(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/205895 Al 07 December 2017 (07.12.2017) W !P O PCT

(51) International Patent Classification: A61K 8/14 (2006.01) A61K 35/16 (20 15.0 1) A61K 9/127 (2006 .01) A61K 35/1 7 (20 15.0 1) A61K 35/14 (2015.01) (21) International Application Number: PCT/AU20 17/000 124 (22) International Filing Date: 02 June 2017 (02.06.2017) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/345,036 03 June 2016 (03.06.2016) US 62/369,240 0 1 August 2016 (01.08.2016) US (71) Applicant: EMBRYOGENESIS PTY LTD [AU/AU]; 1/65 Connels Point Road, South Hurstville, New South Wales 2221 (AU). (72) Inventors: BRITTON, Peter; 325 Princes Highway, Carl ton, New South Wales 2218 (AU). FRENCH, Andrew; 325 Princes Highway, Carlton, New South Wales 2218 (AU). (74) Agent: ALLENS PATENT & TRADE MARK ATTOR¬ NEYS; Deutsche Bank Place, Corner Hunter & Phillip Streets, Sydney, New South Wales 2000 (AU). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 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. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG).

Published: — with international search report (Art. 21(3)) © l (54) Title: SKIN CARE FORMULATION © (57) Abstract: There is provided a skin care formulation for transdermal administration of a component of a blood product, the for- mulation comprising a blood product, a transdermal carrier; and a liposomal base, wherein at least a portion of the blood product and transdermal carrier is contained within liposomes of the liposomal base. SKIN CARE FORMULATION

Related Applications

[001] This application claims the benefit of US Provisional Patent Application No 62/345,036, filed on 3 June 201 6 and US Provisional Patent Application No 62/369,240, filed on 1 August 201 6 the disclosures of which are hereby expressly incorporated by reference in their entireties.

Technical Field

[002] The technology relates to liposomal skin care formulations comprising blood serum, plasma or components thereof contained within liposomes. In particular, the technology relates to liposomal skin care formulations for systemic application of a component of blood serum or plasma by a transdermal route.

Background

[003] Human skin is subject to deterioration due to numerous factors including aging and dermatological disorders conditions or diseases such as dermatitis, psoriasis, eczma, pruritus, acne, rash, dryness and wounding. In addition, deterioration occurs from environmental factors such as from wind, air conditioning, and central heating, or through the normal ageing process, which may be accelerated by exposure of skin to sun. In particular, ageing is characterized by the appearance of wrinkles, variations in skin pigmentation and the loss of elasticity and compactness.

[004] The pathogenesis of skin ageing is characterized by a decrease in collagen synthesis and an increase in collagen breakdown. The loss of dermal collagen is contributes to or facilitates wrinkling. [005] Alopecia (Hair loss, either complete or partial) affects both men and women but increases in prevalence as age increases. The hair loss process typically involves a process of follicular miniaturization, in which the cells in the hair follicle begin to deteriorate. Consequently, the hair's growth phase is shortened and hair is prevented from maturing into the pigmented terminal hair typically seen on the head. Over time the follicle goes dormant and ceases producing hair completely. [006] Numerous cosmetic and therapeutic skin care products are currently available for topical use to reduce the effects of skin ageing, skin conditions or hair loss. These typically comprise various chemical components, polymers, oils, antioxidants and the like. [007] It is believed that biological factors that stimulate collagen production and cell growth in wound healing might provide benefits for ageing skin and hair loss and such factors, including growth factors, peptide fragments, and other biologically active molecules have been incorporated into anti-aging cosmetics and therapeutics. [008] While the use of biological factors to treat aging skin is gaining favor there remains an unmet need for effective topical formulations for the prevention and treatment of skin damage, wrinkles and other defects associated with aging or caused by environmental factors. [009] The present inventors have developed a formulation for transdermal delivery of one or more components of a blood product such as plasma or serum.

Summary

[01 0] In a first aspect, there is provided a skin care formulation for transdermal administration of a component of a blood product, the formulation comprising: a blood product;

a transdermal carrier; and

a liposomal base; wherein at least a portion of the blood product and transdermal carrier is contained within liposomes of the liposomal base.

[01 1] The skin care formulation may be present in a nasal dosage form or an oral dosage form for transdermal delivery of the component of the blood product. The oral dosage form may be selected from a sublingual troche, tablet, wafer or lozenge. In some embodiments the oral dosage form is a buccal troche, tablet, wafer, lozenge or orally disintegrating tablet.

[01 2] In one embodiment the formulation may comprise a therapeutically effective dose of a component of the blood product.

[01 3] The formulation may additionally comprise an transdermal enhancer. [01 4] The blood product may be selected from plasma, serum, platelet rich plasma, conditioned plasma, conditioned serum , and combinations thereof. [01 5] In some embodiments the conditioned serum is autologous conditioned serum .

[01 6] The blood product may be derived from a subject of any age, for example and 18-25 year old, a 25-35 year old, a 35-45 year old, a 45-55 year old, a 55-65 year old or a subject that is 65 or more years old. [01 7] The blood product may be derived from a placenta and/or an umbilical cord.

[01 8] The blood product may be a human blood product. In some embodiments the blood product may be pooled from a number of humans or produced from blood pooled from a number of humans. The blood product may be from an umbilical cord, placenta or donated blood. [01 9] In some embodiments the blood product may comprise fragments of regenerative cells. The regenerative cell fragments may be selected from mesenchymal stem cells, endothelial progenitor cells, hematopoietic stem cells, monocytes, macrophages, keratinocytes, and fibroblasts. The skin care formulation may include a blood product comprising fragments of regenerative cells [020] The blood product may be lyophilized. [021] The component of serum or plasma may be a growth factor, cytokine, chemokine, hormone, vitamin, or cell fragment. [022] The growth factor may be selected from endothelial growth factor (EGF), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF), transforming growth factor alpha (TGF-a), TGF-P1 , TGF-p2, TGF^3, platelet-derived growth factor (PDGF)-AA, PDGF-AB,

PDGF-BB, insulin-like growth factor-1 (IGF-1 ) , BMP, BDNF, EGF, HGF.PDGF, FGF, PGF, GDF-8, NGF, Epo, TPO, TCGF, IGF-I , IGF-I I, KGF, VEGF, and any combination thereof. [023] The cytokines may be pro-inflammatory or anti-inflammatory. [024] The pro-inflammatory cytokine may be for example granulocyte macrophage colony- stimulating factor (GM-CSF), interleukin (IL)-1 a , IL- Ι β, IL-2, IL-2R, IL-3, , IL-6, IL-7, IL-8, IL-

9 , IL-1 0 , IL-1 1, IL-1 2 , IL-1 2p40/p70, IL-1 3 , IL-1 4 , IL-1 5 , IL-1 7 , tumour necrosis factor

(TN F)a, TNF- β, interferon (IFN)-a, INF- β, INF-y or any combination thereof.

[025] The anti-inflammatory cytokine may be for example IL-1 RA, IL-4, IL-5, IL-1 0 , IL-1 3 , IFNa or any com bination thereof. [026] The chemokine may be eotaxin, protein 10 (IP-1 0), monocyte chemoattractant protein-1 (MCP-1 ), IFNy-induced monokine, macrophage inflammatory protein (MI P)-1 a ,

ΜΙΡ - 1β, RANTES or any combination thereof. [027] The hormone may be selected from an am ino acid hormone, eicosanoid hormone, a peptide hormone, and a steroid hormone. [028] The amino acid hormone may be selected from epinephrine, melatonin, triiodothyronine, and thyroxine. [029] The eicosanoid hormone may be selected from prostaglandins, leukotrienes, prostacyclin, and thromboxane. [030] The peptide hormone may be selected from amylin, anti-mullerian hormone, adiponectin, angiotensinogen, angiotensin, vasopressin, atrial natriuretic peptide, brain natriuretic peptide, calcitonin, cholecystokin, corticotropin-releasing hormone, cortistatin, encephalin, endothelin, erythropoietin, galanin, gastric inhibitory peptide, gastrin, ghrelin, glucagon, glucagon-like-peptide-1 , Gonadotropin-releasing hormone, Growth hormone- releasing hormone, hepcidin, Human chorionic gonadotropin, Human placental lactogen, human growth hormone, Inhibin, Insulin, Insulin-like growth factor, leptin, lipotropin, melanocyte stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, parathyroid hormone, pituitary adenylate cyclase-activating peptide, prolactin, prolactin releasing hormone, relaxin, renin, secretin, somatostatin, thrombopoietin, thyroid-stimulating hormone, and vasoactive intestinal peptide. [031 ] The steroid hormone may be selected from testosterone, dehydroepiandrosterone, androstenedione, dihydrotestosterone, aldosterone, estradiol, estrone, estriol, Cortisol, progesterone, calcitriol, and calcidiol. The liposomal base may be an emulsion that includes a lipophilic component and an aqueous component. The liposomal base may be a lotion, a cream, a gel or a paste. Examples of suitable liposomal bases include PCCA Lipoderm®, Lipoderm ActiveMax™ , Anhydrous Lipoderm and Lipoderm High Molecular Weight™ PCCA, Houston, Texas.

