WO2012065065A9 - Procédés et compositions pour moduler la pousse de cheveux, la cicatrisation de plaie et la révision de cicatrice - Google Patents

Procédés et compositions pour moduler la pousse de cheveux, la cicatrisation de plaie et la révision de cicatrice Download PDF

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WO2012065065A9
WO2012065065A9 PCT/US2011/060375 US2011060375W WO2012065065A9 WO 2012065065 A9 WO2012065065 A9 WO 2012065065A9 US 2011060375 W US2011060375 W US 2011060375W WO 2012065065 A9 WO2012065065 A9 WO 2012065065A9
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alkyl
group
amino
independently selected
hydrogen
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WO2012065065A1 (fr
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Shikha P. Barman
William D. Ju
Scott C. Kellogg
Stephen M. Prouty
Eric Schweiger
Seth Lederman
Mary Osbakken
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Follica, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • A61K8/492—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid having condensed rings, e.g. indol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • IPC International Patent Classification
  • Form PCT/ISA/210 (second sheet) (July 2009) follicles that produce "vellus hair” while certain other hair follicles may contain or produce no hair (see Figure 1).
  • follicles that produce "vellus hair” while certain other hair follicles may contain or produce no hair (see Figure 1).
  • the glaborous skin on palmar and plantar aspects of hands and feet, respectively, and the lips and labia lack hair follicles.
  • Only a minority of human hair follicles produce a hair fiber that can be appreciated visibly (a "terminal hair") and these specialized follicles are localized on specific regions of skin. Accordingly, both the presence and absence of visible hair on human non-glaborous skin is mediated by regulation of activity of specialized follicles.
  • Hair follicles and particularly human hair follicles, are crypt structures comprised of distinct components, each comprised of several different specialized cells (see Figures 2 and 3).
  • the vast majority of hair follicles contain units called sebaceous glands (which produce sebum).
  • Some hair follicles have apocrine glands attached to them, and are located in the axilla and other specific areas of the body.
  • the structures of the hair follicle include the follicular papilla (FP) and the germinative epithelium (GE) (together, the bulb).
  • the FP is comprised of mesenchymal cells (and connective tissue).
  • the other cells of the follicle are epithelial and include at least 8 cellular lineages including the outer root sheath (ORS), the companion layer (CL), the internal root sheath Henle's layer (He), internal root sheath Huxley's layer (Hu), the cuticle of the internal root sheath (Csth), the cuticle of the hair shaft (Csft), the cortex of the hair shaft, and the medulla of the shaft (Med).
  • ORS outer root sheath
  • CL the companion layer
  • He internal root sheath Henle's layer
  • Csth internal root sheath Huxley's layer
  • Csth cuticle of the internal root sheath
  • Csft the
  • a follicular unit of scalp hair is typically composed of one to four terminal hair follicles; one to two vellus hair follicles; their associated sebaceous glands, neurovascular plexus, an erector pilorum muscle and a circumferential band of adventitial collagen, termed the
  • Hair follicles are believed to produce approximately 20 individual hair shafts over the life of the follicle as the follicle progresses through cycles of hair production, shedding (ejection), involution and new growth.
  • the regulation of hair growth and follicle regeneration have been investigated in murine systems.
  • the biology of hair follicles in the mouse is different from those of the human in several important aspects.
  • a thick fur coating is essential to healthy life (because hair plays roles in thermoregulation and other functions.)
  • Mouse skin is covered with hair follicles that produce terminal hair (fur), whereas significant regions of human skin are covered with hair follicles that produce vellus hair, which is invisible.
  • Mouse and other non-primate mammals have synchronous Follicle Cycles, whereas human follicles progress through the Follicle Cycle in an asynchronous fashion. While the mouse has certain specialized follicles (e.g., whiskers, guard, awl, suchene, and zigzag hair), mouse follicles are generally not subject to developmental and gender-specific hair patterning. In contrast, a significant number of human follicles are individual participants in choreographed hair patterning that affects the . type, length and color of shaft produced at different times in development and aging and in a gender specific manner.
  • follicles e.g., whiskers, guard, awl, suchene, and zigzag hair
  • mouse follicles are generally not subject to developmental and gender-specific hair patterning.
  • a significant number of human follicles are individual participants in choreographed hair patterning that affects the . type, length and color of shaft produced at different times in development and aging
  • Hair growth in each follicle occurs in a cycle that includes the following principal phases: anagen (growth phase), catagen (involuting regressing stage), telogen (the quiescent phase), exogen (shedding phase), and re-entry into anagen (sometimes referred to herein as the "Follicle Cycle”).
  • anagen growth phase
  • catagen involuting regressing stage
  • telogen the quiescent phase
  • exogen shedding phase
  • re-entry into anagen sometimes referred to herein as the "Follicle Cycle”
  • kenogen a latent phase
  • the Follicle Cycle has been relied on to explain many phenomena associated with hair growth and hair loss.
  • Human hair follicles are relatively unique among mammals (and particularly non- primates) since hair follicles in a region of skin are not synchronized. On an adult human scalp, at any particular time approximately 90% are in anagen; 10- 14% in telogen and 1 -2% in catagen.
  • each hair follicle belongs to a class of follicles that accounts for the distinctive length, temporal appearance, regulation by sex hormones, etc., of the hair shaft it produces.
  • the duration of the Follicle Cycle length is believed to be a characteristic of each distinct specialized human hair follicle that accounts for the length of hair produced and other aspects of the follicle function.
  • the anagen stage for eyebrow hair follicles is approximately 4 months and for scalp hair follicles is approximately 3-4 years. It has been proposed that eyebrow hairs have a shorter length compared to scalp hairs because the former have a shorter anagen phase.
  • the Follicle Cycle has also been used to distinguish two different types of pathologic hair loss (effluvium): Anagen effluvium and Telogen effluvium.
  • Anagen is associated with intense mitotic activity; therefore, follicles in anagen are sensitive to cancer chemotherapeutic agents.
  • Anagen effluvium is believed to be the process in which certain hair follicles undergo hair loss and involution during chemotherapy because these agents typically target cells with high metabolic or mitotic activity (e.g., 5- . fluorouracil, methotrexate, cyclophosphamide, vincristine).
  • Anagen effluvium can be caused by other toxins, radiation exposure, radiation overdose, endocrine diseases, trauma, pressure, and certain diseases like alopecia areata (an autoimmune disease that attacks anagen follicles.)
  • Telogen effluvium is a premature interruption of anagen and early entry of anagen follicles into the Telogen (or resting) phase. The proportion of telogen hairs on the scalp increases to 25-50% and telogen follicles remain in telogen for more than the usual 3-6 months. Telogen effluvium is caused frequently by drugs like lithium and other drugs like valproic acid and carbamazepine and numerous other drugs including the commonly used beta blockers and oral contraceptives. In addition to psychiatric drugs, telogen effluvium can be induced by childbirth, traction, febrile illnesses, surgery, stress, or poor nutrition (see Mercke et ai, 2000, Ann. Clin. Psych. 12:35-42).
  • human skin is essentially covered with hair follicles.
  • the portions of human skin that lack visible hair contain, for the most part, hair follicles that produce "vellus hair” which is thin and short (i.e., less than 2 cm in length) and often colorless. Certain other hair follicles may contain or produce no hair. Only a minority of human hair follicles produce a hair fiber that can be appreciated visibly (a "terminal hair") and these specialized follicles are localized on specific regions of skin.
  • Another follicle type is the "sebaceous" follicle, which has a large sebaceous gland and a vellus-like hair shaft localized in the acne-prone areas. Accordingly, both the presence and absence of visible hair on human skin is mediated by regulation of the activity of specialized hair follicles.
  • follicle types By the time of birth, distinct specialized follicle types are positioned in specific areas of the skin where they will each play a programmed role in hair patterning over the life of the human individual, producing various hair types (lanugo, vellus or terminal hair) either constitutively or depending on certain signals, such as sex hormones or other factors (e.g., lanugo hair can reappear in starvation or in eating disorders such as anorexia nervosa and bulimia).
  • Gender is associated with specific patterning of human hair.
  • the growth and loss of visible hair in specific areas of the skin, in stereotypical gender dimorphic patterns, are regarded as “Secondary Sexual Characteristics.”
  • This terminology relates "secondary” features such as hair patterning to the genitals and reproductive organs, which are termed “Primary Sexual Characteristics.”
  • Primary Sexual Characteristics The distinctive genitals and reproductive organs of males and females acquired during embryonic development undergo further changes in puberty and menopause/andropause. In addition to hair growth and loss, breasts in females are also considered Secondary Sexual Characteristics.
  • Certain human hair follicles are targeted to specific skin areas and develop specialized characteristics during embryogenesis under the influence of sex hormones such as testosterone and dihydrotestosterone ("androgens") and/or estrogens. Further, certain human hair follicles are driven to change activity by sex hormones during puberty and in
  • the appearance and intensity of secondary sex characteristics can be described as being regulated by ratios of androgens and estrogens, since to a certain extent either of these groups of hormones (androgens and estrogens) can act to induce certain activities or to inhibit the effect of the other group (i.e., androgens inhibit estrogen effects and estrogens inhibit androgen effects).
  • androgens induce male characteristics and suppress female characteristics while estrogens induce female characteristics and suppress male
  • Male and female refer to the extremes of genetic gender dimorphism and include by reference the various conditions and states that represent a spectrum of male and female features (such as XO syndromes or conditions that result from exogenous sex steroid administration).
  • Specialized human hair follicles have quantitative variation in activity as well as qualitative variation.
  • sex steroids have qualitative effects on hair patterning either in embryogenesis or in adult life or both (e.g., males have beard hair follicles that produce terminal hair after puberty whereas females do not).
  • Males and females also vary in the amount of gender-specific hair patterning (e.g. , a higher density of leg hair follicles produce terminal hair on male rather than female legs).
  • individuals of the same gender exhibit quantitative variation. For example, male chest and back hair presents in different individuals as a spectrum from almost hairless to dense hair and from small regions of follicles producing terminal hair to large regions.
  • Gender specific human hair patterning highlights the distinct biological programming of specific hair follicles. Distinct hair follicles in relative proximity on the male scalp and face respond to high androgen/estrogen ratios in diametrically opposite ways: high androgen/estrogen ratios induce vellus to terminal hair transformation in male moustache/beard skin (particularly during puberty), but induce terminal to vellus follicle transformation change in male frontal/temporal scalp (progressively post puberty) in male pattern hair loss (MPHL). [0025] The effects of androgen/estrogen levels on other regions evidences further variations in the biological programming of specific hair follicles.
  • Hair follicles on the occipital scalp are relatively insensitive to high androgen/estrogen ratios (but later, after more prolonged androgen exposure, undergo age-related thinning). Hair follicles in the axillary and pubic regions (anogenital region) appear to be more sensitive to androgen than moustache/beard follicles; since terminal hair in axillae/pubis grows: (a) in females with relatively low levels of androgen; (b) early in male puberty before beard/moustache; and (c) in patients with genetic 5-alpha-Reductase Type II deficiency.
  • MHL Male pattern hair loss
  • Androgenetic alopecia is a genetically-mediated disorder that occurs in approximately 50% of men by the age of 50 years (see review, Stough et al, 2005). In women, the histological features of the condition are the same as in men, but susceptibility, age at onset, rate of progression and pattern of hair loss differ between genders (Dinh and Sinclair, 2007).
  • the loss of scalp hair in men is known to be a process driven by the androgen, DHT, which can be inhibited and to some extent reversed by finasteride, which inhibits 5-alpha-reductase II (which converts testosterone to DHT).
  • DHT androgen
  • finasteride which inhibits 5-alpha-reductase II (which converts testosterone to DHT).
  • DHT androgen
  • finasteride which inhibits 5-alpha-reductase II (which converts testosterone to DHT).
  • the affected hair follicles on the bald vertex or temples are considered to be atrophied, or perhaps involuted irreparably ("senescent").
  • senescent irreparably
  • Telogen hairs are more loosely anchored and prone to shedding or being pulled out (for example, by combing or brushing hair).
  • a club hair is produced that is a fully keratinized hair.
  • the hair follicles on MPHL affected areas also undergo follicular miniaturization in which a growing proportion of terminal follicles become vellus follicles.
  • androgenetic alopecia is thought to involve the progressive conversion of hair follicle units with 3 or more terminal hairs to follicular units having fewer terminal hairs (e.g., units with 2 terminal hairs progress to units with 1 terminal hair).
  • MPHL is associated with specific polymorphisms of the androgen receptor, the EDA2R gene. Men who are genetically deficient in Type II 5-alpha-reductase do not experience MPHL (see Jenkins et al., 1992, J Clin Invest 89:293-300).
  • Hic-5/ARA55 mRNA expression was high in dermal papilla cells from the beard and bald frontal scalp but low in cells from the occipital scalp.
  • ARA70 ELE1 Another androgen receptor coactivator ARA70 ELE1 had decreased expression of a splice variant form (ARA70beta/ELEl beta) in the dermal papilla of balding recipient areas than non- balding areas (Lee et al., 2005, J Cutan Pathol 32:567-571 ).
  • FPHL is thought to share some features with MPHL in terms of progressive reduction in the duration of anagen and progressive follicular miniaturization, although recent studies have found a prolongation of kenogen.
  • transplanted which has been referred to as "donor dominance" (Orentreich N, 1959, Ann NY Acad Sci. 83:463-479).
  • donor dominance Orentreich N, 1959, Ann NY Acad Sci. 83:463-479.
  • MPHL e.g. occipital scalp
  • androgens e.g. frontal/temporal; crown or vertex scalp.
  • the transplanted follicles retain the programmed terminal hair producing features from their original location.
  • the recipient site may affect some characteristics of transplanted hairs. See Hwang et al. , 2002, Dermatol. Surg. 28:795-799.
  • the mechanism for the switch from regeneration to repair with age in mammals is not fully known, but involves cytokines and an immune response that promotes rapid epidermal closure, dermal fibroplasia and increased collagen deposition.
  • hair follicles do not form, thus contributing to the lack of adnexal structures in a scar.
  • the abnormal structure of scars contributes to the their associated morbidity. Due to lack of eccrine glands, there is poor thermoregulation. Increased fibroplasia. and collagen can lead to contracture and loss of mobility in affected areas of the body.
  • hair follicle keratinocytes contribute to epidermal closure, and hair follicle dermal ( sheath fibroblasts play central roles in dermal healing. See, Ito et al., 2005; Jahoda & Reynolds, 2001 ; Stenn & Paus, 2001 , Physiol. Revs. 81 :449-494.
  • the only skin tissue (aside from scar tissue) that normally lacks hair follicles is the glabrous skin on palmar and plantar aspects of hands and feet, respectively, and the lips and labia.
  • human glabrous skin lacks hair follicles, it is rich in eccrine sweat glands.
  • Wound healing studies in pig have shown that sweat glands, by themselves, are capable of regenerating epidermis, which likely accounts for lack of scarring in glabrous skin wounds that spare the base of sweat glands.
  • palmar Barret at al., 2000
  • plantar Barret & Herndon, 2004 wounds can result in scarring, a sequelae related to increased depth of wound and delayed wound healing.
  • hair follicles were not understood to be capable of neogenesis and bulge cells were not proven to be a source of stem cells for hair follicle neogenesis.
  • Fathke In animal studies designed to explore the role of Wnt in tissue patterning following wounding, Fathke showed that prolonged activation of ⁇ -catenin dependent Wnt signaling (by continuous topical administration of lithium chloride for two weeks until wound closure) during wound healing in mice resulted in generation of rudiments of hair follicles but did not result in the formation of hair follicles or growth of more hair (Fathke et al, 2006, BMC Cell Biol. 7:4). Fathke also noted that the epithelium that typically forms over the wound during wound healing was covered with cysts. Id. Fathke then turned the focus of their investigation to the ⁇ -catenin- independent Wnts expressed in the skin - which are not activated by lithium chloride.
  • mice are an imperfect model for human wound healing and scar formation. Mice tend to heal most wounds rapidly, with little or no scarring. In humans, however, severe wounds and burns are usually associated with cutaneous repair that results in scar tissue, no hair follicles, and the loss of regenerative capability that hair follicles may provide (see, Fathke et al, 2006, BMC Cell Biol. 7:4).
  • One reason for the difference in wound healing capability between humans and mouse may be that the biology of hair follicles in humans and mice differs in several significant respects. In the mouse, a thick fur coating is essential to healthy life (because hair plays roles in
  • Wound healing is an intricate process in which the skin (or some other organ) repairs itself after injury.
  • the epidermis outermost layer
  • dermis inner or deeper layer
  • the classic model of wound healing is divided into three or four sequential, yet overlapping, phases: (1 ) hemostasis (not considered a phase by some authors); (2) inflammation; (3) proliferation (involving angiogenesis, granulation tissue formation and fibroplasia, re-epithelialization, and contraction, the latter phase reducing the size of the wound); and (4) maturation and remodeling.
  • wounds may heal by primary intention.
  • Such wounds may be referred to as "closed wounds.” These wounds are usually surgically closed in layers along tissue planes by a physician. In primary intention, a linear scar results at the intersection of the approximated tissues.
  • Scarring is often minimal, but can be variable depending on the size and location of the wound, the tension on tissue and other factors. Most surgical wounds are sutured closed, so they heal by primary intention. In primary intention, wound closure is usually performed with sutures, staples, or an adhesive. Other examples of wounds that heal by primary intention are well repaired lacerations, well reduced bone fractures, and wounds that heal after flap surgery (the edges of which tend to appear scarred).
  • wounds are referred to as "open wounds.”
  • wounds formed by blast injury, shrapnel e.g., from improvised explosive devices ("IEDs")
  • blunt trauma e.g., blunt trauma
  • dental wounds e.g., gingivectomy, gingivoplasty, tooth extraction sockets
  • poorly reduced fractures e.g., gingivectomy, gingivoplasty, tooth extraction sockets
  • third degree burns heal by secondary intention.
  • Healing by secondary intention follows the same basic steps as wounds that heal by primary intention, i.e., inflammation, proliferation, and remodeling, but each sequence may take much longer, especially the proliferative phase.
  • Wound care must be performed daily to encourage wound debris removal to allow for granulation tissue formation. Depending on the size and location of the wound, placement of a partial or full-thickness skin graft may be considered if no infection is present and the area is of sufficient size that healing may not be complete for at least 2 or 3 weeks. Infection and inflammation of the wound can dysregulate repair and transform the wound into a clinically non-healing wound.
  • wound healing by tertiary intention the wound is initially cleaned, debrided, and observed, and typically 4 or 5 days elapse before closure.
  • the wound is purposely left open. Examples include healing of wounds by use of tissue grafts.
  • a major component of wound healing in humans is scar formation.
  • a scar (“cicatrix”; plural, “cicatrices”) is an area of fibrous tissue that forms as part of the healing process to replace normal skin after injury.
  • a hallmark of scars is altered extracellular matrix, notably a reduction of elastin fibers (De Vries ef al., 1995).
  • Scars result from damage to the dermis, and with the exception of very minor lesions, every wound results in some degree of scarring. Scars generally form in proportion to the extent of damage.
  • Scar tissue is also usually of inferior functional quality.
  • a scar is a collagen-rich, elastin-poor dermal matrix with a simple stratified epithelial covering. Deposition of such a collagen-rich matrix in the neo- dermis is prone to contracture, loss in elasticity, and reduced tensile strength. Scars in the skin are also less resistant to ultraviolet radiation. For example, scars from skin transplants are typically dysfunctional, discolored, etc. Skin flaps and grafts are common methods of achieving rapid closure of large defect wounds. Not only do these methods tend to result in scarring at the donor site, but the sites of apposition of flap or graft edges to the wound edges can also result in linear scars.
  • TGFs Transforming Growth Factors
  • RS Ribosomal s6 kinase
  • scarring is likely to be extensive when wounds heal by secondary intention.
  • the wound heals by granulation, wherein epithelial cells grow over the wound from all sides of the normal skin, which results in a shiny layer of epithelial cells and fibrous tissue that is rich in collagen but does not contain underlying structures ("adnexal structures," including hair follicles).
  • adnexal structures including hair follicles
  • the scar also lacks the suppleness of normal skin. This type of scar can result in contractures when it occurs' over the mouth or eyes or on the skin around joints, and can be disfiguring.
  • atrophic scars In addition to scars that form by secondary intention, there are numerous other types of scars that we distinguish, including atrophic scars, hypertrophic scars, keloid scars, hypopigmented scars, hyperpigmented scars, depressed scars (which, compared with atrophic scars, also have contour abnormality, while "atrophic" scars are implied to have only thinning), ice-pick scars (a type of depressed scar), spread scars (scars that widen due to tension over a time period, and which may become somewhat atrophic in the center), fineiine scars, widespread (or stretched) scars, scar contractures, and other "intermediate" types of scars that are difficult to categorize.
  • Human hair loss can be categorized as ( 1 ) gender specific hair patterning, (2) pathological hair loss, or (3) hair loss after wounding, all which can be associated with effects on self-esteem and self-image, and many individuals explore whether their hair loss process can be treated.
  • Current treatments offered involve a limited selection of agents and regimens, such as chemical and surgical approaches that either stimulate or transplant pre-existing hair - none are associated with true follicular neogenesis.
  • Chemical treatments involve the use of drugs for the treatment of certain MPHL. These include, for example, minoxidil (an antihypertensive drug that opens the K+ channel); and antiandrogens such as finasteride, dutasteride or ketoconazole. While these types of treatments are reasonably effective in preventing or delaying MPHL, they are less effective in stimulating the growth of significant terminal hair in scalp of MPHL after baldness has been present for 6 months or more. Moreover, minoxidil and finasteride require continuous treatment for lasting effects. Consequently, patients with advanced MPHL may express dissatisfaction with even statistically significant, but cosmetically insignificant increase in hair counts and such frustration may contribute to poor compliance and further unsatisfactory outcomes.
  • minoxidil an antihypertensive drug that opens the K+ channel
  • antiandrogens such as finasteride, dutasteride or ketoconazole.
  • bimatoprost a prostaglandin analog used to control the progression of glaucoma in the management of ocular hypertension
  • Latisse® a prostaglandin analog used to control the progression of glaucoma in the management of ocular hypertension
  • a device that uses low level light energy directly on the scalp has received FDA clearance as a 51 OK device. Although the device is advertised as a "Laser,” it operates by applying low level monochromatic light energy directly to the scalp, which is thought to stimulate hair growth through "photo-biostimulation" of hair follicles.
  • Various types of devices operating on similar principles were referenced as the predicate for HairMax (see, Lolis et al. , 2006, J. Cosmetic Dermatol. 5:274-276).
  • hair transplantation in which scalp strips, hair follicles or follicular units from the occipital scalp (which are resistant to the effects of androgens in inducing MPHL type alopecia) are excised and transplanted to a person's balding or thinning areas.
  • Another surgical method that has been used is scalp reduction; in this procedure, the skin in the balding area of the scalp is surgically excised and the surrounding skin (with hair) is pulled together and sutured.
  • Surgical methods are best for focal hair loss, and are less effective for diffuse hair loss, are less effective for women and younger patients are not ideal candidates because the pattern and extent of hair loss is variable, and may be inconvenient because of the expense of the surgery, duration of time to show a cosmetic effect, creation of scarring.
  • cosmetic coverage is constrained by the area of and the number of hairs in a patient's donor sites.
  • Depilation affects the part of the hair above the surface of the skin.
  • the most common form of depilation is shaving.
  • Another popular option is the use of chemical depilatories (e.g., Nair®), which work by breaking the disulfide bonds that link the protein chains that give hair its strength, making the hair disintegrate.
  • Epilation is removal of the entire hair, including the part below the skin, and is believed to be longer- lasting.
  • Methods include plucking with tweezers, waxing, sugaring, epilation devices, threading, home pulsed light, and can include the use of hair growth retardants (e.g., Vaniqa® (eflornithine)).
  • Electrology electrolysis
  • laser and intense pulsed light are used for permanent hair removal.
  • permanent hair removal is an imperfect process.
  • laser hair removal does not work well on light hair and/or on dark skin.
  • multiple sessions with trained medical personnel are required.
  • Acute treatment of wounds is generally focused on hemostasis , cleaning and closing the wound, and preventing and treating infection.
  • the treatment depends on the type, cause, and depth of the wound as well as whether other structures beyond the skin are involved. If a laceration occurred some time ago, it may be allowed to heal by secondary intention due to the high rate of infection associated with immediate closure. Minor wounds like bruises tend to heal on their own with skin discoloration that usually disappears within 1 - 2 weeks. Abrasions usually require no active treatment except keeping the area clean with soap and water, although scarring may occur. Puncture wounds may be prone to infection depending on the depth of penetration. The entry of a puncture wound is usually left open to allow for bacteria or debris to be removed from the inside.
  • Appropriate treatment of chronic wounds seeks to address the problems at the root of chronic wounds, including ischemia and hypoxia, bacterial load, and imbalance of proteases.
  • Various methods exist to ameliorate the problems associated with wounds including antibiotic and antibacterial use, debridement, irrigation, vacuum-assisted closure, warming, oxygenation, moist wound healing, removing mechanical stress, and adding cells or other materials to secrete or enhance levels of healing factors.
  • many of the foregoing treatments are good temporary measures but are not concerned with, and thus not designed for, optimal wound recovery.
  • the addition of exogenous hair follicle cells to acute wounds can result in regenerated skin, after healing, as long as the hair follicles formed. See, e.g., Prouty et ai, 1997, Lab. Invest. 76: 179-189; and Prouty et ai, 1996, Am. J. Pathol. 148: 1871-1885.
  • chronic wound healing may be speeded by replacing or stimulating those factors and by preventing the excessive formation of proteases like elastase that break them down.
