U.S. patent application number 15/354743 was filed with the patent office on 2017-05-18 for system and method for preventing alopecia.
The applicant listed for this patent is Ofer A. GOREN, John MCCOY. Invention is credited to Ofer A. GOREN, John MCCOY.
Application Number | 20170135988 15/354743 |
Document ID | / |
Family ID | 55955138 |
Filed Date | 2017-05-18 |
United States Patent
Application |
20170135988 |
Kind Code |
A1 |
GOREN; Ofer A. ; et
al. |
May 18, 2017 |
SYSTEM AND METHOD FOR PREVENTING ALOPECIA
Abstract
Traction alopecia and other disorders related to mechanical
pulling on hair are treated or prevented by administering a topical
composition comprising an alpha-1 adrenergic receptor agonist, a
muscarinic receptor agonist, a nicotinic receptor agonist, and/or a
cholinesterase inhibitor, or electrical stimulation to contract the
arrector pili muscle. Compositions and methods are disclosed herein
for the treatment and prevention of hair loss disorders caused at
least in part by repeated application of tensile force to hair,
including, without limitation, traction alopecia.
Inventors: |
GOREN; Ofer A.; (Irvine,
CA) ; MCCOY; John; (Irvine, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GOREN; Ofer A.
MCCOY; John |
Irvine
Irvine |
CA
CA |
US
US |
|
|
Family ID: |
55955138 |
Appl. No.: |
15/354743 |
Filed: |
November 17, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/US2015/060663 |
Nov 13, 2015 |
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15354743 |
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62080137 |
Nov 14, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4174 20130101;
A61K 31/137 20130101; A61K 9/0014 20130101; A61Q 7/00 20130101;
A61K 8/41 20130101; A61K 8/9789 20170801; A61K 9/08 20130101; A61P
17/14 20180101; A61K 36/752 20130101 |
International
Class: |
A61K 31/4174 20060101
A61K031/4174; A61K 31/137 20060101 A61K031/137; A61K 36/752
20060101 A61K036/752; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method for treatment or prevention of traction alopecia
comprising applying a pilomotor effective amount of an active agent
selected from the group consisting of muscarinic receptor agonists,
nicotinic receptor agonists, and cholinesterase inhibitors
topically to a portion of skin on the head that includes at least
one hair follicle.
2. The method of claim 1, wherein the at least one hair follicle is
under tension.
3. The method of claim 1, wherein the portion of skin is at risk
for developing traction alopecia.
4. The method of claim 1, wherein the active agent is selected from
the group consisting of agonists of muscarinic M.sub.2-type
receptors, agonists of muscarinic M.sub.3-type receptors, agonists
of a N.sub.N-type receptor, agonists of a N.sub.M-type receptor,
and cholinesterase inhibitors.
5. The method of claim 1, wherein the active agent is a muscarinic
receptor agonist.
6. The method of claim 1, further comprising administering a
therapeutically effective amount of an agonist of an alpha 1
adrenergic receptor topically to the portion of skin on the
head.
7. A method of reducing hair shedding during brushing, combing or
showering, the method comprising applying a pilomotor effective
amount of an active agent selected from the group consisting of
muscarinic receptor agonists, nicotinic receptor agonists, and
cholinesterase inhibitors topically to a portion of skin on the
head that includes at least one hair follicle.
8. The method of claim 7, wherein the composition is applied to the
skin prior to the brushing or combing.
9. The method of claim 7, wherein the at least one hair follicle is
under tension.
10. The method of claim 7, wherein the active agent is selected
from the group consisting of agonists of muscarinic M.sub.2-type
receptors, agonists of muscarinic M.sub.3-type receptors, agonists
of a N.sub.N-type receptor, agonists of a N.sub.M-type receptor,
and cholinesterase inhibitors.
11. The method of claim 7, wherein the composition comprises a
muscarinic acetylcholine receptor agonist.
12. The method of claim 7, further comprising administering a
therapeutically effective amount of an agonist of an alpha 1
adrenergic receptor topically to the portion of skin on the
head.
13. A method for increasing epilatory force of the hair, the method
comprising applying a pilomotor effective amount of an active agent
selected from the group consisting of muscarinic receptor agonists,
nicotinic receptor agonists, and cholinesterase inhibitors
topically to a portion of skin on the head of a person that
includes at least one hair follicle.
14. The method of claim 13, wherein before, during or after the
active agent is applied, the person undergoes a cosmetic procedure
to the hair selected from the group consisting of braiding, flat
ironing, attaching a hair weave, attaching a hair extension, or
tying the hair back in a ponytail.
15. The method of claim 13, wherein the active agent is selected
from the group consisting of agonists of muscarinic M.sub.2-type
receptors, agonists of muscarinic M.sub.3-type receptors, agonists
of a N.sub.N-type receptor, agonists of a N.sub.M-type receptor,
and cholinesterase inhibitors.
16. The method of claim 13, wherein the active agent is a
muscarinic receptor agonist.
17. The method of claim 13, further comprising administering a
therapeutically effective amount of an agonist of an alpha 1
adrenergic receptor topically to the portion of skin on the
head.
18. The method of claim 13, wherein the active agent is applied to
the portion of the skin once daily.
19. The method of claim 13, wherein the composition is applied to
the portion of the skin twice daily.
20. A method for prevention of traction alopecia comprising:
applying a composition comprising a pilomoter effective amount of
an active agent selected from the group consisting of muscarinic
receptor agonists, nicotinic receptor agonists, and cholinesterase
inhibitors to the scalp to an area with a group of follicles that
will experience a pulling force from a hair augmentation device;
and attaching the hair augmentation device to the group of
follicles.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part application of,
and claims the benefit of, PCT/US2015/060663 (WO 2016/077744) filed
Nov. 13, 2015, which claims the benefit of U.S. Provisional
Application No. 62/080,137 filed on Nov. 14, 2014, U.S. Provisional
Application No. 62/099,830 filed on Jan. 5, 2015, U.S. Provisional
Application No. 62/213,355 filed on Sep. 2, 2015, and U.S.
Provisional Application No. 62/221,863 filed on Sep. 22, 2015. The
entire content of each application referenced above is incorporated
herein by reference.
FIELD
[0002] The present invention is directed to methods for treating,
reducing or preventing alopecia and other hair loss disorders
caused by mechanical pulling of the hair, including but not
necessarily limited to traction alopecia, and compositions, devices
and kits useful in such methods.
BACKGROUND
[0003] Traction alopecia results from the chronic application of
tensile force to scalp hair (1). The condition was described as
early as 1907 in subjects from Greenland who had developed hair
loss due to prolonged wearing of tight ponytails (2).
Traditionally, the term "traction alopecia" has been related to
specific hairstyles that cause increased tension on the scalp
(e.g., ponytails, Afro-Caribbean hair styles with tight braiding or
the tightly wound turbans of Sikh men). It has also been seen in
female ballerinas. It is also seen in cultural traditions where the
hair is voluntarily not cut in religious obeisance, which causes
progressively increasing weight of the hair itself. Traction
alopecia is mechanical in etiology, rather than androgenic.
Management includes cessation of the chronic traction. However,
this is unacceptable to people who favor the specific hairstyles
and styling techniques that give rise to the condition.
[0004] Traction alopecia is a substantial risk in hair extensions
and weaves, which can be worn either to conceal hair loss, or
purely for cosmetic purposes. The latter involves creating a braid
around the head below the existing hairline, to which an
extended-wear hairpiece, or wig, is attached. Because the hair of
the braid is still growing, it requires frequent maintenance, which
involves the hairpiece being removed, the natural hair braided
again, and the piece snugly reattached. The tight braiding and snug
hairpiece cause tension on the hair that is already at risk for
falling out. Traction alopecia is one of the most common causes of
hair loss in African American women. "Traction alopecia" includes
hair loss or shedding due to increased traumatic force on hair
follicles caused by hairstyle or mechanical hair procedures such as
blow drying, flat ironing, hair curling and chronic brushing.
Traction alopecia can also develop in patients constantly pulling
their hair such as in trichotillomania.
[0005] In traction alopecia, affected areas depend on the etiology
of the disorder, but usually hair loss is localized on frontal and
temporal scalp. According to population studies in African women,
prevalence of traction alopecia varies from 17.1% in young women
(6-21 years) to 31.7% in older women (18-86 years). Clinical
features of traction alopecia include itching of the scalp,
perifollicular erythema, scaling, folliculitis, and pustules, but
it can also present as slow onset of hair loss without other
symptoms. Primarily, traction alopecia is considered
noncicatricial, yet excessive tension can lead to permanent
alopecia, due to physical damage of hair follicles. Prolonged force
on hair follicles may lead to inflammatory changes in immune cell
infiltrate and fibrosis can result. Therefore, it is important to
recognize the condition early, while it is still reversible.
[0006] In view of the popularity of hairstyles that result in
traction alopecia, and the desirability of use of hairstyling and
care products that may cause traction alopecia, there is a need for
treatment and prevention of hair loss associated with the
condition.
SUMMARY
[0007] Compositions and methods are disclosed herein for the
treatment and prevention of hair loss disorders caused at least in
part by repeated application of tensile force to hair, including,
without limitation, traction alopecia. Such disorders may be
treated or prevented by the application to the hair follicle or
scalp of a pilomoter effective amount of an active agent selected
from the group consisting of alpha 1 adrenergic receptor agonists
(A1AR agonists), muscarinic receptor agonists, nicotinic receptor
agonists, and cholinesterase inhibitors. In one embodiment, the
active agent is selected from the group consisting of muscarinic
receptor agonists, nicotinic receptor agonists, and cholinesterase
inhibitors.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] The accompanying drawings exemplify embodiments of the
present invention and, together with the description, serve to
explain and illustrate principles of the invention. The drawings
are intended to illustrate major features of the exemplary
embodiments in a diagrammatic manner. The drawings are not intended
to depict every feature of actual embodiments nor relative
dimensions of the depicted elements, and are not drawn to
scale.
[0009] FIG. 1a depicts a cross sectional view of the hair follicle
and the arrector pili muscle in a relaxed state; and
[0010] FIG. 1b depicts a cross sectional view of the hair follicle
and the arrector pili muscle in a tensed state.
[0011] FIGS. 2 and 3 depict hair loss from mechanical pulling
according to the experiment reported in example 3.
[0012] FIGS. 4 and 5 depict epilatory force thresholds on scalp
hair follicles following topical phenylephrine application
according to the procedures described in example 3.
DETAILED DESCRIPTION
[0013] Each hair follicle in the scalp contains an arrector pili
muscle (also referred to as "AP" herein) that, when contracted,
erects the hair. The smooth muscle in the arrector pili expresses
.alpha.1 adrenergic receptors ("A1AR"). Agonists of the adrenergic
receptors directly stimulate the smooth muscle. Also, acetylcholine
and acetylcholine receptor agonists act via axon reflexes to
stimulate smooth muscle contraction. Acetylcholine acts on the
nerves in the central nervous system as a substance mediating the
propagation of impulses across the ganglionic synapse, but it also
has a second pharmacological effect, which is mediated through an
axon reflex. Axon reflexes are peripheral nervous system impulses
independent of the central nervous system. See Rothman and Coon,
"Axon Reflex Responses to Acetyl Choline in the Skin," J.
