U.S. patent application number 13/789575 was filed with the patent office on 2013-11-28 for compositions and methods comprising energy absorbing compoundfs for follicular delivery.
This patent application is currently assigned to The General Hospital Corporation. The applicant listed for this patent is The General Hospital Corporation. Invention is credited to Richard Rox Anderson, Richard Blomgren, Apostolos G. Doukas-Anderson, William A. Farinelli, Dilip Paithankar.
Application Number | 20130315999 13/789575 |
Document ID | / |
Family ID | 49383929 |
Filed Date | 2013-11-28 |
United States Patent
Application |
20130315999 |
Kind Code |
A1 |
Paithankar; Dilip ; et
al. |
November 28, 2013 |
COMPOSITIONS AND METHODS COMPRISING ENERGY ABSORBING COMPOUNDFS FOR
FOLLICULAR DELIVERY
Abstract
The present invention provides 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. This delivery is
facilitated by application of mechanical agitation (e.g. massage),
acoustic vibration in the range of 10 Hz-20 kHz, ultrasound,
alternating suction and pressure, and microjets.
Inventors: |
Paithankar; Dilip; (Weyland,
MA) ; Blomgren; Richard; (Dacula, GA) ;
Anderson; Richard Rox; (Boston, MA) ; Farinelli;
William A.; (Danvers, MA) ; Doukas-Anderson;
Apostolos G.; (Belmont, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The General Hospital Corporation; |
|
|
US |
|
|
Assignee: |
The General Hospital
Corporation
Boston
MA
|
Family ID: |
49383929 |
Appl. No.: |
13/789575 |
Filed: |
March 7, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61636381 |
Apr 20, 2012 |
|
|
|
Current U.S.
Class: |
424/490 ;
424/649 |
Current CPC
Class: |
A61P 17/08 20180101;
A61K 9/0014 20130101; A61K 9/5115 20130101; A61K 41/0047 20130101;
A61K 9/50 20130101; A61P 17/00 20180101; A61P 43/00 20180101; A61K
33/24 20130101; A61K 9/0009 20130101; A61P 17/10 20180101 |
Class at
Publication: |
424/490 ;
424/649 |
International
Class: |
A61K 33/24 20060101
A61K033/24; A61K 9/50 20060101 A61K009/50 |
Claims
1. A method of treating or ameliorating a follicular skin disease
of a subject, the method comprising a) topically applying a
formulation comprising a sub-micron particle comprising a light
absorbing compound to a subject's skin; b) facilitating delivery of
said compound 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 c) exposing said sub-micron particle to energy
activation, thereby treating the follicular skin disease.
2. The method of claim 1, wherein the submicron particle is a
photoactive compound, photodynamic therapy (PDT) pro-drug or PDT
drug.
3. The method of claim 1, wherein the application of ultrasound
energy is at a frequency in the range of 20 kHz to 500 kHz.
4. A method of improving the appearance of enlarged pores in the
skin of a subject, the method comprising a) topically applying a
formulation of claim 1 to a subject's skin; b) facilitating
delivery of said compound 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 c) exposing said sub-micron particle to
energy activation, thereby treating the follicular skin disease
5. The method of claim 1, wherein the sub-micron particle is coated
with PEG.
6. The method of claim 1, wherein said particle is a nanoparticle
comprising a silica core and a gold shell.
7. The method of claim 1, wherein said nanoparticle is 150 nm in
diameter.
8. The method of claim 1, wherein said nanoparticle is a
nanoshell.
9. The method of claim 6, wherein the nanoparticle is coated with
PEG.
10. The method of claim 1, wherein energy activation is
accomplished with a pulsed laser light that delivers light energy
at a wavelength that is absorbed by the particle.
11. The method of claim 1, wherein said skin is prepared for the
method by heating, by removing the follicular contents, and/or by
epilation.
12. The method of claim 9, wherein the follicular contents are
removed by a method comprising contacting the follicle pore with
adhesive polymers.
13. The method of claim 1, wherein said topically applied
sub-micron particles are wiped from the skin prior to energy
activation.
14. The method of claim 1, wherein said topically applied
sub-micron particles are wiped from the skin with acetone.
