U.S. patent application number 15/271283 was filed with the patent office on 2017-03-23 for devices and methods for enhancing the topical application of a benefit agent.
The applicant listed for this patent is Johnson & Johnson Consumer Inc.. Invention is credited to Jyotsna Paturi, Alexandru Paunescu.
Application Number | 20170080257 15/271283 |
Document ID | / |
Family ID | 58276206 |
Filed Date | 2017-03-23 |
United States Patent
Application |
20170080257 |
Kind Code |
A1 |
Paunescu; Alexandru ; et
al. |
March 23, 2017 |
DEVICES AND METHODS FOR ENHANCING THE TOPICAL APPLICATION OF A
BENEFIT AGENT
Abstract
The present invention relates to devices and methods for
treating, reducing and preventing adverse skin/scalp conditions and
enhancing the topical application of a benefit agent. The devices
are ultrasonic with transducers positioned at an angle other than
90.degree. relative to the surface at which the ultrasound is to be
applied.
Inventors: |
Paunescu; Alexandru;
(Clinton, NJ) ; Paturi; Jyotsna; (Skillman,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Johnson & Johnson Consumer Inc. |
Skillman |
NJ |
US |
|
|
Family ID: |
58276206 |
Appl. No.: |
15/271283 |
Filed: |
September 21, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62221889 |
Sep 22, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 5/0624 20130101;
A61N 2005/0654 20130101; A61M 2037/0007 20130101; A61N 2005/0662
20130101; A61P 43/00 20180101; A61P 29/00 20180101; A61N 7/00
20130101; A61P 17/14 20180101; A61N 5/0617 20130101; A61P 25/04
20180101; A61P 17/00 20180101; A61N 2007/0034 20130101; A61M
37/0092 20130101 |
International
Class: |
A61N 7/00 20060101
A61N007/00 |
Claims
1. An ultrasound device, comprising: a.) a housing having bottom
portion comprising an application surface, b.) a power source
positioned in the housing; c.) an acoustic transducer positioned in
the housing in electrical communication with the power source for
producing ultrasound waves and oriented such that the ultrasound
waves are projected from the transducer at an angle .theta. of
other than 90.degree. relative to the surface of the application
surface.
2. The device of claim 1, wherein the application surface is
adapted to lie on and be substantially parallel with the surface or
the skin of a user.
3. The device of claim 1, further comprising an electrical drive
circuit in electrical communication with the transducer and the
power source.
4. The device of claim 1, wherein the angle .theta. ranges from
5.degree. to 75.degree. relative to the skin surface of affected
area.
5. The device of claim 4, wherein the angle .theta. ranges from
10.degree. to 75.degree. relative to the skin surface of affected
area.
6. The device of claim 5, wherein the angle .theta. ranges from
10.degree. to 60.degree. relative to the skin surface of affected
area.
7. The device of claim 6, wherein the angle .theta. ranges from
10.degree. to 45.degree. relative to the skin surface of affected
area.
8. The device of claim 7, wherein the angle .theta. ranges from
15.degree. to 30.degree. relative to the skin surface of affected
area.
9. The device of claim 1, wherein the transducer is calibrated to
generate acoustic energy at a frequency ranging from about 20 kHz
to about 3000 kHz.
10. The device of claim 9, wherein the frequency ranges from about
100 kHz to about 1000 kHz.
11. The device of claim 10, wherein the frequency ranges from about
250 kHz to about 750 kHz.
12. The device of claim 1, wherein ultrasound pressure generated by
the device is less than any ultrasound pressure generated by
ultrasound waves projected toward the application surface at an
angle which is perpendicular relative to the application surface
when measured, in each case, using the Ultrasound Pressure
Measurement Test described in the Specification hereof.
13. The device of claim 12 wherein the ultrasound pressure is at
least a 5 fold less than ultrasound pressure generated by
ultrasound waves projected toward the application surface at an
angle which is perpendicular relative to the application surface
when measured, in each case, using the Ultrasound Pressure
Measurement Test described in the Specification hereof.
14. The device of claim 13 wherein the ultrasound pressure is at
least 10 fold less than ultrasound pressure generated by ultrasound
waves projected toward the application surface at an angle which is
perpendicular relative to the application surface when measured, in
each case, using the Ultrasound Pressure Measurement Test described
in the Specification hereof.
15. The device of claim 14 wherein the ultrasound pressure is at
least 15 fold less than ultrasound pressure generated by ultrasound
waves projected toward the application surface at an angle which is
perpendicular relative to the application surface when measured, in
each case, using the Ultrasound Pressure Measurement Test described
in the Specification hereof.
16. A method of treating skin using the device of claim 1.
17. A method of enhancing penetration of a benefit agent into skin
using the device of claim 1.
18. A method of conditioning skin for application of a benefit
agent using the device of claim 1.
Description
[0001] The present invention relates to devices and methods for
treating, reducing and preventing adverse skin/scalp conditions and
enhancing the topical application of a benefit agent. The devices
are ultrasonic with transducers positioned at an angle other than
90.degree. relative to the surface at which the ultrasound is to be
applied.
CROSS-RELATED APPLICATION
[0002] The present application claims the benefit of the earlier
filing date of U.S. provisional patent application 62/221,889,
filed Sep. 22, 2015, the entirety of which application is hereby
incorporated by reference herein as if fully set forth herein.
BACKGROUND OF THE INVENTION
[0003] Compositions for delivering benefit agents are well known.
Typical formulations include solutions, emulsions, suspensions and
gels. The viscosity may vary based on intended area for
application, intended use (leave on or rinse off), or consumer
preference. When applied to skin, the benefit agent penetrates the
skin to some extent, depending on the agent and the
formulation.
[0004] There is a need for devices and methods that control skin
penetration of benefit agents. U.S. Pat. No. 6,419,913 relates to
micellar compositions that enhance skin penetration. However, these
compositions can be difficult to manufacture and the cost of the
products are relatively high. There is also no means for
controlling the degree of skin penetration. Ultrasound devices have
been utilized to help analgesic compositions and anti-inflammatory
agents penetrate skin to help reduce muscle pain and the like.
United States Patent application 2009/0318852 teaches an ultrasound
device for applying agents to skin, which application is herein
incorporated by reference. The transducers of the described devices
are not oriented within the housing of such devices so as project
the generated ultrasound waves at an angle other than at 90.degree.
(perpendicular) relative to the surface where the ultrasound is to
be applied (e.g., the surface of the skin of a user).
SUMMARY OF THE INVENTION
[0005] Applicants have now discovered that specific skin benefits
and improved penetration of benefit agents through skin may
achieved by controlling the angle at which the ultrasound is
applied. The methods and devices according to the present invention
include an ultrasound transducer oriented at an angle to the
surface where it will be applied such that the angle .theta. (as
illustrated in FIG. 3) ranges from 5.degree. to 75.degree., for
example 15.degree., 45.degree. or 60.degree.. The desired angle
will change based on the ultrasound intensity desired for a
specific skin benefit or degree of skin penetration desired for
skin benefit agents.
[0006] The devices and methods for delivering ultrasound energy can
be used, either alone or with active benefit agents, for hair
growth or regrowth, cosmetic, skin care, wound care, dermatologic,
and other personal care applications, as well as in other
applications and industries.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 is a bottom perspective view of a device according to
the present invention.
[0008] FIG. 2 is a top perspective view of a portion of the handle
and housing of the device of FIG. 1.
[0009] FIG. 3 is a cross-sectional view of the device of FIG. 1
taken along cross-section indicators 3-3.
[0010] FIG. 4a. depicts the setup/apparatus for the Ultrasound
Pressure Measurement Test described in the Specification hereof
with the transducer positioned such that the propagation/direction
of the ultrasound wave is perpendicular silicone skin 22.
[0011] FIG. 4b. depicts the setup/apparatus for the Ultrasound
Pressure Measurement Test described in the Specification hereof
with the transducer positioned such that the propagation/direction
of the ultrasound wave forms an angle .theta. of about 15.degree.
relative to the planar surface of the silicone skin 22.
SUMMARY OF INVENTION
[0012] The present invention relates to an ultrasound device,
comprising: [0013] a.) a housing having bottom portion comprising
an application surface, [0014] b.) a power source positioned in the
housing; [0015] c.) an acoustic transducer positioned in the
housing in electrical communication with the power source for
producing ultrasound waves and oriented such that the ultrasound
waves are projected from the transducer at an angle .theta. of
other than 90.degree. relative to the surface of the application
surface.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The articles of the present invention can comprise, consist
of, or consist essentially of the essential elements and
limitations of the invention described herein, as well any of the
additional or optional features, components, or limitations
described herein.
[0017] The term "comprising" (and its grammatical variations) as
used herein is used in the inclusive sense of (and, interchangeably
with the terms) "having" or "including" and not in the exclusive
sense of "consisting only of" The terms "a" and "the" as used
herein are understood to encompass the plural as well as the
singular.
[0018] All documents incorporated herein by reference are only
incorporated herein to the extent that they are not inconsistent
with this specification.
[0019] As used herein, "active benefit agent" is a compound (e.g.,
a synthetic compound or a compound isolated from a natural source)
that has a cosmetic or therapeutic effect on tissue (e.g., a
material capable of exerting a biological effect on the human or
mammalian body) such as therapeutic drugs or cosmetic agents.
Examples of benefit agents include small molecules, peptides,
proteins, nucleic acid materials, and nutrients such as minerals
and extracts. The amount of the benefit agent used will depend on
the benefit agent and/or the intended use of the end product.
Benefit agents may be liquid, solid, or semi-solid.
[0020] As used herein, "pharmaceutically acceptable," "cosmetically
acceptable," or "dermatologically acceptable" means suitable for
use in contact with tissues (e.g., the skin (including scalp),
hair, mucosa, epithelium or the like) without undue toxicity,
incompatibility, instability, irritation, or allergic response.