  • VEGF vascular endothelial growth factor
  • IGF insulin-like growth factor 1-2
  • PDGF transforming growth factor- ⁇
  • EGF epidermal growth factor
  • Other treatments include implanting cultured keratinocytes into the wound to re-epithelialize it and culturing and implanting fibroblasts into wounds.
  • SLPI Secretory leukocyte protease inhibitor
  • Some patients are treated with artificial skin substitutes that have fibroblasts and keratinocytes in a matrix of collagen to replicate skin and release growth factors.
  • skin from cadavers is grafted onto wounds, providing a cover to keep out bacteria and preventing the buildup of too much granulation tissue, which can lead to excessive scarring.
  • the allograft skin transplanted from a member of the same species
  • it encourages cellular proliferation and provides a structure for epithelial cells to crawl across.
  • allografts may not work, requiring skin grafts from elsewhere on the patient, which can cause pain and further stress on the patient's system.
  • Collagen dressings are another way to provide the matrix for cellular proliferation and migration, while also keeping the wound moist and absorbing exudate.
  • Skin grafts do not fully address the need for effective scar revision because (1 ) there is a limited supply of donor tissue (typically buttocks, abdomen, legs, in-front or behind the ear, etc.); (2) scarring occurs at donor sites and contractures ⁇ i.e., around the eyes and mouth); and (3) skin grafts typically (but not always) (with the possible exception of scalp) lack qualities of the donor site (porosity, vascularity, color, pigmentation, thickness, texture and overall cosmetic appearance, etc.).
  • the scar is serially excised, and a balloon is implanted at the wound site, which pushes the tissue around the scar to expand.
  • Surgical excision of hypertrophic or keloid scars is often used with other methods such as pressotherapy or silicone gel sheeting (see below). Lone excision of keloid scars shows a high recurrence rate, close to 45%.
  • Surgical excision in combination with the immunomodulator imiquimod 5% cream may also have a benefit on scar reduction.
  • Other intralesional injections can also be used.
  • collagen injections or other soft tissue fillers can be used to raise sunken scars to the level of surrounding skin. Its effects are temporary, however, and it needs to be regularly repeated. There is also a risk in some people of an allergic reaction.
  • Silicone scar treatments improve scar appearance and are often used to prevent and treat hypertrophic scarring.
  • the exact mechanism of action is unknown, though some studies suggest a manipulation of local ionic charges or a decrease in production of "proinflammatory" substances like TGFp2.
  • a manipulation of local ionic charges or a decrease in production of "proinflammatory" substances like TGFp2. See, e.g., uhn et al., 2001 , "Silicone sheeting decreases fibroblast activity and downregulates TGFP2 in hypertrophic scar model," Int J Surg Invest 2:467. Dimethicone silicone gel appears to be is as effective as silicone sheeting in improving scar appearance. See Mustoe TA, 2008, “Evolution of silicone therapy and mechanism of action in scar management," Aesth Plast Surg 32:82-92. Polyurethane bandages are also used.
  • Pressure garments are used under supervision by a medical professional. They are most often used for burn scars that cover a large area, and is only effective on recent scars. Pressure garments are usually custom-made from elastic materials, and fit tightly around the scarring. They work best when they are worn 24 hours a day for six to twelve months. It is believed that they work by applying constant pressure to surface blood vessels and eventually causing scars to flatten and become softer.
  • Needling is an inexpensive process where the scarred area is continuously needled to promote collagen formation. Once needled the area is allowed to fully heal, and needled again if required depending on the intensity of the scar. Scarring needles and needling rollers are available for home use; however, needling should not be done on parts of the face or areas where major nerves are located without professional medical supervision. Needling at home must also be done in line with hygienic and sterilization requirements.
  • Dermabrasion involves the removal of the surface of the skin with specialist equipment and usually involves a general anesthetic. It is useful with raised scars, but is less effective when the scar is sunken below the surrounding skin.
  • Methods for modulating hair growth in human subjects are described, involving the administration of compounds described herein ("Compound") to a human subject in need of such treatment.
  • Methods for inducing or enhancing hair growth in human subjects are described.
  • Methods for hair removal or inhibiting hair growth in human subjects are also described.
  • Methods for promoting or improving wound healing, promoting wound healing with reduced scarring, scar prevention, and scar revision are also described, involving the administration of the Compound to a human subject in need of such treatment.
  • Uses of the Compound for modulating hair growth in human subjects are described. Uses of the Compound for inducing or enhancing hair growth in human subjects are described. Uses of the Compound for hair removal or inhibiting hair growth in human subjects are described. Uses of the Compound for promoting or improving wound healing, promoting wound healing with reduced scarring, scar prevention, and scar revision are also described.
  • compositions comprising the Compound for modulating hair growth in human subjects are described.
  • Pharmaceutical compositions comprising the Compound for inducing or enhancing hair growth in human subjects are described.
  • compositions comprising the Compound for hair removal or inhibiting hair growth in human subjects are described.
  • Pharmaceutical compositions comprising the Compound for promoting or improving wound healing, promoting wound healing with reduced scarring, scar prevention, and scar revision are also described.
  • the Compound inhibits glycogen synthase kinase 3 (GSK-3). In certain embodiments, the Compound inhibits GSK-3beta (GSK-3P). In one embodiment, the Compound is a compound having formula I described hereinbelow. In certain embodiments, the Compound is a compound having formula II or formula III described hereinbelow. In a particular embodiment, the Compound is a compound having formula IV described hereinbelow. In other particular embodiments, the Compound is one of compounds 1-14 described hereinbelow. In another embodiment, the Compound is a compound having formula V described hereinbelow. In particular embodiments, the Compound is one of compounds 15-24 described hereinbelow.
  • the Compound is a compound having formula VI described hereinbelow. In particular embodiments, the Compound is one of compounds 25-32 described hereinbelow. In another embodiment, the Compound is a compound having formula VII described hereinbelow. In another embodiment, the Compound is a compound having formula VIII described hereinbelow. In another embodiment, the Compound is a compound having formula IX described hereinbelow. In another embodiment, the Compound is a compound having formula X described hereinbelow. In particular embodiments, the Compound is one of compounds 33-45. In certain more particular embodiments, the Compound is compound 41.
  • the Compound inhibits the activity of GSK-3P in an in vitro assay, as described in Section 5.7.2 infra. In some embodiments, the Compound inhibits the activity of GS -3P in a cell-based assay, as described in Section 5.7.2 infra. In some embodiments, the Compound modulates the growth of hair in an animal model described herein (see, e.g. , Section 5.7.3 and Sections 10, 16, 24, and 25). In some embodiments, the Compound, either alone or in combination with a therapy described in Section 5.3 infra, promotes hair growth in an animal model described herein.
  • the Compound either alone or in combination with a therapy described in Section 5.3 infra, reduces hair growth in an animal model described herein.
  • the Compound either alone or in combination with a therapy described in Section 5.3 infra, promotes wound healing, e.g., wound healing with reduced scarring, or is used to aid scar revision in an animal model described herein.
  • the Compound is preferably administered topically, but other routes can be employed as well, as such the transdermal, intradermal, cutaneous, subcutaneous, intramuscular, intravenous, oral, sublingual, or buccal routes.
  • Adjuvants that target the Compound to the desired hair follicles or site on the skin may be included in the formulations used. Adjuvants may be incorporated into the formulation to recruit cells from surrounding tissue to the target tissue. Topical formulations and topical treatment methods comprising the Compound are preferred embodiments because high local concentrations can be achieved while minimizing systemic exposure.
  • the Compound may be formulated to be released in a sustained fashion, or in a "pulsed" fashion. In order to achieve a pulsed mode of
  • the Compound may be administered multiple times. Another way to achieve pulsed delivery is to formulate the Compound in beads with multiple coatings, with the Compound contained in alternate coating layers.
  • Other Compound formulations, combinations, and delivery methods for use in the pharmaceutical compositions and treatment methods described herein are described in Sections 5.2 and 5.3 infra.
  • the Compound formulations, including various modified release forms may be delivered topically as additives to shampoos and other hair products, as a lotion, cream, or ointment, or may be delivered using devices such as iontophoresis, micro-needle injection arrays, or auto- injector devices.
  • the Compound may be administered as a single-agent or in combination with other treatments for the enhancement or inhibition of hair growth.
  • the Compound may be administered in combination with other treatments that promote scar revision or wound healing, including wound healing with reduced scarring.
  • Embodiments of the invention include combination therapies involving the addition of other treatment(s) concurrently with, or.before and/or after treatment with the Compound.
  • Such combination therapies can include, but are not limited to, the concurrent or sequential use of other chemical agents, or mechanical or physical treatments including but not limited to low voltage electric current, electrology, laser, intense pulsed light, dermabrasion, or surgical treatments (e.g., hair transplant, strip harvesting, follicular unit extraction (FUE), scalp reduction, etc.) that either promote or inhibit the growth of hair and/or which promote scar revision or wound healing.
  • the Compound is formulated for administration together with the other treatment(s).
  • the Compound is administered concurrently or in
  • treatment with the Compound can be concurrently or in sequential/alternating combination with other agents or treatments that stimulate hair growth.
  • treatment with the Compound can be concurrently or in sequential/alternating combination with other agents or treatments that increase overall hair density in a human subject.
  • the Compound can be administered concurrently or alternating sequentially with one or more of the following agents to promote or induce hair growth: a prostaglandin F2a analog, bimatoprost (Latisse), latanoprost, travoprost, tafluprost, a 5a- reductase inhibitor, minoxidil, kopexil (for example, the product KeraniqueTM), finasteride, CaCb, or adenosine.
  • a prostaglandin F2a analog bimatoprost (Latisse), latanoprost, travoprost, tafluprost, a 5a- reductase inhibitor, minoxidil, kopexil (for example, the product Ker
  • the Compound is administered concurrently or alternating sequentially with one or more agents that prevent hair follicle cells from senescing to promote hair growth and hair follicle formation (which may, in turn, promote wound healing with reduced scarring), for example, anti-oxidants such as glutathione, ascorbic acid, tocopherol, uric acid, or polyphenol antioxidants; activators of Wnt signaling; inhibitors of EGF signaling; inhibitors of BMP signaling; inhibitors of reactive oxygen species (ROS) generation, such as superoxide dismutase inhibitors; stimulators of ROS breakdown, such as selenium; mTOR inhibitors, such as rapamycin; or sirtuins or activators thereof, such as resveratrol, or other SIRT1, SIRT3 activators, or nicotinamide inhibitors.
  • anti-oxidants such as glutathione, ascorbic acid, tocopherol, uric acid, or polyphenol antioxidants
  • activators of Wnt signaling inhibitor
  • the Compound with or without an additional agent for promoting hair growth, can be used in combination with integumental perturbation to promote hair growth and hair follicle formation (which, in turn, may promote wound healing), such as by, e.g., mechanical means, chemical means, electromagnetic means (e.g., using a laser such as one that delivers ablative, non-ablative, non-fractional, superficial, or deep treatment, and/or are CC>2-based, or Erbium- YAG-based, etc.), neodymium:yttrium aluminum garnet (Nd:YAG) laser, etc.), irradiation, radio frequency (RF) ablation, or surgical procedures (e.g., hair transplantation, strip harvesting, follicular unit extraction (FUE), scalp reduction, etc.).
  • a low-level laser therapy treatment e.g., HairMax
  • HairMax can be applied concurrently with administration of the Compound to stimulate hair growth.
  • treatment with the Compound can be in combination with perturbation (e.g., debriding, peeling, or wounding) of the skin and/or other tissues of the integumentary system by methods such as dermabrasion, microneedles, laser treatment, electromagnetic disruption, electroporation, or sonoporation, chemically (e.g., to induce inflammation), or by any other method described herein or known in the art, prior to or concurrent with administration of the Compound.
  • the integumental perturbation procedure can be any "wounding" procedure used for scar revision, or the integumental perturbation has already occurred by virtue of wound formation.
  • the procedure can be controlled to limit perturbation to the epidermis, or extend deeper into the dermis and/or hypodermis.
  • the occurrence of pinpoint bleeding would indicate removal of the epidermis and portions of the upper layer of the dermis.
  • the occurrence of increased bleeding would indicate deeper penetration (and thus perturbation) into the dermis layer.
  • Success of treatment with the Compound can be measured by:
  • Human subjects who are candidates for such treatments include any subject for whom increased hajr growth is desired including, but not limited to, subjects with nonscarring (noncicatricial) alopecia, such as androgenetic alopecia (AGA), including MPHL or FPHL, or any other form of hair loss caused by androgens, toxic alopecia, alopecia areata (including alopecia universalis), scarring (cicatricial) alopecia, pathologic alopecia (caused by, e.g., medication, chemotherapy, trauma, wounds, burns, stress, autoimmune diseases), senescence (age-related hair loss), malnutrition, or endocrine dysfunction), or hypotrichosis, or any other disease, disorder, or form of hair loss as discussed infra and/or known in the art.
  • the invention provides a method for inducing hair growth on the scalp of a male or a female subject with androgenetic alopecia wherein the method comprises in the following order: (a) applying integumental perturbation; (b) administering an inhibitor of GS -3, such as, in particular embodiments, a GS -3beta inhibitor, topically; (c) a period without topical treatment with an inhibitor of GSK-3 and without topical treatment with minoxidil; and (d) administering minoxidil topically.
  • integumental perturbation is performed using dermabrasion with an estimated depth of 100 microns, CHIR99021 is administered topically, and minoxidil is administered in the form of 5% minoxidil foam.
  • an inhibitor of GSK-3 such as, in particular embodiments, a GSK-3beta inhibitor, is administered topically immediately following dermabrasion twice daily for about 1 week, followed by a 3 week period without topical treatment, which in turn is followed by a period of at least 5 months of minoxidil treatment.
  • the invention provides a method for inducing hair growth on the scalp of a male or female subject with androgenetic alopecia, wherein the method comprises:
  • step (d) Immediately following step (c), topical administration of 5% minoxidil foam for at least 5 months.
  • a human subject who is a candidate for treatment with a Compound described herein is a human subject with scarring (cicatricial) alopecia.
  • forms of cicatricial alopecia that may be treated in accordance with the methods described herein include primary cicatricial alopecia (PCA) and secondary cicatricial alopecia.
  • Primary cicatricial alopecias that may be treated in accordance with the methods described herein include lymphocyte-mediated PCAs, such as lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), central centrifugal cicatricial alopecia (CCCA), and pseudopelade (Brocq); neutrophil-mediated PCAs, such as folliculitis decalvans and tufted folliculitis; and PCAs involving a mixed inflammatory infiltrate, such as occurs in dissecting cellulitis and folliculitis keloidalis.
  • lymphocyte-mediated PCAs such as lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), central centrifugal cicatricial alopecia (CCCA), and pseudopelade (Brocq)
  • neutrophil-mediated PCAs such as folliculitis decalvans and tufted folliculitis
  • a method for enhancing hair growth in a patient with scarring alopecia comprising controlled integumental perturbation using a fractional ablative laser, followed by twice daily topical administration of a
  • treatment with a Compound is begun on the same day as the laser treatment.
  • the patient has primary scarring alopecia.
  • the patient has lichen planopilaris.
  • the patient has frontal fibrosing alopecia.
  • Success of treatment such as an intermittent or pulse treatment, with a Compound for scarring alopecia may be measured using the methods described above.
  • successful treatment is determined as an increase in the number of photographically detected hairs.
  • successful treatment is evaluated by a skin biopsy for hair follicle structures and scar attributes. Success may also be measured as a reduction or elimination of itching, burning, pain, and tenderness associated with the condition, or a reduction of scalp redness, scaling, and/or pustules. Success may also be measured as a reduction or elimination of inflammation of the scalp.
  • the Compound is administered concurrently or in sequential combination with a cytotoxic drug, a hair growth retardant, epilation or depilation methods to reduce unwanted hair growth.
  • a cytotoxic drug e.g., a cytotoxic drug, a hair growth retardant, epilation or depilation methods
  • the Compound is administered alternating sequentially with one or more of the following agents or treatments can be used to inhibit unwanted hair growth: eflomithine HC1 (Vaniqa), 5-fluorouracil (5-FU) (e.g., Efudex 5% cream), and/or epilation. Success of treatment can be measured by:
  • Human subjects who are candidates for such treatment include any subject for whom elimination of unwanted visible hair is desired including, but not limited to, those afflicted with hypertrichosis, excess hair in androgen-dependent areas of the skin, idiopathic hirsutism, female post-menopausal facial hair, axillary hair, leg hair, back hair, ear hair, nares or nose hair, or any other disease, disorder, or form of unwanted hair or excessive hair as discussed infra and/or known in the art.
  • the invention is based in part on the realization that human hair follicles and follicular units are relatively unique (among other mammals, particularly non-primates) in that they enter and progress through different stages of the hair Follicle Cycle relatively independently of each other, even independently of neighboring follicles or follicular units. Consequently, the normal biology of human hair patterning is based on a probability distribution of the hair cycle stage that follicles will be in, generated by a stochastic (random) process by which follicles cycle independently.
  • an object of the invention is to synchronize hair follicle growth in the treated area to more effectively promote the growth of terminal hair (in preference to vellus hair); and/or promote the branching of pre-existing hair follicles (seen as an increased number of hair shafts per pore); and/or increase the width of hair follicles (thereby promoting growth of an increased shaft width); and /or promote regeneration of hair follicles or generation of new hair follicles ("follicle neogenesis"); and/or delay or prevent follicle senescence.
  • the object is to inhibit the growth of unwanted hair (as measured by, e.g., decreased terminal hair formation or inhibition of follicle regeneration or generation of new follicles).
  • treatments that promote hair growth may also be used in combination with the Compound in order to promote the establishment of desired hair patterning in a healed wound or revised scar, thereby improving the appearance of the treated skin.
  • treatments that regulate gender-specific specialized human hair follicles including those under the influence of sex-steroid regulation, or that regulate the differentiation of stem cells into gender-specific specialized human hair follicles, possibly resulting in follicles having features that are different from natural follicles in the target location of skin (e.g., normal sized follicles with terminal hair where previously miniaturized follicles with vellus hair were present) may be administered.
  • treatment of grafted skin with a combination of a Compound and a modulator of specific hair patterning may reduce donor dominance and enhance the ability of the graft to acquire properties of the recipient site.
  • Compound treatment such as intermittent or pulse Compound treatment, may be used concurrently or in sequential combination with either a treatment that enhances hair growth (described above) or a cytotoxic drug, a hair growth retardant, such as eflornithine HC1 (Vaniqa), 5-fluorouracil (5- FU) (e.g., Efudex 5% cream), or other epilation or depilation methods to prevent or reduce hair growth, as described supra.
  • a Compound described herein may improve wound healing (including promoting wound healing with reduced scarring) or scar revision, as measured by one or more of the following outcomes:
  • human subjects who are candidates for Compound treatments described herein include any subject in need of improved wound healing, particularly wound healing with reduced scarring, or scar revision.
  • Human subjects who are candidates for such treatments include any subject for whom improved wound healing or scar revision is desired.
  • Such human subjects include, but are not limited to, subjects with photodamaged skin, acne scars, chicken pox scars, scarring (cicatricial) alopecia, chronic non-healing wounds or scars due to, e.g., diabetes, venous or arterial disease, old age or senescence, infection, medication, chemotherapy, trauma, burns, stress, autoimmune disease, malnutrition, or endocrine dysfunction.
  • Surgical subjects who are candidates for such treatments include, but are not limited to, patients with skin graft, hair transplantation, skin cancer surgery, or Mohs surgery.
  • Subjects who are candidates for such treatments also include subjects with any other form of wounding or scarring or disease or disorder associated with wounding or scarring as discussed infra and/or known in the art.
  • the subject has a wound or scar on a cosmetically sensitive location, such as the face or neck.
  • the invention is based in part on the recognition that the timing of the administration of the Compound is important for it to function as an effective modulator of hair follicle formation and wound healing (and thus, scar revision) in human subjects.
  • the Compounds provided herein are potent and specific inhibitors of protein kinase glycogen synthase kinase 3 (GSK-3) (see Ring et ai, 2003, Diabetes 52: 588-595; Bain et ai, 2007, Biochem. J. 408:297-215; Meijer et ai, 2004, Trends in Pharmacological Sciences 25(9): 471 -480).
  • GSK-3P inhibitors are known to increase Wnt signaling, but agents that increase Wnt signaling have had conflicting effects on hair follicle development and wound healing. When continuously present, they stimulate follicle morphogenesis but also induce hair follicle tumors (Gat et ai, 1998, Cell 95: 605- 614) and even lead to decreased hair growth (Millar et ai, 1999, Dev. Biol. 207: 133- 149).
  • the invention is also based, in part, on the principle that human skin is replenished by bone-marrow derived and tissue-derived stem cells throughout life.
  • the Compound is administered in combination with methods that mobilize tissue stem cells (e.g., using integumental perturbation); and/or methods that mobilize bone marrow-derived stem cells (e.g., growth factors such as G-CSF and/or chemical agents such as plerixafor (Mozobil®)); and/or methods that regulate the differentiation of these stem cells into gender-specific specialized human hair follicles (e.g., using agents such as finasteride, fluconazole, spironolactone, flutamide, diazoxide, 17-alpha-hydroxyprogesterone, 1 1 -alpha- hydroxyprogesterone, ketoconazole, RU58841 , dutasteride, fluridil, or QLT-7704, an antiandrogen oligonucleotide, cy
  • Investig. Drugs 14: 177-184 incorporated herein by reference, or any other antiestrogen, an estrogen, or estrogen-like drug (alone or in combination with agents that increase stem cell plasticity; e.g., such as valproate), etc., known in the art), that can result in the appearance of specialized follicles having features that are different from natural follicles in the target location of skin.
  • Such combination treatments can further include the use of agents that enhance the growth of hair (e.g., minoxidil, kopexil (e.g., eranique), finasteride, prostaglandin F2a analogs, bimatoprost (Latisse), latanoprost, travoprost, tafluprost, CaCb, adenosine, a 5a-reductase inhibitor, and others described herein) or aid in the removal of hair (e.g., 5-fluorouracil, eflornithine (Vaniqa), or others described herein).
  • agents that enhance the growth of hair e.g., minoxidil, kopexil (e.g., eranique), finasteride, prostaglandin F2a analogs, bimatoprost (Latisse), latanoprost, travoprost, tafluprost, CaCb, adenosine, a 5
  • the Follicle Stem Cells involved can be derived from (1) other Follicle Stem Cells, (2) from other tissue stem cells, termed “pre-Follicle Stem Cells" (from the interfollicular skin), (3) from bone marrow-derived stem cells (“BMST”), and/or (4) from mesenchymal stem cells such as adipocyte stem cells.
  • pre-Follicle Stem Cells from the interfollicular skin
  • BMST bone marrow-derived stem cells
  • mesenchymal stem cells such as adipocyte stem cells.
  • BMST bone marrow derived stem cells
  • their differentiation into Follicle Stem Cells requires intact follicles, whose cells can play the role of "nurse cells” and provide appropriate signals to guide the differentiation of bone marrow derived stem cells into Follicle Stem Cells.
  • Integumental perturbation (for example, by the induction of inflammation, wounding, or laser treatment) (1 ) provides signals for Follicle Stem Cells to divide symmetrically to begin the process of forming new follicles; (2) mobilizes tissue stem cells ("pre-Follicle Stem Cells") from interfollicular skin to differentiate into stem cells and (3) increases the trafficking of bone marrow derived stem cells to affected areas of skin and promotes their differentiation into Follicle Stem Cells by nurse cells in existing follicles.
  • pre-Follicle Stem Cells tissue stem cells
  • treatment with one or more Compounds provided herein organizes the normally asynchronous state of human hair follicle cells in Cell Cycle and human hair follicles in Follicle Cycle into relatively more synchronous states of human hair follicle cells in Cell Cycle and human hair follicles in Follicle Cycle.
  • the drug spraying device comprises a drug cartridge having two separate chambers that keep drug components isolated until the therapeutic compound is to be dispensed.
  • a device for spraying a therapeutic compound comprising:
  • a device for spraying a therapeutic compound comprises:
  • a hand piece including a housing and a plunger having a connecting portion
  • a drug cartridge housing having a front end and a back end
  • a drug cartridge for use in a device for spraying a therapeutic compound comprises:
  • the drug spraying device disclosed herein enables the sustained release of a GS -3 inhibitor, such as a Compound as defined herein, without the use of highly hydrophobic, occlusive matrices.
  • the drug spraying device enables the delivery of a GSK-3 inhibitor in microspheres (e.g., PLG microspheres) such that the microspheres stay at the wound site for a prolonged period of time and are not cleared rapidly by phagocytosis.
  • a prolonged period of time can be at least 1 , 2, 3 , 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or at least 20 days.
  • the drug spraying device disclosed herein enables the sustained release of a GSK-3 inhibitor and uptake by the skin through a scab.
  • the drug spraying device enables the delivery of a GSK-3 inhibitor such that the delivery system is incorporated into the scab.
  • This can be accomplished by placing a GSK-3 inhibitor containing thin, gauze-like, pliable biodegradable scaffold on the fresh wound. The material properties of the scaffold will be adjusted such the gauze is able to absorb the blood and other exudates from the wound.
  • the biodegradable scaffold has high content of void space, to absorb blood, fibrin and fibrinogen.
  • an in-situ crosslinking hydrogel is applied on top to cover the entire site as a wound dressing.
  • the drug spraying device disclosed herein enables the concurrent delivery of two or more drugs with different solubility properties and/or physical/chemical incompatibilities (such as different excipient requirements; binding and / or reaction of the two or more drugs with each other).
  • the drug spraying device disclosed herein enables the cleansing and administration of one or more drugs with one single device.
  • the contents of each chamber could be sprayed separately.
