WO2015157771A1

WO2015157771A1 - Hair enhancing formulation

Info

Publication number: WO2015157771A1
Application number: PCT/US2015/025602
Authority: WO
Inventors: Chantal Burnison
Original assignee: Bcs Business Consulting Services Pte Ltd
Priority date: 2014-04-11
Filing date: 2015-04-13
Publication date: 2015-10-15
Also published as: WO2015155609A2; WO2015155609A3; EP3129026A4; CN107072998A; EP3129026A1

Abstract

Provided are compositions and methods for ideally suited for improving the appearance of thinning hair in human subjects with a lower alkyl-substituted bicycloalkane, such as 6-(5-ethoxyhept-l-yl)bicyclo[3.3.0]octan-3-one or 6-(5-methoxyhept-l-yl)bicyclo[3.3.0]octan-3-one in combination with minoxidil and optionally catalase, hair dye, temporary hair color, P. sativum, and/or pseudocatalase for improving the appearance of hair, without enhancing collagen destruction potentially caused by minoxidil.

Description

HAIR ENHANCING FORMULATION

RELATED APPLICATION

This application claims the benefit, under 35 USC § 119 of the filing date of United States Patent Application Serial No. 61/978,728, filed April 11, 2014, for "EYEBROW AND EYELASH ENHANCING FORMULATION," the contents of which are incorporated herein by this reference.

TECHNICAL FIELD

The application relates to compositions for topical application generally, and more particularly to a cosmetic composition for enhancing hair growth and restoration in a subject and associated methods of making and using the composition.

BACKGROUND

Hair loss, balding, or alopecia is a common problem for which science has yet to correct. Androgenetic alopecia (AGA) is considered a common chronic dermatologic condition and it affects both men and women, usually occurring in a pattern distribution. AGA is progressive hair loss, with increasing incidence with increasing age. In Caucasians subjects who are at least 70 years old, there is a prevalence of nearly 80% of men and 42% of women who have signs of AGA. A. Blumeyer et al, "Evidence-based (S3) guideline for the treatment of Androgenetic alopecia in women and men," Journal of the German Society of Dermatology, Sept. 6, 2011, at SI, the contents of which are incorporated herein by this reference. While androgens and sensitivity to androgen metabolites is thought to be associated with balding, and specifically with AGA, the exact physiological mechanism is not known. R.M. Trueb, "Molecular mechanisms of androgenic alopecia," 27 Exp. Gerontology at 981 (2002).

Though AGA affects many elderly subjects it often starts at puberty. It can have serious detrimental effects on self-esteem, perceived personal attractiveness, and may lead to depression and other psychological ailments. M. Alfonso et al., "The psychological impact of hair loss among men: a multinational European study," 21 Curr. Med. Res. Opin., at 1829 (2005). And men who have had their hair loss successfully treated have reported psychological benefits with improvement in self-esteem and feelings of attractiveness. Id. As difficult psychologically as it is for men to lose their hair, it is even more distressing for women. T.F. Cash et al., "Psychological effects of androgenetic alopecia on women: comparisons with balding men and with female control subjects," 29 J. Am. Acad. Dermatol, at 568 (1993).

Though hair loss has been shown to have a significant psychological impact on both men and women, studies have shown that many people suffering from it never pursue therapy. See, Alfonso et al. While still others have tried various therapies, and remained dissatisfied with the results leading to poor compliance. See, Blumeyer et al.

One therapy currently in use is minoxidil 5% (w/w) (e.g., ROGAINE^®, from Johnson & Johnson Corp.) applied topically once or twice daily. Minoxidil is an antihypertensive vasodilator medication that reduces hair loss and promotes hair regrowth. It is available over-the-counter for addressing androgenic alopecia. It has been proven clinically effective to both prevent hair loss and in establishing some hair re-growth in subjects suffering pattern baldness. When used for hair growth, minoxidil has to be used regularly and indefinitely to continue the support of existing hair follicles and to maintain any hair regrowth.

Although the daily or twice daily use of minoxidil has been reported to be effective, the compound is also known to be an inhibitor of lysyl hydroxylase, an enzyme involved in collagen production. Minoxidil thus has been established to decrease collagen production in vitro. Saika et al., "Effect of lysyl hydroxylase inhibitor, minoxidil, on ultrastructure and behavior of cultured rabbit subconjunctival fibroblasts," Graefes Arch. Clin. Exp. Ophthalmol., 233(6):347-53 (June 1995), the contents of which are incorporated herein by this reference. This decrease in collagen in the skin may explain some of the other side effects attributed to minoxidil, namely wrinkling of the skin, graying of the hair, increased occurrence of deep pores in the skin, and dark circles under the subject's eyes. This, in part, may also explain the decreased compliance with therapies.

Anti-androgens are among the therapies that have been attempted to reduce hair loss from AGA or other forms of alopecia. However, various studies have shown little to no significant improvement in comparison to placebo when using a topical antiandrogen, such as fluridil. M. Sovak et al., "Fluridil, a rationally designed topical agent for androgenetic alopecia: first clinical experience," 28 Dermatol Surg, at 678 (2002), the contents of which are incorporated herein by this reference. One such study examined the use of fulvestrant (70 mg/ml twice daily), an estrogen receptor antagonist, in comparison to minoxidil 2% and placebo and found no significant difference in hair growth from placebo. J. Gassmueller et al., "Topical fulvestrant solution has no effect on male and postmenopausal female androgenetic alopecia: results from two randomized, proof-of- concept studies," 158 Br. J. Dermatol, at 109 (2008), the contents of which are incorporated herein by this reference. Blumeyer et al. concluded that there is little to no evidence to support the use of oral or topical anti-androgen treatment in men and women with AGA. Blumeyer et al., at SI 1. In addition, there have been no instructive studies of combination therapy with minoxidil and anti-androgens. Id.