15. The method of claim 1, wherein said follicular skin disease is
acne vulgaris.
16. The method of claim 1, wherein energy activation is carried out
by irradiation of the skin with a laser.
17. The method of claim 1, wherein the ultrasound energy has a
frequency in the range of 20 kHz to 500 kHz.
18. The method of claim 1, wherein where the skin is heated before,
during, or after topical application to about 42.degree. C. or to a
temperature sufficient to assist in follicular delivery.
19. The method of claim 16, wherein the heating is accomplished via
ultrasound.
20. The method of claim 16, wherein the heating is not sufficient
to cause pain, tissue damage, burns, or other heat-related effects
in the skin.
21. A method for permanently removing lightly pigmented or thin
hair of a subject, the method comprising a) topically applying a
light-absorbing compound to the skin of a subject, and b) exposing
said compound to energy activation, thereby permanently removing
said hair.
22. The method of claim 21, further comprising epilating hair from
a follicle of the subject prior to topical application of the
light-absorbing compound.
23-26. (canceled)
27. A method of facilitating delivery of a light absorbing compound
to a target volume within the skin of a subject, the method
comprising a) topically applying a formulation comprising a light
absorbing compound to a subject's skin to deliver the compound to a
reservoir within the skin; b) facilitating delivery of said
compound to a target volume within the skin of the subject by
irradiating the skin with a first series of light pulses; and c)
exposing said light absorbing compound to a second series of light
pulses to heat the compound and thermally damage the target volume
to achieve a therapeutic effect.
28. A method of facilitating delivery of a light absorbing compound
to a target volume within the skin of a subject, the method
comprising a) topically applying a formulation comprising a light
absorbing compound to a subject's skin; b) facilitating delivery of
said compound to a reservoir in the skin by mechanical agitation;
c) facilitating delivery of said compound 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 d) exposing said light absorbing compound to a
second series of low-energy laser pulses to heat the compound and
thermally damage the target volume to achieve a therapeutic
effect.
29-34. (canceled)
35. 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.
36-49. (canceled)
50. 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 the
composition of claim 35; 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.
51-53. (canceled)
54. The composition of claim 35, further comprising an effective
amount of sodium dodecyl sulfate, 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.
55. A system for laser ablation of hair or treatment of acne
comprising the composition of claim 35 and a source of plasmonic
energy suitable for application to the human skin.
Description
RELATED APPLICATION DATA
[0001] This application claims the benefit of U.S. provisional
patent application Ser. No. 61/636,381, filed Apr. 20, 2012, the
entire contents of which are incorporated herein by this
reference.
[0002] This application may contain subject matter that is related
to that disclosed and claimed in U.S. patent application
publication No. 2012/0059307 A2, published on Mar. 8, 2012, the
entire contents of which are incorporated herein by this
reference.
BACKGROUND OF THE INVENTION
[0003] 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.
SUMMARY OF THE INVENTION
[0004] As described below, the present invention provides
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 a hair follicle, sebaceous duct, and/or sebaceous
gland. In certain embodiments, this delivery is facilitated by
application of mechanical agitation (e.g. massage), acoustic
vibration in the range of 10 Hz-20 kHz, ultrasound, alternating
suction and pressure, and microjets.
[0005] In one aspect, the invention generally provides methods of
treating or ameliorating a follicular skin disease (e.g., acne) of
a subject (e.g., human). The method involves topically applying a
formulation containing a sub-micron particle containing a light
absorbing compound to a subject's skin; facilitating delivery of
the compound 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 particle to energy
activation, thereby treating the follicular skin disease.
[0006] In another aspect, the invention provides a method of
treating or ameliorating a follicular skin disease of a subject,
the method involving topically applying a formulation containing a
photoactive compound, photodynamic therapy (PDT) pro-drug or PDT
drug to the skin of a subject, facilitating delivery of the
compound 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 photoactive compound, photodynamic
therapy (PDT) pro-drug to energy activation, thereby treating the
follicular disorder.
[0007] In another aspect, the invention provides a method of
improving the appearance of enlarged pores in the skin of a
subject, the method involving topically applying a formulation
containing a sub-micron particle containing a light absorbing
compound to a subject's skin; facilitating delivery of the compound
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 particle to energy
activation, thereby treating the follicular skin disease.