Investigative Dermatology, 3: 79-97 (1940). Without limiting the
invention in any way, it is believed that the smooth muscle in the
arrector pili is served by or associated with both noradrenergic
fibers and a cholinergic system, and therefore agents that
stimulate release of transmitters from these systems or that
activate the axon reflex can be used to stimulate smooth muscle
contraction and thereby increase the epilation force needed to
remove hair. As shown herein, such active agents protect against
hair loss or shedding as shown by an increase in epilation force
needed to remove a hair and reduction in the number of hairs
removed after brushing. Without intending to be limited or bound by
theory, Applicants postulate that contraction of the arrector pili
muscle via an A1AR receptor agonist, a muscarinic receptor agonist,
a nicotinic receptor agonist, and/or a cholinesterase inhibitor
increases the threshold of force required to pluck hair during
cosmetic procedures and while under mechanical stress. Thus, it is
believed that the compounds and agents used in the present
invention stimulate contraction of the AP muscle and thereby reduce
hair loss by increasing the force required to remove the hair.
[0014] Thus, alpha-1adrenergic agonists and cholinergic receptor
agonists, including, but not limited to muscarinic receptor
agonists, nicotinic receptor agonists, and acetylcholine and other
neurotransmitters that stimulate smooth muscle contraction are
contemplated for use in the methods and compositions described
herein. Another manner of accomplishing smooth muscle contraction
is by reducing the destruction of acetylcholine following its
release by administering one or more cholinesterase inhibitors.
Disclosed herein are methods for the treatment and prevention of
disorders associated with mechanical stress or pulling on the hair
comprising topical administration to the scalp or hair follicle of
a an effective amount of a composition comprising one or more A1AR
receptor agonists, muscarinic receptor agonists, nicotinic receptor
agonists, and/or cholinesterase inhibitors.
[0015] The use of A1AR agonists to promote the pilomotor effect is
described in U.S. Pat. No. 4,853,216, which is incorporated herein
by reference in its entirety. There, the A1AR agonists were
recognized as useful for causing hairs to stand up to facilitate
closer shaving or to potentiate the effect of depilatories. That
is, A1AR agonists were described there as agents that facilitate
hair removal, as opposed to prevent hair loss.
[0016] While the disclosure most often specifically refers to A1AR
agonists, muscarinic receptor agonists, nicotinic receptor
agonists, acetylcholine, and cholinesterase inhibitors as agents
useful for treating and preventing the disorders described herein
relating to hair loss, it should be understood that any agent that
stimulates contraction of smooth muscle, and particularly the AP
muscle, can be useful in the compositions and methods described
herein.
[0017] As used herein, the term "traction alopecia" means a form of
alopecia (hair loss or hair shedding) associated with mechanical
forces that pull the hair such as hair brushing hair combing, flat
ironing, wearing of extensions, hair braiding, and ponytail style
hair. Under this definition, although chronic traction on the hair
can lead to traction alopecia, the mechanical forces that pull the
hair do not necessarily need to be chronic to lead to hair loss or
excessive shedding.
[0018] As used herein, the term "pilomotor effective" refers to an
agent or treatment that stimulates contraction of the arrector pili
muscle associated with a hair follicle. A "pilomotor effective
amount" of an agent or treatment is an amount sufficient to
stimulate contraction of the arrector pili muscle.
[0019] As used herein, the term "alpha 1 adrenergic receptor
agonist" or "A1AR agonist" refers to a ligand that binds the alpha
1 adrenergic receptor on smooth muscle cells and activates smooth
muscle contraction.
[0020] As used herein, the terms "prevent" or "prevention" and
other derivatives of the words, when used in reference to alopecia,
e.g., traction alopecia, refer to a reduced likelihood of alopecia
in an individual receiving a given treatment relative to that of a
similar individual at risk for alopecia but not receiving that
treatment. As such, the terms "prevent" and "prevention" encompass
a treatment that results in a lesser degree of alopecia, e.g.,
traction alopecia, than would be otherwise expected for a given
individual. Efficacy for prevention of alopecia, e.g., traction
alopecia, can be established through controlled studies, e.g., in
which a subject is administered a treatment (e.g., a topical
treatment) at one site likely to experience or exhibit alopecia
(e.g., for traction alopecia, a site at which hair is pulled for an
extended period of time) but not at another site subjected to the
same conditions. Under these circumstances, if the site treated
with the topical treatment undergoes 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 beyond, the treatment is effective
for the prevention of alopecia, e.g., traction alopecia. Efficacy
for the prevention of other forms of alopecia can be established in
a similar manner, e.g., by treating one area affected by or likely
to be affected by such alopecia, but not another, substantially
similar area (i.e., subject to the same conditions causing alopecia
or a likelihood of alopecia) and comparing hair loss or retention
in the two areas.
[0021] As used herein, the terms "treat," "treatment," or
"treating" refer to therapeutic treatments, wherein the object is
to reverse, alleviate, ameliorate, inhibit, slow down or stop the
progression or severity of a disease or condition, e.g., traction
alopecia or other form of alopecia. The term "treating" includes
reducing or alleviating at least one adverse effect or symptom of a
disease or condition, e.g., traction alopecia or other form of
alopecia. Treatment is generally "effective" if one or more
symptoms are reduced. Alternatively, treatment is "effective" if
the progression of a disease is reduced or halted. That is,
"treatment" includes not just the improvement of symptoms, but also
a cessation of, or at least slowing of, progress or worsening of
symptoms 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 symptom(s), diminishment
of extent of disease, stabilized (i.e., not worsening) state of
disease, delay or slowing of disease progression, amelioration or
palliation of the disease state, remission (whether partial or
total), and/or decreased mortality. For example, treatment is
considered effective if the extent or amount of hair loss is
reduced, or the progression of hair loss is slowed or halted. The
term "treatment" of a disease also includes providing relief from
the symptoms or side-effects of the disease (including palliative
treatment).
[0022] As used herein, the term "epilatory" relates to the removal
of hair. As used herein, the term "increasing epilatory force"
refers to any treatment that increases the physical force required
to remove a hair. As noted, the increase in force can be viewed as
at least a partial balancing of a traction force by the force
exerted by the arrector pili muscle--the vector direction of the
arrector pili muscle's force of contraction need not necessarily be
directly opposed to a traction force on the hair shaft to increase
the epilatory force required to remove the hair, but the net effect
is that the muscle provides at least a partial counter-acting force
to the traction force, whether it directly pulls back on the hair
or simply holds the hair or hair follicle more tightly in place. An
increase in epilatory force can be measured in several ways,
including empirically, through a reduction in traction alopecia
(e.g., 10% or less reduction in hair loss) despite continued or
ongoing traction, or through measurement of actual force exerted on
the hair follicle, e.g., with a myograph, trichotilometer, or a
device used to measure tensile forces.
[0023] As used herein the tem "comprising" or "comprises" is used
in reference to compositions, methods, etc. refers to component(s)
or method steps that are present in the method or composition, yet
allows for the composition, method, etc. to also include
unspecified elements.
[0024] The term "consisting of" refers to compositions, methods,
and respective components thereof as described herein, which are
exclusive of any element not recited in that description of the
embodiment.
[0025] 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 characteristic(s) of that embodiment.
[0026] The singular terms "a," "an," and "the" include plural
referents unless 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 in the practice
or testing of this 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."
[0027] In various aspects, the technology described herein relates
to the prevention of traction alopecia. One preventive approach
currently available for traction alopecia is to remove, limit or
avoid the application of a traction force to the hair. Thus,
hairstyles or other factors that pull on the hair (e.g., tight
fitting helmets) should normally be avoided to prevent traction
alopecia. However, by using the methods set out herein, one can
limit, reduce or prevent as that term is defined herein the
traction alopecia-inducing effects of such hairstyles or factors
despite the ongoing traction involved. This preventive approach
permits one to wear a hairstyle, helmet, etc., that would normally
have a high risk of inducing traction alopecia without actually
suffering the traction-related hair loss.
[0028] Various aspects of the technology described herein involve
pilomotor stimulation. The measurement or detection of pilomotor
stimulation can be performed, at its simplest, by observation of
the area at the base of the hair shaft--an agent or treatment that
induces arrector pili contraction causes the hair follicle to
"stand up" and causes puckering 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. Measurement of the strength of
arrector pili muscle contraction can be performed, if necessary,
via myograph adapted for that 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 L A,
McNeill G, Prescott G L. Trichotillometry: the reliability and
practicality of hair pluckability as a method of nutritional
assessment. Nutr J 2007: 6: 9; and Chase E S, Weinsier R L, Laven G
T, Krumdieck C L. 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 in its
entirety by reference. Other systems to measure the strength of the
arrector pili muscle can use a trichotillometer or a device used to
measure tensile forces. Traction alopecia is a form of alopecia, or
gradual hair loss, caused primarily by pulling force applied to the
hair. Several different hair styles and hair extensions can cause
or exacerbate traction alopecia. For example, certain styles or
braiding patterns that pull the hairline have been shown to cause
traction alopecia. Particularly tight braids, barrettes, or the
installation of hair extensions can exert sufficient chronic force
on the hair follicles to cause traction alopecia. Generally,
traction alopecia has a mechanical origin based on the force on the
hair. For example, chronic pulling on the hair follicles can cause
inflammation. Eventually, follicular scarring and permanent
alopecia can occur from prolonged pulling.
[0029] Accordingly, the mechanical strain of the pulling force on
the root causes the damage to the follicle in the root.
Additionally, as illustrated in FIGS. 1A-1B, each follicular unit
contains a smooth muscle anchoring the hair to the epidermis. When
the smooth muscle is relaxed as illustrated in FIG. 1A, the muscle
does not supply much restraining force and the follicle can be
removed easily. When the smooth muscle or arrector pili (AP)
contracts as illustrated in FIG. 1B, the follicle stands up and is
restrained by additional force from the smooth muscle rather than
just primarily the surrounding connective tissue of the dermis.
Accordingly, the smooth muscle can provide more retention force in
opposition to a force that would pull on the hair to dislodge the
follicle if it is contracted. Thus, by contracting the arrector
pili (AP) muscle, the root can be more firmly grounded into the
dermis of the skin preventing the mechanical strain from damaging
the root and dermis, i.e. requiring a larger epilation force for
removal of the hair follicle. This would prevent the chronic
stressing from pulling of the hair observed in different hairstyles
from doing as much damage to the root, and thereby would prevent or
reduce the risk of developing traction alopecia.
[0030] In some aspects, then, the technology described herein
relates to the reduction of the force exerted on the root of a
hair. In practice, this "reduction" in force is more akin to
providing a better balancing force against a traction on the hair
itself--that is, the treatments described herein will not
necessarily reduce the amount of traction on the hair, but by
stimulating the contraction of the arrector pili muscles, the
treatments provide a force that at least partially counters the
effect of the traction or pulling force, thereby protecting the
root against the epilatory effect of the traction.
[0031] Accordingly, disclosed herein are methods for contracting
the smooth muscle cells or arrector pili while a patient is wearing
a hair extension, wig, a tightly woven or pulling hairstyle,
combing their hair, or engaging in other behavior that pulls back
on the follicles of the hair. Several methods are disclosed for
contracting the AP muscle including application of a pharmaceutical
composition containing an A1AR agonist, a muscarinic receptor
agonist, a nicotinic receptor agonist, and/or a cholinesterase
inhibitor, electrical stimulation of the hair follicles and
others.
Disorders to be Treated or Prevented
[0032] Applicants disclose herein methods to treat or prevent
various conditions related to mechanical stress on the human hair.