[0021] As used herein, "safe and effective amount" means an amount
sufficient to provide a desired benefit at a desired level, but low
enough to avoid serious side effects. The safe and effective amount
of the ingredient or composition will vary with the area being
treated, the age of the end user, the duration and nature of the
treatment, the specific ingredient or composition employed, the
particular carrier utilized, and like factors.
[0022] As used herein, "targeted delivery" means that the depth of
skin penetration of a benefit agent is controlled for improved
efficacy and safety.
[0023] As used herein, the term "treating" or "treatment" means the
alleviation or elimination of symptoms, cure, prevention, or
inhibition of a disease or medical condition, or improvement of
tissue growth/healing or cosmetic conditions such as reducing
appearance of skin wrinkles/fine lines, under-eye bags, cellulites,
skin marks/hyperpigmentation or uneven tone, promotion of hair
growth or regrowth, or reduction of pain or inflammation.
[0024] As used herein, the term "visual inspection" means that a
human viewer can visually discern the presence of hair or hair
growth with the unaided eye (excepting standard corrective lenses
adapted to compensate for near-sightedness, farsightedness, or
stigmatism, or other corrected vision) in lighting at least equal
to the illumination of a standard 75 watt incandescent white light
bulb at a distance of about 0.25 meter.
[0025] In certain embodiments, the present invention as disclosed
herein may be practiced in the absence of any component, element
(or group of components or elements) or method step which is not
specifically disclosed herein.
[0026] In certain embodiments, the Device 1 includes a housing 2
having bottom portion 3, the bottom portion 3 having a periphery 4
defining a housing opening 5, the edges of periphery 4 forming a
planar (or substantially planar) application surface 6. Optionally,
a handle 9 is attached to housing 2. The outer side of planar
application surface 6 faces in the direction 7 (i.e., towards an
application surface such as a user's skin). In some embodiments,
the application surface 6 is adapted to lie on and be parallel with
(or substantially parallel with) with the planar surface formed by
the skin surface of a user. In certain embodiments, the device
comprises a transducer 8 and a power source (not shown) for
providing electrical power to the transducer 8 through an
electrical drive circuit (not shown). The power source should be
chosen so as to create cavitation bubbles (as described below) in
an ultrasound propagating media. In certain embodiments, the power
source capable of providing electronic signal power of from about
0.1 W to about 100 W, preferably from about 1 W to about 20 W. In
certain embodiments, the various components of the device 1 are
connected using cable/wiring 12. In one embodiment, the transducer
8, power source and an electrical drive circuit are disposed within
the housing 2. In other embodiments, the transducer 8 is disposed
within housing 2 and the power source and optional electrical drive
circuit are disposed within the handle 9. In the case of a cordless
device, the power source is a battery (such as a rechargeable
lithium ion battery or a non-rechargeable battery) or, in the case
of corded devices, the power source is an AC current provided from
a source voltage (e.g., electrical wall outlet) through an
electrical power line cord. In certain embodiments, a rectifier or
other means may be employed to convert AC current to DC.
[0027] In certain embodiments, the power may further flow through
an optional timing controller (not shown) prior to the electrical
drive circuit. The power may also flow to an optional vibrating
motor (not shown). When used, the timing controller provides
timing, motor control, and various control functions for the device
1 and is connected to an electrical drive circuit, which optionally
includes an acoustic module drive circuit to provide the necessary
electrical drive to the transducer 8. When present, the electrical
drive circuit may be further connected to a motor drive, which
provides electrical power to the motor. The motor is not strictly
required, and is provided to vibrate the therapy head (i.e., the
transducer 8) to provide a pleasant massaging effect. Further,
vibrating the head can help disperse the product on the skin. The
electrical drive circuit is further connected to electrical
contacts, which connect to a removable transducer compartment,
providing electrical contact between the transducer and the
electrical drive circuit. The housing 2 (or optional compartments
for the above components) may be molded from conventional plastics
known in the art. Suitable plastics include polyethylene, nylon,
polypropylene and the like.
[0028] Transducers 8 useful herein are well known in the art.
Suitable transducers for use in devices according to the present
invention generate acoustic energy. The acoustic energy employed
has a frequency ranging from 20 kHz or (about 20 kHz) to 3000 kHz
(or about 3000 kHz), optionally from 100 kHz (or about 100 kHz) to
1000 kHz (or about 1000 kHz), or optionally from 250 kHz (or about
250 kHz) to 750 kHz (or about 750 kHz). The transducer is
positioned in the housing 2 in electrical communication with the
power source and the optional electrical drive circuit, for
generating or producing ultrasound waves 11 and transducer 8 is
oriented such that the ultrasound waves 11 are projected from the
transducer 8 and through the opening 5 at an angle .theta. (as
shown in FIG. 3) other than at 90.degree. (or other than
perpendicular), or less than 90.degree., relative to the
application surface 6. Suitable angles .theta., at which the
ultrasound waves 11 are projected/directed, range from 5.degree. to
75.degree., optionally from 10.degree. to 75.degree., optionally
10.degree. to 60.degree., optionally 10.degree. to 45.degree.,
optionally, 15.degree. to 30.degree. relative to the application
surface. In certain embodiments, the angle .theta. at which the
ultrasound waves 11 are projected/directed is selected from the
group consisting of 15.degree., 45.degree., 60.degree. and
75.degree..
[0029] In certain embodiments, the transducer 8 is oriented such
that the ultrasound waves 11 are projected from the transducer 8
and through the opening 5 at an angle .theta. (as shown in FIG. 3)
other than at 90.degree. (or other than perpendicular), or less
than 90.degree., relative to the application surface 6 and is
maintained in such orientation for such projection of ultrasound
waves 11 for from at least 50% (or about 50%), optionally 60% (or
about 60%), optionally 70% (or about 70%), optionally 80% (or about
80%), optionally 90% (or about 90%), or optionally 95% (or about
95%) to, in each case, 100% (or about 100%) of the time period
during which the ultrasound is applied. In certain embodiments, the
transducer 8 is oriented such that the ultrasound waves 11 are
projected from the transducer 8 and through the opening 5 at an
angle .theta. (as shown in FIG. 3) other than at 90.degree. (or
other than perpendicular), or less than 90.degree., relative to the
application surface 6 and is maintained in such orientation for
such projection of ultrasound waves 11 for during the entire time
the ultrasound is applied.
[0030] In certain embodiments, traditional ultrasound devices such
as described in previously incorporated by reference United States
Patent application 2009/0318852 may be used in practicing the
methods of use of the present invention so long as the transducer
is orientated relative to a surface (such as, for example, the
surface or mammalian skin and/or scalp) such that the generated
ultrasound waves 11 are projected at an angle .theta. other than at
90.degree. relative to that surface.
[0031] Ultrasound is useful for providing a variety of skin
benefits, including acne treatment, scar reduction, dermabrasion
and pre-conditioning or preparing the skin for the delivery of
topical actives into skin in the appropriate frequency range. This
is due to ultrasounds' creating cavitation bubbles in the topical
composition in which the ultrasound waves propagate. Once the above
described cavitation bubbles are formed, they migrate towards the
surface of the skin and, due to their unstable nature, implode,
generating "micro-jets" that act as fluid micro-needles which
enhance the penetration of the active benefit agents through the
skin surface The depth of penetration of these micro jets increases
as the frequency of the ultrasound decreases due to the fact that,
at lower frequencies, the size of the cavitation bubbles increases,
packing larger quantities of energy that is conveyed to the tissue
at the moment of the implosion. This cavitation effect may lead to
breaks in the skin surface uniformity through the creation of
micro-lesions. The term "micro-lesions", as used herein, means
discrete lesions caused by implosion of the cavitation bubbles, and
not a wide surface lesion. The present inventors have found that,
because the volume and surface density of the cavitation bubbles
depends on the frequency and power density alone, the position of
the ultrasonic transducer viz-a-viz the skin has a limited
influence on sonophoresis efficiency and outcome. Accordingly, the
transducer can be positioned to avoid directing the generated
ultrasonic energy perpendicular to the skin (and, hence, reduce any
negative effects associated with such perpendicularly directed
energy).
[0032] Ultrasound has also been utilized therapeutically to
accelerate connective tissue healing for a very long time, and its
direct effects on extracellular matrix and cell proliferation have
also been evaluated. Pre-clinical studies have indicated that
ultrasound can stimulate collagen and elastin synthesis in tendon
fibroblasts in response to in-vitro conditions that mimic an injury
of the connective tissue matrix. Additionally, ultrasound has been
shown to stimulate cell division during periods of rapid cell
proliferation and confirmed by other studies which have found
increased cell proliferation in fibroblasts with ultrasound.
[0033] Pulsed-Low Intensity Ultra Sound (PLIUS) has been shown to
induce collagen, and elastin production in fibroblasts, and also
increase levels of Glycosaminoglycans. Furthermore, low-intensity
ultrasound can aid the repair of damaged cartilage by reducing the
expression of matrix metalloproteases MMP-3, 7, 13, inhibit the
secretion of NO, and promote the synthesis of collagen and
proteoglycan in cartilage. Taken cumulatively, these results
suggest that ultrasound may improve extracellular matrix
production.
[0034] Additional benefits may be achieved by using surfactants in
conjunction with ultrasound. This synergism is possibly due to the
dual benefit of stratum corneum disruption by the surfactants along
with the cavitation effect provided by ultrasound.
[0035] Notably, the use of harsh surfactants or high energy probes
can irreversibly damage the skin losing its ability to stabilize or
heal itself post treatment. The device of the present invention
provides improved safety over ultrasound devices and methods which
deliver ultrasound energy directionally perpendicular to the skin
with (or without) formulations containing alcohol, surfactants and
other emulsifiers, substantially reducing the amount of energy
delivered under the skin.
[0036] Additionally, ultrasound is useful in breaking-down of
melanin granules. Melanin present in skin helps in attenuating UV
and visible radiation. The melanin is associated with such skin
optical properties as light scattering; such skin optics aid in
understanding skin health, physiology and pigmentation.
