Compositions and methods for targeted thermomodulation
Abstract
Problem to be solved.To provide nanoparticles and a preparation useful for cosmetic, diagnostic and therapeutic application to mammals such as humans. An amount of a cosmetically acceptable carrier and a plurality of plasmon nanoparticles effective in inducing thermal modulation in the target tissue region, characterized by local contact with the target tissue region. Composition containing. [Selection diagram] Fig. 1

Term
Projected expiry 6 March 2039.
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21 claims: 3 independent, 18 dependent
- 1標的組織領域において熱変調を誘発するのに効果的な量の美容的に許容可能な担体及び複数のプラズモンナノ粒子を含む組成物であって、該組成物は、標的組織領域に局所的に接触されることを特徴とする、組成物。
- 2プラズモンナノ粒子が、非線形の励起表面プラズモン共鳴源から標的組織領域まで送達されるエネルギーへの曝露によって、活性化されることを特徴とする、請求項1に記載の組成物。
- 3前記プラズモンナノ粒子が、金属、金属複合材、金属酸化物、金属塩、導電体、電気的な超伝導体、電気的な半導体、誘電体、量子ドット又はその組み合わせからの複合材を含むことを特徴とする、請求項1に記載の組成物。
- 4前記組成物中に存在する相当な量の前記プラズモンナノ粒子が、幾何学的に調整されたナノ構造を含むことを特徴とする、請求項1に記載の組成物。
- 5前記プラズモンナノ粒子が、現在知られている又は光を吸収し、所望の波長でプラズモン共鳴を生じさせる任意の幾何学的形状を含み、該幾何学的形状が、ナノプレート、固体のナノシェル、中空のナノシェル、ナノロッド、ナノライス、ナノスフェアー、ナノファイバー、ナノワイヤー、ナノピラミッド、ナノプリズム、ナノスター又はその組み合わせを含むことを特徴とする、請求項1に記載の組成物。
- 6前記プラズモンナノ粒子が、銀、金、ニッケル、銅、チタン、シリコン、ガラジウム、パラジウム、白金、又はクロミウムを含むことを特徴とする、請求項1に記載の組成物。
- 7前記美容的に許容可能な担体が、添加剤、着色剤、乳化剤、芳香剤、保湿剤、重合可能なモノマー、安定剤、溶媒、又は界面活性剤を含むことを特徴とする、請求項1に記載の組成物。
- 8前記界面活性剤が、ナトリウムラウレス2-スルファート、硫酸ドデシルナトリウム、ラウリル硫酸アンモニウム、ナトリウムoctech-1/deceth-1スルファート、脂質、タンパク質、ペプチド、又はそれらの誘導体から成る群から選択されることを特徴とする、請求項7に記載の組成物。
- 9担体の重量間で約0.1と約10.0%の間の量の界面活性剤を含むことを特徴とする、請求項7に記載の組成物。
- 10前記溶媒が、水、プロピレングリコール、アルコール、炭化水素、クロロホルム、酸、塩基、アセトン、ジエチル-エーテル、ジメチルスルホキシド、ジメチルホルムアミド、アセトニトリル、テトラヒドロフラン、ジクロロメタン、及び酢酸エチルから成る群から選択されることを特徴とする、請求項7に記載の組成物。
- 111以上のピーク共鳴波長で少なくとも約1O.D.の光学密度を有するプラズモン粒子を含むことを特徴とする、請求項1に記載の組成物。
- 12前記プラズモンナノ粒子が、親水性又は脂肪族のコーティングを含み、前記コーティングが、実質的に哺乳動物被験体の皮膚に吸着せず、前記コーティングが、ポリエチレングリコール、シリカ、シリカ-オキシド、ポリビニルピロリドン、ポリスチレン、タンパク質又はペプチドを含むことを特徴とする、請求項1に記載の組成物。
- 13前記熱変調が、損傷、除去、溶解、変性、非活性化、活性化、炎症の誘発、熱ショックタンパク質の活性化、細胞シグナル伝達の撹乱又は標的組織領域中の細胞微環境に対する破壊を含むことを特徴とする、請求項1に記載の組成物。
- 14前記標的組織領域が、皮脂腺、皮脂腺の構成要素、脂腺細胞、脂腺細胞の構成要素、皮脂、又は毛嚢漏斗を含むことを特徴とする、請求項1に記載の組成物。