  • Once chamber can contain the cleansing solution; the liquid in the other chamber contains a GSK-3 inhibitor. Any wound-cleansing solution known to the skilled artisan can be used with these embodiments. 3.1 GLOSSARY OF TERMS FOR HAIR
  • Alopecia Abnormal hair loss.
  • Alopecia areata Hair loss in patches, thought to be caused by an autoimmune response to hair follicles in the anagen stage; extensive forms of the disorder are called alopecia areata totalis (hair loss over the entire scalp) and alopecia areata universalis (hair loss over the entire body).
  • Anagen Growth stage of the hair-Follicle Cycle.
  • Anagen effluvium Abrupt shedding of hair caused by interruption of active hair- follicle growth (e.g., in patients undergoing chemotherapy).
  • AGA Androgenetic alopecia
  • Catagen Stage of the hair cycle characterized by regression and involution of the follicle.
  • Cicatricial (scarring) Alopecia Abnormal hair loss with scarring. Caused by destruction of hair follicles and replacement with scar tissue as a result of inflammation, trauma, fibrosis, or unknown causes; examples include lichen planopilaris and discoid lupus erythematosus.
  • Club hair Fully keratinized, dead hair—the final product of a follicle in the telogen stage; 50 to 150 club hairs are shed daily from a normal scalp.
  • FPHL Female Pattern Hair Loss
  • Follicle cycle Hair growth in each follicle occurs in a cycle that includes the following phases: anagen (growth phase), catagen (involuting/regressing stage), telogen (the quiescent phase), exogen (shedding phase), and re-entry into anagen.
  • Hirsutism Excessive hair growth in androgen-dependent areas in women.
  • Hypertrichosis Excessive hair growth (usually diffuse) beyond that considered normal according to age, race, sex, and skin region.
  • Integumental Pertaining to the integumentary system, which comprises the skin (epidermis, dermis, hypodermis (or subcutanea)) and all cells contained therein regardless of origin, and its appendages (including, e.g., hair and nails).
  • Kenogen Latent phase of hair cycle after hair shaft has been shed and growth is suspended in follicle.
  • Lanugo hair Fine hair on the body of the fetus, usually shed in utero or within weeks after birth.
  • MHL Male Pattern Hair Loss
  • Miniaturization Primary pathological process in androgenetic alopecia, resulting in conversion of large (terminal) hairs into small (vellus) hairs.
  • Permanent alopecia Caused by destruction of hair follicles as a result of inflammation, trauma, fibrosis, or unknown causes; examples include lichen planopilaris and discoid lupus erythematosus. Include diseases referred to as scarring alopecia.
  • Telogen effluvium Excessive shedding of hair caused by an increased proportion of follicles entering the telogen stage; common causes include drugs and fever.
  • Terminal hair Large, usually pigmented hairs on scalp and body.
  • Vellus hair Very short, nonpigmented hairs (e.g. , those found diffusely over nonbeard area of face and bald scalp as a result of miniaturization of terminal hairs).
  • alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkylene may optionally be substituted as described herein.
  • alkyl also encompasses both linear and branched alkyl, unless otherwise specified.
  • the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (Ci_2o), 1 to 15 (C1.15), 1 to 10 (CMO), or 1 to 6 (Ci- ⁇ ) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3.15), 3 to 10 (C3.10), or 3 to 6 (C3.6) carbon atoms.
  • linear Q.6 and branched C3-6 alkyl groups are also referred as "lower alkyl.”
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).
  • Ci. 6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bonds.
  • the alkenyl may be optionally substituted as described herein.
  • alkenyl also embraces radicals having "cis” and “trans” configurations, or alternatively, “Z” and “E” configurations, as appreciated by those of ordinary skill in the art.
  • alkenyl encompasses both linear and branched alkenyl, unless otherwise specified.
  • C 2 -6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2.20), 2 to 1 5 (C2-15), 2 to 10 (C 2 -io), or 2 to 6 (C 2 .6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3.20), 3 to 15 (03.15), 3 to 10 (C3.1t)), or 3 to 6 (C3.6) carbon atoms.
  • alkenyl groups include, but are not limited to, ethenyl, propen-l -yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bonds.
  • the alkynyl may be optionally substituted as described herein.
  • alkynyl also encompasses both linear and branched alkynyl, unless otherwise specified.
  • the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 1 5 (C2-15), 2 to 10 (CMO), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3.20), 3 to 1 5 (C3.15), 3 to 10 (C3.10), or 3 to 6 (C3.6) carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH).
  • C2.6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • cycloalkyl refers to a cyclic saturated bridged and/or non-bridged monovalent hydrocarbon radical, which may be optionally substituted as described herein.
  • the cycloalkyl has from 3 to 20 (C3-20), from 3 to 1 5 (C3.15), from 3 to 10 (C3.10), or from 3 to 7 (C3.7) carbon atoms.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, and adamantyl.
  • aryl refers to a monocyclic aromatic group and/or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20 from 6 to 15 (C6- 15), or from 6 to 10 (C6_io) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may be optionally substituted as described herein.
  • heteroaryl refers to a monocyclic aromatic group and/or multicyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N.
  • Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
  • bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and
  • tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl.
  • heteroaryl may also be optionally substituted as described herein.
  • heterocyclyl refers to a monocyclic non-aromatic ring system and/or multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms.
  • the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclic radicals include, but are not limited to, acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzoisoxazolyl, benzisoxazinyl, benzodioxanyl, benzodioxolyl,
  • benzofuranonyl benzofuranyl, benzonaphthofuranyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl, ⁇ -carbolinyl, carbazolyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dibenzofuranyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydropyranyl, dioxolanyl, dihydropyrazinyl, dihydropyridinyl,
  • dihydropyrazolyl dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1 ,4-dithianyl, furanonyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazopyridinyl, imidazothiazolyl, indazolyl, indolinyl, indolizinyl, indolyl, isobenzotetrahydrofuranyl,
  • phenanthridinyl phenathrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuryl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, tetrazol
  • alkoxy refers to an -OR radical, wherein R is, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each as defined herein.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, n- propoxy, 2-propoxy, n-butoxy, isobutoxy, /erf-butoxy, cyclohexyloxy, phenoxy, benzoxy, and 2-naphthyloxy.
  • alkoxy may be optionally substituted as described herein.
  • alkoxy is Ci_6 alkyl-oxy.
  • halogen refers to fluorine, chlorine, bromine, and/or iodine.
  • Figure 1 Types of human hair follicles.
  • Figure 2 Architecture of the skin.
  • Figure 3 Diagram of human hair follicle.
  • Figure 4 Cellular structure of the human hair bulb.
  • Figure 5 Hamilton Norwood classification of male pattern hair loss (MPHL).
  • FIG. 7 In vitro release of CHIR99021 from a hydrophilic hydrogel matrix comprised of chitosan gluconate and PEG300. In vitro cumulative release of CHIR99021 from a hydrophilic gel matrix using a Franz Cell-type set-up, with a cellulose membrane. The formulation contained 0.1 mg/ml CHIR99021 , 100 mg/ml PEG300, 30 mg ml chitosan gluconate and water.
  • Figure 8 In vitro release of CHIR99021 from a lecithin/PEO-PPO-PEO organogel matrix. In vitro cumulative release of CHIR99021 from a liquid-crystalline lecithin/PEO-PPO-PEO/Lanolin Alcohol organogel using a Franz Cell-type set-up, with a cellulose membrane. Due to low saturated solubility of CH1R99021 in water, the receptor chamber contained 50% PEG300. Analysis was performed by RP-HPLC.
  • FIG. 9 Study Design, Dose Administration and Sampling Schedule For CHIR99021 Pharmacokinetics (DA Model). Skin and Blood were sampled and analyzed for CHIR99021 by LC/MS MS.
  • CHIR99021 has a sustaining presence in skin, but does have clearance from site (FTE Model).
  • Figure 14. A and B. Dose response achieved at all time-points at all dose levels in the DA Model, for (A) skin and (B) whole blood. Dose response is also maintained 48 h after last dose administration. Blood levels are many-fold lower than skin levels, and blood levels at dose levels 0.01 and 0.001 ⁇ g are below the level of detection by LC/MS MS.
  • C and D Dose response to CHIR99021 in (C) skin and (D) blood at 96 hours in mouse DA and FTE models.
  • Figure 16 Trend toward increased number of germs in 10 ⁇ g CHIR99021 treatment group in mouse FTE study. Graph represents a scatterplot with mean ⁇ SD.
  • Figure 17 Trend toward increased area of germ forming region in 10 ⁇ g CHIR99021 treatment group in mouse FTE study. Graph represents a scatterplot with mean ⁇ SD.
  • FIG. 20 Germ density in the total wound area has a statistically significant increase in the 10 ⁇ g CHIR99021 treatment group in the mouse FTE study.
  • Graph represents a scatterplot with mean ⁇ SD.
  • Figure 22 Representative confocal images of coverage of wound with germs in the FTE CHIR99021 study.
  • Figure 23 Coverage for the three highest responding mice from the 10 ⁇ g CHIR99021 FTE group. Representative images were selected as follows: For each group, the four mice closed to the mean for the %GFR/TWA (germ forming region/total wound area) statistic were ranked by their closeness to the two density measurements (germs per GFR and germs per TWA). If the confocal image for the highest ranking mouse was of poor quality, the next images in the rankings were interrogated until one was found to be suitable.
  • %GFR/TWA germ forming region/total wound area
  • FIG. 24 Shaft diameter in CH1R99021 DA experiment. No statistically significant differences were found in this experiment. A small amount of CHIR99021 contaminated the "Placebo.” The Placebo group experiments were subsequently repeated (shown as "Placebo B"), and the amount of CHIR99021 measured in the Placebo B dose categories was confirmed to be below the level of detection.
  • Figure 25 Hair shafts per pore in CHIR99021 DA experiment. No branching observed, no statistical significance detected for parametric 1 -way ANOVA or non- parametric 1-way ANOVA. A small amount of CHIR99021 contaminated the "Placebo.” The Placebo group experiments were subsequently repeated (shown as "Placebo B"), and the amount of CHIR99021 measured in the Placebo B dose categories was confirmed to be below the level of detection.
  • FIG. 26 Shaft density in CHIR99021 DA experiment. No statistically significant differences were found in this experiment. A small amount of CHIR99021 contaminated the "Placebo.” The Placebo group experiments were subsequently repeated (shown as "Placebo B"), and the amount of CHIR99021 measured in the Placebo B dose categories was confirmed to be below the level of detection.
  • FIG. 27 Hair pore density in CHIR99021 DA experiment. No statistically significant differences were found in this experiment. A small amount of CHIR99021 contaminated the "Placebo.” The Placebo group experiments were subsequently repeated (shown as "Placebo B"), and the amount of CHIR99021 measured in the Placebo B dose categories was confirmed to be below the level of detection.
  • Figure 28 Schematic representation of active treatment and control treatment.
  • Figure 29 is a front perspective view of a spraying device, according to an embodiment of the present invention.
  • Figure 30 is a rear perspective view of a spraying device, according to an embodiment of the present invention.
  • Figure 31 is a front perspective view of a spraying device, according to an embodiment of the present invention.
  • Figure 32 is a plan view of showing the components of a hand piece depicted in Figure 29 and Figure 30.
  • Figure 33 is a rear perspective view of a hand piece, according to an embodiment of the present invention.
  • Figure 34 is a plan view of a drug cartridge, according to an embodiment of the present invention.
  • Figure 35 is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 36 is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 37 is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 38 is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 39 is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 40 is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 41 is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 42 is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 43 shows the release of lithium gluconate can be controlled by blend ratio of polymers. Shown is a plot of Percent Cumulative Release of Li+ as a Function of Time in Days, which demonstrates release profiles of four different blends. The micrographs to the left and bottom of the graph show two different polymer blends.
  • Figure 44 is a cross-linking reaction between PEG-AM and PEG-NHS.
  • Figure 45 is a graph depicting the gel time as a function of pH for PEG- NHS PEG-AM hydrogels.
  • Figure 46 is a graph depicting the gel time as a function of PEG concentration for PEG-NHS/PEG-AM hydrogels.
  • Figure 47 is a graph depicting the gel time as a function of total PEG
  • Figure 48 is graph depicting gel time as a function of PEI concentration in Phosphate buffer (0.1 M, 0.2M and 0.5M) for PEG-NHS/PEL hydrogels.
  • Figure 49 is a graph depicting the degree of swelling for PEG-NHS/PEG-AM hydrogels, PEG-NHS PEI hydrogels, and PEG-NHS PEG-AM/Chitosan hydrogels.
  • Figure 50 is a graph depicting the viscosity of PVA solutions as a function of temperature.
  • the left-hand bar for each concentration (x-axis) represents the viscosity at 25 °C and the right-hand bar for each concentration (x-axis) represents the viscosity at 30 °C.
  • Figure 51 shows a standard calibration curve for Li+ determination in film.
  • Figure 52 shows a method for identification of the regenerating zone, based on changes in hair follicle orientation, thickening of epidermis, morphology of adjacent normal - scar - regenerating zone - scar - adjacent normal, lack of pigmented hair shafts in regenerating zone, immature hair follicles within regenerating zone, and loss of subcutaneous fat.
  • Figure 52B shows an example of pigmented hair follicles in the regenerating zone, which was observed in some samples taken from mice treated with full thickness excision wounding followed by administration of topical CHIR99021.
  • samples with pigmented hair follicles in regenerating zone were not scored; samples with pigmented hair follicles were 23x5 (placebo), 23x8 (placebo), 23x29 (0.01 Mg CHIR99021 ), and 23x44 (0.1 ⁇ g CfflR99021).
  • Figure 53 shows examples of the staging of hair follicles by histology.
  • Stage 1 ( Figure 53A): Germ visible as epidermal thickening and increase in number and change in orientation of cells;
  • Stage 2 (Figure 53B): Elongated hair germ with convex proximal end and condensation of dermal fibroblasts;
  • Stage 3 ( Figure 53C): Hair peg with concave basal border;
  • Stage 4 ( Figure 53D): Bulb-like thickening of hair peg, formation of inner root sheath (IRS), and dermal papilla (DP) is longer than wide and enclosed by more than 50%;
  • Stage 5 (Figure 53E): Elongation of IRS halfway up to the follicle, Bulge visible, and DP now almost completely enclosed;
  • Stage 6 ( Figure 53F): Sebocytes form sebaceous glands (SG), hair canal visible, and hair shaft grows up to level of canal;
  • Stage 7 ( Figure 53G): Tip of hair shaft leaves IRS and enters canal
  • Figure 54 shows representative images from histology samples taken from mice treated with full thickness excision wounding followed by administration of topical CHIR99021 , as follows: placebo ( Figure 54A), 0.01 ⁇ g CHIR99021 (Figure 54B); 0.1 ⁇ g CHIR99021 (Figure 54C); 1 ⁇ g CHIR99021 ( Figure 54D); 10 ⁇ g CHIR99021 ( Figure 54E); and 100 ⁇ g CHIR99021 ( Figure 54F).
  • Figure 55 shows results of histology of samples taken from mice treated with full thickness excision wounding followed by administration of topical CHIR99021.
  • Figure 55A shows proportion of stageable hair follicles at or above stage 5.
  • the numbers above the columns represent the number of follicles at or above stage 5 / total number of stageable follicles.
  • Figure 55B shows numbers of hair follicles at stage 4 and below.
  • the numbers above the columns represent the number of follicles at stage 4 and below / total number of stageable follicles.
  • Figure 55C shows average follicle maturity (average germ stage).
  • the numbers above the columns represent the following: (number of tissue sections that had no germs),, (number of tissue sections that were not readable).
  • the Compounds described herein are potent and specific inhibitors of GS -3, and in particular in some embodiments, GSK-3beta.
  • Y is N or CH
  • Ri, R 2 , R3, and R4 are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, cycioalkyl, aryl, heteroaryl, heterocyclyl, or alkoxy;
  • R5 and R 7 are independently hydrogen or halo or optionionally substituted alkyl, cycioalkyl, aryl, aminoalkyl, aminoaralkyl, aminocycloalkylaryl, arylcarboxamidocycloalkylaralkyl, arylcarboxamidocycloalkylaryl, arylcarboxarnidoalkylcycloalkyl, arylcarboxamidoaryl, ary lcarboxam idoalky 1, ary lcarboxam idoaralky 1, ary lcarboxam idoalkoxyalky 1,
  • R6 is hydrogen, carboxyl, nitro, amino, cyano, or an optionally substituted alkyl, aryl, aralkyl, aminoalkyl, aminoaryl, aminoaralkyl, aminoalkoxyalkyl, arylaminoalkyl, arylaminoaryl, arylaminoaralkyl, arylalkylamino, arylalkylaminoalkyl, arylalkylaminoaralkyl,
  • carboxcycloamido acyloxyalkyl, acyloxyaryl, acyloxyaralkyl, acyloxyalkylcycloalkyl, acyloxyalkylaminoalkyl, sulfonylalkyl, carbamylalkyl, carbamylaryl, carbamylaralkyl, carbamylalkylamino, carbamylalkylaminoalkyl, carbamylalkylaminoaryl, or
  • A is pyridyi, pryrimidinyl, thiazolyl, indolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyrazinyl, triazolyl, thiophenyl, furanyl, quinolinyl, purinyl, naphthyl, benzothiazolyl, benzopyridyl, or benzimidazolyl, which can be optionally substituted with from 0 to 3 of the following substitution groups: nitro, amino, cyano, halo, thioamido, amidino, oxamidino,
  • haloloweralkyl loweralkoxy, haloloweralkoxy, loweralkoxyalkyl, loweralkylamino loweralkoxy, loweralkylcarbonyl, loweralkylcarbonyl, lowerheteroaralkylcarbonyl, alkylthio, aminoalkyl or cyanoalkyl.
  • compositions having Formula I or a pharmaceutically salt, solvate, or prodrug thereof, wherein Ri, R2, R3, and R4 are hydrogen.
  • Compounds having Formula I, or a pharmaceutically salt, solvate, or prodrug thereof wherein Ri, R2, R3, and R4 are hydrogen.
  • Compounds having Formula I, or a pharmaceutically salt, solvate, or prodrug thereof wherein Ri, R2, R3, and R4 are hydrogen.
  • Compounds having Formula I, or a pharmaceutically salt, solvate, or prodrug thereof wherein Ri, R2, R3, and R4 are hydrogen.
  • R5, R6, and R are as defined above;
  • Rg and R9 are independently hydrogen, nitro, amino, cyano, halo, thioamido, sulfonamido, carboxyl, formyl, loweralkyl, haloloweralkyl, aminoloweralkyl, cyanolovveralkyl, loweralkoxy, haloloweralkoxy, loweralkoxyalkyl, loweralkylaminoloweralkoxy, alkylthio, aryl, and aralkyl.
  • provided herein are Compounds having Formula II, or a pharmaceutically salt, solvate, or prodrug thereof, wherein R 7 is H. In certain embodiments, provided herein are Compounds having Formula II, or a pharmaceutically salt, solvate, or prodrug thereof, wherein R 7 is H and R 8 is heterocyclyl. In certain embodiments, provided herein are Compounds having Formula II, or a pharmaceutically salt, solvate, or prodrug thereof, wherein R 8 and R9 are independently hydrogen, nitro, cyano, or halo. In certain embodiments, provided herein are Compounds having Formula II or a pharmaceutically salt, solvate, or prodrug thereof, wherein R 8 and R9 are independently hydrogen or cyano.
  • Ri, R , Rs, and R9 are as defined above;
  • Rio, R11, R12, Ri3, and R14 are independently hydrogen, nitro, amino, cyano, halo, thioamido, carboxyl, hydroxy, or optionally substituted loweralkyl, loweralkoxy, loweralkoxyalkyl, haloloweralkyl, haloloweralkoxy, aminoalkyl, alkylamino, alkylthio, alkylcarbonylamino, aralkylcarbonylamino, heteroaralkylcarbonylamino, arylcarbonylamino,
  • heteroarylcarbonylamino aminocarbonyl, loweralkylaminocarbonyl, aminoaralkyl, loweralkylaminoalkyl, aryl, heteroaryl, cycloheteroalkyl, aralkyl, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, arylcarbonyloxyalkyl; alkyloxycarbonylalkyl, heteroarylcarbonyloxyalkyl, aralkylcarbonyloxyalkyl, or heteroaralkylcarbonyloxyalkyl.
  • provided herein are Compounds having Formula IN, or a pharmaceutically salt, solvate, or prodrug thereof, wherein Rio, Rn > i2, R13, and R14 are independently hydrogen, hydroxy, nitro, amino, cyano, or halo.
  • Compounds having Formula III, or a pharmaceutically salt, solvate, or prodrug thereof wherein Rio, Rn, Ri 2 , R13, and R14 are independently hydrogen, hydroxy, nitro, amino, cyano, or halo, and wherein R 8 and R9 are independently hydrogen, nitro, cyano, or halo.
  • provided herein are Compounds having Formula III, or a pharmaceutically salt, solvate, or prodrug thereof, wherein Rio, Rn, Ri 2; R13, and RH are independently hydrogen or halo.
  • provided herein are Compounds having Formula III, or a pharmaceutically salt, solvate, or prodrug thereof, wherein R 7 is H.
  • provided herein are Compounds having Formula III, or a pharmaceutically salt, solvate, or prodrug thereof, wherein R 7 is H and R 8 is heterocyclyl.
  • provided herein are Compounds having Formula III, or a
  • R ⁇ is heterocyclyl
  • R 7 is hydrogen
  • R 8 is hydrogen
  • R9 is cyano
  • Rio is chloro
  • Rn is hydrogen
  • R12 is chloro
  • Rn is hydrogen
  • Ri4 is hydrogen
  • Z is H or Br
  • R is H or CH 3 ;
  • W is H, CH 3 , CI, NH 2 , or N0 2 ;
  • L is H or CI
  • Z is H; X is H; R is H; W is H; L is H; and Y is NOH.
  • Z is H; X is Br; R is H; W is H; L is H; and Y is NOH.
  • provided herein are Compounds having Formula V, wherein R is H.
  • the Compound for use in the methods described herein is not a compound having Formula V.
  • the Compound for use in the methods described herein is not a compound having Formula V- l 8.
  • X and Y are independently O, S, NR 3 , and CR' R 2 ;
  • n 0, 1 , or 2;
  • t 0, 1 , or 2;
  • R 3 and R 4 are independently H, alkyl, aryl, or heterocyclyl
  • X and Y are independently O, S, or NR 3 where R 3 is heterocyclyl.
  • R 3 is 6-membered heterocyclyl with one heteroatom that is nitrogen, optionally being heteroaryl and optionally being oxidized or quaternized.
  • X and Y are both O.
  • X and Y are both O, R b is alkyl, and R a is CH 2 — aryl
  • aryl is optionally substitute with an alkyl, halo, or alkoxy.
  • X and Y are both O, R b is methyl, and R a is benzyl.
  • the Compound for use in the methods described herein is not a compound having Formula VI. In one embodiment, the Compound for use in the methods described herein is not a compound having the Formula VI, wherein X and Y are both O, R b is methyl, and R a is benzyl. In one embodiment, the Compound for use in the methods described herein is not a compound having the Formula Vl-25.
  • X is O, S, or NH (optionally substituted with a lower alkyl);
  • Y is O or NH (optionally substituted with a lower alkyl);
  • Z is N or CH (optionally substituted with a lower alkyl);
  • A is H, F, CI, Br, CN, N0 2 , or lower alkyl
  • B is H, lower alkyl, lower alkoxy, or NH 2 (optionally substituted with one or two lower alkyl).
  • X is S
  • Y is O
  • Z is N
  • A is N0 2
  • B is OCH 3 .
  • A is CI. In another specific embodiment, A is OH. In another specific embodiment, A is C0 2 .
  • a compound of Formula VII is described in International Patent Application Publication No. WO 03/04478, incorporated by reference herein in its entirety and for all purposes.
  • a Compound for use in the methods described herein is not a compound having Formula VII.
  • the Compound for use in the methods described herein is not a compound having Formula VII, wherein X is S, Y is O, Z is N, A is N0 2 , and B is OCH 3 .
  • a Compound having Formula VIII is provided herein.
  • a and E are independently selected from the group consisting of a hydrogen substituted carbon atom and a nitrogen atom; Z is selected from O; alternatively, Z is selected from dihydro; wherein each hydrogen atom is attached by a single bond;
  • R4 and R.5 are independently selected from CI -8 alkyl, C2-8 alkenyl and C2-8 alkynyl optionally substituted with oxo;
  • R 2 is selected from the group consisting of—CI -8 alkyl-, --C2-8 alkenyl-, --C2-8 alkynyl-, "0-(Cl-8)alkyl-0 ⁇ , -0-(C2-8)alkenyl-0 ⁇ , -0-(C2-8)alkynyl-0 ⁇ , ⁇ C(0)--(Cl-8)alkyl- C(0) ⁇ (wherein any of the foregoing alkyl, alkenyl and alkynyl linking groups are straight carbon chains optionally substituted with one to four substituents independently selected from the group consisting of Cl -8 alkyl, Cl-8 alkoxy, Cl -8 alkoxy(Cl -8)alkyl, carboxyl, carboxyl(C l -8)alkyl, -C(0)0-(Cl -8)alkyl, --C1 -8 alkyl-C(0)0-(C l -8)alkyl, amino (substituted with a substituent independently selected from the group consist
  • substituents are optionally substituted with oxo)), cycloalkyl, heterocyclyl, aryl, heteroaryl (wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four substituents independently selected from the group consisting of CI -8 alkyl, CI -8 alkoxy, Cl -8 alkoxy(Cl-8)alkyl, carboxyl, carboxyl(Cl -8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and Cl-4 alkyl), amino(Cl-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and Cl-4 alkyl), halogen, (halo) 1 -3 (Cl-8)alkyl, (halo) 1-3 (Cl-8)alkoxy, hydroxy and hydroxy(Cl-8)alkyl; and, wherein heterocyclyl is optionally substituted with o
  • R 2 is selected from the group consisting of --C2-8 alkynyl-,— 0 ⁇ (Cl -8)alkyl-0 ⁇ , ⁇ 0 ⁇ (C2-8)alkenyl-0 ⁇ , -0-(C2-8)alkynyl-0-, -C(0)-(Cl -8)alkyl-C(0)- (wherein any of the foregoing alkyl, alkenyl and alkynyl linking groups are straight carbon chains optionally substituted with one to four substituents independently selected from the group consisting of Cl-8 alkyl, Cl-8 alkoxy, Cl-8 alkoxy(Cl -8)alkyl, carboxyl, carboxyl(Cl -8)alkyl, -C(0)0-- (Cl -8)alkyl, --C1 -8 alkyl-C(0)0--(Cl -8)alkyl, amino (substituted with a substituent
  • R 8 is selected from the group consisting of Cl -8 alkyl, Cl -8 alkoxy(Cl - 8)alkyl, carboxyl(Cl -8)alkyl, amino(Cl-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and Cl-4 alkyl), hydroxy(Cl -8)alkyl, heterocyclyl(Cl -8)alkyl, aryl(Cl -8)alkyl and heteroaryl(Cl-8)alkyl (wherein the foregoing heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of Cl-8 alkyl, Cl-8 alkoxy, Cl-8 alkoxy(Cl -8)alkyl, carboxyl, carboxyl(Cl -8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and Cl-4 alkyl), amino(Cl-8)
  • a compound of Formula VIII is described in U.S. Patent No. 6,828,327, incorporated herein by reference in its entirety and for all purposes.
