Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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LIQUID VEHICLE FOR SUSPENSION OF UNDELIVERED PARTICLES
INCORPORATION BY REFERENCE
This application includes subject matter that may be related to subject matter
described in U.S. Ser. No. 12/787,655, U.S. Patent Application Publication No.
2012/0059307, and U.S. Pat. No. 6,183,773, each of which is incorporated
herein in its
entirety. All
publications and patent applications mentioned in this specification are
herein incorporated by reference in their entirety to the same extent as if
each individual
publication or patent application was specifically and individually indicated
to be
incorporated by reference.
FIELD
This application relates to methods of enhanced delivery of particles and
other
light absorbing materials into pores by reuse of undelivered materials via
addition of liquid
vehicle to re-suspend or dissolve the material.
BACKGROUND
Acne vulgaris is a follicular skin disease that is characterized by the
appearance of
comedones, papules, nodules, and cysts. Comedones are hair follicles that are
blocked
with a keratin plug. Open comedones, those in which the keratin plug is
visible, form
"black heads" and closed comedones form "whiteheads" that often progress to
inflamed
papules, nodules, and cysts. The presence of bacteria in a follicle attracts
white blood cells
to the follicle, which can cause an inflammatory response seen as papules (red
bumps),
pustules, and nodules. Acne may be minor, where only a few comedones or
papules are
present, or it may be highly inflammatory and leave disfiguring scars.
Improved methods
of treating or ameliorating follicular skin diseases, such as acne vulgaris,
are required.
Selective photothermolysis with externally added light absorbing material into
the
sebaceous follicle followed by laser irradiation has been developed as a
treatment of acne.
An example of the light absorbing material is the silica core: gold shell
microparticles
called nanoshells that were developed by Halas and others at Rice University.
These
materials can be expensive and it is desired to reduce the amount used. An
exemplary
treatment involves application of a suspension of the particles to the skin
surface followed
by mechanical methods such as a massage or other techniques described below.
These
particles are commonly suspended in a liquid that typically consists of water,
ethanol,
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diisopropyl adipate, and polyethyelene glycol. These are typically low
viscosity
formulations and as mentioned earlier, the particle delivery is aided by one
or more
different techniques. The bulk flow of the fluid containing the particles from
the skin
surface through the pores to the target sebaceous follicles is the primary
method of
transport of the particles. With this method, the fraction of particles
delivered into the
follicles compared to the total applied to the skin surface is very small. For
example, it is
estimated that only about 1% of the particles that are applied to the facial
skin make it into
the follicles. Also, the fluid (vehicle) portion of the suspension evaporates
within a short
time, for instance, in less than a minute. After the substantial evaporation,
the transport of
the particles into the sebaceous follicles is minimal or zero.
What is needed are methods to achieve more effective utilization of the
particles
within a formulation.
SUMMARY OF THE DISCLOSURE
As described below, the present invention provides methods for treating or
ameliorating follicular skin diseases (e.g., acne) in a subject (e.g., a
human) and
compositions comprising energy (e.g., light) absorbing submicron particles
(e.g.,
nanoparticles comprising a silica core and a gold shell) and methods for
delivering such
particles via topical application into, e.g., a hair follicle, sebaceous duct,
and/or sebaceous
gland, for use in accordance with those methods.
Thus, in one aspect, the invention provides a method of treating or
ameliorating a
follicular skin disease in a subject, the method comprising: topically
applying a
formulation comprising sub-micron particles comprising a light absorbing
material to the
subject's skin; facilitating delivery of the material into a hair follicle,
sebaceous gland,
sebaceous gland duct, infundibulum of the skin, an eccrine duct or an eccrine
gland by
mechanical agitation, acoustic vibration, ultrasound, alternating suction and
pressure, or
microjets; and exposing the sub-micron particles to energy activation, thereby
treating or
ameliorating the follicular skin disease in the subject.
In another aspect, the invention provides a method of improving the appearance
of
enlarged pores in the skin of a subject, the method comprising: topically
applying a
formulation comprising sub-micron particles comprising a light absorbing
materials to the
subject's skin; facilitating delivery of the materials to a hair follicle,
sebaceous gland,
sebaceous gland duct, or infundibulum of the skin by mechanical agitation,
acoustic
vibration, ultrasound, alternating suction and pressure, or microjets; and
exposing the sub-
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micron particles to energy activation, thereby improving the appearance of
enlarged pores
in the skin of the subject.
In yet another aspect, the invention provides a method of improving the
appearance
of oily skin of a subject, the method comprising: topically applying a
formulation
comprising sub-micron particles comprising a light absorbing materials to the
subject's
skin; facilitating delivery of the sub-micron particles to a hair follicle,
sebaceous gland,
sebaceous gland duct, or infundibulum of the skin by mechanical agitation,
acoustic
vibration, ultrasound, alternating suction and pressure, or microjets; and
exposing the sub-
micron particles to energy activation, thereby improving the appearance of
oily skin of the
subject.
Another aspect of the invention provides a method for permanently removing
hair
of a subject, the method comprising: topically applying a light-absorbing
material to the
skin of the subject, and exposing the material to energy activation, thereby
permanently
removing the hair. In one embodiment, the hair is lightly pigmented or thin
hair. In
another embodiment, the method further comprises epilating hair from the
follicle of the
subject before topically applying the light-absorbing material to the skin of
the subject and
exposing the material to energy activation.
In another aspect, the invention provides a method for treating hyperhidrosis
by
thermally damaging eccrine glands or their surrounding area, the method
comprising:
topically applying a light-absorbing material to the skin of a subject, and
exposing the
material to energy activation, thereby permanently removing the glands and
treating
hyperhidros is .
In yet another aspect, the invention provides a method of facilitating
delivery of a
light absorbing material to a target volume within the skin of a subject to
achieve a
therapeutic effect, the method comprising: topically applying a formulation
comprising a
light absorbing material to a subject's skin to deliver the material to a
reservoir within the
skin; facilitating delivery of the material to a target volume within the skin
of the subject
by irradiating the skin with a first series of light pulses; and exposing the
light absorbing
material to a second series of light pulses to heat the material and thermally
damage the
target volume to achieve a therapeutic effect.
In still another aspect, the invention provides a method of facilitating
delivery of a
light absorbing material to a target volume within the skin of a subject to
achieve a
therapeutic effect, the method comprising: topically applying a formulation
comprising a
light absorbing material to a subject's skin; facilitating delivery of the
material to a
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reservoir in the skin by mechanical agitation; facilitating delivery of the
material to a
target volume within the skin by applying a train of low-energy laser pulses
each pulse
lasting for a microsecond or less to drive the material into the target
volume; and exposing
the light absorbing material to a second series of low-energy laser pulses to
heat the
material and thermally damage the target volume to achieve a therapeutic
effect.
Still another aspect of the invention provides a method of treating or
ameliorating a
follicular skin disease of a subject, the method comprising: topically
applying a
formulation comprising a sub-micron particle comprising a light absorbing
material to a
subject's skin; facilitating delivery of the material from the skin into a
hair follicle by
acoustically created microjets in the formulation; and exposing the sub-micron
particle to
energy activation, thereby treating the follicular skin disease.
In yet another aspect, the invention provides a method of treating or
ameliorating a
follicular skin disease of a subject, the method comprising: exposing the
subject's skin to a
formulation comprising sub-micron particles comprising a light absorbing
material; and
facilitating delivery of the material from the skin into a hair follicle by
low frequency
ultrasound induced cavitation within the formulation near the surface of the
skin adjacent
to the hair follicle; and exposing the sub-micron particles to energy
activation, thereby
treating the follicular skin disease.
Still another aspect of the invention provides a method of facilitating
delivery of a
light absorbing material to a target volume within the skin of a subject, the
method
comprising: topically applying a formulation comprising a light absorbing
material to a
subject's skin to deliver the material to a reservoir within the target volume
of the skin;
facilitating delivery of the material to a target volume within the skin of
the subject
substantially via a transfollicular pathway; and exposing the light absorbing
material to a
series of light pulses to heat the material and thermally damage the target
volume to
achieve a therapeutic effect.
In another aspect, the invention provides a method of treating or ameliorating
a
follicular skin disease of a subject, the method comprising: topically
applying a
formulation comprising particles of a light absorbing material to a subject's
skin;
acoustically cavitating the formulation for selectively facilitating delivery
of the particles
in the formulation into a sebaceous gland primarily through the corresponding
hair
follicle; and irradiating the particles with light to treat the follicular
skin disease.
Another aspect of the invention provides a method of treating or ameliorating
a
follicular skin disease of a subject, the method comprising: topically
applying a
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formulation comprising sub-micron particles comprising a light absorbing
material to a
subject's skin; delivering the formulation into one or more sebaceous glands
substantially
via a transfollicular pathway; and exposing the sub-micron particles to energy
activation,
thereby treating the follicular skin disease.
Still another aspect of the invention provides a method of treating or
ameliorating a
follicular skin disease of a subject, the method comprising: topically
applying a
formulation comprising a sub-micron particle comprising a light absorbing
material to a
subject's skin; facilitating delivery of the material into a hair follicle by
low frequency
ultrasound induced cavitation near the surface of the skin adjacent to the
hair follicle; and
treating or ameliorating the follicular skin disease adjacent to the sub-
micron particle
using heat produced by irradiating the sub-micron particle with light.