[0008] In another aspect, the invention provides a method for
permanently removing lightly pigmented or thin hair of a subject,
the method involving topically applying a light-absorbing compound
to the skin of a subject, and exposing the compound to energy
activation, thereby permanently removing the hair.
[0009] In another aspect, the invention provides a method for
permanently removing lightly pigmented or thin hair of a subject,
the method involving epilating hair from a follicle of the subject;
topically applying a light-absorbing compound to the skin of a
subject, and exposing the compound to energy activation, thereby
permanently removing the hair. In one embodiment, the compound is a
nanoparticle containing a silica core and a gold shell. In another
embodiment, energy activation is accomplished with a pulsed laser
light that delivers light energy at a wavelength that is absorbed
by the particle. In another embodiment, the skin is prepared for
the method by heating, by removing the follicular contents, and/or
by epilation. In another embodiment, the topically applied
sub-micron particles are wiped from the skin prior to energy
activation using acetone.
[0010] In another aspect, the invention provides a method of
facilitating delivery of a light absorbing compound to a target
volume within the skin of a subject, the method involving topically
applying a formulation containing a light absorbing compound to a
subject's skin to deliver the compound to a reservoir within the
skin; facilitating delivery of the compound 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 compound
to a second series of light pulses to heat the compound and
thermally damage the target volume to achieve a therapeutic
effect.
[0011] In another aspect, the invention provides a method of
facilitating delivery of a light absorbing compound to a target
volume within the skin of a subject, the method involving topically
applying a formulation containing a light absorbing compound to a
subject's skin; facilitating delivery of the compound to a
reservoir in the skin by mechanical agitation; facilitating
delivery of the compound 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 compound to a second series of
low-energy laser pulses to heat the compound and thermally damage
the target volume to achieve a therapeutic effect.
[0012] In various embodiments of any of the above aspects or other
aspects of the invention delineated herein, the sub-micron
particle, nanoparticle, or nanoshell is coated with PEG. In other
embodiments of the above aspects, the sub-micron particle is a
nanoparticle containing a silica core and a gold shell, optionally
coated with PEG. In certain embodiments, the nanoparticle or
nanoshell is about 50-300 nm (e.g., 50, 75, 100, 125, 150, 175,
200, 300 nm). In particular embodiments, the nanoparticle is coated
with PEG. In embodiments of the invention, energy activation is
accomplished with a pulsed laser light that delivers light energy
at a wavelength that is absorbed by the particle. In other
embodiments, the skin is prepared for the method by heating (e.g.,
to at least about 35-42.degree. C.), by removing the follicular
contents, and/or by epilation. In other embodiments, the follicular
contents are removed by a method comprising contacting the follicle
pore with adhesive polymers. In other embodiments, the topically
applied sub-micron particles are wiped from the skin prior to
energy activation. In still other embodiments, the topically
applied sub-micron particles are wiped from the skin with acetone.
In other embodiments, the follicular skin disease is acne vulgaris.
In other embodiments, energy activation is carried out by
irradiation of the skin with a laser. In other embodiments, the
ultrasound energy has a frequency in the range of 20 kHz to 500
kHz. In other embodiments, the skin is heated before, during, or
after topical application to about 42.degree. C. or to a
temperature sufficient to assist in follicular delivery. In other
embodiments, the heating is accomplished via ultrasound. In other
embodiments, the heating is not sufficient to cause pain, tissue
damage, burns, or other heat-related effects in the skin. In other
embodiments, the formulation contains a component (e.g., ethanol)
having high volatility. In other embodiments, the formulation
contains one or more of ethanol, isopropyl alcohol, propylene
glycol, a surfactant, and/or isopropyl adipate. In other
embodiments, the formulation contains hydroxypropylcellulose (HPC)
and carboxymethyl cellulose (CMC). In other embodiments, the
formulation contains any one or more of water, ethanol, propylene
glycol, polysorbate 80, diisopropyl adipate, phospholipon, and
thickening agents. In other embodiments, the formulation is a
liposomal formulation.
Composition.
[0013] 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.