Hyperpigmentation is a skin condition which is caused by excess
production of melanin due to hormonal changes, excess sun exposure
etc. To treat hyperpigmentation, typically topical treatments like
alpha hydroxyl acids, retinoids, have been used as peels, masks or
lotions to reduce pigmentation. Breaking-down melanin granules into
smaller particles enables easier removal through skin exfoliation
which can potentially modify the skin's optical properties and
attenuate hyperpigmentation.
[0037] Without being limited by theory, the present inventers
believe that by directing ultrasound wave to the skin surface at
angles other than at 90.degree. relative to the application
surface, transducer frequency ranges of 20 kHz or (about 20 kHz) to
3000 kHz (or about 3000 kHz), optionally from 100 kHz (or about 100
kHz) to 1000 kHz (or about 1000 kHz), or optionally from 250 kHz
(or about 250 kHz) to 750 kHz (or about 750 kHz) can be utilized to
enhance or improve the above mentioned ultrasound skin benefits
while preventing and/or reducing any negative, detrimental or
otherwise harmful effects on a user's skin (where ultrasound
application as occurred).
[0038] In certain embodiments, the ultrasound waves or energy
projected/directed to the application surface (e.g., skin surface)
at an angle .theta. (as shown in FIG. 3) other than at, or less
than, 90.degree. relative to the application surface by the device
and methods of the present invention generate an ultrasound
pressure which is lower than, optionally at least a 5 fold lower
than, optionally 10 fold lower than, optionally 15 fold lower than
the ultrasound pressure generated by ultrasound waves or energy
projected/directed to the application surface at an angle .theta.
of 90.degree. (or perpendicular) relative to the application
surface when measured, in each case, using the Ultrasound Pressure
Measurement Test described below. The higher the ultrasound
pressure under the skin, the more tissue damage occurs under the
skin.
[0039] In certain embodiments, the device and methods of the
present invention are used to improve skin penetration of benefit
agents.
[0040] A topical composition useful for propagation of ultrasound
waves to and from an ultrasound device is preferably used in
conjunction with the ultrasound device to facilitate transmission
of ultrasound energy between the device and the skin surface. The
topical composition may take the form of a wide variety of water or
water-based products that include, but are not limited to,
conventional leave-on products (such as water, liquids, lotions,
creams, gels, sticks, sprays, and ointments), skin cleansing
products (such as liquid washes, solid bars, and wipes), hair
products (such as shampoos, conditioners, sprays, and mousses),
film-forming products (such as masks) and the like. These product
types may contain any of several cosmetically- or
pharmaceutically-acceptable carrier forms including, but not
limited to solutions, suspensions, emulsions such as microemulsions
and nanoemulsions, gels, and solids carrier forms. Other product
forms can be formulated by those of ordinary skill in the art. In
certain embodiments, the topical composition is substantially free
of (or free of) air bubbles in order to ensure good ultrasound
transmission. The topical composition can include or not include
(i.e., be free of) an active benefit agent.
[0041] In certain embodiments, the topical composition further
comprises an active benefit agent for topical administration to a
subject (e.g., a human) in need of treatment for a condition or
disease treatable by such active benefit agent, or to otherwise
provide the therapeutic effect associated with the active benefit
agent. Such therapeutic effects include, but are not limited to:
antimicrobial effects (e.g., antibacterial, antifungal, antiviral,
and anti-parasitic effects); anti-inflammation effects including
effects in the superficial or deep tissues (e.g., reduce or
elimination of soft tissue edema or redness); elimination or
reduction of pain, itch or other sensory discomfort; regeneration
or healing enhancement of hard tissues (e.g., enhancing growth rate
of the nail or regrowth of hair loss due to alopecia) or increase
soft tissue volume (e.g., increasing collagen or elastin in the
skin or lips); increasing adipocyte metabolism or improving body
appearance (e.g., effects on body contour or shape, and cellulite
reduction); and increasing circulation of blood or lymphocytes. The
topical composition (with or without the benefit agent, may be
spread directly by the fingers and then the ultrasound may be
applied by the devices according to the present invention for a
period of time sufficient to provide targeted delivery of the
benefit agent. The period of time may vary from about 5 seconds to
about 1 minute, or optionally from about 20 seconds to about 40
seconds. Alternatively, the composition may be applied to one area
of the skin and spread out through contact with devices according
to the present invention and a spreading motion of the device.
[0042] In one embodiment, a composition contains a safe and
effective amount of an active benefit agent, for example, from
about 0.001 percent to about 20 percent, such as from about 0.01
percent to about 10 percent, by weight of the composition of the
active benefit agent.
[0043] In one embodiment, the topical composition contains at least
one benefit agent useful for the treatment of skin conditions
(including scalp conditions). Examples of such skin conditions
include, but are not limited to acne (e.g., blackheads and
whiteheads), rosacea, nodule-cystic, and other microbial infections
of the skin; visible signs of skin aging (e.g., wrinkles, sagging,
sallowness, and age-spots); loose or lax skin, folliculitis and
pseudo-folliculitis barbae; excess sebum (e.g., for sebum reduction
or oily/shining skin appearance inhibition or control);
pigmentation (e.g., for reduction of hyperpigmentation such as
freckles, melasma, actinic and senile lentigines, age-spots,
post-inflammatory hypermelanosis, Becker's naevus, and facial
melanosis or enhancing the pigmentation of light skin); excess hair
growth (e.g., skin on the leg), or insufficient hair growth (e.g.,
on the scalp, such as in hypotrichosis [e.g., the scalp condition
alopecia]); dermatitis (e.g., atopic, contact, or seborrheic
dermatitis), dark circles under the eye, stretch marks, cellulite,
excessive sweating (e.g., hyperhidrosis), and/or psoriasis.
(a) Topical Anti-Acne/Anti-Rosacea Compositions
[0044] In one embodiment, the topical composition also contains an
anti-acne and/or anti-rosacea active benefit agent. Examples of
anti-acne and anti-rosacea active benefit agents include, but are
not limited to: benzoyl peroxide; sulfur; retinoids such as
tretinoin, isotretinoin, motretinide, adapalene, tazarotene,
azelaic acid, and retinol; salicylic acid; resorcinol;
sulfacetamide; urea; antibiotics such as tetracycline, clindamycin,
metronidazole, and erythromycin; anti-inflammatory agents such as
corticosteroids (e.g., hydrocortisone), ibuprofen, naproxen, and
hetprofen; and imidazoles such as ketoconazole and elubiol; and
salts and prodrugs and mixtures thereof. Other examples of
anti-acne active benefit agents include essential oils,
alpha-bisabolol, dipotassium glycyrrhizinate, camphor,
.beta.-glucan, allantoin, feverfew, flavonoids such as soy
isoflavones, saw palmetto, chelating agents such as EDTA, lipase
inhibitors such as silver and copper ions, hydrolyzed vegetable
proteins, inorganic ions of chloride, iodide, fluoride, and their
nonionic derivatives chlorine, iodine, fluorine, and synthetic
phospholipids and natural phospholipids such as ARLASILK.TM.
phospholipids CDM, SV, EFA, PLN, and GLA (commercially available
from Croda, Edison, USA).
(b) Topical Anti-Aging Compositions
[0045] In one embodiment, the topical composition also contains an
anti-aging active benefit agent. Examples of suitable anti-aging
active benefit agents include, but are not limited to; cross-linked
hyaluronic acid; retinoids; dimethylaminoethanol (DMAE), copper
containing peptides, vitamins such as vitamin E, vitamin A (retinol
and its derivatives, e.g., retinyl palmitate), vitamin C (ascorbic
acid and its derivative, e.g., Ascorbic Acid 2-Glucoside/AA2G), and
vitamin B (e.g., niacinamide, niacin) and vitamin salts or
derivatives such as ascorbic acid di-glucoside and vitamin E
acetate or palmitate; alpha hydroxy acids and their precursors such
as glycolic acid, citric acid, lactic acid, malic acid, mandelic
acid, ascorbic acid, alpha-hydroxybutyric acid,
alpha-hydroxyisobutyric acid, alpha-hydroxyisocaproic acid,
atrrolactic acid, alpha-hydroxyisovaleric acid, ethyl pyruvate,
galacturonic acid, glucoheptonic acid, glucoheptono 1,4-lactone,
gluconic acid, gluconolactone, glucuronic acid, glucuronolactone,
isopropyl pyruvate, methyl pyruvate, mucic acid, pyruvic acid,
saccharic acid, saccharic acid 1,4-lactone, tartaric acid, and
tartronic acid; beta hydroxy acids such as beta-hydroxybutyric
acid, beta-phenyl-lactic acid, and beta-phenylpyruvic acid;
tetrahydroxypropyl ethylene-diamine,
N,N,N',N'-Tetrakis(2-hydroxypropyl)ethylenediamine (THPED); and
botanical extracts such as green tea, soy, milk thistle, algae,
aloe, angelica, bitter orange, coffee, goldthread, grapefruit,
hoellen, honeysuckle, Job's tears, lithospermum, mulberry, peony,
puerarua, nice, and safflower; and salts and prodrugs and mixtures
thereof
(c) Topical Depigmentation Compositions
[0046] In one embodiment, the topical composition contains a
depigmentation active benefit agent. Examples of suitable
depigmentation active benefit agents include, but are not limited
to: soy extract; soy isoflavones; retinoids such as retinol; kojic
acid; kojic dipalmitate; hydroquinone; arbutin; transexamic acid;
vitamins such as niacinamide, niacin and vitamin C (ascorbic acid
and AA2G; azelaic acid; linolenic acid and linoleic acid;
placertia; licorice; and extracts such as chamomile, grape seeds
and green tea; natural actives (e.g., Un-denatured soy, mulberry,
paper mulberry (family Moraceae, Broussonetia kazinokiB
papyrifera), isoflavones, feverfew, goji berry, milk thistle
extract, amaranth oil, pomegrenate, yerbe mate, white lily flower
extract, olive leaf extract, phloretin and mixtures thereof), and
salts and prodrugs and mixtures thereof
(d) Topical Antipsoriatic Compositions
[0047] In one embodiment, the topical composition contains an
antipsoriatic active benefit agent. Examples of antipsoriatic
active benefit agents (e.g., for use as a seborrheic dermatitis
treatment) include, but are not limited to, corticosteroids (e.g.,
betamethasone dipropionate, betamethasone valerate, clobetasol
propionate, diflorasone diacetate, halobetasol propionate,
triamcinonide, dexamethasone, fluocinonide, fluocinolone acetonide,
halcinonide, triamcinolone acetate, hydrocortisone, hydrocortisone
verlerate, hydrocortisone butyrate, aclometasone dipropionte,
flurandrenolide, mometasone furoate, methylprednisolone acetate),
methotrexate, cyclosporine, calcipotriene, anthraline, shale oil
and derivatives thereof, elubiol, ketoconazole, coal tar, salicylic
acid, zinc pyrithione, selenium sulfide, sulfur, menthol, and
pramoxine hydrochloride, and salts and prodrugs and mixtures
thereof
(e) Topical Hair Growth or Regrowth Actives
[0048] In one embodiment, the topical composition contains hair
growth or hair regrowth active benefit agent for growing or
thickening hair of the scalp, eye brow or eye lash, may be used to
treat hair conditions (such as hypotrichosis) topically. Such hair
growth/regrowth agents stimulate hair growth and/or prevent hair
loss. Examples of hair growth or hair regrowth active benefit
agents include, but are not limited to, potassium channel opener,
ATP-sensitive potassium channel, minoxidil, diazoxide or phenytoin,
5.alpha.-reductase inhibitors, finasteride, dutasteride (e.g.