The above-described method aspects of the invention or other aspects of the
invention described herein include a plurality of useful embodiments that are
universally
applicable to the methods of the invention described herein.
Thus, in one embodiment, delivery of the light absorbing material into, e.g.,
the
hair follicle, is facilitated by ultrasound-created microjets within the
formulation.
In another embodiment, the sub-micron particles to energy activation comprises
irradiating the sub-micron particle with light, thereby heating the particle.
In another embodiment, the sub-micron particles are within a sebaceous gland
during irradiation. In one embodiment, the sub-micron particles are
substantially
completely within the sebaceous gland during irradiation. In another
embodiment, the sub-
micron particles are within a sebaceous gland duct during irradiation. In yet
another
embodiment, the sub-micron particles are substantially completely within the
sebaceous
gland duct during irradiation. In still another embodiment, the sub-micron
particles are
within an infundibulum involved in the follicular skin disease.
In certain embodiments, the light absorbing material in the formulation
comprises
a photoactive compound, photodynamic therapy (PDT) pro-drug or PDT drug.
In one embodiment, the application of ultrasound is at a frequency in the
range of
20 kHz to 500 kHz. In another embodiment, the application of ultrasound is at
a frequency
in the range of 20 kHz to 100 kHz. In yet another embodiment, the application
of
ultrasound is at a frequency in the range of 20 kHz to 60 kHz. In still
another embodiment,
the application of ultrasound energy is at a frequency in the range of 30 kHz
to 50 kHz.
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In one embodiment, the ultrasound power density is from about 0.5-50 W/cm2. In
another embodiment, the ultrasound horn face peak-to-peak amplitude
displacement is in
the range of 0.5 to 30 microns.
In certain other embodiments, the sizes of sub-micron particles according to
the
invention are selected for passage through the hair follicle and into a
sebaceous gland of
the hair follicle. In one embodiment, the hair follicle is a terminal
follicle. In another
embodiment, the hair follicle is a vellus follicle. In yet another embodiment,
the hair
follicle is a sebaceous follicle.
In one embodiment, the sub-micron particle size is between about 0.01 microns
to
about 1.0 microns. In another embodiment, the sub-micron particle size is
between about
0.05 to about 0.25 microns.
In one embodiment, the facilitating step further comprises selecting
characteristics
for the ultrasound-created microjets to create bubbles in the formulation
about the same
size as the hair follicle pore. In another embodiment, the facilitating step
further comprises
selecting characteristics for low frequency ultrasound induced cavitation for
creating
bubbles in the formulation about the same size as the hair follicle.
In other embodiments, the ultrasound-created microjets in the formulation are
within about 50 microns to about 100 microns of the surface of the skin of the
subject.
In certain embodiments, delivery of the light absorbing matter is facilitated
by an
immersion cavitation step. In one embodiment, the facilitating step produces
cavitation
within about 50-100 microns of the surface of the skin. In another embodiment,
the
portion of the stratum corneum of the portion of the subject's skin exposed to
the delivery
step remains intact In certain other embodiments, delivery, e.g.,
substantially via a
transfollicular pathway, of the light absorbing material into, e.g., one or
more sebaceous
glands or hair follicles, is facilitated by low frequency ultrasound induced
cavitation near
the surface of the skin adjacent to the hair follicle. In one embodiment, the
induced
cavitation is between about 50 microns to about 100 microns from the surface
of the skin.
In another embodiment, the characteristics of the low frequency ultrasound are
selected
such that the induced cavitation near the surface of the skin leaves the
stratum corneum
intact.
In one embodiment, the follicular disease for treatment is hyperhidrosis. In
certain
embodiments, the facilitating step delivers particles into an eccrine gland
via the eccrine
gland duct.
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In other embodiments, the follicular disease for treatment is acne vulagris.
In yet
other embodiments, the follicular disease for treatment is sebaceous
hyperplasia In still
other embodiments, the follicular disease for treatment is hirsuteness.
In one embodiment, the sub-micron particles are coated with PEG. In another
embodiment the particles have an absorption peaked between 700 and 1,100 nm
wavelength of light. In another embodiment, the sub-micron particles have a
ratio of the
shell diameter to the core diameter between about 1.05 to about 2Ø
In another embodiment, the sub-micron particle is a nanoparticle or nanoshell.
In
certain embodiments, the nanoparticle or nanoshell has a diameter of about 50
to about
300 nm (e.g., 50, 75, 100, 125, 150, 175, 200, 250, 300 nm). In one
embodiment, the
nanoparticle or nanoshell has a diameter of about 50 to about 250 nm. In
another
embodiment, the nanoparticle has a diameter of about 150 nm.
In another embodiment, the nanoparticle is coated with PEG.
In yet another embodiment, the nanoparticle is a nanoshell. In certain
embodiments, the nanoparticle comprises a silica core and a gold shell.
In certain embodiments, the sub-micron particles comprise from about 0.5% to
about 2% of the formulation. In one embodiment, the formulation comprises
about 0.5 to
about 2% of a suspension comprising nanoparticles. In another embodiment, the
formulation comprises about 0.1 to about 10% of a suspension comprising
nanoparticles.
In one embodiment, the formulation contains a surfactant and/or is
hydrophilic. In
another embodiment, the formulation contains a surfactant and/or is
lipophilic. In yet
another embodiment, the formulation contains a surfactant and/or is liposomal.
In certain
embodiments, the surfactant is less than 10% of the formulation.
In certain embodiments, the formulation comprises a component having ability
to
solubilize lipids. In one embodiment, the component is ethanol.
In one embodiment, the formulation comprises one or more of ethanol, isopropyl
alcohol, propylene glycol, a surfactant, and/or isopropyl adipate. In another
embodiment,
the formulation comprises hydroxypropylcellulose (HPC) and carboxymethyl
cellulose
(CMC). In still another embodiment, the formulation comprises any one or more
of water,
ethanol, propylene glycol, polysorbate 80, diisopropyl adipate, phospholipon,
and
thickening agents.
In certain embodiments, the formulation has an optical density of between 5-
500.
In one embodiment, the formulation has an optical density of about 75. In
another
embodiment, the formulation has an optical density of about 125. In another
embodiment,
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the formulation has an optical density of about 250.
In certain embodiments, energy activation, e.g., light activation, is
accomplished
with a pulsed laser light that delivers light energy at a wavelength that is
absorbed by the
particle. In one embodiment, the pulsed laser light delivers light energy at a
wavelength
that is preferentially absorbed by the particle. In another embodiment, energy
activation is
accomplished with a continuous laser that delivers light energy at a
wavelength that is
absorbed by the particle
In one embodiment, the light energy has a wavelength range from about 700 to
about 1,100 nm. In another embodiment, the light energy has a fluence of less
than about
100 J/cm2. In still another embodiment, the light energy has a pulse duration
of from about
0.5 ms-1,000 ms.
In certain embodiments, the skin is prepared for the method by heating, by
removing the follicular contents, and/or by epilation. In one embodiment, the
follicular
contents are removed by a method comprising contacting the follicle pore with
adhesive
polymers.
In certain other embodiments, the topically applied sub-micron particles are
wiped
from the skin prior to energy activation. In one embodiment, the topically
applied sub-
micron particles are wiped from the skin with the aid of a fluid, prior to
application of
optical radiation. In another embodiment, the fluid is water, ethanol,
acetone, or a
combination of two or more of water, ethanol, and acetone. In another
embodiment, the
fluid can be comprised of one or more of water, solvents, surfactants,
alcohols.
In certain other embodiments, the skin is heated before, during, or after
topical
application to a temperature sufficient to assist in follicular delivery. In
one embodiment,
the heating is accomplished via ultrasound. In another embodiment, the heating
is
accomplished via steam. In yet another embodiment, the heating is accomplished
via hot
packs. In still another embodiment, heating is accomplished via hot towels. In
general, the
heating is not sufficient to cause pain, tissue damage, burns, or other heat-
related effects in
the skin. In one embodiment, the temperature is about 35-44 C. In another
embodiment,
the temperature is about 40-44 C. In yet another embodiment, the temperature
is about
42 C.
In certain embodiments, the step of exposing further comprises placing a
volume
of the formulation in a container so that the formulation is in contact with
the subject's
skin. In one embodiment, the step of facilitating further comprises placing an
ultrasound
applicator into the container and immersed in the formulation.
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In one embodiment, the target volume is the sebaceous gland, the target volume
is
within the follicle beneath the skin.
In another aspect, the invention provides a composition comprising a
cosmetically
acceptable carrier and a plurality of plasmonic nanoparticles in an amount
effective to
induce thermomodulation in a target tissue region with which the composition
is topically
contacted.
In one embodiment, the plasmonic nanoparticles are activated by exposure to
energy delivered from a nonlinear excitation surface plasmon resonance source
to the
target tissue region. In another embodiment, the plasmonic nanoparticle
comprises a
metal, metallic composite, metal oxide, metallic salt, electric conductor,
electric
superconductor, electric semiconductor, dielectric, quantum dot or composite
from a
combination thereof. In yet another embodiment, a substantial amount of the
plasmonic
particles present in the composition comprise geometrically-tuned
nanostructures.
