HK1247560B - System and method for preventing alopecia - Google Patents

Description

Systems and methods for preventing hair loss

field

The present invention relates to methods for treating, reducing or preventing hair loss and other hair loss disorders caused by mechanical pulling on the hair, including, but not necessarily limited to, traction alopecia, and compositions, devices and kits useful in such methods.

background

Traction alopecia results from the chronic application of tension to the hair on the scalp (1). The condition was described as early as 1907 in subjects from Greenland who experienced hair loss due to long-term tight ponytails (2). Traditionally, the term "traction alopecia" has been associated with specific hairstyles that cause increased tension on the scalp (e.g., ponytails, Afro-Caribbean hairstyles with tight braids, or the tightly wrapped Muslim turbans of Sikhs). It also occurs in female ballet dancers. It is also seen in cultural traditions where hair cutting is not voluntary during religious rituals, which leads to a gradual increase in the weight of the hair itself. Traction alopecia is mechanical in etiology, not androgenic. Management involves stopping the chronic traction. However, this is unacceptable to people who prefer specific hairstyles and hairstyle techniques that cause the condition.

Traction alopecia is a substantial risk with hair extensions and braids, which can be worn to conceal hair loss or for purely cosmetic purposes. The latter involves creating a braid that is coiled around the head below the existing hairline, while a hairpiece, or wig, is attached to the braid. Because the braided hair is still growing, it requires frequent maintenance, which involves removing the wig, re-braiding the natural hair, and re-tightening the wig. Tightly braided and concealed wigs place tension on hair that is already at risk of falling out. Traction alopecia is one of the most common causes of hair loss in African-American women. "Traction alopecia" refers to hair loss or shedding caused by increased traumatic forces on the hair follicles due to hairstyles or mechanical hair procedures, such as blow-drying, flat ironing, hair curling, and chronic brushing. Traction alopecia can also occur in people who constantly pull their hair, such as those with trichotillomania.

In traction alopecia, the affected area depends on the cause of the condition, but hair loss is typically limited to the frontal and temporal scalp. According to a population study among African women, the prevalence of traction alopecia varies from 17.1% in young women (6-21 years old) to 31.7% in older women (18-86 years old). Clinical features of traction alopecia include scalp pruritus, perifollicular erythema, scaling, folliculitis, and pustules, but it can also present as a slow onset of hair loss without other symptoms. Initially, traction alopecia is considered non-scarring; however, due to the physical damage to the hair follicles, excessive tension can lead to permanent hair loss. The persistent force on the hair follicles may lead to inflammatory changes in immune cell infiltration and possibly fibrosis. Therefore, early identification of the condition is important, although it is still reversible.

Given the prevalence of hairstyles that cause traction alopecia, and the appeal of using hair styling and hair care products that can cause traction alopecia, there is a need for treating and preventing hair loss associated with this condition.

Overview

Disclosed herein are compositions and methods for treating and preventing hair loss disorders caused, at least in part, by the repetitive application of tensile forces to the hair, including, but not limited to, traction alopecia. Such disorders can be treated or prevented by administering to the hair follicles or scalp a compound or agent that induces contraction of the erector pili (AP) muscles, such as, but not limited to, alpha 1 adrenergic receptor agonists (A1AR agonists).

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings illustrate embodiments of the present invention and, together with the description, serve to explain and illustrate the principles of the present invention. The accompanying drawings are intended to illustrate the major features of the exemplary embodiments in a diagrammatic manner. The drawings are not intended to depict every feature of actual embodiments, nor do they depict relative sizes of the depicted elements, and are not drawn to scale.

Figure 1a depicts a cross-sectional view of a hair follicle and arrector pili muscle in a relaxed state; and

Figure 1b depicts a cross-sectional view of the hair follicle and arrector pili muscle in a tense state.

2 and 3 depict hair loss due to mechanical pulling according to the experiments reported in Example 3.

4 and 5 depict the depilatory force thresholds on scalp hair follicles following topical application of phenylephrine according to the procedure described in Example 3.

Detailed description

Each hair follicle of the scalp contains an arrector pili muscle, which, when contracted, raises the hair. The smooth muscle in the arrector pili muscles expresses alpha 1 adrenergic receptors ("A1AR"). Disclosed herein are methods for treating and preventing conditions associated with mechanical stress or pulling on hair, comprising topically administering to the scalp or hair follicles a composition comprising one or more A1AR agonists. As shown herein, such agonists protect hair from loss or shedding, as evidenced by an increase in the depilatory force required to remove the hair and a decrease in the number of hairs removed after brushing. Without intending to be limited or bound by theory, applicants hypothesize that contraction of the arrector pili muscles via A1AR agonists increases the threshold of force required to pull out hair during a hairdressing procedure and while under mechanical stress. Therefore, it is believed that the compounds and agents used in the present invention stimulate contraction of the AP muscles, thereby reducing hair loss by increasing the force required to remove hair.

The use of A1AR agonists to promote piloerection is described in U.S. 4,853,216, which is incorporated herein by reference in its entirety. Therein, A1AR agonists are described as being useful for causing hair to stand upright to facilitate a closer shave or to enhance the effect of depilatories. That is, A1AR agonists are described therein as agents that promote hair removal, as opposed to preventing hair loss.

While the present disclosure most generally relates to A1AR agonists as agents useful for treating and preventing the conditions involving hair loss described herein, it should be understood that any agent that stimulates contraction of smooth muscle, and particularly AP muscle, can be used in the compositions and methods described herein. That is, unless specifically indicated otherwise, the present disclosure relating to the use or formulation of A1AR agonists should be considered to also relate to other agents that stimulate contraction of AP muscle.

As used herein, the term "traction alopecia" means a form of hair loss (hair loss or hair shedding) associated with mechanical forces that pull on the hair, such as brushing, combing, flat ironing, wearing extensions, braiding, and ponytailing. According to this definition, although chronic traction on the hair can lead to traction alopecia, the mechanical forces pulling on the hair do not necessarily need to be chronic to cause hair loss or excessive shedding.

As used herein, the term "piloerectionally effective" refers to an agent or treatment that stimulates contraction of the arrector pili muscles associated with hair follicles. A "piloerectionally effective amount" of an agent or treatment is an amount sufficient to stimulate contraction of the arrector pili muscles.

As used herein, the term "alpha 1 adrenergic receptor agonist" refers to a ligand that binds to the alpha 1 adrenergic receptor on smooth muscle cells and activates smooth muscle contraction.

As used herein, the terms "prevent" or "prevention" and other derivatives of said words, when used in reference to hair loss, e.g., traction alopecia, refer to a reduction in the likelihood of hair loss in an individual receiving a given treatment relative to a similar individual at risk for hair loss who does not receive the treatment. Similarly, the terms "prevent" and "preventing" encompass treatments that result in a lesser degree of hair loss, e.g., traction alopecia, than would otherwise be expected for a given individual. The effectiveness of preventing hair loss, e.g., traction alopecia, can be established by controlled studies, e.g., in which subjects are given a treatment (e.g., a topical treatment) at one site likely to experience or exhibit hair loss (e.g., for traction alopecia, at which the hair is pulled for an extended period of time), but are not given the treatment at another site subject to the same conditions. In these cases, if the site treated with the topical treatment experiences less hair loss over time relative to the untreated site, e.g., at least 5% less, at least 10% less, at least 15% less, at least 20% less, at least 25% less, at least 30% less, at least 35% less, at least 40% less, at least 45% less, at least 50% less, or more, then the treatment is effective in preventing hair loss, e.g., traction alopecia. Efficacy in preventing other forms of hair loss can be established in a similar manner, e.g., by treating an area affected or potentially affected by such hair loss, but not another substantially similar area (i.e., subjected to the same conditions causing or potentially causing hair loss) and comparing hair loss or retention in the two areas.

As used herein, the term "treat" refers to therapeutic treatment in which the goal is to reverse, alleviate, ameliorate, inhibit, slow, or halt the progression or severity of a disease or condition, such as traction alopecia or other forms of hair loss. The term "treat" includes reducing or alleviating at least one adverse effect or symptom of a disease or condition, such as traction alopecia or other forms of hair loss. A treatment is generally "effective" if one or more symptoms are alleviated. Alternatively, a treatment is "effective" if the progression of the disease is slowed or stopped. That is, "treat" includes not only amelioration of symptoms, but also halting or at least delaying the progression or worsening of symptoms, as compared to what would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptoms, reduction in the extent of the disease, stabilization (i.e., non-worsening) of the disease state, delay or slowing of disease progression, improvement or palliation of the disease state, remission (whether partial or complete), and/or reduction in mortality. For example, a treatment is considered effective if the extent or amount of hair loss is reduced, or the progression of hair loss is slowed or stopped. The term "treating" a disease also includes providing relief from the symptoms or side effects of the disease (including palliative care).