Avodart), turosteride, bexlosteride, izonsteride, epristeride,
epigallocatechin, 5.alpha.-reductase type 1 inhibitor, azelaic
acid, and SKF 105, 111, ketoconazole, fluconazole, spironolactone,
flutamide, diazoxide, 17-.alpha.-hydroxyprogesterone,
11-.alpha.-hydroxyprogesterone, RU58841, fluridil, or QLT-7704, an
antiandrogen oligonucleotide, a prostaglandin F2.alpha. analogs,
prostaglandin analogs, a prostaglandin, Latisse and Lumigan (RTM:
Bimatoprost), Xalatan (RTM: Latanoprost), Travatan (RTM:
Travoprost), tafluprost, unoprostone, Prostin F2 Alpha (RTM:
dinoprost), (2S)-3-((1,
1'-biphenyl)-4-ylsulfonyl)-N-((R)-phenyl(2-pyridinyl)methyl)-1,
3-thiazolidine-2-carboxamide, BOL303259X, PF3187207, Hemabate (RTM:
Carboprost), Keranique (RTM: Kopexil), calcium chloride, botilinum
toxin A, adenosine, DoxoRx (RTM: Not defined), docetaxel,
tacrolimus, GP11046, GP11511, LGD 1331, ICX-TRC,
methanethiosulfonate-01 (MTS-01), NEOSH1O1, HYG-102440, HYG-410,
HYG-420, HYG-430, HYG-440, spironolactone, cortexolone
17a-propionate, RK-023, abatacept, Viviscal (RTM: Natural dietary
supplement), morrF, ASC-J9 (RTM: (3Z, 5E)-6-(3,
4-dimethoxyphenyl)-4-hydroxyhexa-3, 5-dien-2-one), NP-619, ammonium
trichloro(dioxoethylene-o, o')tellurate, metron-F1, PSK 3841,
targretin (RTM: Bexarotene), MedinGel (RTM: Biodegradable drug),
PF3187207, BOL303259X, (2S)-3-((1,
1'-biphenyl)-4-ylsulfonyl)-N-((R)-phenyl(2-pyridinyl)methyl)-1,
3-thiazolidine-2-carboxamide, THG11331, PF-277343, PF-3004459,
raptiva, caffeine, coffee, a herb (e.g. saw palmetto, glycine soja,
Panax ginseng, Castanea Sativa, Arnica Montana, Hedera Helix and
Geranium maculatum), triamcinolone acetonide, a topical irritant
(e.g. anthralin) or sensitizer (e.g. squaric acid dibutyl ester or
diphenyl cyclopropenone), clomipramine, unsaturated fatty acids
(e.g. gamma linolenic acid), a fatty acid derivative, salts thereof
and mixtures thereof
(e) NonSteroidal Anti-Inflammatory Agents
[0049] In one embodiment, the topical composition contains certain
analgesic active benefit agents and as such may be prepared for
topical treatment of pain, such as pain at or from the back,
shoulder, joints, muscle sore/pain, menstrual cramps, or pain from
cold sore or canker sore. Such benefit agents to relieve pain
include, but are not limited to, NonSteroidal Anti-Inflammatory
Drugs (NSAIDs) such as ibuprofen, naproxen, salicylic acid,
ketoprofen, and diclofenac and pharmaceutically acceptable salts
thereof. Other topical analgesic active benefit agents for treating
pain and itch include, but are not limited to, methyl salicylate,
menthol, trolamine salicylate, capsaicin, lidocaine, benzocaine,
pramoxine hydrochloride, and hydrocortisone.
(f) Other Topical Ingredients
[0050] In one embodiment, the topical composition contains a plant
extract as the active benefit agent. Examples of plant extracts
include, but are not limited to, feverfew, soy, glycine soja,
oatmeal, what, aloe vera, cranberry, witch-hazel, alnus, arnica,
artemisia capillaris, asiasarum root, birch, calendula, chamomile,
cnidium, comfrey, fennel, galla rhois, hawthorn, houttuynia,
hypericum, jujube, kiwi, licorice, magnolia, olive, peppermint,
philodendron, salvia, sasa albo-marginata, natural isoflavonoids,
soy isoflavones, and natural essential oils.
[0051] In certain embodiments, any of the above described active
benefit agents may be used in combination.
[0052] In certain embodiments, the topical compositions of the
present invention also include sebum miscible compounds for
improving transport of the active benefit agent through sebum
and/or aiding in the cleansing of hair follicles. Suitable sebum
miscible compound include compounds selected from C.sub.10 to
C.sub.35, (optionally C.sub.10-C.sub.22) alkyl lactates such as the
following C.sub.10-C.sub.18 alkyl lactates: cetyl lactate, myristyl
lactate, glyceryl stearate lactate or C.sub.12-C.sub.15 alkyl
lactate and the like and mixtures thereof; volatile silicones such
as Dow Corning--345 fluid, DC 200 fluid, and those described in
U.S. Pat. No. 5,084,577, fatty acid esters (e.g. octyl
isononanoate, octyl palmitate, Isodecyl oleate, propylene
dicaprylate), liquid fatty alcohols (e.g. oleyl alcohol), aromatic
alcohols such as phenyl alcohols with chemical structures of
C.sub.6H.sub.5--R(OH) where R is an aliphatic radical, such as
benzyl alcohol and phenethyl alcohol; aromatic glycol ethers such
as ethylene glycol phenyl ether; propylene or butylene oxide-based
glycol ethers such as propylene glycol methyl ether and those
disclosed in U.S. Pat. No. 5,133,967, incorporated herein by
reference in its entirety; fatty acids, polyunsaturated fatty acids
such as linoleic acid, linolenic acid, stearidonic acid, plant,
fruit, or marine derived extracts rich in essential fatty acid or
polyunsaturated fatty acids such as but not limited to vaccinium
myrtillus (bilberry) seed oil, vaccinium macrocarpon (cranberry)
seed oil, vaccinium vitis-idaea (lingonberry) seed oil, rubus
idaeus (raspberry) seed oil, rubus chamaemorus (cloudberry) seed
oil, ribes nigrum (black currant) seed oil, hippophae rhamnoides
(sea buckthorn) seed oil, echium plantagineum (echium) seed oil,
hordeum vulgare (barley) seed oil, betula alba bud extract, saw
palmetto extract, borage oil, evening primrose oil, soy oil; cetyl
ocenate; isostearyl benzoate; pentaerythiol teraoctenate;
isostearyl benzoate; and combinations thereof. In certain
embodiments, the sebum miscible compound of the present invention
is selected from the group consisting of C.sub.12-C.sub.15 alkyl
lactates, myristyl lactate, cetyl lactate, glyceryl stearate
lactate, ethylene glycol phenyl ether; propylene or butylene
oxide-based glycol ethers, volatile silicones and mixtures thereof.
In certain embodiments, the sebum miscible compound of the present
invention is selected from the group consisting of
C.sub.12-C.sub.15 alkyl lactates, cetyl lactate, myristyl lactate
or mixtures thereof
[0053] In certain embodiments, the sebum miscible compound is
present in the topical composition in an amount of from 0.5% (or
about 0.5%) to 5% (or about 5%), optionally, from 1.0% (or about
1.0%) to 4% (or about 4%), or, optionally, from 1.5% (or about
1.5%) to 3% (or about 3%), by weight of the composition.
[0054] In certain embodiments, the sebum miscible compound is
incorporated in the ultrasound wave propagating topical composition
without further incorporation of an active benefit agent for
purposes of cleansing, or aiding in the cleansing, of skin pores,
hair follicles or other openings/crevasses in the skin.
Alternatively, the sebum miscible compound is incorporated in the
ultrasound wave propagating topical composition with an active
benefit agent for purposes of cleansing the skin openings and
improving transport of the active benefit agent to (and through)
skin surface.
[0055] In an embodiment of the present invention, the ratio of the
active benefit agent to the sebum miscible compound is from 10:1
(or about 10:1) to 1:1 (or about 1:1), optionally 5:1 (or about
5:1) to 1:1 (or about 1:1), optionally 3:1 (or about 3:1) to 1:1
(or about 1:1), or optionally 2:1 (or about 2:1).
