IL304706A

IL304706A - Use of composition comprising casein hydrolysate for the tratment of inflammatory skin conditions

Info

Publication number: IL304706A
Application number: IL304706A
Authority: IL
Inventors: Iscovich Javier; Jose Mario Iscovich
Original assignee: Mileutis Ltd; Iscovich Javier; Jose Mario Iscovich
Priority date: 2023-07-24
Filing date: 2023-07-24
Publication date: 2025-02-01
Also published as: WO2025022394A1; CN121712516A; AU2024300578A1

Description

P- 622254 -IL 1 USE OF COMPOSITION COMPRISING CASEIN HYDROLYSATE FOR THE TRATMENT OF INFLAMMATORY SKIN CONDITIONS SEQUENCE LISTING STATEMENT[001] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on July 23, 2023, is named P-622254-IL-ST26 and is 66,548 bytes in size.

BACKGROUND OF THE INVENTION id="p-2"

[0002] The casein protein comprises three fractions, α, β and κ, according to their electrophoretic mobility. Casein hydrolysate is the hydrolyzed form of casein which includes, among others, the active beta-casein-derived peptide. It has been established that casein hydrolysate plays a role in immune responses against microbial and viral infections. id="p-3"

[0003] Inflammatory skin conditions are a group of diseases that results in inflammation of the skin. These diseases are characterized by itchiness, red skin, and a rash. Psoriasis, also known as psoriasis vulgaris, is a chronic, inflammatory skin disease characterized by red, scaly patches, papules, and plaques, which usually itch. The skin lesions seen in psoriasis may vary in severity from minor localized patches to complete body coverage. The disease affects 2-4% of the general population. id="p-4"

[0004] The skin is the largest and most visible organ of the body and the anatomic and physiologic barrier between animal and environment. Skin is formed by complex arrangements of cells from ectoderm, neural crest, and endoderm origin and has three major layers—the epidermis, dermis, and subcutis (hypodermis). The general functions of the animal skin include enclosing barrier, environmental protection, motion and shape, adnexa protection, thermoregulation, storage, indicator of general health and internal disease, P- 622254 -IL 2 immunoregulation, pigmentation, antimicrobial action, sensory perception, secretion, excretion and vitamin D production. id="p-5"

[0005] For veterinarians, dermatological diseases pose a challenge. Dermatological problems impact both the beauty of the animal and its quality of life—both of which are important to pet owners. Skin diseases can be caused by a wide variety of underlying problems, and because the skin has a limited range of responses to insults, many different diseases have similar clinical appearances. id="p-6"

[0006] No cure is yet available for psoriasis, even though various topical and systemic treatments can help control the symptoms. Topical agents are typically used for mild disease, phototherapy for moderate disease, and systemic agents for severe disease. For topical treatment corticosteroid preparations are the most effective but also Vitamin D analogues such as paricalcitol were shown to be effective. The main disadvantage of steroids is drug resistance in the patient which develops over time. In addition, prolonged use is not recommended since steroids can cause thinning of the skin, stomach ulcers, bone thinning, and premature cataracts.

Psoriasis resistant to topical treatment and phototherapy may be treated with systemic therapies including oral medications or injectable treatments. Non-biologic systemic treatments frequently used for psoriasis include methotrexate, ciclosporin, hydroxycarbamide, fumarates such as dimethyl fumarate, and retinoids. Biologic systemic treatment includes drugs that target T cells are such as efalizumab and alefacept. id="p-7"

[0007] There is still a great need for novel and safe therapies for the treatment of inflammatory skin conditions.

P- 622254 -IL 3 SUMMARY OF THE INVENTION id="p-8"

[0008] In some aspects, disclosed herein is a method for preventing or treating inflammatory skin conditions, by administering to an animal a composition comprising at least one milk derived protein. id="p-9"

[0009] In some related aspects, the inflammatory skin conditions comprises acne; actinic keratosis, alopecia areata, basal cell carcinoma, Bowen's disease, burning mouth syndrome, cellulitis, congenital erythropoietic porphyria, contact dermatitis, Darier's disease, dystrophic epidermolysis bullosa, atopic dermatitis (AD) (eczema), epidermolysis bullosa simplex, skin erosions and ulcerations erythropoietic protoporphyria, fungal infections of nails, Hailey-Hailey disease, hair diseases, herpes simplex, hidradenitis suppurativa, hyperhidrosis, itchy skin (pruritus), ichthyosis, impetigo, keloids, keratosis pilaris, lichen planus, lichen sclerosus, melisma, mucous membrane diseases, nail diseases, nonhealing wounds, pemphigus vulgaris, plantar warts (verrucas), pityriasis lichenoides, polymorphic light eruption, psoriasis, pyoderma gangrenosum, rosacea, scabies, shingles, squamous cell carcinoma, skin infections, sun allergy, Sweet's syndrome, vitiligo, inflammation due to sunburn, hypersensitivity disorders, canine atopic dermatitis, feline atopy-like dermatitis, contact hypersensitivity, food hypersensitivity, fleabite hypersensitivity, bacterial skin diseases, fungal skin diseases, autoimmune and immune mediated dermatoses, parasitic skin disease and combination thereof. id="p-10"

[00010] In some related aspects, the composition promotes wound or rupture closing. In some further related aspects, the composition reduces skin itching, skin burning, skin redness, skin pain, dry skin, peeling skin, rough skin, skin swelling, skin cracking, or any combination thereof. id="p-11"

[00011] In some related aspects, the inflammatory skin condition is psoriasis.

P- 622254 -IL 4 id="p-12"

[00012] In some related aspects, the inflammatory skin condition is atopic dermatitis. id="p-13"

[00013] In some related aspects, the milk derived protein comprises a casein protein or a casein derived peptide. id="p-14"

[00014] In some further related aspects, the casein derived peptide comprises natural peptide, synthetic peptide, semi-synthetic peptide, or any combination thereof. id="p-15"

[00015] In some further related aspects, the casein derived peptide comprises one or more fragments of β-casein, αS1-casein, αS2-casein and κ-casein. In some further related aspects, the casein derived peptide further comprises amino acids with different lengths. id="p-16"

[00016] In some further related aspects, the casein derived peptide comprises a casein hydrolysate. In some further related aspects, the casein derived peptide comprises a phosphopeptide. In some further related aspects, the phosphopeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO. 1 – SEQ ID NO. 26. id="p-17"

[00017] In some aspects, disclosed herein is a method for moisturizing dry skin, skin softening, reducing skin itching, reducing skin peeling, reducing skin redness, reducing rough skin, reducing swelling, reducing cracking, renewal skin cells, preserving hand skin or any combination thereof, comprising administering to an animal a composition comprising at least one milk derived protein. id="p-18"

[00018] In some aspects, the animal is a human, a cow, a bos taurine, a goat, an antelope, cattle, a bison, a sheep, a buffalo, a camel, a donkey, a llama, a horse, a pig, a cat, a dog or an ave or aviary.

BRIEF DESCRIPTION OF THE DRAWINGS id="p-19"

[00019] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and P- 622254 -IL advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which: id="p-20"

[00020] Fig. 1 is an illustration of the differences in the H&E staining between the group treated with high dose 10% bCNH, (right panel) versus the untreated (left panel). id="p-21"

[00021] Fig. 2 is a graphical illustration of the morphometric analysis of the epidermis (a) Ear (b) Back Skin.; bCNH high dose 10%; Positive control. id="p-22"

[00022] Fig. 3 is an illustration of the CD3 IHC staining between the group treated with high dose 10% bCNH, (right panel) versus the untreated (left panel). id="p-23"

[00023] Fig. 4 is a graphical illustration of semi-quantitative analysis for CD3 immuno- staining showing a marked decrease in the number of CD3 positive cells in the dermis and epidermis of the group treated with high dose 10% bCNH compared to the untreated group. id="p-24"

[00024] Fig. 5is a graphical illustration of morphometric, digital image analysis of CD3- IHC Staining. Quantitative digital analysis showing a marked decrease of the % of CD positive cells in the dermis and epidermis of Group 6F treated with high dose 10% bCNH compared to Group 2F, untreated. id="p-25"

[00025] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.

