adhesion modifiers, emulsifiers, emollients, surfactants, thickeners, film formers, humectants, preservatives , cosmetic agents and/or therapeutic agents.
[169] In certain embodiments, the finish formulation comprises optical modifiers or particles, colorants, pearls, patterns and/or designs.
[170] In certain embodiments, the finish formulation may be in various forms, for example, liquid, lotion, cream, ointment, serum, gel, spray, foam, mousse, spray, powder or other suitable forms.
[171] Another aspect of the invention is directed to a kit for use in modifying a patient's skin condition; in treatment of conditions of compromised skin barrier function. In certain embodiments, the kit comprises (i) a composition disclosed herein and (ii) instructions for use.
[172] In certain embodiments, the kit comprises (i) a first part disclosed herein, (ii) a second part disclosed herein, and (iii) instructions for use. In preferred modalities, the first party and the second party are prevented from contacting each other prior to use. In preferred embodiments, the first part and the second part are packaged in separate containers or compartments and applied one at a time or mixed together before use or therewith.
[173] In certain embodiments, the kit additionally comprises a finish formulation. In certain embodiments, the kit further comprises a cleanser suitable for removing the layer from the skin, for example, the cleansers disclosed in U.S. Patent 8,691,202. In certain embodiments, the kit additionally comprises one or more brushes, spatulas and/or mirrors.
[174] Another aspect of the invention is directed to a device formed by applying any of the compositions disclosed herein. Another aspect of the invention is a prosthetic device, for example a prosthetic skin, which modulates hydration retention, oxygen permeability and water vapor permeability in the skin formed by applying any composition disclosed herein. Another aspect of the invention is a prosthetic device, e.g., a prosthetic skin, which modulates the optical appearance on the formed skin by applying any composition disclosed herein. Another aspect of the invention is a prosthetic device, e.g., a prosthetic skin, which modulates mechanical responses of skin formed by application of any composition disclosed herein. Another aspect of the invention is a prosthetic device, eg a prosthetic skin, which modulates electrical responses of the skin (eg by incorporating graphene or magnetic particles, preferably in Part 1) formed by applying any composition disclosed herein. Another aspect of the invention is a prosthetic device, e.g., a prosthetic skin, which modulates magnetic responses of the skin formed by application of any composition disclosed herein. Another aspect of the invention is a prosthetic device, e.g., a prosthetic skin, which modulates skin pressure responses formed by application of any composition disclosed herein. Another aspect of the invention is a prosthetic device, e.g., a prosthetic skin, which modulates the pH responses of skin formed by applying any composition disclosed herein. Another aspect of the invention is a prosthetic device, for example a prosthetic skin, which modulates skin temperature responses formed by applying any composition disclosed herein. Another aspect of the invention is a prosthetic device, e.g., a prosthetic skin, which modulates heat responses of skin formed by applying any composition disclosed herein. Another aspect of the invention is a prosthetic device, e.g., a prosthetic skin, which modulates sound responses of skin formed by applying any composition disclosed herein.
[175] Another aspect of the invention is directed to a method of modifying skin functions, including delivery agents (therapeutics and cosmetics). Non-limiting examples of skin functions that can be modified are skin barrier function; skin pigmentation; skin appearance, including but not limited to caruncles, acne (sebaceous gland), melasma, vitiligo, psoriasis; contact dermatitis or other dermatitis such as stasis dermatitis; and itching. Non-limiting examples of therapeutics that can be included are anti-inflammatories, anticoagulants, antibiotics and antiseptics. Therapeutics and cosmetics are administered to a patient in need thereof by applying a composition as described herein to the patient's skin or body.
[176] Another aspect of the invention is directed to a method of treating conditions of compromised skin barrier function, including dermatological disorders, skin conditions and wounds, in a patient in need thereof, by applying to the skin or body of the patient. patient a composition as described herein.
[177] Another aspect of the invention is directed to a method of treating symptoms of conditions of compromised skin barrier function in a patient in need thereof, which comprises applying to the patient's skin or body a composition as described herein, and thereby treating one or more symptoms of an impaired skin barrier function condition.
[178] Another aspect of the invention is directed to a method of occluding skin of a patient in need thereof, which comprises applying to the patient's skin or body a composition as described herein, and thereby occluding the skin. “Occlude skin” means to form a semi-permeable or impermeable barrier to water vapor directly or indirectly on the skin. In certain embodiments, the layer is semi-occlusive wherein the composition forms a layer that is semi-permeable to water vapor. Alternatively, the layer is completely occlusive wherein the composition forms a layer that is impermeable to water vapor.
[179] In another aspect of the invention, occlusion improves the effectiveness of a topical drug also administered to the patient's skin. In one embodiment, the topical drug is a corticosteroid and the disease for which the corticosteroid is administered is eczema. In one modality, occlusion restores the skin's barrier function. In one modality, occlusion improved drug delivery.
[180] Occlusive therapy with a semi-occlusive or fully occlusive layer has been well established, particularly for the treatment of atopic dermatitis (for detailed reference: Misha M. Heller, Eric S. Lee, Faranak Kamangar, Wilson Liao, and John YM Koo (2012). Therapy in Atopic Dermatitis, Atopic Dermatitis - Disease Etiology and Clinical Management, Dr. Jorge Esparza-Gordillo (Ed.), ISBN: 978(-953):-51-0110 (-9)).
[181] Said layer has been found to impart the benefit of occlusion to modify and/or restore the skin's barrier function.
[182] Another aspect of the invention is directed to a method for treating a patient for a condition of compromised skin barrier function, or for treating a symptom of such a condition, which comprises applying to the patient's skin or body a composition as described. in this document.
[183] Another aspect of the invention is directed to a method of delivering an agent to a patient to treat a condition of compromised skin barrier function, or to treat a symptom of such a condition, which comprises applying to the patient's skin or body. a composition as described herein, and thereby delivering the agent to the patient.
[184] In one aspect, the present invention conveys its benefit by controlling the rate of delivery of therapeutic agents to the skin, or by modifying and/or improving the effectiveness of therapy relative to the administered dosage of therapeutic agents with the time.
[185] Another aspect of the invention is directed to a method of delivering to a patient a therapeutic agent to treat a condition of compromised skin barrier function, or to treat a symptom of such a condition, which comprises applying to the skin or body of the patient. patient a composition as described herein.
[186] In another aspect, the invention conveys its benefit by occlusion and improved (trans)dermal drug delivery, using the presence of permeation enhancers in the composition described herein. The benefit of occlusion in improving (trans)dermal drug delivery modifies and/or improves the efficacy of drugs with respect to potency and corresponding side effects.
[187] Another aspect of the invention is directed to a method of masking, hiding or covering conditions of compromised skin barrier function, symptoms of compromised skin barrier function and/or skin imperfections, which comprises applying to the skin or body from the patient a composition as described herein, and thereby masks, hides or covers the area with the conditions of compromised skin barrier function, symptoms of compromised skin barrier function and/or skin imperfections.
[188] Another aspect of the invention is directed to a method of treating conditions of compromised skin barrier function, symptoms of compromised skin barrier function and/or skin imperfections in conjunction with another treatment agent (or other agents) ( topical medication, cosmetics and/or personal care products, in the form of an ointment, cream, lotion, gel, spray, foam, mousse or other suitable forms), wherein said other treatment agent (or other agents) is applied to the skin are first, then the composition disclosed herein is applied over such other treatment agent (or other agents) to provide a durable barrier to the other treatment agent (or other agents).
[189] In certain modalities, compromised skin barrier function condition is a dermatological disorder selected from eczema, psoriasis, ichthyosis, rosacea, chronic dry skin, cutaneous lupus, chronic lichen simplex, xeroderma, acne, secondary dermatological disorder triggered by disease, ulcer and a combination thereof. In preferred embodiments, the compromised skin barrier function condition is selected from eczema, psoriasis, ichthyosis, rosacea, and chronic dry skin.
[190] Identification and/or pretreatment of the skin area's function (eg, washing, shaving, or otherwise preparing the area for treatment) can be performed. After the optional pretreatment, the composition is applied to the area in need of treatment to form the layer over the entire area or a portion thereof in need of treatment, and thereby treat the skin function conditions. In certain embodiments where the composition is a two-part composition, the first part and second part are applied one at a time or in combination to form the layer.
[191] Another aspect of the invention is directed to a method for modifying the surface of the skin. In some modalities, the skin's surface is chemically modified by altering its surface pH. In some modalities, the skin is modified by covering portions of its surface with melanin for UV protection. In some modalities, the skin is modified by covering portions of its surface with silicone to reduce its friction. In some modalities, the skin is physically modified so that eye bags and/or expression lines are reduced. In some modalities, the skin is modified by covering portions of its surface with pigments for cosmetic purposes. In some modalities, the skin is modified by covering portions of its surface with light focus elements to modify the skin's appearance. In some modalities, the skin is modified by covering portions of its surface with components that allow electrical responses, for example, incorporating graphene or magnetic particles, preferably in Part 1.
[192] Physically such as an eye bag, optically such as pigment and light focus.
[193] Another aspect of the invention is directed to a method for modifying skin traction. The change in skin traction can modify the skin surface contour and/or the skin indentation dynamics after the stress response. As individuals age, they often lose skin traction and the skin's dynamic recoil response.
[194] The amount of composition applied is determined by the size and location of the area to be treated as well as the type of skin function conditions, eg compromised skin barrier function, to be treated.
[195] The layer may remain over the area until the conditions of compromised skin barrier function are resolved, or ameliorated, or perhaps removed after an appropriate period of time as determined by a knowledgeable practitioner (eg, such a medical practitioner. as a doctor) or by the patient. The application can be repeated as many times as necessary in order to achieve a desired result.
[196] The physical properties of the compositions were measured using the methods (standard or described in this document) and defined devices. Such methods and devices are merely exemplary and other tests, methods, materials and/or devices may be known or appropriately developed to test the properties of the disclosed compositions.
[197] Unless otherwise specified, all properties of compositions, layers and/or devices disclosed herein are measured at ambient temperature (about 22 to 25°C) and about 1 atmospheric pressure. REOMETER VISCOSITY MEASUREMENT TEST
[198] The following test method can be used to determine the dynamic viscosity (Pa-s) of fluid materials at 0.5 s-1 using a Bohlin CVO100 Rheometer (Malvern Instruments) mounted with plate geometry 20 mm parallel. Similar rheometers can be used for viscosity measurements. For each material tested, at least 3 samples are measured and mean viscosity and standard deviation of measurements are recorded.
[199] About 1 g of each test sample is required. Visually inspect the specimen to ensure the specimen appears uniform. Activate the Bohlin Rheometer and temperature controller; launch the Bohlin software and load the viscosity stability test template; install the geometry and reset the instrument. Ensure both geometry and plate are clean, which is critical for accurate test results. Place approximately 1 g of the test sample on the bottom plate of the Rheometer in a pile centered below the geometry. Lower the geometry to the correct gap (about 250 μm). Clean any excess swatches from the sides of the geometry using the flat end of a spatula. Start the test and allow the test to run until complete, then record the viscosity data (Pa s). SKIN FILM DURABILITY TEST
[200] Application of Test Composition. Healthy patients (at least 3) are selected regardless of age, race or gender. Tests are conducted at room temperature and around 50% relative humidity. Draw 4x4 cm2 square outlines on selected volar forearm areas using a standard template as a guide. Using a balance, weigh appropriate amounts (eg, about 0.1 g to about 0.3 g) of the test composition (or about 0.1 g of the first part and about 0.15 g of the second part in cases of a two-part composition) on measurement balances (in cases of a two-part composition, do not mix). Apply the test composition evenly over the 4x4 cm2 squares on the forearm using the tip of a finger, preferably using a finger guard. Make sure all areas of the squares are covered by the composition. In case of a two-part composition, a clean fingertip or new finger guard should be used to spread the second part gently over the first part so that it covers the entire area of the first part.
[201] Measurement. The composition is allowed to sit untouched over the area for about 15 minutes. The patient is then allowed to resume daily activities. Patients are allowed to conduct only routine daily activities or routine daily activities with demanding activities, eg exercising, swimming, steam room, sauna and the like. The type and length of each demanding activity is recorded. The layers formed by the test composition are left on the skin for about 24 hours or more. At certain time points after application of the composition, the durability of the layers is assessed by measuring the percentage of intact area on the skin using an 8x8 square grid of 0.5x0.5 cm2 each (total of 64 squares). Any excess layer outside the 4x4 cm2 square area is not considered in the assessment. Each square is only considered durable if there is no visible imperfection, eg seams, flaking, cracking and/or peeling, of the layer. Record the observations. DRYING TIME AND FILM ADHERENCE FREE TIME TEST
[202] This method was modified from ASTM D5895-03 Evaluate Drying or Curing During Film Formation of Organic Coatings Using Mechanical Engravers. The materials and application of test composition for selected patients are the same as described in the Skin Film Durability Test. The test can also be conducted on substrates other than human skin, eg on natural colored bovine hide tool leather substrates, polyurethane or polypropylene with comparable results. For each composition tested, at least 3 samples are tested and the mean drying time, mean tack-free time and standard deviation of measurements are recorded.
[203] Metering. Start a timer when the test build (or the second part in case of a two-part build) is applied to the entire test area on the forearm. Allow the composition to sit untouched over the area for a certain period of time, eg 30 seconds or one minute. At certain time points, touch a corner of the test area lightly with the use of a fingertip, and visually assess: first the presence or absence of any test composition on the fingertip (Drying Time); then the presence or absence of any film surface that is pulled by the fingertip (Film Tack Freetime Test). Repeat fingertip assessment on untouched portions of the test area at a certain time interval, for example, every 15 seconds or 30 seconds or one minute. The time at which test composition is no longer observed on the fingertip is reported as the “drying time” of the test composition. The time at which the film surface is no longer pulled by the fingertip is reported as the “stick free time” of the test composition. DRYING TIME AND IN-VITRO FILM ADHERENCE FREE TIME TEST
[204] This method was modified from ASTM D5895-03 Evaluate Drying or Curing During Film Formation of Organic Coatings Using Mechanical Engravers. Materials and test composition application for selected substrates are described as follows: Place a 50 micron spacer (eg, a layer of 3M Magic Scotch Tape) over the substrate sheet size of 11.43 cm x 3.81 cm, form a rectangular opening of 9.525 cm x 1.905 cm to expose the surface of the substrate. Apply the test composition to the substrate, then slide the glass back and forth along the edges of the spacer to deposit a smooth, even layer of the test composition. The test can also be conducted on many substrates such as natural colored bovine hide tool leather substrates, polyurethane or polypropylene with comparable results. For each composition tested, at least 3 samples are tested and the mean drying time, mean tack-free time and standard deviation of measurements are recorded.