  • specific examples of Compounds provided herein are set forth in U.S. Patent No. 6,828,327 as compounds 1 -29, at cols. 15-17, specifically incorporated herein by reference.
  • the Compound for use in the methods described herein is not a Compound having Formula VIII.
  • Ri and R 2 are independently selected from the group consisting of: hydrogen, Cl - 8 alkyl, C2-8 alkenyl, C2-8 alkynyl ⁇ wherein alkyl, alkenyl and alkynyl are optionally substituted with one to two substituents independently selected from the group consisting of - -0-(Cl -8)alkyl, -0--(Cl -8)alkyl-OH, -0-(Cl -8)alkyl-0-(Cl-8)alkyl, -0--(Cl-8)alkyl- NH 2 , --0 ⁇ (Cl -8)alkyl-NH-(Cl -8)alkyl, -0--(Cl -8)alkyl-N[(Cl-8)alkyl] 2 , ⁇ 0 ⁇ (C l -8)alkyl- S--(Cl-8)alkyl, -0--(Cl-8)alkyl-S02 ⁇ (Cl-8)alky
  • X is selected from the group consisting of N and CR5 ;
  • R3 and R 4 are independently selected from the group consisting of hydrogen, Cl -8 alkyl, C2-8 alkenyl, C2-8 alkynyl, Cl -8 alkoxy, --C(0)H, ⁇ C(0) ⁇ (Cl-8)alkyl, -C0 2 H, --C(O)-- 0 ⁇ (Cl-8)alkyl, -C(O)- NH 2 , -C(NH)- NH 2 , -C(0)-NH-(Cl -8)alkyl, -C(0)-N[(C1 -
  • Y and Z are independently selected from the group consisting of O, S, ( ⁇ , ⁇ ) and (H,H); with the proviso that one of Y and Z is O and the other is selected from the group consisting of O, S, ( ⁇ , ⁇ and (H,H); and
  • R5 is selected from the group consisting of hydrogen, halogen, CI -8 alkyl, C2-8 alkenyl, C2-8 alkynyl ⁇ wherein alkyl, alkenyl and alkynyl are optionally substituted with one to two substituents independently selected from the group consisting of amino (substituted with two substituents selected from the group consisting of hydrogen and CI -8 alkyl), cyano, halo, hydroxy, nitro, oxo, aryl and heteroaryl ⁇ , aryl and heteroaryl ⁇ wherein aryl and heteroaryl are optionally substituted with one to two substituents independently selected from the group consisting of C I -8 alkyl, CI -8 alkoxy, amino (substituted with two substituents selected from the group consisting of hydrogen and Cl-8 alkyl), cyano, halo, hydroxy and nitro ⁇ ;
  • a compound of Formula IX is described in U.S. Patent No. 6,849,643, incorporated herein by reference in its entirety and for all purposes.
  • specific examples of Compounds provided herein are set forth in U.S. Patent No. 6,828,327 as compounds 1 -123, at cols. 14- 19, specifically incorporated herein by reference.
  • the Compound for use in the methods described herein is not a Compound having Formula IX.
  • X is or ⁇ N , wherein A is O or S;
  • Y is S, SO, or S0 2 ;
  • n 1 or 2;
  • Z is hydrogen, halo, COOH, COOR, CH 2 COOH, or CH 2 COOR, wherein R is alkyl.
  • Z is in the 3-position.
  • Z is halo.
  • Z is 3-haIo.
  • Z is 3-iodo.
  • n is 1. In a particular embodiment, n is 2. [00258] In a particular embodiment, Y is S. In a particular embodiment, Y is SO. In a particular embodiment, Y is S0 2 .
  • X is .
  • A is O.
  • Y is S, n is 1 , and Z is halo. In a particular embodiment, Y is S, n is 1 , and Z is 3-halo. In a particular embodiment, Y is S, n is 1 , and Z is 3-iodo.
  • A is O
  • Y is S
  • n is 1.
  • Z is halo.
  • X is , A is O, Y is , and Z is 3-halo.
  • X is , A is O, Y is S, n is 1 , and Z is 3-iodo.
  • the compounds are PEGylated.
  • a compound described in Section 5.1 for use in the methods provided herein inhibits the activity of GSK-3P in an in vitro assay, such as described in Section 5.7.2 infra. In some embodiments, a compound described in Section 5.1 for use in the methods provided herein inhibits the activity of GSK-3P in a cell-based assay, such as described in Section 5.7.2 infra. In some embodiments, a compound described in Section 5.1 for use in the methods provided herein modulates the growth of hair in an animal model described herein (see, e.g. , Section 5.7.3, 10, 16, 24, and 25).
  • the compound either alone or in combination with a therapy described in Section 5.3 infra, promotes hair growth in an animal model described herein.
  • the compound either alone or in combination with a therapy described in Section 5.3 infra, reduces hair growth in an animal model described herein.
  • the compound either alone or in combination with a therapy described in Section 5.3 infra, promotes wound healing, e.g. , wound healing with reduced scarring, or improved scar revision in an animal model described herein.
  • compositions and methods disclosed herein may be formulated with a pharmaceutically acceptable carrier (also referred to as a pharmaceutically acceptable excipients), i. e., a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, an encapsulating material, or a complexation agent.
  • a pharmaceutically acceptable carrier also referred to as a pharmaceutically acceptable excipients
  • each component is "pharmaceutically acceptable” in the sense of being chemically compatible with the other ingredients of a pharmaceutical formulation, and biocompatible, when in contact with the biological tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Suitable excipients are well known to those skilled in the art, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the method of administration. For example, forms for topical administration such as a cream may contain excipients not suited for use in transdermal or intravenous administration. The suitability of a particular excipient depends on the specific active ingredients in the dosage form.
  • Exemplary, non-limiting, pharmaceutically acceptable carriers for use in the Compound formulations described herein are the cosmetically acceptable vehicles provided in
  • the Compounds for use in the pharmaceutical compositions and methods disclosed herein may be formulated to include an appropriate aqueous vehicle, including, but not limited to, water, saline, physiological saline or buffered saline (e.g., phosphate buffered saline (PBS)), sodium chloride for injection, Ringers for injection, isotonic dextrose for injection, sterile water for injection, dextrose lactated Ringers for injection, sodium bicarbonate, or albumin for injection.
  • PBS phosphate buffered saline
  • Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, lanolin oil, lanolin alcohol, linoleic acid, linolenic acid and palm seed oil.
  • Suitable water-miscible vehicles include, but are not limited to, ethanol, wool alcohol, 1 ,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone ( ⁇ ), N,N-dimethylacetamide (DMA), and dimethyl sulfoxide (DMSO).
  • the water-miscible vehicle is not DMSO.
  • Suitable antimicrobial agents or preservatives include, but are not limited to, alkyl esters of p- hydroxybenzoic acid, hydantoins derivatives, propionate salts, phenols, cresols, mercurials, phenyoxyethanol, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), butyl, methyl- and propylparabens, sorbic acid, and any of a variety of quarternary ammonium compounds.
  • Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose.
  • Suitable buffering agents include, but are not limited to, phosphate, glutamate and citrate.
  • Suitable antioxidants are those as described herein, including ascorbate, bisulfite and sodium metabisulfite.
  • Suitable local anesthetics include, but are not limited to, procaine hydrochloride, lidocaine and salts thereof, benzocaine and salts thereof and novacaine and salts thereof.
  • Suitable suspending and dispersing agents include but are not limited to sodium carboxymethylcelluose (CMC), hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP).
  • Suitable emulsifying agents include but are not limited to, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to, EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable complexing agents include, but are not limited to, cyclodextrins, including a-cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl-p-cyclodextrin, sulfobutylether-P-cyclodextrin, and sulfobutylether 7- ⁇ - cyclodextrin (CAPTISOL ® , CyDex, Lenexa, S).
  • cyclodextrins including a-cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl-p-cyclodextrin, sulfobutylether-P-cyclodextrin, and sulfobutylether 7- ⁇ - cyclodextrin (CAPTISOL ® , CyDex, Lenexa, S).
  • Soothing preparations may contain sodium bicarbonate (baking soda), and coal tar based products.
  • Formulations may also optionally contain a sunscreen or other skin protectant, or a waterproofing agent.
  • a product for application to the scalp or face may additionally be formulated so that it has easy rinsing, minimal skin/eye irritation, no damage to existing hair, has a thick and/or creamy feel, pleasant fragrance, low toxicity, good biodegradability, and a slightly acidic pH (pH less than 7), since a basic environment weakens the hair by breaking the disulfide bonds in hair keratin.
  • the Compounds for use in the pharmaceutical compositions disclosed herein can be formulated in forms suitable for topical (e.g., applied directly to the skin, transdermal, or intradermal) subcutaneous, intramuscular, intravenous or by other parenteral means, oral administration, sublingual administration, or bucchal administration.
  • the Compounds for use in the methods and uses disclosed herein can be administered in forms suitable for topical (e.g., applied directly to the skin, transdermal, or intradermal) subcutaneous, intramuscular, intravenous or by other parenteral means, oral administration, sublingual administration, or bucchal administration.
  • the topical (e.g., applied directly to the skin, transdermal, or intradermal) administration is accomplished with the use of a mechanical device, such as, e.g., an iontophoretic device.
  • a mechanical device such as, e.g., an iontophoretic device.
  • the Compounds (or combination treatment) can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed- release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Rathbone et al.
  • the Compounds can be administered by a health care practitioner or by the subject. In some embodiments, the subject administers the Compound to him or herself.
  • topical administration is to the skin, either to the skin surface, transdermal ly, or intradermally. Topical administration can be with or without occlusion with a bandage or other type of dressing. In some embodiments, topical administration is to orifices or mucosa, or conjunctival, intracorneal, intraocular, ophthalmic, auricular, nasal, vaginal, urethral, respiratory, and rectal administration. The formulation used for topical administration can be designed to retain the Compound in the skin or to deliver a dose of the Compound systematically. In some embodiments, topical administration of a Compound is combined with another treatment described herein, such as, but not limited to, a technique of integumental perturbation described in Sections 5.3.5 and 5.3.6 infra.
  • Dosage forms that are suitable for topical administration for preferably local but also possible systemic effect, include emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, powders, crystals, foams, films, aerosols, irrigations, sprays, suppositories, sticks, bars, ointments, bandages, wound dressings, microdermabrasion or dermabrasion particles, drops, and transdermal or dermal patches.
  • the topical formulations can also comprise micro- and nano-sized capsules, liposomes, micelles, microspheres, microparticles, nanosystems, e.g.
  • the nano-sized delivery matrix is fabricated through a well- defined process, such as a process to produce the Compound encapsulated in a polymer.
  • the Compound is spontaneously assembled in aqueous solutions, such as in liposomes and micelles.
  • administration is a shampoo or other hair product, tanning product or sun protectant, skin lotion, or cosmetic.
  • the selected formulation will penetrate into the skin and reach the hair follicle.
  • the stratum corneum and/or epidermis are removed by a method of integumental perturbation described herein (including by wounding or scar revision, by laser, or by dermabrasion or microdermabrasion, which is a less vigorous form of dermabrasion), permitting application of the dosage form for topical administration directly into the exposed dermis.
  • the formulation for topical administration will be lipid-based, so that it will penetrate the stratum corneum.
  • the formulation for topical administration will contain a skin penetrant substance, such as, e.g., propylene glycol or transcutol.
  • a formulation in ointment form comprises one or more of the following ingredients: wool alcohol (acetylated lanolin alcohol), hard paraffin, white soft paraffin, liquid paraffin, and water. See, e.g. , Langtry et al. , supra.
  • the selected formulation is inconspicuous when applied to the skin, for example, is colorless, odorless, quickly-absorbing, etc.
  • the selected formulation is applied on the skin surface as a solution, which can crosslink into a hydrogel within a few minutes, thus creating a biocompatible dressing.
  • the hydrogel may be.
  • the solution will absorb into the skin and crosslink into depots releasing drug.
  • the Compound will be used to crosslink the polymer, with release of the Compound controlled by the rate of degradation of the hydrogel.
  • compositions suitable for use in topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, nonaqueous vehicles, antimicrobial agents or preservatives against the growth of
  • microorganisms such as, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
  • Forms for topical administration can also be in the form of ointments, creams, and gels.
  • Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, mineral oil and other oils, white petrolatum, paraffins; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (OAV) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, wool alcohol (acetylated lanolin alcohol), and stearic acid (see, Remington: The Science and
  • Suitable cream base can be oil-in-water or water-in-oil.
  • Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase.
  • the oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
  • Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL ® ; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylerie copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin.
  • dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
  • topical administration is by electrical current, ultrasound, laser light, or mechanical disruption or integumental perturbation. These include
  • electroporation electroporation, RF ablation, laserporation, laser ablation (fractional or non-fractional), non- ablative use of a laser, iontophoresis, phonophoresis, sonophoresis, ultrasound poration, or using a device that accomplishes skin abrasion, or microneedle or needle-free injection, such as topical spray or POWDERJECTTM (Chiron Co ⁇ . ) Emeryville, CA), BIOJECTTM (Bioject Medical Technologies Inc., Tualatin, OR), or JetPeelTM (from TavTech, Tel Aviv, Israel), which uses supersonically accelerated saline to remove epidermis.
  • POWDERJECTTM Chiron Co ⁇ . ) Emeryville, CA
  • BIOJECTTM Bioject Medical Technologies Inc., Tualatin, OR
  • JetPeelTM from TavTech, Tel Aviv, Israel
  • the device for topical administration of a Compound is an automatic injection device worn continuously but delivers the Compound intermittently.
  • the device for topical administration of a Compound is an automatic injection device that is inconspicuous, for example, can be worn without undue discomfort under clothes, in the hair, under a hairpiece, etc.
  • a device for administration of a Compound delivers the Compound at a controlled depth in the skin so that it reaches hair follicles, but entry into the circulation is minimized.
  • integumental perturbation methods such as dermabrasion, laser treatment, or partial thickness or full thickness excision
  • a transdermal particle injection system such as, e.g., a "gene gun.”
  • a transdermal particle injection system such as, e.g., a "gene gun.”
  • Such systems typically accelerate drug or drug particles to supersonic velocities and "shoot" a narrow stream of drug through the stratum corneum.
  • the stratum corneum and epidermis is previously removed using a method of integumental perturbation described herein, and thus the required delivery pressures and velocities can be reduced.
  • a narrow firing stream is used, particularly to accomplish systemic delivery.
  • the particle injection system administers the Compound over a broad area of skin.
  • An exemplary particle delivery device compatible with broad-based skin delivery includes a low pressure / low velocity firing mechanism with a spray nozzle designed to deliver to a broad area.
  • a single-shot device that delivers to a 25-cm 2 area could be fired or used multiple times on the scalp or other skin surface until the entire area is treated.
  • a dry particle spraying mechanism similar to an airbrush or miniature grit-blaster can be used to "paint" drug or drug particles onto the perturbed area.
  • the stratum corneum and epidermis are already removed, e.g., by a method of integumental perturbation described herein, and thus permits effective use of the mechanism using lowered pressure and velocity requirements to achieve dermal delivery.
  • the Compound (and/or additional drug) is present in an aqueous suspension, permitting use of standard aerosol spray can technology to deliver the Compound to the desired skin area.
  • the Compound can be administered using a two-chamber sprayer device, wherein the Compound is dispersed, solubilized, or emulsified in a liquid contained in one of the chambers.
  • the other chamber of the device would contain a liquid ⁇ that is capable of reacting with the drug-containing liquid in the first chamber, to form a physically crosslinked hydrogel or a covalently linked hydrogel.
  • the liquids can react and form a drug-containing bioadhesive hydrogel to deliver the Compound to the desired area.
  • the drug-containing hydrogel will have additional features of supporting cell attachment and proliferation.
  • the Compound will be sprayed as a dry powder that is adherent to the underlying tissue.
  • dermabrasion e.g., using a mechanical device, including microdermabrasion devices that can be used to dermabrade, or alumina-, silica- or ice-based dermabrasion (as described by Webber, U.S. 6,764,493; U.S. 6,726,693; and U.S. 6,306,1 19
  • a mechanical device including microdermabrasion devices that can be used to dermabrade, or alumina-, silica- or ice-based dermabrasion (as described by Webber, U.S. 6,764,493; U.S. 6,726,693; and U.S. 6,306,1 19
  • the device could also fire smaller drug particles that would simultaneously embed in the exposed dermis.
  • the device could switch over to firing drug particles once it is determined that adequate skin disruption has occurred. See, International Patent Application Publication No. WO 2009/061349, which is incorporated herein by reference in its entirety.
  • a standard dermabrasion device can be modified to incorporate any of the devices described above, e.g., a spraying/painting device.
  • a spray nozzle is located behind the dermabrasion wheel such that drug is sprayed into the dermis as it is exposed by the wheel.
  • the dermabrasion device via internal controls, could turn off the abrasion wheel once it is determined that adequate skin disruption has occurred, and switch on the drug spray to convert to drug painting mode.
  • a non-fractional C0 2 or Erbium-YAG laser is combined with drug spraying either without skin disruption, in conjunction with skin disruption, or following skin disruption.
  • a pulsed dye laser (585-595 nm) is combined with drug spraying either before or without skin perturbation, in conjunction with skin perturbation, or following skin perturbation.
  • a fractional non-ablative laser e.g. , an Erbium- YAG laser used at 1540-1550 nm
  • a fractional ablative laser e.g., an Erbium-YAG laser used at 2940 nm or a C0 2 laser used at 10,600 nm
  • drug spraying either without skin perturbation, in conjunction with
  • fractional ablative laser treatment of the skin e.g., an Erbium-YAG laser used at 2940 nm or a C0 2 laser used at 10,600 nm
  • Compound delivery e.g., by invoking inkjet technology, a fractional laser could be combined with a precise delivery means such that as the laser forms a hole in the skin, the inkjet-like delivery component could fill that same hole with drug.
  • fractional ablative laser treatment of the skin e.g.
  • an Erbium-YAG laser used at 2940 nm or a C0 2 laser used at 10,600 nm is combined with Compound delivery.
  • Compound delivery For example, by invoking inkjet technology, use of a non-ablative, fractional laser could be combined with a precise delivery means such that as the laser forms a hole in the skin, the inkjet-like delivery component could fill that same hole with drug.
  • a non-ablative, fractional laser could be combined with a precise delivery means such that as the laser forms a hole in the skin, the inkjet-like delivery component could fill that same hole with drug.
  • topical administration comprises administration of Compound-containing particles.
  • the particles can be delivered to the skin in combination with any of the means above and described elsewhere infra. Additionally, the particles can be designed for intermittent or pulse delivery of the Compound. In one embodiment, particles with different release properties are be delivered simultaneously to achieve pulse delivery.
  • topical administration comprises administration of a Compound-containing formulation that is delivered through channels that are created by the use of micro-needle technology.
  • the formulation can be, e.g., a liquid, a gel or a dry spray.
  • topical administration may be through delivery of a Compound- containing formulation through hollow needles.
  • topical administration comprises administration of a Compound-containing formulation that is delivered into the skin by an iontophoretic patch.
  • a patch can be developed in which the Compound- containing formulation is incorporated.
  • topical administration comprises administration of a Compound-containing formulation that is incorporated into micro-needle shaped
  • biodegradable polymers In one such embodiment, the biodegradable microneedles penetrate the targeted skin tissue, and are optionally left in place to deliver the Compound in a sustained fashion over time.
  • the device or drug sprayer 2 includes a control unit or generator 4, a foot switch 6, a hand piece 8, and a power module 10.
  • the control unit 4 is the interface between the foot switch 6, the hand piece 8, and the power module 10. It serves as the central point of connectivity and provides a user with a means to power the system on or off, load/eject a drug cartridge into/from the hand piece 8, and select the drug delivery speed. To control all of this functionality, the control unit 4 includes at least one circuit board that controls operation of the hand piece 8 via embedded software.
  • the control unit 4 comprises a housing 12 that includes a hand piece connection port 14, a load/eject button 16, a means 18 to control the drug delivery or spray speed, a means 20 to display the drug delivery speed, an on/off switch 22, and a handle 24.
  • the means 18 to control the drug delivery speed includes a pair of up/down buttons and the means 20 to display the drug delivery speed comprises 8 discreet LEDs (light-emitting diodes) that light up to indicate the drug delivery speed.
  • the housing 12 can be made from an injection molded thermoplastic material such as, for example, acrylonitrile butadiene styrene.
  • FIGS 32 and 33 depict an embodiment of the drug sprayer's hand piece 8.
  • the hand piece 8 comprises a housing 26, a drive motor 28, a universal joint 30 and at least one plunger 32. Attached to the end of the hand piece 8 is a drug cartridge 34 that can either be disposable or reusable.
  • the hand piece's housing 26 can be made from an injection molded thermoplastic material such as, for example, acrylonitrile butadiene styrene. It will be readily apparent to those skilled in the art that other materials may be used to construct the hand piece's housing 26.
  • Some therapeutic compounds may quickly become unstable after their components are mixed or some may have a short shelf life unless they are refrigerated. Thus, in order to keep these compounds stable and increase shelf life, the components of the compounds are isolated from each other until the compounds are ready to be administered when they are mixed together forming, for example, a gel, controlled release, drug delivery matrix.
  • Prior devices such as those described in U.S. Patent No. 4,381 ,778, U.S. Patent No. 4,689,042, U.S. Patent No. 5,122,1 17, and U.S. Patent No. 5,423,752, the entirety of each are expressly incorporated herein by reference thereto, have been developed to store drug components separately and then mix the components prior to being dispensed.
  • Figures 34-42 depict embodiments of a drug cartridge having two separate chambers that keep the drug components isolated until the therapeutic compound is to be dispensed.
  • Figures 34-37 depict a drug cartridge 40 that contains two liquid components and its associated hand piece 42.
  • the drug cartridge 40 includes a housing 44 having a front end 46, a back end 48, a nozzle 50, a static mixer 52 having a mixing chamber 54 and two piercing elements 56 that extend from the back end 48 thereof and which are in fluid communication with the mixing chamber 54, two liquid component chambers 58, 60, a first liquid component 62 stored in the first component chamber 58, a second liquid component 64 stored in the second component chamber 60, and a piston 66 inserted into the back end 48 of each component chamber 58, 60 to rearwardly confine each liquid component 62, 64 within its respective component chamber 58, 60.
  • the pistons 66 form an airtight seal with the interior walls of their respective component chambers 58, 60.
  • a pierceable seal 68 is included to seal off the front end of each chamber 58, 60.
  • the piercing elements 56 penetrate the pierceable seals 68 of the first and second component chambers 58, 60, thereby forming a fluid connection between the static mixer 52 and the first and second component chambers 58, 60.
  • the mixing chamber 54 includes mixing elements 70 therein.
  • these mixing elements 70 can be pathways or channels formed in the interior walls of the mixing chamber 54 or can be mixing vanes that cause the liquid components 62, 64 to swirl as they travel through the mixing chamber 54 resulting in turbulent fluid flow, thereby mixing the liquid components 62, 64 together.
  • a user inserts the drug cartridge 40 into the front end 72 of the hand piece 42.
  • detents 74 on the drug cartridge 40 engage detents 76 on the hand piece 42 and lock the drug cartridge 40 and the hand piece 42 together.
  • the connecting portions 78 of each plunger 80 engage a corresponding cavity 82 in the pistons 66, forming a press-fit connection between the two.
  • the pistons 66 move in a corresponding manner.
  • the user When a user desires to dispense the therapeutic compound, the user activates the hand piece 42 via the control unit 4. Activation of the hand piece 42 in turn energizes the drive motor 28, which acts through a universal joint (see Figures 32 and 33) to move or drive the plungers 80 towards the front end 46 of the drug cartridge 40.
  • the pistons 66 move into the component chambers 58, 60 in a corresponding manner, forcing each separate liquid component 62, 64 through the piercing elements 56 and into the mixing chamber 54.
  • the turbulent flow created therein causes the liquid components 62, 64 to mix with each other.
  • the newly mixed components then exit the nozzle 50 as the mixed therapeutic compound 81.
  • the drug sprayer 2 can be used with a drug cartridge 84 that contains a liquid component 86 and a solid component 88.