DETAILED DESCRIPTION OF THE PRESENT INVENTION id="p-26"

[00026] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific P- 622254 -IL 6 details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

Method of treatment – inflammatory skin conditions [00027] In some embodiments, disclosed herein is a method for preventing or treating inflammatory skin conditions, by administering to an animal a composition comprising at least one milk derived protein. id="p-28"

[00028] "Treating" embraces in another embodiment, the amelioration of an existing condition. The skilled artisan would understand that treatment does not necessarily result in the complete absence or removal of symptoms. Treatment also embraces palliative effects: that is, those that reduce the likelihood of a subsequent medical condition. The alleviation of a condition that results in a more serious condition is encompassed by this term. id="p-29"

[00029] A skilled artisan would understand the phrase "inflammatory skin conditions" as characterized by the activation of the innate and adaptive immune system via the production of pro-inflammatory cytokines. id="p-30"

[00030] In some embodiments, the inflammatory skin conditions comprises acne, actinic keratosis, alopecia areata, basal cell carcinoma, Bowen's disease, burning mouth syndrome, cellulitis, congenital erythropoietic porphyria, contact dermatitis, Darier's disease, dystrophic epidermolysis bullosa, atopic dermatitis (eczema), epidermolysis bullosa simplex, skin erosions and ulcerations erythropoietic protoporphyria, fungal infections of nails, Hailey-Hailey disease, hair diseases, herpes simplex, hidradenitis suppurativa, hyperhidrosis, itchy skin (pruritus), ichthyosis, impetigo, keloids, keratosis pilaris, lichen planus, lichen sclerosus, melisma, mucous membrane diseases, nail diseases, nonhealing wounds, pemphigus vulgaris, plantar warts (verrucas), pityriasis lichenoides, polymorphic light eruption, psoriasis, pyoderma gangrenosum, rosacea, scabies, shingles, squamous cell carcinoma, skin infections, sun allergy, Sweet's syndrome, vitiligo, inflammation due to P- 622254 -IL 7 sunburn, hypersensitivity disorders, canine atopic dermatitis, feline atopy-like dermatitis, contact hypersensitivity, food hypersensitivity, fleabite hypersensitivity, bacterial skin diseases, fungal skin diseases, autoimmune and immune mediated dermatoses, parasitic skin disease, and combination thereof. id="p-31"

[00031] In one embodiment, the inflammatory skin condition is acne. In another embodiment, the inflammatory skin condition is actinic keratosis. In another embodiment, the inflammatory skin condition is alopecia areata. In another embodiment, the inflammatory skin condition is basal cell carcinoma. In another embodiment, the inflammatory skin condition is Bowen’s disease. In another embodiment, the inflammatory skin condition is burning mouth syndrome. In another embodiment, the inflammatory skin condition is cellulitis. In another embodiment, the inflammatory skin condition is congenital erythropoietic porphyria. In another embodiment, the inflammatory skin condition is contact dermatitis. In another embodiment, the inflammatory skin condition is Darier’s disease. In another embodiment, the inflammatory skin condition is dystrophic epidermolysis bullosa.

In another embodiment, the inflammatory skin condition is atopic dermatitis (eczema). In another embodiment, the inflammatory skin condition is epidermolysis bullosa simplex. In another embodiment, the inflammatory skin condition is skin erosions and ulcerations. In another embodiment, the inflammatory skin condition is erythropoietic protoporphyria. In another embodiment, the inflammatory skin condition is fungal infections of nails. In another embodiment, the inflammatory skin condition is Hailey-Hailey disease. In another embodiment, the inflammatory skin condition is hair disease. In another embodiment, the inflammatory skin condition is herpes simplex. In another embodiment, the inflammatory skin condition is hidradenitis suppurativa. In another embodiment, the inflammatory skin condition is hyperhidrosis. In another embodiment, the inflammatory skin condition is itchy P- 622254 -IL 8 skin (pruritus). In another embodiment, the inflammatory skin condition is ichthyosis. In another embodiment, the inflammatory skin condition is impetigo. In another embodiment, the inflammatory skin condition is keloids. In another embodiment, the inflammatory skin condition is keratosis pilaris. In another embodiment, the inflammatory skin condition is lichen planus. In another embodiment, the inflammatory skin condition is lichen sclerosus.

In another embodiment, the inflammatory skin condition is melisma. In another embodiment, the inflammatory skin condition is mucous membrane diseases. In another embodiment, the inflammatory skin condition is nail disease. In another embodiment, the inflammatory skin condition is nonhealing wounds. In another embodiment, the inflammatory skin condition is pemphigus vulgaris. In another embodiment, the inflammatory skin condition is plantar warts (verrucas). In another embodiment, the inflammatory skin condition is pityriasis lichenoides. In another embodiment, the inflammatory skin condition is polymorphic light eruption. In another embodiment, the inflammatory skin condition is psoriasis. In another embodiment, the inflammatory skin condition is pyoderma gangrenosum. In another embodiment, the inflammatory skin condition is rosacea. In another embodiment, the inflammatory skin condition is scabies. In another embodiment, the inflammatory skin condition is shingles. In another embodiment, the inflammatory skin condition is squamous cell carcinoma. In another embodiment, the inflammatory skin condition is skin infections. In another embodiment, the inflammatory skin condition is sun allergy. In another embodiment, the inflammatory skin condition is Sweet's syndrome. In another embodiment, the inflammatory skin condition is vitiligo. In another embodiment, the inflammatory skin condition is inflammation due to sunburn. id="p-32"

[00032] In another embodiment, the inflammatory skin condition is hypersensitivity disorder. In another embodiment, the inflammatory skin condition is canine atopic P- 622254 -IL 9 dermatitis. In another embodiment, the inflammatory skin condition is feline atopy-like dermatitis. In another embodiment, the inflammatory skin condition is contact hypersensitivity. In another embodiment, the inflammatory skin condition is food hypersensitivity. In another embodiment, the inflammatory skin condition is fleabite hypersensitivity. In another embodiment, the inflammatory skin condition is bacterial skin disease. In another embodiment, the inflammatory skin condition is fungal skin disease. In another embodiment, the inflammatory skin condition is autoimmune and immune mediated dermatoses. In another embodiment, the inflammatory skin condition is parasitic skin disease. id="p-33"

[00033] In some embodiments, the bacterial skin disease comprises Pyoderma. A skilled arctician would understand Pyoderma as a bacterial infection confined to the upper layers of the skin and hair follicle. The infection is usually secondary to local trauma, keratinization disorders, parasitic infestation, hormonal factors, or allergies. In dogs, superficial pyoderma is the most common form of pyoderma, and it is also the most common reason for antimicrobial use in small animal practice. Pyodermas are common in dogs and less common in cats. Bacterial pyoderma is usually triggered by an overgrowth/overcolonization of normal resident or transient flora. The primary pathogen of dogs is Staphylococcus pseudintermedius. id="p-34"

[00034] In some embodiments, the fungal skin disease comprises superficial mycoses, subcutaneous (intermediate) mycoses or combination thereof. id="p-35"

[00035] In some embodiments, the autoimmune and immune mediated dermatoses comprises pemphigus complex, vasculitis, lupus or any combination thereof. id="p-36"

[00036] A skilled arctician would understand that pemphigus complex is a complex of diseases includes pemphigus foliaceus, pemphigus erythematosus, pemphigus vulgaris, and P- 622254 -IL pemphigus vegetans. These are vesiculobullous (blistering) and pustular disorders characterized by acantholysis (breakdown of cellular adhesions). id="p-37"

[00037] A skilled arctician would understand that vasculitis is an inflammation of blood vessels, which can result from physical trauma but most often results from an immune response to an infection or a drug reaction (including vaccines). id="p-38"

[00038] A skilled arctician would understand that lupus is a serious, life-threatening symptoms, autoimmune disease in dogs. There are two types of lupus: discoid erythematosus (DLE) and systemic lupus erythematosus (SLE). id="p-39"

[00039] In some embodiments, the parasitic skin disease comprises demodicosis, canine scabies or any combination thereof. id="p-40"

[00040] Common skin diseases in small animals comprise hypersensitivity disorders, canine atopic dermatitis, feline atopy-like dermatitis, contact hypersensitivity, food hypersensitivity, fleabite hypersensitivity, bacterial skin diseases, fungal skin diseases, autoimmune and immune mediated dermatoses, parasitic skin disease, or any combination thereof. id="p-41"

[00041] A skilled artisan would understand the phrase "hypersensitivity disorders" also known as urticaria, as a state of altered reactivity in which the body reacts with an exaggerated or inappropriate immune response to a chemical substance having the properties of an antigen that is in contact with the skin. Although no breed predilection has been published, short-coated dogs, especially atopic pit bulls and boxers, appear to be at increased risk for development of urticaria. id="p-42"

[00042] A skilled artisan would understand the phrase "canine atopic dermatitis" as the most common manifestation of atopic disease in dogs, suggested as the animal model for human atopic dermatitis. Canine AD was classically defined as a type I hypersensitivity P- 622254 -IL 11 toward environmental allergens. Prevalence of canine AD is likely to be affected by geographic regions, methods of survey, and criteria used for diagnosis. In the veterinary literature, canine AD has been reported to affect from as low as 3.3% to as high as 27% in a more recent survey in the United States and 5% in the United Kingdom. In humans, the prevalence of AD has been increasing, particularly in industrialized countries, where it is estimated that 10% to 20% of children have AD. AD is a multifactorial disease, most likely resulting from a complex interaction between host and environment such as genetic factors, skin burrier function, immunologic aberration and allergens. In dogs with AD, clinical lesions most commonly affect ventral hairless areas, the muzzle, periocular areas, pinnae, and flexural surface of the elbow. id="p-43"

[00043] A skilled artisan would understand the phrase "feline atopy-like dermatitis" as the cat model for atopic dermatitis. id="p-44"

[00044] A skilled artisan would understand the phrase "contact hypersensitivity", also known as allergic contact dermatitis, is a type IV hypersensitivity cell-mediated reaction that can occur in response to contact with certain allergens. Clinical signs of contact hypersensitivity include varying degrees of macular papular dermatitis, which tend to be confined to hairless or sparsely haired areas of skin in contact regions: ventral aspect of interdigital areas, ventral abdomen and thorax, ventral tail and neck, scrotum and perineal area, muzzle, and concave aspect of pinnae. Clinically, avoidance is recommended in all cases, treatment of the secondary infections due to skin trauma and inflammation and symptomatic treatment with orally or topically glucocorticoids. id="p-45"

[00045] A skilled artisan would understand the phrase "food hypersensitivity" as a clinical disease which is typically a nonseasonal pruritic dermatosis characterized in erythematous wheals, papules, macules, and plaques. Secondary lesions may develop as a consequence of P- 622254 -IL 12 pruritus and self-trauma and can include excoriations, ulcerations, alopecia, lichenification, and hyperpigmentation. The distribution of lesions and pruritus may range from only otitis to a generalized distribution. Rump, perineal areas, axillae, and groin are frequently affected.