In one embodiment, the invention concerns treating, reducing or
preventing hair loss from disorders such as traction alopecia,
androgenic alopecia (also known as androgenetic alopecia), alopecia
areata, and alopecia universalis, and hair loss due to hair
brushing, combing, etc. comprising topical administration to a
person in need thereof of a therapeutically effective amount of an
A1AR agonist, a muscarinic receptor agonist, a nicotinic receptor
agonist, and/or a cholinesterase inhibitor, or of any of the active
agents described herein. In another embodiment, the invention
concerns a method for the reduction of the force exerted on a root
of a hair comprising topical administration to a person in need
thereof of a therapeutically effective amount of an A1AR agonist, a
muscarinic receptor agonist, a nicotinic receptor agonist, and/or a
cholinesterase inhibitor, or of any of the active agents described
herein. In another embodiment, the invention concerns a method for
increasing hair epilation force comprising topical administration
to a person in need thereof of a therapeutically effective amount
of an A1AR agonist, a muscarinic receptor agonist, a nicotinic
receptor agonist, and/or a cholinesterase inhibitor, or of any of
the active agents described herein. In another embodiment, the
invention concerns a cosmetic method for piloerecting hair or
raising hair comprising topical administration to a person in need
thereof of a therapeutically effective amount of an A1AR agonist, a
muscarinic receptor agonist, a nicotinic receptor agonist, and/or a
cholinesterase inhibitor, or of any of the active agents described
herein.
[0033] In one aspect, the therapeutically effective amount of the
active agent administered is a pilomotor effective amount. In one
aspect, the therapeutic or active agent is applied to a skin
section, such as a section of the scalp, which contains at least
one hair follicle. In a further embodiment, the at least one hair
follicle is under tension.
[0034] The active or therapeutic agent may be administered to the
hair follicle or scalp to promote contraction of the AP muscle and
thereby reduce, treat or prevent alopecia and the other disorders
discussed herein. It is specifically contemplated that the active
agent can be administered to the hair follicle or the scalp in
combination with an agent that retards systemic absorption of the
agent across the dermis. In this manner, agents that might
otherwise have unwanted systemic effects can be used to treat,
reduce or prevent alopecia or other disorders discussed herein
while avoiding such systemic side effects. One formulation of
agents for topical administration in a manner that avoids systemic
absorption is discussed in detail in U.S. Patent App. Pub.
2009/0068287, which is incorporated herein by reference in its
entirety.
[0035] In another aspect, described herein is a method for
prevention of traction alopecia comprising: applying a
therapeutically effective amount, such as a pilomotor effective
amount, of an A1AR agonist, a muscarinic receptor agonist, a
nicotinic receptor agonist, and/or a cholinesterase inhibitor, or
of any of the active agents described herein to the scalp to an
area with a group of follicles that will experience a pulling force
from a hair augmentation device; and attaching the hair
augmentation device to the group of follicles. In one embodiment,
the hair augmentation device is a hair extension or extensions. In
another embodiment the hair augmentation device is a weave. In
another embodiment, the hair augmentation device is a barrette.
[0036] In another aspect, described herein is method of reducing
hair shedding, such as occurs during brushing, combing, weaving,
flat ironing, showering, curling, wift, attaching hair extensions
or wigs, trading, pony tails, or cosmetic procedures, the method
comprising applying a therapeutically effective amount, such as a
pilomotor effective amount, of an A1AR agonist, a muscarinic
receptor agonist, a nicotinic receptor agonist, and/or a
cholinesterase inhibitor, or of any of the active agents described
herein topically to a portion of skin that includes at least one
hair follicle. In one embodiment, the A1AR agonist, muscarinic
receptor agonist, nicotinic receptor agonist, and/or cholinesterase
inhibitor, or other active agent described herein is present on a
brush or comb that may then be used to administer the therapeutic
agent such as the A1AR agonist, muscarinic receptor agonist,
nicotinic receptor agonist, and/or cholinesterase inhibitor, or
other active agent described herein. In another embodiment, the
active agent is applied to the skin prior to the brushing or
combing.
[0037] In another aspect, the cosmetic procedure is selected from
the group consisting of brushing, braiding, flat ironing, and
combinations of two or more thereof. The therapeutic agent may be
topically applied once, twice, or more often per day. In another
embodiment, the active agent is applied to the skin twice daily. In
another embodiment, the active agent is applied to the skin prior
to the cosmetic procedure.
[0038] In another aspect, described herein is a method for
treatment of trichotillomania comprising applying a pilomotor
effective amount of A1AR agonist, a muscarinic receptor agonist, a
nicotinic receptor agonist, and/or a cholinesterase inhibitor, or
other active agent described herein topically to a portion of skin
that includes at least one hair follicle.
[0039] The disclosure also concerns evaluating an individual for
susceptibility to treatment according to the methods disclosed
herein. In one embodiment, the method comprises (1) applying an
A1AR agonist, a muscarinic receptor agonist, a nicotinic receptor
agonist, or a cholinesterase inhibitor, (e.g., without limitation,
synephrine), on a site on the skin of a person; and (2) 30 to 60
minutes after applying, observe whether the person's skin shows
goose bumps or pilioerection at the site; wherein if pilioerection
or goose bumps are observed, diagnosing the person as likely to be
a successful candidate for use of the A1AR agonist, muscarinic
receptor agonist, nicotinic receptor agonist, or cholinesterase
inhibitor for any of the many methods of treatment or prevention
described herein. This method may be combined with any of the other
methods of treatment or prevention or reduction of hair loss
described herein to provide an initial diagnosis of those people
most likely to benefit from the methods described. The step of
application to the skin may be, in one embodiment, applying a
bandage or patch coated with the A1AR agonist, muscarinic receptor
agonist, nicotinic receptor agonist, or cholinesterase inhibitor 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.
Active or Therapeutic Agent
[0040] Useful active agents (referred to as active agents or
therapeutic agents herein) for the methods of use disclosed herein
include agonists of muscarinic acetylcholine receptors (mAChRs,
also known as muscarinic acetylcholine receptors), agonists of
nicotinic acetylcholine receptor (also referred to as nicotinic
receptors, nAChRs, or nicotinic acetylcholine receptors),
acetylcholine receptor agonists such as neuropeptide-Y, and
cholinesterase inhibitors. The agonists may be selective or
nonselective agonists of mAChRs or nAChRs. In other embodiments, a
prodrug that is activated to become a mAChR or nAChR agonist or a
cholinesterase inhibitor can be utilized. Any of the active agents
disclosed herein may be used in combination with another active
agent disclosed herein, including in combination with another
active agent of the same type (such as without limitation one
muscarinic acetylcholine receptor agonist in combination with a
second muscarinic acetylcholine receptor agonist) or in combination
with a different type of active agent (such as without limitation a
muscarinic acetylcholine receptor agonist with a nicotinic
acetylcholine receptor agonist). By "combination" is meant that the
active agents are applied within about one hour of each other to
the skin, or at substantially the same time to the skin, or
otherwise such that the combined active agents are expected to show
effect on the skin or hair follicles at the same time.
[0041] Muscarinic acetylcholine receptors (mAChRs) and nicotinic
acetylcholine receptors (nAChRs) are acetylcholine receptors of an
autonomic nervous system that can be manipulated by agonists.
[0042] mAChRs are found in tissues innervated by postganglionic
parasympathetic neurons, in presynaptic noradrenergic and
cholinergic nerve terminals, in non-innervated sites in vascular
endothelium, and in the central nervous system. There are subtypes
of muscarinic receptors, which are typically referred to as M.sub.i
(e.g., M.sub.1, M.sub.2, M.sub.3, M.sub.4, and M.sub.5). Muscarinic
receptor agonists that may be used according to the present
compositions and methods include without limitation NNC 11-1585,
NNC 11-1607, pentylthio-TZTP, NNC 11-1314, xanomeline, sabcomeline,
arecaidine propargyl ester, acetylcholine, arecoline, oxotremorine,
McN-A-343, milameline, oxotremorine-M, methylfurmethide,
bethanechol, carbachol, furtrethonium, methacholine, aceclidine,
pilocarpine, and muscarine. It has been discovered that at least
M.sub.2-type agonists and M.sub.3-type agonists can be used to
induce direct smooth muscle contraction.
[0043] Suitable M.sub.2 agonists for the compositions and methods
of the present disclosure include, but are not limited to,
methacholine,
(2S,2'R,3'S,5'R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine
3-sulfoxide methyl iodide, [.sup.3H]oxotremorine-M, NNC 11-1585,
NNC 11-1607, pentylthio-TZTP, methacholine, NNC 11-1314,
xanomeline, oxotremorine, acetylcholine, arecaidine propargyl
ester, carbachol, McN-A-343, arecoline, methylfurmethide,
pilocarpine, furtrethonium, bethanechol, iperoxo, aceclidine,
[18F]FP-TZTP, and berberine. Suitable M.sub.3 agonists for the
compositions and methods of the present disclosure include, but are
not limited to, NNC 11-1585, NNC 11-1607, pentylthio-TZTP, NNC
11-1314, xanomeline, sabcomeline, arecaidine propargyl ester,
acetylcholine, arecoline, oxotremorine, McN-A-343, milameline,
oxotremorine-M, methylfurmethide, bethanechol, carbachol,
furtrethonium, methacholine, aceclidine, L-689,660 (mixed
M.sub.1/M.sub.3 agonist), and pilocarpine.
[0044] Nicotinic acetylcholine receptors are located in sympathetic
and parasympathetic ganglia, in the adrenal medulla, in the
neuromuscular junction of the skeletal muscle, and in the central
nervous system. Nicotinic acetylcholine receptors are ligand-gated
ion channels whose activation results in a rapid increase in
cellular permeability to sodium and calcium. They are pentameric
arrays of one to four distinct but homologous subunits, surrounding
an internal channel. The .alpha. subunit, which has binding sites
for ACh, is present in at least two copies. Agonist molecules
induce a conformational change that opens the channel. Antagonist
molecules may bind to these sites, but do not elicit the
conformational change.
[0045] There are at least two subtypes of nicotinic receptors,
generally referred to as N.sub.M and N.sub.N. The N.sub.M nicotinic
receptor mediates skeletal muscle stimulation, while the N.sub.N
nicotinic receptor mediates stimulation of the ganglia of the
autonomic nervous system. Useful nicotinic receptor agonists to
treat conditions and disorders disclosed herein include without
limitation: varenicline tartrate, galantamine hydrobromide,
nicotine, carbachol, suxamethonium chloride (succinylcholine
chloride), and epibatidine.
[0046] The muscarinic and nicotinic receptor agonists mimic
acetylcholine effect by stimulating the relevant receptors
themselves or by acting through the axon reflex. Another way of
accomplishing the same thing is to reduce the destruction of
acetylcholine (Ach) following its release. This can be achieved by
cholinesterase inhibitors, which are also called the
anticholinesterases. They mimic the effect of combined muscarinic
and nicotinic agonists. By inhibiting acetylcholinesterase and
pseudocholinesterase, these drugs allow ACh to build up at its
receptors. Thus, they result in enhancement of both muscarinic and
nicotinic agonist effect. Suitable cholinesterase inhibitors for
the present methods and compositions include without limitation
physostigmine, neostigmine, edrophonium, pyridostigmine,
echotihiophate, ambenonium, demecarium, tacrine, donepezil,
rivastigmine, galantamine, and pralidoxime. In another embodiment,
the active agent useful for treatment of the disorders and diseases
described herein is neuropeptide-Y, which is an acetylcholine
receptor agonist. In one embodiment, the present disclosure
concerns one of the methods disclosed herein, comprising applying a
therapeutically effective amount of an active agent selected from
the group consisting of neuropeptide-Y, muscarinic acetylcholine
receptor agonists, nicotinic acetylcholine receptor agonists, and
cholinesterase inhibitors topically to an area of the skin, such as
an areas of the scalp, containing a hair follicle.
