The skin, mucous membranes, hair and/or nails constitute a physical barrier between the organism and its environment. The skin is composed of two tissues: the epidermis and the dermis. The epidermis is the outermost layer of the skin which is impermeable and therefore provides protection from external agents. It is a keratinized pluristratified epithelium which is continually renewing itself.
The epidermis has a high content in keratin, coming from the main type of cells in the epidermis (keratinocytes), melanin, and a significant content of lipids, which are found either in the stratum corneum or in the hydrolipidic film in the cutaneous surface. Lipids of sebaceous and keratinocyte origin are found in the lipidic film which covers the cutaneous surface, where the main part of these lipids are of sebaceous origin [A. Pappas, “Epidermal Surface Lipids”, Dermato-Endocrinology 2009, 1, 72-76].
The sebaceous secretion is produced in the sebaceous glands, which are found all over the body, but the hands and feet palms, and they are found at densities of 400-900 glands per cm2 in the face [K. R. Smith and D. M. Thiboutot, “Sebaceous gland lipids: friend or foe?”, Journal of Lipid Research 2008, 49, 271-281], mainly associated to the hair follicle, where the sebaceous secretions arrive to the skin surface through its channel. The secretion of the sebaceous glands, the sebum, is an oily and waxy substance consisting of a mixture mainly constituted by fatty acids, diglycerides, triglycerides, cholesterol and squalene, which provides thermoregulating functions and decrease of water loss from the skin surface.
In human beings, the amount of produced sebum ranges according to the population group, depending on the age and hormonal factors of regulation, too. Depending on the amount of sebum, it is distinguished among:                Oily skin. Oily skin is caused by an excessive function of the sebaceous glands. When there is an excess of sebum in the skin, the skin is characterized by a thicker texture, a greasy and brilliant appearance, as well as by the presence of expanded pores and cutaneous imperfections.        Combination skin. It is characterized by the simultaneous presence of dry and oily areas. Commonly, the oily area is located on the forehead, nose and chin (known as T-zone). The part of the face outside of the T-zone is normally the dry area, due to the thinner skin in this area, which increases its desquamation.        Dry skin. The lack of sebum implies a disability to retain enough hydration, which renders in a fragile skin with a higher tendency to desquamation and fine wrinkles. With the characteristic of showing imperceptible pores, the reduced capacity of barrier function implies a higher susceptibility to harmful external factors such as UV, cold and wind.        Normal skin. With an appropriate amount of sebum which allows a good hydric balance, this kind of skin shows a good elasticity and resistance, with almost no visible pores and uniform skin tone.        
Although dependent to a great extent on age and ethnic origin, there is an important average of population showing oily skin, together with the additional existence of the population with combination skin with an oily T-zone.
Some dermatological disorders related with excess sebum are:                Seborrhea, a functional disorder of the sebaceous glands which produce a hypersecretion of sebum, which causes red, irritated and squamous skin.        Acne, an infection which occurs when there is a stopping in the pores of the skin where sebum, dead cells and bacteria are entrapped.        Comedo, an accumulation of hardened sebum and a mass of keratinized cells which cause a blockage of the way in to the follicle.        Milium or milk spots, an accumulation of keratinized cells and sebaceous material entrapped under the skin.        
Inside the sebaceous glands, sebum is released when the mature sebocytes rupture inside of the gland, and sebum goes out to the skin surface through the channel of the hair follicle. Until arriving to the sebum release, the gland function understands that there is a population of non-differentiated cells in the adjacent layer to the hair follicle which start their proliferation as they move to the basal layer of the gland, and they turn into lipid-filled sebocytes as they arrive to the central part of the gland, where they eventually and progressively break out [C. Nieman and V. Horsley, “Development and Homeostasis of the sebaceous gland”, Seminars in Cell & Developmental Biology 2012, 23, 928-936].
A large number of compounds has shown their effects in regulating the function of sebaceous glands such as androgens, estrogens, retinoids, LXR type receptors (liver X receptor), receptors activated by peroxisome proliferators, growth hormones/insulin-like growth factors, and the family of melanocortins [K. R. Smith and D. M. Thiboutot, “Sebaceous gland lipids: friend or foe?”, Journal of Lipid Research 2008, 49, 271-281].