As used herein, the term "depilatory" relates to the removal of hair. As used herein, the term "increasing depilatory force" refers to any process that increases the physical force required to remove hair. As noted above, increasing force can be viewed as a traction force being at least partially balanced by the force exerted by the arrector pili muscles—the vector direction of the contractile force of the arrector pili muscles need not necessarily be directly opposite the traction force on the hair to increase the depilatory force required to remove the hair, but the net effect is that the muscles provide at least a partial reaction to the traction force, whether it pulls directly back on the hair or simply holds the hair or hair follicle more firmly in place. Increased depilatory force can be measured in several ways, including empirically, by a reduction in traction alopecia (e.g., a reduction in hair loss of 10% or less) regardless of continuous or sustained traction, or by measuring the actual force applied to the hair follicle, for example, using a myograph, trichotilometer, or device designed to measure tensile force.

As used herein, the terms "comprising" or "including" when referring to compositions, methods, etc., are used to indicate that components or method steps are present in the method or composition, and also allow that the composition, method, etc. may include unspecified elements.

The term "consisting of refers to the compositions, methods, and individual components thereof as described herein, excluding any elements not described in the description of the embodiment.

As used herein, the term "consisting essentially of refers to those elements required for a given embodiment. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristics of the embodiment.

The singular terms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Similarly, the word "or" is intended to include "and," unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used to practice or test the present disclosure, suitable methods and materials are described below. The abbreviation, "e.g.," is derived from the Latin exempli gratia and is used herein to indicate a non-limiting example. Thus, the abbreviation "e.g." is synonymous with the term "for example."

In various aspects, the technology described herein relates to the prevention of traction alopecia. One currently available method for preventing traction alopecia is to remove, limit or avoid the application of traction forces to the hair. Therefore, hairstyles or other factors that pull on the hair (e.g., tight-fitting helmets) should generally be avoided to prevent traction alopecia. However, by using the methods proposed herein, such as applying an A1AR agonist to the hair follicles or scalp, one can limit, reduce or prevent the traction alopecia-induced effects of such hairstyles or factors as that term is defined herein, regardless of the sustained traction involved. This preventative approach allows people to wear hairstyles, helmets, etc. that would normally have a high risk of inducing traction alopecia without actually suffering from traction-related hair loss.

Various aspects of the technology described herein involve piloerection stimulation. In its simplest form, measurement or detection of piloerection stimulation can be performed by observing the area at the base of the hair shaft—agents or treatments that induce piloerection contraction cause the hair follicles to "stand up" and result in wrinkling of the skin around the hair shaft, commonly referred to as "goose bumps." Thus, if an agent is applied and the hair stands up, goose bumps form, or both, the agent has stimulated the arrector pili muscles. If necessary, measurement of the strength of the arrector pili muscle contraction can be performed using a myograph suitable for this purpose. Examples are described in, e.g., Zeveke & Gladysheva, Bull. Exp. Biol. Med. 71: 102-105 (1971); Hellmann, J. Physiol. 169: 603-620 (1963); Wyness LA, McNeill G, Prescott GL. Trichotillometry: the reliability and practicality of hair pluckability as a method of nutritional assessment. Nutr J 2007: 6: 9; and Chase ES, Weinsier RL, Laven GT, Krumdieck CL. Trichotillometry: the quantitation of hair pluckability as a method of nutritional assessment. Am J Clin Nutr 1981: 34(10): 2280-2286, each of which is incorporated herein by reference in its entirety. Other systems for measuring arrector pili muscle strength may use a dynamometer or a device designed to measure tensile force. Traction alopecia is a form of hair loss, or progressive hair loss, caused primarily by tensile forces applied to the hair. Several different hairstyles and hair extensions can cause or exacerbate traction alopecia. For example, certain hairstyles or braiding patterns that pull on the hairline have been shown to cause traction alopecia. In particular, tight braids, hair clips, or hair extension devices can exert sufficient sustained force on the hair follicles to cause traction alopecia. Generally, traction alopecia has a mechanical origin based on the forces acting on the hair. For example, prolonged traction on the hair follicles can cause inflammation. Ultimately, follicular scarring and permanent hair loss can occur due to prolonged traction.

Therefore, mechanical traction forces applied to the hair root damage the hair follicles within the root. Furthermore, as shown in Figures 1A-1B, each follicular unit contains smooth muscle that anchors the hair to the epidermis. When the smooth muscle is relaxed, as shown in Figure 1A, the muscle does not provide much restraining force, and the hair follicle can be easily removed. When the smooth muscle, or arrector pili (AP) muscle, contracts, as shown in Figure 1B, the hair follicle stands upright and is restrained by the additional force from the smooth muscle, rather than being primarily restrained by the surrounding connective tissue of the dermis. Therefore, when the smooth muscle contracts, it provides a greater holding force that opposes the forces pulling the hair out of the follicle. Therefore, by contracting the arrector pili (AP) muscle, the hair root can be more firmly rooted in the dermis of the skin, preventing mechanical traction forces from damaging the hair root and dermis, which would require greater removal force to remove the hair follicle. This prevents the long-term stress that causes excessive hair root damage, as observed with various hair styles, thereby preventing or reducing the risk of traction alopecia.

In some aspects, then, the techniques described herein involve reducing the forces exerted on the hair root. In reality, this "reduction" in force is more akin to providing a better balance of forces opposing the pull on the hair itself—that is, the treatments described herein will not necessarily reduce the amount of pull on the hair, but by stimulating the contraction of the arrector pili muscles, the treatments provide a force that at least partially opposes the effects of the pulling or pulling force, thereby protecting the hair root from the depilatory effects of the pull.

Thus, disclosed herein are methods for contracting smooth muscle cells or arrector pili muscles while a patient is wearing hair extensions, wigs, tightly braided or pulled hairstyles, combing their hair, or engaging in other activities that pull on hair follicles. Several methods for contracting AP muscles are disclosed, including application of a pharmaceutical composition containing an A1AR agonist, electrical stimulation of hair follicles, and others.

Condition to be treated or prevented

Applicants disclose herein methods for treating or preventing various conditions associated with mechanical stress on human hair. In one embodiment, the present invention relates to treating, reducing or preventing hair loss due to conditions such as traction alopecia, androgenic alopecia (also known as androgenic alopecia), alopecia areata and alopecia universalis, and hair loss due to brushing, combing, etc., comprising topically administering a therapeutically effective amount of an A1AR agonist to a person in need. In another embodiment, the present invention relates to a method for reducing the force applied to the root of the hair, comprising topically administering a therapeutically effective amount of an A1AR agonist to a person in need. In another embodiment, the present invention relates to a method for increasing hair depilatory force, comprising topically administering a therapeutically effective amount of an A1AR agonist to a person in need. In another embodiment, the present invention relates to a hairdressing method for standing hair or raising hair, comprising topically administering a therapeutically effective amount of an A1AR agonist to a person in need.

In one aspect, the therapeutically effective amount of an agent, such as an A1AR agonist, administered is a piloerection-effective amount. In one aspect, the therapeutic agent, such as an A1AR agonist, is applied to a portion of the skin, such as a portion of the scalp, containing at least one hair follicle. In a further embodiment, the at least one hair follicle is under tension.

A1AR agonists can be administered to the hair follicles or scalp to promote contraction of the AP muscle, thereby reducing, treating, or preventing hair loss and other conditions discussed herein. It is specifically contemplated that A1AR agonists, or any other agonists of smooth muscle contraction known in the art or disclosed herein, can be administered to the hair follicles or scalp in combination with an agent that hinders systemic absorption of the agent across the dermis. In this manner, agents that may otherwise have undesirable systemic effects can be used to treat, reduce, or prevent hair loss or other conditions disclosed herein while avoiding such systemic side effects. One formulation for topical administration of drugs in a manner that avoids systemic absorption is discussed in detail in U.S. 2009/0068287, which is incorporated herein by reference in its entirety.

In another aspect, described herein is a method for preventing traction alopecia comprising: applying a therapeutically effective amount, such as a piloerection-effective amount, of an AlAR agonist to an area of the scalp having a population of hair follicles that will experience tension from a hair augmentation device; and attaching the hair augmentation device to the population of hair follicles. In one embodiment, the hair augmentation device is one or more hair extensions. In another embodiment, the hair augmentation device is a braid. In another embodiment, the hair augmentation device is a hair clip.

In another aspect, described herein are methods for reducing hair loss that occurs during, for example, brushing, combing, braiding, flat ironing, shampooing, curling, wifting, attaching hair extensions or wigs, trading, ponytailing, or hair styling procedures, the methods comprising topically applying a therapeutically effective amount, for example, a piloerection-effective amount, of an A1AR agonist to a portion of the skin that includes at least one hair follicle. In one embodiment, the A1AR agonist is present on a brush or comb that can then be used to administer a therapeutic agent, such as an A1AR agonist. In another embodiment, the A1AR agonist is applied to the skin prior to brushing or combing the hair.