[0047] In another embodiment, the active agent used in the
inventive methods herein is an A1AR agonist. "Alpha-1 adrenergic
receptor agonist" or "A1AR agonist" refers to a ligand that binds
the alpha-1adrenergic receptor on smooth muscle cells and activates
smooth muscle contraction. In some embodiments, the AIAR agonist is
selective for the alpha-1adrenergic receptor. Additionally, the
term "alpha-1 adrenergic receptor agonist" can include agents that
when applied will induce the release of endogenous alpha-1
adrenergic receptor agonists (e.g. epinephrine) that activates
smooth muscle contraction or agents that when applied inhibit the
"re-uptake" or degradation of endogenous alpha-1adrenergic receptor
agonists (e.g. epinephrine) that activates smooth muscle
contraction. In another embodiment, the active agent used is a
"smooth muscle agonist," which is an agent that promotes or results
in contraction of the smooth muscle. Thus, an alpha-1adrenergic
receptor agonist that promotes or results in smooth muscle
contraction is a smooth muscle agonist, but so also are, e.g., an
alpha 2 adrenergic receptor agonist that promotes smooth muscle
contraction, agents that that induce the release of endogenous
alpha 2 adrenergic receptor agonist that results in smooth muscle
contraction, and agents that inhibit the re-uptake or degradation
of endogenous alpha 2 adrenergic receptor agonists that activate
smooth muscle contraction. Suitable A1AR agonists for use in the
present description include without limitation phenylephrine,
phenylephrine pivalate, amediphrine, synephrine, cirazoline,
desvenlafaxine, etilfrine, metaraminol, methoxamine, naphazoline,
oxymetazoline, pseudoephrine, m-synephrine, p-synephrine,
octopamine, hordenine, tetrahydrozoline, isometheptene,
metaraminol, nicergoline, ergonovine, levonordefrin,
phendimetrazine, methoxamine, midodrine, clonidine, pergolide,
xylometazoline, droxidopa, epinephrine, mephentermine,
4-methoxyamphetamine, benzphetamine, naphazoline, apraclondine,
bromocriptine, oxymetazoline, phenylpropanolamine, pseudoephedrine,
dipivefrin, noradrenaline, chloroethylclonidine, norepinephrine,
A61603, NS-49, [.sup.125I]HEAT, noradrenaline, adrenaline,
clonidine, St 587, SKF 89748, 6-fluoro-noradrenaline,
methylnoradrenaline, inanidine, NS-49, amidephrine, and dabuzalgron
and dopamine. In certain embodiments, the A1AR agonist is
synephrine, or is selected from phenylephrine, synephrine,
oxymetazoline, and methoxamine. In one embodiment, the therapeutic
agent is norepinephrine. Another suitable therapeutic agent for use
in the inventive methods herein is extract of Bitter orange (Citrus
aurantium), which contains synephrine alkaloids and
para-octopamine. See Satoh, Y., Tashiro, S., Satoh, M., Fujimoto,
Y., Xu, J. Y., and Ikekawa, T. [Studies on the bioactive
constituents of Aurantii Fructus Immaturus]. Yakugaku Zasshi
1996;116(3):244-250. Additionally, derivatives of A1AR agonists can
be utilized including derivatives of the compounds mentioned above.
In other embodiments, a prodrug that is activated to become an A1AR
agonist can be utilized. For example, midodrine is one such
prodrug. A particular prodrug can be activated by endogenous
enzymes in the scalp such as Caspase-1 when follicular inflammation
is present, e.g., at the location of application of a hair
extension. In one embodiment, the A1AR agonist is synephrine. In
one embodiment, the A1AR agonist is phenylephrine or synephrine,
including compositions comprising the 1-enantiomer of synephrine,
which is R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol, that are
essentially free of other enantiomers of synephrine, or in which
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 may be obtained from
natural bitter orange extract. In one embodiment, the therapeutic
agent is derived from bitter orange, Citrusaurantium, or is an
extract of bitter orange, such as a bitter orange extract that
contains 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 from
5-10%, 10-15%, 5-1YYo, 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%
of one enantiomer of synephrine,
R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol. Extracts of bitter
orange contain high levels of only one synephrine enantiomer,
namely, R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol, and are
preferred for use in the present methods and compositions of the
disclosure.
[0048] Additionally, derivatives of alpha-ladrenergic receptor
agonists, muscarinic acetylcholine receptor agonists, nicotinic
acetylcholine receptor agonists, or cholinesterase inhibitors can
be utilized including derivatives of the compounds mentioned above.
In other embodiments, a prodrug that is activated to become an A1AR
agonist, muscarinic acetylcholine receptor agonist, nicotinic
acetylcholine receptor agonist, or cholinesterase inhibitor can be
utilized. Midodrine, phenylephrine oxazolidine, and phenylephrine
pivalate are examples of three such prodrugs. Phenylephrine
pivalate is an A1AR agonist in addition to being a prodrug of
phenylephrine. A particular prodrug can be activated by endogenous
enzymes in the skin such as Caspase-1. Another embodiment is a
method comprising applying a therapeutically effective amount of an
alpha-ladrenergic receptor antagonist or a beta adrenergic receptor
agonist to the skin or scalp to treat an overdose of
alpha-ladrenergic receptor agonist.
[0049] As used herein, a "prodrug" refers to compounds that can be
converted via some chemical or physiological process (e.g.,
enzymatic processes and metabolic hydrolysis) to an active agent.
Thus, the term "prodrug" also refers to a precursor of a
biologically active compound that is pharmaceutically acceptable. A
prodrug may be inactive when administered to a subject, i.e. an
ester, but is converted in vivo to an active compound, for example,
by hydrolysis to the free carboxylic acid or free hydroxyl. The
prodrug compound often offers advantages of solubility, tissue
compatibility or delayed release in an organism. The term "prodrug"
is also meant to include any covalently bonded carriers, which
release the active compound in vivo when such prodrug is
administered to a subject. Prodrugs of an active compound may be
prepared by modifying functional groups present in the active
compound in such a way that the modifications are cleaved, either
in routine manipulation or in vivo, to the parent active compound.
Prodrugs include compounds wherein a hydroxy, amino or mercapto
group is bonded to any group that, when the prodrug of the active
compound is administered to a subject, cleaves to form a free
hydroxy, free amino or free mercapto group, respectively. Examples
of prodrugs include, but are not limited to, acetate, formate and
benzoate derivatives of an alcohol or acetamide, formamide and
benzamide derivatives of an amine functional group in the active
compound and the like. See Harper, "Drug Latentiation" in Jucker,
ed. Progress in Drug Research 4:221-294 (1962); Morozowich et al,
"Application of Physical Organic Principles to Prodrug Design" in
E. B. Roche ed. Design of Biopharmaceutical Properties through
Prodrugs and Analogs, APHA Acad. Pharm. Sci. 40 (1977);
Bioreversible Carriers in Drug in Drug Design, Theory and
Application, E. B. Roche, ed., APHA Acad. Pharm. Sci. (1987);
Design of Prodrugs, H. Bundgaard, Elsevier (1985); Wang et al.
"Prodrug approaches to the improved delivery of peptide drug" in
Curr. Pharm. Design. 5(4):265-287 (1999); Pauletti et al. (1997)
Improvement in peptide bioavailability: Peptidomimetics and Prodrug
Strategies, Adv. Drug. Delivery Rev. 27:235-256; Mizen et al.
(1998) "The Use of Esters as Prodrugs for Oral Delivery of
(3-Lactam antibiotics," Pharm. Biotech. 11:345-365; Gaignault et
al. (1996) "Designing Prodrugs and Bioprecursors I. Carrier
Prodrugs," Pract. Med. Chem. 671-696; Asgharnejad, "Improving Oral
Drug Transport", in Transport Processes in Pharmaceutical Systems,
G. L. Amidon, P. I. Lee and E. M. Topp, Eds., Marcell Dekker, p.
185-218 (2000); Balant et al., "Prodrugs for the improvement of
drug absorption via different routes of administration", Eur. J.
Drug Metab. Pharmacokinet., 15(2): 143-53 (1990); Balimane and
Sinko, "Involvement of multiple transporters in the oral absorption
of nucleoside analogues", Adv. Drug Delivery Rev., 39(1-3): 183-209
(1999); Browne, "Fosphenytoin (Cerebyx)", Clin. Neuropharmacol.
20(1): 1-12 (1997); Bundgaard, "Bioreversible derivatization of
drugs--principle and applicability to improve the therapeutic
effects of drugs," Arch. Pharm. Chemi 86(1): 1-39 (1979); Bundgaard
H. "Improved drug delivery by the prodrug approach," Controlled
Drug Delivery 17: 179-96 (1987); Bundgaard H. "Prodrugs as a means
to improve the delivery of peptide drugs," Arfv. Drug Delivery Rev.
8(1): 1-38 (1992); Fleisher et al. "Improved oral drug delivery:
solubility limitations overcome by the use of prodrugs," Arfv. Drug
Delivery Rev. 19(2): 115-130 (1996); Fleisher et al. "Design of
prodrugs for improved gastrointestinal absorption by intestinal
enzyme targeting," Methods Enzymol. 112 (Drug Enzyme Targeting, Pt.
A): 360-81, (1985); Farquhar D, et al., "Biologically Reversible
Phosphate-Protective Groups," Pharm. Sci., 72(3): 324-325 (1983);
Freeman S, et al., "Bioreversible Protection for the Phospho Group:
Chemical Stability and Bioactivation of Di(4-acetoxy-benzyl)
Methylphosphonate with Carboxyesterase," Chem. Soc., Chem. Commun.,
875-877 (1991); Friis and Bundgaard, "Prodrugs of phosphates and
phosphonates: Novel lipophilic alphaacyloxyalkyl ester derivatives
of phosphate- or phosphonate containing drugs masking the negative
charges of these groups," Eur. J. Pharm. Sci. 4: 49-59 (1996);
Gangwar et al., "Pro-drug, molecular structure and percutaneous
delivery," Des. Biopharm. Prop. Prodrugs Analogs, [Symp.] Meeting
Date 1976, 409-21. (1977); Nathwani and Wood, "Penicillins: a
current review of their clinical pharmacology and therapeutic use,"
Drugs 45(6): 866-94 (1993); Sinhababu and Thakker, "Prodrugs of
anticancer agents," Adv. Drug Delivery Rev. 19(2): 241-273 (1996);
Stella et al., "Prodrugs. Do they have advantages in clinical
practice?" Drugs 29(5): 455-73 (1985); Tan et al. "Development and
optimization of anti-HIV nucleoside analogs and prodrugs: A review
of their cellular pharmacology, structure-activity relationships
and pharmacokinetics," Adv. Drug Delivery Rev. 39(1-3): 117-151
(1999); Taylor, "Improved passive oral drug delivery via prodrugs,"
Adv. Drug Delivery Rev., 19(2): 131-148 (1996); Valentino and
Borchardt, "Prodrug strategies to enhance the intestinal absorption
of peptides," Drug Discovery Today 2(4): 148-155 (1997); Wiebe and
Knaus, "Concepts for the design of anti-HIV nucleoside prodrugs for
treating cephalic HIV infection," Adv. Drug Delivery Rev.:
39(1-3):63-80 (1999); Waller et al., "Prodrugs," Br. J. Clin.
Pharmac. 28: 497-507 (1989), which are incorporated by reference
herein in their entireties.
Formulations
[0050] The therapeutic agents, particularly the A1AR agonist,
muscarinic receptor agonist, nicotinic receptor agonist, and
cholinesterase inhibitor, described herein and used in the present
methods may be formulated into compositions according to the
knowledge of one of skill in the art. In one embodiment, the
therapeutic agent is formulated for topical slow or prolonged
release. As but one example, in one embodiment the AP stimulating
agent is encapsulated for slow release and integrated into a hair
extension.
