Hair loss abstract
Improved preparations for the treatment of androgenetic alopecia
comprise saw palmetto berry extract containing phytosterols and
one or more low irritability constituents that enhance penetration
of the extract into hair follicular pores. The low irritability
penetration enhancer(s) may be selected from the group consisting
of adapalene, tretinoin, retinaldehyde, tazarotene, salicylic acid,
azelaic acid, and glycolic acid. Also provided is a method for reducing
hair loss by application to the scalp of the improved preparations.
Hair loss claims
What is claimed is:
1. A low irritability topical preparation for the treatment of
hair loss comprising:
(A) saw palmetto berry alcohol extract containing phytosterols;
(B) one or more members of the group consisting of adapalene; retinaldehyde,
tazarotene, salicyclic acid, glycolic acid and azelaic; and
(C) polyoprepolymer-2.
2. The preparation of claim 1 which further comprises a member
of the group consisting of tretinoin and tretinoin gel microsponges.
3. A topical preparation according to claim 1 containing the combination
of adapalene and glycolic acid.
4. A topical preparation according to claim 1 containing polyolprepolymer-2
and a member of the group consisting of salicylic acid and glycolic
acid.
5. A topical preparation according to claim 1 comprising salicylic
acid or glycolic acid together with adapalene and further comprising
tretinoin gel microsponges.
6. A topical preparation as recited by claim 1, wherein the concentration
of phytosterols in the preparation ranges from about 0.01 wt.% to
about 1 wt.%.
7. A topical preparation as recited by claim 1, wherein the concentration
of phytosterols in the preparation ranges from about 0.01 wt.% to
about 0.5 wt.%.
8. A topical preparation as recited by claim 1, wherein the adapalene
concentration ranges from about 0.01 wt.% to about 1 wt.%.
9. A topical preparation as recited by claim 1, wherein the glycolic
acid concentration ranges from about 0.1 wt.% to about 20 wt.%.
10. A topical preparation as recited by claim 1, wherein the tretinoin
concentration in the form of gel microsponges ranges from about
0.005 wt.% to about 0.2 wt.%.
11. A topical preparation as recited by claim 1, wherein the retinaldehyde
concentration ranges from about 0.01 wt.% to about 1.0 wt.%.
12. A topical preparation as recited by claim 1, wherein the azelaic
acid concentration ranges from about 0.1 wt% to about 40 wt.%.
13. A topical preparation as recited in claim 1, wherein the total
concentration of azelaic acid and glycolic acid ranges from about
0.1% to about 40%.
14. A topical preparation as recited in claim 1, wherein the proportion
of azelaic acid to glycolic acid ranges from about 10:90 to about
90:10.
15. A topical preparation as recited by claim 1, wherein the tazarotene
concentration ranges from about 0.01 wt.% to about 1.0 wt.%.
16. A topical preparation as recited by claim 1, wherein the salicylic
acid concentration ranges from about 0.1 wt.% to about 10 wt.%.
17. A topical preparation as recited by claim 1, wherein the preparation
further contains a topical vehicle for application to the scalp
selected from the group consisting of liquid, gel, foam, styling
mousse, styling hair tonic and styling hair spray.
18. A method for the treatment of male pattern hair loss, comprising
applying to the scalp a low irritability preparation comprising
saw palmetto berry alcohol extract containing phytosterols; and
one or more penetration enhancing constituents selected from the
group consisting of adapalene, tretinoin, retinaldehyde, tazarotene,
salicylic acid, azelaic acid, and glycolic acid; polyolprepolymer-2;
and, optionally, tretinoin gel microsponges.
Hair loss description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to an improved preparation and method for
treating androgenetic alopecia; and more particularly to a preparation
comprising an active extract of saw palmetto berries and a compound
which exhibits low irritability and enhances penetration of the
extract into hair follicular pores.
2. Description of the Prior Art
Human hair undergoes a normal growth cycle, known as the pilar
cycle where each hair grows continuously for about 2 to 4 years,
stops growing for 2 to 4 months, and then falls out. In its place,
healthy new hair begins to grow, thereby restarting the cycle. Androgen
receptors located in the hair follicle and sebaceous gland sensitize
hair follicles to androgens. There is evidence that the pilar cycle
of hair follicles on the scalp respond to higher levels of androgens
by displaying shortened growth phases, and by displaying a greater
fraction of increasingly thinner and shorter hairs.