In another aspect, the hair styling procedure is selected from the group consisting of brushing, braiding, flat ironing, and combinations of two or more thereof. The therapeutic agent, such as an A1AR agonist, can be topically applied once, twice, or more times daily. In another embodiment, the A1AR agonist is applied to the skin twice daily. In another embodiment, the A1AR agonist is applied to the skin prior to the hair styling procedure.

In another aspect, described herein is a method of treating trichotillomania comprising topically applying a piloerection-effective amount of an A1AR agonist to a portion of the skin comprising at least one hair follicle.

The present disclosure also relates to evaluating an individual's sensitivity to treatment according to the methods disclosed herein. In one embodiment, the method comprises (1) applying an A1AR agonist (e.g., without limitation, synephrine) to a site on a person's skin; and (2) observing the person's skin 30-60 minutes after application to see if goose bumps or piloerection are observed at the site; wherein if piloerection or goose bumps are observed, the person is diagnosed as a likely candidate for a successful treatment or prevention method using an α1 adrenergic receptor agonist. The method can be combined with any other method for treating, preventing, or reducing hair loss described herein to provide a preliminary diagnosis of those populations most likely to benefit from the described methods. In one embodiment, the step of applying to the skin can involve applying a bandage or patch coated with an α1 adrenergic receptor agonist to the person's arm or thigh. In another embodiment of any composition or method involving an A1AR agonist, the agonist is synephrine or phenylephrine.

preparation

Therapeutic agents, particularly the A1AR agonists described herein and used in the present methods, can be formulated into compositions according to the knowledge of those skilled in the art. In one embodiment, the A1AR agonist or other AP muscle contraction stimulator is formulated for localized slow or extended release. However, as an example, in one embodiment, the AP stimulator is encapsulated for slow release and incorporated into a hair extension.

In another embodiment, the A1AR agonist or other stimulator of AP muscle contraction is formulated as a shampoo (which can reduce hair loss during brushing), a foam, an ointment, a spray, a solution, a gel, a sustained-release capsule, an oral tablet, or any similar compound or delivery vehicle or method. Topical application is preferred. In one embodiment, the composition is formulated as a topical cream. In another embodiment, the composition is formulated as a hair styling product selected from the group consisting of a hair spray, a styling foam, and a hair conditioner.

In another embodiment, the composition may include an exfoliating agent to promote abrasion of the scalp surface. Examples of exfoliating agents include (1) inorganic and/or metallic particles such as: boron nitride in body-centered cubic form (Borazon®); aluminum silicates (e.g., nepheline); zircon; mixed oxides of aluminum such as corundum; zinc oxide; aluminum oxides such as alumina or corundum; titanium oxide; titanium oxide-coated mica; carbides, particularly silicon carbide (corundum); or other metal oxides; metals, and metal alloys such as iron shot, steel shot, and particularly perlite; silicates such as glass, quartz, sand, or vermiculite; calcium carbonate (e.g., Bora-Bora sand or Rose de Brignoles sand) or magnesium carbonate; sodium chloride; pumice; amorphous silica; diamond; ceramics, and (2) organic particles such as: fruit stones, particularly apricot stones, such as Scrubami® apricots; lignocellulose, such as ground bamboo stalks; stem); coconut shell, such as coconut exfoliant; polyamide, in particular nylon-6; sugar; plastic microbeads, such as polyethylene or polypropylene; ground walnuts; ground almond seeds; ground shells, and (3) mixed particles associated with organic and inorganic compounds, and particles coated with the above compounds. The exfoliant may be in the form of microbeads having an exfoliating effect, the largest dimension of which is less than 5 mm.

In one embodiment, the composition comprising an A1AR agonist can be formulated as a medicament. In one embodiment, the composition comprising an A1AR agonist can be formulated as a cosmetic product.

In another embodiment, the AP muscles can be contracted via electrical stimulation of the scalp. The stimulation can be controlled by a battery and a control unit embedded in a hair extension, or in, for example, a hair brush or comb. The control unit can include an accelerometer to detect the optimal time to contract the AP muscles based on the posture of the subject or the subject's hair.

The amount of therapeutic agent present in the composition can be determined by one skilled in the art using known methods. In certain embodiments, the A1AR agonist or other stimulator of AP muscle contraction is present in the composition at a concentration of about 0.20%-0.30%, or about 0.25% by weight. In another embodiment, the therapeutic agent, such as an A1AR agonist, is present in the composition at a concentration of about 0.25%, 0.33%, 0.5%, 1%, 2%, 2.5%, or 10% by weight.

In other embodiments, the therapeutic agent, e.g., an A1AR agonist, is present in a topical composition for use in the methods disclosed herein at a concentration of from about 0.1%-35%, about 1.0%-30%, about 0.2%-30%, about 0.2%-25%, about 0.2%-20%, about 0.2%-15%, about 0.2%-10%, about 0.2%-5%, about 0.2%-4%, about 0.2%-3%, about 0.2%-2%, about 0.2%-1%, about 10.0%-30%, about 15.0%-30%, about 20.0%-30%, about 10%-20%, about 10%-15%, about 15%-20%, about 15%-60%, about 20%-60%, about 50%-60%, and about 45%-55% by weight. For certain therapeutic agents, such as synephrine (racemic mixture), concentrations of about 25%-60%, 30%-50%, 30%-60%, 25%-30%, 40%-50%, or 50%-55% by weight of the total weight of the composition are desirable.

In one embodiment, the composition comprises an A1AR agonist at a concentration of about 0.25%, about 0.33%, about 0.5%, about 1%, about 2%, about 2.5%, about 3.0%, about 4.0%, about 10%, about 15%, about 20%, or about 25% by weight.

The compositions used in the present disclosure, particularly compositions containing an A1AR agonist, can be formulated with preservatives such as EDTA (0.1-0.5% by weight of the formulation) and/or sodium metabisulfite (0.1-0.5% by weight of the formulation). In some embodiments, the compositions contain a penetration enhancer, such as one selected from the group consisting of alcohols, glycols, fatty acids, fatty esters, fatty ethers, blocking agents, surfactants, dimethylaminopropionic acid derivatives, terpenes, sulfoxides, cyclic ethers, amides, and amines. Other components of the formulations used herein can be selected from cosmetically approved excipients known in the art, including water, thickeners, and the like.

For application to the skin, the composition can be packaged in a kit with an applicator. The present invention also relates to a composition comprising a therapeutic agent (e.g., an A1AR agonist) and a kit of applicators, and to a kit of applicators comprising a composition comprising a therapeutic agent (e.g., an A1AR agonist) and a hair brush or comb, particularly a brush or comb that provides exfoliation of the scalp, such that there is slight wear after use thereof to promote penetration of the therapeutic agent into the AP muscles. In one embodiment, the therapeutic agent is provided in a metered dose applicator that provides a metered volume of the composition to be administered at each administration, for example, 1 ml of the topical composition per administration.

It should be understood that the ranges described above (and throughout this document) are also intended to cover the individual values included within these ranges. For example, for a formulation containing a particular ingredient within a range of 1-50%, a percentage of 5% or 49% is also intended to be disclosed.

therapeutic agents

The methods of the present disclosure can be used with A1AR agonists or other compounds that cause direct or indirect contraction of AP muscles. Suitable A1AR agonists that can be used include phenylephrine, cirazoline, desvenlafaxine, etilfrine, metaminol, methoxamine and naphazoline, oxymetazoline, pseudoephedrine, m-synephrine, p-synephrine, synephrine, octopamine, hordenine, tetrahydrozoline, isometheptene, metaminol, nicergoline, and bromociprofloxacin. line), ergonovine, levodopine, phendimetrazine, methoxamine, midodrine, clonidine, pergolide, xylometazoline, droxidopa, epinephrine, mephentermine, 4-methoxyamphetamine, benzphetamine, naphazoline, ergocriptine, apraclondine, bromocriptine, oxymetazoline, phenylpropanolamine, pseudoephedrine, dipivefrin, xylometazoline, and bitter orange (e.g., bitter orange extract). In addition, derivatives of A1AR agonists may be used, including derivatives of the above-mentioned compounds. In other embodiments, prodrugs that are activated to become A1AR agonists may be used. For example, midodrine is one such prodrug. When inflammation of the hair follicles is present, such as at the site of application of hair extensions, specific prodrugs can be activated by endogenous enzymes in the scalp, such as caspase-1. In one embodiment, the A1AR agonist is synephrine. In one embodiment, the A1ARA is phenylephrine or synephrine, including compositions comprising the 1-enantiomer of synephrine, which is R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol, substantially free of the other enantiomer of synephrine, or wherein less than 30%, 25%, 20%, 15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of the synephrine present in the composition is a different enantiomer. The synephrine enantiomer, R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol, can be obtained from a natural bitter orange extract. In one embodiment, the therapeutic agent is derived from bitter orange ( Citrus aurantium ), or is an extract of bitter orange, such as a bitter orange extract comprising 95%, 96%, 97%, 98%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, or 2% by weight or 5-10%, 10-15%, 5-15%, 20-25%, 15-20%, 25-30%, 30-35%, 35-40%, 40-45%, 45-55%, 50-60%, 60-70%, 70-80%, 80-90%, 85-95%, or 90-99% R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol, one enantiomer of synephrine. Extracts of bitter orange contain high levels of a single enantiomer of synephrine, R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol, and are preferably used in the methods and compositions of the present disclosure. In one embodiment, the compositions of the present invention comprise 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 16%, 27%, 28%, 29%, 30%, or 31% by weight of bitter orange extract, for example, 3-5%, 5-10%, 6%, 9%, 10-15%, 15-20%, 20-40%, 40-60%, 60-80%, or 80-95% synephrine, or a composition comprising about 5-10%, 10-15%, 15-20%, 25-30%, or 30-40% by weight bitter orange extract, for example, an extract comprising about 3-5%, 5-10%, 6%, 9%, 10-15%, 15-20%, 20-30%, 30-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 80-99% synephrine. In a preferred embodiment, the composition of the present invention comprises 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 16%, 27%, 28%, 29%, 30% or 31% by weight of bitter orange extract, wherein the extract comprises 50-90%, 50-60%, 60-70%, 70-80%, 80-90%, 85-95% or 90-99% synephrine, and substantially all of the synephrine in the extract is the enantiomer R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol.