- 15前記標的組織領域が、バルジ、鱗茎、幹細胞、幹細胞微小環境、真皮乳頭、皮質、表皮、毛鞘、骨髄、幽門筋、ハックスリー層、又はヘンレ層を含むことを特徴とする、請求項1に記載の組成物。
- 16それを必要とする哺乳動物被験体を処置するために組織の標的とされた除去を実行する方法であって、該方法は、i)請求項1の組成物を被験体の皮膚表面に局所投与する工程;ii)皮膚表面から外皮組織の構成要素までプラズモン粒子を再分配するための浸透手段を提供する工程;及びiii)光により皮膚表面の照射を引き起こす工程を含むことを特徴とする、方法。
- 17光源が、水銀、キセノン、重水素、又は金属ハロゲン化物の励起、リン光、白熱状態、ルミネセンス、発光ダイオード、又は日光を含むことを特徴とする、請求項16に記載の方法。
- 18前記浸透手段が、高周波超音波、低周波超音波、マッサージ、イオン浸透療法、高圧気流、高圧液流、真空、分留された光熱分解或いは皮膚擦傷法による前処置、又はそれらの組み合わせを含むことを特徴とする、請求項16に記載の方法。
- 19前記照射が、約200nmと約10,000nmの間の光の波長、約1乃至約100ジュール/cm 2 のフルエンス、約1フェムト秒乃至約1秒のパルス幅、及び約1Hz乃至約1THzの反復周波数を有する光を含むことを特徴とする、請求項16に記載の方法。
- 20組成物であって、該組成物は、該組成物が局所的に接触される標的組織領域において熱損傷を誘発するのに十分な量の、美容的に許容可能な担体、効果的な量の硫酸ドデシルナトリウム、及びプラズモンナノ粒子を含み、ここで、前記ナノ粒子が、約810ナノメーター又は1064ナノメーターの共鳴波長で少なくとも約1O.D.の光学密度を有し、ここで、前記プラズモン粒子が、約5から約35ナノメーターまでのシリカコーティングを含み、前記許容可能な担体が、水とプロピレングリコールを含むことを特徴とする、組成物。
- 21請求項1に記載の組成物と、ヒトの皮膚への適用に適切なプラズモンのエネルギー源を含むことを特徴とする、毛のレーザー切除又は挫瘡処置のためのシステム。
Independent claims21
89 paragraphs, as filed
<Mutual Reference> This application is based on 35 USC Article 119 of the United States Code, US Patent Application No. 61 / 402,305 filed on August 27, 2010; US filed on December 13, 2010. It claims the benefits of 35 USC 61 / 422,612 and 35 USC 61 / 516,308 filed April 1, 2011; each application for the benefits claimed in this application is in its entirety. Incorporated herein by reference.
<Area of the present invention> The area of the present invention is nanoparticles used in cosmetic, diagnostic and / or therapeutic means.
Laser treatment of the skin is widely known and has been highly marketed for its therapeutic and cosmetic benefits. Therapeutically, potential uses for laser skin treatment include laser ablation of cancer cells in cancer patients and laser ablation of injured tissue in burn victims. The cosmetic applications for laser skin treatment are quite enormous: hair removal / hair loss, pigment discoloration treatment, liposuction, contusion treatment, chemical or physical exfoliation of unwanted markings on the skin. Includes surgical procedures including nose reduction and face lift and neck lift, and other uses to reconstruct aesthetic skin.