Saw palmetto (serenoa repens) is a small berry-bearing palm native
to the southeast United States. Saw palmetto berry extract ("SPBE")
has been shown to block 5-alpha reductase, the enzyme that converts
the hormone testosterone into dihydrotestosterone ("DHT"),
the major androgen implicated in changes in the pilar cycle. This
enzyme also blocks the binding of DHT to androgen receptors. Thus,
in treating the balding scalp, SPBE may act by blocking the formation
of DHT, by inhibiting binding of DHT to the androgen receptors,
or both. The use of SPBE in reducing hair loss is well known and
has been cited for example in "The Green Pharmacy", pp.
78-79, Rodale Press, Emmaus, Penn., 1996.
In U.S. Pat. No. 5,972,345, SPBE has been combined with the extracts
of African Pygeum and stinging nettle to produce a formulation for
administration to the scalp for the treatment of male pattern hair
loss. Stinging nettle extract is a known rubefacient that may open
the follicle entrance by producing irritation.
In U.S. Pat. No. 5,750,108, SPBE is administered to the scalp as
the third step in a procedure comprising lengthy, sequential preparatory
treatments, first with tea tree oil, and then with an acidic solution
of chlorine dioxide. The purpose of these preparatory treatments
is to remove sebum from the follicle entrance and improve the effectiveness
of the SBPE. However, chlorine dioxide is an irritant and an extremely
hazardous material. The Occupational Safety and Health Administration
of the U.S. Department of Labor, in a list published by Government
Institutes, Inc. Rockville, Md., 1990, shows a Permissible Exposure
Level (PEL) for chlorine dioxide vapor as 0.1 ppm. To understand
this level of toxicity, it should be noted that elemental chlorine
that has been used as a war gas, has a PEL that is five fold greater
than that of chlorine dioxide.
SPBE has also been disclosed in U.S. Pat. Nos. 5,624,673, 5,653,983,
and 5663,160 as an optional minor ingredient in topical formulations.
Other known topical formulations for treatment of hair loss are
minoxodil, and a combination of minoxodil with tretinoin. The efficacy
of minoxidil is limited as only a relatively small percentage of
patients using it develope mild to moderate regrowth of hair. Further,
Pharmacia and Upjohn, manufacturers of ROGAINE.RTM. minoxodil solution,
warn that the most common side effect of minoxodil is itching and
skin irritation of the treated area of the scalp. Tretinoin may
also act as an irritant as indicated by the publication "Topical
Tretinoin in Acne Therapy", by G.F. Webster, Journal of the
American Academy of Dermatology, S38-S43, (1998).
A need exists for an SPBE formulation and method of preventing
hair loss/promoting hair growth that exploits the merits of SPBE
without requiring lengthy and hazardous pretreatment of the scalp.
Especially needed is an SPBE formulation that offers enhanced effectiveness
without causing scalp irritation.
SUMMARY OF THE INVENTION
The invention provides an improved preparation and a method for
treating androgenetic alopecia. The preparation comprises an extract
of saw palmetto berries containing phytosterols and a non-irritating
compound to enhance the penetration of the extract into the follicles.
More specifically, the improved low irritability topical preparation
comprises saw palmetto berry extract containing phytosterols and
one or more penetration enhancing constituents selected from the
group consisting of adapalene, tretinoin gel microsponges, tretinoin
and polyolprepolymer-2, retinaldehyde, tazarotene, salicylic acid,
azelaic acid, and glycolic acid. Preferably the penetration enhancing
constituents consist of one member selected from the group consisting
of adapalene, tretinoin and polyolprepolymer-2, and tretinoin gel
microsponges, and another member selected from the group consisting
of salicylic acid and glycolic acid.
In another embodiment, the improved low irritability topical preparation
comprises an active saw palmetto berry extract containing phytosterols,
polyolprepolymer-2 and one or more penetration enhancing constituents
selected from the group consisting of adapalene, tretinoin, retinaldehyde,
tazarotene, salicylic acid, azelaic acid, and glycolic acid. Preferably
the penetration enhancing constituents consist of one member selected
from the group consisting of adapalene and tretinoin and another
member selected from the group consisting of salicylic acid and
glycolic acid.