[0014] 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.
[0015] 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 nanoshells, 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.
[0016] 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-1/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.
[0017] 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.
[0018] 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.
[0019] 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.
[0020] 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.
[0021] 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.
[0022] 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.
[0023] In one embodiment, the light source comprises excitation of
mercury, xenon, deuterium, or a metal-halide, phosphorescence,
incandescence, luminescence, light emitting diode, or sunlight.
[0024] 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.
[0025] 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/cm.sup.2, a pulse
width of about 1 femptosecond to about 1 second, and a repetition
frequency of about 1 Hz to about 1 THz.
[0026] 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
target tissue 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.
[0027] 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.
[0028] The invention provides compositions, methods and systems for
treating follicular skin diseases. Compositions and articles
defined by the invention were isolated or otherwise manufactured in
connection with the examples provided below. Other features and
advantages of the invention will be apparent from the detailed
description, and from the claims.
DEFINITIONS
[0029] 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.
[0030] 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
[0031] 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.
[0032] "Detect" refers to identifying the presence, absence or
amount of the analyte to be detected.
[0033] 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 appropriate
amount and dosage regimen. Such amount is referred to as an
"effective" amount.
[0034] 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 compound absorbs the energy and
become thermally or chemically active.
[0035] As used herein, "obtaining" as in "obtaining an agent"
includes synthesizing, purchasing, or otherwise acquiring the
agent.
[0036] 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 a 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.
[0037] By "reduces" is meant a negative alteration of at least 10%,
25%, 50%, 75%, or 100%.
[0038] By "reference" is meant a standard or control condition.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] Any compositions or methods provided herein can be combined
with one or more of any of the other compositions and methods
provided herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] FIG. 5 is a photograph showing the skin surface.
Accumulation of nanoshells in the follicles is seen.
[0051] FIG. 6 is a micrograph showing a follicle having a
significant accumulation of nanoshells.
[0052] FIG. 7 is a micrograph showing localized thermal damage to a
follicule encompassing the sebaceous gland visualized using H&E
stain.
[0053] FIG. 8 is a table showing the efficacy of nanoshell delivery
followed by laser treatment in a human clinical trial of back
acne.
DETAILED DESCRIPTION OF THE INVENTION
[0054] The invention features compositions comprising light/energy
absorbing compounds 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.
Follicular Disease Pathogenesis
[0055] 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 abnormally shed
keratinocytes of the infundibulum (upper portion of the hair
follicle) in the setting of excess sebum production by hyperactive
sebaceous glands.
[0056] 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 Compounds
[0057] The invention provides delivery of light/energy absorbing
compounds via topical application into skin appendages of the
follicle, specifically follicular infundibulum and the sebaceous
gland. In one embodiment, such compounds are useful for the
treatment of follicular diseases, such as acne (e.g., acne
vulgaris). The introduction of a energy activatable compounds 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.
[0058] Skin Preparation
[0059] If desired, the skin is prepared by one or a combination of
the following methods. Delivery of light absorbing compounds may be
facilitated by epilation of hair, which is performed prior to
topical application of the light absorbing compounds.
[0060] Optionally, the skin is degreased prior to application of
the light absorbing compounds. For example, acetone wipes are used
prior to application of sebashells to degrease the skin, especially
to remove the sebum and follicular contents.
[0061] 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.
[0062] Optionally, the skin may be heated prior to application of
the light absorbing compounds. Heating reduces the viscosity of the
sebum and may liquefy components of the sebum. This can facilitate
delivery of light absorbing compounds (e.g., formulated as
nanoshells) to the follicle.
[0063] Topical Delivery of Light Absorbing Compounds
[0064] Light absorbing compounds, 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.
[0065] Delivery of light absorbing compounds 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
compounds 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 compounds are quantum dots. Preferably, the light
absorbing compounds 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.
[0066] Ultrasound Facilitated Delivery
[0067] 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, 150 nm size
silica-core and gold shell structures are being used that are much
smaller than the infundibular diameter while showing low deposition
in skin through the stratum corneum.
[0068] 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 compound 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.
[0069] Ultrasound is often be accompanied by heating of the target
organ, skin. Some heating, for example, up to about 42.degree. 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.