<p> Despite the prospect of laser therapy for dermatology and cosmetology, current laser means have a limited effect that requires a banned number of repetitive treatments and results in increased costs. Suboptimal laser therapy also has a limited effect, resulting in diminished clinical side effects such as non-specific skin damage, skin irritation and scarring.</p><p> Light-based hair removal systems suffer from particularly inefficient effects when removing bright hair (downy hair, blonde hair, gray hair, red hair). Multiple (or more than 6) treatments, even with locally applied chromophores such as carbon, are inadequate to achieve therapeutic outcomes for blonde, gray or redhead patients. In addition to bright hair removal, thermoablative techniques have untapped potential in the areas of wound healing, tissue remodeling, vascular repair, and contusion treatment.</p><p> Contusion vulgaris consists of hair follicles, hair follicles, sebaceous glands and pili muscles and results from obstruction of the sebaceous gland unit, which is the accumulation of sebum oil made from the sebaceous glands and the subsequent accumulation of bacteria in the follicles. It causes fixation. Microcomedones formed as a result of sebum accumulation progress to non-inflamed skin spots (white / black comedones) or skin spots that replenish inflammatory cells and are filled with papules, nodules, and pus. Causes the formation of comedones. The sequelae of untreated vulgaris vulgaris often include hyperpigmentation, scarring and aesthetic distress, as well as significant psychological distress. Therefore, the treatment of contusion is widely endeavored to reduce the accumulation of sebum and microorganisms in the follicles and sebaceous glands.</p><p> Light and laser-related methods are promising for the treatment of skin disorders, but are still inadequately effective. Ultraviolet (UV) / blue light relieves only boil by its anti-inflammatory action mediated on skin cells (keratinocytes), potentially by the action of endogenous porphyrin photosensitizers in the follicles. Approved by the FDA for mild treatment of. Exogenous porphyrin precursors, such as 5-aminolevulinic acid (5-ALA), are formulated for local or oral delivery, accumulate in the sebaceous glands, absorb photons from red light exposure, and directly damage cell membranes and proteins. It has been shown to form reactive oxygen species. This method, called "photodynamic therapy", which combines porphyrin application with high-intensity red light, has been demonstrated to reduce sebum production and contusion by up to 50% 20 weeks after luminescence. However, high intensity energy (50-150J / cm)<sup>2</sup>) Need to damage the sebaceous skin structure, percutaneous porphyrin penetration includes off-target (off), including sensitivity to light, pain, inflammation, hyperpigmentation / hypopigmentation, and permanent scarring -Target) causes side effects.</p><p> In order for laser therapy to achieve its full utility in the treatment of human skin disorders, a method must be achieved that locally induces photodestruction within the skin structure without affecting surrounding tissues.</p><p> In certain embodiments, new compositions and methods useful for cosmetological treatment and targeted thermal modulation of target cell populations and target tissues for the treatment and prevention of chronic and acute diseases and injuries are described herein. Provided in the book.</p><p> In one embodiment, the composition of the subject is described herein. For example, in one embodiment, a cosmetically acceptable carrier and a plurality of plasmonic nanoparticles in an amount effective to induce thermal modulation in the target tissue region to which the composition is locally contacted. A composition comprising the above is provided.</p><p> In some embodiments, the composition comprises plasmon nanoparticles that are activated by exposure to energy delivered from a non-linear excited surface plasmon resonance source for the target tissue region. In further or additional embodiments, composites from metals, metal composites, metal oxides, metal salts, conductors, electrical superconductors, electrical semiconductors, dielectrics, quantum dots or combinations thereof. Compositions comprising at least one plasmon nanoparticles comprising, are described herein. In a further or additional embodiment, a composition is provided herein characterized in that a significant amount of plasmon particles present in the composition comprises geometrically adjusted nanostructures. In certain embodiments, compositions comprising any of the currently known or light-absorbing plasmon particles that cause plasmon resonance at a desired wavelength are described herein. The geometric shapes include nanoplates, solid nanoshells, hollow nanoshells, nanorods, nanorices, nanospheres, nanofibers, nanowires, nanopyramids, nanoprisms, nanostars or combinations thereof. In yet additional embodiments, compositions are described herein characterized by the plasmon particles comprising silver, gold, nickel, copper, titanium, silicon, galadium, palladium, platinum, or chromium.