Most preferably, in both of the above embodiments, the penetration
enhancing constituents are adapalene and glycolic acid.
The preparations of the invention may include a vehicle suitable
for topical application to the scalp in the form of a liquid, a
gel, a foam, a styling hair tonic, a styling mousse, a styling hair
spray, a pad dampened with a liquid, or any other means suitable
for application to the scalp.
The method for the treatment of androgenetic alopecia comprises
applying to the scalp a low irritability preparation comprising
saw palmetto berry extract containing phytosterols, and one or more
penetration enhancing constituents selected from the group consisting
of adapalene, tretinoin gel microsponges, retinaldehyde, tazarotene,
salicylic acid, azelaic acid, and glycolic acid. In another embodiment,
the method for the treatment of androgenetic alopecia comprises
applying to the scalp a low irritability preparation comprising
saw palmetto berry extract containing phytosterols, polyolprepolymer-2
and one or more penetration enhancing constituents selected from
the group consisting of adapalene, tretinoin, retinaldehyde, tazarotene,
salicylic acid, azelaic acid, and glycolic acid.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides low irritability formulations of
SPBE offering enhanced effectiveness in reducing hair loss by their
greater ability to penetrate the pores of the scalp. In addition,
there is provided by the invention a method for reducing hair loss
by application to the scalp of a preparation comprised of the improved
formulations.
The pilar cycle in humans is measured in years, typically two to
four years. Consequently, a topical preparation to be effective
in reducing hair loss or promoting hair growth must be used for
extended periods of time. It is evident that a preparation or a
method that causes irritation of the scalp often cannot be used
for the time essential to be effective.
The SPBE constituent of the preparation of the invention may be
obtained from a number of commercial sources. Satisfactory non-irritating
SPBEs include Permixon.RTM. from P.F. Medicaments, Paris, France,
SPBE from McZand Herbal Inc., Santa Monica, Calif., and others.
In a preferred embodiment of the preparation of the present invention,
the SPBE constituent is the alcohol soluble material sold by Saw
Palmetto Harvesting Company, Frostproof Fla. This SPBE is non-irritating
when applied to the scalp. Typically, it has the following major
components and concentrations:
Phytosterols capesterol about 0.01 to about 0.1 wt.wt. % beta-sitosterol
about 0.1 to about 0.4 wt. % stimasterol about 0.01 to about 0.1
wt. % Total sterols greater than about 0.15 wt. % Fatty Acids caprylic
about 1.0 to about 3.0 wt. % capric about 1.0 to about 3.0 wt. %
lauric about 25 to about 32 wt % cis-linoleic about 3.0 to about
5.0 wt. % linolenic about 0.5 to about 1.5 wt. % myristic about
10 to about 1.5 wt. % oleic about 26 to about 35 wt. % palmitic
about 7 to about 11 wt. % stearic about 1.0 to about 2.0 wt. %
Other phytosterols, other fatty acids and other minor components
may also be present without effecting the utility of the SPBE. The
phytosterols are believed to be the active agents in the SPBE.
In another embodiment of the preparation of the present invention,
all or a portion of the fatty acids have been removed from the above
composition by further purification, as for example by extraction
with aqueous alkaline solution. In this embodiment, the phytosterol
composition of the SPBE is as follows:
Phytosterols capesterol greater than about 0.02 wt. % beta-sitosterol
greater than about 0.2 wt. % stimasterol greater than about 0.02
wt. % Total sterols greater than about 0.3 wt. %
The SPBE is present in the preparations of the invention in a concentration
such that the concentration of pbytosterols in the total preparation
is between about 0.01 wt. % and 1 wt. %. Preferably, the concentration
of the SPBE is such that the concentration of the phytosterols in
the total preparation is between about 0.01 wt. % and 0.5 wt. %.
Most preferably the phytosterol concentration is about 0.10 wt.
%.
The preparation of the invention comprises the SPBE and one or
more penetration enhancing constituents selected from the group
consisting of adapalene, tretinoin gel microsponges, retinaldehyde,
tazarotene, salicylic acid, azelaic acid, and glycolic acid. In
another embodiment, the preparation of the invention comprises the
SPBE, polyolprepolymer-2 and one or more penetration enhancing constituents
selected from the group consisting of adapalene, tretinoin, retinaldehyde,
tazarotene, salicylic acid, azelaic acid, and glycolic acid.
