(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2015/009325 Al 22 January 2015 (22.01.2015) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C12N 5/00 (2006.0 1) C12N 1/00 (2006.0 1) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C12N 5/02 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, PCT/US2013/051394 MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (22) International Filing Date: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, 19 July 2013 (19.07.2013) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 13/945,120 18 July 2013 (18.07.2013) US UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (63) Related by continuation (CON) or continuation-in-part EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (CIP) to earlier application: MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, US 13/04 1,197 (CIP) TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Filed on 4 March 201 1 (04.03.201 1) KM, ML, MR, NE, SN, TD, TG). (72) Inventor; and Declarations under Rule 4.17 : (71) Applicant : AL-QAHTANI, Ahmed H. [AE/US]; 105 — as to the identity of the inventor (Rule 4.1 7(Ϊ)) Capeberry, Irvine, California 92603 (US). — as to applicant's entitlement to apply for and be granted a (74) Agent: LILA, Ben T.; Mandour & Associates, APC, patent (Rule 4.1 7(H)) 16870 W. Bernardo Dr., Suite 400, San Diego, California 92127 (US). — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.1 7(in)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, — of inventorship (Rule 4.17(iv)) [Continued on next page] (54) Title: SKIN CREAM Before and After © Acne Scars © (57) Abstract: Skin care compositions, including cosmeceuticals, for topical application, and more particularly, a skin cream, com o prising exosomes and cell culture medium conditioned by cells grown in two-dimensional culture. Also included are methods of us ing such compositions and kits comprising the skin cream therein. Published: with sequence listing part of description (Rule 5.2(a)) SKIN CREAM BACKGROUND OF THE INVENTION FIELD OF THE INVENTION [0001] The present invention is generally related to skin care compositions, and more specifically to cosmeceuticals and medicaments for topical application, including a skin cream, comprising exosome enriched cell culture medium conditioned by foreskin-derived fibroblast cells grown in two-dimensional culture. BACKGROUND INFORMATION [0002] Currently there is no cure for aging skin and treatments for aging and/or wrinkled skin are temporary and suffer from drawbacks and side effects. The loss of collagen and elastic proteins present in the dermal layers causes a breakdown of resiliency and skin thickness over time, which may result in fine lines and wrinkles. The most common surgical interventions available for treatment of facial wrinkles include face-lifts, laser surgery, skin peels, and injection therapies, such as BOTOX®. However, surgical methods may result in detrimental complications, are often painful, and must be repeated with time. Non-invasive remedies include topical formulations consisting of alpha/beta hydroxy, retinoic acids, argirelines, and vitamins. However, none of these methods completely eliminate wrinkles, and require multiple, and often expensive treatments. Some topical formulations may act as irritants to the skin, to elicit wound healing responses, but do not successfully replenish the thinning skin with adequate proteins for treatment and/or prevention of age-related defects. [0003] The pathogenesis of skin aging is well defined; it is characterized by a decrease in collagen synthesis and an increase in collagen breakdown, mediated by metalloproteinases (Arch. Dermatol. 138[11]: 1462-70, 2002). This net loss in dermal collagen is believed to contribute to and/or permit wrinkling. Biologic factors that stimulate collagen production in wound healing might provide benefits for aging skin. Accordingly, growth factors, peptide fragments, and other biologically active molecules are being incorporated into anti-aging cosmeceuticals. [0004] Growth factors are typically peptides with diverse biological effects. Some growth factor families that have been identified as useful in wound healing and/or epidermal remodeling include, e.g., transforming growth factor- β (TGF- β), epidermal growth factor (EGF), insulin like growth factors (IGFs), platelet-derived growth factor (PDGF), and fibroblast growth factors (FGFs). [0005] Living cells cultured in vitro secrete extracellular proteins and peptides, including growth factors, into the nutrient medium in which they are cultured. Medium exposed to cells in culture is referred to as "conditioned medium." Naughton et al, in U.S. Patent No. 6,372,494, teach that conditioned medium from cell cultures comprising a three-dimensional extracellular matrix and multiple layers of stromal and tissue specific cells (i.e., a three-dimensional culture system) may be used advantageously to prepare growth factor-enriched cosmeceutical compositions; U.S. Patent No. 6,372,494 is herein incorporated in its entirety by reference thereto. Indeed, Naughton et al. assert that the complex three-dimensional culture systems have numerous advantages over simple two-dimensional culture systems, e.g., greater surface area; more analogous to tissues in vivo; absence of "contact inhibition" (a limitation on the growth of cells in two-dimensional cultures); creation of localized microenvironments; increased cell-cell interactions and potential cell migration; maintenance of a differentiated phenotype and elaboration of differentiation factors, etc. Unfortunately, three-dimensional culture systems are substantially more expensive and technically challenging to establish and maintain than conventional two-dimensional culture systems. Moreover, the complex biological systems formed in three-dimensional culture create so many variables (e.g., cell-cell and cell-matrix interactions, tissue differentiation, etc.), that quality control with respect to the harvested conditioned medium becomes nearly impossible, and batch-to-batch variability in growth factor composition may be commercially unacceptable. [0006] In addition, cultured cells also produce extracellular vesicles. Extracellular vesicles, or exosomes, have emerged as potent vehicles for cell-to-cell communication since the discovery that they contain functional mRNA, miRNA, DNA, and protein molecules that can be taken up by target cells. The genetic information contained in exosomes can influence or even direct the fate of the target cell, for example by triggering target cell activation, migration, growth, differentiation or de-differentiation, or by promoting apoptosis or necrosis. As such, exosomes can provide additional cell factors which assist in wound healing and/or epithelial remodeling. [0007] Accordingly, while the use of growth factors to treat aging skin is gaining favor among skin care professionals, there remains an important and unmet need for more effective topical formulations for the treatment and/or prevention of skin damage, wrinkles and/or other defects due to aging and environmental factors, where the formulations comprise conditioned medium enriched with vesicles, growth factors, and/or extracellular matrix compositions produced by economical, well-controlled cell culture methods. SUMMARY OF THE INVENTION [0008] The present invention relates to skin care compositions, including cosmeceutical, for topical application, and a skin cream, comprising cell culture medium conditioned by cells, which medium may be exosome enriched. The present invention also discloses methods of using such compositions for the treatment of skin disorders. [0009] In embodiments, a skin cream for treating a skin defect is disclosed, including exosome enriched conditioned medium from cultured substantially homogenous foreskin derived fibroblast cells, where the exosomes are isolated from cultures of cells under conditions adapted to promote secretion of at least one growth factor into nutrient medium. [0010] In one aspect, the exosomes are isolated from conditioned medium that is the same as or is different from the exosome enriched conditioned medium. In a related aspect, the conditioned media are different. In a further related aspect, the exosome enriched conditioned medium is generated from transformed cells and the exosomes are isolated from conditioned medium generated from non-transformed cells or the exosome enriched conditioned medium is generated from non-transformed cells and the exosomes are isolated from conditioned medium generated from transformed cells. [0011] In another related aspect, the transformed cells are from a cell line designated as ATCC Accession No. PTA-1 1680 and the non-transformed cells are from a cell line designated as ATCC Accession No. PTA- 11681. [0012] In one aspect, the skin cream further includes one or more solvents, a base solvent, one or more botanicals, and one or more emollients. [0013] In another aspect, the exosomes include at least one molecule selected from a protein, DNA, RNA, and combinations thereof. [0014] In one aspect, the skin cream includes TGF Beta-1, TGF Beta-2, TGF Beta-3, IL-3, IL- 6, IL-7, and IL-8, and the conditioned media is present at a concentration of at least about 5-20% (wt%).