Secondary recurrent bacterial and/or yeast otitis is frequent. Bacterial folliculitis, Malassezia dermatitis, seborrhea, acral lick granulomas, and pyotraumatic dermatitis are other possible manifestations of adverse food reactions. Prognosis for adverse food reactions is good once offending allergens are identified. Therapy consists of avoiding offending foods and use of antipruritic agents and or antiinfectives to address clinical signs when relapses occur. Poor response to glucocorticoids has been reported in the literature. id="p-46"

[00046] A skilled artisan would understand the phrase "fleabite hypersensitivity" as a flea bite allergy that tends to cause itching on the "back half" of the body, meaning the tail base, rump, belly, and rear legs. Generalized distribution can, however, occur in severe cases.

Pruritus is typically focused on the caudal areas and tail, although some dogs express generalized pruritus. Papules in the umbilical area are also very suggestive of flea hypersensitivity. Dogs also develop acral lick granulomas or pyotraumatic dermatitis, typically on the rump or side of the face. Additionally, secondary skin infections frequently complicate the clinical picture of dogs that develop bacterial folliculitis and/or Malassezia dermatitis. Because fleabite hypersensitivity frequently occurs with other allergies, control of other allergies is as important as aggressive flea control. Symptomatic relief can be provided with anti-inflammatory doses of glucocorticoids combined with topical therapy. id="p-47"

[00047] A skilled artisan would understand the phrase "bacterial skin disease", as an infection that is usually secondary to local trauma, keratinization disorders, parasitic infestation, hormonal factors, or allergies. In dogs, superficial pyoderma is the most common form of pyoderma, and it is also the most common reason for antimicrobial use in small P- 622254 -IL 13 animal practice. Bacterial pyoderma is usually triggered by an overgrowth/overcolonization of normal resident or transient flora. The primary pathogen of dogs is Staphylococcus pseudintermedius. The typical treatment for pyoderma is antibiotic therapy for a minimum of three to four weeks. In chronic or recurrent cases, antibiotics may be needed for 8 to weeks. id="p-48"

[00048] A skilled artisan would understand the phrase "fungal skin disease" as comprising superficial mycoses (fungal infections that involves the superficial layers of the skin, hair and claws), and subcutaneous (intermediate) mycoses (infections that have invaded beyond the skin and follicles). Topical therapy is often curative in superficial yeast infections (Malassezia, Candida) and Systemic therapy is necessary to treat subcutaneous and deep mycoses and accelerate resolution of many superficial fungal infections. id="p-49"

[00049] A skilled artisan would understand that the phrase "autoimmune and immune mediated dermatoses" as when the immune system fails to tolerate self or foreign antigens.

As a group, all immune-mediated dermatoses are characterized by an inappropriate immune response that, to be adequately controlled, may require use of potent immunosuppressive and immunomodulating drugs. The autoimmune and immune mediated dermatoses comprise Pemphigus Complex- This complex of diseases includes pemphigus foliaceus, pemphigus erythematosus, pemphigus vulgaris, and pemphigus vegetans. id="p-50"

[00050] A skilled artisan would understand that the phrase "parasitic skin diseases" as a heterogeneous category of infectious diseases in which parasite–host interactions are confined to the upper layer of the skin. The six major epidermal parasitic skin diseases (EPSD) are scabies, pediculosis (capitis, corporis and pubis), tungiasis and hookworm- related cutaneous larva migrans. One example is dermodicosis, which are a cigar shaped microscopic parasitic mites that live within the hair follicles of all dogs. These mites are P- 622254 -IL 14 passed to puppies from their mothers in the first few days of life, and then live within the hair follicles for the duration of animal's life without causing problems. In one embodiment, the composition promotes wound or rupture closing. In another embodiment, the composition promotes wound closing. In another embodiment, the composition promotes rupture closing. id="p-51"

[00051] In one embodiment, the composition reduces skin itching, skin burning, skin redness, skin pain, dry skin, peeling skin, rough skin, skin swelling, skin cracking, or any combination thereof. In another embodiment, the composition reduces skin itching. In another embodiment, the composition reduces skin burning. In another embodiment, the composition reduces skin redness. In another embodiment, the composition reduces skin pain. In another embodiment, the composition reduces dry skin. In another embodiment, the composition reduces peeling skin. In another embodiment, the composition reduces rough skin. In another embodiment, the composition reduces skin swelling. In another embodiment, the composition reduces skin cracking. id="p-52"

[00052] In one embodiment the inflammatory skin condition is psoriasis. id="p-53"

[00053] A skilled artisan would understand that psoriasis is a skin disease that causes a rash with itchy, scaly patches, most commonly on the knees, elbows, trunk and scalp. It is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete body coverage. Psoriasis is an immune mediated disease, that causes inflammation in the body. Inflammation caused by psoriasis can impact other organs and tissues in the body. One in three people with psoriasis may also develop psoriatic arthritis, with symptoms of swelling, stiffness, and pain in the joints and areas surrounding the joints.

P- 622254 -IL id="p-54"

[00054] In one embodiment the psoriasis comprises plaque, guttate, inverse, pustular, erythrodermic, or any combinations thereof. In another embodiment, the psoriasis is plaque psoriasis. In another embodiment, the psoriasis is guttate psoriasis. In another embodiment, the psoriasis is inverse psoriasis. In another embodiment, the psoriasis is pustular psoriasis.

In another embodiment, the psoriasis is erythrodermic psoriasis. id="p-55"

[00055] In one embodiment, the psoriasis causes symptoms in the back of the forearms, elbow, shins, navel area, and scalp. In another embodiment, the psoriasis causes symptoms in the back of the forearms. In another embodiment, the psoriasis causes symptoms in the elbow. In another embodiment, the psoriasis causes symptoms in the shins. In another embodiment, the psoriasis causes symptoms in the navel area. In another embodiment, the psoriasis causes symptoms in the scalp. id="p-56"

[00056] In one embodiment the inflammatory skin condition is atopic dermatitis. id="p-57"

[00057] A skilled artisan would understand that atopic dermatitis (eczema) is a condition that causes dry, itchy and inflamed skin. It's common in young children but can occur at any age. Atopic dermatitis is long lasting (chronic) and tends to flare sometimes. It can be irritating but it's not contagious. People with atopic dermatitis are at risk of developing food allergies, hay fever and asthma. id="p-58"

[00058] In some embodiments, atopic dermatitis symptoms include dry, cracked skin, itchiness, rash on swollen skin that varies in color, small, raised bumps on brown or slack skin, oozing and crusting, thickened skin, darkening of the skin around the eyes, raw, sensitive skin from scratching, or any combination thereof.

Method of treatment – cosmetic skin use [00059] In some embodiments, disclosed herein is a method for moisturizing dry skin, skin softening, reducing skin itching, reducing skin peeling, reducing skin redness, reducing rough skin, reducing skin swelling, reducing skin cracking, renewal skin cells, preserving P- 622254 -IL 16 hand skin or any combination thereof, comprising administering to an animal a composition comprising at least one milk derived protein. id="p-60"

[00060] In one embodiment, disclosed herein is a method for moisturizing dry skin. In another embodiment, disclosed herein is a method for skin softening. In another embodiment, disclosed herein is a method for reducing skin itching. In another embodiment, disclosed herein is a method for reducing skin peeling. In another embodiment, disclosed herein is a method for reducing skin redness. In another embodiment, disclosed herein is a method for reducing rough skin. In another embodiment, disclosed herein is a method for reducing skin swelling. In another embodiment, disclosed herein is a method for reducing sling cracking. In another embodiment, disclosed herein is a method for renewal skin cells.

In another embodiment, disclosed herein is a method for preserving hand skin.