[0051] In another embodiment, the therapeutic agent is formulated
in a shampoo (which can reduce hair shedding during hair brushing),
a foam, ointment, spray, solution, gel, slow release capsule, oral
tablet, or any similar compound or delivery vehicle or methodology.
Topical application is preferred. In one embodiment, the
composition is formulated in a topical cream. In another
embodiment, the composition is formulated in a hair styling product
selected from the group consisting of a styling gel, a styling
foam, and a hair conditioner.
[0052] In another embodiment, the composition may comprise an
exfoliating agent to promote abrasion of the surface of the scalp.
Examples of the exfoliating agent include (1) inorganic and/or
metallic particles such as: boron nitride, in body-centered cubic
form (Borazon.RTM.); aluminosilicate (e.g. nepheline); zircon;
mixed oxides of aluminum such as emery; zinc oxide; aluminum oxides
such as aluminas or corundum; titanium oxide; titanium oxide coated
mica; carbides, in particular silicon carbide (carborundum); or
other metal oxides; metals, and metal alloys such as iron shot,
steel shot, and in particular 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 stone; amorphous silica; diamond; ceramics, and
(2) organic particles such as: fruit stones, in particular apricot
stones, e.g. Scrubami.RTM. apricot; wood cellulose, e.g. ground
bamboo stem; coconut shell, e.g. coconut exfoliator; polyamides, in
particular Nylon-6; sugars; plastic microbeads, e.g. polyethylenes
or polypropylenes; ground walnut; ground apricot seed; ground
shells, and (3) mixed particles associating organic and inorganic
compounds, and particles coated in the above compounds. The
exfoliating agents may be in the form of microbeads of less than
five millimeters in its largest dimension that have an exfoliating
effect.
[0053] In one embodiment, the composition comprising an A1AR
agonist, a muscarinic receptor agonist, a nicotinic receptor
agonist, and/or a cholinesterase inhibitor can be formulated as a
drug. In one embodiment, the composition comprising an A1AR
agonist, a muscarinic receptor agonist, a nicotinic receptor
agonist, and/or a cholinesterase inhibitor can be formulated as a
cosmetic product.
[0054] In another embodiment, the AP muscle can be contracted via
electrical stimulation to the scalp. The stimulation can be
controlled by a battery and control unit embedded into a hair
extension, or in, e.g., a hair brush or comb. The control unit can
contain an accelerometer to detect the optimal time to contract the
AP muscles based on the posture of the subject or the subject's
hair.
[0055] The amount of therapeutic agent present in the composition
may be determined by one of skill in the art using known
methodologies. In certain embodiments, the A1AR agonist or other
stimulator of AP muscle contraction, such as a muscarinic receptor
agonist, a nicotinic receptor agonist, and/or a cholinesterase
inhibitor, is present in the composition in a concentration from
about 0.20% to 0.30%, or about 0.25% by weight. In another
embodiment, the therapeutic agent such as an A1AR agonist, a
muscarinic receptor agonist, a nicotinic receptor agonist, and/or a
cholinesterase inhibitor is present in the composition in a
concentration of about 0.25%, 0.33%, 0.5%, 1%, 2%, 2.5%, or 10% by
weight.
[0056] In other embodiments, the therapeutic agent, such as an A1AR
agonist, a muscarinic receptor agonist, a nicotinic receptor
agonist, and/or a cholinesterase inhibitor, is present in the
topical composition for use in the methods disclosed herein in a
concentration from about 0.1% to 35%, about 1.0% to 30%, about 0.2%
to 30%, about 0.2% to 25%, about 0.2% to 20%, about 0.2% to 15%,
about 0.2% to 10%, about 0.2% to 5%, about 0.2% to 4%, about 0.2%
to 3%, about 0.2% to 2%, about 0.2% to 1%, about 10.0% to 30%,
about 15.0% to 30%, about 20.0% to 30%, about 10% to 20%, about 10%
to 15%, about 15% to 20%, about 15% to 60%, about 20% to 60%, about
50% to 60%, and about 45% to 55% by weight. For certain therapeutic
agents, such as synephrine (racemic mixture), a concentration of
about 25% to 60%, 30% to 50%, 30% to 60%, 25% to 30%,40% to 50%, or
50% to 55% by weight of the total weight of the composition is
desirable.
[0057] In one embodiment, the composition comprises an A1AR
agonist, a muscarinic receptor agonist, a nicotinic receptor
agonist, and/or a cholinesterase inhibitor in 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.
[0058] The compositions used in the present disclosure,
particularly compositions containing an A1AR agonist, a muscarinic
receptor agonist, a nicotinic receptor agonist, and/or a
cholinesterase inhibitor, may be formulated with a preservative
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 composition includes a penetration enhancer, such
as a penetration enhancer selected from one or more of the group
consisting of alcohols, glycols, fatty acids, fatty esters, fatty
ethers, occlusive agents, surface active agents,
dimethylaminopropionic acid derivatives, terpenes, sulfoxides,
cyclic ethers, amides, and amines. Other components of the
formulations used herein may be chosen from cosmetically approved
excipients known in the art, including water, thickeners, etc.
[0059] The composition may be packaged in a kit with an applicator
for application to the skin. The invention is also directed to a
kit comprising a composition of the therapeutic agent and an
applicator, and to a kit comprising a composition of the
therapeutic agent and a hair bush or comb, particularly a brush or
comb that provides exfoliating effect on the scalp such that there
is light abrasion after its use that enhances penetration of the
therapeutic agent to the AP muscle. In one embodiment, the
therapeutic agent is provided in a metered dose applicator that
provides for a fixed volume of the composition to be administered
with each administration, such as 1 ml of the topical composition
per administration.
[0060] It will be understood that the ranges described above, and
throughout this document, are also intended to encompass single
values contained within these ranges. For example, for a
formulation comprising a particular ingredient in a range between
1-50%, a percentage of 5% or 49% is also intended to be
disclosed.
[0061] In one embodiment, the compositions of the present invention
contain 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, such as an extract that contains 3-5%, 5-10%, 6%, 9%,
10-15%, 15-20%, 20-40%, 40-60%, 60-80%, or 80-95% synephrine, or
the composition contains from about 5-10%, 10-15%, 15-20%, 25-30%
or 30-40% by weight of bitter orange extract, such as an extract
containing from 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 compositions of the present invention
contain 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 a
bitter orange extract, wherein the extract contains 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.
[0062] In one embodiment, the A1AR agonist is phenylephrine, or a
pharmaceutically acceptable salt or hydrate thereof, in a
composition in a concentration of 0.25% to 40%, 0.25% to 25% by
weight, or 0.5% to 22.5% by weight, or 0.75% to 20% by weight, or
1% to 17.5% by weight, or 1.5% to 15% by weight, or 2% to 14.5% by
weight, or 2.5% to 14% by weight, or 5% to 13.5% by weight, or 7.5%
to 12.5% by weight, or 8% to 12% by weight, or 8.5% to 11.5% by
weight, or 9% to 11% by weight, or 9.25% to 10.75% 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.
[0063] In one embodiment, the A1AR agonist is phenylephrine, or a
pharmaceutically acceptable salt or hydrate thereof, in a
composition in a concentration at a range of 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 weight limit of the range to an upper weight limit of
10.01%, 10.02%, 10.03%, 10.04%, 10.05%, 10.1%, 10.2%, 10.3%, 10.4%,
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., a
range of0.25% to 10.01%, 0.25% to 10.02%, 0.5% to 10.01%, 0.5% to
10.02%, etc.).
[0064] In one embodiment, the A1AR agonist is phenylephrine, or a
pharmaceutically acceptable salt or hydrate thereof, in a
composition in a concentration of 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 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.
[0065] In another embodiment, the composition comprises an A1AR
agonist that is synephrine, or a pharmaceutically acceptable salt
or hydrate thereof, or that comprises one enantiomer of synephrine,
namely R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol and is
substantially free of other enantiomer(s) of synephrine or has less
than 30%, 25%, 20%, 15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of
the synephrine present in the composition as a different
enantiomer, wherein the synephrine is present in the composition in
a concentration of 30% to 70% by weight, or 35% to 65% by weight,
or 37.5% to 62.5% by weight, or 40% to 60% by weight, or 42.5% to
57.5% by weight, or 45% to 55% by weight, or 45.5% to 54.5% by
weight, or 46% to 54% by weight, or 46.5% to 53.5% by weight, or 4
7% to 53% by weight, or 47.5% to 52.5% by weight, or 48% to 52% by
weight, or 48.25% to 51.75% by weight, or 48.5% to 51.5% by weight,
or 48.75% to 51.25% by weight, or 49% to 51% by weight, or 49.25%
to 50.75% by weight, or 49.5% to 50.5% by weight, or 49.6% to 50.4%
by weight, or 49.7% to 50.3% by weight, or 49.8% to 50.2% by
weight, or 49.9% to 50.1% by weight.
[0066] In another embodiment, the composition comprises an A1AR
agonist that is synephrine, or a pharmaceutically acceptable salt
or hydrate thereof, or that comprises one enantiomer of synephrine,
namely R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol and is
substantially free of other enantiomer(s) of synephrine or has less
than 30%, 25%, 20%, 15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of
the synephrine present in the composition as a different
enantiomer, wherein the synephrine is present in the composition in
a concentration of 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 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 to 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.
[0067] In one embodiment, the composition comprises an A1AR agonist
that is R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol
substantially free of the other enantiomer of synephrine (or having
less than 25%, 20%, 15%, 10%, 5%, 1% or 0.1% of the other
enantiomer of synephrine) or a pharmaceutically acceptable salt or
hydrate thereof, in a composition in a concentration 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.
[0068] In another embodiment, the composition comprises an A1AR
agonist that is synephrine, or a pharmaceutically acceptable salt
or hydrate thereof, or that comprises one enantiomer of synephrine,
namely R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol and is
substantially free of other enantiomer(s) of synephrine or has less
than 30%, 25%, 20%, 15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of
the synephrine present in the composition as a different
enantiomer, wherein the synephrine is present in the composition in
a concentration of 10% to 60% by weight, or 12.5% to 50% by weight,
or 10% to 50% by weight, or 15% to 40% by weight, or 20% to 30% by
weight, or 20% to 40% by weight, or 17.5% to 30% by weight, or 20%
to 25% by weight, or 20.5% to 24.5% by weight, or 21% to 24% by
weight, or 21.5% to 23.5% by weight, or 21.75% to 23.25% by weight,
or 22% to 23% by weight, or 22.1% to 22.9% by weight, or 22.2% to
22.8% by weight, or 22.3% to 22.7% by weight, or 22.4% to 22.6% by
weight.
[0069] In another embodiment, the composition comprises an A1AR
agonist that is synephrine, or a pharmaceutically acceptable salt
or hydrate thereof, or that comprises one enantiomer of synephrine,
namely R-0-4-[1-hydroxy-2-(methylamino)ethyl)phenol and is
substantially free of other enantiomer(s) of synephrine or has less
than 30%, 25%, 20%, 15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of
the synephrine present in the composition as a different
enantiomer, wherein the synephrine is present in the composition in
a concentration of 10% by weight, or 12.5% by weight, or 15% by
weight, or 17.5% by weight, or 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.
[0070] In one embodiment, the composition comprises one enantiomer
of synephrine, namely
R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phcnol, and is
substantially free of other enantiomer(s) of synephrine or has less
than 30%, 25%, 20%, 15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of
the synephrine present in the composition as a different
enantiomer, wherein the
R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol is present in the
composition in a concentration of 20% to 25% by weight.