[205] Metering. Start a timer when the test build (or the second part in case of a two part build) is applied to the entire test area on the substrate. Allow the test composition to sit untouched on the area at room temperature and room humidity for a certain period of time, eg 30 seconds or one minute. At certain time points, place a 1.5 cm x 4 cm propylene sheet on the surface of the test composition, then place a 15g weight on the propylene sheet. Wait for 2 seconds before removing the weight and polypropylene sheet from the surface of the test composition. Visually assess: first the presence or absence of any test composition on the polypropylene sheet. Repeat polypropylene sheet evaluation on untouched portions of the test area at a certain time interval, eg every 15 seconds or 30 seconds or one minute. The time at which test composition is no longer observed on the polypropylene sheet is reported as the “drying time” of the test composition. After the “drying time” is reported, transfer the specimen to the 30 degree inclined surface to assess the “tack free time”. Place the specimen 6 inches (15.24 centimeters) up along the slope surface away from the lowest point and secure the specimen to the slope surface. Drop a 1/32” diameter stainless steel ball onto the top of the film surface from a distance of 2.5 centimeters (one inch) above the film surface. Observe the movement of the stainless steel ball on the film surface as the ball tries to roll down in its own gravity. Report “tack free time” when the ball can roll from the top to the bottom of the film surface continuously, without any interruption of the film friction surface as the film becomes tack free. HULL ADHESION TEST
[206] This test method for adhesive strength was developed in accordance with ASTM C794 Elastomeric Joint Sealant Shell Adhesion. Instron 3342 single column tensile/compression testing system (Instron, Norwood, MA) with 100N load cell (Instron #2519-103) mounted with extension handle geometry can be used, with a sheet of polypropylene. thickness 1/32” as test substrate. Other similar equipment and other soft, flexible substrates can also be used to measure peel strength. Materials and test composition application for selected substrates are described as follows: Place a 50 micron spacer (eg, a layer of 3M Magic Scotch Tape) over the substrate sheet size of 11.43 cm x 3.81 cm, form a rectangular opening of 9.525 cm x 1.905 cm to expose the surface of the substrate. Apply the test composition to the substrate, then slide the glass back and forth along the edges of the spacer to deposit a smooth, even layer of the test composition. Allow the test composition to sit untouched over the area at room temperature and room humidity for 3 hours. Then, place a 1.90 cm (0.75 inch) wide silicone adhesive sheet (Mepitac) over the film to completely cover the film surface on the polypropylene substrate, ready for measurement. For each material tested, at least 3 samples are measured and the average peel strength and standard deviation of the measurements are recorded.
[207] Measurement. Partially peel the silicone-tape-covered test specimen on one end by hand to separate enough of the silicone-tape-covered film from the polypropylene substrate for effective grip by the instrument's extension grip geometry mounts. Attach each side of peeling to its own instrument handle. Ensure that the strips are secured substantially parallel to the geometry. Carry out the extension test at a rate of 1 mm/sec until the two peeling strips completely separate from each other. Record stripping force against time data. The mean sample peeling force (N/m) is calculated by the average instantaneous force (N) measured by the instrument during the experiment normalized by the sample width (0.75 inch or 0.019 m). WAVE TEST FOR CURVED SPECIMEN SURFACE TENSION
[208] Deposition of the test article on a substrate such as skin or elastic band or parafilm results in residual compressive stress on the film due to loss of volume (tension), which in turn translates to tensile stress on the underside of the substrate. The combined result of film deposited on substrate can be observed and quantified based on the level of substrate surface curvature after film deposition.
[209] To prepare the test article for curl testing, the test article was first deposited onto an elastic synthetic rubber sheet or a parafilm substrate as described above in applying test composition to selected substrates. Materials and test composition application for selected substrates are described as follows: Place a 50 micron spacer (eg, a layer of 3M Magic Scotch Tape) over the substrate sheet size of 11.43 cm x 3.81 cm, form a rectangular opening of 9.525 cm x 1.905 cm to expose the surface of the substrate. Apply the test composition to the substrate, then slide the glass back and forth along the edges of the spacer to deposit a smooth, even layer of the test composition. Allow the test composition to set untouched over the area at room temperature and room humidity for 24 hours.
[210] Measurement. Use a Vernier Forceps to measure the end-to-end distance of the wide side of the test specimen that is curved upstream. The end-to-end distance refers to the chord length, which forms an incomplete upstream circle on which the subsequent calculation of the circle's corresponding radius is computed. Report the radius value and its reciprocal as the "curvature" value. Use the curvature value to calculate the surface tension incurred on the substrate. In the case of originally curved surface with inherent surface traction such as skin, the change in surface traction incurred by the deposited top layer will modify the inherent surface traction accordingly. CYCLIC PULL AND EXTENSION TEST
[211] These test methods for Cyclic Tensile Residual Stress (Instant Residual Stress), Cyclic Tensile Hysteresis Lost Energy, Tensile Modulus (of Young), Shear Modulus, Tensile Strength/Maximum Stress, Fracture Stress, and Fracture Toughness was developed to be more closely matched to the specimens disclosed herein in accordance with ASTM D638, ASTM D412, ASTM D1876 test guidelines. Instron 3342 single column tensile/compression testing system (Instron, Norwood, MA) with 100N load cell (Instron #2519-103) mounted with extension handle geometry can be used. Other similar equipment can also be used to measure the properties tested in this document. For each material tested, at least 3 samples are measured and mean and standard deviation results of the measurements are recorded.
[212] About 10 g of the tested composition is needed for each sample. Samples are poured into Teflon-mounted alter-shaped molds, consistent with ASTM D638 guidelines. The dimensions of the “neck” of the mold are about 20mm long, about 5mm wide and about 1.5mm deep. The dimensions of the mold “handles/bell” are about 20mm long, about 15mm wide and about 1.5mm deep, which provides an adequate area to ensure a slip-free fixed grip during testing. . Flatten the top surface of the filled mold with a smooth microscope slide. Ensure the molds are filled with no gaps and the top surface is smooth. Dumped samples are allowed to cure and dry completely for about 20 to about 30 hours. The formed specimens are extracted from their individual molds using a spatula. The width and thickness of the “neck” of the finished specimens are measured with forceps, recorded and inserted into the instrument. The area of the “neck” portion of the specimen is calculated from its width and thickness.
[213] Layers formed by compositions disclosed herein can also be tested once separated from the substrates. Such a layer can be formed or cut into a rectangular shape, and the cross-sectional area of a layer can be calculated from its width and thickness. In such a case, the ends of the rectangular specimen would be considered the “handle/bell” portions while the middle of the rectangular specimen would be considered the “neck” portion.
[214] Mechanical characterization of specimens is performed on the Instron 3342 (Instron, Norwood MA) equipped with a 100 N cell load. Dumbbell or rectangular specimens are mounted on the instrument by means of Instron 2710101 handles at each end , which are modified to ensure that specimens do not slip or fail inside the handles during testing. The specimen is mounted on the instrument such that all rectangular “handle/bell” portions of the specimen and none of the specimen “neck” are attached to the instrument handles. Make sure the specimen is mounted substantially vertically in both vertical planes. The instrument grip distance is adjusted so that the sample is at a neutral extent as indicated by the instrument force being close to zero (±0.01 N).
[215] Two types of tests are performed sequentially on each specimen, first the Cyclic Test followed by the Extension Pull Test. It is observed that the Cyclic Test has negligible effects on the result of the Extension Pull Test on the same specimen. Each test is pre-programmed into the instrument.
[216] Cyclic Test: The Cyclic Test is designed to determine the elasticity of tested materials by measuring Cyclic Tensile Residual Stress (Instant Residual Stress). Generally, the more elastic the material, the faster it returns to its original shape after deformation. Lower Cyclic Traction Residual Stress counts indicate better elasticity. For perfectly elastic materials, the Cyclic Tensile Residual Stress and cycle test area should approach zero.
[217] The specimen is mounted on the instrument as described above. Stretch the specimen slightly by about 1 mm/s by raising the geometry until a force of 0.06 to 0.08 N is registered by the instrument, record the stretched length of the “neck” portion of the specimen as the length of initial specimen. A cyclic extension is performed at about 1 mm/sec to the maximum extension of 15% of the initial specimen length. A total of 15 (and up to 100) cycles are performed and stress stress data is recorded.
[218] Cyclic Traction Modulus is calculated as the straight-line slope of the first cycle stress-strain curve between 1% and 4% stress. The R-squared value of the linear fit must be above 0.99 or the test data must be recorded as an off-curve point and discarded. Cyclic Tensile Residual Stress is calculated for each cycle as the voltage difference between the loading and unloading curves at half of the maximum stress achieved during the first cycle. The Cyclic Tensile Residual Stress for the first cycle as well as the average Cyclic Tensile Residual Stress for the 2nd to 12th cycles are recorded. The area bounded by the loading and unloading curves for each cycle is also calculated as Cyclic Traction Hysteresis Lost Energy. A good understanding is observed between the Cyclic Traction Residual Stress and the calculated cycle area.
[219] Most specimens formed by the compositions disclosed in this document are sufficiently flexible and elastic that the Cyclic Test can be repeated on the same sample without a significant change in calculated properties, which suggests that this test did not result in lasting changes for the specimens tested.
[220] Extension Pull Test: The Extension Pull Test was used to determine the stiffness and stretchability/flexibility of a material by measuring Tensile Modulus/Young and Fracture Stress, respectively.
[221] The specimen is mounted on the instrument as described above. Stretch the specimen slightly at about 10 mm/s by raising the geometry until a force of 0.01 to 0.02 N is registered by the instrument, record the stretched length of the “neck” portion of the specimen as “Original Length ”. The Tensile Modulus/Young extension is calculated as the straight-line slope of the stress-strain curve between 6% and 11% stress. The R squared value of the linear fit must be above 0.99 or the Tensile/Young Modulus is calculated from a more linear stress range of 5% on the stress stress curve.
[222] The Shear Modulus is determined from the same voltage range as the Traction/Young Modulus. The Shear Modulus is calculated as the slope of the best line fit between recorded stress and α - 1/α2, where α is 1 plus instantaneous stress.
[223] Stretch the specimen at about 10 mm/sec until it is broken on one side or completely. Record the force applied at the time when the specimen is broken as the “Maximum Pull Force”. Record the length of the “neck” portion of the specimen when it is broken and extended beyond the Original Length of the specimen as the “Maximum Elongation Length”. Maximum Tensile Strength/Stress is calculated as the Maximum Tensile Force over the Area of the “neck” portion of the specimen. Fracture Stress is calculated as the Maximum Elongation Length as a percentage of the Original Length.
[224] Fracture Toughness (kJ/m3) is calculated as the area under the stress-stress curve in the Pull-Extension Test. Deformation Stress is determined as the stress at which the measured stress differed by more than 10% from the Neo-Hookean stress; the multiple of shear modulus e (α - 1/α2). TRANSEPIDERMAL WATER LOSS MEASUREMENT TEST (TEWL)
[225] Evaporative water loss measurements provide an instrumental assessment of skin barrier function. TEWL Probe Evaporimetry is fully described in Grove et al., Comparative metrology of the evaporimeter and the DermaLab® TEWL probe, Skin Res. & Tech. 1999, 5:1 to 8 and Grove et al., Computerized evaporimetry using the DermaLab® TEWL probe, Skin Res. & Tech. 1999; 5:9 to 13]. The established guidelines for using the Servo Med Evaporimeter described by Pinnagoda (Pinnagoda et al., Guidelines for transepidermal water loss (TEWL) measurement, Contact Dermatitis 1990, 22:164 to 178) are appropriate for the TEWL DermaLab® Probe as well.
[226] Evaporative water loss measurements can be made using a newly calibrated Servo Med Evaporimeter. Alternatively, these measurements can be made using a newly calibrated cyberDERM RG1 Evaporimeter System (Broomall, PA) with TEWL Probes (manufactured by Cortex Technology of Hadsund, Denmark and available in the US from cyberDERM, Inc. Broomall, PA) or other similar equipment.
[227] Both Evaporimeters are based on the vapor pressure gradient estimation method pioneered by Gert E. Nilsson (eg, Nilsson, GE, Measurement of water exchange through skin, Med Biol Eng Comput 1977, 15:209a 218). There are slight dimensional differences and sensor technology is greatly improved in the TEWL DermaLab® Probe, but the underlying principles of measurement remain the same. Both probes contain two sensors that measure temperature and relative humidity at two fixed points along the normal geometric axis on the skin surface. This arrangement is such that the device can electronically derive a value that corresponds to the evaporative water loss expressed in gm/(m2 -h). The Evaporimeter System extracts average evaporative water loss rate value collected over a twenty second interval once steady state conditions have been reached.
[228] Patients are treated with test compositions on selected volar forearm test areas as described in the Skin Film Durability Test. Measurements are taken from each of the volar forearm sites before treatment and at various time points (eg at a time point of about 1 hour, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 30 hours, about 36 hours, about 48 hours or between 48 hours and one week) after application of the composition. Measurements are taken following an acclimatization period of at least 25 minutes in a controlled environment with relative humidity maintained at less than about 50% and temperature maintained at about 19 to 22 °C. Duplicate water loss readings are taken from each location. The TEWL properties (g/(m2 •h)) are calculated based on the data recorded by the instrument. OPTICAL MEASUREMENT BASED ON COLOR TEST L*A*B*
[229] This test uses a Minolta CR-400 chroma meter in accordance with the manufacturer's instructions, which are generally known in the art. Triplicate measurements of L*(D65), a*(D65), and b*(D65) are then collected at >6 different locations on the test articles. BARRIER PROTECTION TEST BASED ON VIRAL PENETRATION
[230] Viral penetration-based barrier protection testing is performed to assess the barrier performance of protective materials, which are intended to protect against pathogen hazards caused by blood. The test articles were conditioned for a minimum of 24 hours at 21 ± 5 oC and 60 ± 10% relative humidity (%RH) and then tested for viral penetration using an Ü174 bacteriophage suspension. At the end of the test, the observed side of the test article was rinsed with a sterile medium and evaluated for the presence of Ü174 bacteriophage. The viral penetration method complies with ISO 16604. Triplicate readings are taken from each test article. BARRIER PROTECTION TEST BASED ON CHEMICAL PROTECTION AGAINST NICKEL CONTACT
[231] Nickel can be detected at the ppm level with a simple spot test that contains 1% dimethylglyoxime and 10% ammonium hydroxide solution, which turns pink upon contact with nickel. A 0.2 M solution of nickel(II) sulfate hexahydrate solution is added to a substrate, and both are covered by the test article. The spot test solution is subsequently applied to the test. A color change to pink indicates that nickel has penetrated the test article and comes into contact with a color solution, or vice versa. In contrast, no color change indicates that the test article is not penetrated and that its barrier function is intact. BARRIER PROTECTION TEST BASED ON ULTRAVIOLET RADIATION PROTECTION
[232] The presence of the test article can help reduce skin absorption of ultraviolet light, particularly when the test article contains SPF active ingredients such as titanium dioxide, zinc oxide, avobenzone, octinoxate, octocrilene, homosalate or oxybenzone .
[233] To prepare the test article for barrier protection against UV radiation, the test article was first deposited onto a blank cellophane sheet substrate as described above in applying test composition to selected substrates. A 12.78 cm (W) x 8.55 cm (W) cellophane sheet is employed to abutment with the UV-Vis Spectrophotometer plate retainer. Measure UV absorbance with UV-Vis Spectrophotometer from 260 nm to 400 nm wavelength with 1 nm scan interval. Report absorption data based on mean value of at least 4 different point locations. EXAMPLES EXAMPLE 1: TESTING THE PROPERTIES OF THE COMPOSITIONS AND LAYERS FORMED BY THE COMPOSITIONS TABLE 1. EXEMPLARY METHODS FOR MEASUREMENT OF PHYSICAL PROPERTIES