The family of melanocortins is composed by a group of peptides structurally related with propiomelanocortin (POMC), and with the melanocortin receptors (MCRs) which regulate the effects of the melanocortinic peptides. MCRs are associated to G proteins (GPCRs) and transfer the signalling by different pathways: production of cyclic adenosine monophosphate (cAMP), activation of the protein kinase A, and increase of the concentration of [Ca2+] cation.
MC5R is one of the different melanocortin receptors that have been characterized in various human tissues, and it is involved in lipid production [M. A. Bednarek et al, “Potent and Selective Peptide Agonists of α-Melanocyte Stimulating Hormone (αMSH) Action at Human Melanocortin Receptor 5; their Synthesis and Biological Evaluation in vitro”, Chem. Biol. Drug. Des. 2007, 69, 350-355]. For example, transgenic mice that lacked expression of MC5R receptor showed a marked reduction in sebum production [D. M. Thibotout et al, “The Melanocortin 5 Receptor is Expressed in Human Sebaceous Glands and Rat Preputial Cells”, J. Invest. Dermatol. 2000, 115, 614-619]. Furthermore, MC5R is considered a marker of sebocyte differentiation since MC5R is not detected in undifferentiated sebaceous cells while it is detected in sebaceous cells in the later stages of differentiation, but not in basal, undifferentiated sebaceous cells. Similarly, MC5R is only detectable in in-vitro cultures at the onset of differentiation and in fully differentiated sebaceous cells showing prominent lipid granules [L. Zhang et al, “Melanocortin-5 receptor: A marker of human sebocyte differentiation”, Peptides 2006, 27, 413-420]. Since MC5R is a marker that correlates with the sebaceous differentiation process that leads to the production of sebum, the inhibition of this receptor MC5R may be used as a strategy for the reduction of sebum production and consequently for the treatment and/or prevention of disorders and/or diseases related with excess of sebum.
Furthermore the inhibition of MC5R receptor has been shown to be beneficial in the treatment of seborrheic dermatitis, cancer and inflammatory diseases (US 2009/221558). For example, the Muir-Torre syndrome consists of adenomas in sebaceous glands associated with an internal adenocarcinoma (usually in colon, prostate, breast or ovary) and the prevention of sebaceous cell differentiation through the inhibition of the MC5R receptor can be effective in the treatment of tumor growth (US 2009/221558). It has also been seen that the inhibition of receptor MC5R is beneficial for the treatment of anorexia or cachexia (US 2003/110518) and for treating hidradenitis suppurativa and excessive production of cerumen (WO 03/040118 A1).
It is also known that certain compounds, such as estrogens, which inhibit sebaceous glands have a stimulatory effect on collagen synthesis, and therefore have a skin firming effect [A. Parchami, R. A. Fatahian Dehkordi, “Effect of ovariectomy and chronic sex steroid administration on rabbit skin”, Global Veterinaria, 2010, 4(6), 610-615].
It is described in the prior art an extracellular polymeric substance coming from the sea, Matmarine™, which acts on MC5R receptor [Soap, Perfumery & Cosmetics, Product Innovation 2013, page 39]. Matmarine™ is said to decrease the sebum rate (8.4%), number (20.5%) and area of pores (18.8%).
Surprisingly, the applicant of the present invention has found that extracts of molecular weight below 10 kDa produced by strains of Pseudoalteromonas antarctica inhibit the MC5R receptor and increase collagen synthesis in the skin.
It is known from the prior art that a glycoprotein produced by the species Pseudoalteromonas antarctica has properties of healing (EP 1402898 B1), moisturizing and it repairs skin keratinization disorders (EP 2337556 A1). The prior art also discloses a profile of proteins at the membrane vesicle of Pseudoalteromonas antarctica with molecular weights of 109 KDa, 52.5 KDa, 48 KDa, 44 KDa, 42 KDa, 34.5 KDa, 33 KDa, 31 KDa and 24 KDa. The average molecular weight of the main protein is between 98 and 112 KDa [Morphological and physiological study of Pseudoalteromonas antarctica NF3 and characterization of membrane vesicles present in the produced extracellular material, Doctoral Thesis of Maria Nevot, filed at the University of Barcelona].
USPTO Backgrounds
USPTO Backgrounds