In one embodiment, the plasmonic particles comprise any geometric shape
currently known or to be created that absorb light and generate plasmon
resonance at a
desired wavelength, including nanoplates, solid nano shells, hollow
nanoshells, nanorods,
nanorice, nanospheres, nanofibers, nanowires, nanopyramids, nanoprisms,
nanostars or a
combination thereof. In another embodiment, the plasmonic particles comprise
silver,
gold, nickel, copper, titanium, silicon, galadium, palladium, platinum, or
chromium.
In one embodiment, the cosmetically acceptable carrier comprises an additive,
a
colorant, an emulsifier, a fragrance, a humectant, a polymerizable monomer, a
stabilizer, a
solvent, or a surfactant. In one particular embodiment, the surfactant is
selected from the
group consisting of sodium laureth 2-sulfate, sodium dodecyl sulfate, ammonium
lauryl
sulfate, sodium octech- l/deceth-1 sulfate, lipids, proteins, peptides or
derivatives thereof.
In another specific embodiment the surfactant is present in the composition in
an amount
between about 0.1 and about 10.0% weight-to-weight of the carrier.
In one embodiment, the solvent is selected from the group consisting of water,
propylene glycol, alcohol, hydrocarbon, chloroform, acid, base, acetone,
diethyl-ether,
dimethyl sulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran,
dichloromethane,
and ethylacetate.
In another embodiment, the composition comprises plasmonic particles that have
an optical density of at least about 1 O.D. at one or more peak resonance
wavelengths.
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In yet another embodiment, the plasmonic particles comprise a hydrophilic or
aliphatic coating, wherein the coating does not substantially adsorb to skin
of a
mammalian subject, and wherein the coating comprises polyethylene glycol,
silica, silica-
oxide, polyvinylpyrrolidone, polystyrene, a protein or a peptide.
In one embodiment, the thermomodulation comprises damage, ablation, lysis,
denaturation, deactivation, activation, induction of inflammation, activation
of heat shock
proteins, perturbation of cell-signaling or disruption to the cell
microenvironment in the
target tissue region.
In another embodiment, the target tissue region comprises a sebaceous gland, a
component of a sebaceous gland, a sebocyte, a component of a sebocyte, sebum,
or hair
follicle infundibulum.
In a specific embodiment, the target tissue region comprises a bulge, a bulb,
a stem
cell, a stem cell niche, a dermal papilla, a cortex, a cuticle, a hair sheath,
a medulla, a
pylori muscle, a Huxley layer, or a Henle layer.
In another aspect, the invention provides a method for performing targeted
ablation
of a tissue to treat a mammalian subject in need thereof, comprising the steps
of i)
topically administering to a skin surface of the subject a composition of the
invention as
described above; ii) providing penetration means to redistribute the plasmonic
particles
from the skin surface to a component of dermal tissue; and iii) causing
irradiation of the
skin surface by light.
In one embodiment, the light source comprises excitation of mercury, xenon,
deuterium, or a metal-halide, phosphorescence, incandescence, luminescence,
light
emitting diode, or sunlight.
In another embodiment, the penetration means comprises high frequency
ultrasound, low frequency ultrasound, massage, iontophoresis, high pressure
air flow, high
pressure liquid flow, vacuum, pre-treatment with fractionated photothermolysis
or
dermabrasion, or a combination thereof.
In yet another embodiment, the irradiation comprises light having a wavelength
of
light between about 200 nm and about 10,000 nm, a fluence of about 1 to about
100
joules/cm2, a pulse width of about 1 femptosecond to about 1 second, and a
repetition
frequency of about 1 Hz to about 1 THz.
In another aspect, the invention provides a composition comprising a
cosmetically
acceptable carrier, an effective amount of sodium dodecyl sulfate, and a
plurality of
plasmonic nanoparticles in an amount effective to induce thermal damage in a
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region with which the composition is topically contacted, wherein the
nanoparticles have
an optical density of at least about 1 O.D. at a resonance wavelength of about
810
nanometers or 1064 nanometers, wherein the plasmonic particles comprise a
silica coating
from about 5 to about 35 nanometers, wherein the acceptable carrier comprises
water and
propylene glycol.
In still another aspect, the invention provides a system for laser ablation of
hair or
treatment of acne comprising a composition of the invention as described above
and a
source of plasmonic energy suitable for application to the human skin.
Various aspects of the invention provides compositions, methods and systems
for
treating follicular skin diseases as well as more effective utilization of
particles within a
provided formulation or above described treatment technique.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a micrograph showing thermal damage to the follicular epithelium and
part of the sebaceous gland following delivery of a nanoshell suspension by
massage.
FIG. 2 is a photograph showing the skin surface after application of the
nanoshell
formulation with ultrasound facilitated delivery. Excess formulation was wiped
from the
skin before this photograph was taken.
FIG. 3 is a micrograph showing a follicle filled with dark colored nanoshells
following ultrasound facilitated delivery. No nanoshells are noted in the
epidermis or the
dermis.
FIG. 4 is a micrograph showing a hair follicle and surrounding skin after
ultrasound delivery of nanoshells and laser irradiation visualized by
hematoxylin and eosin
(H&E stain). Selective thermal damage around the follicle is shown by the
added black
delineation.
FIG. 5 is a photograph showing the skin surface. Accumulation of nanoshells in
the
follicles is seen.
FIG. 6 is a micrograph showing a follicle having a significant accumulation of
nanoshells.
FIG. 7 is a micrograph showing localized thermal damage to a follicle
encompassing the sebaceous gland visualized using H&E stain.
FIG. 8 is a table showing the efficacy of nanoshell delivery followed by laser
treatment in a human clinical trial of back acne.
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DETAILED DESCRIPTION
The invention features compositions comprising light/energy absorbing
materials
and methods that are useful for their topical delivery to a target (e.g., a
follicle, follicular
infundibulum, sebaceous gland) for the treatment of a follicular disease.
DEFINITIONS
Unless defined otherwise, all technical and scientific terms used herein have
the
meaning commonly understood by a person skilled in the art to which this
invention
belongs. The following references provide one of skill with a general
definition of many of
the terms used in this invention: Singleton et al., Dictionary of Microbiology
and
Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and
Technology
(Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al.
(eds.), Springer
Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology
(1991). As
used herein, the following terms have the meanings ascribed to them below,
unless
specified otherwise.
By "ameliorate" is meant decrease, suppress, attenuate, diminish, arrest, or
stabilize the development or progression of a skin disease or condition. One
exemplary
skin condition is acne vulgaris
The terms "compounds" and "materials" are used interchangeably and refer to o
active moieties in accordance with the invention.
In this disclosure, "comprises," "comprising," "containing" and "having" and
the
like can have the meaning ascribed to them in U.S. Patent law and can mean
"includes,"
"including," and the like; "consisting essentially of" or "consists
essentially" likewise has
the meaning ascribed in U.S. Patent law and the term is open-ended, allowing
for the
presence of more than that which is recited so long as basic or novel
characteristics of that
which is recited is not changed by the presence of more than that which is
recited, but
excludes prior art embodiments.
"Detect" refers to identifying the presence, absence or amount of the analyte
to be
detected.
By "effective amount" is meant the amount of a required to ameliorate the
symptoms of a disease relative to an untreated patient. The effective amount
of active
compound(s) used to practice the present invention for therapeutic treatment
of a disease
varies depending upon the manner of administration, the age, body weight, and
general
health of the subject. Ultimately, the attending physician or veterinarian
will decide the
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appropriate amount and dosage regimen. Such amount is referred to as an
"effective"
amount.
By "energy activation" is meant stimulation by an energy source that causes
thermal or chemical activity. Energy activation may be by any energy source
known in the
art. Exemplary energy sources include a laser, ultrasound, acoustic source,
flashlamp,
ultraviolet light, an electromagnetic source, microwaves, or infrared light.
An energy
absorbing material absorbs the energy and become thermally or chemically
active.
The terms "light", "light energy", "optical energy" and "optical radiation"
are used
interchangeable herein.
As used herein, "obtaining" as in "obtaining an agent" includes synthesizing,
purchasing, or otherwise acquiring the agent.
The phrase "pharmaceutically acceptable carrier" as used herein means a
pharmaceutically acceptable material, composition or vehicle, such as a liquid
or solid
filler, diluent, excipient, solvent or encapsulating material, involved in
carrying or
transporting an energy activatable material of the present invention within or
to the subject
such that it can performs its intended function. Each carrier must be
"acceptable" in the
sense of being compatible with the other ingredients of the formulation and
not injurious
to the patient. Some examples of materials which can serve as pharmaceutically
acceptable
carriers include: sugars, such as lactose, glucose and sucrose; starches, such
as corn starch
and potato starch; cellulose, and its derivatives, such as sodium
carboxymethyl cellulose,
ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin;
talc; excipients,
such as cocoa butter and suppository waxes; oils, such as peanut oil,
cottonseed oil,
safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such
as propylene
glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;
esters, such
as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium
hydroxide and
aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;
Ringer's solution;
ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible
substances
employed in pharmaceutical formulations. Preferred carriers include those
which are
capable of entering a pore by surface action and solvent transport such that
the energy
activatable material is carried into or about the pore, e.g., into the
sebaceous gland, to the
plug, into the infundibulum and/or into the sebaceous gland and infundibulum.
By "reduces" is meant a negative alteration of at least 10%, 25%, 50%, 75%, or
100%.
By "reference" is meant a standard or control condition.