EXAMPLE 2: FIRST PART (FORMULA P1-001) TABLE 2. ACTIVE INGREDIENTS OF FORMULA P1-001

[234] All compositions in this document were mixed using a Dual Asymmetric Laboratory Centrifugal Mixing System (Hauschild, Germany).
[235] Components 1 and 2 were added to a container and mixed for 2 minutes at 2000 rpm. Then Component 3 was added to the mix and mixed for 12 minutes at 2000 rpm (with manual scraping of the container walls at an interval every 2 minutes to ensure complete dispersion of Component 3). EXAMPLE 3: FIRST PART (FORMULA P1-002) TABLE 3. ACTIVE INGREDIENTS OF FORMULA P1-002


[236] Formula P1-002 was prepared using the same method as Formula P1-001. EXAMPLE 4: FIRST PART (FORMULA P1-003) TABLE 4. ACTIVE INGREDIENTS OF FORMULA P1-003

[237] Components 1 to 3 were added into a container and mixed for 2 minutes at 2000 rpm. Component 4 was added to the mix and mixed for 12 minutes at 2000 rpm (with manual scraping of the container walls at an interval every 2 minutes to ensure complete dispersion of Component 4). Component 5 was slowly added into the mix and blended for 5 minutes at 500 rpm. Component 6 was slowly added into the mix and blended for 30 minutes at 500 rpm. EXAMPLE 5: FIRST PART (FORMULA P1-004) TABLE 5. ACTIVE INGREDIENTS OF FORMULA P1-004

[238] Components 1 to 3 were added into a container and mixed for 2 minutes at 2000 rpm. Component 4 was added to the mix and mixed for 12 minutes at 2000 rpm (with manual scraping of the container walls at an interval every 2 minutes to ensure complete dispersion of Component 4). Component 5 was added to the mix and mixed for 12 minutes at 2000 rpm (with manual scraping of the container walls at an interval every 2 minutes to ensure complete dispersion of Component 5). EXAMPLE 6: FIRST PART (FORMULA P1-005) TABLE 6. ACTIVE INGREDIENTS OF FORMULA P1-005

[239] Components 1 to 3 were added to a container and mixed for 2 minutes at 2000 rpm. Then Component 4 was added into the mix and mixed for 12 minutes at 2000 rpm (with manual scraping of the container walls at an interval every 2 minutes to ensure complete dispersion of Component 4). EXAMPLE 7: FIRST PART (FORMULA P1-006) TABLE 7. ACTIVE INGREDIENTS OF FORMULA P1-006

[240] Formula P1-006 was prepared using the same method as Formula P1-005. EXAMPLE 8: FIRST PART (FORMULA P1-007) TABLE 8. ACTIVE INGREDIENTS OF FORMULA P1-007


[241] Formula P1-007 was prepared using the same method as Formula P1-005. EXAMPLE 9: FIRST PART (FORMULA P1-008) TABLE 9. ACTIVE INGREDIENTS OF FORMULA P1-008

[242] Formula P1-008 was prepared using the same method as Formula P1-005. EXAMPLE 10: FIRST PART (FORMULA P1-009) TABLE 10. ACTIVE INGREDIENTS OF FORMULA P1-009


[243] Formula P1-009 was prepared using the same method as Formula P1-005. EXAMPLE 11: FIRST PART (FORMULA P1-010) TABLE 11. ACTIVE INGREDIENTS OF FORMULA P1-010

[244] Components 1 to 3 were blended to form Formula P1-002 as described. Then Component 4 was slowly added into the mix and blended for 30 minutes at 500 rpm. EXAMPLE 12: FIRST PART (FORMULA P1-011) TABLE 12. ACTIVE INGREDIENTS OF FORMULA P1-011

[245] Components 1 to 3 were mixed to form Formula P1-002 as described. Then Component 4 was slowly added into the mix and blended for 30 minutes at 500 rpm. EXAMPLE 13: FIRST PART (FORMULA P1-012) TABLE 13. ACTIVE INGREDIENTS OF FORMULA P1-012


[246] Components 1 to 3 were blended to form Formula P1-002 as described. Component 4 was added to the mix and blended for 5 minutes at 500 rpm. Then Component 5 was slowly added into the mix and blended for 30 minutes at 500 rpm. EXAMPLE 14: FIRST PART (FORMULA P1-013) TABLE 14. ACTIVE INGREDIENTS OF FORMULA P1-013


[247] Components 1, 2 and 3 were added into a container and mixed for 2 minutes at 2000 rpm. Then Component 4 was added to the mix and mixed for 12 minutes at 2000 rpm (with manual scraping of the container walls at an interval every 2 minutes to ensure complete dispersion of Component 4). EXAMPLE 15: FIRST PART (FORMULA P1-014) TABLE 15. ACTIVE INGREDIENTS OF FORMULA P1-014

[248] Components 1 to 4 were mixed to form Formula P1-013 as described. Then Component 5 was slowly added into the mix and blended for 30 minutes at 500 rpm. EXAMPLE 16: FIRST PART (FORMULA P1-015) TABLE 16. ACTIVE INGREDIENTS OF FORMULA P1-015

[249] Components 1 to 3 were blended to form Formula P1-002 as described. Then Component 4 was slowly added into the mix and blended for 30 minutes at 500 rpm. EXAMPLE 17: FIRST PART (FORMULA P1-016) TABLE 17. ACTIVE INGREDIENTS OF FORMULA P1-016


[250] Components 1 to 4 were mixed to form Formula P1-013 as described. Component 5 was slowly added into the mix and blended for 30 minutes at 500 rpm. EXAMPLE 18: FIRST PART (FORMULA P1-017) TABLE 18. ACTIVE INGREDIENTS OF FORMULA P1-017


[251] Components 1 to 3 were mixed to form a premix, before Component 4 was slowly added to the premix and mixed for 30 minutes at 500 rpm. EXAMPLE 19: FIRST PART (FORMULA P1-018) TABLE 19. ACTIVE INGREDIENTS OF FORMULA P1-018

[252] Components 1 to 3 were mixed to form a premix, before Component 4 was slowly added to the premix and mixed for 30 minutes at 500 rpm. EXAMPLE 20: FIRST PART (FORMULA P1-019) TABLE 20. ACTIVE INGREDIENTS OF FORMULA P1-019


[253] Components 1 to 3 were mixed to form a premix, before Component 4 was slowly added to the premix and mixed for 30 minutes at 500 rpm. EXAMPLE 21: FIRST PART (FORMULA P1-020) TABLE 21. ACTIVE INGREDIENTS OF FORMULA P1-020

[254] Components 1 to 3 were blended to form a premix, before Component 4 was slowly added to the premix and blended for 30 minutes at 500 rpm. EXAMPLE 22: FIRST PART (FORMULA P1-021) TABLE 22. ACTIVE INGREDIENTS OF FORMULA P1-021

[255] Components 1 to 3 were blended to form a premix, before Component 4 was slowly added to the premix and blended for 30 minutes at 500 rpm. EXAMPLE 23: FIRST PART (FORMULA P1-022) TABLE 23. ACTIVE INGREDIENTS OF FORMULA P1-022


[256] Components 1 to 3 were blended to form a premix, before Component 4 was slowly added to the premix and blended for 30 minutes at 500 rpm. EXAMPLE 24: FIRST PART (FORMULA P1-023) TABLE 24. ACTIVE INGREDIENTS OF FORMULA P1-023

[257] Components 1 to 3 were blended to form a premix, before Component 4 was slowly added to the premix and blended for 30 minutes at 500 rpm. EXAMPLE 25: FIRST PART (FORMULA P1-024) TABLE 25. ACTIVE INGREDIENTS OF FORMULA P1-024

[258] Components 1 to 3 were blended to form a premix, before Component 4 was slowly added to the premix and blended for 30 minutes at 500 rpm. EXAMPLE 26: FIRST PART (FORMULA P1-025) TABLE 26. ACTIVE INGREDIENTS OF FORMULA P1-025


[259] Components 1 to 3 were blended to form a premix, before Component 4 was slowly added to the premix and blended for 30 minutes at 500 rpm. EXAMPLE 27: FIRST PART (FORMULA P1-026) TABLE 27. ACTIVE INGREDIENTS OF FORMULA P1-026

[260] Components 1 to 5 were blended to form a premix, before Component 6 was slowly added to the premix and blended for 30 minutes at 500 rpm. EXAMPLE 28: FIRST PART (FORMULA P1-027) TABLE 28. ACTIVE INGREDIENTS OF FORMULA P1-027

[261] Components 1 to 4 were mixed to form Formula P1-013 as described. Components 5 to 7 were slowly added into the mix and blended for 30 minutes at 500 rpm. The resulting blend of Components 1 through 7 is Phase A. In a separate container, Components 7 through 12 were blended for 10 minutes at 400 rpm. The resulting blend of Components 8 through 9 is Phase B. Phase B was then slowly added to Phase A while blending at 500 rpm, then stirred for 15 minutes at 500 rpm. The resulting emulsion is then homogenized for 15 minutes at 1150 rpm. EXAMPLE 29: FIRST PART (FORMULA P1-028) TABLE 29. ACTIVE INGREDIENTS OF FORMULA P1-028


[262] Components 1 to 4 were mixed to form Formula P1-013 as described. Components 5 to 7 were slowly added into the mix and blended for 30 minutes at 500 rpm. EXAMPLE 30: FIRST PART (FORMULA P1-029) TABLE 30. ACTIVE INGREDIENTS OF FORMULA P1-029

[263] Components 1 to 4 were mixed to form Formula P1-013 as described. Components 5 to 7 were slowly added into the mix and blended for 30 minutes at 500 rpm. EXAMPLE 31: FIRST PART (FORMULA P1-030) TABLE 31. ACTIVE INGREDIENTS OF FORMULA P1-030


[264] Components 1 to 4 were mixed to form Formula P1-013 as described. Components 5 to 9 were slowly added into the mix and blended for 30 minutes at 500 rpm. EXAMPLE 32: FIRST PART (FORMULA P1-031) TABLE 32. ACTIVE INGREDIENTS OF FORMULA P1-031


[265] Components 1 to 4 were mixed to form Formula P1-013 as described. Components 5 to 8 were slowly added into the mix and blended for 30 minutes at 500 rpm. The resulting blend of Components 1 through 8 is Phase A. In a separate container, Components 10 through 12 were gradually added into Component 9 and then blended for 10 minutes at 400 rpm until the blend was uniform. Then add dropwise the Component 13 then mixed for 10 minutes at 400 rpm. The resulting blend of Components 9 to 13 is Phase B. Phase B was then slowly added to Phase A while blending at 500 rpm, then stirred for 15 minutes at 500 rpm. The resulting emulsion is then homogenized for 15 minutes at 1150 rpm. EXAMPLE 33: FIRST PART (FORMULA P1-032) TABLE 33. ACTIVE INGREDIENTS OF FORMULA P1-032


[266] Components 1 to 3 were blended to form Formula P1-013 as described. Component 4 was slowly added into the mix and blended for 30 minutes at 500 rpm. EXAMPLE 34: FIRST PART (FORMULA P1-033) TABLE 34. ACTIVE INGREDIENTS OF FORMULA P1-033

[267] Components 1 to 3 were blended to form Formula P1-013 as described. Component 4 was slowly added into the mix and blended for 30 minutes at 500 rpm. EXAMPLE 35. SECOND PART (FORMULA P2-001) TABLE 35. ACTIVE INGREDIENTS OF FORMULA P2-001

[268] Component 2 was added to Component 1 and mixed for 15 minutes at 250 rpm. EXAMPLE 36: SECOND PART (FORMULA P2-002) TABLE 36. ACTIVE INGREDIENTS OF FORMULA P2-002


[269] Component 2 was slowly added to Component 1 while mixing at 500 rpm, then stirred for 20 minutes at 500 rpm. Components 3 to 6 were mixed in a separate container for 5 minutes at 500 rpm. The Component 1 to 2 mixture was added to the container containing the Component 3 to 6 mixture, then stirred for 10 minutes at 500 rpm. The resulting blend of Components 1 through 6 is Phase A. In a separate container, Components 7 through 12 were blended for 10 minutes at 400 rpm. The resulting blend of Components 7 through 12 is Phase B. Phase B was then slowly added to Phase A while blending at 500 rpm, then stirred for 15 minutes at 500 rpm. The resulting emulsion is then homogenized for 15 minutes at 1150 rpm. EXAMPLE 37: SECOND PART (FORMULA P2-003) TABLE 37. ACTIVE INGREDIENTS OF FORMULA P2-003