[032] One example of a commercially available liposomal base suitable for use in the formulations provided herein includes, but is not limited to, Lipoderm ® lipophilic liposome cream (a mixture of about 60-80% wt/wt water, with glycerin, C 12-1 5 alkyl benzoate, glyceryl stearate, dimethicone, cetearyl alcohol, cetearyl glucoside, polyacrylamide, cetyl alcohol, magnesium aluminum silicate, xanthan gum , aloe vera (aloe barbadensis), tocopheryl acetate (vitamin E acetate), prunus amygadalus amara (bitter almond) kernel oil, vitis vinifera (Grape) seed extract, triticum vulgare (wheat) germ oil, retinyl palmitate (vitamin A palmitate), ascorbyl palmitate (vitamin C palmitate), Pro-Lipo Multi-emulsion Liposom ic System , tetrasodium EDTA, phenoxyethanol, sodium hydroxymethylglycinate. PCCA, Houston, Texas.

[033] The composition in LIPODERM ™ lipophilic liposomic cream is particularly suitable when formulated in accordance with the guidance provided herein. For example, the inventors have discovered that surprisingly, to formulate a composition that does not separate, it is important that the blood product be dissolved in a suitable mixed phase emulsion such as LIPODERM ™. [034] The transdermal carrier may be selected from isopropyl alcohol, dipropylene glycol methyl-ether, butylated hydroxytoluene dipropylene glycol monomethyl-ether, 1-methoxy 2- propanol (glysolv PM/lcinol PM), Ethylene glycol monobutylether (butyl glyxolv/butyl icinol), Butyl di glysolv (butyl-icinol), Transcutol, propylene glycol (PG), N-methyl-2 pyrrolidone (NMP), methylene chloride, diethyl ether, ethanol, acetonitrile, ethyl acetate, benzyl alcohol, a combination of natural oil; ethylene glycol, propylene glycol, dimethyl polysiloxane (DMPX), oleic acid, caprylic acid, 1-octanol, ethanol (denatured or anhydrous), liposomal compositions, suitable plant oils, such as Aloe vera derivatives or sesame seed oil or derivatives thereof, acrylic polymers, rubber-based polymers, polysiloxane-based polymers, polyvinylpyrrolidone-based polymers, dimethylsulfoxide (DMSO), dimethylformamide (DMF), lecithin, Transfersomes® (bi-component vesicular aggregates), ethosomes, azone, castor oil derivatives, such as ethoxylated castor oil, jojoba oil derivatives, corn oil derivatives, and emu oil derivatives. [035] In one embodiment the administration is systemic administration.

[036] The transdermal carrier may be present in the formulation in an amount from about 1% (w/w) to about 50% (w/w). For example the transdermal carrier may be present in the formulation at about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), about 10% (w/w), about 11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w), about 15% (w/w), about 16% (w/w), about 17% (w/w), about 19% (w/w), about 20% (w/w), about 2 1% (w/w), about 22% (w/w), about 23% (w/w), about 24% (w/w), about 25% (w/w), about 26% (w/w), about 27% (w/w), about 28% (w/w), about 29% (w/w), about 30% (w/w), about 3 1% (w/w), about 32% (w/w), about 33% (w/w), about 34% (w/w), about 35% (w/w), about 36% (w/w), about 37% (w/w), about 38% (w/w), about 39% (w/w), about 40% (w/w), about 4 1% (w/w), about 42% (w/w), about 43% (w/w), about 44% (w/w), about 45% (w/w), about 46% (w/w), about 47% (w/w), about 48% (w/w), about 49% (w/w), or about 50% (w/w).

[037] The transdermal enhancer may be present in the formulation in an amount from amount from about 1% (w/w) to about 30% (w/w). For example the transdermal carrier may be present in the formulation at about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), about 10% (w/w), about 11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w), about 15% (w/w), about 16% (w/w), about 17% (w/w), about 19% (w/w), about 20% (w/w), about 2 1% (w/w), about 22% (w/w), about 23% (w/w), about 24% (w/w), about 25% (w/w), about 26% (w/w), about 27% (w/w), about 28% (w/w), about 29% (w/w) or about 30% (w/w). [038] In an embodiment the formulation comprises:

1% to 80% (v/w) of the blood product;

1% to 50% (w/w) of the transdermal carrier; and

up to 80% (w/w) of the liposomal base.

[039] For example the blood product can be present in the formulation in an amount from about 1% to about 80% (w/w) or (v/w). For example the blood product can be present in the formulation in an amount of about 1% , about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11% , about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 19%, about 20% , about 2 1% , about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about

30%, about 3 1% , about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 4 1% , about 42%, about 43%, about 44%, about

45%, about 46%, about 47%, about 48%, about 49%, about 50% , about 5 1% , about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about

60%, about 6 1% , about 62%, about 63%, about 64%, about 65% , about 66%, about 67%, about 68%, about 69%, about 70%, about 7 1% , about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80%.

[040] The transdermal carrier may be present in the formulation in an amount from about 1% (w/w) to about 50% (w/w). For example the transdermal carrier may be present in the formulation at about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), about 10% (w/w), about 11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w), about 15% (w/w), about 16% (w/w), about 17% (w/w), about 19% (w/w), about 20% (w/w), about 2 1% (w/w), about 22% (w/w), about 23% (w/w), about 24% (w/w), about 25% (w/w), about 26% (w/w), about 27% (w/w), about 28% (w/w), about 29% (w/w), about 30% (w/w), about 3 1% (w/w), about 32% (w/w), about 33% (w/w), about 34% (w/w), about 35% (w/w), about 36% (w/w), about 37% (w/w), about 38% (w/w), about 39% (w/w), about 40% (w/w), about 4 1% (w/w), about 42% (w/w), about 43% (w/w), about 44% (w/w), about 45% (w/w), about 46% (w/w), about 47% (w/w), about 48% (w/w), about 49% (w/w), or about 50% (w/w). [041] The liposomal base may be present in the formulation in any amount. For example the base may be present in the formulation in an amount of about 1%(w/w), about 2%(w/w), about 3%(w/w), about 4%(w/w), about 5%(w/w), about 6%(w/w), about 7%(w/w), about 8%(w/w), about 9%(w/w) about 10%(w/w), about 11%(w/w), about 12%(w/w), about 13%(w/w), about 14%(w/w), about 15%(w/w), about 16%(w/w), about 17%(w/w), about 19%(w/w), about 20%(w/w), about 2 1%(w/w), about 22%(w/w), about 23%(w/w), about 24%(w/w), about 25%(w/w), about 26%(w/w), about 27%(w/w), about 28%(w/w), about

29%(w/w), about 30%(w/w), about 3 1%(w/w), about 32%(w/w), about 33%(w/w), about 34%(w/w), about 35%(w/w), about 36%(w/w), about 37%(w/w), about 38%(w/w), about

39%(w/w), about 40%(w/w), about 4 1%(w/w), about 42%(w/w), about 43%(w/w), about 44%(w/w), about 45%(w/w), about 46%(w/w), about 47%(w/w), about 48%(w/w), about 49%(w/w), about 50%(w/w), about 5 1%(w/w), about 52%(w/w), about 53%(w/w), about 54%(w/w), about 55%(w/w), about 56%(w/w), about 50%(w/w), about 58%(w/w), about

59%(w/w), about 60%(w/w), about 6 1%(w/w), about 62%(w/w), about 63%(w/w), about 64%(w/w), about 65%(w/w), about 66%(w/w), about 67%(w/w), about 68%(w/w), about

69%(w/w), about 70%(w/w), about 7 1%(w/w), about 72%(w/w), about 73%(w/w), about 74%(w/w), about 75%(w/w), about 76%(w/w), about 77%(w/w), about 78%(w/w), about 79%(w/w), or about 80%(w/w). [042] In an embodiment the blood product is Human plasma or plasma lysate, Human serum, Human PRP (platelet rich plasma), or Human Autologous conditioned serum; the transdermal carrier is Propylene Glycol; and the Liposomal base is PCCA Lipoderm ® q.s. . [043] In a second aspect there is provided a method of treating, preventing or ameliorating a symptom or sign of a skin defect comprising: topically administering to the skin of a subject in need thereof a formulation of the first aspect in an amount sufficient to treat, prevent or ameliorate a symptom or sign of the skin defect. [044] The formulation may be administered at least once per day. For example the formulation may be administered may be applied daily, twice daily, three times or more than three times daily. [045] Application of the formula may be continued until the skin defect is resolved or prevented or until at least one symptom or sign of the skin defect is ameliorated. For example the formulation may be applied over a period of one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, twelve weeks or longer. [046] The skin defect may be selected from poor skin texture, wrinkles, fine lines, UV induced skin damage, skin aging, dry skin, hair follicle deterioration, alopecia, dermatitis, eczma, rash, pruritus, sun burn, burns, stretch marks, acne scars, and surgical scars. [047] The treatment may reduce the number of wrinkles or fine lines by about 5%, 10%, 15%, 20%, 25%, 30%, 35%., 40%, 45% or at least about 50% compared to the number of wrinkles or fine lines before treatment.

[048] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[049] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this specification. Description

[050] The present inventors have developed a topically applied formulation for transdermal delivery of one or more components of a blood product such as blood serum or blood plasma. In some embodiments the component is systemically administered via the transdermal route.