In one embodiment, the A1AR agonist is present at 0.25%-40%, 0.25%-25% by weight, or 0.5%-22.5% by weight, or 0.75%-20% by weight, or 1%-17.5% by weight, or 1.5%-15% by weight, or 2%-14.5% by weight, or 2.5%-14% by weight, or 5%-13.5% by weight, or 7.5%-12.5% by weight, or 8%-12% by weight, or 8.5%-11.5% by weight, or 9%-11% by weight, or 9.25%-10.7 5% by weight, or 9.5% to 10.5% by weight, or 9.6% to 10.4% by weight, or 9.7% to 10.3% by weight, or 9.8% to 10.2% by weight, or 9.9% to 10.1% by weight, or 9.95% to 10.05% by weight, or 9.96% to 10.04% by weight, or 9.97% to 10.03% by weight, or 9.98% to 10.02% by weight, or 9.99% to 10.01% by weight of phenylephrine, or a pharmaceutically acceptable salt or hydrate thereof, is present in the composition at a concentration of 5% by weight, or 9.5% to 10.5% by weight, or 9.6% to 10.4% by weight, or 9.7% to 10.3% by weight, or 9.8% to 10.2% by weight, or 9.9% to 10.1% by weight, or 9.95% to 10.05% by weight, or 9.96% to 10.04% by weight, or 9.97% to 10.03% by weight, or 9.98% to 10.02% by weight, or 9.99% to 10.01% by weight.

In one embodiment, the A1AR agonist is present at 0.25%, 0.5%, 0.75%, 1%, 1.5%, 2%, 2.5%, 5%, 7.5%, 8%, 8.5%, 9%, 9.25%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 9.95%, 9.96%, 9.97%, 9.98%, or 9.99% by weight as the lower end of the range to 10.01%, 10.02%, 10.03%, 10.04%, 10.05%, 10.1%, 10.2%, 10.3%, 10.4%, 10.6%, 10.7%, 10.8%, 10.9%, 10.10%, 10.2%, 10.3%, 10.9%, 10.11%, 10.2%, 10.4%, 10.6%, 10.8%, 10.99%, 10. Phenylephrine, or a pharmaceutically acceptable salt or hydrate thereof, is present in the composition at a concentration of 0.4%, 10.5%, 10.75%, 11%, 11.5%, 12%, 12.5%, 13.5%, 14%, 14.5%, 15%, 17.5%, 20%, 22.5%, 25%, 30%, 35%, 40%, 45%, or 50% by weight (e.g., ranges of 0.25%-10.01%, 0.25%-10.02%, 0.5%-10.01%, 0.5%-10.02%, etc.).

In one embodiment, the A1AR agonist is present at 0.25% by weight, or 0.5% by weight, or 0.75% by weight, or 1% by weight, or 1.5% by weight, or 2% by weight, or 2.5% by weight, or 5% by weight, or 7.5% by weight, or 8% by weight, or 8.5% by weight, or 9% by weight, or 9.25% by weight, or 9.5% by weight, or 9.6% by weight, or 9.7% by weight, or 9.8% by weight, or 9.9% by weight, or 9.95% by weight, or 9.96% by weight, or 9.97% by weight, or 9.98% by weight, or 9.99% by weight, or 10% by weight, or 10.01% by weight, or 10.02% by weight, or 10.03% by weight, or Phenylephrine, or a pharmaceutically acceptable salt or hydrate thereof, is present in the composition at a concentration of 10.04% by weight, or 10.05% by weight, or 10.1% by weight, or 10.2% by weight, or 10.3% by weight, or 10.4% by weight, or 10.5% by weight, or 10.75% by weight, or 11% by weight, or 11.5% by weight, or 12% by weight, or 12.5% by weight, or 13.5% by weight, or 14% by weight, or 14.5% by weight, or 15% by weight, or 17.5% by weight, or 20% by weight, or 22.5% by weight, or 25% by weight, or 30% by weight, or 40% by weight, or 45% by weight, or 50% by weight, or 55% by weight.

In another embodiment, the composition comprises an A1AR agonist which is synephrine, or a pharmaceutically acceptable salt or hydrate thereof, or which comprises one enantiomer of synephrine, i.e., R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol, and is substantially free of the other enantiomer of synephrine or has less than 30%, 25%, 20%, 15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of synephrine as a different enantiomer present in the composition, wherein synephrine is present in the composition at 30%-70% by weight, or 35%-65% by weight, or 37.5%-62.5% by weight, or 40%-60% by weight, or 42.5%-57.5% by weight, or 45%-55. % by weight, or 45.5%-54.5% by weight, or 46%-54% by weight, or 46.5%-53.5% by weight, or 47%-53% by weight, or 47.5%-52.5% by weight, or 48%-52% by weight, or 48.25%-51.75% by weight, or 48.5%-51.5% by weight, or 48.75%-51.25% by weight, or 49%-51% by weight, or 49.25%-50.75% by weight, or 49.5%-50.5% by weight, or 49.6%-50.4% by weight, or 49.7%-50.3% by weight, or 49.8%-50.2% by weight, or 49.9%-50.1% by weight.

In another embodiment, the composition comprises an A1AR agonist which is synephrine, or a pharmaceutically acceptable salt or hydrate thereof, or which comprises one enantiomer of synephrine, i.e., R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol, and is substantially free of the other enantiomer of synephrine or has less than 30%, 25%, 20%, 15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of synephrine as a different enantiomer present in the composition, wherein synephrine is present in the composition at 20% by weight, or 25% by weight, or 30% by weight, or 35% by weight, or 37.5% by weight, or 40% by weight, or 42.5% by weight, or 45% by weight, or 45.5% by weight, or 46% by weight, or 46.5% by weight, or 47% by weight, or 48% by weight, or 49% by weight. 8.25% by weight, or 48.5% by weight, or 48.75% by weight, or 49% by weight, or 49.25% by weight, or 49.5% by weight, or 49.6% by weight, or 49.7% by weight, or 49.8% by weight, or 49.9% by weight - 50.1% by weight, or 50.2% by weight, or 50.3% by weight, or 50.4% by weight, or 50.5% by weight, or 50.75% by weight % by weight, or 51% by weight, or 51.25% by weight, or 51.5% by weight, or 51.75% by weight, or 52% by weight, or 52.5% by weight, or 53% by weight, or 53.5% by weight, or 54% by weight, or 54.5% by weight, or 55% by weight, or 57.5% by weight, or 60% by weight, or 62.5% by weight, or 65% by weight, or a concentration of 70% by weight is present in the composition.

In one embodiment, the composition comprises an A1AR agonist which is R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol or a pharmaceutically acceptable salt or hydrate thereof which is substantially free of the other enantiomer of synephrine (or has less than 25%, 20%, 15%, 10%, 5%, 1% or 0.1% of the other enantiomer of synephrine) and which is present in an amount of 20% by weight, or 21% by weight, or 25% by weight, or 26% by weight, or 30% by weight, or 35% by weight, or 37.5% by weight, or 40% by weight, or 42.5% by weight, or 45% by weight, or 45.5% by weight, or 46% by weight, or 46.5% by weight, or 47% by weight, or 47.5% by weight, or 48% by weight, or 48.25% by weight, or 48.5% by weight, or 48. .75% by weight, or 49% by weight, or 49.25% by weight, or 49.5% by weight, or 49.6% by weight, or 49.7% by weight, or 49.8% by weight, or 49.9% by weight, or 50% by weight, or 50.1% by weight, or 50.2% by weight, or 50.3% by weight, or 50.4% by weight, or 50.5% by weight, or 50.75% by weight, or 51% by weight, or 51.25% by weight, or 51.5% by weight, or 51.75% by weight, or 52% by weight, or 52.5% by weight, or 53% by weight, or 53.5% by weight, or 54% by weight, or 54.5% by weight, or 55% by weight, or 57.5% by weight, or 60% by weight, or 62.5% by weight, or 65% by weight, or 70% by weight is present in the composition.