Casein peptides [00061] In one embodiment, the method comprises administering to an animal a composition comprising at least one milk derived protein. id="p-62"

[00062] In one embodiment, the milk-derived protein comprises a casein protein or casein derived peptide . In another embodiment, the milk-derived protein comprises a casein protein. In another embodiment, the milk-derived protein comprises a casein derived peptide. id="p-63"

[00063] In one embodiment, the milk derived protein further comprises β-Lactoglobulin, α-Lactalbumin, Serum albumin, Immunoglobulin G1 (IgG1), Immunoglobulin G2 (IgG2), Immunoglobulin A7 (IgA), Immunoglobulin M(IgM), Secretory component (SC), Lactoferrin (LF) or any combination thereof. id="p-64"

[00064] Casein is a protein in non-human mammal’s milk, also found in human mammal’s milk known to include the subgroups αSl, αS2, β and κ. Casein is defined according to the amino acid sequences of each of the subgroups αS1, αS2, β and κ. In the P- 622254 -IL 17 context of the present disclosure, when referring to casein, it is to be understood as also including acid casein, salts of casein (for example Sodium, Calcium, Sodium-Calcium, or Potassium Caseinates), phosphorous containing casein and rennet casein. id="p-65"

[00065] The term "protein" as used herein refers to amino acid residues, connected by peptide bonds. A protein sequence is generally reported from the N-terminal end containing free amino group to the C-terminal end containing free carboxyl group. Amino acids, as used herein, refer to naturally occurring and synthetic amino acids, as well as amino acid analogs, and amino acid mimetics, that function in a manner similar to the naturally occurring amino acids. Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. id="p-66"

[00066] The casein-derived peptide may be a single peptide or a mixture of different peptides which may be independently selected from a naturally occurring peptide, a semi- synthetic peptide, a synthetic peptide or a recombinant peptide. It should be further noted that the peptides according to the present disclosure may be produced synthetically, or by recombinant DNA technology, or by any other technology. Methods for producing peptides are well known in the art. id="p-67"

[00067] In some embodiments, the casein-derived peptide may comprise a casein protein breakdown product which occurs when casein protein is cleaved by enzymes or acids to peptide fragments (also known in the art by the term "casein hydrolysate"). A casein hydrolysate is to be understood as the hydrolyzed form of casein (protein). Casein hydrolysate includes, for example, the active beta-, alpha S1-, alpha S2-, kappa-casein- derived peptide known to those versed in the art. In some embodiments, the casein-derived peptide is or comprises a casein hydrolysate.

P- 622254 -IL 18 id="p-68"

[00068] In some embodiments, the casein derived peptide comprises natural peptide, synthetic peptide, semi-synthetic peptide, or any combination thereof. In another embodiment, the casein derived peptide comprises a natural peptide. In another embodiment, the casein derived peptide comprises a synthetic peptide. In another embodiment, the casein derived peptide comprises a semi-synthetic peptide. In another embodiment, the casein derived peptide comprises a combination of natural peptide and synthetic peptide. In another embodiment, the casein derived peptide comprises a combination of natural peptide and semi-synthetic peptide. In another embodiment, the casein derived peptide comprises a combination of synthetic peptide and semi-synthetic peptide. In another embodiment, the casein derived peptide comprises a combination of natural peptide, synthetic peptide and semi-synthetic peptide. id="p-69"

[00069] In another embodiment, the casein derived peptide comprises a combination of natural peptide, synthetic peptide and semi-synthetic peptide. id="p-70"

[00070] Natural casein-derived peptides are typically obtained following enzymatic hydrolysis, the enzyme may be any mammal peptidase, such as, without being limited thereto, plasmin, pancreatin, trypsin, chymotrypsin, neutrase, alcalase, pepsin, carboxypeptidase, cathepsin, as well as plant peptidase such as, without being limited thereto, papain, bromelain, as well as enzymes from microorganism source. For example, a naturally occurring casein-derived peptide may be the result of an enzyme activity such as plasmin on casein subunits β-casein, αs1- and αs2-casein or κ-casein. In some embodiments, a casein hydrolysate is obtained by cleavage of the casein protein with trypsin.

P- 622254 -IL 19 id="p-71"

[00071] A synthetic peptide may be obtained by any methods known in the art of peptide synthesis including chemical synthesis and recombinant DNA technology. For example, the peptides may be synthesized by using standard solid phase techniques. id="p-72"

[00072] In one embodiment, the synthetic peptide is a recombinant peptide. id="p-73"

[00073] A semi-synthetic casein-derived peptide may be obtained by chemical hydrolysis of casein, e.g. by prolonged boiling in a strong acid (acid-HVP) or strong base or using a chemical agent such as Cyanogen bromide (CNBr). The casein-derived peptide may also be obtained by molecular engineering, e.g. using recombinant DNA, in molecular techniques known in the art. In such embodiments, the casein-derived peptide is a recombinant peptide. id="p-74"

[00074] In one embodiment, the recombinant peptide is produced by fermentation, tissue culture or combination thereof. In another embodiment, the recombinant peptide is produced by fermentation. In another embodiment, the recombinant peptide is produced by tissue culture. In another embodiment, the recombinant peptide is produced by a combination of fermentation and tissue culture. id="p-75"

[00075] In one embodiment, the tissue culture comprises mammary gland bovine tissue . id="p-76"

[00076] In some embodiments, the casein derived peptide comprises one or more fragments of β-casein, αS1-casein, αS2-casein, κ-casein or any combination thereof. In one embodiment, the casein derived peptide comprises one or more fragments of β-casein. In another embodiment, the casein derived peptide comprises one or more fragments of αS1- casein. In another embodiment, the casein derived peptide comprises one or more fragments of αS2-casein. In another embodiment, the casein derived peptide comprises one or more fragments of κ-casein. In another embodiment, the casein derived peptide comprises one or more fragments of combination of β-casein, αS1-casein, αS2-casein and κ-casein.

P- 622254 -IL id="p-77"

[00077] In one embodiment, the casein derived peptide further comprises amino acids with different lengths. id="p-78"

[00078] In one embodiment, the casein derived peptide comprises a casein hydrolysate. id="p-79"

[00079] In one embodiment, the casein derived peptide comprises a phosphopeptide. id="p-80"

[00080] As used herein, the term "phosphopeptide" designates a phosphorylated peptide in form of a conjugated peptide in which the non-peptide portion is a residue of phosphoric acid. The expression "phosphopeptide" or "phosphoserine" designates conjugated serine in which the non-peptide portion is a residue of phosphoric acid. id="p-81"

[00081] In some embodiments, the casein-derived peptide is a single peptide or mixture of a phosphopeptide, namely, which contains a single phosphorous group or is a phosphorus- enriched peptide. In some embodiments, the casein-derived peptide is any phosphoserine, phosphotyrosine, phosphothreonine, and/or phosphohystidine-enriched casein-derived peptides (casein phosphopeptide, CPP) and monovalent cation phosphocaseinates, such as sodium, potassium, calcium or ammonium phosphocaseinates. id="p-82"

[00082] In some embodiments, the casein-derived peptide is a phosphor-peptide. id="p-83"

[00083] The phosphor-peptide may be genetically engineered casein-derived peptides as well as peptidomimetics of casein-derived peptides. For example, phosphorylation of amino acids such as at least one serine residue may be performed by any method as is known in the art. The term "casein-derived peptide" also encompasses peptide fragments or peptidomimetic products obtained from or corresponding to one or more sections of casein protein. The peptidomimetic peptide may be for example a peptoid or a semipeptoid, which are peptide analogs, having, for example, modifications such as, but are not limited to, cyclization, N-terminus modification, C-terminus modification, peptide bond modification, P- 622254 -IL 21 including, but not limited to, CH2-NH, CH2-S, CH2-S-O, O-C-NH, CH 2-O, CH 2-CH2, S-C- NH, CH-CH or CF-CH, backbone modification and residue modification. id="p-84"

[00084] As used herein, the term "casein-derived peptide" further encompasses any derivatives, analogues, variants or homologues of any of the peptides. The term "derivative" is used to define amino acid sequences (peptide), with any insertions, deletions, substitutions and modifications to the amino acid sequences (peptide) that do not alter the activity of the original peptides. By the term "derivative" it is also referred to homologues, variants and analogues thereof, as well as covalent modifications of polypeptides made according to the present invention. id="p-85"

[00085] In some embodiments, the modified, synthetic, semi-synthetic or other types of analogs of the naturally occurring casein-derived peptides are in some embodiments at least 75%, at times 85%, 90%, 95% and even 99% identical (in sequence) to a naturally occurring casein-derived peptide when the two sequences are optimally aligned. Further, any non- naturally occurring casein-derived peptide to be used in accordance with the present disclosure may retain at least part of the biological activity of the naturally occurring casein protein. id="p-86"

[00086] The present disclosure also encompasses homologues of the casein-derived peptide. The term "homologues" is used to define amino acid sequences (peptide) which maintain a minimal homology to the amino acid sequences defined by the invention, e.g. have at least about 65%, at least about 75%, at least about 85%, or at least about 95% overall sequence homology with the amino acid sequence of any of the peptide as structurally defined above, e.g. of a specified sequence. id="p-87"

[00087] In some embodiments, the casein-derived peptide may also include a chemical modification of a naturally occurring peptide, e.g. where one or more amino acids are P- 622254 -IL 22 deleted, substituted or modified, e.g. by removal of a side group, substitution of a side group or the introduction of a chemical group. Without being limited thereto, the chemical modification may include acetylation, acylation, amidation, ADP-ribosylation, glycosylation, GPI anchor formation, covalent attachment of a lipid or lipid derivative, methylation, myristoylation, pegylation, prenylation, phosphorylation, ubiquitination, or any similar process. When referring to replacement of an amino acid sequence by another, it is likely that the replacement is a conservative substitution. For example, one or more amino acid residues within a casein sequence is substituted by another amino acid of a similar polarity or charge. For example, the non-polar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan and methionine. The polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine. The positively charged (basic) amino acids include arginine, lysine and histidine. The negatively charged (acidic) amino acids include aspartic acid and glutamic acid. Nonetheless, non-conservative substitutions may also take place as long as it does not significantly change the desired (casein like) biological activity of the resulting casein- derived peptide analog. id="p-88"

[00088] A casein-derived peptide in accordance with the present disclosure is characterized by a molecular weight of between about an average 100 to an average 10,0 Dalton (e.g. between 2 to 100 amino acids) at times between about an average 100 to an average 7,000 Dalton and at times between an average 1,000 to an average 5,000 Daltons. id="p-89"

[00089] A casein-derived peptide in accordance with the disclosure is characterized by a length of from 2 to 200, from 2 to 100 amino acids, at times between 4 amino acids to amino acids, at times from 4 amino acids to 30 amino acids, at times 4 amino acids to amino acids, at times between 10 amino acids to 50 amino acids.