[0071] In a further embodiment, the A1AR agonist is oxymetazoline,
or a pharmaceutically acceptable salt or hydrate thereof, in a
composition in a concentration of 0.01% to 2% by weight, or 0.02%
to 1.75% by weight, or 0.03% to 1.5% by weight, or 0.04% to 1.25%
by weight, or 0.05% to 1% by weight, or 0.1% to 0.9% by weight, or
0.15% to 0.85% by weight, or 0.2% to 0.8% by weight, or 0.25% to
0.75% by weight, or 0.3% to 0.7% by weight, or 0.35% to 0.65% by
weight, or 0.4% to 0.6% by weight, or 0.41% to 0.59% by weight, or
0.42% to 0.58% by weight, or 0.43% to 0.57% by weight, or 0.44% to
0.56% by weight, or 0.45% to 0.55% by weight, or 0.46% to 0.54% by
weight, or 0.47% to 0.53% by weight, or 0.48% to 0.52% by weight,
or 0.49% to 0.51% by weight.
[0072] In a further embodiment, the A1AR agonist is oxymetazoline,
or a pharmaceutically acceptable salt or hydrate thereof, in a
composition in a concentration 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 0.48% by weight, or 0.49% by weight to 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 2% by weight.
[0073] In a further embodiment, the Al ARA is oxymetazoline, or a
pharmaceutically acceptable salt or hydrate thereof, in a
composition in a concentration 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 0.48% by weight, or 0.49% by weight, or 0.5% by
weight, or 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 2% by weight.
[0074] In some embodiments, provided herein is an active agent
formulated with a carrier or delivery vehicle optimized for
delivery of the active agent to the scalp. An A1AR agonist, a
muscarinic receptor agonist, a nicotinic receptor agonist, and/or a
cholinesterase inhibitor can be released using several different
formulations or release methods including time release, creams,
ointments, sprays, capsules, or other release methods. For instance
the active agent can be incorporated into a shampoo for utilization
during showering so that when a user brushes his or her hair, the
follicles will be tightly held by the AP muscles to prevent
brushing from unnecessarily pulling out healthy hair. In other
embodiments, the active agent can be included in ointments or other
topical creams that could be applied to the scalp so that it can be
slowly absorbed into the skin and stimulate the smooth muscle. In
other embodiments, the active agent can be included in a liquid
spray or aerosol medium to be applied to the scalp. In other
embodiments, the active agent can be incorporated into capsules or
other slow release vehicles that would allow the chemical or agent
to be slowly released into the dermis of the scalp. Capsules or
vehicles that encapsulate the active agent can include, but are not
limited to, liposomes, non-ionic liposomes, niosomes, novasome I,
erythromycin-Zn complex, microspheres, nanoparticles, solid lipid
nanoparticles, and nanoemulsions. In some embodiments, this can
include a gel or foam that is applied to the scalp. It is
specifically contemplated that the active agent can be formulated
in hair care products such as styling gel, styling foam, hair
conditioner, hair serum, a hair mask, etc.
[0075] Any of the active agents described herein can be applied by
a user before the application of a hair extension device or other
device or condition that exerts force on the hair follicle.
Alternatively, an active agent can be used routinely (e.g. twice
daily) after such a device has been installed. Routine use of an
active agent would be indicated as a prophylactic against traction
alopecia for users of a hair extension device or other device that
exerts force on the hair follicle.
[0076] Creams or other formulations with different A1AR agonists,
muscarinic receptor agonists, nicotinic receptor agonists, and/or
cholinesterase inhibitors can be applied prior to a user utilizing
a hair piece or brushing the hair. In some embodiments, a hair
piece or hair extensions can contain pads or other absorbent
material that can absorb the active agent in a foam or cream
applied prior to application to a user's head. In other
embodiments, slow release capsules can be incorporated into the
hair extensions or hair pieces, or can be included in barrettes. In
some embodiments, barrettes will include pads with an absorbent
layer for application of the active agent-containing cream or other
topical formulation.
[0077] Efficacy of treatment to treat or prevent traction alopecia
can be determined by monitoring the density of hairs on a given
area of the subject's body, e.g., a given area of the scalp. If the
rate of hair loss is reduced, e.g., by 10% or more following
treatment, the treatment is effective for the prevention of
traction alopecia. Similarly, if hair density remains the same,
despite ongoing traction that would normally have been expected to
cause traction alopecia, the treatment is effective for the
prevention of traction alopecia. If the density of hair increases,
e.g., by 5% or more, e.g., by 10% or more following treatment and
despite ongoing traction, the treatment is also considered
effective for the treatment and/or prevention of traction
alopecia.
[0078] As noted above, it is contemplated that all forms of
alopecia can benefit from the technology described herein. For
example, the technology described herein can be applicable to
prevent or treat androgenic alopecia. The AP muscle degenerates in
the process of androgenic alopecia (reviewed, e.g., in Torkamani et
al., Int. J. Trichology 6:88-94 (2014)); without wishing to be
bound by theory, it is contemplated that regular stimulation of AP
muscle contraction may slow or reduce the loss of the muscle and
thereby benefit the treatment or prevention of androgenic
alopecia.
[0079] It is also contemplated that the technology described herein
can be broadly applicable to any type of condition of which at
least one hair follicle is under tension. Using the active agents
that stimulate AP muscle contraction as described herein, it is
contemplated that one can limit or reduce hair shedding under such
conditions.
[0080] In one aspect, the condition of which at least one hair
follicle is under tension is brushing or combing. Accordingly, the
technology described herein relates to a method of reducing hair
shedding during brushing or combing. As used herein, the term
"reducing hair shedding" means that the amount of hair shedding
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, as compared to what
would be expected in the absence of the method. An A1AR agonist or
other agent that stimulates AP muscle contraction, such as a
muscarinic receptor agonist, a nicotinic receptor agonist, and/or a
cholinesterase inhibitor, can be present on the brush or comb used
for the brushing or combing. In one embodiment, the A1AR agonist or
other agent (e.g., a muscarinic receptor agonist, a nicotinic
receptor agonist, and/or a cholinesterase inhibitor) can be applied
to the brush or comb prior to brushing or combing, e.g., in the
form of a liquid, gel, cream or spray. In one embodiment, the brush
or comb can dispense the A1AR agonist or other active agent.
[0081] Agents that promote the contraction of the AP muscle can
optionally be administered by iontophoresis, which uses an electric
field to drive the passage of ionic agents or drugs into the skin.
As but 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 incorporate an iontophoresis device, which can dispense
the A1AR agonist or other agent and/or be used for transdermal
delivery of the agent(s). The iontophoresis device can comprise one
or more metal contacts. Optionally, the iontophoresis device can
comprise one or more compartments for containing the A1AR agonist
or other agent(s). For example, the iontophoresis device can
comprise one or more compartments for containing at least one of an
A1AR agonist, a muscarinic receptor agonist, a nicotinic receptor
agonist, and/or a cholinesterase inhibitor.
[0082] In another aspect, the condition in which at least one hair
follicle is under tension is a hair-related cosmetic procedure.
Accordingly, the technology described herein relates to a method of
reducing hair shedding during a hair-related cosmetic procedure.
Examples of hair-related cosmetic procedures include, but are not
limited to, brushing, braiding, flat ironing, and combinations
thereof.
[0083] In another aspect, the condition in which at least one hair
follicle is under tension is trichotillomania, a disorder
characterized by the compulsive urge to pull out one's hair.
Accordingly, to the extent that increasing the force required to
remove the hair can help counter hair loss due to this condition,
the stimulation of AP muscle contraction as described herein can
provide a method to reduce the hair loss.
Electrical Stimulation
[0084] In another embodiment of the invention, the AP muscle can be
contracted via electrical stimulation to the scalp or dermis of the
skull. The electrical stimulation can be controlled, e.g., by a
unit contained in a brush or a comb, or, e.g., embedded in a hair
extension. In some embodiments, the control unit can contain an
accelerometer to detect the optimal time to contract the AP muscles
based on the posture of the subject or the subject's hair. In some
embodiments, a strain or other force gauge attached to a portion of
a hair extension can test the force pulling on the patient's hair.
Then, the electrical stimulator could vary the amount of current,
voltage or other component of the electrical stimulation applied to
vary the strength of smooth muscle contraction based on the amount
of force pulling on the hair at a certain time. In other
embodiments, the control unit can deliver a standard amount of
current to the hair in order to reach the electrical threshold for
contraction of the AP muscle. This can advantageously minimize the
amount of current being applied to the scalp overall and the amount
of electricity. Accordingly, one advantage of utilizing electrical
stimulation to contract the muscle, is that the strength of the
contraction can be varied accordingly.
[0085] Examples of applying electrical forces to contract the AP
muscles are described in, for example, US Patent Publication US20
13/0199348 published on Aug. 8, 2013, titled Pilomotor Effect
Stimulating Device and Method, which is incorporated by reference
herein in its entirety. For example, in some embodiments, the
voltage or amplitude of the signal applied to the scalp can be in
the range of 35 to 75 volts, 25 to 50 volts, 10-30 volts or other
suitable ranges to reach the threshold for muscle contraction. The
current applied to a scalp by a device as disclosed herein can, in
some embodiments, preferably be in the microamps to avoid
electrocution of the user. A frequency of 10 KHz to 15 KHz can be
applied, or a lower or higher frequency. In some embodiments, the
pulse length applied will be from 1 to 50 milliseconds, 1 to 100
milliseconds, or other suitable lengths to contract the AP muscle
or any other pilomotor effective amount of current. In some
embodiments, a control unit will automatically pulse the electrical
stimulation at random intervals that are enough to keep the AP
muscle relatively contracted. In other embodiments, the pulses will
be spaced out enough to allow the AP muscle to relax in between
pulses.
[0086] The disclosure also concerns 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 an electrical stimulus; and a controller in
communication with the battery, memory, and electrical stimulation
and memory wherein the controller commands the electrical stimulus
generator to output a pilomotor effective amount of electrical
stimulus. In certain embodiments, the pilomotor effective amount of
electrical stimulus is between 10-100 volts, or between 10-15 kHz.
In some embodiments the pilomotor effective amount of electrical
stimulus is applied for 1 to 100 milliseconds. In some embodiments,
the pilomotor effective amount of electrical stimulus is applied
periodically with rest periods long enough to allow the AP muscle
to relax between stimuli. In other embodiments, the pilomotor
effective amount of electrical stimulus is applied periodically
with rest periods short enough to prevent the AP muscle from
relaxing between stimuli. The hair augmentation device may be any
product that when applied to the hair exelts a pulling force on the
hair. For example, the hair augmentation device may be a hair
extension, a weave, or a barrette.
[0087] In some embodiments, a probe or electrical prongs can be
attached to a hair extension or other hair piece that would deliver
the charge to the scalp. In some embodiments, the probe can be
connected to a control unit with an on switch, a processor, and
memory with firmware or other software instructions for delivering
the desired pulses. Different control units can contain more
advanced circuitry and algorithms for processing accelerometer or
force data and varying the electrical stimulus accordingly. In some
embodiments, the probe can be connected to any portion of a hair
piece using any suitable apparatus and method.
Other Agents or Approaches to Contract the Smooth Muscle
[0088] Other agents or approaches can be used to contract the
smooth muscle for the prevention or treatment of alopecia, e.g.,
traction alopecia. As noted above, any agent or treatment that
stimulates AP muscle contraction is of potential use in methods of
treating, reducing or preventing alopecia as described herein.