</p><p> In some embodiments, compositions comprising additives, colorants, emulsifiers, air fresheners, moisturizers, polymerizable monomers, stabilizers, solvents, or surfactants are provided herein. In one 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. The compositions are provided herein. In one embodiment, there is provided a composition characterized in that the surfactant is present in an amount between about 0.1 and about 10.0% by weight of the carrier. In yet another embodiment, the solvent is a group consisting of water, propylene glycol, alcohols, hydrocarbons, chloroform, acids, bases, acetone, diethyl-ether, dimethyl sulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, and ethyl acetate. Is selected from. In one embodiment, the composition comprises plasmon particles having an optical density of at least about 1 O.D. at one or more peak resonance wavelengths.</p><p> In a further or additional embodiment, the plasmon particles comprise a hydrophilic or aliphatic coating, the coating substantially does not adhere to the skin of a mammalian subject, and the coating is polyethylene glycol, silica,. Compositions comprising silica-oxide, polyvinylpyrrolidone, polystyrene, proteins or peptides are described herein. In a further embodiment, thermal modulation is damage, elimination, lysis, denaturation, deactivation, activation, induction of inflammation, activation of heat shock proteins, disruption of cell signaling or cell microscopicity in target tissue regions. Including destruction to the environment. Furthermore, in certain presentations, the target tissue region includes sebaceous glands, sebaceous gland components, sebaceous cells, sebaceous cell components, sebum, or hair follicle funnels. In a further embodiment, the target tissue region comprises a bulge, bulb, stem cell, stem cell microenvironment (niche), dermal papilla, cortex, epidermis, hair sheath, bone marrow, pyloric muscle, Huxley layer, or Henle layer.</p><p> In another aspect, methods of performing targeted removal of tissue are described herein. For example, in one embodiment, methods of performing targeted removal of tissue to treat a mammalian subject in need thereof, including the following steps, are described herein. i) The step of topically administering the composition of claim 1 to the skin surface of a subject; ii) the step of providing a penetrating means for redistributing plasmon particles from the skin surface to the components of the rind tissue; and iii) light. The process of causing irradiation of the skin surface. In a further or additional embodiment, a method characterized in that the light source comprises excitation of mercury, xenone, deuterium, or metal halide, phosphorescence, incandescent state, luminescence, light emitting diode, or sunlight. Provided. Also in further or additional embodiments, the permeation means is pre-existed by high frequency ultrasound, low frequency ultrasound, massage, ion penetration therapy, high pressure airflow, high pressure fluid flow, vacuum, fractionated photothermal decomposition or skin scratching. A method is provided that comprises treatment, or a combination thereof. In a further embodiment, the irradiation is a wavelength of light between about 200 nm and about 10,000 nm, about 1 to about 100 joules / cm.<sup>2</sup>The method provided is characterized by comprising light having a fluence of, a pulse width of about 1 femtosecond to about 1 second, and a repetition frequency of about 1 Hz to about 1 THz.</p><p> In a further embodiment, a aesthetically acceptable amount of carrier, an effective amount of dodecyl sodium sulfate, and plasmon nanoparticles in an amount sufficient to induce thermal damage in the target tissue region to which the composition is locally contacted. A composition comprising the above is provided herein, 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 plasmon. The particles include a silica coating from about 5 to about 35 nanometers, the acceptable carrier containing water and propylene glycol.</p><p> In yet another embodiment, a system for the treatment of contusion is provided, including laser ablation of hair, or a composition and an energy source for plasmons suitable for application to human skin.</p>
<figref num="1">FIG. 1 is a schematic diagram depicting a particular embodiment of the use of a pharmaceutical product for hair removal and treatment of contusion. (A) on hair removal is drawn, and the plasmon nanoparticle formulation (black) is 1) applied topically to human skin, 2) deeply delivered to the follicles, washed off the skin surface, and 3) of plasmon particles. Irradiated by a clinical laser at a wavelength that resonates with the peak absorption wavelength, 4) shed from the follicle with damaged hair sac; and (B) on the treatment of sebum is depicted, the plasmon nanoparticle formulation (black) , 1) applied topically to human skin, 2) specifically delivered to the sebaceous glands, washed off the skin surface, and 3) irradiated by a clinical laser with a wavelength that resonates with the peak absorption wavelength of plasmon particles. , 4) If the accumulated sebum and the ability of the sebaceous glands to make sebum are destroyed, it is shed from the target site.</figref><figref num="2">Figure 2 shows 1064 nm, 20 J / cm<sup>2</sup>Compared to typical current clinical dye carbon lotions (circular), meladine sprays (diamond) and indocyanine green (square), after exposure to a 55 ms laser pulse, herein. FIG. 5 is a diagram of a temperature profile of a particular embodiment of a formulation of plasmon nanoparticles (SL-001, triangles) provided. SL-001 and dye were equally diluted 1: 1000 from clinical concentrations (SL-001 1000 O.D., carbon 20-200 mg / ml, melazine 1 mg / ml, ICG 5 mg / ml). n = 3, standard deviation of mean.