[0056] In one embodiment, the topical composition contains one or
more buffering agents such as citrate buffer, phosphate buffer,
lactate buffer, gluconate buffer, or gelling agent, thickener, or
polymer.
[0057] In one embodiment, the composition or product contains a
fragrance effective for reducing stress, calming, and/or affecting
sleep such as lavender and chamomile.
[0058] In one embodiment, the composition is applied into wounds to
provide healing enhancement or scar prevention. Wounds or lesions
that may be treated include, but are not limited to acute wounds as
well as chronic wounds including diabetic ulcer, venus ulcer, and
pressure sores.
[0059] The composition may include an antifungal drug or an
antibiotic as the active benefit agent. Examples of antifungal
drugs include but are not limited to miconazole, econazole,
ketoconazole, sertaconazole, itraconazole, fluconazole,
voriconazole, clioquinol, bifoconazole, terconazole, butoconazole,
tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole,
undecylenic acid, haloprogin, butenafine, tolnaftate, nystatin,
ciclopirox olamine, terbinafine, amorolfine, naftifine, elubiol,
griseofulvin, and their pharmaceutically acceptable salts and
prodrugs. In one embodiment, the antifungal drug is an azole, an
allylamine, or a mixture thereof.
[0060] Examples of antibiotics (or antiseptics) include but are not
limited to mupirocin, neomycin sulfate bacitracin, polymyxin B,
1-ofloxacin, tetracyclines (chlortetracycline hydrochloride,
oxytetracycline-10 hydrochloride and tetrachcycline hydrochloride),
clindamycin phosphate, gentamicin sulfate, metronidazole,
hexylresorcinol, methylbenzethonium chloride, phenol, quaternary
ammonium compounds, tea tree oil, and their pharmaceutically
acceptable salts and prodrugs.
[0061] Examples of antimicrobials that may be useful in the
composition include but are not limited to salts of chlorhexidine,
such as lodopropynyl butylcarbamate, diazolidinyl urea,
chlorhexidene digluconate, chlorhexidene acetate, chlorhexidene
isethionate, and chlorhexidene hydrochloride. Other cationic
antimicrobials may also be used, such as benzalkonium chloride,
benzethonium chloride, triclocarbon, polyhexamethylene biguanide,
cetylpyridium chloride, methyl and benzethonium chloride. Other
antimicrobials include, but are not limited to: halogenated
phenolic compounds, such as 2,4,4',-trichloro-2-hydroxy diphenyl
ether (Triclosan); parachlorometa xylenol (PCMX); and short chain
alcohols, such as ethanol, propanol, and the like. In one
embodiment, the alcohol is at a low concentration (e.g., less than
about 10% by weight of the carrier, such as less than 5% by weight
of the carrier) so that it does not cause undue drying of the
barrier membrane.
[0062] Examples of anti-viral agents that may be useful as the
active benefit agent in the topical composition for such viral
infections as herpes and hepatitis, include, but are not limited
to, imiquimod and its derivatives, podofilox, podophyllin,
interferon alpha, acyclovir, famcyclovir, valcyclovir, reticulos
and cidofovir, and salts and prodrugs thereof.
[0063] Examples of anti-inflammatory agents that may also be useful
as the active benefit agent in the topical composition include, but
are not limited to, suitable steroidal anti-inflammatory agents
such as corticosteroids such as hydrocortisone,
hydroxyltriamcinolone alphamethyl dexamethasone,
dexamethasone-phosphate, beclomethasone dipropionate, clobetasol
valerate, desonide, desoxymethasone, desoxycorticosterone acetate,
dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone
valerate, fluadrenolone, fluclarolone acetonide, fludrocortisone,
flumethasone pivalate, fluosinolone acetonide, fluocinonide,
flucortine butylester, fluocortolone, fluprednidene
(fluprednylidene)acetate, flurandrenolone, halcinonide,
hydrocortisone acetate, hydrocortisone butyrate,
methylprednisolone, triamcinolone acetonide, cortisone,
cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,
fluradrenalone acetonide, medrysone, amciafel, amcinafide,
betamethasone, chlorprednisone, chlorprednisone acetate,
clocortelone, clescinolone, dichlorisone, difluprednate,
flucloronide, flunisolide, fluoromethalone, fluperolone,
fluprednisolone, hydrocortisone valerate, hydrocortisone
cyclopentylproprionate, hydrocortamate, meprednisone,
paramethasone, prednisolone, prednisone, beclomethasone
dipropionate, betamethasone dipropionate, triamcinolone, and salts
are prodrugs thereof. In one embodiment, the steroidal
anti-inflammatory for use in the present invention is
hydrocortisone. A second class of anti-inflammatory agents which is
useful in the compositions of the present invention includes the
nonsteroidal anti-inflammatory agents.
[0064] Examples of wound healing enhancing agents that may be
useful as the active benefit agent in the topical composition
include platelet rich plasma (i.e., plasma having a platelet
concentration of at least 1 million per microliter), recombinant
human platelet-derived growth factor (PDGF) and other growth
factors, ketanserin, iloprost, prostaglandin El and hyaluronic
acid, scar reducing agents such as mannose-6-phosphate, analgesic
agents, anesthetics, hair growth retarding agents such as
eflornithine hydrochloride, antihypertensives, drugs to treat
coronary artery diseases, anticancer agents, endocrine and
metabolic medication, neurologic medications, medication for
cessation of chemical additions, motion sickness, protein and
peptide drugs. In certain embodiments of the present invention, the
platelet rich plasma, recombinant human platelet-derived growth
factor (PDGF) and other growth factors are also useful as hair
growth or regrowth agents.
[0065] In one embodiment, the composition is used, with or without
other antifungal active agents, to treat or prevent fungal
infections (e.g., dermatophytes such as trichophyton
mentagrophytes), including, but not limited to, onychomycosis,
sporotrichosis, tinea unguium, tinea pedis (athlete's foot), tinea
cruris (jock itch), tinea corporis (ringworm), tinea capitis, tinea
versicolor, and candida yeast infection-related diseases (e.g.,
candida albicans) such as diaper rash, oral thrushm, cutaneous and
vaginal candidiasis, genital rashes, Malassezia furfur
infection-related diseases such as Pityriasis versicolor,
Pityriasis folliculitis, seborrhoeic dermatitis, and dandruff.
[0066] In another embodiment, the topical composition is used, with
or without other antibacterial active agents, to treat and prevent
bacterial infections, including, but not limited to, acne,
cellulitis, erysipelas, impetigo, folliculitis, and furuncles and
carbuncles, as well as acute wounds and chronic wounds (venous
ulcers, diabetic ulcers and pressure ulcers).
[0067] In another embodiment, the topical composition is used, with
or without other antiviral active agents, to treat and prevent
viral infections of the skin including, but not limited to,
molluscum contagiosum and warts.
[0068] In another embodiment, the topical composition is used, with
or without other antiparasitic active agents, to treat and prevent
parasitic infections, including, but not limited to, hookworm
infection, lice, scabies, sea bathers' eruption and swimmer's
itch.
[0069] The composition can also be used to stimulate nail growth,
enhance nail strength, and reduce nail infection or discoloration.
The composition can be incorporated into compositions for the
treatment of onychomychosis with active benefit agents such as, but
not limited to miconazole, econazole, ketoconazole, sertaconazole,
itraconazole, fluconazole, voricoriazole, clioquinol, bifoconazole,
terconazole, butoconazole, tioconazole, oxiconazole, sulconazole,
saperconazole, clotrimazole, undecylenic acid, haloprogin,
butenafine, tolnaftate, nystatin, ciclopirox olamine, terbinafine,
amorolfine, naftifine, elubiol, griseofulvin, and their
pharmaceutically acceptable salts and prodrugs. The composition can
be incorporated into compositions for improving the look and feel
of nails with ingredients such as, but not limited to: biotin,
calcium panthotenate, tocopheryl acetate, panthenol, phytantriol,
cholecalciferol, calcium chloride, Aloe Barbadensis (Leaf Juice),
silk protein, soy protein, hydrogen peroxide, carbamide peroxide,
green tea extract, acetylcysteine and cysteine.
Method of Practicing
[0070] More specifically, in certain embodiments, the topical
compositions containing the active benefit agents of the present
invention are applied to the affected areas of the skin or scalp
(i.e., areas in need of treatment from the active benefit agents)
followed by application ultrasound at the area of application of
the topical composition. The ultrasound device is calibrated to
provide acoustic energy at a frequency ranging from about 20 kHz to
about 3000 kHz the head of the ultrasound comprising the transducer
is positioned over the area of application such the ultrasound
waves are directed towards the affected area at an angle .theta.
other than at 90.degree. (perpendicular) relative to the surface of
the affected area (or as further described herein above). Also, a
topical composition (with or without an active benefit agent) is
usually applied between the subject's skin for efficient
propagation of ultrasound waves to and from the transducer of the
ultrasound device. The duration of each application of ultrasound
acoustic energy ranges from about 5 seconds to about 1 minute. The
above method is repeated for at least two consecutive applications,
optionally, at least 2 consecutive applications at a frequency of
at least once daily.
[0071] In certain embodiments, the ultrasound devise can be
configured and/or sized for stationary application on the skin such
as by means of a "cap", "band", "wrap with attachable ends" or
"patch".
[0072] Several examples are set forth below to further illustrate
the nature of the invention and the manner of carrying it out.
However, the invention should not be considered as being limited to
the details thereof
EXAMPLES
[0073] Examples are set forth below to further illustrate the
nature of the invention and the manner of carrying it out. However,
the invention should not be considered as being limited to the
details thereof
Example 1
Ibuprofen Gel Preparation
[0074] A topical ibuprofen gel composition was prepared with the
ingredients in Table 1 below, following the procedures described
below.
TABLE-US-00001 TABLE 1 Ibuprofen Source of Gel Formulation No.