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By "subject" is meant a mammal, including, but not limited to, a human or non-
human mammal, such as a bovine, equine, canine, ovine, or feline.
Ranges provided herein are understood to be shorthand for all of the values
within
the range. For example, a range of 1 to 50 is understood to include any
number,
combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5,
6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,
30, 31, 32, 33, 34,
35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
As used herein, the terms "treat," treating," "treatment," and the like refer
to
reducing or ameliorating a disorder and/or symptoms associated therewith. It
will be
appreciated that, although not precluded, treating a disorder or condition
does not require
that the disorder, condition or symptoms associated therewith be completely
eliminated.
Unless specifically stated or obvious from context, as used herein, the term
"or" is
understood to be inclusive. Unless specifically stated or obvious from
context, as used
herein, the terms "a", "an", and "the" are understood to be singular or
plural.
Unless specifically stated or obvious from context, as used herein, the term
"about"
is understood as within a range of normal tolerance in the art, for example
within 2
standard deviations of the mean. About can be understood as within 10%, 9%,
8%, 7%,
6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value.
Unless
otherwise clear from context, all numerical values provided herein are
modified by the
term about.
The recitation of a listing of chemical groups in any definition of a variable
herein
includes definitions of that variable as any single group or combination of
listed groups.
The recitation of an embodiment for a variable or aspect herein includes that
embodiment
as any single embodiment or in combination with any other embodiments or
portions
thereof.
Any compositions or methods provided herein can be combined with one or more
of any of the other compositions and methods provided herein.
Follicular Disease Pathogenesis
Sebaceous glands are components of the pilosebaceous unit. They are located
throughout the body, especially on the face and upper trunk, and produce
sebum, a lipid-
rich secretion that coats the hair and the epidermal surface. Sebaceous glands
are involved
in the pathogenesis of several diseases, the most frequent one being acne
vulgaris. Acne is
a multifactorial disease characterized by the occlusion of follicles by plugs
made out of
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abnormally shed keratinocytes of the infundibulum (upper portion of the hair
follicle) in
the setting of excess sebum production by hyperactive sebaceous glands.
The infundibulum is an important site in the pathogenesis of many follicular
diseases (e.g., acne). There is evidence that abnormal proliferation and
desquamation of
infundibular keratinocytes leads to the formation of microcomedones and,
subsequently, to
clinically visible follicular "plugs" or comedones. Because the architecture
of the
infundibulum is important in the pathogenesis of acne, the selective
destruction of this
portion of the follicle through energy activatable material-assisted energy,
e.g., laser,
targeting eliminates or reduces the site of pathology.
Topical Delivery of Light/Energy Absorbing Materials
The invention provides delivery of light/energy absorbing materials via
topical
application into skin appendages of the follicle, specifically follicular
infundibulum and
the sebaceous gland. In one embodiment, such materials are useful for the
treatment of
follicular diseases, such as acne (e.g., acne vulgaris). In another
emobidment, such
materials are useful for the treatment of eccrine conditions such as
hyperhidrosis. The
introduction of energy activatable materials in sebaceous glands followed by
exposure to
energy (light) with a wavelength that corresponds to the absorption peak of
the
chromophore will increase the local absorption of light in tissue and lead to
selective
thermal damage of sebaceous glands.
In another aspect, there is a treating of hyperhidrosis by thermally damaging
eccrine glands or their surrounding area by applying a light-absorbing
material to the skin
of a subject, facilitating delivery into an eccrine gland via the eccrine
gland duct and
exposing said material to energy activation. The method thereby permanently
removes the
glands. In one aspect, the method of treating a follicular disease is for
treatment of
hyperhidrosis.
Skin Preparation
If desired, the skin is prepared by one or a combination of the following
methods.
Delivery of light absorbing materials may be facilitated by epilation of hair,
which is
performed prior to topical application of the light absorbing materials.
Optionally, the skin is degreased prior to application of the light absorbing
compounds. For example, acetone wipes are used prior to application of gold
nanoshells
from Sebacia, Inc. (of Duluth, Ga.) to degrease the skin, especially to remove
the sebum
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and follicular contents.
For certain subjects, delivery may be facilitated by reducing or clearing
clogged
follicles prior to application of the light absorbing material. Such clearing
can enhance the
delivery of the nanoshells. The follicles, especially in acne prone patients,
are clogged by
shed keratinocytes, sebum, and bacteria P. Acnes. The follicle can be emptied
by
application of vacuum. Other methods are cyanoacrylate stripping, strips with
components
such as Polyquaternium 37 (e.g., Biore pore removal strips). The polymers flow
into the
follicle and dry over time. When the dry polymer film is pulled out, the
follicular contents
are pulled out, emptying the follicle.
Optionally, the skin may be heated prior to application of the light absorbing
materials. Heating reduces the viscosity of the sebum and may liquefy
components of the
sebum. This can facilitate delivery of light absorbing materials (e.g.,
formulated as
nanoshells) to the follicle.
Topical Delivery of Light Absorbing Materials
Light absorbing materials, such as non-toxic dyes (e.g., indocyanine green or
methyelene blue) are topically applied to the skin following any desired
preparation. The
topically applied formulations containing the light absorbing materials may
comprise
ethanol, propylene glycol, surfactants, and acetone. Such additional
components facilitate
delivery into the follicle.
Delivery of light absorbing materials is facilitated by application of
mechanical
agitation, such as massage, acoustic vibration in the range of 10 Hz-20 kHz,
ultrasound,
alternating suction and pressure, and jets. In one embodiment, light absorbing
materials
are delivered as nanoparticles, such as nanoshells or nanorods that absorb
light in the
visible and the near-IR region of the electromagnetic spectrum. In another
embodiment,
light absorbing materials are quantum dots. Preferably, the light absorbing
materials are
formulated for topical delivery in a form that facilitates follicular
delivery. In one
embodiment, such formulations comprise water, ethanol, isopropyl alcohol,
propylene
glycol, surfactants, and isopropyl adipate and related compounds. In one
embodiment, the
formulation is hydrophilic and contains a surfactant. In another embodiment,
the
formulation is lipophilic and contains a surfactant. In still another
embodiment, the
composition is liposomal and contains a surfactant. In any of the above
embodiments, the
surfactant is less than 10% of the formulation. In another embodiment, the
formulation is
hydrophilic. In still another embodiment, the formulation is lipophilic. In
still another
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embodiment, composition is liposomal.
Ultrasound Facilitated Delivery
Ultrasound has been used to achieve transdermal delivery of compounds into the
body. Ultrasound appears to generate shock-waves and micro-jets resulting from
bubble
cavitation that causes the formation of channels in the skin, which provide
for the transport
of molecules of interest. Previous efforts have been directed toward the
delivery of the
compounds through the stratum corneum. Small molecules, for example, with
sizes less
than 5 nm, can be delivered through the stratum corneum. The delivery rate
through the
stratum corneum goes down significantly as particle size increases. For
example, for
particles with size of 50 nm and higher, the delivery rate through the stratum
corneum is
very low. However, this size is still much smaller than the pore opening and
the
infundibulum of a follicle. For example, in some embodiments of the present
invention,
150 nm size silica-core and gold shell structures are used as a chromophore in
treating a
condition affecting a subject. Such gold nanoshells are much smaller than the
infundibular
diameter, but are not readily deposited in skin through the stratum corneum.
These findings provide the basis of acne treatment in which the infundibulo-
sebaceous unit is selectively targeted for first delivery of light absorbing
material of
appropriate size and then selective thermal damage to the unit with pulsed
laser
irradiation. Here, ultrasound specifically facilitates the delivery of a light
absorbing
material into the follicular structure. The shock waves, microjet formation,
and streaming
deliver the light absorbing particles into the follicular infundibulum and the
associated
sebaceous gland duct and the sebaceous gland.
Ultrasound is often be accompanied by heating of the target organ, skin. Some
heating, for example, up to about 42 C. may help in follicular delivery.
However,
excessive heating is undesirable, causing pain, tissue damage, and burns. In
one
embodiment, excessive heating can be avoided by cooling the skin, for example.
In
another embodiment, the topically applied formulation or a coupling gel can be
pre- or
parallel-cooled. A low duty cycle with repeated ultrasound pulse bursts can
also be used to
avoid excessive heating, where during the off-time, the body cools the skin
that is being
subjected to ultrasound energy.
In certain embodiments, the invention provides two methods of ultrasound
delivery
are suggested. One is "contact ultrasound "and another is "immersion
ultrasound".
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In accordance with an embodiment of the contact ultrasound method, a
formulation
of the invention is topically applied to the skin by spreading into a thin
layer and a horn
vibrating at an ultrasound frequency is brought into close contact with the
formulation-
covered skin.
In accordance with an embodiment of the immersion ultrasound method, a
reservoir filled with the formulation is placed on top of the skin, a horn is
immersed in it
without the horn touching the skin at a distance ranging from about 2 mm to
about 30 mm,
and the horn is then vibrated at ultrasound frequency.