SUMMARY OF THE DISCLOSURE

Described is a composition ideal for enhancing hair growth and maintenance on a human scalp that includes minoxidil and an anti-androgen. The anti-androgen is a lower alkyl-substituted bicycloalkane, e.g., 6-(5-ethoxyhept-l-yl)bicyclo[3.3.0]octan-3-one, which both enhances hair growth on its own and simultaneously maintains collagen in the subject's skin. The compounds are present in such an amount in the composition that they enhance hair growth in a subject, but do not unnecessarily decrease collagen production.

In addition, the composition may include Pisum sativum sprout extract (e.g., ANAGAIN®, from Migros-Genossenschafts-Bund Corp. Switzerland).

Use of the composition comprising minoxidil and the lower alkyl-substituted bicycloalkane, as well as the composition comprising minoxidil, the lower alkyl-substituted bicycloalkane, and optionally P. sativum sprout extract to enhance hair on a human scalp (e.g., growth, thickness, color, number, etc.) is also described. Hair growth may be measured by increased vellus hair on the scalp of a human subject.

Provided herein is a composition comprising, in the composition, an amount of minoxidil sufficient to increase the growth of hair on the scalp of a human subject; an amount of a lower alkyl-substituted bicycloalkane sufficient to increase the growth of hair on the scalp of a human subject while simultaneously inhibiting collagen destruction in the subject caused by the minoxidil; and optionally an amount of P. sativum sprout extract sufficient to increase the growth of hair on the scalp of a human subject; and a cosmetically acceptable carrier.

Such a composition may further include other active or inactive ingredient(s). In certain embodiments, the composition includes catalase in an amount sufficient to increase the natural pigmentation of the subject's hair, the loss of which may be induced by the minoxidil. Similarly, in certain embodiments, the composition includes a hair dye of a desired hair dye to color the subject's hair to a desired color.

Again similarly, in certain embodiments a color, rather than a dye, is included in the composition and/or formulation to mask the gray hair.

Also provided is a topical formulation for enhancing hair on the scalp of a human subject (e.g., growth, thickness, color, number, etc.), the topical formulation comprising one of the aforementioned compositions. Such a topical formulation will typically be selected from the group consisting of a solid, an ointment, oil, a lotion, a cream, a gel, a foam, a mousse, an aerosol, a shampoo, a hair conditioner, and a liquid.

In certain embodiments, the topical formulation is a sustained-release formulation, particularly for once a day application or dosing.

In certain embodiments, the formulation includes percutaneous permeability enhancers to improve penetration of the composition into the dermis and dermal layers through the skin barrier represented by the epidermal stratum corneum. The permeability enhancers can either be chemical or physical.

When applied to the skin of a subject, the topical formulation reduces existing wrinkles in the skin and/or decreases the appearance of new wrinkles in the skin over time, as compared to an otherwise identical topical formulation lacking the lower alkyl- substituted bicycloalkane.

In the topical formulation, the lower alkyl-substituted bicycloalkane will be present in an amount between about 0.001% and about 5.000% (w/w), while the minoxidil will typically be present in an amount between about 2%> and about 5%> (w/w), but amounts from about 0.1 %> to about 20%> (w/w) are also contemplated.

Also provided is an improved method of enhancing the appearance of hair on the scalp of a subject by topically applying a composition comprising minoxidil and/or P. sativum sprout extract to the scalp, the improvement comprising: incorporating, into the composition, a sufficient amount of lower alkyl-substituted bicycloalkane (e.g., 6-(5- ethoxyhept-l-yl)bicyclo[3.3.0]octan-3-one) to increase hair growth when applied topically to the subject and to reduce collagen destruction in the subject's skin caused by the minoxidil.

The lower alkyl-substituted bicycloalkane in the composition is believed to act synergistically with the minoxidil by enhancing minoxidil's hair growth effects, while also decreasing its side effects associated with collagen depletion and/or destruction. Incorporating the lower alkyl-substituted bicycloalkane also may help to reduce the total dosage of minoxidil needed to achieve the desired hair growth since, in the composition with another compound that enhances hair growth by an anti-androgen mechanism of action, less minoxidil and/or lower alkyl-substituted bicycloalkane may be needed to achieve the same result. Such a method improves the appearance of the subject's hair by increasing hair growth, and enhances the appearance of the skin by reducing existing wrinkles in the skin and/or decreasing the appearance of new wrinkles in the skin. In such a method, the composition might also include catalase and/or a hair dye to address concerns associated with the graying of hair. In such a method, the composition might also include P. sativum sprout extract, to further reduce hair loss.

Methods of making and using the composition and formulation are also described herein.

MODE(S) FOR CARRYING OUT THE INVENTION

The term "topical," as used herein, means application onto the surface of the skin of a mammalian subject (e.g., a human subject).