In another embodiment, the composition comprises an A1AR agonist which is synephrine, or a pharmaceutically acceptable salt or hydrate thereof, or which comprises one enantiomer of synephrine, i.e., R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol, and is substantially free of the other enantiomer of synephrine or has less than 30%, 25%, 20%, 15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of synephrine as a different enantiomer present in the composition, wherein synephrine is present in an amount of 10% to 60% by weight, or 12.5% to 50% by weight, or 10% to 15% by weight. 50% by weight, or 15%-40% by weight, or 20%-30% by weight, or 20%-40% by weight, or 17.5%-30% by weight, or 20%-25% by weight, or 20.5%-24.5% by weight, or 21%-24% by weight, or 21.5%-23.5% by weight, or 21.75%-23.25% by weight, or 22%-23% by weight, or 22.1%-22.9% by weight, or 22.2%-22.8% by weight, or 22.3%-22.7% by weight, or 22.4%-22.6% by weight is present in the composition.

In another embodiment, the composition comprises an A1AR agonist which is synephrine, or a pharmaceutically acceptable salt or hydrate thereof, or which comprises one enantiomer of synephrine, i.e., R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol, and is substantially free of the other enantiomer of synephrine or has less than 30%, 25%, 20%, 15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of synephrine as a different enantiomer present in the composition, wherein synephrine is present at 10% by weight, or 12.5% by weight, or 15% by weight, or 17.5% by weight. 20% by weight, or 20.5% by weight, or 21% by weight, or 21.5% by weight, or 21.75% by weight, or 22% by weight, or 22.1% by weight, or 22.2% by weight, or 22.3% by weight, or 22.4% by weight to 22.6% by weight, or 22.7% by weight, or 22.8% by weight, or 22.9% by weight, or 23% by weight, or 23.25% by weight, or 23.5% by weight, or 24% by weight, or 24.5% by weight, or 25% by weight, or 30% by weight, or 40% by weight, or 50% by weight, or 60% by weight is present in the composition.

In one embodiment, the composition comprises one enantiomer of synephrine, i.e., R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol, and is substantially free of the other enantiomer of synephrine or has less than 30%, 25%, 20%, 15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of synephrine present as a different enantiomer in the composition, wherein R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol is present in the composition at a concentration of 20%-25% by weight.

In a further embodiment, the A1AR agonist is oxymetazoline, or a pharmaceutically acceptable salt or hydrate thereof, which is present in an amount of 0.01%-2% by weight, or 0.02%-1.75% by weight, or 0.03%-1.5% by weight, or 0.04%-1.25% by weight, or 0.05%-1% by weight, or 0.1%-0.9% by weight, or 0.15%-0.85% by weight, or 0.2%-0.8% by weight, or 0.25%-0.75% by weight, or 0.3%-0.7% by weight. 54% by weight, or 0.47%-0.53% by weight, or 0.48%-0.52% by weight, or 0.49%-0.51% by weight.

In a further embodiment, the A1AR agonist is oxymetazoline, or a pharmaceutically acceptable salt or hydrate thereof, which is present in an amount of 0.01% by weight, or 0.02% by weight, or 0.03% by weight, or 0.04% by weight, or 0.05% by weight, or 0.1% by weight, or 0.15% by weight, or 0.2% by weight, or 0.25% by weight, or 0.3% by weight, or 0.35% by weight, or 0.4% by weight, or 0.41% by weight, or 0.42% by weight, or 0.43% by weight, or 0.44% by weight, or 0.45% by weight, or 0.46% by weight, or 0.47% by weight. % by weight, or 0.48% by weight, or 0.49% by weight - 0.51% by weight, or 0.52% by weight, or 0.53% by weight, or 0.54% by weight, or 0.55% by weight, or 0.56% by weight, or 0.57% by weight, or 0.58% by weight, or 0.59% by weight, or 0.6% by weight, or 0.65% by weight, or 0.7% by weight, or 0.75% by weight, or 0.8% by weight, or 0.85% by weight, or 0.9% by weight, or 1% by weight, or 1.25% by weight, or 1.5% by weight, or 1.75% by weight, or a concentration of 2% by weight is present in the composition.

In a further embodiment, A1ARA is oxymetazoline, or a pharmaceutically acceptable salt or hydrate thereof, which is present in an amount of 0.01% by weight, or 0.02% by weight, or 0.03% by weight, or 0.04% by weight, or 0.05% by weight, or 0.1% by weight, or 0.15% by weight, or 0.2% by weight, or 0.25% by weight, or 0.3% by weight, or 0.35% by weight, or 0.4% by weight, or 0.41% by weight, or 0.42% by weight, or 0.43% by weight, or 0.44% by weight, or 0.45% by weight, or 0.46% by weight, or 0.47% by weight, or 0. % by weight, or 0.75% by weight, or 0.8% by weight, or 0.85% by weight, or 0.9% by weight, or 1% by weight, or 1.25% by weight, or 1.5% by weight, or 1.75% by weight, or 2% by weight.

In some embodiments, provided herein is an A1AR agonist formulated with a carrier or delivery vehicle that is most suitable for delivering the A1AR agonist to the scalp. The A1AR agonist can be released using several different formulations or release methods, including timed release, creams, ointments, sprays, capsules, or other release methods. For example, the A1AR agonist can be incorporated into a shampoo used during shampooing so that when the user brushes their hair, their hair follicles will be tightly secured by the AP muscles to prevent unnecessary pulling out of healthy hair when brushing. In other embodiments, the A1AR agonist can be contained in an ointment or other topical cream that can be applied to the scalp so that it can be slowly absorbed into the skin and stimulate smooth muscle. In other embodiments, the A1AR agonist can be contained in a liquid spray or aerosol medium to be applied to the scalp. In other embodiments, the A1AR agonist can be incorporated into a capsule or other slow-release medium that will allow the chemical or agent to be slowly released into the dermis of the scalp. The capsule or vehicle for encapsulating the A1AR agonist may include, but is not limited to, liposomes, non-ionic liposomes, niosomes, novasome I, erythromycin-Zn complexes, microspheres, nanoparticles, solid lipid nanoparticles, and nanoemulsions. In some embodiments, this may include a gel or foam applied to the scalp. It is particularly contemplated that the A1AR agonist may be formulated into hair care products such as hair gels, hair styling foams, hair conditioners, hair serums, hair masks, and the like.

Any of the aforementioned AlAR agonists can be applied by the user prior to applying a hair extension device or other device or condition that exerts force on the hair follicles. Alternatively, the AlAR agonist can be used regularly (e.g., twice a day) after such a device has been installed. Regular use of the AlAR agonist would be suitable as a prophylactic for traction alopecia in users of hair extension devices or other devices that exert force on the hair follicles.

Creams or other formulations with various A1AR agonists can be applied to a user before using a wig or brushing their hair. In some embodiments, the wig or hair extension can include a pad or other absorbent material that can absorb the A1AR agonist in the applied foam or cream and then be applied to the user's head. In other embodiments, a sustained-release capsule can be incorporated into the hair extension device or wig, or can be included in a hair clip. In some embodiments, the hair clip will include a pad with an absorbent layer to which the A1AR agonist cream or other A1AR agonist topical formulation is applied.

The effectiveness of a treatment or prevention of traction alopecia can be determined by monitoring hair density in a given area of a subject's body, e.g., a given area of the scalp. If the rate of hair loss decreases, e.g., by 10% or more, after treatment, the treatment is effective for preventing traction alopecia. Similarly, if hair density remains the same despite continued traction that would normally be expected to cause traction alopecia, the treatment is effective for preventing traction alopecia. If hair density increases, e.g., by 5% or more, e.g., 10% or more, after treatment and despite continued traction, the treatment is also considered effective for treating and/or preventing traction alopecia.

As noted above, it is expected that all forms of hair loss can benefit from the technology described herein. For example, the technology described herein may be applicable to preventing or treating androgenetic alopecia. AP muscles degenerate during androgenetic alopecia (e.g., reviewed in Torkamani et al., Int. J. Trichology 6:88-94 (2014)); without wishing to be bound by theory, it is expected that frequent stimulation of AP muscle contraction may slow or reduce muscle loss, thereby benefiting the treatment or prevention of androgenetic alopecia.