Acoustic cavitation is often an effect observed with ultrasound in liquids. In
acoustic cavitation, a sound wave imposes a sinusoidally varying pressure upon
existing
cavities in solution. During the negative pressure cycle, the liquid is pulled
apart at 'weak
spots'. Such weak spots can be either pre-existing bubbles or solid nucleation
sites. In one
embodiment, a bubble is formed which grows until it reaches a critical size
known as its
resonance size (Leong et al., Acoustics Australia, 2011--acoustics.asn.au, THE
FUNDAMENTALS OF POWER ULTRASOUND--A REVIEW, p 54-63). According to
Mitragotri (Biophys J. 2003; 85(6): 3502-3512), the spherical collapse of
bubbles yields
high pressure cores that emit shock waves with amplitudes exceeding 10 kbar
(Pecha and
Gompf, Phys. Rev. Lett. 2000; 84:1328-1330). Also, an aspherical collapse of
bubbles
near boundaries, such as skin yields microjets with velocities on the order of
100 m/s
(Popinet and Zaleski, 2002; J. Fluid. Mech. 464:137-163). Such bubble-collapse
phenomena can assist in delivery of materials into skin appendages, such as
hair and
sebaceous follicles. Thus, various embodiments of the invention provide for
immersion
ultrasound methods for optimizing bubble size before collapse to promote
efficient
delivery of light absorbing materials into the intended target (e.g.,
sebaceous glands, hair
follicles).
The resonance size of the bubble depends on the frequency used to generate the
bubble. A simple, approximate relation between resonance and bubble diameter
is given
by F (in Hz)×D (in m)=6 mHz, where F is the frequency in Hz and D is the
bubble
diameter (size) in m. In practice, the diameter is usually smaller than the
diameter
predicted by this equation due to the nonlinear nature of the bubble
pulsation.
Table 1 below gives the size of the resonance size of the bubble as a function
of
frequency, calculated from the above relationship.
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TABLE 1
F, kHz 10 20 30 40 50 100
200 300 400 500 1,000
D_microns 600 300 200 150 120 60 30 20 15 12 6
Computer simulations of bubble oscillations give more accurate estimates of
the
bubble size. For example, in work by Yasui (J. Acoust. Soc. Am. 2002; 112:
1405-1413),
three frequencies were investigated in depth. The sizes for single bubble
sonoluminescing
(SBSL) stable bubbles are lower and ranges are given in the Table 2 below
(estimated
from FIGS. 1, 2, and 3 of Yasui, 2002):
TABLE 2
F, kHz 20 140 1,000
D_microns 0.2 - 200 0.6 - 25 0.2 - 6
For efficient delivery into the follicles with cavitation bubbles, there is an
optimal
cavitation bubble size range. Strong cavitational shock waves are needed,
which are
generated with relatively large bubbles. However, if the bubble size is too
large, it
produces strong shock waves, which may compress the skin, reducing the pore
size, and
reducing efficient delivery to a target (e.g., sebaceous gland, follicle). For
example, if the
bubble size is much larger than the follicle opening, the resulting shock
waves compress
not only the pore opening, but also the skin surrounding the pore opening.
This inhibits
efficient delivery into the follicle opening. Desirably, bubble sizes should
be about the
same size as the target pore. Typical pore sizes of follicles on human skin
are estimated to
be in the range of 12-300 microns. Thus, an advantageous ultrasound frequency
range is
20 kHz to 500 kHz. In other alternatives, the application of ultrasound
frequency is in the
range of 20 kHz to 100 kHz, or 20 kHz to 60 kHz or even 30 kHz to 50 kHz. The
desired
power density is estimated to be in the range of 0.5-50 W/cm2. This is
sufficient to
generate cavitation bubbles in the desired size range.
"Immersion cavitation" as used herein is defined as formation and collapse of
cavitation bubbles due to the ultrasound energy within the fluid formulation.
In light of the above description, there is also provided a method of
facilitating
delivery of light absorbing materials into a hair follicle by selecting
characteristics for the
acoustically created microjets to create bubbles in the formulation about the
same size as
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the hair follicle pore. Selecting the characteristics permits the bubbles to
be about the same
size as a terminal follicle, a vellus follicle, or a sebaceous follicle. In
another alternative
implementation in light of the above description, there is also provided a
method of
facilitating delivery of light absorbing materials into a hair follicle by
selecting
characteristics for the low frequency ultrasound induced cavitation for
creating bubbles in
the formulation about the same size as the hair follicle. In one
implementation, the hair
follicle is a terminal follicle. In another implementation, the hair follicle
is a vellus follicle.
In still another implementation, the hair follicle is a sebaceous follicle. In
still other
aspects the ultrasound created microjects or low frequency ultrasound induced
cavitation
occurs in the formulation between about 50 microns to about 100 microns of the
surface of
the skin.
In another embodiment, there is also provided a method of treating or
ameliorating
a follicular skin disease of a subject. The method includes the step of
exposing the
subject's skin to a formulation comprising a sub-micron particle comprising a
light
absorbing material to a subject's skin. Next, there is a step of facilitating
delivery of said
material from the skin into a hair follicle by low frequency ultrasound
induced cavitation
within the formulation near the surface of the skin adjacent to the hair
follicle. Thereafter,
exposing said sub-micron particle to energy activation, thereby treating the
follicular skin
disease. In one alternative, there is also a step of exposing by placing a
volume of the
formulation in a container so that the formulation is in contact with the
subject's skin. Still
further, there is also a step of facilitating the method by placing an
ultrasound applicator
into the container and immersed in the formulation.
In still another embodiment, there is provided a method of facilitating
delivery of a
light absorbing material to a target volume within the skin of a subject. The
method
includes the step of topically applying a formulation comprising a light
absorbing material
to a subject's skin to deliver the material to a reservoir within the target
volume of the skin.
Next, there is a step of facilitating delivery of said material to a target
volume within the
skin of the subject substantially via a transfollicular pathway. Next, there
is a step of
exposing the light absorbing material to a series of light pulses to heat the
material and
thermally damage the target volume to achieve a therapeutic effect. In one
alternative, the
formulation has an optical density of between 5-500. In another alternative,
the
formulation has an optical density of about 75. In still another alternative,
the formulation
has an optical density of about 125. In still another alternative, the
formulation has an
optical density of about 250. In one aspect, the target volume is the
sebaceous gland. In
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another aspect, the target volume is within the follicle beneath the skin.
In still another aspect, the facilitating step includes an immersion
cavitation step.
In another alternative, there is provided a step of facilitating delivery into
a sebaceous
gland using immersion ultrasound. In one alternative, the facilitating step
includes forming
microjets within the formulation. In one aspect, the facilitating using
ultrasound produces
cavitation within a formulation and about 50 to 100 microns of the surface of
the skin. In
any of the above described methods, there is also the step of acoustically
cavitating the
formulation for selectively facilitating delivery of said particles in the
formulation into a
sebaceous gland primarily through the corresponding hair follicle. Thereafter,
there is the
step of irradiating said particles with light to treat the follicular skin
disease. In one
embodiment, the particles are sized from about 0.01 micron to about 1 micron.
In another
aspect, the particles are sized to enter into and along a follicle pore. In
still other
embodiments, the particles are between about 50 nm about 250 nm in diameter.
In another
embodiment, the particles are nanoshells.
Energy (Light) Activation
After the topical application and facilitated delivery (e.g., by mechanical
agitation,
ultrasound), the top of the skin is wiped off to remove the residual light
absorbing
material. This is followed by energy (light) irradiation. The light is
absorbed by the
material inside the follicle or sebaceous gland leading to localized heating.
The light
source depends on the absorber used. For example, for nanoshells that have
broad
absorption spectrum tuned to 800 nm resonance wavelength, sources of light
such as 800-
nm, 755-nm, 1,064-nm or intense pulsed light (IPL) with proper filtering can
be used. In
one aspect, the nanoparticles in a suspension have a peak absorption between
700 and
1,100 nm wavelength of light. Such pulsed laser irradiation leads to thermal
damage to the
tissue surrounding the material. In one aspect, the light energy has a fluence
of less than
about 100 J/cm2. Damage to infundibular follicular stem cells and/or sebaceous
glands
leads to improvement in the follicular conditions, such as acne. Such methods
can be used
not only for particulates in suspensions but for small dissolved molecules in
solution as
well. These can include pharmaceutical drugs, photodynamic therapy (PDT) pro-
drugs, or
PDT drugs.
Suitable energy sources include light-emitting diodes, incandescent lamps,
xenon
arc lamps, lasers or sunlight. Suitable examples of continuous wave apparatus
include, for
example, diodes. Suitable flash lamps include, for example pulse dye lasers
and
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Alexandrite lasers. Representative lasers having wavelengths strongly absorbed
by some
chromophores, e.g., laser sensitive dyes, within the epidermis and
infundibulum but not
sebaceous gland, include the short-pulsed red dye laser (504 and 510 nm), the
copper
vapor laser (511 nm) and the Q-switched neodymium (Nd):YAG laser having a
wavelength of 1064 nm that can also be frequency doubled using a potassium
diphosphate
crystal to produce visible green light having a wavelength of 532 nm. In the
present
process, selective photoactivation is employed whereby an energy (light)
source, e.g., a
laser, is matched with a wave-length to the absorption spectrum of the
selected energy
activatable material, preferably a chromophoric agent.
It is easier to achieve a high concentration of the light absorbing material
in the
infundibulum than the sebaceous duct and the gland, which provide a higher
resistance to
material transport. The follicle including the sebaceous gland can be
irreversibly damaged
just relying on light absorption principally but the material in the
infundibulum. This is
mediated through damage to the keratinocytes in the follicular epithelium.