  • the drug cartridge 84 includes a housing 90 having a front end 92, a back end 94, a lower chamber 96, a nozzle 98, a liquid component chamber 100 that houses the liquid component 86, a solid component chamber 102 that houses the solid component 88, a first piston 104 inserted into the back end of the liquid component chamber 100 to rearwardly confine the liquid component 86 therein, and a second piston 106 inserted into the back end of the solid component chamber 102 to rearwardly confine the solid component 88 therein.
  • the first and second pistons 104, 106 form an airtight seal with the interior walls of the liquid and solid component chambers 100, 102.
  • the front end 92 of the liquid component chamber 100 includes a first one-way or check valve 108 that confines the liquid component 86.
  • the front end 92 of the solid component chamber 102 does not include a check valve. Instead, a second check valve 1 10 is included at the back end of the of the lower chamber 96.
  • An example of such a one-way valve that can be used with the present drug cartridge 84 is a duck bill valve.
  • This configuration of the first and second check valves 108, 1 10 allows the liquid component 86 and the solid component 88 to be stored separate from each other and also closes the front ends of the liquid and solid component chambers 100, 102 forming a sealed volume of air between the first and second pistons 104, 106 and the first and second check valves 108, 1 10.
  • the drug cartridge 84 containing a liquid component 86 and a solid component 88 with the drug sprayer 2, as can be seen in Figures 38-42, a user inserts the drug cartridge 84 into the front end 1 12 of the hand piece 1 14. When inserted, detents 1 16 on the drug cartridge 84 engage detents 1 18 on the hand piece 1 14 and thereby lock the drug cartridge 84 and the hand piece 1 14 together.
  • the hand piece 1 14 for use with the liquid-solid drug cartridge 84 includes a single plunger 120, which is inserted into the solid component chamber 102.
  • the user When a user desires to dispense the therapeutic compound, the user activates the hand piece 1 14 via the control unit 4. Activation of the hand piece 1 14 in turn energizes the drive motor 28, which acts through a universal joint 30 (see Figures 32 and 33) to move the plunger 120. Initially, the plunger 120 is retracted in the direction shown by arrow 126 in Figure 41 causing the second piston 106 to move in a corresponding manner. Because of the air tight seals created by the first and second pistons 104, 106 and the first and second check valves 108, 1 10, as can be seen in Figure 41 , as the second piston 106 retracts, negative pressure or suction is created in the solid component chamber 102.
  • This negative pressure or suction causes the first piston 104 to move in the direction of arrow 128 forcing the liquid component 86 through the first check valve 108 and into the liquid component chamber 102.
  • turbulent fluid flow is created, which operates to mix the liquid and solid components 86, 88 together.
  • the negative pressure within the closed system acts to keep the second check valve 1 10 closed.
  • a user can dispense the mixed drug by reversing the direction of travel of the plunger 120 as shown by arrow 130 in Figure 42. This forces the mixed therapeutic compound 132 through the second check valve 1 10, into the lower chamber 96, and out through the nozzle 98. Pressure acting on the front end of the first check valve 108, forces the first check valve 108 to remain closed during the dispensing operation.
  • the amount of the liquid component 86 that is added to the solid component 88 and, hence, the concentration of the mixed drug can be controlled by adjusting the distance that the plunger 120 is retracted before reversing the direction of travel of the plunger 120 and dispensing the mixed drug. Therefore, for example, the further back that the plunger 120 is retracted, the more liquid component 86 enters into the solid component chamber 102 and thus, the more dilute the therapeutic compound becomes.
  • the first liquid component 62 is a solution comprising a GSK-3 inhibitor salt and the second liquid component 64 is a polymeric solution that comprises a water-soluble polymer that is a solution at room temperature (20-25°C) and below, but gels at physiological temperatures of 32-37°C.
  • the GSK-3 inhibitor concentration in the GSK-3 inhibitor solution can be at least 1.2 times, 1.4 times, 1.6 times, 1.8 times, 2 times, 2.2 times, 2.4 times, 2.6 times, 2.8 times, 3 times, 4 times, or at least 5 times the concentration of the final concentration.
  • the GSK-3 inhibitor solution can be a water-based solution.
  • the liquid component 86 is a polymeric solution that comprises a water-soluble polymer that is a solution at room temperature (20-25°C) and below, but gels at physiological temperatures of 32-37°C and the solid component 88 comprises a GSK-3 inhibitor as described herein (see, e.g. , Section 5.1).
  • either the drug spraying device, the drug cartridge, or both may be manufactured as a disposable.
  • the drug spraying device may be altered so that it is battery powered.
  • the components of the present device can be modified to dispense a therapeutic compound that comprises more than two components that need to be mixed together prior to dispensing.
  • a device for spraying a therapeutic compound comprises:
  • a device for spraying a therapeutic compound comprises:
  • a hand piece including a housing and a plunger having a connecting portion
  • a drug cartridge housing having a front end and a back end
  • a drug cartridge for use in a device for spraying a therapeutic compound comprises:
  • the drug spraying device disclosed herein enables the sustained release of GSK-3 inhibitor, without the use of highly hydrophobic, occlusive matrices.
  • the drug spraying device enables the delivery of GSK-3 inhibitor in microspheres (e.g., PLG microspheres) such that the microspheres stay at the wound site for a prolonged period of time and are not cleared rapidly by phagocytosis.
  • a prolonged period of time can be at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or at least 20 days.
  • the drug spraying device enables the
  • GSK-3 inhibitor microspheres administration of GSK-3 inhibitor microspheres to the tissue such that the microspheres are sequestered to the wound surface by an in-situ crosslinking hydrogel that will form molecular bonds with the tissue surface.
  • An in-situ crosslinking hydrogel cannot be "rubbed” off like an ointment or a cream.
  • the microspheres (that contain the GSK-3 inhibitor) will be sequestered in the hydrogel, releasing GSK-3 inhibitor in a sustained manner.
  • the issue of phagocytosis of the microspheres is overcome.
  • the solid component 88 comprises a polymer macromonomer (Polymer 1 ) (a polymer that can further crosslink - with another component) and microspheres containing a GSK-3 inhibitor.
  • the liquid component 86 comprises another polymer macromonomer (Polymer 2) that is capable of reacting with Polymer 1.
  • Polymer 2 does not contain hydrolytically labile linkages and is stable in water.
  • Example 15 Illustrative embodiments of the use of the presently disclosed drug spraying device to deliver cross-linked microspheres to a wound site are set forth in Example 15 (Section 20).
  • the drug spraying device disclosed herein enables the sustained release of GSK-3 inhibitor and uptake by the skin through a scab.
  • the drug spraying device enables the delivery of GSK-3 inhibitor such that the delivery system is incorporated into the scab. This can be accomplished by placing a GSK-3 inhibitor containing thin, gauze-like, pliable biodegradable scaffold on the fresh wound. The material properties of the scaffold will be adjusted such the gauze is able to absorb the blood and other exudates from the wound.
  • the biodegradable scaffold has high content of void space, to absorb blood, fibrin and fibrinogen.
  • this incorporation of the scaffold into the fibrin clot during its formation results in its incorporation into the fibrous network, also called a scab, after it solidifies.
  • an in-situ crosslinking hydrogel may be applied on top to cover the entire site as a wound dressing.
  • the solid component 88 comprises a polymer
  • polymer 1 (a polymer that can further crosslink with another component) and the liquid component 86 comprises another polymer macromonomer (Polymer 2) that is capable of reacting with Polymer 1.
  • Polymer 2 does not contain hydrolytically labile linkages and is stable in water. Mixing of these two components yields a cross-linking hydrogel that is applied to the wound.
  • the cross-linking hydrogel is applied together with a biodegradable scaffold that comprises GSK-3 inhibitor.
  • the biodegradable scaffold can be in the form a pliable, gauze-like material that is a blend of PLG polymers.
  • Other polymers may be added to the main component (PLG) to impart attributes such as biodegradability, pliability, etc.
  • GS -3 inhibitor can be incorporated in the biodegradable scaffold.
  • the cross-linking hydrogel is applied to the wound before the scaffold is applied; the cross-linking hydrogel is applied to the wound at the same time when the scaffold is applied; the cross-linking hydrogel is applied to the wound after the scaffold is applied.
  • the biodegradable scaffold has an "open-cell” structure that would allow cells to attach themselves, differentiate and proliferate.
  • the scaffold can have other components such as RGD peptides, etc. incorporated to encourage cell attachment.
  • the scaffold can have bioadhesive attributes to keep it "in place.”
  • the drug spraying device disclosed herein enables the concurrent delivery of two or more drugs with different solubility properties and/or physical/chemical incompatibilities (such as different excipient requirements; binding and / or reaction of the two or more drugs with each other).
  • the first liquid component 62 is a first formulated drug and the second liquid component 64 is a second formulated drug.
  • the presently disclosed drug spray device can be engaged for spraying each drug separately.
  • an alcoholic solution ⁇ drug
  • both chambers could contain the same drug, but in different forms and formulated differently to achieve different release profiles.
  • the first liquid component 62 could contain micronized GSK-3 inhibitor suspended in a FDA-approved liquid excipient and the second liquid component 64 can be a dissolved GSK-3 inhibitor in an aqueous sprayable gel. Co-spraying both forms of GSK-3 inhibitor provides instantly-bioavailable, GSK-3 inhibitor and a sustained form of GSK-3 inhibitor made available as the micronized GSK-3 inhibitor dissolves.
  • the drug spraying device disclosed herein enables the cleansing and administration of one or more drugs with one single device.
  • the contents of each chamber could be sprayed separately.
  • Once chamber can contain the cleansing solution; the liquid in the other chamber contains a GSK-3 inhibitor. Any wound-cleansing solution known to the skilled artisan can be used with these embodiments.
  • Example 18 Illustrative embodiments of the use of the presently disclosed drug spraying device to deliver cross-linked biodegradable scaffold to a wound site are set forth in Example 18 (Section 23).
  • Administration can be parenterally by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
  • Compositions for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • compositions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
  • aqueous vehicles water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents,
  • compositions for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot.
  • the compositions are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
  • Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutyl-methacr late, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene- vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
  • Suitable outer polymeric membranes include but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
  • compositions comprising the Compounds disclosed herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration.
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • Compositions for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
  • the Compound treatments may also be administered to skin-derived cells or skin tissue ex vivo.
  • a Compound treatment may be used to enhance the re-association of dissociated hair follicle cells into follicles and their growth and expansion in culture for their implantation into fresh wounds and scar revisions.
  • hair follicles promoted by a Compound treatment are added to the wound before, at the time of, and/or subsequent to, either acute wounding or, more typically, during the wounding that is induced in scar revision.
  • traditional approaches to scar revision such as human skin transplantation, can be efficiently replaced with transplantation of follicular units or other smaller appendage structures from skin.
  • hair follicles can be introduced to the wound by migration or de novo hair follicle neogenesis, or by transplanting one or more of the following skin elements: full skin (xeno-; autologous human), follicular units, dissociated cells (donor dominance; recipient effects), ex vivo-expanded skin and/or follicular units, or human skin equivalents in vivo (universal donors).
  • Engineered human skin, or human skin equivalents can also be used for hair follicle neogenesis and scar revision platforms.
  • Human skin equivalents can be grown and assembled in vitro, with the advantage that they can be grown to theoretically to any size/shape; can be comprised of different types of cells, including keratinocytes (hair follicle derived and non-hair follicle derived), dermal cells (hair follicle derived and non-hair follicle derived), other cell types (e.g., mesenchymal stem cells); can contain cells that are genetically modified to include, e.g. , markers or "inducible" signaling molecules; provide an unlimited and uniform source of human cells; from normal skin based on histology and marker studies; are generally devoid of skin appendages; and can be wounded and show similar wound healing events as in vivo.
  • keratinocytes hair follicle derived and non-hair follicle derived
  • dermal cells hair follicle derived and non-hair follicle derived
  • other cell types e.g., mesenchymal stem cells
  • modified release dosage form refers to a dosage form in which the rate or place of release of the Compound or other active ingredient(s) is different from that of an immediate dosage form when administered by the same route.
  • Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-re lease, and gastric retention dosage forms.
  • compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof.
  • the release rate of the active ingredient(s) can also be modified by varying the particle sizes and
  • the controlled release is achieved by using an adjuvant that causes a depot effect, i.e., that causes an active agent or antigen to be released slowly, leading to prolonged exposure to a target cell or tissue (e.g., cells of the follicle, or, in the case of immunostimulatory adjuvants, prolonged exposure to the immune system).
  • an adjuvant that causes a depot effect i.e., that causes an active agent or antigen to be released slowly, leading to prolonged exposure to a target cell or tissue (e.g., cells of the follicle, or, in the case of immunostimulatory adjuvants, prolonged exposure to the immune system).
  • Examples of formulations for modified release to skin or hair include those described in International Patent Application Publication No. WO 2008/1 15961 , published September 25, 2008, which is incorporated herein by reference in its entirety.
  • Other examples of modified release include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595;
  • the modified release dosage form can be fabricated using a matrix controlled release device known to those skilled in the art. See, Takada et ai, 1999, in Encyclopedia of Controlled Drug Delivery, Mathiowitz E, ed., Vol. 2, Wiley.
  • the modified release dosage form is formulated using an erodible matrix device, which is water-swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • an erodible matrix device which is water-swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen;
  • cellulosics such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT ® , Rohm America, Inc., Piscataway, NJ);
  • degradable lactic acid-glycolic acid copolymers poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methyl methacrylate, ethyl methacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.
  • the compositions are formulated with a non-erodible matrix device.
  • the active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered.
  • Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene,
  • the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
  • modified release dosage forms can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.
  • the modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • an osmotic controlled release device including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • AMT asymmetric membrane technology
  • ECS extruding core system
  • such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core.
  • the semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
  • the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device.
  • an osmotic agent which creates a driving force for transport of water from the environment of use into the core of the device.
  • osmotic agents water- swellable hydrophilic polymers, which are also referred to as "osmopolymers" and
  • hydrogels Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxy ethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid,
  • hydrophilic vinyl and acrylic polymers polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxy ethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid,
  • PVP polyvinylpyrrolidone
  • PVA polyvinyl alcohol
  • PVA/PVP copolymers PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium
  • croscarmellose hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.
  • HEC hydroxyethyl cellulose
  • HPMC hydroxypropyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • CMC carboxymethyl cellulose
  • CEC carboxyethyl
  • sodium alginate sodium alginate
  • polycarbophil gelatin
  • gelatin xanthan gum
  • sodium starch glycolate sodium alginate
  • the other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating.
  • Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, ed
  • Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form.
  • amorphous sugars such as MANNOGEMTM EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time.
  • the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
  • the core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
  • Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water- permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking.
  • Suitable polymers useful in forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG PPG copoly
  • a semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,1 19.
  • Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • the delivery port(s) on the semipermeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos.
  • the total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
  • An osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
  • the osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21 ; Verma et al, Drug Development and Industrial Pharmacy 2000, 26, 695-708; and Verma et al. , J. Controlled Release 2002, 79, 7-27.
  • compositions are formulated as AMT controlled- release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers.
  • AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
  • compositions are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers.
  • the Compound can be loaded into a polymeric solution that consists of a water-soluble polymer that is a solution at room temperature (20-25°C) and below, but gels at physiological temperatures of 32-37°C.
  • the Compound - containing solution can be cooled to 2-8°C to impart a soothing effect, while being sprayed as a liquid spray on the tissue surface. Once sprayed on, the Compound-loaded solution will thicken into a gel, releasing the Compound-containing compound slowly over time.
  • the Compound-loaded solution can be injected as a liquid, to form an in situ depot within the tissue.
  • the Compound-loaded solution can be delivered as a solution, which can flow into orifices of the tissue, such as hair follicles and then, form a gel to release the Compound for follicle-associated conditions, such as MPHL, folliculitis, or another condition described herein.
  • the temperature and time of gelation can be correlated to the concentration of the polymers and the length of the polymer blocks that constitute the polymers.
  • the a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 ⁇ to about 3 mm, about 50 ⁇ to about 2.5 mm, or from about 100 ⁇ to about 1 mm in diameter.
  • Such multiparticulates can be made by the processes known to those skilled in the art, including microfluidization, membrane-controlled emulsification, oil-in-water, water-oil-water and oil-in oil emulsification and homogenization processes, complex coacervation, wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores.
  • microfluidization membrane-controlled emulsification
  • compositions to aid in processing and forming the multiparticulates can themselves constitute the multiparticulate device or can be coated by various film- forming materials, such as enteric polymers, water-swellable, and water-soluble polymers.
  • the multiparticulates can be further processed as a capsule or a tablet.
  • the Compounds for use herein may be formulated with a carrier that delivers the r Compound to the site of action, for example, a follicle in a particular tissue. Such targeted delivery may be preferable in formulations for systemic administration, in order to reduce side effects associated with therapy with the Compound and/or ensure that the Compound reaches only follicles of particular tissues.
  • the carrier may be an aptamer targeted to a particular protein or cell type in the follicle, an antibody or antigen-binding fragment thereof, a virus, virus-like particle, virosome, liposome, micelle, microsphere, nanoparticle, or any other suitable compound.
  • compositions for use in the methods provided herein can also be formulated to be targeted to a particular tissue, follicle, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Pat. Nos. 5,709,874; 5,759,542;
  • targeting is accomplished by the attachment of specific targeting moieties to the delivery systems containing the drug.
  • Targeting moieties can be in the form of antibodies, aptamers or small molecules that bind to specific proteins expressed in specific tissues.
  • Specific or guided targeting can "channel" the drug only to the specific tissue type, thus minimizing distribution to all tissues. This concept is especially useful if the drug causes side effects.
  • microspheres and nanospheres have been utilized, to deliver drugs into the hair follicle. Entry into the hair follicle is governed by the size of the drug-containing spheres, with microspheres of size 0.5-0.7 microns of ideal size for entry.
  • the surface of the microspheres can be functionalized with moieties that bind to specific surfaces in the follicular orifice to "retain" them at the site.
  • These moieties can be non-specific, such as hydrophobic coatings, or cationic coatings, in order to be bioadhesive to cells within the follicle.
  • the moieties can be specific and targeted to certain proteins that are expressed specifically on specific cell membranes. For example, proteins over-expressed on the follicular lymphoma cell surfaces can be targeted by delivery systems that have antibodies or aptamers designed to bind to these proteins.
  • the surface of the delivery systems can also be functionalized with cell-penetrating moieties such as cell-permeable peptides, positively charged polymers that bind to anionic cell surfaces.
  • circumvented is to deliver the Compound locally to the site where hair growth modulation is desired.
  • the Compounds described herein may be delivered locally to any part of the subject in which modulation of hair growth is desired, including, e.g. , the head e.g. , the scalp, cheek, chin, upper lip, lower lip, ears, nose, eyelashes, or eyebrow), neck, abdomen, chest, breast, e.g., the nipples, back, arms, armpits (axillary hair), stomach, genital area, buttocks, legs, hands, or feet of a subject.
  • Compound is applied or administered to wounded or scarred skin.
  • Such local delivery of the Compound can be achieved by topical administration, transdermal, intradermal, subcutaneous (depot effect), or by intramuscular, intravenous and oral routes of delivery in formulations for targeting systemically delivered Compound to desired follicles. Such modes of delivery are discussed supra.
  • enhancement of hair follicle formation, and wound healing or scar revision, in wounded or otherwise integumentally perturbed skin is accomplished by a Compound treatment described herein in combination with a pre-designed biomaterial dressing that may serve as a substrate to encourage a step-wise attachment of keratinocytes and epithelial cells to it, such that formation of an organized extra-cellular matrix (ECM) is enhanced in order to promote wound healing.
  • ECM organized extra-cellular matrix
  • the scaffold for use in combination with a Compound treatment may be comprised of a mesh of a biocompatible, bioabsorbable material that cells recognize and attach to, preferably with ease.
  • these materials can be collagen type I III, hyaluronic acid, chitosan, alginates, or combinations and derivatives thereof or any other such material described herein or known in the art.
  • the mesh scaffold may be neutral, or charged. If the mesh is positively charged, it may permit cells (which are negatively charged) to adhere to it more effectively. If the mesh scaffold is negatively charged, it may contain signaling moieties that the cells will recognize and attach to. For example, polymers such as hyaluronic acid are present already in skin, and thus a mesh comprised of this material is thought to be compatible with cells.
  • the scaffold is pre-fabricated with a fine microstructure that is of the dimension of cells, for example, red blood cells that will initially diffuse throughout the scaffold, or epithelial cells and keratinocytes from surrounding tissue.
  • epitophelial tongue can move with greater ease and organization by crawling on the scaffold mesh.
  • the mesh scaffold has an "open-cell” structure, with the pores inter-connected, much like an open-celled foam.
  • the open, interconnecting nature of the scaffold may allow free diffusion of oxygen and cells, so that optimal organized wound healing can occur.
  • the mesh scaffold has the capacity to hydrate and remain hydrated throughout the wound healing period. This is useful because, without being bound by any theory, drying out of the wound results in an impermeable granular structure that the keratinocytes cannot "crawl upon.”
  • the mesh scaffold has moieties that act as molecular signals to the cells, for example, to aid their proliferation.
  • moieties include, but are not limited to, peptidoglycans and RGD integrin recognition sequences that encourage cell attachment and subsequent proliferation.
  • the mesh scaffold has incorporated within it one or more active agents, for example, a small molecule, or a nucleic acid, or a protein.
  • the additional active agent is a protein, such as noggin or WNT, or is a nucleic acid that encodes noggin or WNT.
  • a small molecule is incorporated into the scaffold, such as, e.g. , a GSK-3 inhibitor (such as one or more Compounds described herein, or another GSK-3 inhibitor), BMP inhibitor, or PPAR antagonist.
  • the compound incorporated in the mesh scaffold is a compound considered for use in the combination therapies described herein, for example, in Section 5.3, especially Sections 5.3.4 and 5.3.7 to 5.3.10.
  • the scaffold may incorporate superoxide dismutase, a free radical quenching molecule that functions in the reduction of inflammation.
  • compounds are included in the mesh scaffold that alter the kinetics of wound healing, for example, that slow wound healing. Such compounds are known in the art and described elsewhere herein.
  • Other compounds that may be incorporated in the mesh scaffold include growth factors that aid in cell proliferation and tissue regeneration.
  • the compounds aid in hair follicle migration or hair follicle neogenesis in the integumentally perturbed or wounded site.
  • the Compound itself is incorporated within the mesh scaffold.
  • the Compound is incorporated within one or more layers of a multilayered mesh scaffold.
  • the mesh scaffold contains the Compound in alternating layers, which may achieve a pulsatile delivery of Compound.
  • the Compound is incorporated in microspheres in the scaffold, enabling a controlled release of Compound from the scaffold.
  • the mesh scaffold can be fibrin gels that additionally contain Compound.
  • a fibrin network is the first scaffold that a cell encounters as it performs its role in healing wounds due to trauma or other insults to tissue.
  • the fibrin network (the "scab") assemble rapidly by a modified polycondensation reaction from fibrinogen, an abundant constituent of blood plasma, as soon as the protease thrombin is activated in the clotting cascade— the result is a three-dimensional network of branching fibers, What is envisioned is a fibrin delivery matrix containing Compound, fibrinogen and thrombin, that "gels" in situ.
  • One issue that is encountered is the ability of Compound to diffuse through the fibrin "scab” - making the drug part of the scab solves this issue.
  • the mesh scaffold is a synthetic biodegradable dressing and Compound delivery system that also acts as a "sponge" and absorbs the exudates bloods from a wound or otherwise integumentally perturbed site.
  • These exudates intercalating with the synthetic scaffold contain an abundance of fibrinogen, thrombin, fibronectin, cell adhesion proteins, growth factors and hyaluronic acid, all of which create an integrated structure that is an attractive matrix for cell attachment /differentiation and delivery of Compound.
  • the release rate of Compound can be modulated by varying the composition of polymers that comprise the synthetic scaffold, or sponge.
  • a synthetic scaffold fabricated out of poly(lactide)-co-(glycolide) (PLG) and poly(lactide) (PLA) can be developed to have varied release profiles of Compound. Changing the ratio of PLA to PLG will change the release profile of the Compound from the scaffold.
  • Other polymers that can utilized to generate synthetic scaffolds are chitosan, carrageenan, alginate, poly(vinyl alcohol), poly(ethylene oxide) (PEO), poly(ethylene oxide)-co-poly(propylene oxide)-co- poly(ethylene oxide) (PEO-PPO-PEO), poly(acrylates) and poly(vinyl pyrrolidone) (PVP).
  • the rate of Compound release from the formulation can be controlled, so that it takes anywhere from 2 hours to 30 days for most (e.g., 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 1 00%) of the Compound to be released.
  • most of the Compound is released from the formulation within 2 hours, within 4 hours, within 8 hours, within 16 hours, within 24 hours, within 36 hours, within 48 hours, within 3 days, within 5 days, within 7 days, within 10 days, within 14 days, within 30 days, or within 2 months or more.
  • the mesh scaffold releases the aforementioned compounds in a timed release manner, acting as a controlled release formulation such as described in Section 5.2.4 above.
  • the compounds may be bound to the mesh scaffold, and are then released at a sustained release manner as a result of de-binding kinetics from the mesh.
  • the compound may be bound to a polymer, which is then incorporated to the mesh scaffold, and which may allow the compound to diffuse from the mesh at a slow rate, resulting in sustained release.
  • the mesh scaffold is extruded as a gel, with certain components of the gel precipitating out to form a mesh in situ.
  • the in situ mesh can be sprayed on the wounded or otherwise perturbed surface, such as tissue that has been extensively burned. A large area can be covered in this manner.
  • the mesh scaffold is pre-fabricated as a dressing or a wrap, to cover large areas of wounded or otherwise perturbed tissue.