[0070] 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, the invention provides methods for
optimizing bubble size before collapse to promote efficient
delivery of light absorbing compounds into the intended target
(e.g., sebaceous glands, hair follicles).
[0071] 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).times.D (in
m)=6 m.Hz, 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.
[0072] Table 1 below gives the size of the resonance size of the
bubble as a function of frequency, calculated from the above
relationship.
TABLE-US-00001 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
following Table (estimated from FIGS. 1, 2, and 3 of Yasui,
2002):
TABLE-US-00002 F, kHz 20 140 1,000 D_microns 0.2-200 0.6-25
0.2-6
[0073] 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, the
preferred ultrasound frequency range is 20 kHz to 500 kHz. The
desired power density is estimated to be in the range of 0.5-10
W/cm 2. This is sufficient to generate cavitation bubbles in the
desired size range.
[0074] Energy (Light) Activation
[0075] 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. Such pulsed laser irradiation leads to
thermal damage to the tissue surrounding the material. 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.
[0076] 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
Alexandrite lasers. Representative lasers having wavelengths
strongly absorbed by 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.
[0077] 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.
[0078] 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 Compound Formulations
[0079] The invention provides compositions comprising light/energy
absorbing compounds for topical delivery. In one 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. 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.
[0080] 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
.about.150-350 nm in diameter is achieved.
[0081] If desired, light/energy absorbing compounds are provided in
vehicles formulated for topical delivery. In one embodiment, a
compound 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 compound 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.
[0082] 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
compositions.
[0083] Liquid dosage forms for topical administration of the
compounds 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.
[0084] 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.
[0085] 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
a natural or a synthetic surfactant or emulsifier.
[0086] 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
non-greasy, water miscible, easy to apply and wash off, and are
especially suitable for treating hairy parts of the body.
Subject Monitoring
[0087] 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
[0088] 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 compound (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.
[0089] 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 compounds 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.
[0090] 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.
[0091] 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
[0092] 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
compounds, such as carbon particles, extracts from squid ink, known
commercially as meladine, or dyes into the follicle. These methods
have been largely ineffective.
[0093] 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 compounds 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 using a wavelength that is absorbed by
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.
[0094] 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 Calos,
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.
[0095] 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
[0096] 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.
Example 2
Topical Delivery of Nanoshells to the Follicular Epithelium for
Laser Hair Removal
[0097] 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
[0098] 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 conditions associated with the
presence or activity of sebaceous glands.
[0099] 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
[0100] 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.times.9 mm spot, approximately 50 J/cm2 total radiant exposure,
and 30-ms pulse duration.
[0101] 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).
[0102] 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.
Example 5
Ultrasound Facilitated Delivery
[0103] 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.degree. C.
[0104] 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.
[0105] 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
[0106] 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 treatment regimen was clinically effective.
Example 7
Human Clinical Efficacy Demonstrated in Sebaceous Gland Damage
[0107] 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.times.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 .about.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)
[0108] In experiments with ultrasound, the follicle provided easier
access for delivery of light absorbing compounds than the stratum
corneum. This may be due to a differential in the transport rates
into the stratum corneum 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.
[0109] 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 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.
[0110] In another embodiment, compounds of interest are attached to
microparticles and delivered to the target volume. Light
irradiation may be used to disassociate the compound, 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
[0111] 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 1 below.
TABLE-US-00003 TABLE 1 Table showing compositions of four of the
formulations tested in a human back acne study. Components F74 F76
F78 F80 PEGylated nanoshell 12% 25% 25% 65% suspension in water
(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% Benzyl
Alcohol 9% 1% 1% Diisopropyl Adipate 20% Total 100% 100% 100%
100%
Other Embodiments
[0112] 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.
[0113] 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.
[0114] This application includes subject matter that may be related
to subject matter described in U.S. Ser. No. 12/787,655, US Patent
Publication No. 2012/0059307, and U.S. Pat. No. 6,183,773, each of
which is incorporated herein in its entirety. All patents and
publications mentioned in this specification are herein
incorporated by reference to the same extent as if each independent
patent and publication was specifically and individually indicated
to be incorporated by reference.
* * * * *