The term "dermatologically-acceptable," as used herein, means that the composition or components thereof are suitable for use in contact with human skin without undue toxicity, incompatibility, instability, allergic response, and so on.

The term "cosmetically acceptable" as used herein, means that it is approved or approvable by a regulatory agency of e.g., the U.S. or other national government or a state or local government as a cosmetic for use in humans. The term "cosmetically acceptable carrier" as used herein refers to an approved or approvable diluent, adjuvant, excipient or carrier, such as, but not limited to, a liposome, with which a compound is incorporated or administered.

The term "therapeutically effective amount" as used herein refers to the amount of a compound or composition that, when administered to a subject for treating a condition is sufficient to affect such treatment for the condition. The "therapeutically effective amount" will vary depending on the compound or composition, the condition and its severity and the age and weight of the subject to be treated.

The term "about" as used herein refers to an amount within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, and/or 1% of a disclosed or claimed quantity. The term "androgen" or "androgen receptor" as used herein refers to the intracellular protein receptor that specifically binds androgens, testosterone and DHT.

The term "extended release" or "sustained release" as used herein means a dosage form that provides for the delayed, slowed over a period of time, continuous, discontinuous, or sustained release of a compound or composition.

The term "aging skin" includes, but is not limited to, all outward visible and tactilely perceptible manifestations, as well as any other macro or micro effects due to skin aging. Such signs may be induced or caused by extrinsic factors or intrinsic factors, e.g., chronological aging or damage from environmental stressors (e.g. exposure to the sun). These signs may result from processes which include, but are not limited to, the development of textural discontinuities such as wrinkles, including both fine superficial wrinkles and coarse deep winkles, skin lines, crevices, bumps, pores and/or other forms of skin unevenness or roughness, sagging (including puffmess in the eye area, and jowls), loss of skin firmness, loss of skin tightness, loss of skin recoil, discoloration, blotching, sallowness, hyperpigmentation skin regions such as age spots and freckles, keratosis, hyperkeratinization, elastosis, collagen breakdown, and other histological changes in the stratum corneum, dermis, epidermis, the vascular system in the skin (e.g., telangiectasias), and underlying tissues, especially those proximate to the skin.

Minoxidil is a hydrophobic compound, which is readily commercially available and which has been incorporated into various compositions for topical (e.g., scalp) application. Dosages are well known to those of ordinary skill in the art, but typically vary between 0.5% and 7% (w/w), preferably 2% to 5%, and more preferably about 5%. For example, ROGAINE^® Topical Solution 5% contains minoxidil, at a concentration of 50 mg minoxidil per mL in a solution composed of alcohol, propylene glycol, and water, and is typically applied twice daily, although daily application is also used.

Various dosage forms are also well known. For example, foam formulations of minoxidil are known in the art. See, e.g., M.A. Shatalebi and Y. Rafiei, "Preparation and evaluation of minoxidil foamable emu oil emulsion," Research in Pharmaceutical Sciences, 9(2): 123-133 (April 2014).

Minoxidil is also commercially available as a foam formulation (Minoxidil topical foam, MTF), which is propylene glycol free. It is typically liquid (60 grams) pressurized in an aluminum can with a hydrocarbon propellant, which on valve actuation forms a foam lattice. This matrix is thermolabile and breaks down rapidly as soon as it comes into contact with skin. The volatile constituents evaporate and after a minute or so, little or no residue remains on the skin. This causes the active ingredient to concentrate at the vehicle- skin interface, and facilitates penetration through the skin. Foam has the ability to deliver a greater amount of the active drug at an increased rate compared with other vehicles.

Preferably, the lower alkyl-substituted bicycloalkane is 6-(5-ethoxyhept-l- yl)bicyclo[3.3.0]octan-3-one (available under the trade name ETHOCYN^®, from BCS Business Consulting Services Pte Ltd Corp. of Singapore) or 6-(5-methoxyhept-l- yl)bicyclo[3.3.0]octan-3-one. Methods of manufacture, and uses of skin care compositions comprising a lower alkyl-substituted bicycloalkane such as 6-(5-ethoxyhept-l- yl)bicyclo[3.3.0]octan-3-one ("ETHOCYN^®") or 6-(5-methoxyhept-l- yl)bicyclo[3.3.0]octan-3-one (CYTOCTOL^®, from BCS Business Consulting Services Pte Ltd Private limited company Singapore) are described in great detail in U.S. Patents 4,689,349, 4,689,345, 4,855,322, and 8,410,314.

These lower alkyl-substituted bicycloalkanes are non-steroidal anti-androgens and act to preserve collagen and inhibit androgen receptors. See, e.g., C. Guttman, "New nonsteriodal antiandrogen topical benefits aging skin," Dermatology Times, 17(1):41 (Jan. 1996) ("a nonsteriodal antiandrogen (ETHOCYN^®), which is clinically known as 6-(5- ethoxy-hept-l-yl)bicyclo[3.3.0]octan-3-one and helps to restore the elastic tissue in aging skin").

In certain embodiments, the composition reduces elastin degradation. This is especially useful in prophylactically treating loss of skin elasticity and tactile or visible signs of loss of skin elasticity associated with skin aging. Such signs of loss of elasticity include skin sagging, loss of skin firmness, loss of skin tightness and loss of skin recoil. The composition improves the function of elastin in the dermis. Without intending to be bound or otherwise limited by theory, it is believed that the loss of functional elastin results from the degradation of existing functional elastin, generally by the action of a proteolytic enzyme such as elastase.