[270] Component 2 was slowly added to Component 1 while mixing at 500 rpm, then stirred for 20 minutes at 500 rpm. Components 3 to 6 were mixed in a separate container for 5 minutes at 500 rpm. The Component 1 to 2 mixture was added to the container containing the Component 3 to 6 mixture, then stirred for 10 minutes at 500 rpm. Component 7 was slowly added to the mixture of Components 1 to 6 while mixing at 500 rpm, then stirred for 5 minutes at 500 rpm. Component 8 was added to the mixture of Components 1 to 7 and stirred for 5 minutes at 500 rpm. The resulting blend of Components 1 through 8 is Phase A. In a separate container, Components 9 through 13 were blended for 10 minutes at 400 rpm. The resulting blend of Components 9 to 13 is Phase B. Phase B was then slowly added to Phase A while blending at 500 rpm, then stirred for 15 minutes at 500 rpm. The resulting emulsion was then homogenized for 15 minutes at 1150 rpm. EXAMPLE 38: SECOND PART (FORMULA P2-004) TABLE 38. ACTIVE INGREDIENTS OF FORMULA P2-004


[271] Formula P2-004 was prepared using the same method as Formula P2-003. EXAMPLE 39: SECOND PART (FORMULA P2-004) TABLE 39. ACTIVE INGREDIENTS OF FORMULA P2-004


[272] Each component was added and mixed together for 15 minutes at 250 rpm. EXAMPLE 40: SECOND PART (FORMULA P2-005) TABLE 40. ACTIVE INGREDIENTS OF FORMULA P2-005

[273] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 41: SECOND PART (FORMULA P2-006) TABLE 41. ACTIVE INGREDIENTS OF FORMULA P2-006

[274] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 42: SECOND PART (FORMULA P2-007) TABLE 42. ACTIVE INGREDIENTS OF FORMULA P2-007


[275] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 43: SECOND PART (FORMULA P2-008) TABLE 43. ACTIVE INGREDIENTS OF FORMULA P2-008

[276] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 44: SECOND PART (FORMULA P2-009) TABLE 44. ACTIVE INGREDIENTS OF FORMULA P2-009


[277] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 45: SECOND PART (FORMULA P2-010) TABLE 45. ACTIVE INGREDIENTS OF FORMULA P2-010

[278] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 46: SECOND PART (FORMULA P2-011) TABLE 46. ACTIVE INGREDIENTS OF FORMULA P2-011

[279] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 47: PART TWO (FORMULA P2-012) TABLE 47. ACTIVE INGREDIENTS OF FORMULA P2-012


[280] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 48: PART TWO (FORMULA P2-013) TABLE 48. ACTIVE INGREDIENTS OF FORMULA P2-013

[281] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 49: PART TWO (FORMULA P2-014) TABLE 49. ACTIVE INGREDIENTS OF FORMULA P2-014


[282] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 50: SECOND PART (FORMULA P2-015) TABLE 50. ACTIVE INGREDIENTS OF FORMULA P2-015

[283] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 51: SECOND PART (FORMULA P2-016) TABLE 51. ACTIVE INGREDIENTS OF FORMULA P2-016

[284] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 52: PART TWO (FORMULA P2-017) TABLE 52. ACTIVE INGREDIENTS OF FORMULA P2-017


[285] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 53: SECOND PART (FORMULA P2-018) TABLE 53. ACTIVE INGREDIENTS OF FORMULA P2-018

[286] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 54: PART TWO (FORMULA P2-019) TABLE 54. ACTIVE INGREDIENTS OF FORMULA P2-019


[287] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 55: SECOND PART (FORMULA P2-020) TABLE 55. ACTIVE INGREDIENTS OF FORMULA P2-020


[288] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 56: SECOND PART (FORMULA P2-021) TABLE 56. ACTIVE INGREDIENTS OF FORMULA P2-021


[289] Each component was added and mixed together for 5 minutes at 50 rpm. EXAMPLE 57: SECOND PART (FORMULA P2-022) TABLE 57. ACTIVE INGREDIENTS OF FORMULA P2-022


[290] Formula P2-004 was prepared using the same method as Formula P2-003. EXAMPLE 58: SECOND PART (FORMULA P2-023) TABLE 58. ACTIVE INGREDIENTS OF FORMULA P2-023


[291] Formula P2-004 was prepared using the same method as Formula P2-003. TABLE 59. DURABILITY AND DRYING TIME OF DIFFERENT FORMULATIONS

Notes: * VS165K represents Andisil VS 165,000, a high viscosity alkenyl organopolysiloxane; + VS10K represents Andisil VS 10,000, a low viscosity alkenyl organopolysiloxane; Φ Silica represents Aerosil R812s, a fumed silica. EXAMPLE 60: COMPARISON OF DURABILITY OF P1-016/P2-004 WITH A COMMERCIAL PRODUCT TABLE 60. COMPARE DURABILITY OF P1-016/P2-004 WITH A COMMERCIAL PRODUCT AT AN ABOUT 24 HOUR TIME POINT


[292] Skin Film Durability Tests were conducted that compare P1-016/P2-004 and a commercial product in agreement with Yu et al. (US 20130078209), with four healthy patients who have both formulas applied to areas of skin on opposite volar forearms. Durability was determined at time points of about 24 hours. The results are also shown in Figure 1. EXAMPLE 61: COMPARISON OF DRYING TIME OF P1-016/P2-004 WITH A COMMERCIAL PRODUCT TABLE 61. COMPARE DRYING TIME OF P1-016/P2-004 WITH A COMMERCIAL PRODUCT

[293] Film Drying Time Tests were conducted that compare P1-016/P2-004 and a commercial product in agreement with Yu et al. (US 20130078209). The results are also shown in Figure 2. EXAMPLE 62: COMPARISON OF IN-VIVO DRYING TIME AND IN-VIVO ADHERENCE FREE TIME OF DIFFERENT FORMULATIONS
EXAMPLE 63: COMPARISON OF IN-VITRO DRYING TIME AND IN-VITRO TACK FREE TIME OF DIFFERENT FORMULATIONS IN-VITRO DRYING AND IN-VITRO TACK FREE TIME OF DIFFERENT FORMULATIONS

[294] Drying Time and Film Adhesion Free Time Tests were conducted comparing P1-017/P2-004 to P1-023/P2-004 and classification based on relative molar ratio vinylhydride in the first part. The results are also shown in Figure 3. EXAMPLE 64: COMPARISON OF IN-VIVO DRYING TIME AND IN-VIVO TACK FREE TIME OF DIFFERENT FORMULATIONS TABLE 64. IN-VIVO DRYING TIME AND IN-VIVO TACK FREE TIME OF DIFFERENT FORMULATIONS FORMULATIONS
EXAMPLE 65: COMPARISON OF IN-VITRO DRYING TIME AND IN-VITRO TACK FREE TIME OF DIFFERENT FORMULATIONS TABLE 65. IN-VITRO DRYING TIME AND IN-VITRO TACK FREE TIME OF DIFFERENT FORMULATIONS Prime Molar Ratio Second Low MW Time of Time of

[295] Drying Time and Film Adhesion Free Time Tests were conducted which compare the classification of P1-016/P2-005 to P1-016/P2-013 based on the relative viscosity of vinyl polysiloxane which is directly related to molecular weight in the second part. EXAMPLE 66: COMPARISON OF IN-VITRO DRYING TIME AND IN-VITRO TACK FREE TIME OF DIFFERENT FORMULATIONS TABLE 66. IN-VITRO DRYING TIME AND IN-VITRO TACK FREE TIME OF DIFFERENT FORMULATIONS

[296] Drying Time and Film Adhesion Free Time Tests were conducted that compare rating of P1-016/P2-013 to P1-016/P2-016 based on relative weight percent vinyl polysiloxane content of viscosity 250 cSt in the second part. EXAMPLE 67: COMPARISON OF IN-VITRO DRYING TIME AND IN-VITRO ADHERENCE FREE TIME OF DIFFERENT FORMULATIONS TABLE 67. IN-VITRO DRYING TIME AND IN-VITRO ADHERENCE FREE TIME OF DIFFERENT FORMULATIONS

[297] Drying Time and Film Adhesion Free Time Tests were conducted that compare classification of P1-016/P2-017 to P1-016/P2-019 based on relative weight percentage content of P2-001 in the second part. EXAMPLE 68: IN-VIVO COMPARISON DURABILITY OF DIFFERENT FORMULATIONS AFTER 24 HOURS TABLE 68. DURABILITY IN FOREARM SKIN OF DIFFERENT FORMULATIONS AFTER 24 HOURS
EXAMPLE 69: COMPARISON OF IN-VITRO PEELING ADHERENCE TEST OF DIFFERENT FORMULATIONS TABLE 69. IN-VITRO PEELING ADHERENCE TEST OF DIFFERENT FORMULATIONS ON POLYPROPYLENE SUBSTRATE


[298] In-vitro Peel Adhesion Tests were conducted that compare classification of P1-017/P2-004-P1023/P2-004 on the basis of relative molar ratio vinyl hydride in the first part. The results are also shown in Figure 4. EXAMPLE 70: DEMONSTRATION OF IN-VIVO FILM STRENGTH AGAINST SCRUB
[299] The in-vivo film rub resistance of test composition P1-030/P2-021 (full coverage color film) and P1-028/P2-004 (clear color film) on the skin was demonstrated visually in Figure 5. EXAMPLE 71: CLINICAL EVALUATION OF IN-VIVO DURABILITY AFTER 6 HOURS AND 24 HOURS
[300] The clinical study (S16-01) was based on 25 healthy volunteers with normal skin. The test composition was self-applied under medical instructions at 4 test sites (forearm, inner elbow, leg, behind knee). Each test site covered an area of 4 cm x 4 cm (~0.1% BSA). Durability was assessed visually after 6 hours and 24 hours by percentage of test composition area remaining after 24 hours and self-taken photographs at 12 hours. Furthermore, durability was further evaluated with the exclusion of dye on the arm after 24 hours with photos, which also visually showed film barrier properties. The results are also shown in Figure 6. EXAMPLE 72: COMPARISON OF IN-VITRO MECHANICAL PROPERTIES OF DIFFERENT FORMULATIONS
[301] In-vitro mechanical properties were conducted comparing classification of P1-017/P2-004-P1023/P2-004 based on relative molar ratio of vinyl hydride in the first part. TABLE 70. IN-VITRO TENSION FRACTURE TEST FOR MECHANICAL PROPERTIES OF DIFFERENT FORMULATIONS

TABLE 71. IN-VITRO CYCLIC TRACTION TEST FOR ELASTICITY OF DIFFERENT FORMULATIONS

EXAMPLE 73: COMPARISON OF IN-VITRO WAVE TEST OF DIFFERENT FORMULATIONS
[302] In-vitro Ripple Tests were conducted that compare classification of P1-017/P2-004-P1023/P2-004 based on relative molar ratio of vinyl hydride in the first part. TABLE 72. IN-VITRO WAVE TEST OF DIFFERENT FORMULATIONS

EXAMPLE 74: IN-VIVO OPTICAL EVALUATION OF TEST FORMULATION ON FOREARM SKIN TABLE 73. IN-VIVO OPTICAL EVALUATION OF L*A*B* COLOR SCALES IN TEST FORMULATION ON FOREARM SKIN


[303] Optics were quantified using Minolta Color Meter from volar forearm site to (i) control skin, (ii) P1-016/P2-004 on skin, (iii) 3M Tegaderm™ wound dressing on skin. The assessment of optical invisibility is based on grouping as distance scale L*a*b* of control skin color. The results are also shown in Figure 7. EXAMPLE 75: IN-VITRO EVALUATION OF SKIN SURFACE MODULATION
[304] The in-vivo assessment of skin surface modulation was visually assessed and demonstrated in Figure 8 in facial contour modulation near the areas below the eye as well as near the expression line areas. Photos were taken before, after 15 minutes and after 6 hours of application of the test composition by P1-031/P2-022 (below the eye and right expression line) and P1-032/P2-022 (below the eye and left expression line) in female test patient (upper) and by P1-033/P2-023 (below the eye and right expression line) and P1-032/P2-023 (below the eye and left expression line) in male test patients. Every test composition exhibited the flattened appearance of the facial contour. EXAMPLE 76: IN-VITRO EVALUATION OF OPTICAL SKIN MODIFICATION
[305] In-vivo evaluation of optical skin modification was visually assessed and demonstrated in Figure 9 in full optical coverage of natural hyperpigmentation and full coverage of tattoo. Photos were taken before and after application of the test composition by P1-030/P2-021 on the patient's forearm skin. EXAMPLE 77: IN-VIVO DEMONSTRATION OF THE INCORPORATION OF STIMULUS RESPONSIVE COMPONENTS IN TEST COMPOSITIONS TO IMPROVE SKIN FUNCTION
[306] The demonstration for improving skin function by incorporating stimulus-responsive components into the test compositions was shown in Figure 10, which illustrates the incorporation of two different stimulus-responsive components into the test composition in the skin. (Left) P1-029/P2-004 with graphene and (Right) P1-028/P2-004 with pH sensitive dye. EXAMPLE 78: IN-VIVO BARRIER ASSESSMENT AGAINST LIQUID WATER PENETRATION
[307] In-vivo barrier evaluation against liquid water penetration was conducted through a waterproof property demonstration of test composition P1-016/P2-004, compared to petrolatum and control skin. First, a water-soluble dye was deposited on all three places on the skin prior to topical application of test compositions. After topical application of the test composition, each skin site was then subjected to a water bath, in which the water-soluble dye on the control skin site was observed to wash off the skin. Then, the two remaining sites were washed with soap and scrubbed meticulously by hand, whereby the water-soluble dye in the petrolatum site was also observed to wash away from the skin after scrubbing. The only remaining site of the water-soluble dye on the skin was the skin site protected by test composition P1-016/P2-004. The results were illustrated in Figure 11. EXAMPLE 79: IN-VITRO BARRIER EVALUATION AGAINST VIRAL PENETRATION TABLE 74. IN-VITRO BARRIER EVALUATION AGAINST VIRAL PENETRATION