P- 622254 -IL 23 id="p-90"

[00090] In some embodiments, the casein-derived peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO. 1 – SEQ ID NO. 26. id="p-91"

[00091] In one embodiment, the phosphopeptide comprises an amino acid sequence denoted as Ser-Ser-Ser-Glu (SEQ ID NO:1), wherein at least one Ser residue, at least two Ser residues or three Ser residues are phosphorylated (phosphorylated serine is denoted herein as Ser(p) or S(p)). id="p-92"

[00092] In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Ser-Ser-Ser-Glu-Glu (SEQ ID NO:2), wherein at least one Ser residue, at least two Ser residues or three Ser residues are phosphorylated. id="p-93"

[00093] In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Ser(p)-Ser(p)-Ser(p)-Glu-Glu (SEQ ID NO:3). id="p-94"

[00094] In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as RELEELNVPGEIVES(p)LS(p)S(p)S(p)EESITR (SEQ ID NO:4). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as QMEAESIS(p)S(p)S(p)EEIVPDSVEQK (SEQ ID NO:5). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as KNTMEHVS(p)S(p)S(p)EESIISNETYK (SEQ ID NO:6). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as KVNELSKNIGS(p)ES(p)TEDQ (SEQ ID NO:7). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as PTLNREQLS(p)TS(p)EENSKKTVD (SEQ ID NO:8). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as ELEELNVPGEIVES(p)LS(p)S(p)S(p)EESITR (SEQ ID NO:9). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as P- 622254 -IL 24 RELEELNVPGEIES(p)LS(p)S(p)S(p)EESITR (SEQ ID NO:10). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as QMEAES(p)IS(p)S(p)S(p)EEIVPNS(p)VEQK (SEQ ID NO:11). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as KNTMEHVS(p)S(p)S(p)EESIIS(p)QETYK (SEQ ID NO:12). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as KVNELSKDIGS(p)ES(p)TEDQ (SEQ ID NO:13). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as ESIIS(p)QETYKQEKNMAINPSKENLCSTFCKEVVRNANEEETSIGS(p)S(p)S(p)EES( p)AEVATEEVKITVDDKHYQKALNEINQFYQKFPGYLQYLYQGPIVLNPWNQVLR NAVPITPTLNREQLS(p)TS(p)EENSKKTVN (SEQ ID NO:14). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as ELEELNVPGEIES(p)LS(p)S(p)S(p)EESITR(SEQ ID NO:15). id="p-95"

[00095] In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as X1(n)- Ser(P)-Ser(P)-Ser(P)-X 2(m)-Lys (SEQ ID NO:16), wherein at least one of X 1 and X 2 is independently selected from a positively charged amino acid and wherein each one of n and m is independently selected from 0, 1 and 2. id="p-96"

[00096] In some embodiments, the positively charged amino acid is selected from the group consisting of lysine, arginine and histidine. In some embodiments, the positively charged amino acid is lysine. In some other embodiments, the positively charged amino acid is arginine. In some other embodiments, the positively charged amino acid is histidine. id="p-97"

[00097] According to some embodiments, the formula of SEQ ID NO:l6 further comprises a blocking group (also denoted herein as a protecting group) at the C-terminus.

In some embodiments, the carboxyl group at the C terminus of the peptide is protected with P- 622254 -IL a protecting group. The protecting group is selected from, but not limited to an amide (i.e., the hydroxyl group at the C terminus is replaced with a primary amine (NH2), secondary amine, or tertiary amine) or ester (i.e. the hydroxyl group at the C terminus is replaced with an ester). According to some embodiments, the blocking group is selected from the group consisting of amide and ester. According to some embodiments, the blocking group is amide. id="p-98"

[00098] In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Lys-Lys-Ser(P)-Ser(P)-Ser(P) (SEQ ID NO:17). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Lys-Lys-Ser(P)-Ser(P)- Ser(P)-Lys (SEQ ID NO:18). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Lys-Lys-Ser(P)-Ser(P)-Ser(P)-Lys-Lys (SEQ ID NO:19).

In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Lys-Ser(P)- Ser(P)-Ser(P)-Lys-Lys (SEQ ID NO:20). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Lys- Ser(P)-Ser(P)-Ser(P)- Lys (SEQ ID NO:21). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Lys-Ser(P)-Ser(P)-Ser(P) (SEQ ID NO:22). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Ser(P)-Ser(P)-Ser(P)- Lys-Lys (SEQ ID NO:23). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Ser(P)-Ser(P)-Ser(P)-Lys (SEQ ID NO:24). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as Lys-Lys- Ser(p)-Ser(p)-Ser(p)-NH2 (SEQ ID NO:25). In another embodiment, the phosphopeptide comprises an amino acid sequence denoted as RELEELNVPGEIVES(p)LS(p)S(p)S(p)EESITRINK (SEQ ID NO:26). id="p-99"

[00099] The casein-derived peptide according to the invention may comprise "L" as well as "D" form residues. While the amino acid residues of the peptide sequences set forth in P- 622254 -IL 26 SEQ ID NOs:1-26 are all in the "L" isomeric form, residues in the "D" isomeric form can substitute any L-amino acid residue so long as the resulting peptide analog retains at least part of the biological activity of the corresponding "L" isomer. One reason for designing casein-derived peptides comprising at least one D-amino acid is to increase stability of the peptide to proteolytic degradation. id="p-100"

[000100] In one embodiment, the composition is free of antimicrobials and comprises an acceptable carrier. id="p-101"

[000101] In one embodiment, the milk derived protein is measured by UV at range from 204 to 220 nm.

Dosage and administration [000102] In some embodiments, the methods of the present disclosure comprise administering between 10ng/ml to 700mg/ml of the milk derived protein, per administration. In one embodiment, the methods of the present disclosure comprise administering between 1mg/ml to 500mg/ml of the milk derived protein, per administration.

In another embodiment, the methods of the present disclosure comprise administering between 10mg/ml to 450mg/ml of the milk derived protein, per administration. In another embodiment, the methods of the present disclosure comprise administering between 50mg/ml to 400mg/ml of the milk derived protein, per administration. In another embodiment, the methods of the present disclosure comprise administering between 50mg/ml to 70mg/ml of the milk derived protein, per administration. In another embodiment, the methods of the present disclosure comprise administering between 100mg/ml to 350mg/ml of the milk derived protein, per administration. In another embodiment, the methods of the present disclosure comprise administering between 150mg/ml to 300mg/ml of the milk derived protein, per administration. In another embodiment, the methods of the present disclosure comprise administering between P- 622254 -IL 27 200mg/ml to 250mg/ml of the milk derived protein, per administration. In another embodiment, the methods of the present disclosure comprise administering between 5mg/ml to 30mg/ml of the milk derived protein, per administration. id="p-103"

[000103] In one embodiment, the milk derived protein concentration in the composition is between 0.05% to 30%. In another embodiment, the milk derived protein concentration in the composition is 0.05%. In another embodiment, the milk derived protein concentration in the composition is 0.1%. In another embodiment, the milk derived protein concentration in the composition is 1%. In another embodiment, the milk derived protein concentration in the composition is 5%. In another embodiment, the milk derived protein concentration in the composition is 10%. In another embodiment, the milk derived protein concentration in the composition is 10%. In another embodiment, the milk derived protein concentration in the composition is 15%. In another embodiment, the milk derived protein concentration in the composition is 20%. In another embodiment, the milk derived protein concentration in the composition is 25%. In another embodiment, the milk derived protein concentration in the composition is 30%. id="p-104"

[000104] In one embodiment, the administration comprises oral, intraoral, topical, epicutaneous, transdermal, subcutaneous, or any combination thereof. In another embodiment, the administration comprises oral administration. In another embodiment, the administration comprises intraoral administration. In another embodiment, the administration comprises topical administration. In another embodiment, the administration comprises epicutaneous administration. In another embodiment, the administration comprises transdermal administration. In another embodiment, the administration comprises subcutaneous administration.