It is also expected that the technology described herein will be broadly applicable to any type of situation in which at least one hair follicle is under tension. Using A1AR agonist compositions or other agents that stimulate AP muscle contraction as described herein, it is expected that one can limit or reduce hair loss in such situations.

In one aspect, the situation in which at least one hair follicle is under tension is brushing or combing the hair. Thus, the technology described herein relates to a method for reducing hair loss during brushing or combing. As used herein, the term "reducing hair loss" means that the amount of hair lost from a subject is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or more compared to what would be expected in the absence of the method. An A1AR agonist or other agent that stimulates AP muscle contraction may be present on a brush or comb used to brush or comb the hair. In one embodiment, the A1AR agonist or other agent may be applied to the brush or comb prior to brushing or combing the hair, for example, in the form of a liquid, gel, cream, or spray. In one embodiment, the brush or comb can disperse the A1AR or other agent.

Agents that promote AP muscle contraction can optionally be administered via iontophoresis, which uses an electric field to drive ionic agents or drugs into the skin. As just one example, iontophoresis has been used to deliver agents such as phenylephrine to the skin to stimulate AP muscle contraction (see, e.g., Siepmann et al., Neurology April 25, 2012; 78 (Meeting Abstracts 1): P05.197). Thus, in one embodiment, a brush or comb can be combined with an iontophoresis device that can disperse A1ARA or other agents and/or be used to deliver agents transdermally. The iontophoresis device can include one or more metal contacts. Optionally, the iontophoresis device can include one or more compartments for containing A1AR agonists or other agents.

In another aspect, the condition in which at least one hair follicle is under tension is a hair-related styling procedure. Accordingly, the technology described herein relates to a method for reducing hair loss during a hair-related styling procedure. Examples of hair-related styling procedures include, but are not limited to, brushing, braiding, flat ironing, and combinations thereof.

In another aspect, the condition in which at least one hair follicle is under tension is trichotillomania, a condition characterized by a compulsive urge to pull out one's hair. Thus, to the extent that increasing the force required to remove hair can help combat hair loss due to this condition, stimulating AP muscle contraction as described herein can provide a method for reducing hair loss.

electrical stimulation

In another embodiment of the present invention, AP muscles can be contracted via electrical stimulation of the scalp or dermis of the head. The electrical stimulation can be controlled, for example, by a unit contained in a brush or comb, or embedded in a hair extension set. In some embodiments, the control unit can include an accelerometer to detect the optimal time to contract the AP muscles based on the position of the subject or their hair. In some embodiments, a tensiometer or other force gauge attached to a portion of the hair extension set can measure the pull on the patient's hair. The electrical stimulator can then vary the amount of current, voltage, or other component of the applied electrical stimulation to alter the strength of the smooth muscle contraction based on the amount of pull on the hair at a given time. In other embodiments, the control unit can deliver a standardized amount of current to the hair to reach the electrical threshold for AP muscle contraction. This can advantageously minimize the amount of current and power applied to the entire scalp. Therefore, one advantage of using electrical stimulation to contract muscles is that the strength of the contraction can be varied accordingly.

Examples of applying electrical power to contract the AP muscle are described, for example, in U.S. Patent Publication No. US2013/0199348 (published on August 8, 2013, entitled Piloerectile Effect Stimulating Device and Method), which is incorporated herein by reference in its entirety. For example, in some embodiments, the voltage or amplitude of the signal applied to the scalp may be in the range of 35-75 volts, 25-50 volts, 10-30 volts, or other suitable ranges to reach the threshold for muscle contraction. In some embodiments, the current applied to the scalp by a device as disclosed herein may preferably be microamperes to avoid electric shock to the user. Frequencies of 10 KHz-15 KHz, or lower or higher frequencies, may be applied. In some embodiments, the pulse length applied will be from 1-50 milliseconds, 1-100 milliseconds, or other suitable length to contract the AP muscle or any other piloerection-effective amount of current. In some embodiments, the control unit will automatically pulse the electrical stimulation at random intervals sufficient to maintain relative contraction of the AP muscle. In other embodiments, the pulses will be spaced sufficiently apart to allow the AP muscles to relax between pulses.

The present disclosure also relates to a device for hair augmentation and prevention of traction alopecia, comprising: a hair augmentation device; and an electrical stimulation device connected to the hair augmentation device, the electrical stimulation device comprising: a battery; a memory; an electrical stimulation generator; a scalp probe in electrical communication with the electrical stimulation generator for applying electrical stimulation; and a controller in communication with the battery, the memory, and the electrical stimulation generator, wherein the controller instructs the electrical stimulation generator to deliver a piloerection-effective amount of electrical stimulation. In certain embodiments, the piloerection-effective amount of electrical stimulation is between 10-100 volts, or between 10-15 kHz. In some embodiments, the piloerection-effective amount of electrical stimulation is applied for 1-100 milliseconds. In some embodiments, the piloerection-effective amount of electrical stimulation is applied periodically, with rest periods long enough to allow the AP muscles to relax between stimulations. In other embodiments, the piloerection-effective amount of electrical stimulation is applied periodically, with rest periods short enough to prevent the AP muscles from relaxing between stimulations. The hair augmentation device can be any product that, when applied to hair, applies a pulling force to the hair. For example, the hair augmentation device may be a hair extension, a braid, or a hair clip.

In some embodiments, the probe or electroacupuncture can be attached to a hair extension or other hairpiece, which delivers the electrical charge to the scalp. In some embodiments, the probe can be connected to a control unit having a switch, a processor, and a memory with firmware or other software instructions for delivering the desired pulses. Different control units may contain more advanced circuitry and algorithms for processing accelerometer or force data and changing the electrical stimulation accordingly. In some embodiments, the probe can be attached to any part of the hairpiece using any suitable device and method.

Other agents or methods for contracting smooth muscle

Other agents or methods can be used to contract smooth muscle to prevent or treat hair loss, for example, traction alopecia. As noted above, any agent or treatment that stimulates contraction of the AP muscle has potential use in methods of treating, reducing, or preventing hair loss as described herein.

In one embodiment, smooth muscle can be contracted by stimulating or activating cold receptors. Cold receptors can be stimulated, for example, by activating TRPM8 channels. Exemplary agents that can stimulate cold receptors include, but are not limited to, menthol and icilin. Compositions and methods for stimulating cold receptors are disclosed, for example, in U.S. Patent No. 4,034,109, the contents of which are incorporated herein by reference in their entirety.

Although AP muscles function through or are associated with both noradrenergic fibers and the cholinergic system, agents that stimulate the release of transmitters from these systems can be used to stimulate AP muscle contraction. Thus, not only α1 adrenergic agonists, but also cholinergic agonists, including, but not limited to, acetylcholine and other neurotransmitters that stimulate smooth muscle contraction are contemplated for use in the methods and compositions described herein.

The α1 adrenergic receptor is a G protein-coupled receptor. Agonists for other G protein-coupled receptors (e.g., α2 adrenergic receptors) can also be used to stimulate contraction of smooth muscle. Examples of α2 adrenergic receptor agonists include, but are not limited to, 4-NEMD, 7-Me-marsanidine, agmatine, apraclonidine, brimonidine, clonidine, detomidine, dexmedetomidine, faldomidine, guanabenz, guanfacine, lofexidine, marsanidine, medetomidine, methamphetamine, mivacyclidine, rilmenidine, romifidine, talipexol, tizanidine, tolonidine, xylazine, and xylometazoline. As noted above, systemic administration of these or other agents would be disadvantageous to some extent, as they may allow for absorption by AP muscles in the dermis, but administration of formulations that limit systemic absorption would be limited.

In one embodiment, halostachine (also known as N-methylphenylethanolamine) is contemplated for use as a therapeutic agent in the methods and compositions described herein for stimulating smooth muscle contraction.

It should be noted that the agonists described herein also encompass their inorganic or organic salts. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, succinate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, methanesulfonate, glucoheptonate, lactobionate, and laurylsulfonate, etc.

It should be noted that combinations of the above methods and agents may be used to promote smooth muscle contraction.

Acne treatment

The compositions described herein can also be used to treat acne. Contraction of the AP muscle is known to play a role in sebum secretion (see Mahfouz et al., J. Egypt Wom. Dermatol. Soc. 2005, 2, 25-29). The compositions can be applied as lotions, creams, sprays, or wipes. The compositions can be combined with benzoyl peroxide or other topical medications for acne treatment.

The various methods and techniques described above provide many ways to perform the present invention. Of course, it is to be understood that not all objects or advantages described may be achieved according to any particular embodiment described herein. Thus, for example, one skilled in the art will recognize that the method may be performed in such a way as to achieve or optimize one advantage or a group of advantages as described herein without necessarily achieving other objects or advantages as described or proposed herein. Various options are mentioned herein. It is to be understood that some embodiments specifically include one, another, or several features, while other embodiments specifically include one, another, or several features, while still other embodiments mitigate particular features by including one, another, or several advantageous features.