Ingredients Ingredient (weight %) 1 Ethyl Alcohol 20 2 Ibuprofen,
USP 5 3 Propylene glycol 2 4 Butylated hydroxytoluene (BHT) 0.1 5
Water, USP 69.1 6 Carbopol (Ultrez 30) 1 7 Triethylamine 2.8 Total
100
[0075] Procedure: Ingredients No. 1-4 were weighed into a container
and mixed until uniform. Ingredients Nos. 5 and 6 were weighed and
added, then mixed to form a uniform suspension. Ingredient 7 was
added under mixing until a uniform clear gel was formed with a
final gel pH of 6.8.
Example 2
[0076] The experimental setup to run sonophoresis (ultrasound)
studies with Franz cell diffusion cells consisted of a custom-built
universal generator capable of driving ultrasonic transducers in
the 20 kHz-2 MHz range with electronic power up to 60 W
(Voltage+/-30V, Current: 2 A, duty cycle 50%) with a square
waveform. The real power delivered to the transducer depended on
the specific experimental conditions and is specified for each
experiment. The driving waveform was delivered to the transducer
through a coaxial cable having a BNC connector at one end and a
custom non-coaxial connector at the transducer end.
[0077] The transducer was piezoelectric and had either a disk
shaped form (either 20 or 25 mm in diameter) or a rectangular shape
10.times.20 mm.sup.2). The thickness of the transducer depended on
its fundamental frequency being inversely proportional with it. In
order to prevent the liquid or the gel from perturbing the
electrical connection, each transducer was encapsulated in a
plastic case leaving only one side of the transducer exposed to the
topical composition. The case was made out of a rigid plastic and
the transducers were sealed with silicone adhesive to enable them
to oscilalte more or less freely. The case also enabled the
electrical connections to be isolated from the topical
composition.
[0078] For sonophoresis experiments where the ultrasonic wave
energy was delivered perpendicular to the skin, disk-shaped
transducers were used in the encapsulation setup described above.
For the angled ultrasound application the case encapsulating the
ultrasonic transducer was assembled in a hinged configuration,
enabling angles between 15 and 90 degrees (perpendicular). Note: an
angle of 0 degrees would send the ultrasonic wave parallel with the
skin surface.
[0079] In order to have a tight control over the experimental
conditions the following sequence was used in all the studies:
[0080] 1. Test the impedance/frequency parameters of the
encapsulated transducer with the help of an Agilent 4294A impedance
tester--which is the tester of choice for any ultrasonic material
and device in the industry and research. Parameters were recorded
and traced during the entire life of the transducer being measured
always before and after a study was performed.
[0081] The parameters of interest were: Series resonance value--it
should be the smallest possible for the given transducer; phase
angle below and after the series resistance--it should be the
closest possible to -90 degrees before and +90 degrees above the
series resonance frequency, and no parasitic resonances in the
capture band of the driver (the driver is capable to adjust its
frequency to the specific study parameters and needs "smooth" phase
transitions).
[0082] 2. Test the ultrasonic energy delivered to a specified
amount of water through the acoustic pressure method. The test
setup used a plastic dish placed on a scale in which the transducer
was lowered in the water keeping a fixed distance from the bottom
and being held at that fixed height by an external support (not in
contact with the scale). The transducer was driven with the
universal driver at the resonance frequency and the additional
weight produced by the acoustic pressure was recorded in
correlation with the electrical power. The method is a qualitative
one meant to characterize if the transducer works repeatedly.
[0083] 3. Study with the diffusion Franz cells at the specified
power and test conditions.
[0084] 4. Repeat the test with the ultrasonic energy--check against
the initial values.
[0085] 5. Repeat the test with the impedance tester--check against
the initial values.
In Vitro Skin Permeation Studies
[0086] Procedures of Ibuprofen Skin Permeation Studies with
Ultrasound or without Ultrasound:
[0087] In vitro skin permeation studies on 5% Ibuprofen gel
compositions without ultrasound (passive diffusion), or facilitated
by the application of ultrasound (sonophoresis), through human
cadaver skin were performed as follows:
[0088] A skin penetration study evaluated the penetration of
ibuprofen through the human skin for the inventive sample prepared
as disclosed in Example 1. A commercial ibuprofen gel product,
IBULEVE Ibuprofen Gel (by DDD ltd, Watford, Herts, WD18 7JJ, UK)
was used as a benchmark, which contains 5% W/W ibuprofen, also IMS
(Industrial Methylated Spirits), carbomer, propylene glycol,
diethylamine and purified water according to the product label on
its package. A well-known Franz diffusion cell method (taught in
US20020006418 A1 which is hereby incorporated by reference) was
used. Franz cells had a diameter of 3.0 cm, and surface area 7.07
cm.sup.2 for the donor cell, and a volume of receptor compartment
of 25 ml. A magnetic stirrer bar was added in the donor
compartment. The liquid receptor was filled with Phosphate-buffered
saline (PBS) solution. Air bubbles in the donor compartment were
removed. The system was thermostated at 37.degree. C. above a
magnetic stirrer to ensure the homogeneity of the liquid receptor
during the experiment. A human cadaver skin sample from a
commercial tissue bank (Ohio Valley Tissue and Skin Center,
Cincinnati, Ohio, dermatomed to approximately 0.4 mm) was cut to
fit the glass diffusion cell and the skin was mounted on the Franz
cell.
[0089] For the diffusion cells designated to be tested for passive
diffusion, a test gel sample of 0.2 ml was applied on the skin
surface. For the diffusion cells designated to test for
sonophoresis, additional test sample (2-5 ml) was added in order to
assure the entire, or at least a large portion, of the ultrasonic
transducer tip was immersed by the test gel during the ultrasound
treatment. The excess gel was promptly removed from the donor cell
after the ultrasound treatment so that the remaining test gel was
approximately 0.2 ml.
[0090] Ultrasound treatments were carried out with the following
test conditions: [0091] a) Conventional ultrasound treatment with
90 degree angle (.degree.) between the ultrasound direction and the
skin surface; [0092] b) Angled Ultrasound treatment with less than
90 degree angle between the ultrasound direction and the skin
surface.
[0093] Samples were collected from the receptor compartment at
pre-determined time points, e.g., 0, 0.5, 1, 2, 4, 6 and up to 24
hours. At the end of the study, samples collected from the receptor
compartments of the Franz cells were analyzed for ibuprofen levels
with a High-performance liquid chromatography (HPLC) system and the
amount of ibuprofen that penetrated across the skin layer was
calculated.
Ibuprofen Skin Permeation Results:
[0094] The results are shown in Tables 2-4. The final average of
the calculated ibuprofen levels in different skin layers are
reported in micrograms (.mu.g) for 3 different replicates.
[0095] Table 2 shows the ibuprofen skin permeation results from
Study 1, in which ultrasound treatment (UT) was applied, at a
signal power of 3 W, in such a way that the ultrasound transducer
delivered the ultrasound energy at a frequency of 700 kHz to the
skin surface with a 45 degree angle for one group of three
diffusion cells. For comparison purpose, another group of three
diffusion cells was run with passive diffusion without any
ultrasound treatment.
TABLE-US-00002 TABLE 2 Ibuprofen Diffusion (.mu.g) Time
Non-UT.sub.Gel 1 (Passive (hr) Diffusion with Gel 1) UT (Diffusion
with Non-UT.sub.Gel 2 (Passive Gel 1 and 45.degree. Diffusion with
Gel 2, Sonophoresis) IBULEVE) 0.5 653 .+-. 949 25 .+-. 20 1* 1 1073
.+-. 1321 85 .+-. 29 16 .+-. 4 2 1918 .+-. 1945 254 .+-. 21 71 .+-.
17 3 2744 .+-. 2652 425 .+-. 17 134 .+-. 36 4 3253 .+-. 3009 563
.+-. 34 193 .+-. 49 6 4017 .+-. 3377 927 .+-. 231 333 .+-. 66 20
6450 .+-. 4294 2185 .+-. 776 1237 .+-. 70 22 6511 .+-. 4235 2224
.+-. 654 1372 .+-. 95 24 6833 .+-. 4147 2483 .+-. 891 1472 .+-. 67
UT.sub.45.degree./ UT.sub.45.degree./Non- Non-UT.sub.Gel 1
UT.sub.Gel 2 6 hr 4.3 12.1 24 hr 2.8 4.6
[0096] The results in Table 2 indicate that 45 degree angled
sonophoresis significantly enhanced ibuprofen permeation through
the human skin to reach the receptor compartment. For example, the
ibuprofen skin permeation enhancement factors for ibuprofen
traveled across the skin from the 45 degree UT sonophoresis from
the ibuprofen gel from Example 1, compared to that without
ultrasound from the same ibuprofen gel were approximately 4.3 fold
at the 6.sup.th hour and 2.8 fold at the 24.sup.th hour,
respectively. When compared to ibuprofen passive diffusion from the
commercial ibuprofen gel, IBULVE, the ibuprofen skin permeation
enhancement factors were 12.1 fold at the 6.sup.th hour and 4.6
fold at the 24.sup.th hour, respectively.
[0097] Table 3 shows the ibuprofen skin permeation results from
Study 2, in which ultrasound treatment (UT) was applied, at a
signal power of 3 W, in such a way that the ultrasound transducer
delivered the ultrasound energy at frequency of 700 kHz to the skin
surface with a 60 degree angle for one group of three diffusion
cells (middle column or column 2). For comparison purpose, another
group of three diffusion cells was run with passive diffusion
without any ultrasound treatment (the last column or column 3). The
first column (column 1) was intended for ultrasound treatment also.
However, it was found out that the ultrasound transducer did not
work during ultrasound treatment because a test on the ultrasound
transducer after the ultrasound treatment revealed that there was
no ultrasound pressure coming out of the transducer tip, therefore,
this group of diffusion cells was in fact passive diffusion without
any ultrasound treatment, just like the test condition for the last
column (column 3).