[051 ] The formulations include three components: a liposomal base, a blood product and a transdermal carrier.

[052] The blood product in the formulation is present in the aqueous and/or lipophilic portions but is also encapsulated in liposomes of the base. The liposomes have a lipophilic membrane surrounding an aqueous interior compartment. The structure of the liposomes may include multilamellar or unilamellar liposomes or unstructured liposomal aggregates and/or combinations of the same. A portion of the blood product is present in the aqueous compartments of the liposome.

[053] The formulations described herein are useful for preventing, reducing and/or eliminating skin defects such as poor skin texture, wrinkles, frown lines, UV induced skin damage, skin ageing, dry skin, hair follicle deterioration, alopecia, dermatitis, eczema, rash, psoriasis pruritus, sun burn, burns, stretch marks, acne scars and surgical scars (wound healing). Accordingly, the formulations may be used as an alternative or in addition to cosmetic surgery, injectable cosmetic treatments such as fillers (Hyaluronic Acid) BOTOX®, silicone or other products.

[054] Skin ageing is a complex process characterized by decreased in collagen synthesis and increased collagen degradation. A number of growth factors stimulate collagen production. In some embodiments the blood products used in the formulations contain growth and/or inflammatory mediators such as, for example, PDGF, IGFs, FGFs, TGFs, EGF, VEGF, HGF, IL-6, G-SCF and KGF as well as extracellular matrix proteins such as type I and type III collagens, fibronectin, terascin, glycosaminoglycans, versican, decorin and other secreted dermal matrix proteins, which may be useful in preventing or repairing skin defects. In addition peptides such as KTTKS and palmitoyl-KTTKS, which promote collagen synthesis, and argireline, a synthetic peptide that inhibits muscle-induced wrinkling of the skin, may also be added to the formulation. [055] The formulations may include one of more of the following general types of ingredients: • Emollients: for example plant oils, mineral oils, shea butter, cocoa butter, petrolatum , cholesterol, silicones or animal oils (including emu, mink and lanolin). These emollients contribute to softening and smoothing the skin while functioning to assist in moisture retention. In some embodiments, jojoba, squalene and lanolin are used because of their similarity to and are the least comedogenic (pore-clogging). • Humectants: for example sorbitol, glycols, glycerins and sodium PCA. Humectants

act to attract water to the skin and are desirable inclusions in the formulations for applications of the formulations to treat/prevent skin damaged by sun and dehydration. • Soothing agents and anti-irritants: for example bisabolol, allantoin, burdock root, aloe, licorice root, glycyrrhetinic acid, green tea and chamomile extract, may be added to the formulations. • Vitamins and antioxidants: for example vitamins A , B group (in particular vitamins B3, B5 and B9), C and E . • Alpha hydroxy acids (AHAs) and beta hydroxy acids (BHAs): these compounds are believed to be useful to clear pores and remove dead skin thereby promoting smoother, moister skin. Examples of useful AHAs formulations include glycolic acid and lactic acid, fruit or citrus acid, and sugarcane extracts. Examples of a useful BHA is salicylic acid. AHA increases sun sensitivity and so formulations containing AHA typically also include physical and/or chemical sunscreen agents. • Antioxidants: Suitable antioxidants include ascorbic acid, sodium sulfite, sodium metabisulfite, sodium bisulfite, sodium thiosulfite, sodium formaldehyde sulfoxylate, isoascorbic acid, thioglycerol, thiosorbitol, thiourea, thioglycolic acid, cysteine hydrochloride, 1,4-diazobicyclo-(2,2,2)-octane, butylated hydroxytoluene (BHT), ascorbyl palmitate, butylated hydroxyanisole, a-tocopherol, phenyl-a-naphthylamine, and mixtures thereof; and • Polysaccharides such as glucomannan or guar gum . [056] In one embodiment the formulation comprises hyaluronic acid (HA) or a salt thereof.

The HA or salt thereof may be present in an amount of 0 .1% to 10% by weight of the formulation. For example the For example the HA or salt thereof may be present in the formulation at about 0 .1%(w/w), about 0.5%(w/w), about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w) or about 10% (w/w). [057] The formulations are topically applied to a subject for example by rubbing, smearing or massaging into an area of skin.

[058] Assays commonly employed by those of skill in the art may be utilized to test the activity of the particular components, thereby ensuring that an acceptable level of biological activity (e.g. , a therapeutically effective amount) is retained. . Doses of such therapeutic factors are well known to those of skill in the art and may be found in pharmaceutical compendia such as the Physicians' Desk Reference, Medical Economics Data Publishers; Remington's Pharmaceutical Sciences, Mack Publishing Co. ; Goodman & Gilman, The Pharmacological Basis Of Therapeutics, McGraw Hill Publ. [059] The effective doses of any of the components described herein may routinely be determined using techniques well known to those of skill in the art. A "therapeutically effective" dose refers to that amount of the component sufficient to result in amelioration of at least one sign or symptom of skin defect.

[060] The formulations can have a pH of about 6 to about 9 , in some embodiments the pH is from 6.0 to 7.0. In other embodiments the pH can be , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 0 , 11,

12 , 13 , or 14 .

[061] In some embodiments the formulations have UVA and UVB absorption properties. In these embodiments, the formulations have a sun protection factor (SPF) of 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11, 12 , 13 , 14 , 15 , 20, 25, 30, 35, 40, 45, 50, 55, 60, or more, or any integer or derivative therein. The formulation may comprise any UVA and UVB absorbing compound known in the art. For example the formulation may comprise oxybenzone, avobenzone, octisalate, octocrylene, homosalate, octinoxate, zinc oxide titanium dioxide or any combination thereof. [062] The formulation is applied topically and can be prepared in the form of a hand or body cream, hair shampoo, under eye cream , bath gel or soap, shaving or after shaving lotion. These forms can be prepared using the formulations described herein in conjunction within methods known in the art. [063] The formulations can provide systemic delivery via a transdermal route of at least one component of the blood product. The component crosses the skin and enters the circulation (for example the blood or lymph) and is distributed substantially throughout the body (i.e. systemically). Accordingly, while the effect of the formulation will be observable at the site of administration (for example a portion of the skin) the effects will also be observable at sites distal to the site of administration due to the systemic delivery of one or more components of the blood product.

Liposomal base

[064] Any suitable liposomal base known in the art may be used in the formulations provided herein. Typically the liposomal base is an emulsion that includes a lipophilic component and an aqueous component that are emulsified such that the lipophilic component forms liposomes containing a portion of the aqueous component. [065] The liposomal base may take any form. For example the liposomal base may be a lotion, a cream , a gel or a paste. Preferably the liposomal base is a lotion or a cream. [066] One example of a commercially available liposomal base suitable for use in the formulations provided herein includes, but is not limited to, LIPODERM ™ cream or gel (a mixture of about 60-80% wt/wt water, with glycerin, C 12-1 5 alkyl benzoate, glyceryl stearate, dimethicone, cetearyl alcohol , cetearyl glucoside, polyacrylamide, cetyl alcohol, magnesium aluminum silicate, xanthan gum, aloe vera (aloe barbadensis), tocopheryl acetate (vitamin E acetate), prunus amygadalus amara (bitter almond) kernel oil, vitis vinifera (Grape) seed extract, triticum vulgare (wheat) germ oil, retinyl palmitate (vitamin A palmitate), ascorbyl palmitate (vitamin C palmitate), Pro-Lipo Multi-emulsion Liposomic System, tetrasodium EDTA, phenoxyethanol, sodium hydroxymethylglycinate). PCCA, Houston, Texas. [067] Other suitable liposomal bases include, but are not limited to, DEMI-GEL™ emulsion (which is a mixture of 4% lecithin isopropyl palmitate containing lecithin soya granular, isopropyl palmitate NF, sorbic acid NF). [068] Although use of commercially available liposomal bases, gels and diluents is convenient the formulations provided herein may be prepared with any suitable emulsion.