In addition, a skilled person will recognize the applicability of various features from different embodiments. Similarly, the various elements, features, and steps discussed above, as well as other known equivalents for each such element, feature, or step, can be used by one of ordinary skill in the art in various combinations to perform methods according to the principles described herein. Among the various elements, features, and steps, some will be explicitly included in different embodiments, while others will be explicitly excluded from different embodiments.

Although the present application has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the embodiments of the present application extend beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and modifications and equivalents thereof.

The description of numerical ranges is intended to be used herein merely as a shorthand method for each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or there is an obvious contradiction in the context. Any and all examples provided herein, or the use of exemplary language (e.g., "such as"), are intended to better illustrate the present application and do not constitute a limitation on the scope of the application otherwise claimed. No language in the specification should be deemed to indicate any non-required element essential to the implementation of the present application.

Certain embodiments of the present application are described herein. Variations on those embodiments will become apparent to those of ordinary skill in the art after reading the foregoing description. It is expected that skilled artisans may utilize such variations as appropriate and may implement the present application in a manner different from that specifically described herein. Therefore, many embodiments of the present application include all modifications and equivalents of the subject matter recited in the claims appended hereto, as permitted by applicable law. Moreover, any combination of the above elements in all their possible variations is included in the present application, unless otherwise indicated herein or otherwise clearly contradicted by the context.

All patents, patent applications, patent application publications, and other materials, such as articles, books, specifications, publications, documents, things, and/or the like, cited herein are hereby incorporated by reference in their entirety for all purposes, except any prosecution history with respect to such documents, any such documents that are inconsistent or contradictory with this document, or any such documents that may have a limiting effect on the broadest scope of the claims now or later with respect to this document. For example, in the event of an inconsistency or conflict between the descriptions, definitions, and/or usage of terms in any incorporated material and the descriptions, definitions, and/or usage of terms in this document, the descriptions, definitions, and/or usage of terms in this document shall control.

Example

Example 1: 0.1%, 0.2%, 0.5% by weight of oxymetazoline HCl

A study was conducted to evaluate the dose of topical oxymetazoline solution required to elicit a piloerection motor response in the erector pili muscles of the hair. Five subjects participated in the study. Three formulations were used: Formulation A: 0.1% topical oxymetazoline hydrochloride solution; Formulation B: 0.2% topical oxymetazoline hydrochloride solution; and Formulation C: 0.5% topical oxymetazoline hydrochloride solution.

The study was conducted over three days. On day 1, subjects were instructed to apply Formulation A to their arm. On day 2, subjects were instructed to apply Formulation B to their arm. On day 3, subjects were instructed to apply Formulation C to their arm. 0.1 mL of each formulation was applied to each arm using a metered dose dispenser. Table 1 summarizes the results from the study.

Table 1: Oxymetazoline Studies

The 0.5% topical oxymetazoline solution (Formulation C) induced clinical responses in all subjects, whereas the 0.1% and 0.2% formulations (Formulations A and B) failed to induce responses. With the 0.5% topical oxymetazoline solution, responses in erector-piloerection muscle contraction were obtained within approximately 1 hour and persisted for 8 hours.

Because of the long-lasting effects of oxymetazoline, it may be beneficial to apply it once daily, every other day, or, if needed, before mechanical procedures that apply depilatory forces to the hair follicles.

Example 2: 5.0%, 7.5%, 10% by weight phenylephrine HCl

A study was conducted to evaluate the dose of topical phenylephrine solution required to elicit a piloerection motor response in the erector pili muscles of the hair. Five subjects participated in the study. Three formulations were used: Formulation A: 5.0% topical phenylephrine hydrochloride solution; Formulation B: 7.5% topical phenylephrine hydrochloride solution; and Formulation C: 10.0% topical phenylephrine hydrochloride solution.

The study was conducted over three days. On Day 1, subjects were instructed to apply Formulation A to their arm. On Day 2, subjects were instructed to apply Formulation B to their arm. On Day 3, subjects were instructed to apply Formulation C to their arm. 0.1 mL of each formulation was applied to each arm using a metered dose dispenser. Table 2 summarizes the results from the study.

Table 2: Phenylephrine Studies – 1

The 10.0% topical phenylephrine solution (Formulation C) induced clinical responses in all subjects, whereas the 5.0% and 7.5% formulations (Formulations A and B) failed to induce responses. With the 10.0% topical phenylephrine solution, responses in erector-piloerection muscle contractions were obtained within approximately 20-30 minutes and persisted for 3 hours.

Because of the shorter duration of action of phenylephrine compared to oxymetazoline, its application prior to a mechanical procedure that applies depilatory forces to the hair follicles (if necessary) may be beneficial.

Example 3: 10% by weight Phenylephrine HCl

In another study, 10.0% phenylephrine hydrochloride was used to evaluate the use of a topical phenylephrine hydrochloride solution as a new agent for preventing/reducing hair loss due to mechanical traction. Participants included in the study were female subjects aged between 18 and 60 who frequently used invasive hair care practices such as tight braids, turbans, ponytails, extensions, curlers, hair weaves, and heat styling appliances such as hair dryers, irons, heat setters, and curling irons. Excluded subjects were those who experienced uncontrolled hypertension, were pregnant or nursing mothers, had been diagnosed with model hair loss, or experienced other hair loss associated with model hair loss in women. In total, 15 female subjects aged 24-40 years participated in the study.

The study was conducted over four days. On Day 1, subjects were instructed to wash their hair. On Day 2, subjects were instructed to apply 1 mL of a placebo solution containing a vehicle and brush the target area 30 minutes later. Brushing was performed on the frontal hair using a standard 8 x 10 cm brush. On Day 3, subjects were again instructed to wash their hair. On Day 4, subjects were instructed to apply 1 mL of a 10% phenylephrine hydrochloride solution to the target area and brush their hair 30 minutes later. Figures 2-5 summarize the results from this study.

Figures 2 and 3 show that application of a 10% phenylephrine hydrochloride solution resulted in a reduction in hair loss in 80% of patients, with an average reduction of approximately 42% compared to a placebo solution containing the vehicle. Figures 4 and 5 show that the depilatory force threshold for plucked hair follicles increased by approximately 172% after topical application of 10% phenylephrine hydrochloride. Thus, after topical application of 10% phenylephrine hydrochloride, there was a significant reduction in hair loss due to mechanical traction and an increase in depilatory force. This new study demonstrates the use of α1-AR agonists in the treatment of traction alopecia and excessive hair loss caused by mechanical hair styling procedures.

Example 4: 40%, 50% by weight Synephrine HCl

A study was conducted to evaluate the dose of topical synephrine solution required to elicit the piloerection reflex in the erector pili muscles. Five premenopausal subjects participated in the study. Two formulations were used: Formulation A, a 40% topical synephrine hydrochloride solution; and Formulation B, a 50% topical synephrine hydrochloride solution. In both solutions, synephrine was present as a racemic mixture of approximately (+/-) synephrine HCl.

The study was conducted over two days. On Day 1, subjects were instructed to apply Formulation A to their arm. On Day 2, subjects were instructed to apply Formulation B to their arm. 0.1 mL of each formulation was applied to each arm using a metered dose dispenser. Table 3 summarizes the results from this study.

Table 3: Synephrine Studies

A 50% topical synephrine hydrochloride solution (Formulation B) elicited a clinical response in 4 of 5 subjects, whereas Formulation A failed to elicit a response.

Example 5: Phenylephrine

Female subjects aged 18-40 were recruited to study the effects of topically applied phenylephrine, a selective α1-AR agonist, on hair removal force and hair loss during a hair styling procedure. In the blinded study, 80% of subjects showed reduced hair loss during the phenylephrine treatment period compared to the placebo solution treatment period. The average reduction in hair loss was approximately 42%. In addition, the force threshold required for hair removal increased by approximately 172% following topical phenylephrine application. To the inventors' knowledge, this is the first study demonstrating the use of an α1-AR agonist in the treatment of traction alopecia and hair loss during a hair styling procedure.

method:

Patients: Fifteen female subjects aged 18-40 years were included in the study. Subjects were recruited based on their frequent use of invasive hair care practices, such as tight braids, turbans, ponytails, extensions, curlers, braids, and heat styling devices such as hair dryers, irons, heat presses, and curling irons. Subjects with uncontrolled hypertension, those who were pregnant or breastfeeding, those diagnosed with model hair loss, or those with other hair loss conditions associated with model hair loss in women were excluded from the study. Prior to the pilot study, the efficacy of a 10% phenylephrine solution was tested by applying a small aliquot (50 μL) of the solution to the forearms of three subjects. Piloerection and bleaching were visible after 30 minutes; the effects lasted approximately 2-3 hours.