a VALUE OF < 1 PLATE FORMATION UNITS (PRIMO IS REPORTED FOR TEST PLATES WHICH DO NOT SHOW PLATES. EXAMPLE 80: IN-VITRO BARRIER ASSESSMENT AGAINST NICKEL CONTACT
[308] In-vitro nickel contact barrier evaluation was conducted that compares P1-016/P2-004 (right side) against control (left side with no test composition). Control (left) exhibited color change to pink indicating direct contact with nickel. Test composition containing P1-016/P2-004 (right) exhibits no change in color which indicates barrier protection of the test article against chemicals such as nickel contact. The results are also shown in Figure 12. EXAMPLE 81: IN-VITRO BARRIER ASSESSMENT AGAINST UV RADIATION
[309] An in-vitro UV barrier evaluation was conducted that compares P1-026/P2-004 against blank control and against SPF 50 over-the-counter sprinkler (Banana Boat). P1-026/P2-004 demonstrated barrier protection against UV radiation, although not as good as SPF 50 spray. The results are also shown in Figure 13. EXAMPLE 82: IN-VITRO WATER VAPOR TRANSMISSION RATE
[310] The water vapor transmission test was done following the guidelines of ASTM D1653 in Standard Test Methods for Water Vapor Transmission of Organic Coating Films, but under the condition of 10% RH at 37 oC . The test is to compare the humidification occlusive barrier level by measuring how water vapor can carry through the films a reflection of the water loss in the reservoir inside the cup under the defined condition of 10% RH at 37 oC. The results are also shown in Figure 14. EXAMPLE 83: IN-VITRO WATER VAPOR TRANSMISSION RATE TABLE 75. IN-VITRO WATER VAPOR TRANSMISSION RATE
EXAMPLE 84: IN-VITRO OXYGEN TRANSMISSION RATE TABLE 76. IN-VITRO OXYGEN TRANSMISSION RATE
EXAMPLE 85: CLINICAL EVALUATION OF IN-VIVO TRANSEPIDERMAL WATER LOSS (TEWL) AFTER 2, 6 AND 24 HOURS BY EVAPORIMETER MEASUREMENT
[311] The clinical study (S15-28) was based on 8 healthy volunteers with normal skin. The test composition was applied by a physician to a volar forearm site with an arm guard dressed for 6 hours. P1-016/P2-024 was compared with petrolatum at two different test sites, normal skin versus damaged skin (shaved and dry). Each test site covered an area of 4 cm x 4 cm (~0.1% BSA). TEWL was measured by Evaporimeter before test article application and after 2, 6 and 24 hours. Before each TEWL measurement, patients were balanced for 45 minutes. Initial reports of TEWL for all intact skin sites averaging 4.85 g/m2/h, in contrast to all shaved and dry skin sites averaging 16.92 g/m2/h. The results are shown in Figure 15. EXAMPLE 86: EX-VIVO DERMIC DRUG DELIVERY BY FRANZ DIFFUSION CELL
[312] The ex-vivo study using a Franz diffusion cell in cadaver skin was to determine the rate and extent of skin permeation of a steroid drug "Triamcinolone Acetonide" from three different formulation combinations in cadaver skin human intact and through it using a Franz diffusion cell system.
[313] Test articles comprised of (1) over-the-counter commercial 0.1% Triamccinolone Acetonide (TA) lotion from Versa Pharma, (2) P1-016/P2-004 layered on top of TA from Versa Pharma, and (3) P1-027/P2-004. They each contained 0.1% Triamcinolone Acetonide. Active concentrations were measured in the receptor chamber of the diffusion cell at varying time points. Upon completion of the diffusion study, the skin was sequentially placed in strips of tape and divided into epidermal and dermal layers. The concentration of triamcinolone acetonide in each of the stored tape strips and epidermal and dermal tissues was extracted using an extraction solvent and was also analyzed with an Agilent G6120 HPLC system with an LC-MS detector.
[314] Skin Preparation: A dermatomed intact human cadaver skin was purchased from the New York Fire Department Tissue Bank (NYFFTB). The tissue bank donor ID number was: AV011816 #5. Donor information provided by NYFFTB was: race: Caucasian, gender: male, age: 47, donor site: hind leg. Upon receipt of the skin from the tissue banks, the skin was stored frozen at -20 °C until the morning of the experiment. Prior to use, the skin was removed from the freezer and allowed to thaw completely at room temperature. Only areas of skin that were visually intact were used during the experiment.
[315] Receptor Fluid Preparation: Based on the results of solubility studies, a phosphate-buffered saline (PBS) receptor fluid at pH 7.4 with 2% by weight hydroxypropyl-beta-cyclodextrin (HPBCD) was chosen . The solubility of triamcinolone acetonide in this recipient fluid was measured to be ~282 μg//ml - which is sufficient to maintain sink conditions in the recipient fluid throughout the course of the flow study. The preparation and degassing of the recipient fluid was prepared at an appropriate pH and degassing was performed by filtering the recipient fluid through a 0.2 μm ZapCap CR membrane while pulling vacuum.
[316] Diffusion cell assembly: Custom Franz diffusion cells (FDCs) with a receiver volume of 3.3 ml were used for the experiment. The available diffusion surface area of the skin for each cell is 0.55 cm2. The receiving fluid was maintained at 32°C ± 0.5°C during the experiment with the use of a shake drying block heater and the fluid was continuously shaken with a stir bar. The steps to assemble the diffusion cells are outlined below: The cadaver skin was removed from the freezer and allowed to thaw in a biosafety hood for 30 minutes. The skin was completely thawed before opening the package. The cadaver skin was removed from the package and placed on the biosafety hood bench with the stratum corneum facing up. The skin was touch dried with a Kimwipe, then sprayed with fresh PBS and touch dried again. This process was repeated 3 more times to remove any residues present on the skin. The recipient wells were then filled with the degassed recipient fluid. A Teflon coated stir bar was added to each receiver well. Thawed cadaver skin was examined and only areas of equal thickness and no visible surface damage were used. The skin was cut into approximately 2 cm x 2 cm squares. The piece of skin was centered on the donor cells, stratum corneum (SC) facing upwards. The skin was centered again and the edges flattened. The donor and recipient cavities were then aligned and clamped together with a clamping forceps. Additional receiver fluid was added where needed. Any air bubbles present were removed by tilting the cell, which allows air to escape along the sample port. The diffusion cells were then placed in the shake dry block heaters and allowed to rehydrate for 20 minutes from the recipient fluid. Block heaters were maintained at 32 °C ± 0.5 °C throughout the experiment with continuous agitation. After 20 minutes, the skin surface was examined. If the skin was wet or showed signs of “sweating”, SC was considered compromised and discarded.
[317] Membrane Integrity Check: Once the cells were assembled and the skin was allowed to hydrate for 20 minutes, the barrier integrity of each skin section was used using a tritiated water test prior to dosing of the formulation on the skin. The specific method for measuring skin barrier integrity is outlined as follows and detailed in Tioga Research SOP Lab.011.
[318] A 150 µl aliquot of tritiated water (with addition of 25 µCi water/10 ml water) was added to each FDC donor well.
[319] After 5 minutes, the tritiated water from the donor wells was removed and the skin taped dry using a Kimwipe.
[320] Recipient wells were agitated for an additional 1 hour after the tritiated donor fluid was removed.
[321] After 1 hour of shaking, a 300 µl aliquot sample was taken from each receiver well. The remaining recipient fluid was discarded and replaced with fresh PBS (membrane integrity study uses only PBS in recipient fluid)
[322] 600 μl of scintillation cocktail (Ultima Gold XR) was added to each sample aliquot.
[323] The tritium content of the receiver cavity aliquot was then measured using a liquid scintillation counter (LSC).
[324] After the LSC analysis was complete, the results were analyzed. Any FDCs that anomalously show high water flow have been discarded.
[325] FDCs were then classified according to 3H water flow. The FDCs were then distributed so that each formulation was assigned to FDCs with nearly equivalent mean tritiated water flux values.
[326] Once the membrane integrity check study was completed, the entire receiving chamber volume was replaced by the receiving fluid.
[327] Formulation application procedure: After the membrane integrity test is complete, and the cells are properly organized, the formulations are ready to be applied to the stratum corneum of the skin. The donor cell was first removed from the FDC - this step was necessary to allow proper dosing of the formulations across the exposed surface area. Next, a plastic washer with an opening of approximately 0.55 cm2 was placed on the cadaver skin so that the opening was aligned with the receiving chamber. A one-time dosing regimen was then used for this study. For dosing protocol #1, 5 μl of TA was applied to the skin and spread over the skin surface using a glass rod (care was taken to ensure that the formulation remained within the confines of the plastic gasket). For dosing protocol #2, 5 μl of TA was applied to the skin, then spread using a glass stick. 5 μl of formulation P1-016 was then applied over the TA and spread, followed lastly by 5 μl of formulation P2-004 which is applied over both formulations and spread across the surface area of 0.55 cm2. For dosing protocol #3, 5 μl of formulation P1-027 was applied to the skin and spread using a glass stick, followed by 5D of formulation P2-004 which is applied over P1-027. In all dosing protocols, the FDC weight was measured before and after each dosing step to ensure the amount of formulation that remains after spreading. The Active dose per cell and the corresponding dosing protocol are shown. TABLE 77: DOSE OF TRIANCINOLONE PER CELL FOR EACH FORMULATION COMBINATION. THE DOSE OF TRIANCINOLONE ASSUMES A SPECIFIC GRAVITY OF 1.0 FOR THE FORMULATION AND THAT 100% OF THE 5 DOSES REMAIN ON THE SKIN AFTER SPREADING THE FORMULATION.