The compositions may comprise a wide variety of optional components, provided that such optional components are physically and chemically compatible with the essential components described herein, and do not unduly impair stability, efficacy or other use benefits associated with the compositions of the disclosure.

In certain embodiments, the composition includes one or more additional ingredients. Such ingredients may include biotin, hair dye, catalase (see, e.g., U.S. Patent 6,309,656 to Pugliese et al, October 31, 2001), "PC-KUS" or pseudocatalase (see, e.g., U.S. Patent Publication No. 20030166570 to Woods et al. (Sept. 4, 2003), solvents, thickeners, gelling agents, coloring materials, fillers, pigments, antioxidants, preservatives, fragrances, electrolytes, neutralizing agents, polymers, UV blocking agents, and combinations thereof.) For example, as previously identified, application of minoxidil is thought by some to increase the amount of a subject's gray hair. Thus, in certain embodiments, the method(s) and composition(s) for enhancing the appearance of the eyelashes and/or eyebrow(s) also include(s) changing (e.g., via a readily commercially available hair dye or hair colorant) or attempting to restore the natural pigmentation (e.g., by including, e.g., 2,000 IU to 4,000 IU catalase into the composition) of the subject's hair. The catalase and/or pseudocatalase is present in the composition such that there is an amount sufficient to bring back the natural pigmentation of at least some of the subject's hair. Such a method is effective in bringing back the natural pigmentation of hair if, e.g., its usage results in at least 15% of re-growing hair strands growing from the skin to which the composition has been applied having pigmentation (as opposed to lacking pigmentation e.g., by being clear to gray).

Catalase is believed to work by breaking down hydrogen peroxide, which is also produced by hair cells and which causes hair to lighten. In a July 2009 study by the Federation of American Societies for Experimental Biology, English researchers found that gray hair had lower-than-normal levels of catalase. Wood et al, "Senile hair graying: H₂0₂- mediated oxidative stress affects human hair color by blunting methionine sulfoxide repair," The FASEB Journal, 23(7):2065-2075 (2009). PC-KUS or pseudocatalase cream is thought to work similarly, particularly when combined with the subsequent application of narrowband ultraviolet B light. See, e.g., Schallreuter et al, "Basic evidence for epidermal H₂0₂/ONOO— mediated oxidation/nitration in segmental vitiligo is supported by repigmentation of skin and eyelashes after reduction of epidermal H₂0₂ with topical NB-UVB-activated pseudocatalase PC-KUS," FASEB J., 27(8):3113-22 (Aug. 2013).

Hair dyes are well known and described in the art. For example, European Directive 2012/21/EU (August 2, 2012), identifies various substances that can be used as hair dyes, and guidelines for their use including field of application, maximum authorized concentration in the finished cosmetic product, other limitations and requirements, and conditions of use and warnings to be printed on any associated labeling (e.g., resorcinol is not to be used to dye eyelashes or eyebrows). For convenience or efficacy of application, the composition comprising the selected ingredients may be provided in various forms such as application stick, wand cream, mascara, eyebrow coloring, lotions, creams, aerosols, sprays, gels, foams, ointments, oils, mousse, emulsions, colloidals, solutions, suspensions, spray-on formulations, brush-on formulations, hair spray, moisturizer, and combinations of any thereof. The ingredients may be incorporated into such forms via, e.g., liposomes, niosomes (see, e.g., Balakrishnan et al, "Formulation and in vitro assessment of minoxidil niosomes for enhanced skin delivery," International Journal of Pharmaceutics, 377: 1-8 (2009), or emulsions (see, e.g., Sakr et al, "Preparation and evaluation of a multimodal minoxidil microemulsion versus minoxidil alone in the treatment of androgenic alopecia of mixed etiology: a pilot study," Drug Design, Development and Therapy, 2013:7413-423 (May 2013)).

Particularly when molecules of different hydrophobicity are present in the composition or formulation (e.g., relatively hydrophobic ETHOCYN® together with relatively hydrophilic pseudocatalase PC-KUS), a topical dosage form that can topically deliver both hydrophobic and hydrophilic molecules is preferred.

In some embodiments, the composition is formulated into a sustained-release formulation for transdermal application of the composition to the skin of a subject. A preferred sustained-release formulation is capable of maintaining active compounds of the composition at the skin, while permitting release of the compounds to the skin over an extended period of time (e.g., from about 6 to about 8 hours). Such a sustained-release formulation may comprise, for example and without limitation: a high molecular weight alcohol (e.g., a polyvinyl alcohol having a molecular weight of at least 8000 Da). In a sustained-release formulation, the concentration of a lower alkyl-substituted bicycloalkane and minoxidil (e.g., an anhydrous means for increasing collagen content of skin by topical application to the skin) may be higher than in a formulation for administration of these compounds without sustained-release. For example and without limitation, a sustained- release formulation may include from about 0.025% to about 3.00% (w/w) of a lower alkyl-substituted bicycloalkane. See, also, Gelfuso et al, "Chitosan microparticles for sustaining the topical delivery of minoxidil sulphate," J. Microencapsul ., 28(7):650-658 (2011).