Adapalene is a synthetic retinoid manufactured by Galderma having
the following structural formula: ##STR1##
A research article by B. Shroot, "Pharmacodynamics and Pharmacokinetics
of Topical Adapalene", Journal of the American Academy of Dermatology,
S17-24, (1998) has shown that adapalene has several useful properties.
First, adapalene has significant comedolytic activity, that is,
it opens comedones or clogged pores. In the preparation of the invention,
adapalene acts to enhance the effectiveness of the SPBE. Second,
a 0.1 wt. % adapalene gel has a low irritative potential only slightly
greater than a petroleum jelly control. Third, adapalene has anti-inflammatory
effects both in vitro and in vivo. Each of these documented properties
provides superiority to the preparations of the invention over the
SPBE formulations of the prior art. Lastly, as adapalene is a retinoid,
it may be expected to have direct benefits on stimulating hair regrowth.
Adapalene is present in a preparation of the invention in a concentration
from about 0.01 wt. % to about 1 wt. %. Preferably, the adapalene
concentration is from about 0.05 wt. % to about 0.5 wt. %. Most
preferably, the adapalene concentration is about 0.1 wt. %.
Tazarotene is a retinoid having the following structural formula:
##STR2##
Pharmacologically, tazarotene normalizes keratinocyte differentiation
and minimizes proliferation of keratinocytes. These actions serve
to inhibit microcomedo formation and prevent follicular plugging.
Tazarotene also decreases epidermal inflammation and has been shown
to down-regulate biochemical markers of inflammation. In the preparation
of the invention, tazarotene acts to enhance the effectiveness of
the SPBE.
Tazarotene is present in a preparation of the invention in a concentration
from about 0.01 wt. % to about 1 wt. %. Preferably, the tazarotene
concentration is from about 0.02 wt. % to about 0.2 wt. %. Most
preferably, the tazarotene concentration is about 0.05 to 0.1 wt.
%.
Glycolic acid, a naturally occurring a-hydroxy acid has the formula:
Glycolic acid been shown to exfoliate the stratum corneum. In the
preparation of the invention, glycolic acid acts to enhance the
effectiveness of the SPBE by increasing its penetration. Additionally,
a research article by N. V. Perricone et al, "Photoprotective
and Anti-inflammatory Effects of Topical Glycolic Acid", Dermatological
Surgery, 22, 435-437 (1996) has shown glycolic acid acts as both
a photoprotective agent and as an anti-inflammatory. These photoprotective
and anti-inflammatory properties lend superiority to the preparations
of the invention over the SPBE formulations of the prior art. Glycolic
acid is present in a preparation of the invention in a concentration
from about 0.1 wt. % to about 20 wt. %. Preferably, the glycolic
acid concentration is from about 0.5 wt. % to about 10 wt. %. Most
preferably, the glycolic acid concentration is about 5 wt. %.
Tretinoin has been used in acne therapy and in combination with
minoxodil for the prevention of hair loss. Tretinoin is all-trans
retinoic acid, also known as (all E) 3,7-dimethyl-9-(2,6,6-trimethyl-1-cylclohexen-1-yl)-2,4,6,8,-nonatetraenoi
c acid having the following structural formula: ##STR3##
Tretinoin inhibits comedo formation and enhances comedolysis. Thus,
it acts to prevent pores from becoming clogged and enhances removal
of debris from clogged pores. There is also evidence that tretinoin
itself increases hair growth factors. Additionally, a new form of
topical tretinoin, RETIN-A MICRO.RTM., has become available from
Ortho Dermnatological, Raritan N.J. in which 0.1 wt. % of tretinoin
is entrapped in a microscopic particle termed a "microsponge".
This particle localizes to the follicle after topical application
and then releases tretinoin. The slow release minimizes irritation.
By virtue of their increased effectiveness and low irritation potential,
a preparation of the invention containing tretinoin in the form
of gel microsponges is superior to SPBE preparations of the prior
art. Tretinoin is present in a preparation of the invention in a
concentration from about 0.005 wt. % to about 0.2 wt. %. Preferably
tretinoin concentration is from about 0.025 wt. % to about 0.1 wt.