[0089] In one embodiment, the smooth muscle can be contracted by
stimulating or activating a cold receptor. A cold receptor can be
stimulated, for example, by activating the TRPM8 channel. Exemplary
agents that can stimulate a cold receptor include, but are not
limited to, menthol and icilin. Compositions and methods for
stimulating a cold receptor are disclosed, for example, in U.S.
Pat. No. 4,034,109, the contents of which are incorporated by
reference in its entirety.
[0090] Where the AP muscle is served by or associated with both
noradrenergic fibers and a cholinergic system, agents that
stimulate release of transmitters from these systems can be used to
stimulate AP muscle contraction. Thus, not only alpha 1 adrenergic
receptor agonists, but also cholinergic receptor 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.
[0091] The arrector pili muscle is innervated by sympathetic
adrenergic as well as sympathetic cholinergic neurons. Primer on
the Autonomic Nervous System, third Edition, Edited by David
Robertson, Italo Biaggioni, Page 415. The adrenergic neurons
release norepinephrine (NE), which binds to alpha-1 adrenergic
receptors to induce piloerrection. The cholinergic neurons release
acetylcholine (ACh), which binds primary to muscarinic
acetylcholine receptors mAChRs (predominantly M.sub.3 and possibly
M.sub.2, see Eglen R M et al., "Muscarinic acetylcholine receptor
subtypes in smooth muscle," Trends Pharmacol Sci 1994 April;
15(4):114-9) to induce piloerrection. Thus, the inventive method
provides an alternative mechanism of action to that of the A1AR
agonists in the treatment of traction alopecia, and this
alternative mechanism provides for increasing the epilatory force
required to pull hair or reducing hair shedding during cosmetic
procedures that apply force on the hair root.
[0092] The alpha 1 adrenergic receptor is a G protein-coupled
receptor. Agonists of other G protein-coupled receptors (e.g.,
alpha 2 adrenergic receptor) can also be used to stimulate
contraction of the smooth muscle. Examples of alpha 2 adrenergic
receptor agonists include, but are not limited to, 4-NEMD,
7-Me-marsanidine, agmatine, apraclonidine, brimonidine, clonidine,
detomidine, dexmedetomidine, fadolmidine, guanabenz, guanfacine,
lofexidine, marsanidine, medetomidine, methamphetamine, mivazerol,
rilmenidine, romifidine, talipexole, tizanidine, tolonidine,
xylazine, and xylometazoline. As noted above, to the extent that it
would be disadvantageous to administer these or other agents
systemically, they can be administered in a formulation that
permits uptake by the AP muscle in the dermis but limits systemic
uptake.
[0093] In one embodiment, halostachine (also known as
N-methylphenylethanolamine) is contemplated for use as a
therapeutic agent in the methods and compositions described herein
to stimulate smooth muscle contraction.
[0094] It should be noted that agonists described herein also
encompass their inorganic or organic salts. Representative salts
include the hydrobromide, hydrochloride, sulfate, bisulfate,
phosphate, nitrate, acetate, succinate, valerate, oleate,
palmitate, stearate, laurate, benzoate, lactate, phosphate,
tosylate, citrate, maleate, fumarate, succinate, tartrate,
napthylate, mesylate, glucoheptonate, lactobionate, and
laurylsulphonate salts and the like.
[0095] It should be noted that combinations of the above methods
and agents can be used to promote the contraction of the smooth
muscle.
Treatment of Acne
[0096] The compositions described herein can also be used for the
treatment of acne. It is known that contraction of the AP muscle
plays a role in the secretion of the sebum (see Mahfouz et al., J.
Egypt wom. Dermatol. Soc. 2005, 2, 25-29). The compositions can be
applied in the form of lotion, cream, spray, or wipe. The
compositions can be used in combination with benzoyl peroxide or
other topical medications for acne treatment.
Representative Methods
[0097] In an exemplary embodiment, a method for treatment or
prevention of traction alopecia can include applying a composition
comprising a pilomotor effective amount of a muscarinic receptor
agonist, a nicotinic receptor agonist, or a cholinesterase
inhibitor topically to a portion of skin on the head that includes
at least one hair follicle. In some embodiments, the at least one
hair follicle is under tension. In some embodiments, the portion of
skin is at risk for developing traction alopecia. In some
embodiments, the composition comprises a muscarinic acetylcholine
receptor agonist. In some embodiments, the composition or the
method of treatment further comprises a second active agent or
applying a second active agent, such as without limitation an alpha
1 adrenergic receptor agonist.
[0098] In another exemplary embodiment, a method of reducing hair
shedding during brushing, combing or showering can include applying
a composition comprising a pilomotor effective amount of a
muscarinic receptor agonist, a nicotinic receptor agonist, and/or a
cholinesterase inhibitor topically to a portion of skin on the head
that includes at least one hair follicle. In some embodiments, the
composition is applied to the skin prior to the brushing or
combing. In some embodiments, the at least one hair follicle is
under tension. In some embodiments, the composition comprises a
muscarinic acetylcholine receptor agonist. In some embodiments, the
composition or method further comprises a second active agent or
administering a second active agent, such as without limitation an
alpha 1 adrenergic receptor agonist.
[0099] In another exemplary embodiment, a method for increasing
epilatory force of the hair can include applying a composition
comprising a pilomotor effective amount of at least one of a
muscarinic receptor agonist, a nicotinic receptor agonist, and/or a
cholinesterase inhibitor topically to a portion of skin on the head
of a person that includes at least one hair follicle. In some
embodiments, before, during or after the composition is applied,
the person undergoes a cosmetic procedure to the hair selected from
the group consisting of braiding, flat ironing, attaching a hair
weave, attaching a hair extension, or tying the hair back in a
ponytail. In some embodiments, the composition comprises an agonist
of (1) a muscarinic M.sub.2-type receptor, (2) a muscarinic
M.sub.3-type receptor, (3) a N.sub.N-type receptor, and/or (4) a
N.sub.M-type receptor, and/or comprises a cholinesterase inhibitor.
In some embodiments, the composition comprises a muscarinic
acetylcholine receptor agonist. In some embodiments, the
composition further comprises an alpha 1 adrenergic receptor
agonist. In some embodiments, the composition is applied to the
skin once daily. In some embodiments, the composition is applied to
the skin twice daily.
[0100] In another exemplary embodiment, method for prevention of
traction alopecia can include applying a composition comprising a
pilomoter effective amount of at least one of a muscarinic receptor
agonist, a nicotinic receptor agonist, and/or a cholinesterase
inhibitor to the scalp to an area with a group of follicles that
will experience a pulling force from a hair augmentation device.
The method can further include attaching the hair augmentation
device to the group of follicles.
[0101] The various methods and techniques described above provide a
number of ways to carry out the invention. Of course, it is to be
understood that not necessarily all objectives or advantages
described can be achieved in accordance with any particular
embodiment described herein. Thus, for example, those skilled in
the art will recognize that the methods can be performed in a
manner that achieves or optimizes one advantage or group of
advantages as taught herein without necessarily achieving other
objectives or advantages as taught or suggested herein. A variety
of alternatives are mentioned herein. It is to be understood that
some embodiments specifically include one, another, or several
features, while others specifically exclude one, another, or
several features, while still others mitigate a particular feature
by inclusion of one, another, or several advantageous features.
[0102] Furthermore, the skilled artisan 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 employed in various combinations by one of
ordinary skill in this art to perform methods in accordance with
the principles described herein. Among the various elements,
features, and steps some will be specifically included and others
specifically excluded in diverse embodiments.
[0103] Although the 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 application extend
beyond the specifically disclosed embodiments to other alternative
embodiments and/or uses and modifications and equivalents
thereof.
[0104] The recitation of ranges of values herein is merely intended
to serve as a shorthand method of referring individually to each
separate 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 otherwise clearly contradicted
by context. The use of any and all examples, or exemplary language
(for example, "such as") provided with respect to certain
embodiments herein is intended merely to better illuminate the
application and does not pose a limitation on the scope of the
application otherwise claimed. No language in the specification
should be construed as indicating any non-claimed element essential
to the practice of the application.
[0105] Certain embodiments of this application are described
herein. Variations on those embodiments will become apparent to
those of ordinary skill in the art upon reading the foregoing
description. It is contemplated that skilled artisans can employ
such variations as appropriate, and the application can be
practiced otherwise than specifically described herein.
Accordingly, many embodiments of this 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-described elements in all possible
variations thereof is encompassed by the application unless
otherwise indicated herein or otherwise clearly contradicted by
context.
[0106] All patents, patent applications, publications of patent
applications, and other material, such as articles, books,
specifications, publications, documents, things, and/or the like,
referenced herein are hereby incorporated herein by this reference
in their entirety for all purposes, excepting any prosecution file
history associated with same, any of same that is inconsistent with
or in conflict with the present document, or any of same that can
have a limiting affect as to the broadest scope of the claims now
or later associated with the present document. By way of example,
should there be any inconsistency or conflict between the
description, definition, and/or the use of a term associated with
any of the incorporated material and that associated with the
present document, the description, definition, and/or the use of
the term in the present document shall prevail.
EXAMPLES
Example 1
Oxymetazoline HCl at 0.1%, 0.2%, 0.5% by Weight
[0107] A study was conducted to assess the dosage of topical
oxymetazoline solution required to elicit the pilomotor reflex of
the hair arrector-pili muscle. Five subjects participated in the
study. Three formulations were used: Formula A: 0.1% topical
oxymetazoline hydrochloride solution; Formula B: 0.2% topical
oxymetazoline hydrochloride solution; Formula C: 0.5% topical
oxymetazoline hydrochloride solution.
[0108] The study was conducted over 3 days. On day 1, subjects were
instructed to apply Formula A to their arm. On day 2, subjects were
instructed to apply Formula B to their arm. On day 3, subjects were
instructed to apply Formula C to their arm. 0.1 mL of each formula
was applied using a metered dosage dispenser to each arm. Table 1
summarizes the finding from this study.
TABLE-US-00001 TABLE 1 Oxymetazoline study Subject No. Formula A
Formula B Formula C 1 NR NR R 2 NR NR R 3 NR NR R 4 NR NR R 5 NR NR
R R = Response, i.e. goose bumps; NR = No response
Table 1: Oxymetazoline Study
[0109] The 0.5% topical oxymetazoline solution (Formula C) elicited
a clinical response in all subjects while the 0.1% and 0.2%
formulations (Formula A and B) failed to elicit a response. With
the 0.5% topical oxymetazoline solution, response in the
contraction of the arrector.pilomotor muscle was obtained
approximately within 1 hour and lasted over 8 hours.
[0110] Due to the long acting effect of oxymetazoline it may be
beneficial to apply once daily, every other day, or as needed prior
to mechanical procedures that may exert epilatory forces on hair
follicles.
Example 2
Phenylephrine HCl at 5.0%, 7.5%, 10% by Weight
[0111] A study was conducted to assess the dosage of topical
phenylephrine solution required to elicit the pilomotor reflex of
the hair arrecto-pili muscle. Five subjects participated in the
study. Three formulations were used: Formula A: 5.0% topical
phenylephrine hydrochloride solution; Formula B: 7.5% topical
phenylephrine hydrochloride solution; Formula C: 10.0% topical
phenylephrine hydrochloride solution.
[0112] The study was conducted over 3 days. On day 1, subjects were
instructed to apply Formula A to their arm. On day 2, subjects were
instructed to apply Formula B to their arm. On day 3, subjects were
instructed to apply Formula C to their arm. 0.1 mL of each formula
was applied using a metered dosage dispenser to each arm. Table 2
summarizes the finding from this study.