P- 622254 -IL 28 id="p-105"

[000105] In one embodiment, the methods of the present disclosure comprise oral administration, intraoral administration, rectal administration, parenteral administration, topical administration, epicutaneous administration, transdermal administration, subcutaneous administration, intramuscular administration, intravenous administration, intranasal administration, otic administration, intra rectal administration, intravaginal administration, sublingual administration, buccal administration, intradural administration, intrarespiratory administration, nasal inhalation, or any combination thereof. id="p-106"

[000106] In some embodiments, the methods of the present disclosure comprise between one to thirty (30) administrations. In one embodiment, the methods of the present disclosure comprise one administration. In another embodiment, the methods of the present disclosure comprise two administrations. In another embodiment, the methods of the present disclosure comprise three administrations. In another embodiment, the methods of the present disclosure comprise four administrations. In another embodiment, the methods of the present disclosure comprise five administrations. In another embodiment, the methods of the present disclosure comprise six administrations. In another embodiment, the methods of the present disclosure comprise seven administrations. In another embodiment, the methods of the present disclosure comprise eight administrations. In another embodiment, the methods of the present disclosure comprise ten administrations. In another embodiment, the methods of the present disclosure comprise fifteen administrations. In another embodiment, the methods of the present disclosure comprise twenty administrations. In another embodiment, the methods of the present disclosure comprise twenty-five administrations. In another embodiment, the methods of the present disclosure comprise thirty (30) administrations. In another embodiment, the methods of the present disclosure comprise constant administration.

P- 622254 -IL 29 id="p-107"

[000107] In another embodiment, the methods of the present disclosure comprise constant administration as needed. id="p-108"

[000108] In another embodiment, the methods of the present disclosure comprise chronic administration. id="p-109"

[000109] A skilled artisan would understand the meaning of "chronic administration" as administration over a long period of time, varying from weeks to months and years. Chronic administration can also mean treating a condition or disease that is persistent, constantly, recurring or otherwise long-lasting in its effects or a disease that comes with time, therefore the chronic administration can be periodically administration. id="p-110"

[000110] In one embodiment, treatment is repeated after a period of lapse time. In one embodiment, the lapse time comprises between 10 minutes and 96 hours. In another embodiment, the lapse time is between 1 hour and 72 hours. In another embodiment, the lapse time is between 1 hour and 40 hours. In another embodiment, the lapse time is between hours and 30 hours. In another embodiment, the lapse time is between 20 hours and hours. In another embodiment, the lapse time is 10 minutes. In another embodiment, the lapse time is 30 minutes. In another embodiment, the lapse time is 60 minutes. In another embodiment, the lapse time is 2 hours. In another embodiment, the lapse time is 5 hours. In another embodiment, the lapse time is 10 hours. In another embodiment, the lapse time is hours. In another embodiment, the lapse time is 20 hours. In another embodiment, the lapse time is 25 hours. In another embodiment, the lapse time is 30 hours. In another embodiment, the lapse time is 35 hours. In another embodiment, the lapse time is 40 hours. In another embodiment, the lapse time is 45 hours. In another embodiment, the lapse time is 46 hours.

In another embodiment, the lapse time is 72 hours. In another embodiment, the lapse time is 96 hours.

P- 622254 -IL id="p-111"

[000111] In another embodiment, the lapse time comprises several days. In another embodiment, the lapse time comprises several weeks. In another embodiment, the lapse time comprises several months. In another embodiment, the lapse time comprises several years. id="p-112"

[000112] In some embodiments, the administrations of the present disclosure comprise intervals of from about 1 hour to about 72 hours . In one embodiment, the administrations comprise intervals of about 1 hour. In one embodiment, the administrations comprise intervals of about 4 hours. In one embodiment, the administrations comprise intervals of about 5 hours. In one embodiment, the administrations comprise intervals of about 8 hours.

In one embodiment, the administrations comprise intervals of about 10 hours. In one embodiment, the administrations comprise intervals of about 12 hours. In one embodiment, the administrations comprise intervals of about 15 hours. In one embodiment, the administrations comprise intervals of about 16 hours. In one embodiment, the administrations comprise intervals of about 20 hours. In one embodiment, the administrations comprise intervals of about 24 hours. In one embodiment, the administrations comprise intervals of about 25 hours. In one embodiment, the administrations comprise intervals of about 28 hours. In one embodiment, the administrations comprise intervals of about 30 hours. In one embodiment, the administrations comprise intervals of about 35 hours. In one embodiment, the administrations comprise intervals of about 36 hours. In one embodiment, the administrations comprise intervals of about 40 hours. In one embodiment, the administrations comprise intervals of about 45 hours. In one embodiment, the administrations comprise intervals of about 50 hours. In one embodiment, the administrations comprise intervals of about 55 hours. In one embodiment, the administrations comprise intervals of about 60 hours. In one embodiment, the P- 622254 -IL 31 administrations comprise intervals of about 65 hours. In one embodiment, the administrations comprise intervals of about 70 hours. In one embodiment, the administrations comprise intervals of about 72 hours. id="p-113"

[000113] In one embodiment, the administration comprises intervals of from about 1 hour to about 24 hours. id="p-114"

[000114] In some embodiments, the animal is a human, a cow, a bos taurine, a goat, an antelope, cattle, a bison, a sheep, a buffalo, a camel, a donkey, a llama, a horse, a pig, a cat, a dog or an ave or aviary. In one embodiment, the animal is a human. In another embodiment, the animal is a cow. In another embodiment, the animal is a bos taurine. In another embodiment, the animal is a goat. In another embodiment, the animal is an antelope. In another embodiment, the animal is cattle. In another embodiment, the animal is a bison. In another embodiment, the animal is sheep. In another embodiment, the animal is a buffalo.

In another embodiment, the animal is a camel. In another embodiment, the animal is a donkey. In another embodiment, the animal is a llama. In another embodiment, the animal is a horse. In another embodiment, the animal is a pig. In another embodiment, the animal is a cat. In another embodiment, the animal is a dog. In another embodiment, the animal is an ave or aviary. id="p-115"

[000115] In one embodiment, the animal is a mammalian. id="p-116"

[000116] In one embodiment, the animal is bovid. A skilled artisan would understand the term "bovid" as any hoofed mammal in the family Bovidae (order Artiodactyla), which includes the antelopes, sheep, goats, cattle, buffalo, and bison. id="p-117"

[000117] In one embodiment, the method comprises administration of one or more additional pharmaceutically active agents.

P- 622254 -IL 32 id="p-118"

[000118] In one embodiment, the method comprises administration of one or more additional cosmetic active agents. id="p-119"

[000119] In one embodiment, the composition is in the form of a cream, a gel, a spray, a lotion, an ointment, an oil, a wash, a serum, a toner, a mask, a cleanser, a shampoo, a soap or a spray. In another embodiment, the composition is in the form of a cream. In another embodiment, the composition is in the form of a gel. In another embodiment, the composition is in the form of a spray. In another embodiment, the composition is in the form of a lotion. In another embodiment, the composition is in the form of an ointment. In another embodiment, the composition is in the form of an oil. In another embodiment, the composition is in the form of a wash. In another embodiment, the composition is in the form of a serum. In another embodiment, the composition is in the form of a toner. In another embodiment, the composition is in the form of a mask. In another embodiment, the composition is in the form of a cleanser. In another embodiment, the composition is in the form of a shampoo. In another embodiment, the composition is in the form of a soap. In another embodiment, the composition is in the form of a spray. id="p-120"

[000120] The term "casein" as used herein generally refers to a family of related proteins (αS1, αS2, β, κ) commonly found in mammalian milk. id="p-121"

[000121] The term "treatment" concerns improvement of at least one undesired manifestation of the disease such as increase in disease free periods, decrease in acute disease periods (in time and severely), decrease in severity of the disease, improvement in life quality, improvement in comfort and welfare, decreased mortality, decrease in the rate of disease progression as well as prophylactic treatment before disease occurs. More specifically, the term "treatment or prevention" as used herein, refers to the complete range of therapeutically positive effects of administrating to a subject including inhibition, P- 622254 -IL 33 reduction, alleviation and relief from a disorder or any related condition and illness, symptoms or undesired side effects or related disorders. It should be appreciated that the term "reduction" or as referred to herein, relate to the retardation, restraining or reduction of a process by any one of about 1% to 99.9%, about 1% to about 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, about 75% to 80%, about 80% to 85% about 85% to 90%, about 90% to 95%, about 95% to 99%, or about 99% to 99.9%. id="p-122"

[000122] The term "about" as used herein indicates values that may deviate up to 1%, more specifically 5%, more specifically 10%, more specifically 15%, and in some cases up to 20% higher or lower than the value referred to, the deviation range including integer values, and, if applicable, non-integer values as well, constituting a continuous range. As used herein the term "about" refers to ± 10 %. id="p-123"

[000123] As used herein, the term "average molecular weight" refers to the mean plus or minus standard deviation of the molecular weight of the peptide or protein as measured by a method known to a person skilled in the art. Such methods include, for example, SDS- gel electrophoresis and size exclusion chromatography in an apparatus such as HPLC, wherein the sample is run against Standards with known molecular weight.