[328] Receptor Fluid Sampling: At 1, 2, 4, 6, 8, and 24 hours, a 300 sample aliquot was withdrawn from the receiver wells using a Hamilton-type graduated syringe injector. Fresh receptor medium was added to replace the 300 sample aliquot. Samples were then filtered with a 0.2 GHP membrane filter plate.
[329] Tape Striping and Heat Splitting: Within 24 h, the skin was tape dried using a KimWipe soaked in PBS/EtOH. Next, a piece of Mepitac tape was applied to the skin, allowed to settle for ten minutes, then removed. This Mepitac step was done a second time to ensure that the formulation film is completely removed. After the second Mepitac tape was removed, the skin was successively placed on strips of tape. This involved applying a piece of cellophane tape to the skin with light pressure, then peeling the tape off and collecting the tape. With each strip of tape, a layer of the stratum corneum is removed. Nine strips of tape were taken per cell. Tape strips have been stored together in the following sections: Tape Strip 1, Tape Strip 2, Tape Strip 3, Tape Strip 4, Tape Strip 5, and Tape Strips 6 to 9.
[330] After the skin was placed on strips of tape, the epidermis of each piece of skin was then separated from the underlying dermal tissue using forceps. Epidermal and dermal tissues were collected and placed separately in 4 ml glass vials of boron silicate.
[331] After all the strips of tape and skin pieces were collected, the Active was then extracted from the strips of tape or skin. For the strips of tape, this consisted of adding 4 ml of methanol to the vial, and shaking the vial for 24 hours at room temperature, after which a sample was collected. For skin pieces, extraction was performed by adding 2 ml of dimethyl sulfoxide (DMSO) to the vials containing the skin pieces, then incubating the vials at 40 °C for 24 hours with gentle shaking. After 24 hours, sample aliquots were taken and filtered with the 0.20 GHP membrane filter plate.
[332] Sample Analysis: Sample aliquots were analyzed with an Agilent G6120 HPLC system with an LC-MS detector. Samples were stored, refrigerated at 4 to 8°C prior to analysis to help prevent any unwanted degradation of triamcinolone acetonide.
[333] Comparative delivered doses of triamcinolone for different formulations for transdermal, stratum corneum (ie, tape strips), epidermal, and dermal delivery have been reported. It appears that the addition of P1-016 and P2-004 over TA (Versa Pharma formulation) increased the flux of triamcinolone into deeper tissue versus applying the Versa Pharma formulation TA alone. Dosing the skin with P1-027 and with P2-004 layered on top led to higher epidermal absorption. The results are shown in Figure 16. EXAMPLE 87: CLINICAL EVALUATION OF IN VIVO OCCLUSION BENEFIT IN IMPROVING STEROID POWER THROUGH VASOCONSTRICTION ASSAY
[334] The clinical trial to assess in vivo occlusion benefit in improving steroid potency was adapted from a traditional single-point vasoconstriction trial due to the presence of the film layer. The study was based on 37 healthy volunteers (23 women and 14 men) with normal skin. The test articles were applied by a physician in a volar forearm site at 6 test sites per patient in order to test three increasing potency steroids, which compare the result of vasoconstriction of the steroids with the presence versus absence of film occlusion. P1-016/P2-024: Triamcinolone Acetonide Lotion (TA), 0.1% - Class 5, Fluticasone Propinoate Lotion (FP), 0.05% - Class 5, Hydrocortisone (HC) 2.5% of solution - Class 7. Vasoconstriction readings were reported at 18 hours without washing at 16 hours.
[335] Methodology: Single-center, blind evaluator, randomized in patient, vehicle, and reference-controlled visual assessment.
[336] Patients: 36 planned, 37 enlisted, 37 analyzed (ITT population), 36 analyzed (PP population).
[337] Diagnosis and key inclusion criteria: Healthy male and female patients 18 to 65 years of age with skin on the forearms that allowed vasoconstriction to be readily assessed and had a history or documentation of a positive skin whitening response to corticosteroids topics.
[338] Duration of Treatment: A single application for 16 (±1) hours of the following steroids, administered with and without occlusion using P1-016/P2-004 film:
[339] 1. Triamcinolone Acetonide Lotion, 0.1% (Class 5)
[340] 2. Fluticasone Propinoate Lotion, 0.05%, (Class 5)
[341] 3. Hydrocortisone Solution, 2.5% (Class 7)
[342] Criteria for Evaluation:
[343] Efficacy: Degree of skin whitening assessed visually on a four-point ordinal scale ranging from 0 (none) to 3 (marked whitening).
[344] Safety: All adverse events (AEs) reported during the study were listed, and documents course, severity, and outcome.
[345] Statistical Methods: Data were entered using double-entry method using Excel. All statistical processing was performed using SAS®, version 9.4. Since this was a design within the subject, demographic characteristics such as gender and race were summarized as frequency distributions, while age was summarized as a mean and a standard deviation.
[346] Study Populations: All patients enrolled in the study who were randomized and had at least one trial article applied were included in the safety and efficacy analysis. This was the population destined to treat (ITT). Patients were included in population-by-protocol (PP) efficacy analyzes if they completed the study without significant protocol deviations.
[347] Efficacy Analyses: The sums and means of the skin whitening counts for each test article, with or without occlusion, were calculated. All statistical tests were performed at a significance level of 5% (two-tailed).
[348] The primary analysis tests the null hypothesis that the visually assessed treatment whitening count means were equal to each other. Since this was an in-subject design, the visual skin whitening data was analyzed for mean differences between treatments using a random block analysis of variance (ANOVA) with patient as the blocking variable.
[349] In this analysis, pairwise comparisons of mean visual assessment scores were performed using the Ryan-Einot-Gabriel-Welsch Multiple Range Test (REGWQ) which controls the Type I error rate in the experiment sense in 5% under the complete null hypothesis. The null hypothesis states that the treatment bleach count means are equal to each other.
[350] Safety Analyzes: All AEs reported during the study were listed, documenting course, severity, and relationship to test articles and outcome. All reported AEs should be summarized by the number of patients reporting AEs, system organ class (SOC), preferred term (PT), severity, and ratio to test article by treatment if possible. CLINICAL RESULTS
[351] Results Summary: Thirty-seven patients were enrolled and treated in the study. All but one enlisted patient (Patient 01-106) completed the study (N=36). There were 24 (64.9%) women and 13 (35.1%) men enrolled in the study. Approximately 86% (32/37) of the patients were white, 8.1% (3/37) were Asian, and the remaining two patients were Native American Indian/Alaska (1/37, 2.7%) and white and black /African American (1/37, 2.7%). About two-thirds of patients were not of Hispanic or Latino origin (25/37, 67.6%). Mean age was 34.2 years with patient ages ranging from 19 to 62 years. All but one of the patients (Patient 01-106) who cleaned the test sites within the specified time windows, had the film removed, and had vasoconstriction assessments performed within the specified time windows. Patient 01-106 was included in the ITT population, but excluded from the PP population. This patient did not have vasoconstriction assessments; thus, it was not included in the summary of vasoconstriction evaluations.
[352] Efficacy Results: Fluticasone propionate lotion, 0.05% (Class 5) with occlusion and 0.1% triamcinolone acetonide lotion (Class 5) with occlusion were not statistically significantly different from each other, but were statistically significantly different from triamcinolone and fluticasone without occlusion, hydrocortisone (Class 7) with and without occlusion. Triamcinolone without occlusion was statistically significantly different from all other products as was hydrocortisone without occlusion. Hydrocortisone with occlusion and fluticasone without occlusion were not statistically significantly different from each other.
[353] Safety Results: No patient experienced an AE and no patient discontinued the study due to safety reasons. TABLE 78. CLINICAL EVALUATION OF IN-VIVO OCCLUSION BENEFIT IN IMPROVING STEROID POTENCY THROUGH VASOCONSTRICTION TEST
CLINICAL CONCLUSION
[354] The vasoconstriction assessment results for the ITT and PP populations were essentially the same in that one patient in the ITT population did not have the assessment. The Class 5 fluticasone and triamcinolone reference lotion products with P1-016/P2-004 occlusion were not statistically different from each other and were statistically significantly different (more potent) than all other reference products (with occlusion of P1-016/P2-004 or no occlusion). The Class 5 triamcinolone reference product without occlusion was statistically significantly different (more potent) than the Class 7 reference product (hydrocortisone) (with P1-016/P2-004 occlusion or without occlusion) and the Class 5 fluticasone reference product without occlusion. This result is somewhat different in that the published potency rating of fluticasone and triamcinolone lotion products that are identical (ie, Class 5 potency). Such variability, however, is not unanticipated in VCA from time to time. The Class 7 hydrocortisone reference product with P1-016/P2-004 occlusion and the Class 5 fluticasone reference product without occlusion were not statistically different from each other and statistically significantly different (more potent) than the Class 7 reference product without occlusion. The Class 7 hydrocortisone reference product was statistically significantly different (less potent) than all other reference products.
[355] These results consistently demonstrated a potency increase based on film occlusion of P1-016/P2-004 for all three RLDs tested. Relative to the test product of 2.5% hydrocortisone occluded from P1-016/P2-004 film, the equivalence to the fluticasone lesson RLD implies an increase to a potency of Class 5 from Class 7 due to occlusion with the P1-016/P2-004 film. Similarly, both the reference products occluded from the Class 5 0.05% fluticasone lotion and the 0.1% triamcinolone lotion were more potent than their non-occluded counterparts. This implies an increase from Class 5 power to at least Class 4 to Class 3 power. EXAMPLE 88. CLINICAL EFFICIENCY ASSESSMENT FOR MANAGING SKIN BARRIER FUNCTION CONDITIONS
[356] Evaluation of clinical effectiveness for management of specific conditions of compromised skin barrier function by application of the compositions disclosed herein are described below. PATIENTS:
[357] A number of patients suitable for statistical analysis (eg, 24 to 64) with a specific condition of compromised skin barrier function (eg, atopic dermatitis, psoriasis, eczema, ichthyosis vulgaris, xeroderma, rosacea) are selected for the study. For example, patients with atopic dermatitis or eczema are selected based on the widely accepted criteria proposed by Hanifin and Rajka, Diagnostic features of atopic dermatitis, Acta. Derm Venereol Suppl (Stockh) 1980; 92: 44 to 47 Patients with ichthyosis vulgaris are selected based on the widely accepted criteria described in Williams et al., The U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis. III. Independent hospital validation, Br J Dermatol 1994; 131(3):406 to 416. Anyone with marks, scars, scratches or any skin condition is NOT excluded.
[358] Patients are evaluated for the severity of their specific skin condition upon arrival at the testing site by a dermatologist and are followed during their 2-week testing period, preferably by the same dermatologist. Patients are interviewed about the duration of the skin condition, other atopic disorders including asthma or allergic rhinitis, and other seasonal differences in specific skin condition severity and their treatment history such as oral steroids, moisturizers, or antihistamines. Patient questionnaires are also given to patients for self-assessments on severity of conditions and quality of life such as sleep pattern. Patients can be further classified into mild, moderate and severe conditions.
[359] Inclusion Criteria: 1. Male and female at any age (eg for atopic dermatitis), between 6 and 70 years of age (eg for eczema, ichthyosis vulgaris), or between 18 and 70 years of age (for example, for psoriasis); 2. Agree to forgo exercise and/or drink hot or caffeinated beverages for the 2 hours prior to your appointment on the test day (this may affect measurements); 3. Will and can follow all study requirements and restrictions; and 4. Can read, understand and sign the consent form.
[360] Exclusion Criteria: 1. Is pregnant, nursing, or planning a pregnancy as determined by interview; 2. Currently suffering from menopause (ie experiencing hot flashes); 3. Is a smoker; 4. Any other condition or other factor, the investigator or his duly designated representative believes may affect skin response or interpretation of test results.
[361] Patients are NOT instructed to stop using all moisturizing products (soaps, lotions, sunscreens, insect repellent, etc.) for a 3-day preconditioning period prior to testing which is normally instructed below for regular hydration studies. However, patients are instructed not to exercise or drink hot or caffeinated beverages for 2 hours prior to their test visit day as this may affect measurements. Patients are instructed not to apply ointment or oil prior to examination. TREATMENTS AND PROCEDURES:
[362] Two to six 5 cm by 5 cm test sites are delineated, using a standard template as a guide, on the patient's skin including two or more areas with the specific skin condition (“skin lesion”) and one or more areas with normal-looking skin using a standard template.
[363] Test products are applied over one to four identified skin lesions and above two or three areas of normal-looking skin. At least one, and preferably two, identified skin lesions are left untreated as a control. Test products are applied once a day for 2 weeks daily.
[364] An aliquot of about 0.08 to 0.1 ml of the test composition is dispensed onto a finger using a finger guard and then directly applied to the test area. In the case of a two-part test composition, the two compositions are applied to the same test area, with the first test composition (about 0.08 ml per 25 cm2 area) being applied to the skin first and the second composition test (about 0.1 ml per 5 cm2) dispensed with a new finger guard and applied over the same area treated with the first test composition by sliding motion to coat the treated area, but not rubbing, to minimize mixing the two test materials. PRODUCT REMOVAL BEFORE CLINICAL MEASUREMENTS:
[365] All test areas are cleaned to remove test compositions prior to clinical measurements. The remover is shaken well until smooth before use. The remover (1.5 ml by 25 cm2) is poured onto a round cotton pad and then the wet pad is placed in the test area to remove the test compositions. CLINICAL MEASUREMENTS
[366] Clinical measurements are conducted in one or more of the following aspects.
[367] • Severity of illness:
[368] the SCORAD or OSCORAD (Objective Count of Atopic Dermatitis, European Task Force on Atopic Dermatitis, Severity scoring of atopic dermatitis: the SCORAD index, Dermatology 1993, 186:23 to 31) uses the rule of nines with six clinical features of atopic dermatitis disease intensity (erythema/darkening, swelling/population, oozing/crust, excoriations, lichenification/pruritic/itching, and dryness), count ranges from 0 to 103.
[369] PASI (Area of Psoriasis and Severity Index, Fredriksson and Pettersson, Severe psoriasis - oral therapy with a new retinoid, Dermatologica 1978;157:238 to 244) is based on the quantitative assessment of three typical signs of psoriatic lesions : erythema (redness), infiltration (thickness) and desquamation (scaling), on a scale of 0 ± 4, combined with the involved skin surface area. The basis for the PASI score is the assessment of four separate areas of the body: head, torso, and upper and lower extremities. Counting them separately for erythema, infiltration and desquamation, after establishing the extent of the skin surface involved, is time consuming and may take 10±15 minutes even for experienced workers. An example count form is provided in Figure 17. The PASI count is calculated as follows: PASI = 0.1(Eh + Ih +Dh)Ah + 0.3(Et + It +Dt)At + 0.2( Eu + Iu +Du)Au + 0.4(El + Il +Dl)Al where E= erythema; I = infiltration; D= scaling; A= area; h = head; t = trunk; u = upper extremities; and l = lower extremities
[370] the CRTT (Skin Resonance Running Time, Song et al., Decreased cutaneous resonance running time in cured leprosy subjects, Skin Pharmacol Physiol 2009, 22:218 to 224 and Xin et al., Cutaneous resonance running time varies with age, body site and gender in a normal Chinese population, Skin Res Technol 2010, 16: 413 to 421) in psoriatic lesions by Revicometer RVM 600: A Courage-Khazaka RVM600 Reviscometer (CKelectronic GmbH, Koln, Germany) is used to measure the CRRTs in psoriatic lesions in the forearm extensor and the contralateral uninvolved sites served as controls. The measuring area with this probe is 8 mm. And the acoustic shock wave path distance is 2 mm with 1.77 lJ energy. Measurements start at the 12-hour clock position, which is determined with the right forearms placed on the table as described above. Measurements are then taken clockwise at every 1 h interval or every 30°. These measurements give the CRRTs in the 0-6 hour, 1-7, 2-8, and so on. Readings towards 1 to 7, 2 to 8, 3 to 9, 4 to 10 and 5 to 11 o'clock on the left forearm are compared with the same readings towards 5 to 11, 4 to 10, 3 to 9, 2 to 8, 1 to 7 hours, respectively, on the right forearm. All patients rested at 20 to 24 °C, in a relative humidity of about 50 to 55% for 30 min before measurements were taken.
[371] the HECSI (Hand Eczema Severity Index, Held et al., The Hand Eczema Severity Index (HECSI): a scoring system for the clinical assessment of hand eczema, Contact Dermatitis 2005, 152:302 to 307) is a hand dermatitis clinical grading system used to assess product tolerability. HECSI assesses erythema, induration/papulation, vesicles and fissures from dermatitis of the hands, and the patient's perception of burning, burning, and itching.
[372] o NESS (Nottingham Eczema Severity Score, Emerson et al., The Nottingham Eczema Severity Score: preliminary refinement of the Rajka and Langeland grading, Br J Dermatol 2000, 142: 288-297 and Hon et al., Validation of a self-administered questionnaire in Chinese in the assessment of eczema severity, Pediatr Dermatol 2003, 20:465 to 469) is used to assess clinical severity.
[373] o Visual analogue scale (VAS), Investigator's Global Assessment (IGA) and Ichthyosis Vulgar Area and Severity Index (EASI), Dry Skin (Itching Severity Index Score) are also used to assess clinical severity, as described in Lee et al., Effectiveness of acupressure on pruritus and lichenification associated with atopic dermatitis: a pilot trial, Acupunct Med. March 2012; 30(1): 8 to 11.
[374] • Quality of Life: Adult DLQI Questionnaires (Finlay and Khan, Dermatology Life Quality Index (DLQI)--a simple practical measure for routine clinical use, Clin Exp Dermatol. May 1994;19(3):210 to 216) and CDLQI for Children (Lewis-Jones and Finlay, The Children's Dermatology Life Quality Index (CDLQI): initial validation and practical use, Br J Dermatol. June 1995;132(6):942 to 949) are used for measure how much a patient's illness has affected their lives over the past few weeks. The response for each questionnaire was defined as 0 to 3 (0 = not affected at all; 3 = very affected). The DLQI was summarized through six subscales: “Symptoms and sensations”; "Recreation"; "Personal relationships"; "Treatment"; “Work and school”; and “Daily Activities”. The CDLQI was summarized through six subscales: “Symptoms and sensations”; "Recreation"; "Personal relationships"; "Treatment"; “School or holidays”; and “Sleep”. The total quality of life score (QOL) was calculated by adding the score for each question. The total QOL count and the six subscales were expressed as a percentage of the respective maximum counts. The reliability and validity of DLQI were assured in the review by Basra et al., Dermatology Life Quality Index 19942007: a comprehensive review of validation data and clinical results, Br J Dermatol. November 2008;159(5):997 to 1,035.
[375] • Transepidermal Water Loss: TEWL and Skin Conductance or Capacitance (Yamamoto Y, Measurement and analysis of skin electrical impedance, Acta Derm Venereol Suppl (Stockh), 1994; 185:34 to 38)
[376] • Stratum Corneum Integrity and Cohesion: A strip of tape is used as the quantification of the amount of sequential D-squared tape strips required to increase TEWL by 20 g/m2 per hour
[377] • Stratum corneum thickness: The stratum corneum thickness is calculated by the corneometer as (square root of low frequency susceptance)/(high frequency admittance) by the corneometer. Stratum corneum thickness is also visualized by conventional immunohistoblotting. The thickness of the stratum corneum is also measured using light microscopy, such as a Scanning Tandem Confocal Microscope (TSM), to measure the depth measurement (200 µM) of the thickness of the different layers of skin.
[378] • Skin Biopsy/Immunohistochemical Stain: Immunoperoxidase staining of paraffin-embedded sections is performed using the ChemMate Peroxidase/DAB system (Dako Cytomation, Hamburg, Germany) to visualize the stratum corneum and epidermal, epidermal structure thickness and extracellular lamellar membranes.
[379] o Epidermal cell proliferation and hyperplasia can be examined using PCNA immunohistochemical staining, Ki67, Ki-S3 or other markers of proliferation.
[380] o Epidermal differentiation can be examined using immunohistochemical staining of Involucrin, Keratins CK 5, 6, 17, 1, 5, 10, 14 or other differentiation markers
[381] o Laboratory Tests: Peripheral blood EOS count (quantity 100 per ml; normal 40 to 440), serum LDH (IU l-1; normal 119 to 229), total serum IgE (IU ml-1 ; normal 0.0 to 400.0) and allergen-specific IgE (SRL Inc., Tokyo, Japan) are measured. Allergen-specific IgE were estimated by fluoroenzyme immunoassays for house dust, mite allergen, grass pollen (Tancy), cedar pollen, fungal allergen (Candida), animal dander, and food. With regard to sensitivity for detection of specific IgE, 100 lumicount and values greater than or equal to 100 lumicount are considered positive (+).
[382] o In addition, serum cathelicidins (LL-37) concentration is measured using enzyme immunoassay (Bachem, San Carlos, CA, USA, as described in Leung et al., Circulating LL-37 is a biomarker for eczema severity in children, J Eur Acad Dermatol Venereol.2012;26:518 to 522] Samples are diluted 90-fold prior to measurement.The sensitivity of this assay was 1ng/ml.
[383] • Statistical Analysis: Simple regression analyzes are also used to identify significant associations of hydration, thickness, or TEWL with stratum corneum SCORAD or PASI. Data with P values less than 0.05 are assessed as significant and P values less than 0.005 as highly significant. Wilcoxon rank sum test and simple regression analyzes are performed to assess the association or correlation between different biological markers including IgE, LDH, EOS and the SCORAD or PASI. TABLE 79: CLINICAL OUTCOMES AND BIOMARKERS