Blood products

[069] The formulations described herein contain a blood product. Typically the blood product is serum , plasma or platelet rich plasma (plasma lysate, autologous conditioned serum). However any blood product known in the art may be used in the formulations. [070] The source of the blood product may be umbilical cord blood or blood retrieved from a placenta from a normal or C-section childbirth delivery. Alternatively or in addition the source of the blood for the blood product blood donated to blood banks or from frozen cord blood units stored in public or family cord blood banks. The source of the blood for the blood product may be from the patient's own blood. [071 ] The blood product may be pooled from a number of donors. For example blood from individual donors may be typed, cross-matched or both and pooled according to type and or cross-matching characteristics before preparation of a blood product from the pooled samples. The blood may be pooled from adult donors or from umbilical cords or placentas. [072] The blood product may comprise fragments of regenerative cells or products from regenerative cells. The term regenerative cells refers to any one or combination (in any proportion) of mesenchymal stem cells, progenitor cells, hematopoietic stem and progenitor cells, monocytes, macrophages, keratinocytes, fibroblasts, and any other cell type, excluding embryonic stem cells, that produces or secretes growth factors, hormones, cytokines or regulatory factors. The fragments of regenerative cells or products thereof may naturally be present in the blood product or may be added from an exogenous source (for example from cultured cells). The regenerative cells may be selected from the group consisting of mesenchymal stem cells, endothelial progenitor cells, hematopoietic stem cells, monocytes, macrophages, keratinocytes and fibroblasts. When added from an exogenous source the regenerative cells may be used immediately or after being frozen for a time. In embodiments where regenerative cells are donated they may be used immediately or after being frozen for a time. [073] In some embodiments the blood product is lyophilised (also known as freeze drying or cryodesiccation) prior to incorporation into the formulation. Lyophilisation can be achieved by any means known in the art and typically includes four steps, pre-treatment, freezing, primary and secondary drying. The pre-treatment step may include concentrating the blood product, the addition of stability enhancers or preservatives or increasing the surface area of the blood product. [074] In the second step (freezing) the blood product is cooled to below its triple point (the lowest temperature at which the solid and liquid phases coexist) in order to ensure that sublimation occurs in the drying steps. In some embodiments the freezing step includes annealing in which the temperature is reportedly raised and lowered. In other embodiments freezing is done as rapidly as practical to lower the blood product to below its eutectic point quickly to avoid ice crystal formation. Usually, the freezing temperatures are between -30°C and -80°C. [075] During primary drying the pressure is lowered and enough heat is supplied to the blood product for the ice to sublime. The amount of heat necessary can be calculated by a skilled person with consideration of the blood products latent heat of sublimation. Pressure on the blood product is controlled through the application of partial vacuum . Application of a vacuum increases the rate of sublimation. In the primary drying phase about 90-95% of the water in the blood product is sublimated. [076] The secondary drying phase removes unfrozen water from the blood product and is dependent on the blood product's adsorption isotherms. The temperature is raised higher than in the primary drying phase, and can even be above 0°C in order to break physicochemical interactions between water molecules and frozen material in the blood product. In some embodiments the pressure on the blood product is further decreased to facilitate desorption of water. The residual water content of the blood product is around 1% to 5%, for example 0.5% , 1% , 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5% or about 5%.

[077] The blood product can be present in a formulation in an amount from about 1% to about 80% (w/w) or (v/w). For example the blood product can be present in a formulation in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11% , about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 19%, about 20%, about 2 1%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about

3 1% , about 32%, about 33%, about 34%, about 35%, about 36% , about 37%, about 38%, about 39%, about 40%, about 4 1% , about 42%, about 43%, about 44%, about 45%, about

46%, about 47%, about 48%, about 49%, about 50%, about 5 1%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about

6 1% , about 62%, about 63%, about 64%, about 65%, about 66% , about 67%, about 68%, about 69%, about 70%, about 7 1% , about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80%. [078] The blood product may contain one or more components such as metabolites, am ino acids, proteins, growth factors, hormones, trace elements, vitamins and minerals. [079] For example the blood product component may be selected from acetoacetate, acetone, acetylcholine, adenosine triphosphate, adrenocorticotrophic hormone, alanine, albumin, aluminum , aldosterone, amino acids, alpha-aminobutyric acid, d-aminolevulinic acid, ammonia nitrogen, cAMP, androstenedione, androsterone, angiotensin I, angiotensin

II, alpha 1-antitrypsin, arginine, arsenic, ascorbic acid (vitamin C), aspartic acid, aspartic acid (in WBCs), bicarbonate, bile acids, bilirubin, biotin (vitamin H), bradykinin, bromide, cadmium, calciferol (vitamin D2), calcitonin (CT), calcium, carbon dioxide, carboxyhemoglobin (as HbCO), carcinoembryonic antigen, beta-carotene, carotenoids, cephalin, ceruloplasmin, cholecalciferol (vitamin D3), cholecystokinin (pancreozymin), cholesterol, choline, chorionic gonadotropin, citric acid, citrulline, coagulation factors (such as fibrinogen, prothrombin, tissue thromboplastin, proaccelerin, proconvertin, antihemophilic factor, Christmas factor, stuart factor, plasma thromboplastin antecedent (zymogen form of factor XI), Hageman factor, fibrin-stabilizing factor, fibrin split products, Fletcher factor,

Fitzgerald factor and von Willebrand factor), cobalamin (vitamin B 12), Cocarboxylase, complement system (including C 1q , C 1r, C 1s , C2, C3, factor B (C3 proactivator), C4 (b1 E- globulin), C4 binding protein, C5 (b1 F-globulin), C6, C7, C8, C9 and properdin), compound S, copper, corticosteroids, corticosterone, Cortisol, c-peptide, c-reactive protein, creatine, creatinine, cysteine, dehydroepiandrosterone (DHEA), DHEA sulfate, DHEA sulfate, 11- deoxycortisol, dihydrotestosterone (DHT), diphosphoglycerate (phosphate), DNA, dopam ine, enzymes, epidermal growth factor (EGF), epinephrine, ergothioneine, erythrocytes and fragments thereof, erythropoietin, estradiol (E2), estriol (E3), estrogen, estrone (E1 ), fat, free fatty acids, fatty acids, ferritin, alpha-1 -fetoprotein, flavin adenine dinucleotide, fluoride, folate, folic acid, fructose, furosemide glucuronide, galactose, gastric inhibitory peptide (GIP), gastrin, globulin, alpha-1 -globulin, alpha-2-globulin, beta globulin, gamma globulin, glucagon, glucosamine, glucose, glucuronic acid, glutamic acid, glutamine, glutathione, reduced, glycerol, glycine, glycogen, glycoprotein, cgmp, gonadotropin- releasing hormone, guanidine, haptoglobin, hemoglobin, hexosephosphate p, histam ine, histidine, beta-hydroxybutyric acid, 17-hydroxycorticosteroids, 17-hydroxyprogesterone, antibodies (including immunoglobulin A , immunoglobulin D, ilmmunoglobulin G , immunoglobulin M and immunoglobulin E), indican, inositol, insulin, insulin-like growth factor, iodine, iron, isoleucine, ketone bodies, alpha-ketonic acids, lactate, lecithin, leptin, leucine, leukocytes and fragments thereof (including neutrophil granulocytes, neutrophils, eosinophil granulocytes, eosinophils, basophil granulocytes, basophils, lymphocytes, monocytes and phagocytes), lipase p, lipids, lipoproteins, lithium , lysine, lysozyme (muramidase), alpha 2-macroglobulin, magnesium , malic acid, manganese, melatonin, methemoglobin, methionine, methyl guanidine, beta-2-microglobulin, MIP-1 a , MIP-1 b, mucopolysaccharides, mucoproteins, nerve growth factor (NGF), niacin, norepinephrine, nucleotides, ornithine, oxalate, oxytocin, pancreatic polypeptide, pantothenic acid (vitamin B5), para-aminobenzoic acid, parathyroid hormone (PTH), pentose, phenylalanine, phospholipid, phosphatase, phosphorus, phytanic acid, platelets or fragments thereof, platelet-derived growth factor, polysaccharides, potassium, pregnenolone, progesterone, proinsulin, prolactin, proline, prostaglandin, protein, protoporphyrin, prostate specific antigen, pseudoglobulin I, pseudoglobulin ii, purine, pyrimidine nucleotides, pyridoxine (vitamin B6), pyruvic acid, RANTES, relaxin, retinol (vitamin A), riboflavin (vitamin B2), RNA, secretin, serine, serotonin (5-hydroxytryptamine), silicon, sodium , somatotropin (growth hormone), sphingomyelin, succinic acid, sulfates, sulfur, taurine, testosterone, thiamine, thiocyanate, threonine, thyroglobulin (Tg), thyroid hormones, thyrotropin-releasing hormone, thyroxine (FT4), thyroxine-binding prealbumin, thyroxine-binding globulin, tin, alpha-tocopherol (vitamin e), transcortin, transferrin, triglycerides, triiodothyronine, tryptophan, tyrosine, urea, uric acid, valine, vasointestinal peptide (vip), vasopressin, zinc and any combination thereof. [080] The blood product component may be a growth factor, cytokine, chemokine, hormone, vitamin, or cell fragment. [081 ] The growth factor may be selected from the group consisting of endothelial growth factor (EGF), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF), transforming growth factor alpha (TGF-a), TGF- β Ι , TGF-P2, TGF^3, platelet-derived growth factor (PDGF)-AA, PDGF-AB, PDGF-BB, insulin-like growth factor-1 (IGF-1 ) , BMP, BDNF, EGF, HGF.PDGF, FGF, PGF, GDF-8, NGF, Epo, TPO, TCGF, IGF-I, IGF-I I, KGF, VEGF, and any combination thereof. [082] The cytokines may be pro-inflammatory or anti-inflammatory. [083] The proinflammatory cytokine may be for example granulocyte-macrophage colony- stimulating factor (GM-CSF), interleukin (IL)-1 a , IL-1 , IL-2, IL-2R, IL-3, , IL-6, IL-7, IL-8, IL-

9 , IL-1 0 , IL-1 1, IL-1 2 , IL-1 2p40/p70, IL-1 3 , IL-1 4 , IL-1 5 , IL-1 7 , tumour necrosis factor

(TNF)a, TNF- β, interferon (IFN)-a, INF- β, INF-y or any combination thereof.