Also, with
higher energy pulses can be used to extend the thermal damage to include the
stem cells in
the outer root sheath, the bulge, as well as the outside periphery of the
sebaceous glands.
However, such high energy should not lead to undesired side effects. Such side
effects can
be mitigated by use of cooling of the epidermis and also use of longer pulse
durations, on
the order of several milliseconds, extending up to 1,000 ms.
Thermal alteration of the infundibulum itself with only limited involvement of
sebaceous glands may improve acne. Appearance of enlarged pores on the face is
a
common issue for many. This is typically due to enlarged sebaceous glands,
enlarged
infundibulum, as well as enlarged pore opening. Heating of tissue, especially
collagen,
shrinks the tissue. The delivery of nanoshells and thermal targeting of the
same in the
infundibulo-sebaceous unit that includes the upper, lower infundibulum, as
well as the
sebaceous gland, will improve the appearance of enlarged pores.
Energy Absorbing Material Formulations
The invention provides compositions comprising light/energy absorbing
materials
for topical delivery. In one embodiment, a particle in the composition is a
nanoparticle
comprising a silica core and a gold shell. In still another embodiment, a
compound of the
invention comprises a silica core and a gold shell (150 nm). In another
embodiment,
nanoshells used are composed of a 120 nm diameter silica core with a 15 micron
thick
gold shell, giving a total diameter of 150 nm.
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The nanoshell is covered by a 5,000 MW PEG layer. The PEG layer prevents
and/or reduces nanoshell aggregation, thereby increasing the nanoshell
suspensions
stability and shelf-life. In one embodiment, the nanoparticle has a diameter
of about 50 to
about 250 nm. In some embodiments, the ratio of the shell diameter to the core
diameter of
the particles used herein are between about 1.5 to about 2Ø In another
aspect, the particles
in a formulation comprise from about 0.5% to about 2% of the formulation.
Nanoparticles of the invention exhibit Surface Plasmon Resonance, such that
Incident light induces optical resonance of surface plasmons (oscillating
electrons) in the
metal. The Wavelength of peak absorption can be "tuned" to the near-infrared
(IR) portion
of the electromagnetic spectrum. The submicron size of these nanoparticles
allows their
entry into the infundibulum, sebaceous duct and sebaceous gland of the
epidermis, and
minimizes their penetration of the stratum corneum. In particular embodiment,
selective
transfollicular penetration of nanoparticles ¨150-350 nm in diameter is
achieved. In one
aspect, there is provided a method of treating or ameliorating a follicular
skin disease of a
subject. There is a step of topically applying a formulation comprising a sub-
micron
particle comprising a light absorbing material to a subject's skin. Next there
is a step of
delivering said formulation into one or more sebaceous glands substantially
via a
transfollicular pathway. Next, there is a step of exposing said sub-micron
particle to
energy activation, thereby treating the follicular skin disease. In one
aspect, a portion of
the stratum corneum within the portion of the skin exposed to the delivering
step remains
intact. Still further, the delivering step is completed using an immersion
ultrasound step
whereby the portion of the stratum corneum within the portion of the skin
exposed to the
delivering step remains intact.
If desired, light/energy absorbing materials are provided in vehicles
formulated for
topical delivery. In one embodiment, a composition of the invention is
formulated with
agents that enhance follicular delivery, including but not limited to, one or
more of
ethanol, isopropyl alcohol, propylene glycols, surfactants such as polysorbate
80,
Phospholipon 90, polyethylene glycol 400, and isopropyl adipate. In other
embodiments, a
composition of the invention is formulated with one or more thickening agents,
including
but not limited to, hydroxypropylcellulose (HPC) and carboxymethyl cellulose
(CMC), to
enhance handling of the formulations.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and
magnesium stearate, as well as coloring agents, release agents, coating
agents, sweetening
and perfuming agents, preservatives and antioxidants can also be present in
the
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compositions.
Liquid dosage forms for topical administration of the compositions of the
invention
include pharmaceutically acceptable emulsions, microemulsions, solutions,
creams,
lotions, ointments, suspensions and syrups. In addition to the active
ingredient, the liquid
dosage forms may contain inert diluents commonly used in the art, such as, for
example,
water or other solvents, solubilizing agents and emulsifiers, such as ethyl
alcohol,
isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed,
groundnut, corn,
germ, olive, castor, peach, almond and sesame oils), glycerol, tetrahydrofuryl
alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Suspensions, in addition to the active compounds, may contain suspending
agents
as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and
sorbitan
esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-
agar and
tragacanth, and mixtures thereof.
The ointments, pastes, creams and gels may contain, in addition to an active
compound of this invention, excipients, such as animal and vegetable fats,
oils, waxes,
paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols,
silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. The term
"cream" is art
recognized and is intended to include semi-solid emulsion systems which
contain both an
oil and water. Oil in water creams are water miscible and are well absorbed
into the skin,
Aqueous Cream BP. Water in oil (oily) creams are immiscible with water and,
therefore,
more difficult to remove from the skin. These creams are emollients, lubricate
and
moisturize, e.g., Oily Cream BP. Both systems require the addition of either a
natural or a
synthetic surfactant or emulsifier.
The term "ointment" is art recognized and is intended to include those systems
which have oil or grease as their continuous phase. Ointments are semi-solid
anhydrous
substances and are occlusive, emollient and protective. Ointments restrict
transepidermal
water loss and are therefore hydrating and moisturizing. Ointments can be
divided into
two main groups--fatty, e.g., White soft paraffin (petrolatum, Vaseline), and
water soluble,
e.g., Macrogol (polyethylene glycol) Ointment BP. The term "lotion" is art
recognized and
is intended to include those solutions typically used in dermatological
applications. The
term "gel" is art recognized and is intended to include semi-solid
permutations gelled with
high molecular weight polymers, e.g., carboxypolymethylene (Carbomer BP) or
methylcellulose, and can be regarded as semi-plastic aqueous lotions. They are
typically
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non-greasy, water miscible, easy to apply and wash off, and are especially
suitable for
treating hairy parts of the body.
Subject Monitoring
The disease state or treatment of a subject having a skin disease or disorder
can be
monitored during treatment with a composition or method of the invention. Such
monitoring may be useful, for example, in assessing the efficacy of a
particular agent or
treatment regimen in a patient. Therapeutics that promote skin health or that
enhance the
appearance of skin are taken as particularly useful in the invention.
Kits
The invention provides kits for the treatment or prevention of a skin disease
or
disorder, or symptoms thereof. In one embodiment, the kit includes a
pharmaceutical pack
comprising an effective amount of a light/energy absorbing material (e.g., a
nanoshell
having a silica core and a gold shell (150 nm)). Preferably, the compositions
are present in
unit dosage form. In some embodiments, the kit comprises a sterile container
which
contains a therapeutic or prophylactic composition; such containers can be
boxes,
ampules, bottles, vials, tubes, bags, pouches, blister-packs, or other
suitable container
forms known in the art. Such containers can be made of plastic, glass,
laminated paper,
metal foil, or other materials suitable for holding medicaments.
If desired compositions of the invention or combinations thereof are provided
together with instructions for administering them to a subject having or at
risk of
developing a skin disease or disorder. The instructions will generally include
information
about the use of the compositions for the treatment or prevention of a skin
disease or
disorder. In other embodiments, the instructions include at least one of the
following:
description of the compound or combination of compounds; dosage schedule and
administration for treatment of a skin condition associated with acne,
dermatitis, psoriasis,
or any other skin condition characterized by inflammation or a bacterial
infection, or
symptoms thereof; precautions; warnings; indications; counter-indications;
overdosage
information; adverse reactions; animal pharmacology; clinical studies; and/or
references.
The instructions may be printed directly on the container (when present), or
as a label
applied to the container, or as a separate sheet, pamphlet, card, or folder
supplied in or
with the container.
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The recitation of a listing of chemical groups in any definition of a variable
herein
includes definitions of that variable as any single group or combination of
listed groups.
The recitation of an embodiment for a variable or aspect herein includes that
embodiment
as any single embodiment or in combination with any other embodiments or
portions
thereof.
The following examples are provided to illustrate the invention, not to limit
it.
Those skilled in the art will understand that the specific constructions
provided below may
be changed in numerous ways, consistent with the above described invention
while
retaining the critical properties of the compounds or combinations thereof.
Laser Hair Removal
The invention features compositions and methods that are useful for laser hair
removal, particularly in light colored hair. In laser hair removal, a specific
wavelength of
light and pulse duration is used to obtain optimal effect on a targeted tissue
with minimal
effect on surrounding tissue. Lasers can cause localized damage to a hair
follicle by
selectively heating melanin, which is a dark target material, while not
heating the rest of
the skin. Because the laser targets melanin, light colored hair, gray hair,
and fine or thin
hair, which has reduced levels of melanin, is not effectively targeted by
existing laser hair
removal methods. Efforts have been made to deliver various light absorbing
materials,
such as carbon particles, extracts from squid ink, known commercially as
meladine, or
dyes into the follicle. These methods have been largely ineffective.
The present invention provides microparticles in a suspension form that is
topically
applied after skin preparation as delineated herein above. In particular, the
skin is prepared
by epilation of the hair shaft and light absorbing materials are delivered to
the hair follicle.