  • the mesh scaffold can be cut to size to fit the size of the wound or perturbed site to present a compatible surface for favorable movement of the epithelial tongue.
  • the scaffold is prepared by melt spinning, electrospinning, micromachining, weaving, or other methods known in the art in which open cell foams are fabricated.
  • the mesh scaffold can be fabricated by these methods, with the optional incorporation of additional compound(s) (which are optionally sterilized), then sterilized by gentle ethylene oxide sterilization.
  • the additional compounds are sterilized, and then added to the sterile mesh scaffold.
  • a combinatorial strategy that uses a biodegradable scaffold combined with administration of a Compound formulation described herein (alone or in combination with another treatment, such as described in Section 5.3, especially Sections 5.3.4 and 5.3.7 to 5.3.10) is applied, which may result in the in situ generation of embryonic stem cells or recruitment of cells required for healing following wounding or other form of integumental perturbation.
  • integumental perturbation may be used together with another form of integumental perturbation described in Sections 5.3.5 and 5.3.6 (e.g., dermabrasion accomplished by a standard dermabrader or a laser, deep full-thickness excision (as for deep burns) accomplished by a bulk ablative laser) or integumental perturbation by acute wounds, chronic wounds, or wounds generated for the purpose of scar revision. While not being bound by any theory of how the invention works, such integumental perturbation in combination with a scaffold that administers drug results in the in situ generation of stem cells or recruitment of other cells required for the wound healing process and may facilitate more effective wound healing with little or no scarring. 5.2.5.1 BIODEGRADABLE PROPERTIES
  • the scaffold is biodegradable. Placement of a 3-dimensional biodegradable scaffold in the wound assists the attachment, growth and differentiation of cells.
  • tissue repair has been by autologous cell/tissue transplantation— however, autografts are associated with donor site morbidity and limited availability.
  • An alternative is allografts, but these are susceptible to immune responses and also carry the risk of disease transfer.
  • tissue engineering has emerged as an interdisciplinary field that makes use of biomaterials, cells and factors either alone, or in combination to restore tissues. The tissue engineering strategy generally involves isolation of healthy cells from a patient, followed by their expansion in vitro.
  • a fibrin network is the natural network that forms rapidly due to a polycondensation reaction from fibrinogen, an abundant constituent of blood plasma, as soon as the protease thrombin is activated in the clotting cascade. The fibrin clot then forms a three-dimensional network for cells to attach, for re-epithelialization.
  • the biodegradability of the scaffold is modulated.
  • the biodegradability of the scaffold should be matched to the formation of the new epithelium due to wound healing or other form of integumental perturbation.
  • One skilled in the art would know how to measure whether a synthetic matrix is biodegradable.
  • biodegradability can be measured ex vivo in implants or using rats or another animal model, by histological and HPLC analysis.
  • biodegradability by hydrolysis can be assessed.
  • the scaffold structure of choice is incubated in phosphate buffered saline, pH 7.4 and 37 °C.
  • the incubation buffer includes enzymes.
  • the scaffolds are weighed prior to incubation.
  • the scaffolds are retrieved two-at-a-time at predetermined time points and dried in a vacuum oven.
  • the scaffolds are weighed at each time point and a plot of weight versus time is generated to develop the rate of biodegradability.
  • the biodegradability of the scaffold matrix is modulated to coincide with the healing process, and can be modulated by changing the composition of polymers utilized to fabricate the mesh.
  • a percentage of polyethylene glycol (PEG) can be included in a composition with PLG to increase biodegradation (for example, see ASTM El 279 - 89, 2008, Standard Test Method for Biodegradation By a Shake-Flask Die-Away Method).
  • Biodegradable synthetic matrices can be created to mimic the extra-cellular micro- environment for the enhanced cellular attachment necessary for tissue regeneration.
  • cell-recognition motifs such as RGD peptides may be incorporated to encourage cells to attach themselves to the scaffold.
  • biomimetic nature of the scaffold is judged on the basis of the content of the mesh and resultant intercalating fibrin.
  • the properties of the synthetic scaffold are dependent upon the three-dimensional geometry, matching of the modulus of the matrix with the tissue type and the porosity. It has been shown that the differentiation process can be modulated if the modulus of the tissue type is matched with the modulus of the scaffold.
  • the modulus of the scaffold is matched with the modulus of the tissue type.
  • the compressive modulus of a scaffold or hydrogel can be measured by a standard Instron instrument (e.g., using the TA Instruments DMA Q800).
  • the micro-environment created by the cells is optimally highly biocompatible to the cells present at the site, namely keratinocytes and stem cells derived from the dermal papilla.
  • this can be accomplished through the use of hydrophilic components that can absorb water.
  • hydrophobic components such as petrolatum is likely to be occlusive and prevent rapid cell proliferation.
  • the scaffold is incubated with human foreskin fibroblasts (HFF) in vitro and the scaffold is considered to be biocompatible if the cells maintain their shape and attach appropriately.
  • HFF human foreskin fibroblasts
  • the biodegradable scaffold is permeable to water, nutrients, oxygen and growth factors, enabling easy exchange of nutrients between tissues and.cells (see, e.g., ASTM D39857). In some embodiments, a non-occlusive, non-permeable barrier is avoided.
  • the scaffold is used to "fill" a deep wound, as is common in a deep burn, to provide a matrix for the cells to attach, grow and differentiate - existence of the scaffold will likely minimize the scar formation normally observed in deep, large-area wounds.
  • a loose, dry, highly poroiis network or scaffold or mesh is placed in the bleeding site of the wound or otherwise integumentally perturbed site to gently absorb the blood and the cell adhesion proteins released at the site.
  • biocompatible hydrogel suitable for cell attachment and growth suitable for cell attachment and growth.
  • inclusion of blood components and cell adhesion proteins into the network is critical for establishment of the ECM (extracellular matrix) necessary to form continuous tissue ingrowth, particularly in the case of large-area and deep wounds.
  • a dry scaffold has the added advantage of absorbing the blood at the wound or otherwise integumentally perturbed site.
  • a person's own blood components can be used to create a combined synthetic/natural ECM.
  • the scaffold has an added advantage of serving as a blood absorbing gauze.
  • the scaffold has cell-recognition motifs, such as RGD peptides, to recruit cells to the site and attachment, thereof. Once attached, cells will proliferate. Without being bound by any theory, it is hypothesized that the primary attachment of cells to the scaffold is a critical step to prevent premature cell death.
  • a dry, sterile biodegradable scaffold is placed onto the freshly formed wound or perturbed skin site. The properties of the scaffold will be such that it will transform into an adherent hydrogel upon water absorption.
  • Methods that may be employed to fabricate the scaffold are known in the art, and include electrospinning, micromachining, and others. Nano-fiber meshes fabricated by electrospinning, hydrogel imprint technologies have been utilized to create three-dimensional microstructures that match the supramolecular architecture of the tissue type. In situ forming scaffolds are also contemplated.
  • the active agents are administered using an active agent-containing spray-on hydrogel.
  • the active agent after placement of the biodegradable scaffold, the active agent is sprayed on the tissue.
  • the active agent (or combination of active agents, e.g., a Compound and a stem cell signaling agent) may be incorporated into a spray-on hydrogel that will be sprayed on as a liquid, but which transforms into a hydrogel after it is sprayed on the tissue. This will be especially useful if the area of the wound or integumental perturbation is large and uniform coverage is needed.
  • the active agent-containing spray-on hydrogel is applied on the wound or otherwise integumentally perturbed site, forming a cross-linked hydrogel that releases active agent over the time period of healing or a shorter or longer time period, as nec.essary.
  • the active agent will either be incorporated in micro-encapsulates or nano-encapsulates and suspended into the pre-hydrogel solution.
  • the active agent can also be dissolved into the pre-hydrogel solution.
  • the "pre-hydrogel" solution is defined as the solution that will be sprayed on the tissue and which also contains the active agent.
  • the active agent is contained within microspheres that can be positively charged to rapidly bind themselves to the negatively charged collagen present in the dermis. Binding the microspheres to the dermis renders the active agent-releasing moiety immobile at the site.
  • integumentally perturbed site may be covered with a breathable, non-occlusive spray-on hydrogel to cover the site from infection during healing.
  • the Compound or formulation thereof can be administered topically, subcutaneously, orally, etc. Regardless of the route of administration used for Compound delivery, the dosing regimen should be adjusted so that maximum benefit is achieved while reducing potential side effects.
  • a Compound is administered in a formulation ⁇ e.g., a topical form) such that the maximum level of Compound measured in the blood is below the IC50 for GSK-3P inhibition.
  • a Compound that is topically administered reaches a maximum level greater or equal to the IC50 for GS -3P inhibition in skin. In one such embodiment, the Compound never reaches a level greater than the IC50 for GSK-3p in blood.
  • the target concentration of Compound should be maintained in the skin or blood, and preferably the skin, for at least 1 day; at least 2 days; at least 3 days; at least 4 days; at least 5 days; at least 6 days; at least 7 days; at least 8 days; at least 9 days; at least 10 days; at least 1 1 days; at least 12 days; at least 13 days; at least 14 days; at least 15 days; at least 16 days; at least 19 days; or at least 21 days; and, in certain embodiments, not more than 28 days.
  • This can be accomplished using, e.g., repeated applications of the Compound or a single application of a sustained release or extended release Compound formulation.
  • either a single pulse protocol or intermittent treatments can be used to achieve the target concentration of Compound for the shorter maintenance periods ⁇ i.e., for at least 1 , 2 or 3 days). Maintenance periods longer than 3 days may require repeated application of the Compound treatments, such as intermittent
  • Compound treatments or the single pulse protocol In some embodiments, it is preferable to allow the concentration of Compound to decline between dosages, in order to achieve a pulsatile effect.
  • topical administration of a Compound is preferred over oral or subcutaneous administration.
  • a topically administered Compound may achieve a higher concentration of Compound in skin than in the blood, thereby reducing the risk of toxicity that may be associated with elevated blood levels of Compound.
  • a subcutaneously or orally administered Compound may be preferred in order to achieve a controlled release of Compound from the blood to the skin.
  • care should be taken to avoid toxicity.
  • a dosage should be chosen that maximizes efficacy while minimizing toxicity. Such a dosage may be chosen using the assays described in Section 5.7. Patients should be monitored for toxic side effects according to standard clinical practice.
  • Compound doses should be adjusted on the basis of the blood concentration (serum or plasma) drawn (by convention) 12 or 24 hours after the last dose of the Compound. It may be possible to predict dosage requirements for an individual patient based on the results of administration of a single test dose, followed by a skin and/or blood sample assay (plasma or serum) at the peak concentration time; followed by blood sample assays to monitor toxicity at the 12 hour or 24 hour trough concentration; and 24 or 48 or 96 hours later (when Compound is generally eliminated) which serves as the control value. Once the dose is established for a patient, routine monitoring for toxicity is recommended.
  • an effective amount of Compound is administered such that the target concentration of Compound in plasma or serum, as measured 30 minutes to 1 hour after the Compound treatment, is 0.1 -1.0 nM, 1.0-l O nM, 10-50 nM, 50-100 nM, 100- 500 nM, 0.5-1.0 ⁇ , 1.0 ⁇ -2.0 ⁇ , 2.0-2.5 ⁇ , 2.5-3.0 ⁇ , or 3.0 ⁇ or greater.
  • an effective amount of Compound is administered such that the plasma or serum Compound concentration measured either 8 hours, 16 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month after the Compound treatment is 0.1 to 1 nM, 0.5 to 1.5 nM, 1 to 10 nM, 10 to 50 nM, 50 to 100 nM, 100 to 150 nM, 150 to 200 nM, 250 to 300 nM, 100 to 250 nM, 100 to 500 nM, 200 to 400 nM, 500 to 1000 nM; or 1000 to less than 100000 nM.
  • the plasma or serum Compound concentration reaches at least 1 nM.
  • the peak plasma level never reaches greater than 1 ⁇ .
  • Compound concentration may be measured using methods of liquid chromatography and/or mass spectrometry, which are well known in the art.
  • an amount of Compound is administered such that the target concentration of Compound in the skin is 0.1 nM to 1 nM, 1 nM to 10 nM, 10-100 nM, 100-500 nM, 500-1000 nM, 1 to 1.5 ⁇ , 1. to 2.5 ⁇ , 1 to 5 ⁇ , 5 to 10 ⁇ , 10 ⁇ 50 ⁇ , 50 to 100 ⁇ , 100 to 150 ⁇ , 150 to 200 ⁇ , 250 to 300 ⁇ , 100 to 250 ⁇ , 100 to 500 ⁇ , 200 to 400 ⁇ , 500 to 1000 ⁇ , 1 to 10 mM, 10 to 100 mM, 100 to 200 mM, or 500 to 1000 mM.
  • the concentration of Compound achieved in the skin is greater than 0.1 nM. In some embodiments, the concentration of Compound achieved in the skin is greater than 1 nM. In some embodiments, the concentration of Compound achieved in the skin is greater than 100 nM. In some embodiments, the concentration of Compound achieved in the skin is greater than 500 nM. In one embodiment, the concentration of Compound achieved in the skin is approximately 10-100 nM. In one embodiment, the concentration of Compound achieved in the skin is approximately 100-1000 nM. In one embodiment, the concentration of Compound achieved in the skin is approximately 1 ⁇ to 10 ⁇ . In one embodiment, the concentration of Compound achieved in the skin is approximately 10-100 ⁇ .
  • an amount of Compound is administered such that the concentration of Compound delivered to the skin is 0.0000001 mg/ml to 0.000001 mg ml, 0.000001 mg/ml to 0.00001 mg/ml, 0.00001 mg/ml to 0.0001 mg/ml, 0.0001 mg/ml to 0.001 mg/ml, 0.001 mg/ml to 0.01 mg/ml, 0.01 mg/m
  • the concentration of Compound delivered to the stratum corneum is 0.0000001 mg/ml to 0.000001 mg/ml, 0.000001 mg/ml to 0.00001 mg/ml, 0.00001 mg/ml to 0.0001 mg/ml, 0.0001 mg/ml to 0.001 mg/ml, 0.001 mg/ml to 0.01 mg/ml, 0.01 mg/ml to 0.1 mg/ml, 0.1 mg/ml to 1 mg/ml, 1 mg/ml to 10 mg/ml.
  • One of skill in the art would be able to measure Compound
  • mass spectroscopy e.g., inductively coupled plasma mass spectroscopy (ICP-MS), of the LC/MS/MS assay used herein.
  • ICP-MS inductively coupled plasma mass spectroscopy
  • the Compound concentration is measured in the hair shaft using techniques known in the art, e.g., Tsanaclis & Wicks, 2007, Forensic Science Intl. 176: 19-22, which is incorporated by reference herein in its entirety.
  • the Compound can be applied topically, e.g., as a cream, gel, ointment, or other form for topical administration as described in Section 5.2.2.1 supra.
  • the Compound can be formulated as a pharmaceutical composition for topical administration.
  • topical Compound is administered twice daily. In some embodiments, topical Compound is administered once daily.
  • the form of the Compound for topical administration e.g., gel, cream, ointment, salve, etc.
  • the form of the Compound for topical administration comprises, w/w, 0.000001 %, 0.00001 %, 0.0001 % Compound, 0.001% Compound, 0.01 % Compound, 0.1 % Compound, 0.5% Compound, 1 % Compound, and 10% Compound.
  • the form of the Compound for topical administration comprises, w/w, 0.000001 % to 0.00001 % Compound, 0.00001 % to 0.0001 % Compound, 0.0001 % to 0.001% Compound, 0.001 % to 0.01 % Compound, 0.01 % to 0.1 % Compound, 0.1% to 1.0%
  • the form of the Compound for topical administration is 0.00001% to 1.0% w/w Compound.
  • a topical formulation is formulated such that 0.01 mg Compound per kg of patient weight (mg/kg) is administered, or 0.02 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2 mg/kg, 5.0 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 550 mg/kg, 600 mg/kg, 650 mg/kg, 700 mg/kg, 750 mg/kg, 800 mg/kg, 850 mg/kg, 900 mg/kg, 950 mg/kg, 1000 mg/kg, or 1500 mg/kg is administered.
  • the topical formulation contains a dose in the range of about 0.01 mg/kg to about 0.1 mg/kg, 0.02 mg/kg to about 0.2 mg/kg, 0.1 mg/kg to about 1 mg/kg, 0.2 mg/kg to about 2 mg/kg, 0.01 mg/kg to about 2 mg/kg, 0.1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, about 2 mg/kg to about 10 mg/kg, about 100 mg/kg to about 1 g/kg, about 125 mg/kg to about 500 mg/kg, or about 150 mg/kg to about 300 mg/kg of Compound.
  • the topical formulation contains a dose in the range of about 0.01 mg/kg to about 1 mg/kg.
  • the topical formulation contains a dose in the range of about 0.02 mg/kg to about 2 mg/kg.
  • the concentration of Compound in a particular topical formulation to deliver the intended dose of Compound will depend on the release properties of the Compound, the hydrophobic ity of the Compound, the partition coefficient of the Compound, etc.
  • the amount of Compound to generate a topical formulation with one of the aforementioned concentrations of Compound is readily deducible by one of ordinary skill in the art, and depends upon several factors including, e.g. , its salt form, stability, release properties, its hydrophobic ity or hydrophilicity, etc.
  • an oral formulation is administered.
  • the Compound can be formulated for oral administration.
  • the oral formulation is administered, as determined by the medical practitioner, once daily; in other embodiments, the oral formulation is administered twice daily.
  • the oral formulation contains a dose in the range of about 0.1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, about 2 mg/kg to about 10 mg/kg, about 100 mg/kg to about 1 g/kg, about 125 mg/kg to about 500 mg/kg, or about 150 mg/kg to about 300 mg/kg of Compound.
  • the maximum dosage that may be administered at any one time may vary depending on the release kinetics of the Compound and the concentration of efficacy of the formulation.
  • a pulse Compound treatment can be administered one time, or multiple times at intervals of time.
  • the Compound is administered one time per week. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • a pulse Compound treatment is administered before wounding or other form of integumental perturbation.
  • a pulse Compound treatment is administered at the time of wounding or other form of integumental perturbation.
  • a pulse Compound treatment is administered following wounding or other form of integumental perturbation.
  • the pulse Compound treatment in which a pulse Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the pulse Compound treatment is administered before scab formation. In one embodiment, in which a pulse Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the pulse Compound treatment is administered during scab formation. In one embodiment, in which a pulse Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the pulse Compound treatment is administered periscab detachment.
  • the pulse Compound treatment in which a pulse Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, is administered immediately after scab detachment. In one embodiment, in which a pulse Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the pulse Compound treatment is administered 1 hour after scab detachment. In one embodiment, in which a pulse Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the pulse
  • Compound treatment is administered up to 6 hours after scab detachment.
  • a pulse Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the pulse
  • Compound treatment is administered 6-12 hours after scab detachment. In one embodiment, in which a pulse Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the pulse Compound treatment is administered 12-18 hours after scab detachment. In one embodiment, in which a pulse Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the pulse Compound treatment is administered 18-24 hours after scab detachment. In one embodiment, in which a pulse Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the pulse Compound treatment is administered 1 day after scab detachment.
  • the pulse Compound treatment in which a pulse Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, is administered 2 days after scab detachment. In one embodiment, in which a pulse Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the pulse
  • Compound treatment is administered 3 days after scab detachment.
  • the pulse Compound treatment is administered within 2 days, 3 days, 5 days, 7 days, 10 days, 2 weeks, 3 weeks, or 4 weeks after wounding or other form of integumental perturbation.
  • the pulse Compound treatment is administered at the time of wounding or other form of integumental perturbation and then maintained for 1 or 2 or 3 or 4 or 5 days thereafter (in some embodiments, a scab forms during this time).
  • a pulse Compound treatment is administered as soon as the scab falls off and maintained for 3 or 4 or 5 days. In one embodiment, the pulse Compound treatment is administered at the time of integumental perturbation and then maintained for 7 or 10 or 12 or 14 days thereafter (in some embodiments, a scab forms during this time). In some embodiments, a pulse Compound treatment is administered as soon as the scab falls off and maintained for 7 or 10 or 12 or 14 days. In one embodiment, the pulse Compound treatment is administered at the time of integumental perturbation and then maintained for 19 or 21 days thereafter (in some embodiments, a scab forms during this time). In some embodiments, a pulse Compound treatment is administered as soon as the scab falls off and maintained for 19 or 21 days.
  • the pulse Compound treatment is administered in order to modulate the neoepidermis that forms underneath the scab.
  • the pulse Compound treatment is administered at the time of wounding or other form of integumental perturbation and is maintained up to some time after scab falls off, for example, between 5 - 14 days following integumental perturbation.
  • the course of treatment with Compound is short, for example, limited to one or a few days just following scab detachment, or even continued only for as long as the scab is still attached.
  • the timing of wounding or other form of integumental perturbation and Compound administration is preferably monitored and adjusted so that optimal results are achieved.
  • a pulse treatment is combined with a form of wounding or other form of integumental perturbation that does not lead to formation of a scab.
  • the pulse Compound treatment is administered before wounding or other form of integumental perturbation.
  • the pulse Compound treatment is administered at the time of wounding or other form of integumental perturbation.
  • a pulse Compound treatment is administered following wounding or other form of integumental perturbation.
  • the pulse Compound treatment is administered following wounding or other form of integumental perturbation that does not lead to formation of a scab
  • the pulse Compound treatment is administered within 15 minutes of, or 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 10 days, 2 weeks, or 3 weeks after the wound or other form of integumental perturbation.
  • An intermittent Compound treatment can be administered one time (e.g., using a controlled release formulation), or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • Compound can be administered daily (e.g., once, twice or three times daily) for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days; at least 7 days; and in some embodiments not more than 14 days.
  • Compound can be administered daily (e.g. , once, twice or three times daily) for at least 12 days, 14 days, at least 16 days, at least 19 days, or at least 21 days; in some embodiments not more than 21 days.
  • Holidays can be interspersed for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 7 days; and in some embodiments not more than 14 days.
  • the holiday is one week.
  • holidays are interspersed for at least 14 days, 21 days, 28 days, or longer.
  • an intermittent Compound treatment is begun before wounding or other form of integumental perturbation. In some embodiments, an intermittent Compound treatment is begun at the time of wounding or other form of integumental perturbation. In some embodiments, an intermittent Compound treatment is begun following wounding or other form of integumental perturbation.
  • an intermittent Compound treatment is begun following a wound or other form of integumental perturbation that leads to formation of a scab
  • the intermittent Compound treatment is begun following wounding or other form of integumental perturbation.
  • the intermittent Compound treatment is begun before scab formation.
  • the intermittent Compound treatment is begun during scab formation.
  • the first administration of Compound in the intermittent Compound treatment is before scab detachment. In one embodiment, in which an intermittent Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the first administration of Compound in the intermittent Compound treatment is periscab detachment. In one embodiment, in which the intermittent Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the first administration of Compound is immediately after scab detachment.
  • the first administration of Compound is up to 6 hours after scab detachment. In one embodiment, in which the intermittent Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the first administration of Compound is 6-12 hours after scab detachment. In one embodiment, in which the intermittent Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the first administration of Compound is 12-18 hours after scab detachment.
  • the first administration of Compound is 18-24 hours after scab detachment. In one embodiment, in which the intermittent Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the first administration of Compound is 1 day after scab detachment. In one embodiment, in which the intermittent Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the first administration of Compound is 2 days after scab detachment.
  • the first administration of Compound is 3 days after scab detachment. In one embodiment, in which the intermittent Compound treatment is administered following a wound or other form of integumental perturbation that leads to formation of a scab, the first administration of Compound is administered immediately after scab detachment, followed by another administration each day for several days to 1 week.
  • Compound treatment is begun following a wound or other form of integumental perturbation that leads to formation of a scab.
  • Compound treatment is begun within 3 days, 5 days, 7 days, 10 days, 2 weeks, or 3 weeks after integumental perturbation.
  • the intermittent Compound treatment is begun at the time of wounding or other form of integumental perturbation and then administered daily (or twice daily) for 1 or 2 or 3 or 4 or 5 days thereafter (in some embodiments, a scab forms during this time). In some embodiments, the intermittent Compound treatment is begun as soon as the scab falls off, and administered daily for 5 days. In some embodiments, the intermittent Compound treatment is begun at the time of integumental perturbation and then maintained for 7 or 10 or 12 or 14 days thereafter (in some embodiments, a scab forms during this time). In some embodiments, an intermittent Compound treatment is begun as soon as the scab falls off and maintained for 7 or 10 or 12 or 14 days.
  • the intermittent Compound treatment is begun at the time of integumental perturbation and then maintained for 19 or 21 days thereafter (in some embodiments, a scab forms during this time). In some embodiments, an intermittent Compound treatment is begun as soon as the scab falls off and maintained for 19 or 21 days. In some embodiments, the intermittent Compound treatment is to modulate the neoepidermis that forms underneath the scab. In some such embodiments, the intermittent Compound treatment is begun at the time of wounding or other form of integumental perturbation and is continued with daily dosing up to some time after scab falls off, for example, between 5 - 14 days following integumental perturbation.
  • the course of treatment with Compound is short, for example, limited to daily doses for one or a few days just following scab detachment, or even continued only for as long as the scab is still attached.
  • the timing of wounding or other form of integumental perturbation and Compound administration is preferably monitored and adjusted so that optimal results are achieved.
  • an intermittent Compound treatment is combined with a form of wounding or other form of integumental perturbation that does not lead to formation of a scab.
  • the intermittent Compound treatment is begun before wounding or other form of integumental perturbation.
  • the intermittent Compound treatment is begun at the time of wounding or other form of integumental perturbation.
  • an intermittent Compound treatment is begun following wounding or other form of integumental perturbation.