As previously identified, in certain embodiments, the formulation may include a percutaneous permeability enhancer to improve penetration of the composition into the dermis and dermal layers through the skin barrier represented by the epidermal stratum corneum.

Non- limiting examples of chemical permeability enhancers are: enzymes, cyclodextrins, liposomes, ehtosomes, sulfoxides, alcohols, fatty acids, fatty acid esters, amides surfactants, terpene, and/or alkanones organic acids. Specifically these can be: ethanol, glyceryl monoethyl ether, monoglycerides, isopropylmyristate, lauryl alcohol (also, lauric acid, lauryl lactate), terpinol, menthol, D-limonene, beta-cyclodextrin, DMSO (dimethyl sulfoxide), polysorbates, fatty acids e.g. oleic, N-methylpyrrolidone, polyglycosylated glycerides, 1-dodecylaza cycloheptan-2-one known as AZONE® (from Nelson Research and Development Company Corp.), cyclopentadecalactone known as CPE-215™, alkyl-2-(N,N-disubstituted amino)-alkanoate ester, known as NEXACT® (from NexMed, Inc. Corp.), 2-(n-nonyl)-l,3-dioxolane known as SEPA® (from MacroChem Corp).

Non-limiting examples of physical permeability enhancers can be microdermabrasion and/or dermabrasion. These physical permeability enhancers may be used alone or in combination with chemical permeability enhancers, as described above.

In certain embodiments, the formulation includes P. sativum sprout extracts which has been integrated into a cosmetic preparation for topical uses for the skin and/or hair of a human subject. The formulation comprises between 0.05% and 40%> by weight, preferably between about 1% and 40% by weight, an extract of P. sativum in dehydrated form or not. P. sativum has been used in topical preparations to act as a photoprotective agent in a cosmetic preparation for topical use. (see, e.g., U.S. Patent 6,184,199 to Pauly (Feb 6, 2001), and U.S. Patent 8,063,005 to Kalidindi (Nov. 22, 2011)). Pisum sativum sprout extract has been shown to initiate the growth of new hair by stimulating specific signaling molecules, Noggin (a protein that shortens the telogen phase) and FGF-7 (fibroblast growth factor-7 which promotes proliferation activity of the matrix keratinocytes to start a new anagen phase). D. Schmid, et al., "The FGF7 and Noggin genes are key targets to treat hair loss," SOFW-Journal, 139(9) at 18 (2013).

In certain embodiments, the formulation includes additional compounds including a bactericide, an antibiotic, an anti-microbial peptide, vitamin A, a vitamin A derivative, or a retinoid, and an inflammatory compound. Combinations with these types of compounds in combination with the formulation, provides effective treatments for skin disorders while reducing adverse effects in comparison to current treatments. The formulation may also decrease oil, or sebum, from sebaceous glands, reduce proliferation of sebocytes or inhibit or reduce sebocyte differentiation. The additional compounds may target bacteria colonies or will provide additional anti-inflammatory assistance as needed when treating a variety of skin disorders. Thus the disclosure allows for the treatment of symptoms as well as modulation of pathways to prevent or limit the occurrence of skin disorders.

In certain embodiments, the additional components include aesthetic agents and other active agents. For example, the composition may include absorbents, abrasives, anticaking agents, antifoaming agents, antimicrobial agents, binders, biological additives, buffering agents, bulking agents, chemical additives, cosmetic biocides, denaturants, cosmetic astringents, drug astringents, external analgesics, film formers, humectants, opacifying agents, fragrances, pigments, colorings, essential oils, skin sensates, emollients, skin soothing agents, skin heling agents, pH adjusters, plasticizers, preservatives, preservative enhancers, propellants, reducing agents, additional skin-conditioning agents, skin penetration enhancing agents, dandruff therapies, skin protectants, solvents, suspending agents, emulsifiers, thickening agents, sunless tanning agents, antioxidants and/or radical scavengers, chelating agents, sequestrants, anti-acne agents, antiinflammatory agents, depilation agents, desquamation agents/exfo Hants , organic hydroxyl acids, vitamins and derivatives thereof, and other natural extracts.

In a further embodiment, the composition can be used to treat, or alleviate conditions associated with inappropriate activation of the androgen receptor. Examples of such conditions for antagonists include, but are not limited to, acne, excess sebum secretion, androgenic alopecia, hormone dependent cancers (e.g., prostate cancer), benign hyperplasia of the prostate, acne, hypertrichosis, precocious puberty, prostamegaly, virilization, polycystic ovarian syndrome, and hirsutism. The compounds may be used topically in the treatment of excess sebum and/or acne, or for hirsutism. The disclosure is also directed to compositions as described herein, in amounts effective to modulate activation of the androgen receptor. A further embodiment is directed to an article of manufacture containing at least one of the compounds packaged for retail distribution, in association with instructions advising the consumer on how to use the compound to alleviate a condition associated with an androgen receptor.

In order to exhibit the therapeutic properties described above, the compounds need to be administered in a quantity sufficient to modulate androgen receptor activation. This amount can vary depending upon the particular disease or condition being treated, the severity of the subject's disease or condition, the subject, the particular method of administration of the composition, and the presence of other underlying comorbid disease states within the subject. In a further embodiment the composition can be administered systemically, with dosing adjusted according to the condition being treated.