Preferably, the formulation is optimized for follicular delivery with
mechanical agitation
for a certain period of time. After wiping off the formulation from the top of
the skin, laser
irradiation is performed, preferably with surface cooling. The laser is
pulsed, with pulse
duration approximately 0.5 ms-400 ms or, alternatively, from 0.5 ms-1,000 ms
using a
wavelength that is absorbed by the particle or the nanoshells. This method
will
permanently remove unpigmented or lightly pigmented hair by destroying the
stem cells
and other apparatus of hair growth which reside in the bulge and the bulb area
of the
follicle.
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The practice of the present invention employs, unless otherwise indicated,
conventional techniques of molecular biology (including recombinant
techniques),
microbiology, cell biology, biochemistry and immunology, which are well within
the
purview of the skilled artisan. Such techniques are explained fully in the
literature, such
as, "Molecular Cloning: A Laboratory Manual", second edition (Sambrook, 1989);
"Oligonucleotide Synthesis" (Gait, 1984); "Animal Cell Culture" (Freshney,
1987);
"Methods in Enzymology" "Handbook of Experimental Immunology" (Weir, 1996);
"Gene Transfer Vectors for Mammalian Cells" (Miller and Cabs, 1987); "Current
Protocols in Molecular Biology" (Ausubel, 1987); "PCR: The Polymerase Chain
Reaction", (Mullis, 1994); "Current Protocols in Immunology" (Coligan, 1991).
These
techniques are applicable to the production of the polynucleotides and
polypeptides of the
invention, and, as such, may be considered in making and practicing the
invention.
Particularly useful techniques for particular embodiments will be discussed in
the sections
that follow.
The following examples are put forth so as to provide those of ordinary skill
in the
art with a complete disclosure and description of how to make and use the
assay,
screening, and therapeutic methods of the invention, and are not intended to
limit the
scope of what the inventors regard as their invention.
EXAMPLES
Example 1
Topical Delivery of Nanoshells to the Follicular Epithelium for the Treatment
of Follicular
Diseases
An example of massage as a mechanical means of follicular delivery is
described.
Nanoshell suspension tuned to 800-nm was massaged in an epilated pig skin in
an in vivo
live pig. Laser energy with parallel contact cooling was applied after wiping
off the
suspension on the top of the skin. A biopsy was taken, and routine histology
was
performed. A micrograph of the histology is shown at FIG. 1. Thermal damage to
the
follicular epithelium and part of the sebaceous gland is noted. Such damage is
useful for
the treatment of follicular diseases, such as acne or for improving the
appearance of oily
skin of a subject.
One exemplary method for the treatments above includes the step of topically
applying a formulation comprising a sub-micron particle comprising a light
absorbing
materials to a subject's skin. Next, there is a step of facilitating delivery
of said materials
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to a hair follicle, sebaceous gland, sebaceous gland duct, or infundibulum of
the skin by
mechanical agitation, acoustic vibration, ultrasound, alternating suction and
pressure, or
microjets. Thereafter, there is the step of exposing said sub-micron particle
to energy
activation, thereby treating the follicular skin disease.
Example 2
Topical Delivery of Nanoshells to the Follicular Epithelium for Laser Hair
Removal
In preparation for laser hair removal, a pig flank was epilated by waxing.
Skin was
subsequently heated, and a vacuum was applied to empty the follicular contents
of the
skin. Silica core: gold shell microparticles, of approximate dimensions of
0.150
micrometers diameter coated with PEG were then delivered by massaging. Skin
was
wiped to remove the material from the top of the skin. This was followed by
pulsed laser
irradiation at 800 nm. Samples were excised, fixed in formalin, and processed
via routine
histology (H&E staining). Thermal injury to the follicular structure was noted
via
histology.
Example 3
Light-Pulse Induced Pressure Pulse Facilitated Delivery
A formulation containing a light-absorbing material is applied on top of skin.
This
is moved into the infundibulum of the infundibulo-sebaceous unit by methods
known in
the art, including but not limited to, passive diffusion, heating, mechanical
assistance such
as pressure pulsing, vibration, acoustic coils, ultrasound, nozzles or a
combination of the
above. Then, pulses of light are applied with a handpiece with an integrated
cooling plate
that can be pressed on to the skin. The first pulse(s) of light heat the
material, resulting in
expansion, with or without steam bubble formation. A pressure pulse is thereby
created.
Pressure is applied to the skin by the plate during the pressure pulse.
Because the pressure
cannot escape from the skin, the material flows through low resistance
channels within the
skin, such as the sebaceous gland duct, to reach the sebaceous gland. This
pulse typically
has short pulse duration, e.g., 1 ns-1 ms, preferably, 10 ns-100 microseconds,
to maximize
the magnitude of the pressure pulse, for example, through steam bubble
formation. Once
the material is within the target sebaceous gland, light is applied with a
pulse duration and
radiant exposure appropriate to the size of the sebaceous glands being
targeted. The light
absorbing material is heated, causing thermal damage to the sebaceous gland,
thus
inactivating it, and causing improvement in acne vulgaris and other follicular
diseases and
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conditions associated with the presence or activity of sebaceous glands.
In a related approach, a train of low-energy laser pulses, 1 microsecond or
less in
pulse duration, preferably in the acoustic range for pulse repetition rate, is
used to activate
the particles. This activation violently 'stirs' the particles, some of which
will be propelled
from the infundibulum into the sebaceous glands.
Example 4
Use of Ultrasound to Deliver Light Absorbing Material to the Follicle and
Sebaceous
Glands
Pig ear skin was kept frozen. Before the experiment, it was thawed. Hair was
epilated with waxing and a piece of the pig ear with skin facing up was placed
at the
bottom of a cup. It was filled with formulation of 150-nm diameter silica-
core/gold-shell
nanoshells (Sebacia, Inc., Duluth, Ga.) with an optical density of
approximately 250. A
Sonics, 20 kHz device horn was immersed into the formulation so that the
distance
between the far surface of the horn at the top of the skin was approximately 5-
mm. The
horn diameter was 13 mm and the power output was approximately 6 W. Thus, the
power
density during the on-time was 4.5 W/cm2. The device was turned on with 50%
duty
cycle, with the on-time and off-time per cycle of 5 s and 5 s, respectively.
Four cycles
were applied. After wiping the skin to remove excess formulation, the skin was
irradiated
with laser light at 800-m wavelength with a 9 mm×9 mm spot,
approximately 50
J/cm2 total radiant exposure, and 30-ms pulse duration.
The skin was observed via a dissecting microscope and photographs were taken
(FIG. 2). Cuts perpendicular to the skin surface were made through follicle
openings and
the cut surface was observed through an optical microscope (FIG. 3). Some
samples were
placed in 10% buffered formalin solution and observed via routine histology
(FIG. 4).
The skin was intact and unperturbed except punctuate dots were noted on the
follicle openings (FIG. 2). Upon cutting and observing through a microscope,
the presence
of dark nanoshells was noted within the follicle infundibulum, as well as in
the sebaceous
glands (FIG. 3). No nanoshells were seen in the epidermis or the dermis
surrounding the
follicles. Similarly, histology showed thermal damage to the follicular
infundibulum and
the sebaceous glands (FIG. 4). There was no or minimal damage to the epidermis
and the
dermis surrounding the follicles.
In one alternative aspect, in a method employing an ultrasound horn used for
immersion ultrasound, the ultrasound horn face peak-to-peak amplitude
displacement is in
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the range of 0.5 to 30 microns.
In still other aspects, there is provided a sub-micron particle size is
selected for
passage through the hair follicle and into a sebaceous gland of the hair
follicle. In one
embodiment, the hair follicle is a terminal follicle. In another embodiment,
the hair follicle
is a vellus follicle. In still another embodiment, the hair follicle is a
sebaceous follicle. In
still further implementations of the inventive methods described herein, the
sub-micron
particle size is between about 0.01 microns to about 1.0 microns. In still
another
exemplary implementation, the sub-micron particle size is between about 0.05
to about
0.25 microns.
Example 5
Ultrasound Facilitated Delivery
A transducer from APC International of Mackeyville, Pa. was driven by a
sinusoidal wave of 300 Vp-p from a waveform generator and an amplifier with
500 Ohm
source impedance. A formulation of 250 OD (F78, Sebacia, Inc.) containing the
150 nm
diameter silica core: gold shell was placed topically on epilated pig ear
skin. This was
followed by wiping of the top surface and laser irradiation with Lumenis
Lightsheer at 800
nm. The skin temperature was noted after the ultrasound application and did
not exceed
41 C.
Significant accumulation of the nanoshells in the follicles was noted (FIG.
5).
Vertical cuts were made through follicles and the cut surfaces were observed
under a
microscope. An exemplary follicle is shown in FIG. 6. A significant
accumulation of
nanoshells inside and outside the infundibulum is noted.
Histological analysis of a sample is shown in FIG. 7. Localized thermal damage
to
the follicle including thermal damage to the sebaceous glands is observed
(FIG. 7).
Example 6
Human Clinical Efficacy Demonstrated in Back Acne
The efficacy of nanoshell topical delivery followed by laser treatment was
evaluated in a clinical study of back acne. Nanoshells were topically applied
to the back of
each subject and laser treatment was initiated as described herein above. This
treatment
regimen was administered twice to each subject. Results were evaluated twelve
weeks
following the second treatment. Efficacy was determined by weighted
inflammatory lesion
counts. Results are shown in FIG. 8. This study of back acne study indicates
that the
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treatment regimen was clinically effective.