[084] The anti-inflammatory cytokine may be for example IL-1 RA, IL-4, IL-5, IL-1 0 , IL-1 3 , IFNa or any com bination thereof. [085] The chemokine may be eotaxin, protein 10 (IP-1 0), monocyte chemoattractant protein-1 (MCP-1 ), IFNy-induced monokine, macrophage inflammatory protein (MI P)-1 a ,

ΜΙΡ - 1 , RANTES or any combination thereof. [086] The cytokines may be isolated from the blood product. For example the cytokine [087] In some embodiments the cytokines are freeze dried or lyophilised. These methods are well known in the art and are commonly used to preserve the function of temperature sensitive products, such as enzymes and blood products like cytokines. [088] The hormone may be selected from the group consisting of an amino acid hormone, eicosanoid hormone, a peptide hormone and a steroid hormone. [089] The amino acid hormone may be selected from the group consisting of epinephrine, melatonin, triiodothyronine and thyroxine. [090] The eicosanoid hormone may be selected from the group consisting of prostaglandins, leukotrienes, prostacyclin and thromboxane. [091 ] The peptide hormone may be selected from the group consisting of amylin, anti- mullerian hormone, adiponectin, angiotensinogen, angiotensin, vasopressin, atrial natriuretic peptide, brain natriuretic peptide, calcitonin, cholecystokin, corticotropin-releasing hormone, cortistatin, encephalin, endothelin, erythropoietin, galanin, gastric inhibitory peptide, gastrin, ghrelin, glucagon, glucagon-like-peptide-1 , gonadotropin-releasing hormone, growth hormone-releasing hormone, hepcidin, human chorionic gonadotropin, human placental lactogen, human growth hormone, inhibin, insulin, insulin-like growth factor, leptin, lipotropin, melanocyte stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, parathyroid hormone, pituitary adenylate cyclase-activating peptide, prolactin, prolactin releasing hormone, relaxin, renin, secretin, somatostatin, thrombopoietin, thyroid-stimulating hormone and vasoactive intestinal peptide. [092] The steroid hormone may be selected from the group consisting of testosterone, dehydroepiandrosterone, androstenedione, dihydrotestosterone, aldosterone, estradiol, estrone, estriol, Cortisol, progesterone, calcitriol and calcidiol.

[093] In some embodiments, each component may be present in an amount from about

0 .1- 1000 pg/ml, about 1- 1000 pg/ml, about 50-1 000 pg/ml, about 100-1 000 pg/ml, about 200-1 000 pg/ml, about 300-1 000 pg/ml, about 400-1 000 pg/ml, about 500-1 000 pg/ml, about 600-1 000 pg/ml, about 700-1 000 pg/ml, about 800-1 000 pg/ml, about 900-1 000 pg/ml, about 1 - 100 ng/ml, about 10-1 00 ng/ml, about 10-1 00 ng/ml, about 20-1 00 ng/ml, about 30-1 00 ng/ml, about 40-1 00 ng/ml, about 50-1 00 ng/ml, about 60-1 00 ng/ml, about 170-1 00 ng/ml, about 80-1 00 ng/ml, about 90-1 00 ng/ml, or at least about 100 ng/ml.

Transdermal carriers and enhancers

[094] The formulation comprises a transdermal carrier facilitates passage of the component of the plasma or serum through the skin. Preferably, the transdermal carrier facilitates passage of the component of the plasma or serum through the skin and into the circulation to so that the component is administered systemically. [095] It is to be understood that any suitable transdermal carrier or solvent which facilitates transdermal absorption of the component may be used. Examples of suitable transdermal carriers include carriers such as isopropyl alcohol, dipropylene glycol methyl- ether, butylated hydroxytoluene dipropylene glycol monomethyl-ether, 1-methoxy 2- propanol (glysolv PM/lcinol PM), Ethylene glycol monobutylether (butyl glyxolv/butyl icinol), Butyl di glysolv (butyl-icinol), Transcutol, propylene glycol (PG), N-methyl-2 pyrrolidone (NMP), methylene chloride, diethyl ether, ethanol, acetonitrile, ethyl acetate, benzyl alcohol, a combination of natural oil; ethylene glycol, propylene glycol, dimethyl polysiloxane (DMPX), oleic acid, caprylic acid, 1-octanol, ethanol (denatured or anhydrous), liposomal compositions, suitable plant oils, such as Aloe vera derivatives or sesame seed oil or derivatives thereof, acrylic polymers, rubber-based polymers, polysiloxane-based polymers, polyvinylpyrrolidone-based polymers, dimethylsulfoxide (DMSO), dimethylformamide (DMF), lecithin, Transfersomes® (IDEA AG). Transfersomes® are artificial vesicles designed to mimic a cell vesicle and deliver component into a cell. The bounding membrane of a Transfersomes® is more flexible than that of a liposome, allowing it to deform and pass through openings in a barrier, such as the skin, whose diameters are much smaller than the average vesicle size. A Transfersome® is a bi-component, most often vesicular, aggregate. The main functional characteristic of the aggregate is the extreme flexibility and permeability of its bilayer-like membrane coating. Its basis is the interdependency of local membrane shape and composition, which makes the bilayer self- regulating and self-optimising. The bilayer is thus capable of stress adaptation, via local and reversible bilayer component demixing. [096] Additional transdermal carriers include, but are not limited to, ethosomes, azone, castor oil derivatives, such as ethoxylated castor oil, jojoba oil derivatives, corn oil derivatives, emu oil derivatives, or any other suitable transdermal or transcutaneous carrier or carrier composition. [097] In an embodiment the transdermal carrier is propylene glycol, DMSO, or alcohol.

[098] The transdermal carrier is typically used in an amount of about 1% (w/w) to about 35% (w/w). For example the amount of enhancer used may be about 1% (w/w), or about 2% (w/w), or about 3% (w/w), or about 4% (w/w), or about 5% (w/w), or about 6% (w/w), or about 7% (w/w), or about 8% (w/w), or about 9% (w/w), or about 10% (w/w), or about 11% (w/w), or about 12% (w/w), or about 13% (w/w), or about 14% (w/w), or about 15% (w/w), or about 16% (w/w), or about 17% (w/w), or about 18% (w/w), or about 19% (w/w), or about

20% (w/w), or about 2 1% (w/w), or about 22% (w/w), or about 23% (w/w), or about 24% (w/w), or about 25% (w/w), or about 26% (w/w), or about 27% (w/w), or about 28% (w/w), or about 29% (w/w), or about 30% (w/w) or about 29% (w/w), or about 30% (w/w),or about

3 1% (w/w), or about 32% (w/w), or about 33% (w/w), or about 34% (w/w), or about 35% (w/w), or about 36% (w/w), or about 37% (w/w), or about 38% (w/w), or about 39% (w/w), or about 40% (w/w), or about 4 1% (w/w), or about 42% (w/w), or about 43% (w/w), or about 44% (w/w), or about 45% (w/w), or about 46% (w/w), or about 47% (w/w), or about 48% (w/w), or about 49% (w/w), or about 50% (w/w). [099] In certain embodiments a transdermal enhancer is incorporated into the formulation. The term "transdermal enhancer" as used herein refers to substances used to increase permeability and/or accelerate the delivery of a component of a blood product through the skin. Enhancers include monohydric alcohols such as ethyl, isopropyl, butyl and benzyl alcohols; or dihydric alcohols such as ethylene glycol, diethylene glycol, or propylene glycol dipropylene glycol and trimethylene glycol; or polyhydric alcohols such as glycerin, sorbitol and polyethylene glycol, which enhance drug solubility; polyethylene glycol ethers of aliphatic alcohols (such as cetyl, lauryl, oleyl and stearyl) including polyoxyethylene-4-lauryl ether, polyoxyethylene-2-oleyl ether and polyoxyethylene-1 0-oleyl ether; vegetable, animal and fish fats and oils such as cotton seed, corn, safflower, olive and castor oils, squalene, and lanolin; fatty acid esters such as propyl oleate, decyl oleate, isopropyl palmitate, glycol palmitate, glycol laurate, dodecyl myristate, isopropyl myristate and glycol stearate which enhance drug diffusibility; fatty acid alcohols such as oleyl alcohol and its derivatives; fatty acid amides such as oleamide and its derivatives; urea and urea derivatives such as allantoin which affect the ability of keratin to retain moisture; polar solvents such as dimethyldecylphosphoxide, methyloctylsulfoxide, dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide and dimethylformamide; salicylic acid; benzyl nicotinate; or higher molecular weight aliphatic surfactants such as lauryl sulfate salts, esters of sorbitol and sorbitol anhydride such as polysorbate. Other suitable enhancers include oleic and linoleic acids, triacetin, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopherol acetate, tocopheryl linoleate. [01 00] Other suitable transdermal enhancers include alcohols, amino acids, Azone® Azone-like compounds, so called soft penetration enhancers, sulphoxides, essential oils, fatty acids and fatty acid esters, macrophilic compounds, phospholipids and phospholipid derivatives and 2-pyrolidone derivatives.