TABLE-US-00003 TABLE 3 Ibuprofen Diffusion (.mu.g) No-UT (due to a
Non-UT.sub.Gel 1 Time failed ultrasonic (Passive Diffusion (hr)
transducer) with Gel 1) UT.sub.60.degree. (Diffusion with Gel 1 and
60.degree. Sonophoresis) 0.5 14 .+-. 12 128 .+-. 154 4 .+-. 4 1 81
.+-. 29 358 .+-. 186 39 .+-. 8 2 285 .+-. 56 980 .+-. 313 184 .+-.
16 4 633 .+-. 145 1802 .+-. 765 496 .+-. 27 6 1078 .+-. 281 2687
.+-. 1266 939 .+-. 17 24 2374 .+-. 704 5506 .+-. 3307 2736 .+-. 215
UT.sub.60.degree./Non-UT.sub.Gel 1 6 hr -- 2.9 -- 24 hr 2.0 --
[0098] The results in Table 3 indicate that without any ultrasound
treatment, ibuprofen passive diffusion resulted in similar
ibuprofen permeated across the skin and reached the receptor
compartment as one compares the results in columns 1 and 3. In
contrast, 60 degree angled sonophoresis significantly enhanced
ibuprofen permeation through the human skin to reach the receptor
compartment. The permeation enhancement factors for ibuprofen from
the 60 degree UT sonophoresis to that without ultrasound (column 3)
at the 6.sup.th hour and the 24.sup.th hour were approximately 2.9
fold at the 6.sup.th hour and 2.0 fold at the 24.sup.th hour.
[0099] Table 4 shows the ibuprofen skin permeation results from
Study 3, in which ultrasound treatment (UT) was applied, at a
signal power of 3 W, in such a way that the ultrasound transducer
delivered the ultrasound energy at a frequency of 700 kHz to the
skin surface with a 15 degree angle for one group of three
diffusion cells (column 1), and with a 90 degree angle for another
group of three diffusion cells, which is how ultrasound treatment
was applied in most sonophoresis studies. For comparison purpose,
another group of three diffusion cells was run with passive
diffusion without any ultrasound treatment (the last column or
column 3).
TABLE-US-00004 TABLE 4 Ibuprofen Diffusion (.mu.g) Time
Non-UT.sub.Gel 1 (Passive (hr) Diffusion with Gel 1)
UT.sub.15.degree. (Diffusion with UT.sub.90.degree. Gel 1 and
15.degree. (Diffusion with Gel 1 Sonophoresis) and 90.degree.
Sonophoresis) 0.5 173 .+-. 112 43 .+-. 34 6 .+-. 4 1 654 .+-. 457
410 .+-. 169 31 .+-. 39 2 2589 .+-. 1610 2086 .+-. 1008 477 .+-.
561 4 6512 .+-. 3688 5379 .+-. 2540 1931 .+-. 1910 6 11058 .+-.
6446 8379 .+-. 4147 3640 .+-. 3518 24 54073 .+-. 35886 35725 .+-.
12187 18051 .+-. 18485 UT.sub.15.degree./ Non-UT.sub.Gel 1
UT.sub.90.degree. /Non-UT.sub.Gel 1 6 hr 3.0 2.3 -- 24 hr 3.0 2.0
--
[0100] The results in Table 4 indicate that both 15 degree (column
1) and 90 degree ultrasound (column 2) treatments significantly
enhanced ibuprofen permeation through the human skin, as opposed
that without ultrasound treatment (column 3). The permeation
enhancement factors for 15 degree UT sonophoresis to that without
ultrasound treatment (column 3) at the 6.sup.th hour and the
24.sup.th hour were approximately 3.0 fold at the 6.sup.th hour and
the 24.sup.th hour; and the enhancement factors for 90 degree UT
sonophoresis (column 3) to that without ultrasound (column 3) at
the 6.sup.th hour and the 24.sup.th hour were approximately 2.3
fold at the 6.sup.th hour and 2.0 fold at the 24.sup.th hour. It
was a surprise that the angled ultrasound treatment of 15 degrees
could lead to drug skin permeation enhancement similar, or perhaps
even better, to that from 90 degree ultrasound treatment used
conventionally, in addition to the aforementioned significant
safety benefits of eliminating the deep tissues from unintended
ultrasound exposure.
Ultrasound Pressure Measurement Test.
[0101] To demonstrate the improved safety of orienting the
transducer such that ultrasound waves are directed to the
application site(s) (i.e., skin surface) at angles .theta. (as
described herein), an in vitro, Ultrasound Pressure Measurement
Test was performed. The Ultrasound Pressure Measurement Test
determines the ultrasonic pressure generated by the device or
methods of the present invention using an Onda hydrophone
calibrated for 30 kHz-10 MHz range when delivering the ultrasonic
energy at variable angles ranging from 90 (perpendicular) to 15
degrees. The Ultrasound Pressure Measurement Test uses the setup
illustrated in FIGS. 4a and 4b. FIGS. 4a and 4b show outer vessel
20 in which an inner vessel 30 having a bottom formed from silicone
skin 22 (manufactured by Skindaver/Florida) is positioned. Water is
added to each of vessels 20 and 30 as illustrated in FIGS. 4a and
4b to form topical region 23 (i.e., region between transducer 8 and
the silicone skin 22) and a region "below [or underneath] the skin"
24 (i.e., below the silicone skin 22). Thus formed, the region
"below the skin" 24 simulates the tissue region under the natural
skin of living creatures. The topical region 23 simulates the
topical composition used in conjunction with ultrasound generating
transducer 8. A hydrophone 21 (Onda HNR-1000 connected through an
AH-1100 amplifier to a Tektronix oscilloscope) is positioned in the
region "below the skin" 24 to measure the voltage generated by the
ultrasound waves projected from transducer 8 through silicone skin
22; the measured voltage is directly proportional to the acoustic
pressure of the generated by ultrasound waves at region "below the
skin" 24.
[0102] The ultrasonic energy is applied at 714 kHz with a signal
power of 3 W (40V peak to peak at 0.15 A). Using the setup of FIGS.
4a and 4b, the ultrasonic energy is first applied to the silicone
skin 22 from a transducer 8 which is positioned by positioning
element 26 so that the ultrasonic wave is directed perpendicular to
the silicone skin 22 by positioning element 26 as in FIG. 4a. Using
the setup of FIG. 4b, the ultrasonic energy is again applied to the
silicone skin 22 from a transducer 8 which is positioned by
positioning element 26 so that the ultrasonic energy wave
propagation direction forms an angle .theta. of about 15.degree.
relative to the planar surface of the silicone skin as in FIG. 4b.
The transducer 8 oriented such that the ultrasound waves are
perpendicular to the silicone s generated an amplitude of 10V. The
transducer 8 oriented such that the ultrasound waves are directed
towards the silicone skin 22 at angle .theta. of about 15.degree.
relative to the planar surface of the silicone skin (i.e., as in
the case of angle .theta. as illustrated in FIG. 3) generated an
amplitude of only 0.9V. The roughly 10 fold reduction in amplitude
voltage correlates to a roughly 10 fold reduction in ultrasonic
pressure in the tissue under the skin, suggesting the increased
tissue safety of the angled ultrasound wave projection (towards
skin surface) relative to perpendicular ultrasound wave projection
(towards skin surface).
Mice Hair Growth Study
Experimental Design
Duration of Study
[0103] The in-life phase portion of this study was 60 days in
duration. The in-life phase began with the start of clinical
observations Day -3 and ended with necropsies on Day 56. The day of
the first dose was designated as Day 0.
Group Allocation
[0104] Mice were allocated to 11 groups as they were brought into
the facility and placed in cages. Each group was composed of 5
mice. The last five numeric animals were deemed replacement animals
and enrolled as needed on Day 0.
Test Article and Route of Administration
[0105] For dermal administration of the Test Gel, the mice were
shaved on Day 0 prior to dose application. The mouse was manually
restrained by a technician, a syringe or pipette was used to draw
the dose of the Test Gel, and Test Gel was applied to the back of
the animal.
Frequency and Duration of Dosing
[0106] The Test Gel was administered once daily for 56 days. The
times of dose administration were recorded. Due to the variable
nature of dermal application procedures and due to the need to
perform various evaluations before dosing, the time of dosing of
each animal varied daily.
Observations, Measurements, and Specimens
Physical Examinations
[0107] Prior to study start, each animal was confirmed to be
healthy by a medical record completed by a veterinarian, a
certified veterinary technician, or an approved research
technician. The criteria of health included the absence of abnormal
clinical signs during the 3 days prior to initial dosing and a
normal physical exam. All study animals were in good health.
Clinical Observations
[0108] Animals were observed at least once daily 3 days prior to
initial dosing (pre-study for health assessment). The last clinical
observation was the morning of Day 56 before euthanasia. All
observations were recorded at the time of occurrence. Live phase
assessment included but were not limited to assessment of activity,
posture, respiration, hydration status, and overall body
condition.