TABLE-US-00002 TABLE 2 Phenylephrine study - 1 Subject No. Formula
A Formula B Formula C 1 NR NR R 2 NR NR R 3 NR NR R 4 NR NR R 5 NR
NR R R = Response, i.e. goose bumps; NR = No response
[0113] The 10.0% topical phenylephrine solution (Formula C)
elicited a clinical response in all subjects while the 5.0% and
7.5% formulations (Formula A and B) failed to elicit a response.
With the 10.0% topical phenylephrine solution, response in the
contraction of the arrector-pilomotor muscle was obtained
approximately within 20-30 minutes and lasted over 3 hours.
[0114] Due to the shorter lasting acting effect of phenylephrine
compared to oxymetazoline it may be beneficial to apply as needed
prior to mechanical procedures that may exert epilatory forces on
hair follicles.
Example 3
Phenylephrine HCl at 10% by Weight
[0115] In another study, 10.0% phenylephrine hydrochloride to
assess the use of topical phenylephrine hydrochloride solution as a
novel drug for prevention/reduction of hair loss from mechanical
pulling. Participants included in the study were female subjects
between ages of 18 and 60 who frequently use traumatic hair care
practices, such as tight braids, head scarves, ponytails,
extensions, hair rollers, hair weaves and heated styling appliances
such as blow dryers, flat irons, heat setters and curling irons.
Excluded subjects were those who experienced uncontrolled
hypertension, those who were pregnant or breastfeeding, those who
were diagnosed with pattern hair loss, or those who experienced
other hair loss in conjunction with female pattern hair loss.
Overall, fifteen female subjects, aged 24 to 40 years, participated
in the study.
[0116] The study was conducted over 4 days. On day 1, subjects were
instructed to wash their hair. On day 2, subjects were instructed
to apply 1 mL of placebo solution containing vehicle and brush
targeted area after 30 minutes. Brushing was conducted to frontal
hair with regular brush in size of 8.times.10 cm. On day 3,
subjects were instructed again to wash their hair. On day 4,
subjects were instructed to apply 1 mL of 10% phenylephrine
hydrochloride solution on targeted area and brush after 30 minutes.
FIGS. 2-5 summarize the finding from this study.
[0117] FIGS. 2 and 3 show that application of the 10% phenylephrine
hydrochloride solution resulted in reduced hair shedding in 80% of
the patients, as compared to the placebo solution containing the
vehicle, with the average reduction being approximately 42%. FIGS.
4 and 5 show that the epliatory force threshold for plucking hair
follicles following topical 10% phenylephrine hydrochloride
application increased by approximately 172%. Therefore, there is a
significant reduction hair loss from mechanical pulling and
increase in epilatory force after topical application of 10%
phenylephrine hydrochloride. This novel study demonstrates the
utility of alpha-1-AR agonists in the treatment of traction
alopecia and excessive hair loss resulting from mechanical cosmetic
procedures.
Example 4
Synephrine HCI at 40%,50% by Weight
[0118] A study was conducted to assess the dosage of topical
synephrine solution required to elicit the pilomotor reflex of the
hair arrecto-pili muscle. Five premenopausal subjects participated
in the study. Two formulations were used: Formula A: 40% topical
synephrine hydrochloride solution; Formula B: 50% topical
synephrine hydrochloride solution in both of which solutions the
synephrine was present in approximately a racemic mixture of (+/-)
synephrine HCl.
[0119] The study was conducted over 2 days. On day 1, subjects were
instructed to apply Formula A to their arm. On day 2, subjects were
instructed to apply Formula B to their ann. 0.1 mL of each formula
was applied using a metered dosage dispenser to each arm. Table 3
summarizes the finding from this study.
TABLE-US-00003 TABLE 3 Synephrine study Subject No. Formula A
Formula B 1 NR R 2 NR R 3 NR R 4 NR NR 5 NR R R = Response, i.e.
goose bumps; NR = No response
[0120] The 50% topical synephrine hydrochloride solution (Formula
B) elicited a clinical response in 4 out of 5 subjects while
Formula A failed to elicit a response.
Example 5
Phenylephrine
[0121] Female subjects, ages 18-40, were recruited to study the
effect of topically applied phenylephrine, a selective .alpha.1-AR
agonist, on epilation force and hair shedding during cosmetic
procedures. In the blinded study, 80% of subjects demonstrated
reduced shedding on days using phenylephrine compared to days using
a placebo solution. The average reduction in hair loss was
approximately 42%. In addition, the force threshold required for
epilation increased by approximately 172% following topical
phenylephrine application. To our knowledge this is the first study
demonstrating the utility of .alpha.1-AR agonists in the treatment
of traction alopecia and hair shedding during cosmetic
procedures.
Methods:
[0122] Patients: Fifteen female subjects, ages 18-40, were included
in the study. Subjects were recruited based on their frequent use
of traumatic hair care practices, such as, tight braids, head
scarves, ponytails, extensions, hair rollers, hair weaves and
heated styling appliances such as blow dryers, flat irons, heat
setters and curling irons. Subjects with uncontrolled hypertension,
that were pregnant or breastfeeding, had been diagnosed with
pattern hair loss or with other hair loss in conjunction with
female pattern hair loss were excluded from the study. Prior to
initiating the study, the efficacy of the 10% phenylephrine
solution was tested by applying a small aliquot (50 .mu.L) of the
solution to the forearm of three subjects. Piloerection and
blanching were visible after 30 minutes; the effect lasted for
approximately 2-3 hours.
[0123] Hair Shedding: To measure hair loss during cosmetic
procedures, a 4-day protocol was designed. On the first day
patients were instructed to wash their hair and use styling
products and procedures as they normally would. On the second day,
patients were instructed not to wash their hair and to apply 0.5 mL
of a placebo solution, containing a vehicle only, on the frontal
area of the scalp in an 8.times.10 cm.sup.2 target area. Patients
were instructed to wait 45 minutes, after which, they brushed their
hair 20 times from the front of the scalp to the bottom of head
using a new brush. After the procedure, the brushes were sealed in
a plastic bag. On day three, patients were instructed to wash their
hair and use styling products and procedures as they normally
would. On the fourth day, patients repeated the procedures of day
two; only 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.
Epilation Force:
[0124] To evaluate the effect of a topically applied .alpha.1-AR
agonist on the force required to pluck hairs from the scalp, a
hand-held spring dynamometer, or "trichotillometer" was used (8).
The trichotillometer records the maximum force threshold, in grams,
required to pluck a single hair from the scalp; the performance and
statistical variance of the instrument have been reported
previously (8-10). Force measurements were performed using the
trichotillometer on 10 subjects. The frontal area of scalp was
divided into two 8.times.10 cm2 areas. On the right side 0.5 mL of
a placebo vehicle was applied. On the left side, 0.5 mL a 10%
phenylephrine solution was applied. After 45 minutes, ten hairs
were plucked from each of the target areas with the
trichotillometer.
Results:
[0125] After tabulating the data of 15 subjects studied in the hair
shedding experiment (Table 4), we found a decrease in hair loss in
12 out of 15 patients (80% ) in the target area following the
application of 10% phenylephrine solution compared to hair loss in
the targeted area following the application of a placebo solution.
Reduction in the hair loss varied from 9% to 100%, with an average
reduction of 42%.
TABLE-US-00004 TABLE 4 Table 4. Number of hairs removed with brush
after the application of 10% phenylephrine (10% PE) or placebo.
Patient Number of Hairs Removed with Brush # Placebo 10% PE
Reduction 1 35 16 54% 2 3 0 100% 3 10 10 0% 4 14 8 43% 5 28 17 39%
6 31 11 65% 7 3 2 33% 8 12 6 50% 9 5 2 60% 10 35 32 9% 11 28 8 71%
12 2 2 0% 13 7 7 0% 14 8 2 75% 15 7 5 29% AVERAGE 42%
[0126] Measurements of the epilation force threshold in 10 subjects
showed similar improvements (Table 5). The epilation force
threshold on scalp hair follicles increased 172% on average (range:
5% to 462% ) following the application of a topical 10%
phenylephrine solution.
TABLE-US-00005 TABLE 5 Table 5. Grams of force required for
epilation after the application of 10% phenylephrine (10% PE) or
placebo. Each data point is the average of 10 plucked hairs [avg.
(std.)]. Patient Epilation Force (grams) # Placebo 10% PE Reduction
1 2.6 (2.6) 13.0 (6.6) 400% 2 16.6 (2.7) 24.8 (2.9) 49% 3 15.2
(2.4) 34.8 (2.9) 129% 4 6.8 (6.4) 26.0 (7.9) 282% 5 2.6 (1.5) 14.6
(4.8) 462% 6 18.0 (3.2) 23.6 (11.1) 31% 7 17.6 (4.4) 18.4 (2.3) 5%
8 14.6 (4.2) 20.4 (4.6) 40% 9 11.2 (5.9) 22.0 (5.5) 96% 10 9.4
(4.8) 30.2 (8.3) 221% AVERAGE 172%
Discussion:
[0127] At present, many people use various mechanical hair
procedures, which result in increased traumatic force on hair
follicles and result in traction alopecia. Each hair follicle in
the human skin contains an arrector pili muscle, which expresses al
adrenergic receptors (.alpha.1-AR). Stimulation of the arrector
pili muscle with .alpha.1-AR agonist causes contraction of the
muscle, which can provide a counterforce to resist epilation of
hair follicles. In this experiment, we demonstrated that a 10%
solution of phenylephrine, a selective al agonist, could induce
piloerection on the scalp that reduced hair shedding and increased
the threshold force for epilation. To our knowledge this is the
first study elucidating the novel mechanism of .alpha.1-AR agonist
induced piloerection for the treatment of traction alopecia and
excessive hair shedding resulting from cosmetic procedures.
Example 6
Bitter Orange Extract
[0128] Highly purified (greater than 90% ) natural bitter orange
extract from Citrus aurantium was tested at 25% and 12.5% in a
buffer solution at pH5.2 on the arms of four subjects to determine
piloerection response. The 12.5% dosage failed to elicit a
response. The 25% solution elicited a response. The response
appeared after about 15-30 minutes. The piloerection lasted 3-4
hours.
REFERENCES
[0129] 1. Ozyelik D. Extensive traction alopecia attributable to
ponytail hairstyle and its treatment with hair transplantation.
Aesthetic Plast Surg 2005: 29(4): 325-327. 2. Hjorth N. Traumatic
marginal alopecia; a special type: alopecia groenlandica. Br J
Dermatol 1957: 69(9): 319-322. 3. Khumalo N P, Jessop S, Gumedze F,
Ehrlich R. Determinants of marginal traction alopecia in African
girls and women. JAm Acad Dermato12008: 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 C H, Illigens B
M, Lafo J A, Brown C M, Freeman R. Quantitative pilomotor axon
reflex test: a novel test of pilomotor function. Arch Neurol2012:
69(11): 1488-1492. 6. Lewis T, Marvin H M. Observations upon a
pilomotor reaction in response to faradism. J Physiol1927: 64(1):
87-106. 7. Piascik M T, Perez D M. Alphal-adrenergic receptors: new
insights and directions. J Pharmacal Exp Ther 2001: 298(2):
403-410. 8. Wyness L A, McNeill G, Prescott G L. Trichotillometry:
the reliability and practicality of hair pluckability as a method
of nutritional assessment. Nutr J 2007:6:9. 9. Chase E S, Weinsier
R L, Laven G T, Krumdieck C L. Trichotillometry: the quantitation
of hair pluckability as a method of nutritional assessment. Am J
Clin Nutr 1981: 34(10): 2280-2286. 10. Smelser D N, Smelser N B,
Kmmdieck C L, Schreeder M T, Laven G T. Field use of hair epilation
force in nutrition status assessment. Am J Clin Nutr 1982: 35:
342-346.
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