The compositions may be administered by a variety of routes. The compounds may be administered by subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, or rectal administration, or by the preferred route, topically. Topical administration is especially appropriate for hirsutism, alopecia, acne, and excess sebum.

As used herein, the term preventing human hair loss means maintaining or increasing the density of hair (e.g., the number of hairs per cm of skin) that is growing in a given area of the human body (e.g., scalp) as compared to the density of hair present in a similar area of the same person's body to which the method has not been applied. In the alternative, hair growth may be measured by increased vellus hair on the scalp of a human subject as compared to the density of hair present in a similar area of the same person's body to which the method has not been applied, or to a similar subject to which the method has not been applied.

The disclosure is not limited to treating androgenic alopecia. As used herein, "alopecia" refers to partial or complete hair loss on the scalp or any part of the body on which hair is psychologically or esthetically desired. The composition may be used to alleviate any type of alopecia (e.g., alopecia areata, alopecia due to radiotherapy or chemotherapy, scarring alopecia, or stress related alopecia).

In a further embodiment, the composition may be applied topically in order to prevent the growth of hair in areas where such air growth is not desired. One such use will be to alleviate hirsutism. Hirsutism is excessive hair growth in areas that typically do not have hair (e.g., the female face). Such hair growth occurs most commonly in women and may be seen at menopause. The topical administration of the compounds will alleviate this condition leading to a reduction, or elimination of this inappropriate, or undesired, hair growth.

The composition may also be used topically to decrease sebum production. Sebum is composed of triglycerides, wax esters, fatty acids, sterol esters and squalene. Sebum is produced in the acinar cells of the sebaceous glands and accumulates as these cells age. At maturation, the acinar cells lyse, releasing sebum into the luminal duct so that it may be deposited on the surface of the skin.

In some individuals, an excessive quantity of sebum is secreted onto the skin. This can have a number of adverse consequences. It can exacerbate acne, since sebum is the primary food source for Propionbacterium acnes, the causative agent of acne. It can cause the skin to have a greasy appearance, typically considered cosmetically unappealing.

Formation of sebum is regulated by growth factors and a variety of hormones including androgen. The cellular and molecular mechanism by which androgens exert their influence on the sebaceous gland has not been fully elucidated. However, clinical experience documents the impact androgens have on sebum production. Sebum production is significantly increased during puberty, when androgen levels are at their highest.

Inhibiting the secretion of sebum and reducing the amount of sebum on the surface of the skin will help treat a variety of dermal diseases such as acne or seborrheic dermatitis. In addition to therapeutic uses, the reduction of sebum on the surface of the skin will be desirable for subjects who feel their skin is oily and thus unattractive appearing.

Preferably, applying the composition to the skin is done carefully to ensure that the topical composition is substantially applied only to the skin and to avoid applying the topical composition to the hair (e.g., more than 90% or 95% of the topical composition is applied to the skin or less than 5% of the topical composition has contact with the outer 50% of the length of the hair strands).

Although something as relatively simple as a dropper can be effectively used to apply a liquid formulation hereof and may be preferred at times, other delivery means may be preferred at other times because, e.g., with application to the scalp, a liquid formulation could run into the subject's eye(s). For instance, while the liquid dropper methods of application certainly saturate the scalp better, having a liquid run down one's face into the eyes and also wetting the hair is not what one wants when rushing out to work or school in the morning.

The composition can be administered directly without any carrier. It can also be formulated into dermatological, or cosmetic carriers.

The compositions hereof can also consist of solid preparations constituting cleansing soaps or bars. These compositions may be prepared according to methods known in the art.

The compositions can also be a hair care composition, and in particular a shampoo or conditioner, a hair-setting lotion, a treating lotion, a styling cream or gel, a dye composition, or a lotion.

A subject could choose to apply a liquid formulation via dropper in the evening, and a wand or stick in the daytime (with a color or dye as part of the formulation) to fill in the balding area while at the same time causing it to eventually become thicker with hair content. Although, this would be a lifetime product— since hair regularly turns over— coloring of the hair and use of wands are parts of a regular regimen of many self-grooming people, so daily lifetime application should not be inconvenient.

A wand is typically used to, e.g., apply color onto scalp hair at the roots in order to cover gray hair. People do not want to dye their hair too often, because hair dyes can be harsh and too frequent use of them may cause hair to break off and/or fall out.

A stick is also used to cover gray scalp hair. A stick formulation comprising, in its reservoir, minoxidil, ETHOCYN®, and optionally catalase and other ingredients (e.g., P. sativum) may be used for enhancing scalp hair. Thus, such a stick formulation forms a part of the disclosure.

Such a stick formulation also including temporary hair color can ideally be used to cover gray color. In certain embodiments, people using a stick comprising hair color use these hair color sticks and wands for the roots of scalp hair to cover gray "grow-in" until the person goes to, e.g., a hairdresser (or has time at home) to use a dye to cover gray scalp hairs.

In certain embodiments, the person using formulations hereof uses the colored wand or stick in the morning application, and the liquid at night before going to sleep. The liquid dropper saturates the scalp, but the wand or stick is a more controlled application as previously described.