[01 0 1] In some embodiments enhancers are incorporated into the formulation in an amount typically up to about 30%. For example the amount of enhancer used may be about 0.05% (w/w), or about 0 .1% (w/w), or about 0.5% (w/w), or about 1% (w/w), or about 2% (w/w), or about 3% (w/w), or about 4% (w/w), or about 5% (w/w), or about 6% (w/w), or about 7% (w/w), or about 8% (w/w), or about 9% (w/w), or about 10% (w/w), or about 11% (w/w), or about 12% (w/w), or about 13% (w/w), or about 14% (w/w), or about 15% (w/w), or about 16% (w/w), or about 17% (w/w), or about 18% (w/w), or about 19% (w/w), or about

20% (w/w), or about 2 1% (w/w), or about 22% (w/w), or about 23% (w/w), or about 24% (w/w), or about 25% (w/w), or about 26% (w/w), or about 27% (w/w), or about 28% (w/w), or about 29% (w/w), or about 30% (w/w).

Preparation of the Formulation

[01 02] In general the formulations are prepared by adding each of the components to the liposomal base and mixing to homogeneity. For example the blood product and transdermal enhancer, and any other optional components such as transdermal enhancers, exogenous cellular extracts, growth factors, hormones, metabolites, or peptides. [01 03] In some embodiments the blood product may be concentrated for example by evaporation, ultrafiltration, cross flow filtration or the like before addition to the liposomal base. In other embodiments the blood product may be fractionated for example by chromatography or precipitation of desired components using for example ammonium chloride to select for and/or concentrate desirable components. The concentration process results in an increased concentration of components such as cytokines, growth factors and chemokines in the blood product that forms part of the formulation. As a result of the concentration the blood products and hence the formulations, comprise supra-physiological levels of the components. [01 04] During preparation of the formulation at least a portion of the blood product and the transdermal carrier is incorporated into the liposomes of the liposomal base such that at least some of the liposomes contain at least a portion of the blood product and the transdermal carrier. [01 05] In embodiments where the formulations comprise a transdermal enhancer, a portion of the enhancer may also be present inside the liposome. [01 06] In some embodiments the skin care formulation for transdermal administration of a component of a blood product comprises a blood product and a transdermal carrier, wherein the skin care formulation is present in an oral dosage form selected from the group consisting on of a sublingual troche, tablet, wafer or lozenge. In some embodiments the dosage form is a buccal troche, tablet, wafer, lozenge or orally disintegrating tablet.

[01 07] In some embodiments the oral dosage form is solid at room temperature. Preferably the oral dosage form at least partially dissolves at body temperature within the mouth of a user.

[01 08] The oral dosage form (e.g. sublingual troche) troche can be prepared using any method known in the art. For example the sublingual troche may be prepared by combining low molecular weight polyethylene glycol (for example with molecular weights of 1300 to 1650 g/mol) with gum acacia, citric acid, a sweetener such as stevia extract powder, and a flavoring such as peppermint oil with the blood product. Preferably the blood product is lyophilized. For example the blood product can be freeze dried plasma from typed and/or cross matched donors.

[01 09] In some embodiments the oral dosage form further comprises a transdermal enhancer.

Methods

[01 10] The formulations and dosage forms described herein can be used to treat, prevent or ameliorate at least one symptom or sign of a skin defect, for example by facilitation the transdermal delivery of a blood product. The methods typically comprise topical administration of the formulation to at least a portion of the skin of a subject having a skin defect in an amount sufficient to treat, prevent or ameliorate at least one symptom or sign the skin defect. In some embodiments the methods comprise administration of a component of a blood product using an oral dosage form selected from a sublingual troche, tablet, wafer or lozenge. In some embodiments the oral dosage form is a buccal troche, tablet, wafer, lozenge or orally disintegrating tablet. [01 11] In other embodiments the formulation is adm inistered to the nasal mucosa for example using a nasal applicator.

[01 12] There is also provided a method of improving the quality of hair. In this embodiment the method includes the step of topically applying the formulation to an area of skin, for example, on the head, that has thinning hair or where hair is absent. It is believed that the blood products in the formulations contain components that assist in the reversal of hair follicle deterioration and are thereby useful in improving the quality of hair. [01 13] The formulations may also include extracts from natural mediums such as placenta extracts, extracts from Wharton's jelly, or amniotic fluids or components extracted from these tissues, or cord blood plasma, cord blood serum or components derived from them . [01 14] The formulation is preferably applied more than once. For example the formulation may be applied daily, twice daily, three times or more than three times daily. Application of the formula may be continued until the skin defect is resolved or prevented or until at least one symptom or sign of the skin defect is ameliorated. For example the formulation may be applied over a period of one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, twelve weeks or longer. [01 15] In some embodiments application of the formulation provides positive effects on skin defects and in some cases assists in the repair of the skin defects. Application of the formulation may have a soothing effect. [01 16] Application of the formulation may also prevent or reduce scar formation. For example the formulation may interfere with scar forming proteolytic enzymes (such as tryptase and chymase) or stimulate the inhibition of leucocytic elastatse to block mast cell activity.

[01 17] Formulations for reducing or preventing scar formation may additionally contain hyaluronic acid (HA) or a salt thereof.

[01 18] Application of the formulation can also enhance the functional capacity of skin, enhance secretion of growth factors in the skin, enhance circulation to enhance skin regeneration, viability and/or elasticity. The formulations may also improve moisture uptake and retention in the skin by protecting against hypertonic and hypotonic stress, desiccation and dehydration, providing a barrier to inhibit tissue and moisture loss, progressively hydrating the different layers of the skin and softening hard tissue.

[01 19] Application of the formulation may enhance repair and reconstruction of the extracellular matrix and normal skin architecture, mitogenic activity, procollagen production, collagen production.

[01 20] It is known that Young's modulus of the skin increases linearly with age. Young's modulus (or the elastic modulus) is a measure of stiffness and defines the relationship between stress (force per unit area) and strain (proportional deformation) in a material. Specifically, Young's modulus is the ratio of stress (pressure) to strain (which is dimensionless). Accordingly, Young's modulus has units of pressure, i.e. pascals or N/m2 or kg rrf s 2). A high Young's modulus indicates that the material is inelastic and a low Young's modulus indicates that the material is elastic. For example rubber has an approximate Young's modulus of 0.01 -0. 1 MPa and concrete has an approximate Young's modulus of 30 GPa. Human skin has a Young's modulus of between 0.42 MPa and 0.85 MPa.

[01 2 1] Young's modulus of skin can be measured by any method known in the art including Optical Coherence Elastography (OCE), mechanical stretching and suction tests. [01 22] Application of the formulations described herein results in a reduction of Young's modulus. For example application of the treatment can result in a reduction of the Young's modulus by up to about 50% compared to the skin before treatment. For example the reduction may be about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% or about 50%.

[01 23] Application of the formulation also reduces the number of visible fine lines and wrinkles. For example the number of visible fine lines may be reduced at least 50% compared to the skin before treatment. The reduction may be about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40% , about 45% or at least about 50%. Similarly the number of wrinkles may be reduced by at least 50% compared to the skin before treatment. The reduction may be about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% or at least 50%.

Skin defects

[01 24] The formulation are useful to treat, prevent or ameliorate at least one symptom or sign of a skin defect. [01 25] The skin defect may be a scar, a cosmetic skin defect, a traumatic skin defect, a chronic defect, a scar resulting from non-surgical/accidental trauma, a scar resulting from surgical trauma, a scar resulting from a chronic disease state, a scar resulting from topical irritation, depleted collagen levels, depleted elastin levels, depleted adhesive plaques at the dermal/epidermal junction, damage caused by age-related skin deterioration, collagen mis¬ alignment, scarring, scar formation, stretch marks, keloids, diabetic neuropathies, hardened-cracked skin, hardened cracked heel tissue, fine lines, wrinkles, or skin sagging. [01 26] The skin defect may also be poor skin texture, wrinkles, UV induced skin damage, skin aging, dry skin, dermatitis, eczema, rash, pruritus, sun burn, burns, stretch marks, acne scars, surgical scars. [01 27] In other embodiments the skin defect may be hair follicle deterioration or alopecia,

Kits

[01 28] In one embodiment, a kit is provided including a formulation as described herein; a container; a label; and instructions which provide methods of applying the formulation. The instructions may be a pamphlet, CD, or other computer readable medium . Further, the instructions may provide information about a website which may contain downloadable content.

[01 29] It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

[01 30] In order that the present invention may be more clearly understood, preferred embodiments will be described with reference to the following drawings and examples.

Example 1 - plasma formulation

[01 3 1] Exemplary Plasma Formulation

Human plasma or plasma lysate: 10 ml

Propylene Glycol 10 g

Liposomal base PCCA Lipoderm ® q.s. 80 gm

Example 2 - serum formulation

[01 32] Exemplary Serum Formulation

Human serum 10 ml

Propylene Glycol 10 gm

Liposomal base PCCA Lipoderm ® q.s. 80 gm

Example 3 - PRP formulation

[01 33] Exemplary Serum Formulation

Human PRP (platelet rich plasma) 10 m l

Propylene Glycol 10 gm

Liposomal base PCCA Lipoderm ® q.s. 80 gm

Example 4 - ACS formulation

[01 34] Exemplary Serum Formulation

Human Autologous conditioned serum 10 ml

Propylene Glycol 10 gm Liposomal base PCCA Lipoderm ® q.s. 80 gm

Example 5 - Manufacturing Method

[01 35] Each of the formulations is prepared using the following general procedure

Weigh Lipoderm (gel or cream) in a suitable container.