Hair Loss: A 4-day protocol was designed to measure hair loss during hair styling procedures. On Day 1, patients were instructed to wash their hair and use styling products and procedures as they would normally use. On Day 2, patients were instructed not to wash their hair and to apply 0.5 mL of a placebo solution containing only vehicle to the frontal area of the scalp (8 x 10 cm2 target area). Patients were instructed to wait 45 minutes, after which they used a new brush to brush their hair 20 times from the front to the back of the head. Following the procedure, the brush was sealed in a plastic bag. On Day 3, patients were instructed to wash their hair and use styling products and procedures as they would normally use. On Day 4, patients repeated the Day 2 procedure, except that they applied 0.5 mL of a 10% phenylephrine solution to the target area. After each clinical procedure, the investigator counted the hairs collected on each brush. A new brush was used for each procedure.

Hair removal power:

To evaluate the effect of topically applied α1-AR agonists on the force required to pluck a hair from the scalp, a handheld spring dynamometer, or "trichotillometer" (8) was used. The trichotillometer records the maximum force threshold (in grams) required to pluck a hair from the scalp; the performance and statistical variance of the device have been reported previously (8-10). Force measurements were performed using the trichotillometer on 10 subjects. The frontal area of the scalp was divided into two 8x10 cm2 areas. On the right side, 0.5 mL of placebo vehicle was applied. On the left side, 0.5 mL of 10% phenylephrine solution was applied. After 45 minutes, 10 hairs were plucked from each target area using the trichotillometer.

result:

After tabulating the data from the 15 subjects studied in the hair loss trial (Table 1), the inventors found that 12 of the 15 patients (80%) experienced reduced hair loss in the target area after applying the 10% phenylephrine solution, compared to hair loss in the target area after applying the placebo solution. The reduction in hair loss ranged from 9% to 100%, with an average reduction of 42%.

Table 1:

Table 1. Number of hairs removed with a brush after application of 10% phenylephrine (10% PE) or placebo.

Measurements of the hair removal force threshold in 10 subjects showed similar improvements (Table 2). Following application of a topical 10% phenylephrine solution, the hair removal force threshold at the scalp hair follicles increased by an average of 172% (range: 5%-462%).

Table 2:

Table 2. Force in grams required for hair removal after application of 10% phenylephrine (10% PE) or placebo. Each data point is the average of 10 plucked hairs [avg. (std.)].

discuss:

Currently, many people use various mechanical hair procedures that result in increased traumatic forces on the hair follicles and lead to traction alopecia. Each hair follicle in human skin contains an arrector pili muscle that expresses α1 adrenergic receptors (α1-AR). Stimulating the arrector pili muscle with an α1-AR agonist causes muscle contraction, which can provide an opposing force that resists pulling out the hair follicle. In this experiment, the inventors demonstrated that a 10% solution of phenylephrine, a selective α1 agonist, can induce a piloerection effect on the scalp that reduces hair loss and increases the threshold force for hair removal. To the best of the inventors' knowledge, this is the first study to elucidate a new mechanism of piloerection induced by an α1-AR agonist for the treatment of traction alopecia and excessive hair loss caused by hairdressing procedures.

Example 6: Bitter Orange Extract

A highly purified (greater than 90%) natural bitter orange extract from bitter orange ( Citrus auranfium ) at 25% and 12.5% concentrations in a buffered solution (pH 5.2) were tested on the arms of four subjects to determine the piloerection response. The 12.5% dose did not elicit a response. The 25% solution did. The response occurred after approximately 15-30 minutes. Piloerection lasted for 3-4 hours.

References:

1.Ozçelik D. Extensive traction alopecia attributable to ponytail hairstyle and its treatment with hair transplantation. Aesthetic Plast Surg2005: 29(4): 325-327.

2.Hjorth N. Traumatic marginal alopecia; a special type: alopeciagroenlandica. Br J Dermatol 1957: 69(9): 319-322.

3.Khumalo NP, Jessop S, Gumedze F, Ehrlich R. Determinants ofmarginal traction alopecia in African girls and women. J Am Acad Dermatol2008: 59(3): 432-438.

4.Hellmann K. The isolated pilomotor muscles as an in vitro preparation. J Physiol 1963: 169: 603–620.

5.Siepmann T, Gibbons CH, Illigens BM, Lafo JA, Brown CM, Freeman R.Quantitative pilomotor axon reflex test: a novel test of pilomotor function.Arch Neurol 2012: 69(11): 1488-1492.

6.Lewis T, Marvin HM. Observations upon a pilomotor reaction inresponse to faradism. J Physiol 1927: 64(1): 87-106.

7. Piascik MT, Perez DM. Alpha1-adrenergic receptors: new insights and directions. J Pharmacol Exp Ther 2001: 298(2): 403-410.

8. Wyness LA, McNeill G, Prescott GL. Trichotillometry: the reliability and practicality of hair pluckability as a method of nutritional assessment. Nutr J 2007: 6: 9.

9.Chase ES, Weinsier RL, Laven GT, Krumdieck CL. Trichotillometry: the quantitation of hair pluckability as a method of nutritional assessment. Am J Clin Nutr 1981: 34(10): 2280-2286.

10.Smelser DN, Smelser NB, Krumdieck CL, Schreeder MT, Laven GT.Field use of hair epilation force in nutritional status assessment. Am J ClinNutr 1982: 35: 342-346.

Claims (20)

1. Use of an α1-adrenergic receptor agonist in the preparation of a composition for the treatment or prevention of traction alopecia, comprising topically applying a composition containing an effective amount of the α1-adrenergic receptor agonist to a portion of the skin on the scalp including at least one hair follicle, wherein the composition comprises an α1-adrenergic receptor agonist as sinefelin, or a pharmaceutically acceptable salt or hydrate thereof. 2. The use of claim 1, wherein the at least one hair follicle is under tension. 3. The use of claim 1, wherein the skin portion is at risk of developing traction alopecia. 4. The use of claim 1, wherein sennafolin is present in the composition at a concentration of 5%-60% by weight. 5. The use of claim 1, wherein the composition comprises a 1-enantiomer of sinefoline, which is R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol and has less than 10% by weight of other enantiomers of sinefoline. 6. The use of claim 5, wherein R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol is present in the composition at 20%-40% by weight. 7. Use of an α1-adrenergic receptor agonist in the preparation of a composition for reducing hair loss during brushing, combing or shampooing, comprising applying topically a composition containing an effective amount of the α1-adrenergic receptor agonist to a portion of the skin on the head including at least one hair follicle, wherein the composition contains an α1-adrenergic receptor agonist as sinefelin, or a pharmaceutically acceptable salt or hydrate thereof. 8. The use of claim 7, wherein the α1-adrenergic receptor agonist is applied to the skin prior to brushing or combing. 9. The use of claim 7, wherein the at least one hair follicle is under tension. 10. The use of claim 7, wherein sennafolin is present in the composition at a concentration of 5%-60% by weight. 11. Use according to claim 7, wherein the composition comprises a 1-enantiomer of sinefoline, which is R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol and has less than 10% by weight of other enantiomers of sinefoline. 12. The use of claim 11, wherein R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol is present in the composition at 20%-40% by weight. 13. Use of an α1-adrenergic receptor agonist in the preparation of a composition for increasing the hair-removing power of hair, comprising applying topically a composition containing an effective amount of the α1-adrenergic receptor agonist to a portion of skin on a human head including at least one hair follicle, wherein the composition contains an α1-adrenergic receptor agonist as sinefelin, or a pharmaceutically acceptable salt or hydrate thereof. 14. Use of claim 13, wherein a person undergoes a hair styling procedure on the hair before, during, or after the application of the composition, said hair styling procedure being selected from braiding, perming, attaching hair braids, attaching hair extensions, or braiding the hair back into a ponytail. 15. The use of claim 13, wherein sennafolin is present in the composition at a concentration of 5%-60% by weight. 16. Use of claim 13, wherein the composition comprises a 1-enantiomer of sinefoline, which is R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol and has less than 10% by weight of other enantiomers of sinefoline. 17. The use of claim 16, wherein R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol is present in the composition at 20%-40% by weight. 18. The use of claim 13, wherein the α1-adrenergic receptor agonist is applied to the skin once a day. 19. The use of claim 13, wherein the composition of the α1-adrenergic receptor agonist is applied to the skin twice a day. 20. Use of α1-adrenergic receptor agonists in the preparation of compositions for the prevention of traction alopecia, comprising: A composition comprising an effective amount of an α1-adrenergic receptor agonist for piloerection is applied to a region of the scalp having a cluster of hair follicles, the region being subjected to tension from a hair-enhancing device; and the hair-enhancing device is attached to the cluster of hair follicles, wherein the composition comprises an α1-adrenergic receptor agonist, such as sinefoline, or a pharmaceutically acceptable salt or hydrate thereof.