%.
Retinaldehyde is the aldehyde analog of retinoic acid having a
terminal aldehyde group in place of the carboxyl group of retinoic
acid. It has been shown by J. W. Fluhr et al, Dermatology, 199,
Suppl 1:57-60 (1999) that retinaldehyde is significantly less irritating
than retinoic acid (tretinoin). It is expected to be equally as
effective in increasing the absorption of SPBE as is tretinoin.
Incorporation of retinaldehyde in the SPBE preparations of the invention
provides superior effectiveness and lower irritation potential of
these preparations over the SPBE formulations of the prior art.
Retinaldehyde is present in a preparation of the invention in a
concentration from about 0.01 wt. % to about 1.0 wt. %. Preferably
the retinaldehyde concentration is from about 0.05 wt. % to about
0.5wt. %. Most preferably, the retinaldehyde concentration is about
0.1 wt. %.
Azelaic acid, also known as 1,7 heptanedicarboxylic acid has the
formula:
This agent has been shown to have antibacterial, antikeratinizing
and anti-inflammatory properties. Thus, its use leads to a reduction
in thickness of the strateum corneum or top layers of the skin,
while preventing the formation of microcomedones or plugged follicles.
These effects allow for increased penetration of SPBE into follicles
while causing little, if any, irritation. Azeleic acid has been
shown to cause less irritation than tretinoin. Incorporation of
azeleic acid in the SPBE preparations of the invention provides
superior effectiveness and lower irritation potential of these preparations
over the SPBE formulations of the prior art.
Azeleic acid is present in a preparation of the invention in a
concentration from about 0.1 wt. % to about 40 wt. %. Preferably,
the azeleic acid concentration is about 20 wt. %.
It has been shown by M. C. Spellman et al, Clinical Therapy, 20(4m
, 711-721 (1998) that a combination of azelaic acid and glycolic
acid is less irritating than tretinoin and equally as effective
in treating facial acne. As both azeleic acid and glycolic acid
lead to a reduction in the thickness of the stratum corneum, and
both have anti-inflammatory properties, this combination increases
the absorption of topically applied SPBE while causing less irritation
than prior art compounds.
Accordingly, incorporation of azelaic acid and glycolic acid in
the SPBE preparations of the invention provides superiority of these
preparations over prior art SPBE formulations.
Azelaic and glycolic acids are present in a preparation of the
invention in relative proportions ranging from about 10:90 azelaic:glycolic
to about 90:10 azelaic:glycolic. The total concentration of azelaic
plus glycolic acids in a preparation of the invention is from about
0.1 wt. % to about 40 wt. %. Preferably, the azelaic plus glycolic
acid concentration is about 20 wt%.
Salicylic acid (2-hydroxy benzoic acid) is a beta hydroxy acid
having the formula:
Salicyclic acid is used topically in numerous products to reduce
scaling. It is well known as a keratolytic and has been used in
combination with glycolic acid to aid in comedolysis or the opening
of clogged follicles. It increases the penetration of SPBE into
follicles and has a low irritancy potential. Incorporation of salicylic
acid in the SPBE preparations of the invention provides superiority
of these preparations over the SPBE formulations of the prior art.
Salicyclic acid is present in a preparation of the invention in
a concentration from about 0.1 wt. % to about 10 wt. %. Preferably,
the salicyclic concentration is between about 1% wt. % and 3 wt%.
Polyolprepolymer-2 is a urethane compound of molecular weight up
to about 200,000 which is prepared by reacting approximately two
moles of a hydroxy terminated linear alkylene or polyalkylene glycol
or polyether with approximately one mole of a monomeric organic
diisocyanate as described in U.S. Pat. No. 5,700,483, the entirety
of which is incorporated by reference herein. Preferably, polyolprepolymer-2
has average molecular weight of about 4000 and is prepared by reacting
about one mole of dicyclohexylmethanediisocyanate with about two
moles of propylene glycol 725.