Transfer blood product (serum , plasma, PRP, ACS etc) under aseptic conditions to the Lidoderm .

Add additives such as hyaluronic acid, vitamins, antioxidants, transdermal carriers or enhancers.

Mix components with gentle agitation.

Seal the container and allow air to diffuse out of the gel.

Fill into appropriate tub or airless container.

Check pH.

[01 36] Typically the formulation will have a pH from 6.0 to 7.0.

Example 6 - Skin Rejuvenation

[01 37] Subjects of good general health and with visible fine or deep wrinkles in the face, were chosen. Subjects with a history of, or active, skin disease were excluded. Subjects were asked to stop their current regime of skin care products. Make-up and sunscreens were permitted.

Treatment Regimen

[01 38] The plasma formulation of Example 1 was applied in mornings and evenings to the facial skin for 6 weeks. A treatment group of 5 subjects were asked to document each application of the formulation. A second group was asked to apply a placebo comprising only the lipodermal base (PCCA Lipoderm ®) according to the same treatment regimen.

Results

[01 39] Subjects were evaluated by a visual assessment of skin quality prior to commencement of the treatment and again after the treatment was complete. Compared to the baseline observations all subjects in the treatment group had significant improvement in texture with the skin feeling firmer and more elastic. There was also a reduction in the number of visible fine lines and wrinkles. In comparison all subjects in the placebo group had no change in skin texture or in the number of visible fine lines and wrinkles compared to baseline observations. [01 40] The num ber of visible fine lines were reduced by 30% compared to the skin before treatment. Similarly the number of visible wrinkles were reduced by 30% compared to the skin before treatment.

[01 4 1] All subjects liked the way the formulation felt and indicated that they would continue its regular use after the study period.

[01 42] It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the technology as shown in the specific embodiments without departing from the spirit or scope of technology as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. Claims:

1. A skin care formulation for transdermal administration of a component of a blood product, the formulation comprising:

a blood product;

a transdermal carrier; and

a liposomal base;

wherein at least a portion of the blood product and transdermal carrier is contained within liposomes of the liposomal base.

2 . The formulation of claim 1 in a nasal dosage form or an oral dosage form selected from the group consisting on of a sublingual troche, tablet, wafer, lozenge, buccal troche, tablet, wafer, lozenge, and orally disintegrating tablet.

3 . The formulation of claim 1or 2 wherein the blood product is selected from the group consisting of plasma, serum, platelet rich plasma, conditioned plasma and combinations thereof . 4 . The formulation of claim 3 wherein the blood product is a human blood product.

5 . The formulation of any one of claims 1 to 4 wherein the blood product comprises regenerative cells or fragments thereof.

6 . The formulation of any one of claims 1 to 5 wherein the blood product is present in an amount of 1% , 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1% , 12%, 13%, 14%, 15%, 16%, 17%, 19%, 20%, 2 1% , 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%,

30%, 3 1% , 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 4 1% , 42%, 43%,

44%, 45%, 46%, 47%, 48%, 49%, 50%, 5 1% , 52%, 53%, 54%, 55%, 56%, 57%,

58%, 59%, 60%, 6 1% , 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 7 1% , 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80%.

7 . The formulation of any one of claims 1 to 6 wherein the blood product includes a component selected from the group consisting of growth factor, cytokine, hormone, vitamin, cell, cell fragment, and combination thereof.

8 . The formulation of claim 7 wherein the growth factor is selected from the group consisting of endothelial growth factor (EGF), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF), transforming growth factor alpha (TGF- a), TGF- βΙ , TGF-p2, TGF-p3, platelet-derived growth factor (PDGF)-AA, PDGF-AB,

PDGF-BB, insulin-like growth factor-1 (IGF-1 ), BMP, BDNF, EGF, HGF.PDGF, FGF, PGF, GDF-8, NGF, Epo, TPO, TCGF, IGF-I , IGF-I I, KGF, VEGF, and any combination thereof. 9 . The formulation of claim 7 wherein the cytokine is selected from the group consisting of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1 a ,

IL-1 (3, IL-2, IL-2R, IL-3, IL-6, IL-7, IL-8, IL-9, IL-1 0 , IL-1 1, IL-1 2 , IL-1 2 , p40/p70, IL-

13 , IL-1 4 , IL-1 5 , IL-1 7 , tumour necrosis factor (TNF)a, TNF-β, interferon ( IFN)-a,

INF- β, INF-Y, IL-1 RA, IL-4, IL-5, IL-1 0 , IL-1 3 , IFNa, and any combination thereof. 10 . The formulation of claim 7 wherein the hormone is selected from the group consisting of epinephrine, melatonin, triiodothyronine, thyroxine, prostaglandin, leukotriene, prostacyclin, thromboxane, amylin, anti-mullerian hormone, adiponectin, angiotensinogen, angiotensin, vasopressin, atrial natriuretic peptide, brain natriuretic peptide, calcitonin, cholecystokin, corticotropin-releasing hormone, cortistatin, encephalin, endothelin, erythropoietin, galanin, gastric inhibitory peptide, gastrin, ghrelin, glucagon, glucagon-like-peptide-1 , Gonadotropin-releasing hormone, Growth hormone-releasing hormone, hepcidin, human chorionic gonadotropin, human placental lactogen, human growth hormone, Inhibin, Insulin, Insulin-like growth factor, leptin, lipotropin, melanocyte stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, parathyroid hormone, pituitary adenylate cyclase- activating peptide, prolactin, prolactin releasing hormone, relaxin, renin, secretin, somatostatin, thrombopoietin, thyroid-stimulating hormone, vasoactive intestinal peptide, testosterone, dehydroepiandrosterone, androstenedione, dihydrotestosterone, aldosterone, estradiol, estrone, estriol, Cortisol, progesterone, calcitriol, calcidiol, and any combination thereof.

11. The formulation of any one of claims 7 to 10 wherein the component is present in an

amount from about 0.1 - 1000 pg/ml, about 1- 1000 pg/ml, about 50-1 000 pg/ml, about 100-1 000 pg/ml, about 200-1 000 pg/ml, about 300-1 000 pg/ml, about 400-1 000 pg/ml, about 500-1 000 pg/ml, about 600-1 000 pg/ml, about 700-1 000 pg/mL, about

800-1 000 pg/mL, about 900-1 000 pg/mL, about 1 - 100 ng/ml, about 10-1 00 ng/ml, about 10-1 00 ng/ml, about 20-1 00 ng/ml, about 30-1 00 ng/ml, about 40-1 00 ng/ml, about 50-1 00 ng/ml, about 60-1 00 ng/ml, about 170-1 00 ng/ml, about 80-1 00 ng/ml, about 90-1 00 ng/ml, or at least about 100 ng/ml. 12 . The formulation of any one of claims 1 to 11 wherein the blood product is lyophilized or freeze-dried. 13 . The formulation of any one of claims 1 to 12 wherein the transdermal carrier is selected from the group consisting of isopropyl alcohol, dipropylene glycol methyl- ether, butylated hydroxytoluene dipropylene glycol monomethyl-ether, 1-methoxy 2- propanol (glysolv PM/lcinol PM), Ethylene glycol monobutylether (butyl glyxolv/butyl icinol), Butyl di glysolv (butyl-icinol), Transcutol, propylene glycol (PG), N-methyl-2 pyrrolidone (NMP), methylene chloride, diethyl ether, ethanol, acetonitrile, ethyl acetate, benzyl alcohol, a combination of natural oil; ethylene glycol, propylene glycol, dimethyl polysiloxane (DMPX), oleic acid, caprylic acid, 1-octanol, ethanol (denatured or anhydrous), liposomal compositions, suitable plant oils, such as Aloe vera derivatives or sesame seed oil or derivatives thereof, acrylic polymers, rubber- based polymers, polysiloxane-based polymers, polyvinylpyrrolidone-based polymers, dimethylsulfoxide (DMSO), dimethylformamide (DMF), lecithin, vesicular aggregates, ethosomes, azone, castor oil derivatives, such as ethoxylated castor oil, jojoba oil derivatives, corn oil derivatives, propylene glycol, and emu oil derivatives. 14 . The formulation of any one of claims 1 to 13 wherein the transdermal carrier s present in an of 1% (w/w) 2% (w/w), 3% (w/w), 4% (w/w), 5% (w/w), or 6%, 7% (w/w), 8% (w/w), 9% (w/w), 10% (w/w), 11% (w/w), 12% (w/w), 13% (w/w), 14% (w/w), 15% (w/w), 16% (w/w), 17% (w/w), 18% (w/w), 19% (w/w), 20% (w/w), 2 1% (w/w), 22% (w/w), 23% (w/w), 24% (w/w), 25% (w/w), 26% (w/w), 27% (w/w), 28%