  • an intermittent Compound treatment is begun following a wound or other form of integumental perturbation that does not lead to formation of a scab
  • the intermittent Compound treatment is begun within 15 minutes of, or 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 10 days, 2 weeks, or 3 weeks after integumental perturbation.
  • Treatment with one or more Compounds in combination with conventional methods for enhancing hair growth or removal of unwanted hair, or for enhancing wound healing or scar revision enhances the effectiveness of the foregoing methods.
  • the effect that each drug offers could be an additive or synergistic improvement, or a combination of two different pharmacologically defined effects, to achieve the desired end result.
  • Most drugs for hair loss aim to retain the existing hair follicles in their active cycling states, or to rejuvenate telogen hair follicles to actively cycling anagen states.
  • a dosage form that encourages the growth of "new" hair follicles combined with one that retains the hair follicles in their actively cycling states offer significant value to the individual who is balding, and may encourage hair follicle formation that in turn promotes wound healing in a wounded individual or an individual for whom a scar revision is desired.
  • the combined modality of treatment could involve alternating treatment of each dosage form or concurrent or simultaneous treatment.
  • the one or more Compounds may be administered in combination with any additional treatment(s) described or incorporated by reference herein or determined to be appropriate by the medical practitioner.
  • the amount of an additional treatment(s) will depend on the desired effect and the additional compound that is selected. Dosages and regimens for administering such additional treatment(s) are the dosages and regimens commonly in use, which can be easily determined by consulting, for example, product labels or physicians' guides, such as the Physicians' Desk Reference (“PDR”) (e.g., 63rd edition, 2009, Montvale, NJ: Physicians' Desk Reference).
  • PDR Physicians' Desk Reference
  • the one or more Compounds may be administered concurrently with or separately from the additional compound(s), or may be administered and/or delivered to the tissue site with different pharmacokinetics.
  • the combination treatment comprises one or more Compounds and an additional compound(s) formulated together.
  • Compound in such formulations may be released concurrently with or separately from the additional compound(s), or may be released and/or delivered to the tissue site with different pharmacokinetics.
  • one or more of the compounds in the formulation undergoes controlled release, whereas one or more of the other compounds does not.
  • one or more of the compounds in the formulation undergoes sustained release whereas one or more of the other compounds undergoes delayed release.
  • the combination treatment comprises one or more Compounds and an additional compound(s) formulated separately.
  • formulations may be administered concurrently, sequentially, or in alternating sequence.
  • the one or more Compounds may be administered sequentially, or concurrently with another compound such as finasteride or minoxidil, to achieve the desired effect of hair retention and growth.
  • the combination treatment comprises administration of one or more Compounds with one or more treatments selected from, e.g., cell therapy (such as a stem cell), a formulation for gene therapy (such as, e.g., a virus, virus-like particle, virosome), an antibody or antigen-binding fragment thereof, an herb, a vitamin (e.g., a form of vitamin E, a vitamin A derivative, such as, e.g.
  • all-trans retinoic acid ATRA
  • ATRA all-trans retinoic acid
  • B vitamin such as, e.g., inositol, panthenol, or biotin, or a vitamin D3 analog
  • a mineral such as, e.g., inositol, panthenol, or biotin, or a vitamin D3 analog
  • a shampoo ingredient e.g., ammonium chloride, ammonium lauryl sulfate, glycol, sodium laureth sulfate, sodium lauryl sulfate, ketoconazole, zinc pyrithione, selenium sulfide, coal tar, a salicylate derivative, dimethicone, or plant extracts or oils
  • a conditioning agent e.g., a soap product, a moisturizer, a sunscreen, a waterproofing agent, a powder, talc, or silica, an oil- control agent, alpha-hydroxy acids, beta
  • sesquichldrohydrate aluminum sesquichlorohydrex PEG, aluminum sesquichlorohydrex PG, aluminum sulfate, aluminum zirconium octachlorohydrate, aluminum zirconium
  • octachlorohydrex GLY (abbreviation for glycine), aluminum zirconium pentachlorohydrate, aluminum zirconium pentachlorohydrex GLY, aluminum zirconium tetrachlorohydrate, aluminum zirconium trichlorohydrate, aluminum zirconium tetrachlorohydrate GLY, and aluminum zirconium trichlorohydrate GLY, potassium aluminum sulphate, (also known as alum (KA1(S0 ) 2 12H20)), aluminum undecylenoyl collagen amino acid, sodium aluminum lactate+ aluminum sulphate (Na 2 HAl(OOCCHOHCH 3 )2-(OH) 6 ) + A1 2 (S0 4 ) 3 ), sodium aluminum chlorohydroxylactate, aluminum bromohydrate (Al 2 Br(OH)snH 2 0), aluminum chloride (AICI36H2O), complexes of zinc salt and of sodium salt, complexes of lanthanum and cerium
  • a massage agent e.g., a massage agent, an exfoliant, an anti-itch agent, a pro-inflammatory agent, an immunostimulant (e.g., cytokines, agonists or antagonists of various ligands, receptors and signal transduction molecules of the immune system, immunostimulatory nucleic acids, an adjuvant that stimulates the immune response and/or which causes a depot effect), a cell cycle regulator, a hormonal agonist, hormonal antagonist (e.g., flutamide, bicalutamide, tamoxifen, raloxifene, leuprolide acetate (LUPRON), LH-RH antagonists), an inhibitor of hormone biosynthesis and processing, a steroid (e.g., dexamethasone, retinoids, deltoids, betamethasone, Cortisol, cortisone, prednisone, dehydrotestosterone, glucocorticoids, mineralocorticoids,
  • an immunostimulant
  • an anti-inflammatory e.g., corticosteroids, NTHEs, and COX-2 inhibitors
  • a retinoid e.g., 13-cis-retinoic acid, adapaiene, all-trans-retinoic acid, and etretinate
  • an immunosuppressant e.g., cyclosporine, tacrolimus, rapamycin, everolimus, and pimecrolimus
  • an antibiotic e.g., an anti-cancer agent (such as, e.g., fluorouracil (5-FU or f5U) or other pyrimidine analogs, methotrexate, cyclophosphamide, vincristine), a mood stabilizer (e.g., valproic acid or carbamazepine) an antimetabolite, an anti-viral agent, and an antimicrobial (e.g., benzyl benzoate, benzalkonium chloride, benzoic acid, benzoste
  • the combination treatment comprises Compound treatment, such as, e.g., intermittent or a pulse Compound treatment, in combination with one or more narcotic analgesics, selected from the group of, e.g., alfentanil, benzylmorphine, codeine, codeine methyl bromide; codeine phosphate, codeine sulfate, desomorphine, dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine, ethylmorphine, hydrocodone,
  • Compound treatment such as, e.g., intermittent or a pulse Compound treatment
  • one or more narcotic analgesics selected from the group of, e.g., alfentanil, benzylmorphine, codeine, codeine methyl bromide; codeine phosphate, codeine sulfate, desomorphine, dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine,
  • hydromorphone methadone hydrochloride, morphine, morphine hydrochloride, morphine sulfate, nicomorphine, normethadone, normorphine, opium, oxycodone, oxymorphone, phenoperidine, and propiram.
  • the combination treatment comprises Compound treatment, such as, e.g., intermittent or a pulse Compound treatment, in combination with one or more non-narcotic analgesics, selected from the group of, e.g., aceclofenac, acetaminophen, acetanilide, acetylsalicylsalicylic acid; aspirin, carbamazepine, dihydroxyaluminum acetylsalicylate, fenoprofen, fluproquazone, ibufenac, indomethacin, ketorolac, magnesium acetylsalicylate, morpholine salicylate, naproxen, phenacetin, phenyl salicylate, salacetamide, salicin, salicylamide, sodium salicylate, and tolfenamic acid.
  • Other pain treatments that may be used in combination with the Compound treatments described herein include nerve blocks or non-traditional pain medications, such as, e.g.,
  • the combination treatment comprises administration of one or more Compounds provided herein in combination with integumental perturbation (e.g., by wounding) and, optionally, also comprises another treatment known in the art or described herein.
  • Integumental perturbation can be achieved by any means known in the art or described herein, such as, for example, using chemical or mechanical means.
  • integumental perturbation comprises disrupting the skin of the subject (for example, resulting in the induction of re-epithelialization of the skin of the subject).
  • a certain area of the epithelium is partially or wholly disrupted.
  • a certain area of both the epithelium and stratum corneum are partially or wholly disrupted.
  • skin disruption and re-epithelialization including methods for disrupting skin and inducing and detecting re-epithelialization, see PCT
  • Integumental perturbation can be used to induce, for example, a burn, excision, dermabrasion, full-thickness excision, or other form of abrasion or wound.
  • Mechanical means of integumental perturbation include, for example, use of sandpaper, a felt wheel, ultrasound, supersonically accelerated mixture of saline and oxygen, tape-stripping, spiky patch, or peels.
  • Chemical means of integumental perturbation can be achieved, for example, using phenol, trichloroacetic acid, or ascorbic acid.
  • Electromagnetic means of integumental perturbation include, for example, use of a laser (e.g., using lasers, such as those that deliver ablative, non-ablative, fractional, non-fractional, superficial or deep treatment, and/or are C0 2 -based, or Erbium- YAG-based, neodymium:yttrium aluminum garnet (Nd:YAG) laser, etc.).
  • Integumental perturbation can also be achieved through, for example, the use of visible, infrared, ultraviolet, radio, or X-ray irradiation.
  • integumental perturbation is by light energy, such as described in Leavitt et ai, 2009, Clin. Drug. Invest.
  • Electrical or magnetic means of disruption of the epidermis can be achieved, for example, through the application of an electrical current, or through electroporation or RF ablation.
  • Electric or magnetic means can also include the induction of an electric or a magnetic field, or an electromagnetic field.
  • an electrical current can be induced in the skin by application of an alternating magnetic field.
  • a radiofrequency power source can be coupled to a conducting element, and the currents that are induced will heat the skin, resulting in an alteration or disruption of the skin.
  • Integumental perturbation can also be achieved through surgery, for example, a biopsy, a skin transplant, hair transplant, cosmetic surgery, etc.
  • integumental perturbation is by laser treatment.
  • Exemplary laser treatments for integumental perturbation include or fractional laser (e.g., Fraxel), laser abrasion, Erbium-YAG laser, Ultrapulse C0 2 fractional laser, Ultrapulse C0 2 ablative laser, Smooth Peel Full-ablation Erbium laser (Candela), neodymium:yttrium aluminum garnet (Nd:YAG) laser, as described, for example, in the examples of Sections 6-8, below.
  • a laser treatment is chosen in which the integumental perturbation achieved most resembles that achieved by dermabrasion (for example, a dermabrasion method described herein).
  • integumental perturbation by laser treatment is by a fractional laser.
  • a fractional laser treatment is treatment with an Erbium-YAG laser at around 1540 nm or around 1550 nm (for example, using a Fraxel® laser (Solta Medical)). Treatment with an Erbium-YAG laser at 1540 or 1550 nm is typically non-ablative, and pinpoint bleeding typical of laser treatment is not observed since the stratum corneum is left intact.
  • integumental perturbation by laser treatment is by a fractional laser, using, e.g., a CO2 laser at 10,600 nm. Treatment with a C0 2 laser at 10,600 nm is typically ablative, and typically leads to the appearance of pinpoint bleeding.
  • a standard C0 2 or Erbium-YAG laser can be used to create superficial and, optionally, broad based, integumental perturbation similar to dermabrasion (discussed below).
  • the pinpoint bleeding clinical endpoint may not be achieved due to the coagulation properties of (particularly non-ablative) lasers, use of a laser has an advantage making it possible to select the specific depth of skin disruption to effectively remove the stratum corneum and epidermis, or portions thereof.
  • the laser treatment is ablative.
  • full ablation of tissue is generated by the targeting of tissue water at wavelengths of 10,600 nm by a C0 2 laser or 2940 nm by an Erbium-YAG laser.
  • the epidermis is removed entirely and the dermis receives thermal tissue damage.
  • the depth of tissue ablation may be a full ablation of the epidermis, or a partial ablation of the epidermis, with both modes causing adequate wounding to the skin to induce the inflammatory cascade requisite for regeneration.
  • the depth of ablation may extend partially into the dermis, to generate a deep wound.
  • the denuded skin surface is then treated with one or more Compounds; alternatively, the one or more Compounds can be delivered into the skin after the initial re-epithelialization has occurred already, to prevent clearance and extrusion of the Compound-containing depots from the tissue site by the biological debris-clearance process.
  • one or more Compounds is delivered by a sustained release depot that is comprised of biocompatible, bioabsorbable polymers that are compatible to tissue.
  • the standard full thickness excision model is created using scissors or with a scalpel in animal models (see, also, the examples of Sections 10, 16, 24, and 25 infra).
  • This procedure while contemplated for use herein (see, e.g. , the example of Sections 10, 16, 24, and 25 infra), carries with it the risk of scarring.
  • various fractional laser modalities could be used to achieve a similarly deep disruption on a grid pattern.
  • a fractional laser can be use to "drill,” for example, 1 -mm diameter holes with a 1 -mm hole spacing (the fractional laser can make holes of smaller dimensions).
  • the laser treatment is ablative and fractional.
  • fractional tissue ablation can be achieved using a C0 2 laser at 10,600 nm or an Erbium- YAG laser at 2940 nm (e.g., the Lux 2940 laser, Pixel laser, or Profractional laser).
  • the lasing beam creates micro-columns of thermal injury into the skin, at depths up to 4 mm and vaporizes the tissue in the process.
  • Ablative treatment with a fractional laser leads to ablation of a fraction of the skin leaving intervening regions of normal skin intact to rapidly repopulate the epidermis. Approximately 15%-25% of the skin is treated per session.
  • micro thermal zones can be varied to create a dense "grid" of injury columns surrounded by intact skin and viable cells.
  • the density of the grid on the treatment area plays an important role. The denser the grid, the more the thermal injury and the type of injury begins to approximate full ablation. Therefore, it is appreciated that there may be an "optimum" MTZ density that is appropriate for use in the methods disclosed herein.
  • one or more Compounds is delivered into the dermis immediately after wounding, or after initial re-epithelialization has occurred.
  • the mode of laser treatment is non-ablative, wherein the stratum corneum and the epidermis are intact after treatment, with the dermis selected for the deep thermal treatment required for the requisite injury to tissue.
  • This can be accomplished by cooling the epidermis during the laser treatment.
  • the depth of treatment may be 1 mm to 3 mm into the skin.
  • contact cooling such as a copper or sapphire tip.
  • Lasers that are non- ablative have emission wavelengths between 1000-1600 nm, with energy fluences that will cause thermal injury, but do not vaporize the tissue.
  • the non-ablative lasers can be bulk, wherein a single spot beam can be used to treat a homogenous section of tissue. In some embodiments, multiple treatments are required to achieve the desired effect. In one embodiment, one or more Compounds is delivered deep into the dermis in polymeric micro- depots and released in a sustained fashion.
  • Lasers that are non-ablative include the pulsed dye laser (vascular), the 1064 Nd:YAG laser, or the Erbium-YAG laser at 1540 nm or 1550 nm (e.g., the Fraxel® laser).
  • the mode of laser treatment is fractional and non-ablative. Treatment with a fractional, non-ablative laser leads to perturbation of a fraction of the skin, leaving intervening regions of normal skin intact to rapidly repopulate the epidermis.
  • the skin barrier function is maintained, while deep thermal heating of dermis can occur.
  • zones of dermis and epidermis are coagulated and the stratum corneum is left essentially intact.
  • This process has been coined "fractional photothermolysis" and can be accomplished, e.g., using the Erbium- Y AG laser with an emission at or around 1540 nm or 1550 nm.
  • one or more Compounds is delivered immediately after the tissue injury, deep into the dermis.
  • a combination of bulk and fractional ablation modes of tissue injury are used.
  • the mode of laser treatment for, e.g., a Caucasian male 30-50 years old is fractional and non-ablative using an Erbium- YAG laser at 1550 nm, with the following settings: 50-70 J/cm 2 , treatment level 8- 10 (density of the "dots"), with 8 passes.
  • the laser device can be equipped with a touch pad screen that offers the operator a menu of options for setting the parameters for operating the laser to promote hair growth.
  • the device can be programmed to offer the operator selections for hair growth vs. removal, choice of skin color, hair follicle density, power settings, etc.
  • a combination treatment comprising use of a laser includes administration to the skin of a compound absorbing light at wavelengths between 1000-1600 nm for the purpose of efficient channeling of light to heat energy.
  • This method of channeling energy may cause micro-zones of thermal injury within the skin.
  • the compound may be delivered to the skin homogenously in the treatment zone, then subsequently irradiated with a non-ablative laser to efficiently capture the vibrational energy of the infrared beam. This method may result in evenly distributed and deep thermal injury, without causing tissue vaporization.
  • a combination treatment comprising use of a laser includes administration of one or more Compounds that is encapsulated in matrices that are highly hydrophilic and charged, for example, linked to the dermis by covalent or ionic bonding to prevent the matrices from being cleared by phagocytosis, as part of the wound healing process.
  • a combination treatment comprising use of a laser includes the step of placing a biocompatible, synthetic skin substitute on the newly created wound, especially if the wound is deep, covers large area and is bulk ablated. This process can help minimize or prevent the rapid wound contraction that occurs after loss of a large area of tissue, frequently culminating in scar tissue formation and loss of skin function.
  • the biocompatible synthetic skin substitute is be impregnated with depots of a slow releasing Compound formulation described herein. This method of treatment may enable treating a large bald area on the scalp in one session at the treatment clinic.
  • other molecules are also co-eluted at the site through the skin substitute, such as, e.g., anesthetics and antibiotics, to prevent further pain and minimization of infection, or any other compound described herein.
  • the skin substitute in the presence or absence of one or more Compounds and/or other compounds described herein, may also be pre-cooled and applied to the wound to provide a feeling of comfort to the patient. This mode of Compound or other compound application may prevent the Compound or other compound from being cleared away from the wound site as the wound heals.
  • a fractional like hole pattern (similar to that achieved with a fractional laser or full thickness excision) is achieved with using an array of punch biopsy needles.
  • 1-mm punch biopsies can be arranged with 1-mm hole spacing.
  • the cored skin samples can be removed and, thus, an effect approximating the full thickness excision model is invoked within each hole.
  • microneedles ⁇ e.g., 19 or 21 gauge needles
  • micro-coring needles could be used.
  • integumental perturbation is by dermabrasion (also referred to herein as "DA"), a well-established dermatological procedure that has been used for decades as a skin resurfacing technique (Grimes, 2005, Microdermabrasion. Dermatol Surg 31 : 1351 -1354). While the popularity of mechanical dermabrasion has decreased in recent years with the advent of laser-based procedures, dermabrasion is still used for removing facial scars resulting from acne and other trauma. Small, portable mechanical dermabrasion equipment uses interchangeable diamond fraises operated at different rotation speeds to remove the epidermis and dermis to differing skin depth levels.
  • Dermabrasion may be carried out using any technique known in the art or as described in the examples of Section 6, 7, 9, 10, 16, 17, 18, and 24, infra.
  • dermabrasion may be carried out using standard DA with aluminum oxide crystals using the Aseptico Econo- Dermabrader, Advance Microderm DX system, or M2-T system; standard DA with Bell Hand Engine with diamond fraise; wire brush; etc.
  • DA is carried out using an abrasive wheel.
  • DA with an abrasive wheel is used in order to achieve pinpoint bleeding.
  • dermabrasion may be carried out using an abrasive wheel to achieve larger globules of bleeding and frayed collagen.
  • dermabrasion may be carried out using an abrasive wheel to, in some embodiments, achieve pinpoint bleeding. In other embodiments, dermabrasion may be carried out using an abrasive wheel to achieve larger globules of bleeding and frayed collagen.
  • Non-powered devices such as abrasive cloths can also be used to achieve the dermabrasion, with the optional achievement of the same endpoint.
  • DA is accomplished using a device typically used for microdermabrasion (also referred to herein as "MDA").
  • MDA microdermabrasion
  • a microdermabrasion device is used to remove a greater depth and/or area of skin than is typical for microdermabrasion.
  • the microdermabrasion device is used under sterile conditions.
  • dermabrasion is achieved by using a device for microdermabrasion to the point where treatment is stopped upon the observation of pinpoint bleeding, which signals the" removal of the stratum corneum and epidermis into the papillary dermis.
  • dermabrasion is achieved by using a device for microdermabrasion to the point where treatment is stopped upon the observation of larger globules of bleeding and frayed collagen, which signals the removal of the stratum corneum and epidermis into the papillary and reticular dermis.
  • this extended use is reduced by using a microdermabrasion device with increased output pressure and increased abrasion particle size, which may accelerate the skin removal process.
  • DA is accomplished by removal of surface skin by particle bombardment (also referred to herein as "particle mediated dermabrasion" (“PMDA”)), for example, with alumina-, ice- or silica-based particles.
  • particle bombardment also referred to herein as "particle mediated dermabrasion” (“PMDA)
  • PMDA particle mediated dermabrasion
  • micron- sized particles are propelled toward the surface of the skin via short strokes of a handpiece, such as a particle gun, as known in the art.
  • the velocity of particles is controlled through positive or negative pressure.
  • the depth of skin removed by particle bombardment DA (e.g., PMDA) is a function of the volume of particles impacting the skin, the suction or positive pressure, the speed of movement of the handpiece, and the number of passes per area of the skin.
  • integumental perturbation by one or more of the aforementioned methods achieves removal of part or all of the epidermis. In some embodiments, integumental perturbation removes the entire epidermis. In some embodiments, integumental perturbation removes the papillary dermis. In some
  • integumental perturbation removes the reticular dermis.
  • the depth of integumental perturbation depends on the thickness of the skin at a particular treatment area. For example, the skin of the eyelid is significantly thinner than that of the scalp.
  • the occurrence of pinpoint bleeding indicates that the epidermis and portions of the dermis have been removed. Deeper penetration can results in much more bleeding, and the perturbation can go as deeps as the hypodermis.
  • integumental perturbation by one or more of the aforementioned methods is to a skin depth of 30 ⁇ . In some embodiments, integumental perturbation by one or more of the aforementioned methods is to a skin depth of 60 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 30- 100 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 60-100 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 100 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 30-200 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 60-200 ⁇ .
  • integumental perturbation is to a skin depth of 100-200 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 100-150 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 150 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 100-500 ⁇ . In some embodiments, integumental perturbation is to a skin depth of less than 500 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 500-1000 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 1 mm or more. In some embodiments, integumental perturbation is to a skin depth of 1 mm to 3 mm. In some embodiments, integumental perturbation is to a skin depth of 1 mm to 5 mm.
  • the present invention is also based, in part, on the appreciation that hair follicles play a role in wound healing.
  • Inducing the formation of new hair follicles in wounds, or enhancing the entry of hair follicles into wounds (for example, by transplanting hair follicles into wounds) harnesses their regenerative capacity and provides a transformational approach to scar revision and the management of wounds.
  • the approaches described herein permit scar revision under sterile and controlled conditions that recreates and harnesses the fetal skin's plastic and regenerative capacity.
  • Fractional laser treatment of scarred tissue creates areas of small micro-injuries with intact epidermis in- between, and the integumental perturbation of the laser activates hair follicle deposition into the injury sites, either by migration from the intact epidermis or by inducing hair follicle neogenesis in the wound.
  • laser-induced wounding of columns (the non- ablative coagulum is a preferred embodiment) triggers the regenerative capacity of the intervening normal skin stem cells.
  • This technique may have utility in, for example, revising small scars (to improve texture, pigmentation and other features).
  • one advantage of using combinations comprising integumental perturbation is that the perturbation provides a signal for hair follicle deposition and/or deposition of other adnexal structures into the wound site, e.g., by their migration and/or by generation of new hair follicles (hair follicle neogenesis) or adnexal structures.
  • hair follicle neogenesis new hair follicles
  • a wound heals by scarring may depend on the efficiency of hair follicle or other adnexal structure deposition into the wound. If these structures, e.g., hair follicles, are not timely deposited into the healing wound, the process will result in a scar.
  • wound healing without scarring may be effected by improving the efficiency of adnexal structure (e.g., hair follicles) deposition into the wound or by slowing wound healing in order to allow sufficient time for deposition of these structures into the wound site.
  • adnexal structure e.g., hair follicles
  • enhancement of wound healing or scar revision is accomplished by Compound treatment alone, for example, in acutely wounded skin or skin affected by a chronic non-healing wound, i.e., skin already subjected to integumental perturbation.
  • the Compound treatment is administered to skin that has been damaged and which no longer contains follicles.
  • the Compound treatment may restore follicle production in that area of skin.
  • an area of skin containing a wound that has not healed correctly, such as a scar (e.g., a keloid scar) is administered a Compound treatment in order to restore hair follicles and/or hair growth to that area of skin.
  • enhancement of wound healing or scar revision is accomplished by a combination of integumental perturbation and a Compound treatment, such as a pulse or intermittent Compound treatment.
  • the combination treatment comprises intermittent or a pulse Compound treatment in combination with integumental perturbation or, optionally, also comprises another treatment known in the art or described herein.
  • Combinations comprising integumental perturbation are preferred for skin that is not already acutely wounded, since wounding itself is a form of integumental perturbation.
  • Integumental perturbation can be achieved by any means known in the art or described herein, such as, for example, using chemical or mechanical means.
  • the Compound treatments described herein potentiate the formation of new hair follicles.
  • Integumental perturbation produces in the affected skin tissue an increase in the number of hair follicle stem cells and in the plasticity of hair follicle cells, such that resident hair follicles may be reprogrammed.
  • integumental perturbation in combination with one or more Compounds provides an environment for the formation of a large number of follicles with desired properties.