EXAMPLE 89. EVALUATION OF CLINICAL EFFICIENCY FOR ADULTS WITH ECZEMA
[384] Evaluation of clinical effectiveness for eczema management by applying the compositions disclosed herein are described below. The study was a single-center open-label study. PATIENTS:
[385] 10 patients (7 women and 3 men) age 18 years and older with mild to severe eczema including atopic dermatitis (Investigator's Global Assessment [IGA] Disease Severity Grade 2 to 4)
[386] Patients are evaluated for the severity of their specific skin condition upon arrival at the testing site by a dermatologist and participate in the study for five (5) days followed by an open-label use period of up to a total of 30 days. Patients are interviewed about the duration of the skin condition.
[387] Inclusion Criteria: 1. The patient is a non-pregnant male or female, aged 18 years or older at the time of consent. 2. Women of childbearing potential (WOCBP) must have a negative pregnancy urine test (UPT) at Visit 1/Referral to qualify; female patients who are postmenopausal,1 cannot conceive due to previous obstetric surgery or use an effective method of contraception. 3. The patient wants and can give written informed consent. 4. The patient has the clinical diagnosis “Eczema” which should include Atopic Dermatitis (AD) based on the criteria of Hanifin and Rajka or another form of eczematous dermatitis in the opinion of the investigator (eg nummular eczema etc.). 5. The patient has a clinical diagnosis of stable eczema [within three (3) months] mild to severe (Grade 2 to 5) as determined by the Investigator's Global Assessment (IGA) in the assigned Treatment area, which includes a minimum of 0 .5% of active disease BSA. 6. The patient is willing and able to apply the test article (or articles) as directed, comply with study instructions, and commit to all follow-up visits for the duration of the study. 7. In the investigator's opinion, the patient is in good general health and is free from any disease state or physical condition that exposes the patient to an unacceptable risk for study participation or impairs the patient's assessment or test article by participating in the study.
[388] Exclusion Criteria:
[389] 1. The patient is pregnant, lactating, or planning to become pregnant during the study. 2. In the investigator's opinion, the patient has a pathology or skin condition that may interfere with the evaluation of the test products or requires the use of topical or systemic therapy that interferes during the study. 3. The patient used any of the following topical preparations in the Treatment Area: a. Topical treatments (including OTC products) treatments including, but not limited to, corticosteroids, immunomodulators (tacrolimus, pimecrolimus, etc.), tar, calcipotriene or other vitamin D preparations, antihistamines (doxepin, diphenhydramine, etc.), or antibiotics within one (1) week of Visit 1/Referral. Note: Stable (>30 days) doses of oral or intranasal antihistamines to treat allergic rhinitis, inhaled or intranasal corticosteroids to treat bronchial asthma, or antibiotics to treat acne will be allowed but need to be documented. B. Retinoids (including tazarotene, adapalene, and tretinoin) within four (4) weeks of Visit 1/Referral. ç. Light treatments (PUVA, UVB, eximere laser, etc.), microdermabrasion or chemical peeling within four (4) weeks of Visit 1/Reference. d. Another topical therapy, which may materially affect the patient's atopic dermatitis in the investigator's opinion. 4. The patient used any of the following systemic medications: a. Corticosteroids (including intramuscular and intralesion injections) within one (1) week of Visit 1/Referral. B. Immunomodulators (including leukotriene) or antimetabolites within one (1) week of Visit 1/Referral. ç. Oral or topical antibiotics (OTC or prescription) in one (1) week, unless in a stable dose for acne (more than 3 months of use), Visit 1/Referral. d. Another systemic therapy, which may materially affect the patient's atopic dermatitis in the investigator's opinion. 5. The patient is currently using or has used an investigational drug or investigational device treatment within 30 days of Visit 1/Referral. 6. The patient is currently enrolled in an investigational study. 7. The patient has a history of sensitivity to any of the ingredients in the test articles (see Section 5.1 in the protocol). 8. The patient is known to be non-compliant or unlikely to comply with the requirements of the study protocol (eg, due to alcoholism, drug addiction, mental disability) in the investigator's opinion. 9. The patient currently has a skin infection. TREATMENTS AND PROCEDURES:
[390] The study will consist of three (3) clinical visits over five (5) days and two follow-up visits on Day 15 (visit 4) and Day 30 (visit 5).
[391] Visit 1 (Screen/Referral): Day 1 Patients may be screened for the study up to 30 days prior to Visit 1. During screening, study requirements will be reviewed, written informed consent obtained and eligibility confirmed . If applicable, laundering of prohibited drugs or treatments will be determined and implemented. Three procedures can be performed as a separate screening visit prior to the Referral Visit, as/if required.
[392] Demographics, inclusion/exclusion criteria, medical/dermatological history, and concomitant medications and therapies will be reviewed to determine patient eligibility. A brief dermatological examination and UPT (if applicable) will be performed. Clinical evaluations (IGA and Clinical Signs and Eczema) and evaluation of itching will be performed before testing article application. The Treatment Area will be defined as a distinct contiguous anatomical unit of up to 3% BSA (eg, an arm, a leg, abdomen, etc.), which must include a minimum of 0.5% BSA of active disease. The percentage of BSA to be treated and the location of the skin affected by Eczema will be documented. The percentage of BSA will be estimated based on the assumption that 1% of BSA is equivalent to the patient's hand area with fingers held together.
[393] The test article will be applied to the Treatment Area using the following instructions: 1. Wash with an antimicrobial soap and thoroughly dry the affected area. 2. Use a clean, dry fingertip to dispense and apply a thin layer of P1-016 formulation to the Treatment Area. Ensure product is in an even layer with no thick areas. Approximately a quarter amount of P1-016 should cover 1% of BSA. 3. Clean your fingertip. 4. Use a fingertip to dispense and apply a thin layer of formulation P2-004. Gently spread P2-004, completely cover area P1-016. Do not rub on P1016 layer; simply slide it until it rests evenly on the top. 1 to 1.5X quantity of P2-004 can be used compared to P1-016. Approximately a quarter amount of P2-004 should cover 1% of BSA. 5. Do not touch or move for at least 2 minutes while the film settles.
[394] Photographs can be taken to document the reference Treatment Area. The patient will be asked (or asked) about their impression of the product and its ease of use; responses will be documented in a patient questionnaire. Any AEs will be documented.
[395] Eczema care use of affected skin areas outside the treatment area is permitted during the study period. Systemic eczema treatments or other topical treatments of any kind in the Treatment Area are prohibited.
[396] A test article and diary will be provided to the patient prior to discharge from the clinic. These materials will be returned by the patient to the site at the next clinical visit. The patient will be instructed to apply the film each day, as needed, until the next clinic visit; if the film remains intact throughout the day, no application is needed until the film begins to peel or break. As required, the patient may apply the film up to twice daily as assigned by the investigator to keep a film intact in the Treatment Area. In most cases, it is anticipated that the patient will apply the film every 1 to 3 days, depending on how well the film wears. Prior to each film application, old film will be removed as directed by protocol. At the investigator's request, as an option, during any clinical visit, the film may be removed and reapplied by the patient under supervision rather than at home. In all cases, during the study, the patient will document film applications in the patient diary provided. The patient will be scheduled for their next return visit and discharged from the clinic.
[397] Visit 2 (Follow-up): Day 3 ± 1 day. Patients will return to the clinic for follow-up and consulted for any changes in health status. Concomitant medications will be reviewed. Clinical assessments (IGA and Clinical Signs and Eczema) and itching and durability assessments of P1-016/P2-004 film will be performed. Photographs can be taken to document the durability of the treatment. Any AEs will be documented.
[398] A test article and journal will be reviewed and, as required, a new test article and/or journal will be provided by the patient prior to discharge from the clinic. These materials will be returned by the patient to the site at the next clinical visit. The patient will be instructed to apply the film each day, as needed, until the next clinic visit; if the film remains intact throughout the day, no application is needed until the film begins to peel or break. As required, the patient may apply the film up to twice daily as assigned by the investigator to keep a film intact in the Treatment Area. In most cases, it is anticipated that the patient will apply the film every 1 to 3 days, depending on how well the film wears. Prior to each film application, old film will be removed as directed by protocol. At the investigator's request, as an option, during any clinical visit, the film may be removed and reapplied by the patient under supervision rather than at home. In all cases, during the study, the patient will document film applications in the patient diary provided. The patient will be scheduled for their next return visit and discharged from the clinic.
[399] Visit 3 (End of Film Durability Assessment): Day 5 ± 1 day. Patients will return to the clinic for follow-up and consulted for any changes in health status. Concomitant medications will be reviewed. Clinical assessments (IGA and Clinical Signs and Eczema) and itching and durability assessments of P1-016/P2-004 film will be performed. Photographs can be taken to document the durability of the treatment. The patient will be instructed how to remove the film and removal will take place at the clinic under the supervision of the study team. Ease of film removal and any reported skin irritation will be noted. The patient will be asked (or asked) about their impression of the product and its ease of use; responses will be documented in a patient questionnaire. Any AEs will be documented.
[400] A test article and journal will be reviewed and, as required, a new test article and/or journal will be provided by the patient prior to discharge from the clinic. These materials will be returned by the patient to the site at the next clinical visit. The patient will be instructed to apply the film each day, as needed, until the next clinic visit; if the film remains intact throughout the day, no application is needed until the film begins to peel or break. As required, the patient may apply the film up to twice daily as assigned by the investigator to keep a film intact in the Treatment Area. In most cases, it is anticipated that the patient will apply the film every 1 to 3 days, depending on how well the film wears. Prior to each film application, old film will be removed as directed by protocol. At the investigator's request, as an option, during any clinical visit, the film may be removed and reapplied by the patient under supervision rather than at home. In all cases, during the study, the patient will document film applications in the patient diary provided. The patient will be scheduled for their next return visit and discharged from the clinic.
[401] Visit 4 (Follow-up): Day 15 ± 2 days. Patients will return to the clinic for follow-up and consulted for any changes in health status. Concomitant medications will be reviewed. Clinical assessments (IGA and Clinical Signs and Eczema) and itching and durability assessments of P1-016/P2-004 film will be performed. Photographs can be taken to document the durability of the treatment. Any AEs will be documented.
[402] A test article and journal will be reviewed and, as required, a new test article and/or journal will be provided by the patient prior to discharge from the clinic. These materials will be returned by the patient to the site at the next clinical visit. The patient will be instructed to apply the film each day, as needed, until the next clinic visit; if the film remains intact throughout the day, no application is needed until the film begins to peel or break. As required, the patient may apply the film up to twice daily as assigned by the investigator to keep a film intact in the Treatment Area. In most cases, it is anticipated that the patient will apply the film every 1 to 3 days, depending on how well the film wears. Prior to each film application, old film will be removed as directed by protocol. At the investigator's request, as an option, during any clinical visit, the film may be removed and reapplied by the patient under supervision rather than at home. In all cases, during the study, the patient will document film applications in the patient diary provided. The patient will be scheduled for their next return visit and discharged from the clinic.
[403] Visit 5 (End of Study, or Early Termination): Day 30 ± 3 days. Patients will return to the clinic for follow-up and consulted for any changes in health status. Concomitant medications will be reviewed. A UPT (if applicable) will be performed. Clinical assessments (IGA and Clinical Signs and Eczema) and itching and durability assessments of P1-016/P2-004 film will be performed. Photographs can be taken to document the durability of the treatment. The movie will be removed. The test article and journal will be collected. Any AEs will be documented. The patient will be excused from the study.
[404] Two to six 5 cm by 5 cm test sites are delineated, using a standard template as a guide, on the patient's skin including two or more areas with the specific skin condition (“skin lesion”) and one or more areas with normal-looking skin using a standard template.
[405] Test products are applied over one to four identified skin lesions and above two or three areas of normal-looking skin. At least one, and preferably two, identified skin lesions are left untreated as a control. Test products are applied once a day for 2 weeks daily.
[406] An aliquot of about 0.08 to 0.1 ml of the test composition is dispensed onto a finger using a finger guard and then directly applied to the test area. In the case of a two-part test composition, the two compositions are applied to the same test area, with the first test composition (about 0.08 ml per 25 cm2 area) being applied to the skin first and the second composition test (about 0.1 ml per 5 cm2) dispensed with a new finger guard and applied over the same area treated with the first test composition by sliding motion to coat the treated area, but not rubbing, to minimize mixing the two test materials. CLINICAL MEASUREMENTS
[407] Effectiveness: Effectiveness will be assessed in the Treatment Area at each visit.
[408] Investigator's Global Assessment (IGA): The overall severity of atopic dermatitis or Eczema using a 6-point ordinal scale from 0=free to 5=very severe. It is a static morphological scale that refers to a point of time and not a comparison with Reference.
[409] Clinical Signs of Atopic Dermatitis/Eczema: The severity of individual signs of AD or Eczema (erythema, induration/papulation, excoriation, lichenification, and exudation/crusting) using a 5-point ordinal scale of 0= none to 4=severe.
[410] Safety: All AEs and concomitant medications will be recorded at each visit.
[411] Durability of film P1-016/P2-004 (Visits 2 to 5) and itchiness (Visits 1 to 5) will be assessed (i) as the percentage of BSA remaining from the test article film, (ii) by questionnaire and (iii) by photographs (optional) to document focal areas of film integrity at the investigator's discretion.
[412] The Durability Questionnaire will contain the following questions: (1) the test article peeled from the Treatment Area: (a) nothing, (b) a light amount, (c) a moderate amount, or (d) a large amount (on Visits 2-5, before film removal); (2) the test article peeled from the Treatment Area: (a) nothing, (b) a light amount, (c) a moderate amount, or (d) a large amount (at Visits 2 to 5, before removal of movie); (3) the test article now covers (a) 0 to 25%, (b) 25.1 to 50%, (c) 50.1 to 75%, (d) 75.1 to 85% or (e) 85.1 to 100% of the original Treatment Area covered with film at the Reference visit (at Visits 2 to 5, before film removal); (4) the film removal process resulted in skin irritation in the Treatment Area: (a) none, (b) a slight amount, (c) a moderate amount, or (d) a large amount (at Visits 2 to 5); (5) the test article lasted between treatment days, on average, for: (a) 12 hours or less or (b) 12 to 24 hours (at Visits 2 to 5); NOTE: this question to be answered by the patient. (6) How would you rate the degree of itching in the Treatment Area in the last 24 hours: 0=none, 1=one stroke, 2=mild; 3= moderate; 4=severe (at Visits 1 to 5m, prior to Visit 1 film application or removal) NOTE: This question must be answered by the patient.
[413] Other Assessments: Patients will complete a Patient Questionnaire to document their impression of the product and its ease of use at Visit 3 and Visit 5/End of Study.
[414] The Patient Questionnaire will contain the following questions: (1) overall satisfaction with the study product: (a) excellent [very satisfied], (b) good [moderately satisfied], (c) fair [mildly satisfied] ] and (d) bad [not satisfied at all]. (2) the study product application was easy to perform: (a) very easy, (b) moderately easy, (c) slightly easy, and (d) not easy. (3) study product removal was easy to accomplish: (a) very easy, (b) moderately easy, (c) slightly easy, and (d) not easy. (4) in general, the study product: (a) improved very significantly, (b) improved, (c) did not improve or worsen (no real change) or (d) made the treated areas of my skin disease worse. (5) Based on your experience, would you consider using this product to treat your condition rather than other topical steroid-like medications: Yes/No, (free text explanation is optional) [Visit 5, EOS only]. STUDY OUTCOMES:
[415] Study Outcomes: Atopic dermatitis severity variables (IGA and Clinical Signs and Eczema) will be descriptively summarized at each visit. The itch ratings from the patient questionnaire will be analyzed.
[416] Safety Outcome (or Outcomes): Outcomes will be descriptively summarized at each visit.
[417] Incidence (severity and causality) of any AEs emerging from systemic and local treatment (TEAEs).
[418] Percentage of test article BSA remaining.
[419] Number of patients per answer for each Durability Questionnaire question.
[420] Other Outcome (or Other Outcome): Number of patients per answer for each Patient Questionnaire question. STATISTICAL METHODS:
[421] All statistical processing will be performed using SAS® unless otherwise stated. Summary tables (descriptive statistics and/or frequency tables) will be provided for all variables. Continuous variables will be described by descriptive statistics (n, mean, median, standard deviation, minimum and maximum). Frequency counts and percentage of patients in each category will be provided for categorical data.
[422] Study Populations: All randomized patients who received and applied the test article will be included in the safety analysis and will be considered the Safety population. Patients who completed the study without significant protocol deviations will be included in the Evaluable Population.
[423] Efficacy Analyzes: Efficacy analyzes will be conducted on the evaluable population.
[424] o Overall Investigator Assessment: Frequency distributions of IGA scores will be summarized by severity at each visit.
[425] o Clinical Signs and Eczema: Frequency distributions of each clinical sign of Eczema will be summarized by severity at each visit. Reduction of self-reported itch ratings on a scale of 0=none, 1=one trait, 2=mild, 3=moderate, 4=severe in patient questionnaires will be analyzed.
[426] Security Reviews: A security review will be conducted on the Security population.
[427] Adverse Events: All AEs reported during the study will be listed, document course, severity, investigator assessment of relationship to test articles, and outcome. All reported AEs will be summarized by the number of patients reporting AEs, SOC, PT, severity and ratio to test article.
[428] Percent Test Article BSA Remaining in Treatment Area: Descriptive statistics will be used to summarize the percentage of test article BSA remaining in the Treatment Area at each visit.
[429] Durability Questionnaire: Each durability questionnaire question will be summarized by frequency and response at each visit.
[430] Urine Pregnancy Tests: UPT results (if applicable) in Reference will be provided in a listing.
[431] Concomitant Medications and Therapies: Concomitant medications and therapies will be provided in a listing.
[432] Other Analyzes: The other analyzes will be conducted on the evaluable population.
[433] Patient Questionnaire: Each patient questionnaire question will be summarized by frequency and response at each visit. CLINICAL RESULTS:
[434] 10 patients applied test composition P1-016/P2-004 up to twice daily in a distinct area (0.5 to 3% BSA) of active disease. Female: 70%, Male: 30% Average age: 31.6 years
[435] Durability on skin (% remaining): P1-016/P2-004 film was durable on average 24 to 48 hours and caused little or no irritation when removed
[436] Safety: No material safety issues
[437] Efficacy (via Investigator's Global Assessment and Clinical Signs of Atopic Dermatitis): Marked improvement in general disease and signs/symptoms over 30 days of treatment. Enhancement of clinical signs parallel IGA enhancements. The results are also shown in Figure 18(A to I).
[438] Overall satisfaction: Most patients were satisfied with the treatment and rated the study product as easy to use and remove. 88.9% of patients were moderately or very satisfied with the product (Day 30). 88.9% of patients found the product moderately or very easy to apply (Day 30). 88.9% of patients would consider using the product instead of other medications (Day 30)
[439] While the present invention has been described with reference to the exemplary embodiments, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. The broadest interpretation of the scope of the following claims should be given to cover all such modifications and equivalent structures and functions.