Incorporation of polyolprepolymer-2 in a topical formulation has
been shown to have the characteristic of moderating the rate of
transmission of a retinoid to the skin. Specifically, it has been
shown that formulations incorporating tretinoin and polyolprepolymer-2
are significantly less irritating and exhibit therapeutically equally
efficacy to identical formulations without polyolprepolymer-2. When
polyolprepolymer-2 is present in a preparation of the invention,
tretinoin need not be in the form of gel microsponges. Incorporation
of the polyolprepolymer-2 in the SPBE preparations of the invention
provides superiority of these preparations over the SPBE formulations
of the prior art. The polyolprepolymer-2 is present in a preparation
of the invention in a concentration from about 1 wt% to about 20
wt%. Preferably, the polyolprepolymer-2 is present in a concentration
from about 2 wt% to about 15 wt%.
The preparations of the invention may include a vehicle for the
application to the scalp such as a liquid, a gel, a foam, a styling
mouse, a styling gel, a styling hair tonic, a styling hair spray
a lotion, a pad dampened with a liquid, or any other means suitable
for application to the scalp. Preferably the SPBE preparations of
the invention are employed as a liquid or as a gel. Most preferred
is a gel.
The formulation of all such topical vehicles is well known to those
skilled in the art. A suitable topical vehicle for formulation of
the SPBE preparation as a liquid includes ethanol, isopropanol,
their mixtures in all proportions. To prepare a liquid preparation
of the invention, the SPBE and the penetration enhancing constituents
are dissolved or dispersed in the alcohol constituents with agitation.
Elevated temperatures may be used to facilitate the dispersion
process.
An example of a suitable topical vehicle for formulation of the
SPBE preparation as a gel is:
Component wt % hydroxypropylcellulose 2.1 70/30 isopropyl alcohol/water
90.9 propylene glycol 5.1 Polysorbate 80 1.9
To prepare a gel preparation of the invention, the 70% isopropanol
and the propylene glycol are first combined. The SPBE and the penetration
enhancing constituents are dispersed in the alcohols with agitation.
The hydroxypropylcellulose and the Polysorbate 80 are then incorporated
with mixing until a gel results.
An example of a suitable topical vehicle formulation for formulation
of the SPBE preparation as a foam is:
Component wt % cetyl alcohol 1.1 stearyl alcohol 0.5 Quaternium
52 (52%) 1.0 propylene glycol 2.0 Ethanol 95 PGF3 61.05 deionized
water 30.05 P75 hydrocarbon propellant 4.30
To prepare a foam preparation of the invention, the SPBE and the
penetration enhancing constituents are first dispersed in the ethanol
at elevated temperature. The cetyl and stearyl alcohols are added
to the heated dispersion and mixed until dissolved. The Quaternium
52, the propylene glycol and water are added and stirred until homogeneous
while maintaining elevated temperature. The mixture is cooled and
dispensed into an aerosol can. A valve is fitted to the can and
the can is then charged with the propellant.
A suitable topical vehicle for formulation of the SPBE preparation
as a hair grooming tonic is the formulation of Example VI of U.S.
Pat. No. 5,997,853, the entirety of which is incorporated by reference
herein. The SPBE and the penetration enhancing constituents are
first incorporated in the ethanol constituent and the remaining
components are added and incorporated by mixing together in a conventional
manner.
A suitable topical vehicle for formulation of the SPBE preparation
as a styling mousse is the formulation of Example XIII of U.S. Pat.
No. 5,997,853. The SPBE and the penetration enhancing constituents
are first incorporated in the ethanol constituent. Then, the remaining
components except the isobutane are added, and blended together
at ambient temperature until well mixed. Aluminum aerosol cans are
filled with 95 parts of this batch, a valve is fitted to the can
and lastly pressure filled with 5 parts isobutane.
A suitable topical vehicle for formulation of the SPBE preparation
as a styling hair spray is the formulation of Example XIV of U.S.
Pat. No. 5,997,853. The SPBE and the penetration enhancing constituents
are first incorporated in the ethanol. The remaining ingredients
are then added and mixed in a conventional manner.
The mode of use of a SPBE preparation of the invention is application
of 1 cc of the preparation to the affected area of the dry scalp
twice a day for a period of four months. The preparation should
be massaged into the scalp and remain in place or at least four
hours before washing, rinsing or showering. After the four month
initial period, a sustaining application of 1 cc once a day is used.
The following examples are presented to provide a more complete
understanding of the invention. The specific techniques, conditions,
materials, and proportions set forth to illustrate the principles
and practice of the invention are exemplary and should not be construed
as limiting the scope of the invention. |