Dose Groups, Concentration, and Application Procedures
[0109] The dosing solutions are outlined in Table 5 below:
TABLE-US-00005 TABLE 5 Design of Study Groups for Test Gels (TG)
Amount Test Article applied (mL) Application procedures Days
Administered Group 1 - Untreated 0 None None Group 2 - Test Gel 1
0.4 Rub in Test Gel onto dorsal 0-55 skin for 30 strokes (about 30
seconds) with a gentle pressure Group 3 - 0.4 1) Rub in Test Gel
onto 0-55 Test Gel 2 dorsal skin for 30 strokes (about 30 seconds
Group 4 - 0.4 1) Apply Test Gel onto dorsal 0-55 Test Gel 1 with
UT1 skin uniformly 2) Apply Ultrasound Treatment on dorsal skin 3
times/week, by pressing the ultrasound device head onto Test Gel
layer on the mouse skin in a circulation motions 30 times (about 30
seconds) to cover the entire dorsal skin Group 5 - Test Gel 0.4 1)
Apply Test Gel onto dorsal 0-55 2 with UT1 skin uniformly 2) Apply
Ultrasound Treatment on dorsal skin 3 times/week, by pressing the
ultrasound device head onto Test Gel layer on the mouse skin in a
circulation motions 30 times (about 30 seconds) to cover the entire
dorsal skin Group 6 -- Test 0.4 1) Apply Test Gel onto dorsal 0-55
Gel 1 with UT2 skin uniformly 2) Apply Ultrasound Treatment on
dorsal skin 3 times/week, by pressing the ultrasound device head
onto Test Gel layer on the mouse skin in a circulation motions 30
times (about 30 seconds) to cover the entire dorsal skin Group 7 -
Test Gel 2 0.4 1) Apply Test Gel onto dorsal 0-55 with UT2 skin
uniformly 2) Apply Ultrasound Treatment on dorsal skin 3
times/week, by pressing the ultrasound device head onto Test Gel
layer on the mouse skin in a circulation motions 30 times (about 30
seconds) to cover the entire dorsal skin Group 8 - Test Gel 1 0.4
1) Apply Test Gel onto dorsal 0-55 with UT3 skin uniformly 2) Apply
Ultrasound Treatment on dorsal skin 3 times/week, by pressing the
ultrasound device head onto Test Gel layer on the mouse skin in a
circulation motions 30 times (about 30 seconds) to cover the entire
dorsal skin Group 9 - Test Gel 2 0.4 1) Apply Test Gel onto dorsal
0-55 with UT3 skin uniformly 2) Apply Ultrasound Treatment on
dorsal skin 3 times/week, by pressing the ultrasound device head
onto Test Gel layer on the mouse skin in a circulation motions 30
times (about 30 seconds) to cover the entire dorsal skin Group 10 -
Test Gel 0.4 1) Apply Test Gel onto dorsal 0-55 1 with UT4 skin
uniformly 2) Apply Ultrasound Treatment on dorsal skin 3
times/week, by pressing the ultrasound device head onto Test Gel
layer on the mouse skin in a circulation motions 30 times (about 30
seconds) to cover the entire dorsal skin Group 11 - Test Gel 0.4 1)
Apply Test Gel onto dorsal 0-55 2 with UT4 skin uniformly 2) Apply
Ultrasound Treatment on dorsal skin 3 times/week, by pressing the
ultrasound device head onto Test Gel layer on the mouse skin in a
circulation motions 30 times (about 30 seconds) to cover the entire
dorsal skin * For ultrasound treatment, the head of the device
(ultrasound transducer) should be pressed against the mouse skin
over the gel formulation layer without any air gap, and be moved in
a circulation motion, and this procedure is repeated to cover the
entire dorsal skin of the animal. For groups 3 through 11, animals
will be treated with the ultrasound device on Day 0 and 3 for week
one dosing and then on a Monday-Wednesday-Friday schedule
thereafter. On days when no ultrasound treatment is indicated, only
Test Gels will be applied to the treated skin area.
Test Groups
1 Untreated (Negative Control)
[0110] 2 Placebo gel daily (Test Gel 1) 3 5% Minoxidil Gel daily
(Test Gel 2) 4 UT1+Placebo Gel (Test Gel 1+UT1, 3.times./week) 5
UT1+5% Minoxidil Gel (Test Gel 2+UT1, 3.times./week) 6 UT2+Placebo
Gel (Test Gel 1+UT2, 3.times./week) 7 UT2+5% Minoxidil Gel (Test
Gel 2+UT2, 3.times./week) 8 UT3+Placebo Gel (Test Gel 1+UT3,
3.times./week) 9 UT3+5% Minoxidil Gel (Test Gel 2+UT3,
3.times./week) 10 UT4+Placebo Gel (Test Gel 1+UT4, 3.times./week)
11 UT4+5% Minoxidil Gel (Test Gel 2+UT4, 3.times./week) Ultrasound
Treatments (UT) 1-4 were adjusted by changing the device setting
and/or the treatment tip to produce the following parameters: (i.
transducer frequency, ii. ultrasound wave projection angle, and
iii. time of ultrasound application): [0111] UT1--Ultrasound
Treatment 1 (50 kHz, 90 Degree, 30 Seconds) [0112] UT2--Ultrasound
Treatment 2 (50 kHz, 15 Degree, 30 Seconds) [0113] UT3--Ultrasound
Treatment 3 (700 kHz, 90 Degree, 30 Seconds) [0114] UT4--Ultrasound
Treatment 4 (700 kHz, 15 Degree, 30 Seconds)
[0115] The 5% minoxidil gel used as Test Gel 2 in the above Test
Groups was prepared by mixing the ingredients shown in Table 6
using conventional mixing technology. The 1% Klucel-thickened
commercial 5% minoxidil solution gel used as Test Gel 1 was
prepared by mixing the Klucel (hydroxypropylcellulose) into a
commercially available Walgreen's 5% Minoxidil Topical Solution
using conventional mixing technology to form a 1% Klucel minoxidil
gel.
TABLE-US-00006 TABLE 6 Chemical Name Trade Name % (w/w) Ethyl
Alcohol SDA Alcohol 40B 190 21.00 Proof Pentylene Glycol Hydrolite
5 supplied by 4.00 Symrise, Teterboro, NJ Glycerin Glycerin USP
12.00 Citric Acid Citric Acid 0.20 Lactic Acid Purac HiPure 90 3.00
Minoxidil Minoxidil USP 5.00 Butylated BHT 0.10 Hydroxytoluene
Water Purified Water 44.20 Sodium Pyruvate Sodium Pyruvate 1.00
Polyquaternium-37 Cosmedia Ultragel 300 2.50 supplied by BASF,
Florham Park, N.J. Steareth-2 Brij S2 1.50 Steareth-10 Brij S10
supplied by 2.00 Croda, Edison, NJ Cetyl Lactate Ceraphyl 28 3.00
Tocopheryl Acetate dl-a Tocopheryl 0.50 Acetate pH = 5.69
100.00
Table 7 is the average of the degree of terminal hair coverage for
the 5 mice in each of Groups 1-11 based on images taken at
different time points. Visual observation of images taken at week 0
(day that mice were shaved) demonstrated that, at this stage of the
study, all the mice of test groups had all terminal hair
removed.
TABLE-US-00007 TABLE 7 AVERAGE MOUSE HAIR COVERAGE SCORE Day Day
Day Day Day Day Day Groups 0 17 24 31 38 45 52 1 (Untreated) 0 0 0
0 0.2 1 1.2 2 (Test Gel 1) 0 1.4 3.8 4.2 4.4 4.8 5 3 (Test Gel 2) 0
0 3.4 4.6 4.8 5 5 4 (Test Gel 1 + 0 1.2 3.2 4.2 4.4 5 5 UT1) 5
(Test Gel 2 + 0 0 2.8 4.4 4.8 5 5 UT1) 6 (Test Gel 1 + 0 0 0.6 3 4
4.8 5 UT2) 7 (Test Gel 2 + 0 0 1.8 2.8 4 4.4 4.8 UT2) 8 (Test Gel 1
+ 0 0.6 1.6 3.4 3 4.2 4.6 UT3) 9 (Test Gel 2 + 0 3.8 4.8 4.6 4.8 5
5 UT3) 10 (Test Gel 1 + 0 1.2 2.6 4 4.8 5 5 UT4) 11 (Test Gel 2 + 0
0 4.8 4.8 5 5 5 UT4) Transducers in ultrasound devices were later
determined to be malfunctioning during the testing of Groups 4-7.
Group 9: 3 of 5 mice developed tissue damage lesions on the skin
two days after three ultrasound treatments during the first week of
the study. Ultrasound treatments were discontinued for this group,
but daily topical minoxidil gel application continued. All tissue
damage lesions healed after stopping ultrasound treatment. Group
10: 2 of 5 mice developed skin lesion after two weeks (6 UT
treatments. UT discontinued. Group 11: No tissue damage lesions
developed during study.
[0116] The average mouse hair coverage score per group as shown in
Table 7 demonstrates that mice skin treated with Test Gel 2 and
ultrasound treatment at a frequency of 700 kHz and angle of 15
degrees for 30 Seconds (Group 11) achieved a faster degree of
terminal hair coverage at day 24 than any of the treatment regimens
of Groups 1-10 without formation of tissue damage lesions. Notably,
the treatment regimen of Group 11 achieved a faster degree of
terminal hair coverage at day 24 than the mice treated with Test
Gel 2 alone (i.e., without ultrasound treatment).
[0117] In contrast, focusing on the overall degree and speed of
terminal hair coverage achieved over 45 day period, the treatment
regimen of Group 10 (Test Gel 1 plus Ultrasound Treatment 3 [700
kHz, 90 Degree, 30 Seconds]) did not show the same hair growth
coverage improvement versus Test Gel 1 alone (Group 2) as was shown
with respect to the Test Gel 2 and ultrasound combination of Groups
9 and 11 (at 700 kHz; 90.degree. and 15.degree., respectively; for
30 Seconds) versus treatment with Test Gel 2 alone (Group 3). This
teaches that the formulation of Test Gel 2 contains ingredients
which improve the combined treatment effect of Test Gel 2 combined
with ultrasound (at 700 kHz; 90.degree. and 15.degree.,
respectively; for 30 Seconds).
[0118] And, as noted by a comparison of the treatment regimens of
Group 10 with Group 6 and a comparison of Group 11 with Group 7,
Table 7 further shows that use of ultrasound at a frequency of 50
kHz and grazing angle of 15.degree., has less of an effect with
when combined with either Test Gel 1 or Test Gel 2, on hair
regrowth than use of ultrasound at a frequency of 700 kHz and
grazing angle of 15.degree. in combination with Test Gel 1 or Test
Gel 2. Combining ultrasound at a frequency of 50 kHz (at grazing
angle of 15.degree.) with Test Gels 1 and 2 actually reduced the
hair regrowth effects of using, Test Gel 1 or Test Gel 2 alone,
respectively, as shown by comparing Group 6 with Group 2 and Group
7 with Group 3.
* * * * *