(w/w), 29% (w/w), 30% (w/w), 29% (w/w), 30% (w/w), 3 1% (w/w), 32% (w/w), 33% (w/w), 34% (w/w), 35% (w/w), 36% (w/w), 37% (w/w), 38% (w/w), 39% (w/w), 40% (w/w), 4 1% (w/w), 42% (w/w), 43% (w/w), 44% (w/w), 45% (w/w), 46% (w/w), 47% (w/w), 48% (w/w), 49% (w/w), or 50% (w/w). 15 . The formulation of any one of claims 1 to 14 wherein the liposomal base is an emulsion that includes a lipophilic component and an aqueous component. 16 . The formulation of claim 15 wherein the liposomal base is a mixture of about 60-

80% wt/wt water, glycerin, C 12-1 5 alkyl benzoate, glyceryl stearate, dimethicone, cetearyl alcohol, cetearyl glucoside, polyacrylam ide, cetyl alcohol, magnesium aluminum silicate, xanthan gum , aloe vera, tocopheryl acetate, prunus amygadalus amara kernel oil, vitis vinifera seed extract, triticum vulgare germ oil , retinyl palmitate, ascorbyl palmitate, Pro-Lipo Multi-emulsion Liposomic System , tetrasodium EDTA, phenoxyethanol, and sodium hydroxymethylglycinate. 17 . The formulation of any one of claims 1 to 16 further comprising a transdermal enhancer. 18 . The formulation of claim 17 wherein the transdermal enhancer is selected from the group consisting of ethyl alcohol , isopropyl alcohol, butyl alcohol, benzyl alcohol, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol trimethylene glycol, glycerin, sorbitol, polyethylene glycol, polyoxyethylene-4-lauryl ether, polyoxyethylene-2-oleyl ether, polyoxyethylene-1 0-oleyl ether, cotton seed oil, corn oil, safflower oil, olive oil, castor oil, squalene, lanolin; propyl oleate, decyl oleate, isopropyl palmitate, glycol palmitate, glycol laurate, dodecyl myristate, isopropyl myristate, glycol stearate, oleyl alcohol, oleamide, dimethyldecylphosphoxide, methyloctylsulfoxide, dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide, dimethylformamide; salicylic acid; benzyl nicotinate; lauryl sulfate, sorbitol, polysorbate, linoleic acid, triacetin, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopherol acetate, and tocopheryl linoleate. 19 . The formulation of any one of claims 1 to 18 comprising:

1 to 80% (v/w) of the blood product;

1% to 50% (w/w) of the transdermal carrier; and

up to 80% (w/w) of the liposomal base.

20. The formulation of claim 18 wherein the blood product is human plasma or plasma lysate, human serum, human PRP (platelet rich plasma), or human autologous conditioned serum; and the transdermal carrier is propylene glycol.

2 1. A method of treating, preventing or ameliorating a symptom or sign of a skin defect, the method comprising adm inistering to the skin of a subject in need thereof a formulation of any one of claims 1 to 19 in an amount sufficient to treat, prevent or ameliorate a sym ptom or sign of the skin defect. 22. The method of claim 20 wherein the formulation is administered at least once per day.

23. The method of claim 20 or 2 1 wherein the skin defect is selected from the group consisting of poor skin texture, wrinkles, fine lines, UV induced skin damage, skin aging, dry skin, hair follicle deterioration, alopecia, dermatitis, eczema, rash, pruritus, sun burn, burns, stretch marks, acne scars, and surgical scars. 24. The method of claim 22 wherein the skin defect is wrinkles or fine lines and the treatment reduces the number of wrinkles or fine lines by up to 5%, 10%, 20%, 30%, 40% or at least 50% compared to the number of wrinkles or fine lines before treatment. INTERNATIONAL SEARCH REPORT International application No. PCT/AU2017/000124

A. CLASSIFICATION OF SUBJECT MATTER A61K 8/14 (2006.01) A61K 9/127 (2006.01) A61K 35/14 (2015.01) A61K 35/16 (2015.01) A61K 35/17 (2015.01)

According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols) IPC- A61K 8/14, A61 9/127; CPC- A61K 8/983, A6 1K 9/0014

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) WPIAP, EPODOC, MEDLINE, BIOSIS, CAPLUS, EMBASE, PATENTSCOPE, AUSPAT, GOOGLE, GOOGLE ADVANCED PATENT SEARCH, GOOGLE SCHOLAR, ESPACENET, PUBMED, IPONZ (Skin, epidermis, blood product, growth factor, hormone, cytokine, transdermal and similar terms)

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

Documents are listed i the continuation of Box C

X Further documents are listed in the continuation of Box C X See patent family annex

* Special categories of cited documents: "A" document defining the general state of the art which is not "T" later document published after the international filing date or priority date and not in considered to be of particular relevance conflict with the application but cited to understand the principle or theory underlying the invention " earlier application or patent but published on or after the "X" document of particular relevance; the claimed invention cannot be considered novel international filing date or cannot be considered to involve an inventive step when the document is taken alone "L" document which may throw doubts on priority claim(s) or "Y" document of particular relevance; the claimed invention cannot be considered to which is cited to establish the publication date of another involve an inventive step when the document is combined with one or more other citation or other special reason (as specified) such documents, such combination being obvious to a person skilled in the art "O" document referring to an oral disclosure, use, exhibition or other means "&" document member of the same patent family "P" document published prior to the international filing date

Date of the actual completion of the international search Date of mailing of the international search report 24 July 201 24 July 2017 Name and mailing address of the ISA/AU Authorised officer

AUSTRALIAN PATENT OFFICE Anita Premkumar PO BOX 200, WODEN ACT 2606, AUSTRALIA AUSTRALIAN PATENT OFFICE Email address: [email protected] (ISO 9001 Quality Certified Service) Telephone No. +61262832013

Form PCT/ISA/210 (fifth sheet) (July 2009) INTERNATIONAL SEARCH REPORT International application No.

C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT PCT /AU2017/000124

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

WO 2014/12693 1 A l (VICTOR, S) 2 1 August 2014 X Abstract, [0015], [0016], [0043], [0052]-[0054], [0086]-[0098], [01 19], [0 124], [0126], 1-14, 16-21 AND 23 [0133], [0171]-[0178], [0182], [0189], page 3 1, claim 15 AND 44-54

WO 2013/007308 A l (GARB IN, S) 17 January 2013 X Abstract, page 4 lines 11-16, page 8 line 29-page 9 line 6, page 10, page 12 line 1, page 1, 3-8, 11, 13, 14, 16-23 18 line 1, Example 4, Claims AND 24

US 2007/0081963 A l (OH et al) 12 April 2007 X Abstract, [0009]-[001 1], [0013], [0030]-[0036], [0039], [0040], [0044], [0050], [0055]- 1, 3-7, 10, 11, 13-19 AND [0058], [0060], Fig 1, Example 1, Claims 1-16 21-23

US 2015/005033 1 A l (NOVO SOLUTIONS MD, LLC.) 19 February 201 5 X Abstract, [0009]-[001 1], [0018], [0027], [0048]-[0054], Examples 1 and 2, Claims 1, 3, 4, 6-8, 11 AND 13-22 AND 23

US 5,63 1,0 19 A (MARX G) 20 May 1997 X Abstract, col 1 line 43-46, col 3, col 4 lines 4-7, col 11 lines 25-30, col 13-14 bridging 1, 4, 6, 12-21 AND 23 para, Examples 4, 5, 10 and 11, Claims 20, 21, 27, 28 and 30, Fig 7

Form PCT/ISA/210 (fifth sheet) (July 2009) INTERNATIONAL SEARCH REPORT International application No. Information on patent family members PCT/AU2 17 0 124 This Annex lists known patent family members relating to the patent documents cited in the above-mentioned international search report. The Australian Patent Office is in no way liable for these particulars which are merely given for the purpose of information.

Patent Document/s Cited in Search Report Patent Family Member/s

Publication Number Publication Date Publication Number Publication Date

WO 2014/12693 A l 2 1 August 2014 WO 201412693 1 Al 2 1 Aug 2014

WO 2013/007308 A 1 17 January 2013 WO 201 3007308 A l 17 Jan 2013

US 2007/0081963 A l 12 April 2007 US 200708 1963 A l 12 Apr 2007 US 884661 1B2 30 Sep 2014

BR PI0520672 A2 19 May 2009

CA 2625806 A l 19 Apr 2007

JP 200951 1574 A 19 Mar 2009 JP 5649278 B2 07 Jan 2015 KR 100705981 B l 04 Apr 2007 KR 20090042871 A 30 Apr 2009 KR 100962566 B l 11 Ju 2010

WO 2007043721 A l 19 Apr 2007

US 20 15/005033 1 A l 1 February 2 15 US 201505033 1 A l 19 Feb 2015 US 2014322368 A l 30 Oct 2014 US 201435773 1 A l 04 Dec 2014

WO 201 5088663 A l 18 Jun 2015

US 5,63 1,019 A 20 May 1997 US 563 1019 A 20 May 1997 CA 2183430 A l 24 Aug 1995

EP 0748215 Al 18 Dec 1996 EP 0748215 Bl 28 May 2003 JP 2001508666 A 03 Jul 2001 JP 3591837 B2 24 Nov 2004 US 5607694 A 04 Mar 1997 US 5651982 A 29 Jul 1997

WO 95223 16 A l 24 Aug 1995

End of Annex

Due to data integration issues this family listing may not include 10 digit Australian applications filed since May 2001. Form PCT/ISA/2 0 (Family Annex)(July 2009)