The wand can come in a spectrum of hair colors (e.g., brown, black, auburn, blond, and clear) and makes the brows look thick and groomed while coloring over gray in the brows. Thus, in certain embodiments, the formulation including the ingredients (e.g., minoxidil, ETHOCYN®, and optionally catalase, pseudocatalase, P. sativum sprout extract, and/or hair dye or color) is contained within reservoir portion for eventual application by the wand.

The contents of each of these publications, patent, and patent applications referenced herein are incorporated herein in their entirety by this reference.

The disclosure is further described with the aid of the following illustrative Examples.

EXAMPLES

Example I

A foam as described in U.S. Patent Publication No. 2005/0079139 to Jacques (April 14, 2005), the contents of which are incorporated herein by this reference, "Minoxidil pharmaceutical foam formulation," is formulated, but to also include 0.025% 6-(5- ethoxyhept-l-yl)bicyclo[3.3.0]octan-3-one (available under the trade name ETHOCYN® from BCS Business Consulting Services Pte Ltd Corp. of Singapore).

Example II

The foam of Example I is applied twice daily to the scalp of a mature human subject experiencing thinning hair for three months. Hair growth reoccurs, increasing the density of hair, and the hair thickens, thus enhancing the subject's hair's appearance.

Example III

A foam as described in Shatalebi and Rafiei, "Preparation and evaluation of minoxidil foamable emu oil emulsion," Research in Pharmaceutical Sciences, 9(2): 123- 133 (April 2014), the contents of which are incorporated herein by this reference, is formulated, but to also include 0.025% 6-(5-ethoxyhept-l-yl)bicyclo[3.3.0]octan-3-one (ETHOCYN®) and pseudocatalase (2.5 grams - 3 grams of PC-KUS powder to 3ml (about 1/2 teaspoon) of distilled water for incorporation into the water phase of the composition).

Example IV

A foam as described in Shatalebi and Rafiei, "Preparation and evaluation of minoxidil foamable emu oil emulsion," Research in Pharmaceutical Sciences, 9(2): 123- 133 (April 2014), the contents of which are incorporated herein by this reference, is formulated, but to also include 0.025% 6-(5-ethoxyhept-l-yl)bicyclo[3.3.0]octan-3-one (ETHOCYN®) and pseudocatalase (2.5 grams - 3 grams of PC-KUS powder to 3ml (about 1/2 teaspoon) of distilled water for incorporation into the water phase of the composition). In addition the formulation also includes P. sativum sprout extract that when applied to the scalp of a human subject is present in an amount between about 1% and about 40% by weight (e.g., 25%).

Example V

The foam of Example III is applied twice daily to the hair of a human subject experiencing thinning hair for four months. Hair growth reoccurs, increasing the density of hair, and the hair thickens, and the hair color returns to that of the subject's natural hair color, enhancing the hair's appearance. Example VI

A nanostructured lipid carrier (NLC) gel as described in Uprit et al., "Preparation and characterization of minoxidil loaded nanostructured lipid carrier gel for effective treatment of alopecia," Saudi Pharm. J, 21(4):379-85 (Oct. 2013), the contents of which are incorporated herein by this reference, and having controlled or sustained release characteristics is formulated, but to also include 0.050% 6-(5-ethoxyhept-l- yl)bicyclo[3.3.0]octan-3-one (ETHOCYN®), P. sativum sprout extract, and catalase.

Example VII

The nanostructured lipid carrier (NLC) gel of Example V is applied once daily to the hair of a human subject experiencing thinning hair for three months. Hair growth reoccurs increasing the density of hair, the hair thickens, and the hair color returns to that of the subject's natural hair color, enhancing the hair's appearance. Example VIII

A foam as described in Shatalebi and Rafiei, "Preparation and evaluation of minoxidil foamable emu oil emulsion," Research in Pharmaceutical Sciences, 9(2): 123- 133 (April 2014), the contents of which are incorporated herein by this reference, is formulated, but to also include 0.025% 6-(5-ethoxyhept-l-yl)bicyclo[3.3.0]octan-3-one (ETHOCYN®), P. sativum sprout extract, and hair dye selected to match the natural hair color of a subject.

Example IX

The foam of Example VII is applied twice daily to the hair of a human subject experiencing thinning hair for three months. Hair growth reoccurs increasing the density of hair, the hair thickens, and the hair color returns to that of the subject's natural hair color, enhancing the hair's appearance.

Example X

A nanostructured lipid carrier (NLC) gel as described in Uprit et al. "Preparation and characterization of minoxidil loaded nanostructured lipid carrier gel for effective treatment of alopecia," Saudi Pharm. J, 21(4):379-85 (Oct. 2013), the contents of which are incorporated herein by this reference, and having controlled or sustained release characteristics is formulated, but to also include 0.025% 6-(5-ethoxyhept-l- yl)bicyclo[3.3.0]octan-3-one (ETHOCYN®) and a hair colorant selected to mask a subject's gray eyebrow hair. Example XI

The NLC gel of Example IX is applied with a wand in the mornings to the hair of a human subject experiencing thinning hair for three months. Before bedtime, the subject applies a clear, liquid alcohol solution of minoxidil 5% together with ETHOCYN®, and P. sativum sprout extract, and pseudocatalase as described herein. Hair growth reoccurs, increasing the density of hair, the hair thickens, and the hair color returns to that of the subject's natural hair color, enhancing the hair's appearance.

