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(12) Patent Application Publication (10) Pub. No.: US 2012/0003300 A1 Isaacs Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2012/0003300 A1 Isaacs Et Al US 2012.0003300A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0003300 A1 Isaacs et al. (43) Pub. Date: Jan. 5, 2012 (54) COMPOSITION COMPRISING VASCULAR A6IR 36/48 (2006.01) ENDOTHELLAL GROWTH FACTOR (VEGF) A6IR 36/15 (2006.01) FOR THE TREATMENT OF HARLOSS A636/II (2006.01) A6II 35/32 (2006.01) (75) Inventors: Elliot Isaacs, London (GB); Toby A 6LX 9/27 (2006.01) Cobbledick, London (GB) A6IP 7/4 (2006.01) A6IP3 L/10 (2006.01) (73) Assignee: Pangaea Laboratories Ltd A6IP3L/00 (2006.01) A6IP 29/00 (2006.01) A6IP 7/8 2006.O1 (22) Filed: Jun. 30, 2011 A638/44 :08: (30) Foreign Application Priority Data (52) U.S. Cl. ......... 424/450; 514/8.1; 424/94.4; 424/729: 424/727; 424/757; 424/59: 424/60; 424/62: Jun. 30, 2010 (GB) - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 101097O.O 424/65; 424/770; 424/725; 424/548 Oct. 19, 2010 (GB) ... ... 1017674.1 Feb. 3, 2011 (GB) ................................... 1101877.7 (57) ABSTRACT Publication Classification A composition to treat hair loss and enhance hair growth and (51) Int. Cl. condition. The composition comprises: i) one or more of A6 IK 38/18 (2006.01) VEGF, a VEGF biomimetic peptide, and/or a VEGFR2 recep A6 IK 36/82 (2006.01) toragonist; ii) ciclopiroX olamine; and iii) a pharmaceutically A6 IK 36/889 (2006.01) acceptable carrier. US 2012/0003300 A1 Jan. 5, 2012 COMPOSITION COMPRISING VASCULAR tions. VEGF also leads to the down-regulation of caspase 9 ENDOTHELLAL GROWTH FACTOR (VEGF) (Manning B. D., Cantley L. C., (2007) Cell, 129(7) p. 1261 FOR THE TREATMENT OF HAIR LOSS 1274), reducing a different apoptotic pathway. VEGF has a clear role in preventing early apoptosis via these two path ways, and the prevention of hypoxia and oxidative stress. This 0001. The present invention relates to the use of ciclopirox will lead to the maintenance of Anagen for longer. olamine, in combination with vascular endothelial growth 0009 Minoxidil is the treatment of choice for most phy factor (VEGF), to improve hair growth and condition. Sicians when treating hair loss. It is surprising then that sev 0002 The process of new hair growth, whether as part of eral modes of action have been theorised, but none of them the natural hair cycle or as a result of a treatment to encourage proven. hair growth, relies on numerous cross-talking signal path 0010. The principle mode of action for minoxidil is ways to bring about the processes necessary for hair growth. thought to be the donation of nitric oxide. This gaseous sig These principal processes are: cell proliferation of the dermal nalling molecule is well known to cause vasodilation and papilla, cell migration to form the appropriate structures, and improve circulation. Nitric oxide signals are degraded rapidly angiogenesis to form blood supply routes to the new hair by free radicals, therefore many treatments utilise antioxi follicle. dants to prolong the signal life. A notable antioxidant is 0003) The three steps are also vital for healthy skin con Superoxide dismutase. As an enzyme with a high turnover dition. In normal skin and normal hair growth cycling, these rate, Superoxide dismutase removes may reactive oxygen spe stages take place without any pharmaceutical or cosmetic cies, and effectively reduces nitric oxide breakdown. intervention. However, in people with various forms of allope 10011. A credible, newer theory is that minoxidil's effects, cia, hair loss, or a slowing of hair growth, one or more of these opening the Na"/K"ATPase channel, promote hair growth. processes might not happen at a normal rate, and can stop This effect has been shown by the classification of two chan altogether. Similarly, these processes often occurata reduced nel subtypes in the follicle, one of which is opened by minoxi rate in UV damaged skin and scar tissue. dil. When opened by a different specific channel opener, hair 0004 Vascular endothelial growth factor (VEGF) is a growth was improved while, when a channel inhibitor was well-documented signal to activate these processes via the used, the growth effect was prevented (Shorter K., et al., VEGFR2 receptor. VEGF leads to downregulation of Bad, (2008) FASEB Journal, 22(6) p. 1725-36). TGF-31 and caspase expression through the Akt/PKB and 0012. The Na"/K ATPase channel has another function, calcium ion dependent pathways, thereby bringing about the regulating Caion levels. Permanently opening the channels end of apoptosis and the telogen phase. Secondly it acts via causes the levels of Ca" ions to stabilise. As the proliferative the MAPKinase pathway to increase cell proliferation. Via and eNOS stimulating effects of VEGF are Ca" mediated, the same Akt/PKB and calcium ion dependent pathways, there is evidence that maintenance of Ca" ion levels is nec VEGF also stimulates nitric oxide (NO) production and cell essary for a VEGFR2 signal transmission to be effective. migration. Interestingly, all of these