  • New hair follicles originate from Hair Follicle Stem Cells (FSCs), oligopotent cells whose progeny can differentiate into the highly differentiated specialized cells of the hair follicle (see Amoh Y, et al. Human hair follicle pluripotent stem (hfPS) cells promote regeneration of peripheral-nerve injury: an advantageous alternative to ES and iPS cells. J Cell Biochem, 2009, 107: 1016-1020; and Amoh Y, et al. Nascent blood vessels in the skin arise from nestin-expressing hair-follicle cells. Proc Natl Acad Sci U S A. 2004 Sep.
  • FSCs originate from one or more of the following: (i) existing follicles ("follicle derived follicle stem cells” or “FDFSC”) (see, e.g., Toscani et al., 2009, Dermatol Surg.
  • FDFSC follicle derived follicle stem cells
  • TDFSC tissue derived follicle stem cells
  • BMDFSC bone marrow derived follicle stem cells
  • FSCs generate new hair follicles that preserve the type of hair follicle that is typical for each location of skin or scalp.
  • FSCs from the coronal scalp of a male with MPHL typically generate atrophic follicles with vellus or club hairs.
  • FSCs from the occipital scalp of the same male typically generate follicles with terminal hair that are not subject to involution in response to DHT.
  • FSCs responsible for follicle formation may be reprogrammed.
  • FSCs in the process of asymmetric division and subsequent differentiation are susceptible to signals (such as estrogen or testosterone) that alter the determinism of their differentiation program.
  • signals such as estrogen or testosterone
  • Such follicles have characteristics usually associated with: (i) pre-alopecia follicles in the coronal scalp; (ii) female-type follicles on the coronal scalp; or (iii) occipital scalp type follicles.
  • pre-alopecia follicles in the coronal scalp e.g., pre-alopecia follicles in the coronal scalp
  • female-type follicles on the coronal scalp e.g., occipital scalp type follicles.
  • treatment with one or more Compounds in combination with integumental perturbation provides a window during which a third treatment that alters the follicle development program may be administered in order to significantly change the number and quality of follicles in a particular area of skin.
  • the third treatment e.g., estrogen or testosterone modulator, such as those described in Poulos & Mirmirani, 2005, Expert Opin. Investig. Drugs 14: 177-184 (incorporated herein by reference
  • the third treatment is administered after integumental perturbation.
  • the third treatment is administered 1 day, 2 days, 3 days, 5 days, 7 days, 10 days, or 2 weeks after integumental perturbation. In one embodiment, the third treatment is administered at the time of integumental perturbation and then daily for 5 days thereafter (in some embodiments, a scab forms during this time). In some embodiments, the third treatment is administered daily for 5 days beginning as soon as the scab falls off. In some embodiments, the third treatment is administered in order to modulate the neoepidermis that forms underneath the scab. In some such embodiments, the third treatment is administered at the time of integumental perturbation and up to some time after scab falls off , for example, between 5 - 14 days following integumental perturbation.
  • the course of treatment with the third treatment is short, for example, limited to a few days just following scab detachment, or even continued only for as long as the scab is still attached.
  • the timing of the integumental perturbation, Compound administration, and the third treatment is preferably monitored and adjusted so that optimal results are achieved.
  • the following sections contain non-limiting examples of combination treatments that are specific for, respectively, (i) enhancing hair growth and/or treating conditions associated with hair loss; (ii) removal of unwanted hair and/or treating conditions associated with excessive hair growth; (iii) modulation of wound healing; and (iv) improvement of scars and scar revisions.
  • the treatments described in these sections may optionally be combined with the aforementioned treatments and/or with one another. For example, in some embodiments, a combination of two or three or four treatments is used in order to achieve optimal results. 5.3.7 COMBINATION TREATMENTS FOR
  • the combination treatment comprises treatment with one or more Compounds in combination with a treatment that enhances hair growth and/or treats a disease or condition associated with excessive hair loss. Any treatment that enhances hair growth and/or treats a disease or condition associated with excessive hair loss that is known in the art or yet to be developed is contemplated for use in such combination treatments.
  • the combination treatment comprises treatment with one or more Compounds in combination with one or more antiandrogens, such as, e.g., finasteride (e.g., marketed as Propecia or Proscar), fluconazole, spironolactone, flutamide, diazoxide, 17- alpha-hydroxyprogesterone, 1 1 -alpha- hydroxyprogesterone, ketoconazole, RU58841 , dutasteride (marketed as Avodart), fluridil, or QLT-7704, an antiandrogen oligonucleotide, or others described in Poulos & Mirmirani, 2005, Expert Opin. Investig.
  • finasteride e.g., marketed as Propecia or Proscar
  • fluconazole e.g., marketed as Propecia or Proscar
  • spironolactone e.g., marketed as Propecia or Proscar
  • fluconazole e.g.
  • the regular dosages may be increased or decreased as directed by the physician. For example, a lower dosage may be used over a shorter duration owing to the synergistic effect of the combination with the one or more Compounds.
  • the combination treatment comprises treatment with one or more Compounds in combination with one or more channel openers (e.g. , potassium channel opener, e.g. , an ATP-sensitive potassium channel (KATP opener), or an activator of such a channel), such as, e.g., minoxidil (e.g., marketed as Rogaine or Regaine), diazoxide, or phenytoin.
  • channel openers e.g., potassium channel opener, e.g. , an ATP-sensitive potassium channel (KATP opener), or an activator of such a channel
  • minoxidil e.g., marketed as Rogaine or Regaine
  • diazoxide e.g., phenytoin.
  • Commonly used dosage forms of minoxidil that may be used in such combination therapies are topical solutions comprising 2% minoxidil or 5% minoxidil, for example, topical minoxidil foam 5%.
  • the regular dosages may be increased or decreased as directed by the physician. For example,
  • the combination treatment comprises treatment with one or more Compounds in combination with a prostaglandin F2a analog.
  • prostaglandin F2a analogs include Bimatoprost, Latanoprost, Travoprost, Unoprostone, Tafluprost, Dinoprost, AS604872, BOL303259X, PF3187207, and Carboprost.
  • the combination treatment comprises treatment with one or more Compounds in combination with a 5a-reductase inhibitor.
  • Non-limiting examples of 5a-reductase inhibitors include Finasteride, Dutasteride, Turosteride, Bexlosteride,
  • Izonsteride Izonsteride, Epristeride, Epigallocatechin, Azelaic acid, FCE 28260, and S F 105, 1 1 1.
  • the combination treatment comprises treatment with one or more Compounds in combination with an antiandrogen (e.g., finasteride, 5-alpha reductase inhibitors) and a channel opener (e.g., minoxidil).
  • an antiandrogen e.g., finasteride, 5-alpha reductase inhibitors
  • a channel opener e.g., minoxidil
  • the combination treatment comprises treatment with one or more Compounds in combination with one or more antiandrogens, such as ketoconazole, or a prostaglandin or a prostaglandin agonist, or a prostaglandin F2 alpha or analog thereof (such as, e.g., bimatoprost, travoprost, or latanoprost), DoxoRx, Docetaxel, FK506, GP1 1046, GP 1 151 1 , LGD 1331 , ICX-TRC, MTS-01 , NEOSH 101 , HYG- 102440, HYG-410, HYG-420, HYG-430, HYG-440, spironolactone, CB-03-01 , RK-023, Abatacept, Viviscal®, MorrF, ASC-J9, NP-619, AS101 , Metron-F-1 , MK-396, PSK 3841
  • antiandrogens such as
  • the combination treatment comprising treatment with one or more Compounds to enhance hair growth in a female subject is not finasteride or ketoconazole.
  • the combination therapy comprising treatment with one or more Compounds to enhance hair growth in a pregnant, female subject is not finasteride or ketoconazole.
  • the combination treatment comprises treatment with one or more Compounds in combination with a copper peptide(s), preferably applied topically, or another compound with superoxide dismutation activity.
  • the combination therapy comprises treatment with one or more Compounds in combination with an agent that increases nitric oxide production (e.g. , arginine, citr'ulline, nitroglycerin, amyl nitrite, or sildenafil (Viagra)).
  • an agent that increases nitric oxide production e.g. , arginine, citr'ulline, nitroglycerin, amyl nitrite, or sildenafil (Viagra)
  • such compounds are administered further in combination with a catalase or catalase mimetic, or other antioxidant or free radical scavenger.
  • the combination treatment comprises treatment with one or more Compounds in combination with one or more agents that counteract hair follicle cell senescence (also referred to herein as "anti-senescence agents"), for example, anti-oxidants such as glutathione, ascorbic acid, tocopherol, uric acid, or polyphenol antioxidants);
  • anti-oxidants such as glutathione, ascorbic acid, tocopherol, uric acid, or polyphenol antioxidants
  • ROS reactive oxygen species
  • the combination treatment comprises administration of Compound in combination with one or more agents that induce an immune response or cause inflammation, such as, e.g. , tetanus toxoid, topical non-specific irritants (anthralin), or sensitizers (squaric acid dibutyl ester [SADBE] and diphenyl cyclopropenone [DPCP]). While not intending to be bound by any theory, it is thought that by contacting these agents to the skin, lymphocytes and hair follicle stem cells may be recruited to skin.
  • agents that induce an immune response or cause inflammation such as, e.g. , tetanus toxoid, topical non-specific irritants (anthralin), or sensitizers (squaric acid dibutyl ester [SADBE] and diphenyl cyclopropenone [DPCP]). While not intending to be bound by any theory, it is thought that by contacting these agents to the skin, lymphocytes and hair
  • the combination treatment comprises treatment with one or more Compounds in combination with a chemical or mechanical (such as those discussed infra) treatment that induces an inflammatory process in the skin. While not intending to be bound by any theory, inducing inflammation in the site where hair growth is desired helps to recruit stem cells to the tissues that drive the formation of new follicles.
  • the combination treatment comprises treatment with one or more Compounds in combination with an antiapoptotic compound.
  • the antiapoptotic compound is not a Wnt or a Wnt agonist.
  • the combination treatment comprises treatment with one or more Compounds in combination with one or more of stem cell therapy, hair cloning, hair transplantation, scalp massage, a skin graft, hair plugs, or any surgical procedure aimed at hair restoration.
  • the combination treatment comprises treatment with one or more Compounds in combination with use of a laser device or other mode of accomplishing "photo-biostimulation" of the hair follicles.
  • a laser device or other mode of accomplishing "photo-biostimulation" of the hair follicles.
  • the Hairmax Lasercomb or the Leimo laser are non-limiting examples of devices that can be used to stimulate growth of hair and can be used in combination with the methods described herein.
  • treatment with one or more Compounds in combination with the aforementioned methods for enhancing hair growth prevents, delays, or reverses scalp hair loss in MPHL and/or diffuse hair thinning associated with aging.
  • treatment with one or more Compounds, alone or in combination with the aforementioned methods for enhancing hair growth synchronizes hair follicle cells in the cell cycle.
  • the one or more Compounds is administered to arrest hair follicle cells in G2 M phase, which synchronizes them; then the Compound treatment is removed; and then their re-entry into the cell cycle and mitotic division is stimulated with other drugs (which leads to anagen follicles and an increased number of follicles).
  • the Compound treatment arrests hair follicle cells in late prophase or metaphase, which synchronizes them; the Compound treatment is removed; and then their reentry into the cell cycle and mitotic division is stimulated with other drugs (which leads to anagen follicles and an increased number of follicles).
  • the Compound treatment arrests hair follicle cells in late prophase or metaphase, which synchronizes them; the Compound treatment is removed; and then their reentry into the cell cycle and mitotic division is stimulated with other drugs (which leads to anagen follicles and an increased number of follicles).
  • Compound treatment arrests hair follicle stem cells in G2 M phase, which synchronizes them; then the Compound treatment is removed; and then their re-entry in to the cell cycle and mitotic division is stimulated with other drugs (which leads to anagen follicles and an increased number of follicles).
  • the Compound treatment arrests hair follicle stem cells in late prophase or metaphase, which synchronizes them; the Compound treatment is removed; and then their re-entry into the cell cycle and mitotic division is stimulated with other drugs(which leads to anagen follicles, and an increased number of follicles).
  • treatment with one or more Compounds alone or in combination with the aforementioned methods for enhancing hair growth, synchronizes hair follicle cells in the Follicle Cycle.
  • the treatment regimen induces follicles to enter anagen.
  • the treatment regimen prevents follicles from entering catagen.
  • the treatment regimen induces follicles in telogen to enter exogen, or induces follicles in exogen to enter anagen.
  • treatment with one or more Compounds in combination with the aforementioned methods for enhancing hair growth improves the effectiveness of these methods, making the treatment more effective, efficient, cost-effective, and/or user friendly. For example, fewer treatments may be required.
  • one of the previously described hair growth enhancement treatments on its own is not cosmetically satisfactory, the benefits are too short-lived, or the hair that results from the treatment is vellus hair, or other thin or patchy hair, or has inadequate pigmentation.
  • the hair that results may be more cosmetically satisfactory, longer lasting, terminal hair or head hair (depending on the type of hair intended as opposed to vellus hair, and/or thicker, more uniform, and properly pigmented hair.
  • more than one hair will emerge from each follicle, leading to the appearance of thicker hair.
  • one of the aforementioned treatments to enhance hair growth is administered following integumental perturbation (as described herein) and treatment with one or more Compounds.
  • integumental perturbation is followed by treatment with one or more Compounds, which is then followed by one of the aforementioned treatments to enhance hair growth.
  • integumental perturbation accompanies treatment with one or more
  • integumental perturbation is prior to treatment with one or more Compounds administered together with one of the aforementioned treatments to enhance hair growth.
  • Integumental perturbation is achieved by either treatment with a fractional Erbium- YAG laser to epidermal or dermal depth, a fractional C0 2 laser to epidermal or dermal depth, or dermabrasion as described herein. This is followed by the stimulation of follicle formation by treatment with one or more Compounds.
  • the follicles are reprogrammed, e.g., a miniaturizing male temporal scalp follicle (or Follicle Stem Cell) is changed to a non- miniaturizing female-type temporal scalp follicle (or Follicle Stem Cell) using one or more of the following drugs: estrogen, finasteride, dutasteride (AvodartTM).
  • the follicle type can be reprogrammed, e.g., a miniaturizing male temporal scalp follicle can be changed to a non-miniaturizing male occipital scalp-type follicle, using a drug such as valproate.) Then, terminal hair growth is stimulated by the application of low energy light (using, e.g., LaserMax or IPL) or minoxidil.
  • low energy light using, e.g., LaserMax or IPL
  • minoxidil minoxidil
  • enhancement of hair growth is accomplished by a combination of integumental perturbation, as described herein, and treatment with one or more Compounds without one of the aforementioned treatments for enhancing hair growth.
  • the combination of integumental perturbation and treatment with one or more Compounds of an area of skin that already contains hair-producing follicles increases production of hair in that area of skin.
  • the combination of integumental perturbation and Compound treatment is administered to skin that has been damaged and which no longer contains follicles. In such embodiments, the combination of integumental perturbation and Compound treatment may restore follicle production in that area of skin.
  • an area of skin containing a wound that has not healed correctly such as a scar (e.g., a keloid scar) is administered a combination treatment of integumental perturbation and one or more Compounds in order to restore hair follicles and/or growth to that area of skin.
  • a scar e.g., a keloid scar
  • enhancement of hair growth is accomplished by treatment with one or more Compounds alone.
  • treatment with one or more Compounds of an area of skin that already contains hair-producing follicles increases production of hair in that area of skin.
  • the one or more Compounds is administered to skin that has been damaged and which no longer contains follicles.
  • treatment with the one or more Compounds may restore follicle production in that area of skin.
  • an area of skin containing a wound that has not healed correctly, such as a scar (e.g., a keloid scar) is administered one or more Compounds in order to restore hair follicles and/or hair growth to that area of skin.
  • Synergism occurs when the combination has an effect that is more than would be expected from merely the additive effect of each element in the combination, for example, if branched hair follicles or multiple shafts per pore were produced by the combination and not by either alone.
  • the following are exemplary combination treatments comprising Compound treatment, including intermittent Compound treatment and pulse Compound treatment, for enhancing hair growth in a patient having scarring alopecia.
  • the combination treatment e.g., comprising an intermittent or pulse Compound treatment, is specific for a particular subtype of scarring alopecia.
  • the combination treatment for enhancing hair growth in a patient having scarring alopecia comprises Compound treatment, such as, e.g., intermittent Compound treatment or a pulse Compound treatment, in combination with one or more antiinflammatory medications and antimalarial drugs.
  • Medications that may be administered orally include hydroxychloroquine, doxycycline, mycophenolate mofetil, cyclosporine, or corticosteroids.
  • Medications that may be administered topically include corticosteroids (such as, e.g., betamethasone, e.g., Luxiq®), tacrolimus, pimecrolimus, or Derma-Smoothe/FS scalp oil.
  • Medications that may be administered by injection include triamcinolone acetonide (a corticosteroid), which may be injected into inflamed, symptomatic areas of the scalp.
  • a corticosteroid triamcinolone acetonide
  • such combinations are used in the treatment of a patient with the lymphocytic group of cicatricial alopecias, including lichen planopilaris, frontal fibrosing alopecia, central centrifugal alopecia, and pseudopelade (Brocq).
  • the combination treatment for enhancing hair growth in a patient having scarring alopecia comprises Compound treatment, such as, e.g., intermittent Compound treatment or a pulse Compound treatment, in combination with one or more antibiotics, such as oral or topical antibiotics.
  • the combination treatment comprises one or more retinoids, such as isotretinoin, or methotrexate, tacrolimus, cyclosporin, or thalidomide.
  • such combinations are used in enhancing hair growth in a patient with the neutrophilic group of cicatricial alopecias (e.g., folliculitis decalvans, tufted folliculitis, and dissecting cellulitis), and successful treatment enhances hair growth while reducing or eliminating microbes that are involved in the inflammatory process.
  • the neutrophilic group of cicatricial alopecias e.g., folliculitis decalvans, tufted folliculitis, and dissecting cellulitis
  • a combination treatment for a patient with the mixed group of cicatricial alopecias may include antimicrobials, isotretinoin, and anti-inflammatory medications.
  • the combination treatment for enhancing hair growth in a patient with scarring alopecia comprises Compound treatment, such as, e.g. , intermittent Compound treatment or a pulse Compound treatment, in combination with a form of integumental perturbation described herein.
  • Compound treatment such as, e.g. , intermittent Compound treatment or a pulse Compound treatment
  • an affected area of the skin is transplanted with hair follicles from an unaffected area.
  • surgical techniques for replacing tissue comprising scarred hair follicles with tissue from another area of the skin (e.g., scalp) comprising unaffected hair follicles are used.
  • Surgical treatment for cosmetic benefit is an option in, for example, some cases after the disease has been inactive for one to two or more years.
  • the Compound treatment such as, e.g. , intermittent Compound treatment or a pulse Compound treatment, is administered in combination with scar revision, such as by skin graft, serial expansion of surrounding skin, or laser treatment.
  • the Compound treatment such as, e.g., intermittent Compound treatment or a pulse Compound treatment
  • steroids e.g., corticosteroid injection
  • silicone scar treatments e.g., dimethicone silicone gel or silicone sheeting
  • porcine fillers or other cosmetic fillers e.g., inserted under a
  • a Compound treatment such as, e.g., intermittent Compound treatment or a pulse Compound treatment, is administered in combination with a treatment that reduces surgical scarring, e.g., by placement of elective incisions parallel to the natural lines of skin tension (Langer's lines) or by applying sutures in a "zigzag" pattern.
  • a treatment that reduces surgical scarring e.g., by placement of elective incisions parallel to the natural lines of skin tension (Langer's lines) or by applying sutures in a "zigzag" pattern.
  • the Compound treatment such as, e.g., intermittent Compound treatment or a pulse Compound treatment
  • a treatment of wounds e.g., surgical wounds
  • administering physical therapy to a subject reducing infection, reducing separation of wound edges, minimizing collagen synthesis, deposition, or accumulation or otherwise causing the process of healing by secondary intention to better resemble healing by primary intention.
  • the combination treatment for a patient with scarring alopecia comprises controlled integumental perturbation using a fractional ablative laser, followed by twice daily topical administration of Compound for 14 days.
  • the Compound treatment is begun on the same day as the laser treatment.
  • the patient has primary cicatricial alopecia.
  • the patient has lichen planopilaris or frontal fibrosing alopecia.
  • treatment with Compound is performed using a formulation as described in Section 5.2 above.
  • treatment with Compound is commenced on the same day as the integumental perturbation and is continued once, twice, three times, four times, or five times daily for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days.
  • the Compound treatment such as, e.g., intermittent Compound treatment or a pulse Compound treatment, may promote wound healing, particularly wound healing with reduced scarring, and scar revision by, at least in part, promoting the entry of hair follicles into the wound as it heals, which in turn leads to healing skin with normal adnexal structures and, therefore, less scarring. This may occur by inducing the generation of new hair follicles and/or promoting migration of hair follicles into the wound site.
  • the Compound treatments, including intermittent and pulse Compound treatments, described herein may (i) promote hair follicle neogenesis ⁇ e.g., de novo formation of hair follicles from tissue or bone-marrow derived stem cells or disintegration of preexisting follicles into cells that mix together and reform the hair follicle); and/or (ii) promote branching ⁇ e.g., with the assistance of stem cells from dissociated hair follicles) and division of existing hair follicles.
  • hair follicle neogenesis e.g., de novo formation of hair follicles from tissue or bone-marrow derived stem cells or disintegration of preexisting follicles into cells that mix together and reform the hair follicle
  • branching e.g., with the assistance of stem cells from dissociated hair follicles
  • a superficial wound is healed by the assistance of hair follicles remaining in the wound.
  • the hair follicles disintegrate and are reorganized and reformed by the presence of stem cells that enter the wound.
  • hair follicle neogenesis promotes wound healing.
  • the combination treatment comprises treatment with one or more Compounds in combination with one or more techniques of depilation (removal of the part of the hair above the surface of the skin) or epilation (removal of the entire hair, including the part below the skin) of a part of the skin affected by unwanted hair.
  • One or more Compounds can be used in combination with any form of epilation or depilation known in the art. Any treatment that inhibits the growth of unwanted hair, removes unwanted hair and/or treats a disease or condition associated with unwanted hair that is known in the art or yet to be developed is contemplated for use in such combination treatments. For example, see U.S. Patent No. 6,050,990, issued April 18, 2000, which is incorporated herein by reference in its entirety.

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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Birds (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des procédés pour (i) moduler la pousse de cheveux et (ii) améliorer la cicatrisation de plaie, par exemple, la cicatrisation de plaie sans cicatrice, et la révision de cicatrice chez des sujets humains, lesquels procédés comprennent l'administration d'un ou plusieurs composés décrits présentement. L'invention porte également sur des compositions et sur des utilisations de compositions contenant les composés décrits présentement. Le composé, sa composition ou le ou les traitements comprenant le composé peuvent être administrés seuls ou en combinaison avec (par exemple, simultanément avec, avant et/ou après) d'autres traitements pour l'amélioration ou l'inhibition de la pousse de cheveux ou l'amélioration de la cicatrisation de plaie ou de la révision de cicatrice. De tels traitements combinés peuvent comprendre des traitements mécaniques ou physiques qui provoquent une perturbation tégumentaire (par exemple, laser, dermabrasion, etc.); une stimulation immunitaire; des traitements chimiques; et/ou des traitements chirurgicaux pour l'amélioration ou l'inhibition de la pousse de cheveux ou l'amélioration de la cicatrisation de plaie ou de la révision de cicatrice.
PCT/US2011/060375 2010-11-12 2011-11-11 Procédés et compositions pour moduler la pousse de cheveux, la cicatrisation de plaie et la révision de cicatrice WO2012065065A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US41314110P 2010-11-12 2010-11-12
US61/413,141 2010-11-12
US201161453838P 2011-03-17 2011-03-17
US61/453,838 2011-03-17
US201161501410P 2011-06-27 2011-06-27
US61/501,410 2011-06-27

Publications (2)

Publication Number Publication Date
WO2012065065A1 WO2012065065A1 (fr) 2012-05-18
WO2012065065A9 true WO2012065065A9 (fr) 2012-10-11

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WO2013148377A1 (fr) * 2012-03-25 2013-10-03 The Board Of Trustees Of The Leland Stanford Junior University Procédés de modulation de la croissance de poils au moyen de laminine-511 tronquée
WO2014197421A1 (fr) 2013-06-05 2014-12-11 Biotime, Inc. Compositions et procédés pour la régénération de tissus induite chez des espèces mammaliennes
CN103626748B (zh) * 2013-12-10 2016-08-17 浙江工业大学 一种含吡啶的噁二唑类化合物及其制备与应用
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US11478437B2 (en) 2016-07-05 2022-10-25 Jenivision Inc. Formulations for hair growth
KR20190058494A (ko) * 2016-08-26 2019-05-29 더 리젠츠 오브 더 유니버시티 오브 캘리포니아 모낭 줄기 세포 활성화 및 모발 성장
WO2018077578A1 (fr) 2016-10-28 2018-05-03 Unilever N.V. Compositions de soins personnels comprenant des particules à surface modifiée et une silicone non volatile fonctionnalisée
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KR102112736B1 (ko) * 2017-08-01 2020-05-20 주식회사 씨케이바이오텍 탈모 방지 또는 발모 촉진용 조성물
US10368502B2 (en) 2017-09-25 2019-08-06 Multiple Energy Technologies Llc Bioceramic and carbon-based hydroponic systems, methods and devices
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JP7417322B2 (ja) * 2019-11-04 2024-01-18 シーケー・リジョン・インコーポレイテッド 神経変性疾患及び／又はその臨床的状態を抑制及び／又は治療するための組成物及び方法
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GB2580226A (en) * 2017-06-30 2020-07-15 Jenivision Inc Formulations for hair growth
GB2580226B (en) * 2017-06-30 2022-08-31 Jenivision Inc Formulations for hair growth

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