Example 7
Human Clinical Efficacy Demonstrated in Sebaceous Gland Damage
IRB approved human clinical studies have been carried out in seventeen
subjects
(6 males, 11 females) with acne. The subjects range in age from 18-40 years
(mean 24
years) phototype I-IV. Treatment was carried out on a 1 square inch area
behind ear
(sebaceous follicles). Nanoshells were delivered followed by laser treatment,
where the
laser was tuned to the nanoshell's absorption peak (40-50 J/cm2, 30-ms,
9×9 mm,
LightSheer (800 nm)). Therapeutic efficacy was histologically evaluated in 31
biopsies,
where 4-7 follicles were present in each biopsy. A 4 mm punch biopsy was
taken, serially
sectioned, and damage to sebaceous follicle was visualized by H&E staining.
Pain,
erythema, edema minimal. Localized damage was observed in ¨60% of sebaceous
follicles. In some specimens, destruction of the entire sebaceous gland was
observed. The
depth of thermal damage in follicles was on average 0.47 mm (maximum 1.43 mm).
No
collateral damage to epidermis or dermis was observed. In-vivo histology study
damage to
infundibulum, bulge and sebaceous glands was observed after treatment.
Example 8
Ultrasound Facilitated Delivery of Photodynamic Therapy (PDT) with
Aminolevulinic
Acid (ALA)
In experiments with ultrasound, the follicle provided easier access for
delivery of
light absorbing materials than the stratum corneum. This may be due to a
differential in
the transport rates into the stratum comeum and the follicle. This difference
can be
exploited to facilitate selective delivery of smaller molecules. This approach
can be used
for either chromophores in a photothermal treatment regimen or for
photodynamic therapy
with compounds or prodrugs leading to photodynamic effect. For example,
convention
acne therapies involving ALA-PDT treatment require long incubation times (on
the order
of 3-4 hours) to deliver sufficient concentration of ALA to the sebaceous
glands to achieve
the desired clinical efficacy.
This treatment results in significant adverse side effects, including
epidermal
crusting, pain, and long-lasting redness. This extended incubation period
results in the
delivery of ALA to non-target areas of the epidermis and the dermis.
Ultrasound-assisted
delivery can be accomplished without these long incubation periods, while
still achieving
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sufficient concentrations in the target infundibulo-sebaceous unit. Because
the long
incubation period is eliminated with ultrasound delivery, little ALA is
delivered to the
non-target epidermis and dermis. After ultrasound delivery, the ALA
formulation can be
removed from the skin surface. The light irradiation is performed once
sufficient time has
passed to ensure that concentrations of the photoactive material have reached
adequate
levels in the target volume. In photothermal treatments, pulsed laser
irradiation can be
initiated soon after delivery.
In another embodiment, materials (compounds) of interest are attached to
microparticles and delivered to the target volume. Light irradiation may be
used to
disassociate the material, leading to its diffusion and subsequent action.
Formation of
cavitation bubbles is facilitated by the presence of nanoparticles that "seed"
bubble
formation. Also, delivery can be facilitated by the use of volatile components
such as
ethanol.
Example 9
Formulations
Various nanoshells formulation were tested in an ex vivo skin model. The
components tested were designed to enhance delivery into follicles.
Formulation
constituents were ethanol, isopropyl alcohol, propylene glycols, surfactants
such as
polysorbate 80, Phospholipon 90, polyethylene glycol 400, isopropyl adipate.
Compatibility of these amongst each other was tested. Three classes were
identified:
hydrophilic, lipophilic, and liposomal. The absorption coefficient of the
formulation is
suggested to be in the range of 10 to 1,000 inverse cm. Four example
formulations were
tested in an in vivo pig skin model; the compositions are as in Table 3 below
showing four
of the formulations tested in a human back acne study.
TABLE 3
Components F74 F76 F78 F80
PEGylated nanoshell suspension in water 12% 25% 25% 65%
(Optical density ¨1,100-1,200)
Ethyl Alcohol 190 proof 73% 55% 54% 20%
Propylene Glycol 5% 10% 5%
Polysorbate 80 1% 9% 1% 9%
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Benzyl Alcohol 9% 1% 1%
Diisopropyl Adip ate 20%
Total 100%
100% 100% 100%
Re-suspension of particles
As described above, there are a wide variety of treatments described that
involve
the application of a particle containing suspension to the skin surface
followed by one or
methods of facilitating penetration of the formulation and particles into a
desired treatment
location for subsequent activation. As described above in the various
formulations and
compositions, these particles are suspended in a liquid that typically
consists of water,
ethanol, diisopropyl adipate, and polyethyelene glycol. These are typically
low viscosity
formulations and as mentioned earlier, the particle delivery is aided by a
technique to
facilitate penetration to a target site. In one aspect, the bulk flow of the
fluid containing
the particles from the skin surface through the pores to the target sebaceous
follicles is the
primary method of transport of the particles. With this method, the fraction
of particles
delivered into the follicles compared to the total applied to the skin surface
is very small.
For example, it is estimated that only about 1% of the particles that are
applied to the
facial skin make it into the follicles. Also, the fluid (vehicle) portion of
the suspension
evaporates within a short time, for instance, in less than a minute.
In one aspect, after the substantial evaporation, the transport of the
particles into
the sebaceous follicles is minimal or zero. As a result, there is a layer of
particles, black in
color that is left on the top of the skin surface. This residue comes from
those particles on
the surface which have not been pushed into the target site. Previously, this
residue is
wiped away before laser irradiation.
In one alternative, the residue is instead re-used or re-mobilized by the
addition of
a suitable vehicle (i.e., a liquid or fluid to free the particles from the
dried state on the skin
surface). In this way, there is provided a method for the 'reuse' of the
particles previously
applied to one part of the skin surface to another part of the skin surface.
Optionally, the
re-use may be for the same treatment area. Once the particle delivery fluid or
formulation
has dried up, part of the skin surface will have a layer of the particles.
Thereafter, rather
than applying more of the particle formulation, a less expensive liquid
vehicle (similar to
the previously used formulation but without the expensive microparticles) can
be added to
this surface. By introducing this vehicle, the user may re-suspend the
particles. Then,
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once the previously applied particles are again mobile in a suspension, a
massager or other
of the above described delivery techniques can be used to move the particles
to another
part of the skin surface. For example, the particles may be applied to one
part of the face
(e.g., left chin). After drying out, the particles are re-suspended and moved
to another part
of the face (e.g., right chin). Thereafter, facilitated delivery using any of
the above
described techniques may be continued. Additionally or optionally depending
upon the
amount of particles that have been re-constituted, an amount of fresh
microparticle
suspension can be added to this new area. Essentially, the particles left on
one part of skin
surface are used in another part of the skin surface.
In another alternative, the method of applying a liquid vehicle described
herein can
be applied to the re-use of particles in the same treatment area. By
continuing to re-
constitute the particles in the same area an increasing percentage of particle
delivery into
target sites may be achieved. In one example, the method described herein is
used to
achieve higher delivery in the follicles in that area. It is to be appreciated
that the method
of particle re-use is applicable to both insoluble particles as well as
soluble materials, e.g.,
dyes or drugs. In still other aspects, there is provided a method of delivery
of materials
relying on liquid phase to drive the particles into target pores and follicles
where
additional areas are treated by applying vehicle to the dry suspension. Still
further, the
method described above may be adapted to the delivery of materials relying on
liquid
phase to drive the particles into target pores and follicles where additional
delivery can be
obtained by treated by applying vehicle to the dry suspension.
The examples and illustrations included herein show, by way of illustration
and not
of limitation, specific embodiments in which the subject matter may be
practiced. In one
aspect, the operation of the delivery device for the delivery of a delivery
fluid is the
desired therapy. In this case, the operation of the delivery device is a
complete treatment
operation. In another aspect, the operation of the delivery device for the
delivery of a
delivery fluid precedes or follows another treatment or another desired
therapy. In this
case, the operation and use of the delivery device is one part of a multi-part
therapy. In
one specific example of a multiple part therapy is the use of the delivery
system to deliver
a fluid, a formulation particles, shells, pharmaceuticals, liposomes, other
treatment agents
or pharmacologic materials onto, into or within a structure within a treatment
or delivery
site followed by a further treatment of the delivery or treatment site. In one
specific
example the further treatment is providing an activating energy to a fluid, a
formulation or
a pharmacologic material. Exemplary fluids, formulations and treatments are
described in
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U.S. Patent 6,183,773; U.S. Patent 6,530,944; U.S. Published Patent
Application US
2013/0315999 and U.S. Published Patent Application US 2012/0059307, each of
which is
incorporated herein in its entirety. Additionally or optionally, one or more
of the delivery
device operating parameters, and/or methods of use of the delivery system
described
herein may be modified based upon one or more characteristics of the delivery
fluid, a
component of the delivery fluid or a particle within the delivery fluid being
used.
Other Embodiments
From the foregoing description, it will be apparent that variations and
modifications may be made to the invention described herein to adopt it to
various usages
and conditions. Such embodiments are also within the scope of the following
claims.
The recitation of a listing of elements in any definition of a variable herein
includes definitions of that variable as any single element or combination (or
subcombination) of listed elements. The recitation of an embodiment herein
includes that
embodiment as any single embodiment or in combination with any other
embodiments or
portions thereof.