Examples Example 1: Evaluation of bCNH cream in imiquimod-induced psoriasis model in mice . id="p-124"

[000124] Formulations of bCNH at 1, 5 and 10% were used. id="p-125"

[000125] The objective of this study was to investigate the efficacy of topical treatment with bCNH cream formulation of psoriasis model induced by Imiquimod (IMQ).

STUDY VARIABLES AND ENDPOINTS P- 622254 -IL 34 · Mortality & morbidity – Twice a day (once over the weekend).

· Histopathology: Back skin and right ear samples were stained (by H&E) and evaluated by a Veterinarian Pathologist.

· Termination: Mice were sacrificed on Day 8. Application sites (back skin and right ear) was excised from naïve, untreated, and half of the animals per treatment group (total=26 mice) and fixed in 10% formalin. id="p-126"

[000126] 46 female Balb/C mice were used. The Test Item and vehicle formulations were administered to eight animals per group, while two animals served as a Naïve control group.

TESTS AND EVALUATIONS id="p-127"

[000127] Morbidity and mortality checks were performed daily. id="p-128"

[000128] Two days before dosing and IMQ administration, the hair on about 5 cm area of the mice back was clipped using an electric clipper. The induction of psoriasis-like skin inflammation was performed by treating the mice, on the back and the right ear with a commercial IMQ cream (5%) (Aldara; 3M Pharmaceuticals) daily, starting on Day 1 until Day 7. Mice received a daily IMQ treatment of about 62.5±1 mg/mouse, to totally cover the areas of the animal’s clipped back (about 5 cm) and the right ear (about 0.25 cm). The animals were allowed to dry for 1 hour. id="p-129"

[000129] Dosing was performed around one hour after IMQ treatment. Three different doses: 1%, 5% and 10% (cream concentrations) of the Test Item were topically administered to the mice daily, on Day 1 to Day 7, by applying a thin layer on the back and the right ear skin surface. id="p-130"

[000130] Mice were sacrificed on Day 8. Skin was collected post-mortem from ear and back of naïve, untreated, and half of the animals per treatment group, total of 26 mice and fixed in 10% formalin. Half of each treatment group and all the untreated groups underwent P- 622254 -IL histological evaluations by Hematoxylin & Eosin (H&E). Additional immunohistochemical (IHC) staining and quantitative analysis by digital morphometry was performed for the high dose 10% bCNH and the untreated mice. The digital quantitative analysis of epidermal area was performed by smart segmentation based on shape, color, and brightness, using the Image Pro software (Media Cybernetics USA). The percentage of epidermal area was calculated out of the total skin area within a chosen rectangular area.

Slide Preparation and Histopathological Examinations- H&E staining id="p-131"

[000131] Samples of skin from ear tissue and the back from 26 mice were harvested, fixed in 4% formaldehyde for 48 hours then transported to the pathology lab. The tissues were trimmed, placed into embedding cassettes, and processed routinely for paraffin embedding.

One cassette was prepared per animal. 4 micron paraffin sections were prepared, placed on glass slides, and stained with Hematoxylin & Eosin (H&E). The slides were subjected to histological evaluation. Pictures were taken using Olympus microscope (BX60, serial No. 7D04032) equipped with microscope camera (Olympus DP73, serial No. OH05504) at objective magnification of X4.

Slide Preparation and Histopathological Evaluation of CD3- IHC staining id="p-132"

[000132] Samples of skin from ear and back tissue from 12 mice were used to evaluate the number of T-cells, using semi-quantitative immunohistochemistry (IHC) analysis of CD3.

Twelve blocks were harvested, fixed in 4% formaldehyde for 48 hours then transported to the pathology lab for histological analysis. The tissues were trimmed, placed into embedding cassettes, and processed routinely for paraffin embedding. One cassette was prepared per animal. 4 micron paraffin sections were prepared, placed on glass slides, and stained with CD3 by IHC.

The slides were subjected to histological evaluation. Pictures were taken using Olympus microscope (BX60, serial No. 7D04032) equipped with microscope camera (Olympus DP73, serial No. OH05504) at objective magnification of X10. A semi-quantitative analysis of the P- 622254 -IL 36 intensity of the immunohistochemical staining reaction as well as the number of positive cells was performed.

RESULTS Morbidity and Mortality Observation id="p-133"

[000133] No animal was found in moribund condition. id="p-134"

[000134] Histopathology Evaluation by H&E id="p-135"

[000135] In general, the H&E-stained sections showed typical characteristics of psoriasis in groups following administration of IMQ exhibiting mild inflammation and moderate mitotic activity. The epidermal thickness increased compared to normal epidermis and showed a wavy shape. Remodeling of the epidermis and adnexa was not observed. The positive control showed skin atrophy (skin degeneration) and was thinner than in other groups. The skin of the naïve, no IMQ, appeared normal. id="p-136"

[000136] Differences in the H&E staining between the group treated with high dose 10% bCNH, (right panel) versus the untreated (left panel) are presented in Fig. 1 . id="p-137"

[000137] The thickness of the epidermis in the treated group (right panel) is markedly reduced compared to the untreated group (left panel). This shows the effectiveness of 10% bCNH treatment. A graphical summary of the morphometric analysis of the ear and the back skin is shown in Fig. 2. id="p-138"

[000138] Treatment with high (10%) of bCNH shows a clear reduction in the % of epidermal area, ie a marked improvement. id="p-139"

[000139] Histopathology Evaluation of CD3 by IHC (immunohistochemical) Staining (Semi-quantitative and quantitative). id="p-140"

[000140] The encouraging results of the staining experiments described in the preceding sections supported further investigation. Therefore, more detailed T-cell specific (ie CD3 P- 622254 -IL 37 specific) histopathological analysis, both semi-quantitative and quantitiative, was performed as described in the following sections. Reduction in the number of T-cells is a beneficial outcome much desired in the treatment of psoriasis. For these additional studies, only the untreated and high dose 10% bCNH groups were examined. id="p-141"

[000141] The tissue samples from untreated (Group 2F) and high dose 10% bCNH were strained with a T-cell specific (ie CD3-specific) antibody. The CD3-positive T-cells are shown as brown dots in Fig. 3 and in the scoring of the stained samples presented in Fig. 4 . The large reduction in CD3 positive cells between groups treated with 10% bCNH, (right panel) versus the untreated Group (left panel) can be clearly seen in Fig. 3 and in the graphical illustration in Fig. 4 . id="p-142"

[000142] In general, a very specific staining reaction for CD3 was observed and positive stained cells were seen within the inflamed dermis and as infiltrating cells to the proliferated epidermis. The high dose 10% bCNH treated mice displayed a marked decrease in the number of positive CD3 cells (average of 2.75) compared to untreated mice, average of 4.5.

Morphometric, digital image analysis of CD3- IHC Staining id="p-143"

[000143] As can be seen in Fig. 5 , very specific CD3 stained cells were observed within the inflamed dermis and inflammatory cells infiltrated to the proliferated epidermis. The digital morphometric analysis supported the semi-quantitative findings. id="p-144"

[000144] CONCLUSIONS id="p-145"

[000145] The pro-inflammatory cascade in psoriasis is caused by release of cytokines from T-cells, therefore reducing the number of T-cells is extremely important for treatment of the disease. IHC of CD3 as a marker for T cells showed a marked decrease in the number of T- cells in the 10% bCNH treated mice, compared to the untreated mice. T-cells were seen mostly in the dermis and also in the epidermis. A clear dose dependence of the different P- 622254 -IL 38 bCNH formulations was shown which indicates that the effect seen is attributable to the bCNH. id="p-146"

[000146] The morphometric analysis of epidermal thickness demonstrated an improvement (reduction in % epidermal area) in the 10% bCNH treated mice, compared to the other treated groups. The digital analysis supported the semi-quantitative analysis results, showing an improvement in the bCNH treated groups. id="p-147"

[000147] A marked decrease in T-cells was found in the 10% bCNH treated mice compared to the untreated mice. Morphometric analysis using precise digital tools ( Fig.4 ) strengthens and corroborates the results obtained using the semi-quantitative method ( Fig.3 ). The histological results showed a clear effect of the Test Item in this Psoriasis model. id="p-148"

[000148] High dose (10%) topical treatment with bCNH cream formulation seemed to be the most effective in this psoriasis model induced by Imiquimod (IMQ) in mice.

Example 2: Evaluation of bovine casein hydrolysate (bCNH) cream in oxazolone- induced atopic dermatitis model in mice id="p-149"

[000149] The objective of the study is evaluation of bCNH cream treatment at three concentrations (5%, 10% and 12.5%) for Atopic Dermatitis (AD) in the oxazolone-induced model in SKH-1 mice.