权利要求:
Claims (11)
[0001]
1. Composition for in-situ formation of a layer on the skin of a patient characterized in that said composition is a two-part composition comprising a first part comprising Polymer B and a second part comprising a catalyst; wherein the first part further comprises Polymer A and the second part further comprises Polymer C; wherein Polymer A comprises one or more organopolysiloxanes having on average at least two alkenyl-functional groups and having a viscosity of 10,000 to 2,000,000 cSt at 25°C; Polymer B comprising one or more organopolysiloxanes having on average at least two Si-H units and having a viscosity of 2 to 500,000 cSt at 25°C; Polymer C comprises one or more organopolysiloxanes which on average have at least one alkenyl-functional group and which have a viscosity of 0.7 to 10,000 cSt at 25°C; and said catalyst facilitates the crosslinking of Polymers A and B.
[0002]
2. Composition according to claim 1, characterized in that said Polymer A has an average molecular weight greater than 60,000 Da, greater than 72,000 Da, greater than 84,000 Da, greater than 96,000 Da, greater than 100,000 Da, greater than 140,000 Da or greater than 150,000 Da, and wherein said Polymer A has an average molecular weight less than 500,000 Da, less than 200,000 Da, less than 190,000 Da, less than 180,000 Da, less than 170,000 Da or less than 160,000 Da; or wherein said Polymer A has an average molecular weight of 155,000 Da; and wherein said Polymer C has an average molecular weight greater than 180 Da, greater than 500 Da, greater than 800 Da, greater than 1,500 Da, greater than 3,000 Da or greater than 6,000 Da, greater than than 9,400 Da, and wherein said Polymer C has an average molecular weight less than 65,000 Da, less than 50,000 Da, less than 45,000 Da, less than 30,000 Da or less than 17,500 Da; preferably wherein said Polymer C has an average molecular weight of 10,000 Da.
[0003]
3. Composition according to claim 1 or 2, characterized in that said Polymer B has an average molecular weight greater than 400 Da, greater than 500 Da, greater than 800 Da, greater than 1,200 Da, greater than 1,800 Da or greater than 2,000 Da, and wherein said Polymer B has an average molecular weight of less than 500,000 Da, less than 250,000 Da, less than 140,000 Da, less than 100,000 Da, less than 72,000 Da, less than 62,700 Da, less than 49,500 Da, less than 36,000 Da, less than 28,000 Da or less than 17,200 Da; or wherein said Polymer B has an average molecular weight between 2,200 and 6,000 Da; and wherein said Polymer C has an average molecular weight greater than 180 Da, greater than 500 Da, greater than 800 Da, greater than 1,500 Da, greater than 3,000 Da or greater than 6,000 Da, greater than than 9,400 Da, and wherein said Polymer C has an average molecular weight less than 65,000 Da, less than 50,000 Da, less than 45,000 Da, less than 30,000 Da or less than 17,500 Da; preferably wherein said Polymer C has an average molecular weight of 10,000 Da.
[0004]
4. Composition, according to any one of claims 1 to 3, characterized in that said composition comprises as ingredients: 5 to 90% by weight of Polymer A; 5 to 75% by weight of Polymer B; and 0 to 25% by weight of reinforcing component; or wherein said composition comprises as ingredients: 50 to 90% by weight of Polymer A; 5 to 30% by weight of Polymer B; and 5 to 15% by weight of reinforcing component; and/or wherein said second part comprises as ingredients: 0.01 to 20% by weight of Polymer C; and 0.005 to 0.05% by weight of catalyst; preferably 0.5 to 10% by weight of Polymer C; and 0.01 to 0.03% by weight of catalyst.
[0005]
5. Composition, according to any one of claims 1 to 4, characterized in that said first part comprises as ingredients: 5 to 90% by weight of Polymer A; 5 to 75% by weight of Polymer B; and 0 to 25% by weight of reinforcing component; and/or wherein said second part comprises as ingredients 0.01 to 20% by weight of Polymer C; and 0.005 to 0.05% by weight of catalyst.
[0006]
6. Composition according to claim 1, characterized in that the molar ratio of the Si-H functional group of Polymer B to the alkenyl functional group of Polymer A is 60:1 1:5; and/or wherein the molar ratio of the Si-H functional group of Polymer B to the alkenyl functional group of polymer A is from 45:1 to 15:1; and/or wherein the molar ratio of the Si-H functional group of Polymer B to the alkenyl functional group of Polymer C is from 60:1 to 1:5; and/or wherein the molar ratio of the Si-H functional group of Polymer B to the alkenyl functional group of Polymer C is from 45:1 to 15:1; and/or wherein the molar ratio of the alkenyl functional group of Polymer A to the alkenyl functional group of Polymer C is from 100:1 to 1:100; and/or wherein the molar ratio of the alkenyl functional group of Polymer A to the alkenyl functional group of Polymer C is from 10:1 to 1:10.
[0007]
7. Kit comprising the composition as defined in any one of claims 1 to 6, characterized in that it additionally comprises instructions for use; and/or additionally comprises a cleanser suitable for removing said layer of skin; and/or additionally comprises one or more brushes, spatulas and/or mirrors.
[0008]
8. Composition according to any one of claims 1 to 6, characterized in that it is for use in a method for modifying the function of the skin, wherein the method comprises applying the composition to the individual in need.
[0009]
9. Kit according to claim 7, characterized in that it is for use in a method for modifying the function of the skin, wherein the method comprises applying the composition to the individual in need.
[0010]
10. Composition according to claim 1, characterized in that said Polymer C is selected from vinyl-terminated polydimethylsiloxane, vinyl-terminated diphenylsiloxane-dimethylsiloxane copolymers, vinyl-terminated polyphenylmethylsiloxane, vinyl-terminated vinylphenylmethylsiloxane-vinylphenylmethylsiloxane copolymer , vinyl-terminated trifluoropropylmethylsiloxane-dimethylsiloxane copolymer, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer, vinylmethylsiloxane-dimethylsiloxane copolymer, triethylsiloxane-terminated, copolymer of vinylmethylsiloxane-dimethylsiloxane-vinylsiloxanes-terminated, vinyl dimethylsiloxanes-terminated vinyl dimethylsiloxane copolymer vinyl, vinylmethylsiloxane homopolymers, vinyl T-structure polymers, vinyl terminated monopolydimethylsiloxanes, vinylmethylsiloxane terpolymers, vinylmethoxysilane homopolymers or combinations thereof; preferably wherein said Polymer C is vinyl dimethicone.
[0011]
11. Composition according to claim 10, characterized in that said Polymer C has a viscosity greater than 0.7 cSt, greater than 1 cSt, greater than 6 cSt, greater than 10 cSt, greater than 20 cSt, greater than 50 cSt, greater than 100 cSt, or greater than 200 cSt at 25 °C and wherein said Polymer C has a viscosity less than 10,000 cSt, less than 5,000 cSt, less than than 4,000 cSt, less than 2,000 cSt, less than 1,000 cSt, or less than 500 cSt at 25 °C; preferably wherein said Polymer C has a viscosity of 250 cSt at 25°C.

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JP2019503396A|2019-02-07|

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法律状态:
2020-06-23| B15K| Others concerning applications: alteration of classification|Free format text: AS CLASSIFICACOES ANTERIORES ERAM: A61K 9/00 , A61K 9/70 , A61K 31/80 , A61L 26/00 , A61Q 17/00 , A61Q 19/00 , C08F 8/00 , C08G 77/04 Ipc: A61K 8/895 (2006.01), A61L 26/00 (2006.01), A61Q 1 |

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2020-06-23| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-11-17| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2021-03-16| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-06-08| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 09/11/2016, OBSERVADAS AS CONDICOES LEGAIS. |

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2021-08-24| B25A| Requested transfer of rights approved|Owner name: SHISEIDO COMPANY, LIMITED (JP) |

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2021-09-28| B16C| Correction of notification of the grant [chapter 16.3 patent gazette]|Free format text: REF. RPI 2631 DE 08/06/2021 QUANTO AO TITULAR (ITEM 73). |

优先权:

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申请号 | 申请日 | 专利标题

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US201562252903P| true| 2015-11-09|2015-11-09|

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US62/252,903|2015-11-09|

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PCT/US2016/061150|WO2017083398A1|2015-11-09|2016-11-09|Compositions and methods for application over skin|

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