pathways, excepting the Therefore minoxidil may make a VEGF signal more efficient Akt/PKB pathway, are calcium ion dependent. and increase the intracellular effects of VEGF. 0005 Without doubt the key to maintaining hair shaft I0013 An interesting corollary to the possibility of minoxi growth is a sufficient supply of oxygen and essential amino dil acting with or via VEGF is the fact that minoxidilupregu acids. This requires blood. As has been shown by repeated lates VEGF expression in anagen dermal papilla cells. This experiments, increasing blood flow and blood vessel forma upregulation ensures adequate vascularisation of the follicle tion to hair follicles improves and maintains hair growth, through the anagen phase and is likely to explain at least part without this hair growth will cease. of the mode of action of minoxidil (Lachgar, et al., (1998) 0006) VEGF is the cytokine solely responsible for blood British Journal of Dermatology, 1998. 138(3) p. 407-411). vessel formation. Via the VEGFR2 receptor, VEGF stimu I0014) Prostaglandins have been another widely lates vascular cells to proliferate to extend the blood vessel, researched treatment option. Research suggests that prostag migrate and organise to form the vessel organ. This rapidly landins are active in the very early stages of anagen, possibly extends new vessels into areas that require blood supply. even at the initiation step, as suggested by the new eyelash VEGF also stimulates eNOS to create nitric oxide, stimulat growth in several clinical trials (Johnstone M. A., Albert D. ing blood vessel and cell membrane permeability for the M., (2002) Survey of Ophthalmology, 47(1): p. S185-202). efficient transfer of nutrients. VEGF is particularly useful The prostaglandin system is complex, made from a large because VEGF upregulation and many related pathways are number of different prostaglandins, and is still not fully stimulated by hypoxia, so it acts where it is needed (Hoeben researched. A. et al., (2004) Pharmacology Review, 56 p. 549-8). I0015 VEGF has been shown to induce prostaglandin I(2) 0007 Dihydrotestosterone has long been studied as a production in epithelial cells. Prostaglandin I(2) is unlikely to major cause of hair loss. It is a hormonal signal which pen stimulate new hair growth, however prostaglandin I(2) recep etrates the follicle, and causes down-regulation of Bcl-2 lead tors have been found to be specifically expressed in hair ing to apoptosis. Bcl-2 interacts with Bax and Bad genes to cuticle layer, suggesting an important role for hair matrix cell prevent apoptosis, and so lowering the concentration of Bcl-2 differentiation to form the outer hair cuticle (Colombe L., allows Bax and Bad to promote apoptosis through the same Michelet J. F., Bernard B. A. (2008) Experimental Derma pathway (Hoeben A., et al., (2004) Pharmacology Review, 56 tology, 17(1) p. 63-72). This outer layer is essential for ter p. 549-8). minal hair formation. 0008 VEGF blocks Bad conversion, maintaining the pre 10016. This may also explain the necessity for VEGF apoptotic state (Manning B. D., Cantley L. C., (2007) Cell, upregulation in the early anagen stage mentioned earlier. 129(7) p. 1261-1274). This means that Bcl-2 only has Bax to 10017 Widely regarded as the most successful treatment interact with, and so prevents apoptosis at lower concentra for alopecia areata, diphency prone is another treatment with US 2012/0003300 A1 Jan. 5, 2012 no definite mechanism. As a potent allergen, topical applica 0027. Ciclopirox, or 6-cyclohexyl-1-hydroy-4-methyl-1, tion of diphency prone as an immunotherapeutic agent stimu 2-dihydropytidin-2-one, is an active antifungal ingredient of lates a response and leads to normalisation of hair growth the family of hydroxyl pyridones which is finding increas (Happle R. (2002) Archives of Dermatology, 138 p. 112 ingly greater use in the treatment of seborrheic dermatitis and 113). dandruff due to its chelating capacity of ferric ions (EP 0018 Recent work shows this “response' is threefold. 2275104). Ciclopirox olamine is also known to induce Firstly, the ratio of CD4/CD8 cells is known to differ signifi hypoxia-inducible factor 1-alpha (HIF-1alpha), VEGF cantly in alopecia areata patients. Diphency prone stimulates expression and angiogenesis in the context of wound healing a normalisation of this ratio to one approaching normal scalp (Linden T., et al., (2003) FASEB Journal, 17 p. 761-763). tissue. Diphencyprone also upregulates the expression of Sur 0028. Accordingly, the present invention encompasses the vivin, thereby helping to preventing the premature apoptosis use of VEGF, in combination with ciclopirox olamine, to treat symptomatic of allopecia areata patients. Lastly, it upregulates hair loss and enhance hair growth and condition. the expression of VEGF in hair follicle keratinocytes, main 0029 Expressed in another way, the present invention taining nutrient and oxygen Supply (Simonetti O., et al., resides in a composition to treat hair loss and enhance hair (2004) British Journal of Dermatology, 150(5) p.
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