Study variables and endpoints id="p-150"

[000150] Mortality & morbidity – Daily (once over weekends and holidays) id="p-151"

[000151] Body weight monitoring – During acclimation, and twice a week thereafter (or daily in case of 10% reduction in body weight) including before termination (on Day 23) id="p-152"

[000152] Atopic Dermatitis model induction –Topical application of Oxazolone (OXA) 1% is applied on the mouse back to all treatment groups on Day 1. Starting from Day 8 and every other day thereafter OXA 0.1% is applied on the mouse back until study termination.

P- 622254 -IL 39 id="p-153"

[000153] Skin evaluation and clinical signs based on skin thickness, erythema and scaling scale at baseline, on Day 8 and then every other day. id="p-154"

[000154] Topical treatment – Daily throughout the study from Day 13. A Vehicle (positive control) or the Test Item is topically applied (a thin uniform layer) on the OXA-exposed back area daily from Day 13 until study termination on Day 23. id="p-155"

[000155] Skin evaluation based on skin thickness, erythema and scaling scale are done at baseline, Day 8 and three times a week thereafter. Erythema - evaluated according to Draize score scale on a 5-point scale from 0 to 4. Scaling - evaluated according to the table of Specific Symptom Sum Score (SRRC) of scaling on a 5-point scale from 0 to 4. id="p-156"

[000156] Body weight is monitored at acclimation, twice a week thereafter and before termination. id="p-157"

[000157] Digital pictures of representative animals are taken on Day 23 prior to termination. id="p-158"

[000158] Study termination – On Day 23, mice are sacrificed. OXA exposed/treated skin areas from all animals are excised and fixed in 4% formaldehyde for histopathological evaluation (H&E staining). Skin areas from naïve and half of the animals’ groups are sent for histopathological evaluation (H&E staining). id="p-159"

[000159] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

P- 622254 -IL 40 CLAIMS

1. A method for preventing or treating inflammatory skin conditions, by administering to an animal a composition comprising at least one milk derived protein.

2. The method according to claim 1, said inflammatory skin conditions comprises acne; actinic keratosis, alopecia areata, basal cell carcinoma, Bowen's disease, burning mouth syndrome, cellulitis, congenital erythropoietic porphyria, contact dermatitis, Darier's disease, dystrophic epidermolysis bullosa, atopic dermatitis (eczema), epidermolysis bullosa simplex, skin erosions and ulcerations erythropoietic protoporphyria, fungal infections of nails, Hailey-Hailey disease, hair diseases, herpes simplex, hidradenitis suppurativa, hyperhidrosis, itchy skin (pruritus), ichthyosis, impetigo, keloids, keratosis pilaris, lichen planus, lichen sclerosus, melisma, mucous membrane diseases, nail diseases, nonhealing wounds, pemphigus vulgaris, plantar warts (verrucas), pityriasis lichenoides, polymorphic light eruption, psoriasis, pyoderma gangrenosum, rosacea, scabies, shingles, squamous cell carcinoma, skin infections, sun allergy, Sweet's syndrome, vitiligo, inflammation due to sunburn, hypersensitivity disorders, canine atopic dermatitis, feline atopy-like dermatitis, contact hypersensitivity, food hypersensitivity, fleabite hypersensitivity, bacterial skin diseases, fungal skin diseases, autoimmune and immune mediated dermatoses, parasitic skin disease and combination thereof.

3. The method according to claims 1 and 2, wherein said composition promotes wound or rupture closing.

4. The method according to claims 1 and 2, wherein said composition reduces skin itching, skin burning, skin redness, skin pain, dry skin, peeling skin, rough skin, skin swelling, skin cracking, or any combination thereof.

5. The method according to claims 1 to 4, said inflammatory skin condition is psoriasis.

6. The method according to claim 5, wherein said psoriasis comprises plaque, guttate, inverse, pustular, erythrodermic, or any combinations thereof.

7. The method according to claims 2 to 6, wherein said psoriasis causes symptoms in the back of the forearms, elbow, shins, navel area, and scalp. P- 622254 -IL 41

8. The method according to claims 1 to 7, wherein said milk derived protein comprises a casein protein or a casein derived peptide.

9. The method according to claim 8, wherein said casein derived peptide comprises natural peptide, synthetic peptide, semi-synthetic peptide, or any combination thereof.

10. The method according to claim 9, wherein said synthetic peptide is a recombinant peptide.

11. The method according to claim 10, wherein said recombinant peptide is produced by fermentation, tissue culture or combination thereof.

12. The method according to claim 11, wherein said tissue culture comprises mammary gland bovine tissue.

13. The method of any one of claims 1 to 12, wherein the casein peptide comprises one or more fragments of β-casein, aS1-casein, aS2-casein, ĸ-casein, optionally further comprises amino acids with different lengths or any combination thereof.

14. The method of any one of claims 1 to 13, wherein the casein derived peptide comprises a casein hydrolysate.

15. The method of any one of claims 1 to 14, wherein the casein derived peptide comprises a phosphopeptide.

16. The method of any one of claims 1 to 15, wherein the casein peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 26.

17. The method according to claims 1 to 16, wherein said composition if free of antimicrobials and comprises an acceptable carrier.

18. The method of any one of claims 1 to 17, comprising administering between ng/ml to 700 mg/ml of said milk derived protein per administration.

19. The method of any of claims 1 to 18, wherein said milk derived protein concentration in said composition is between 0.05% to 30%.

20. The method according to claims 1 to 19, wherein said administration comprises oral, intraoral, topical, epicutaneous, transdermal, subcutaneous, or any combination thereof.

21. The method according to claims 1 to 20, wherein said treatment comprises between one to thirty (30) administrations or constant administration. P- 622254 -IL 42

22. The method according to claims 1 to 20, wherein said treatment comprises chronic administration.

23. The method according to claims 1 to 22, wherein said treatment is repeated after a period of lapse time.

24. The method according to claims 1 to 22, wherein said administration comprises intervals of from about 1 hour to about 72 hours.

25. The method according to claim 24, wherein said administration comprises intervals of from about 1 hour to about 24 hours.

26. The method according to any one of claims 1 to 25, wherein said animal is a human, a cow, a bos taurine, a goat, an antelope, cattle, a bison, a sheep, a buffalo, a camel, a donkey, a llama, a horse, a pig, a cat, a dog or an ave or aviary.

27. The method according to any one of claims 1 to 26, comprising administration of one or more additional pharmaceutically active agents.

28. A method for moisturizing dry skin, skin softening, reducing skin itching, reducing skin peeling, reducing skin redness, reducing rough skin, reducing skin swelling, reducing skin cracking, renewal skin cells, preserving hand skin or any combination thereof, comprising administering to an animal a composition comprising at least one milk derived protein.

29. The method according to claim 28, wherein said milk derived protein comprises a casein protein or a casein derived peptide.

30. The method according to claim 29, wherein said casein derived peptide comprises natural peptide, synthetic peptide, semi-synthetic peptide, or any combination thereof.

31. The method according to claim 30, wherein said synthetic peptide is a recombinant peptide.

32. The method according to claim 31, wherein said recombinant peptide is produced by fermentation, tissue culture or combination thereof.

33. The method according to claim 32, wherein said tissue culture comprises mammary gland tissue.

34. The method of any one of claims 28 to 33, wherein the casein peptide comprises one or more fragments of β-casein, aS1-casein, aS2-casein, ĸ-casein, optionally further comprises amino acids with different lengths or any combination thereof. P- 622254 -IL 43

35. The method of any one of claims 28 to 34, wherein the casein derived peptide comprises a casein hydrolysate.

36. The method of any one of claims 28 to 34, wherein the casein derived peptide comprises a phosphopeptide.

37. The method of any one of claims 28 to 36, wherein the casein peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 26.

38. The method according to claims 28 to 37, wherein said composition if free of antimicrobials and comprises an acceptable carrier.

39. The method of any one of claims 28 to 38, comprising administering between ng/ml to 700 mg/ml per administration of said milk derived protein.

40. The method of any of claims 28 to 39, wherein said milk derived protein concentration in said composition is between 0.1% to 30%.

41. The method according to claims 28 to 40, wherein said administration comprises topical, epicutaneous, transdermal, subcutaneous, or any combination thereof.

42. The method according to claims 28 to 41, wherein said treatment comprises between one to thirty (30) administrations or constant administration.

43. The method according to claims 28 to 41, wherein said treatment comprises chronic administrations.

44. The method according to claims 28 to 43, wherein said treatment is repeated after a period of lapse time.

45. The method according to claims 28 to 43, wherein said administration comprises intervals of from about 1 hour to about 72 hours.

46. The method according to claim 45, wherein said administration comprises intervals of from about 1 hour to about 24 hours.

47. The method according to any one of claims 28 to 46, wherein said animal is a human, a cow, a bos taurine, a goat, an antelope, cattle, a bison, a sheep, a buffalo, a camel, a donkey, a llama, a horse, a pig, a cat, a dog or an ave or aviary.

48. The method according to any one of claims 28 to 47, comprising administration of one or more additional cosmetic active agents.

49. The method according to claims 28 to 48, wherein said composition is in the form of a cream, a gel, a spray, a lotion, an ointment, an oil, a wash, a serum, a toner, a P- 622254 -IL 44 mask, a cleanser, a shampoo, a soap or a spray.