Example XII

A foam as described in U.S. Patent Publication No. 2005/0079139 to Jacques (April 14, 2005), the contents of which are incorporated herein by this reference, "Minoxidil pharmaceutical foam formulation," is formulated, but to also include 0.025% 6-(5- ethoxyhept-l-yl)bicyclo[3.3.0]octan-3-one (ETHOCYN® BCS Business Consulting Services Pte Ltd.) and P. sativum sprout extract which when applied to the scalp of a human subject is present in an amount between about 1% and about 40%> by weight (e.g., 30%).

Example XIII

Example XIV

A gel as described in WIPO Patent Publication No. WO/2011/080743 to Bachar (December 30, 2010), the contents of which are incorporated herein by this reference, "Alcohol gel for reducing hair growth," is formulated, but to also include 0.025%) 6-(5- ethoxyhept-l-yl)bicyclo[3.3.0]octan-3-one (ETHOCYN® BCS Business Consulting Services Pte Ltd Corp.). Example XV

The gel of Example XIII is applied twice daily to the face of a mature female subject experiencing hirsutism for three months. The hair decreases in density, and the hair thins, thus enhancing the subject's appearance.

Claims

What is claimed is: 1. A formulation comprising:

an amount of minoxidil sufficient to increase the growth or restoration of hair in a human subject;

and an amount of a lower alkyl-substituted bicycloalkane sufficient to increase the growth or restoration of hair in a human subject and to inhibit collagen degradation caused by the minoxidil.

2. The formulation of claim 1, further comprising an amount of Pisum sativum sprout extract sufficient to increase the growth or restoration of hair in a human subject.

3. The formulation of claim 1 or claim 2, wherein the lower alkyl-substituted bicycloalkane is present in an amount of between about 0.001% and about 5.0% (w/w)

4. The formulation of any one of claims 1-3, wherein the minoxidil is present in an amount between about 2% and about 5%.

5. The formulation of claim 3, wherein the lower alkyl-substituted bicycloalkane of 6-(5-ethoxyhept-l-yl)bicyclo[3.3.0]octan-3-one or 6-(5-methoxyhept-l- yl)bicyclo[3.3.0]octan-3-one.

6. The formulation of any one of claims 1-5, wherein the formulation further comprises a cosmetically acceptable topical carrier.

7. The formulation of any one of claims 1-6, wherein the formulation is selected from the group consisting of a solid, an ointment, an oil, a lotion, a cream, a gel, a foam, a mousse, a shampoo, a conditioner, an aerosol, and a liquid.

8. The formulation of any one of claims 1-7, further comprising a percutaneous permeability enhancer.

9. The formulation of any one of claims 1-8, wherein the formulation further comprises a means for coloring hair.

10. The formulation of any one of claims 1-9, further comprising catalase and/or pseudocatalase.

11. The formulation of any one of claims 1-10, wherein the formulation is a sustained-release formulation.

12. A method of enhancing the appearance of a subject's hair, the method comprising:

administering a composition to the subject comprising:

minoxidil in an amount to a subject in an amount to reduce hair loss;

a lower alkyl-substituted bicycloalkane in an amount sufficient to inhibit collagen degradation; and

a cosmetically acceptable carrier.

13. The method according to claim 12, wherein the composition further comprises a therapeutically effective amount of Pisum sativum sprout extract sufficient to increase the growth or restoration of hair in the subject.

14. The method according to claim 12 or claim 13, wherein the lower alkyl- substituted bicycloalkane is present in an amount between about 0.001% and about 5.0% (w/w).

15. The method according to any one of claims 12-14, wherein the minoxidil is present in an amount between about 2% and about 5%.

16. The method according to any one of claims 12-15, wherein the lower alkyl- substituted bicycloalkane is 6-(5-ethoxyhept-l-yl)bicyclo[3.3.0]octan-3-one or 6-(5- methoxyhept-1 -yl)bicyclo[3.3.0]octan-3-one.

17. The method according to any one of claims 12-16, wherein the composition reduces elastin degradation in the subject.

18. The method according to any one of claims 12-17, wherein the composition comprising the combination of the minoxidil and the lower alkyl-substituted bicycloalkane when applied to the scalp of a human subject results in at least 5%, 10%, 15%, 20%>, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100% more vellus hair on the scalp compared to an otherwise identical composition lacking one of the minoxidil or the lower alkyl-substituted bicycloalkane.

19. The method according to any one of claims 12-18, wherein the Pisum sativum sprout extract when applied to the scalp of a human subject is present in an amount between about 1% and about 40%> by weight.

20. The method according to any one of claims 12-19 wherein the subject is undergoing androgenetic alopecia.

21. The method according to claim 20, wherein the composition further comprises catalase and/or pseudocatalase in an amount sufficient to increase the natural pigmentation of the subject's hair.

22. The method according to any one of claims 12-21, wherein the composition further comprises a hair dye and/or hair color in an amount sufficient to color the subject's hair.

23. The method according to any one of claims 12-22, wherein the composition when applied to the skin of a subject, reduces existing wrinkles in the skin and/or decreases the appearance of new wrinkles in the skin over time, as compared to an otherwise identical topical formulation lacking the lower alkyl-substituted bicycloalkane.

24. The formulation of any one of claims 1-11, for use in enhancing the appearance of a subject's hair.