</figref><figref num="3">FIG. 3 shows the hair follicle penetration of fluorescently labeled nanoparticles as measured using porcine skin explants and confocal image analysis of specific embodiments of the subject matter described herein. It is a figure. (A) Two consecutive 60 μm planes: treated pigs that are angled, imaged and imaged with respect to the follicles in "face 1" (showing a follicular funnel) and "face 2" (showing a deep follicle). Schematic representation of the skin is drawn; (B) A typical confocal image shows red fluorescent nanoparticles (548 nm) in superficial and deep follicles, not in the underlying dermis; and (C) Red fluorescent nanoparticles were retained in deep follicles (~ 400 μm) at high magnification. Green is tissue autofluorescence.</figref><figref num="4">FIG. 4 is a diagram of hair follicle penetration of plasmon nanoparticles measured using porcine excutaneous implants and darkfield imaging. (A) Schematic representation of treated porcine skin, segmented and imaged for follicles; (B) bright blue plasmon particles were visualized in a 1.2 mm deep section, (C) Unlike untreated (negative control) porcine skin, where the pigment is not visible.</figref><figref num="5">Figure 5 illustrates clinical observations in living human skin treated with laser only (left forearm), or plasmon particles + laser (right forearm) demonstrate non-specific and specific photothermal damage. .. (A, B) In the top panel, human skin is 810 nm laser pulse (30 J / cm)<sup>2</sup>Irradiated by only (2 passes), 30 ms, or after treatment with a 830 nm resonant, uncoated plasmon nanoparticle formulation in 20% propylene glycol (, 30 ms, 2 passes). B). The plasmon nanoparticle formulation was applied by a 3-minute massage and the skin surface was wiped with three alternating applications of water and ethanol prior to laser irradiation. Thirty minutes after laser irradiation, non-specific clinical burns were observed in B compared to A by significant photothermal heating of the remaining uncoated particles on the skin surface. (C, D) In the bottom panel, human skin has a laser pulse of 1064 nm (40 J / cm)<sup>2</sup>Irradiated by (C) alone (, 55 ms, 3 passes), after treatment with a formulation of silica-coated plasmon nanoparticles with resonance at 1020 nm in 20% propylene glycol (D). The plasmon nanoparticle preparation was applied by a 3-minute massage, and the skin surface was wiped with three alternating three applications of water and ethanol prior to laser irradiation. No evidence of skin burns or erythema was observed at D or C, as sufficiently silica-coated particles could be wiped from the skin surface 30 minutes after laser irradiation. Enlarged photography of D showed specific photothermal damage (erythema and edema around the follicles) at the site targeted by the nanoparticles.</figref><figref num="6">FIG. 6 is a photograph showing photothermal damage targeted to live human skin nanoparticles treated with a plasmon nanoparticle formulation and a clinical laser. A 1020 nm resonant, silica-coated (200 nm diameter) plasmon nanoparticles formulation in 20% propylene glycol, and a 3-minute massage were contacted with live humans. This procedure was repeated 3 times and the skin surface was wiped with 3 alternating applications of water and ethanol to remove the remaining particles. Treated skin is 1064 nm laser pulse (40 J / cm)<sup>2</sup>, 55ms, 3 passages). After laser irradiation, clinical observations of erythema and edema around the follicles are visible in the hair follicles where the nanoparticles are targeted, but not in the surrounding or non-particle treated tissue.</figref><figref num="7">FIG. 7 is a diagram of delivery of a plasmon nanoparticle preparation to the sebaceous glands of human skin. (A) Confocal microscopic images of human skin biopsies and sections, collagen IV basement membrane (blue) and PGP9.5 neural markers (green), microanatomical of hair follicles (HF) and sebaceous glands (SG) Shows the structure (microanatomy). Red is silica nanoparticles (200 nm). (B) Schematic and darkfield microscopic images of excised human skin treated with plasmon nanoparticle preparation and then segmented and imaged for follicles. Bright blue plasmon particles are visualized at depths up to 400 μm and within the human sebaceous glands.</figref><figref num="8">FIG. 8 is a diagram of a cosmetic formulation of plasmon nanoparticles for targeting the sebaceous glands, including a surfactant. Silica-coated nanoparticles (200 nm diameter, 100 O.D.) are formulated in 20% propylene glycol with the addition of the surfactants sodium dodecyl sulfate (SDS) or sodium laureth-2 sulfate (SLES). Applied to human skin by massage + ultrasound, the skin was segmented in a horizontal plane for dark field microscopy. (A) The preparation of plasmon particles in 1% SDS / 20% PG penetrated into the sebaceous glands down to 400 μm as shown in FIG. (B) The preparation of plasmon particles in 1% SLES / 20% PG penetrated into the sebaceous glands down to 600 μm. The inset shows a skin section without visible particles (scale bar 40 μm). The sebaceous glands are outlined in a pseudo manner.</figref><figref num="9">FIG. 9 is an image depicting the impact of massage vs. ultrasound on nanoparticles targeting human follicles and sebaceous glands. Silica-coated nanoparticles (200 nm diameter, 100 O.D.) were formulated with 1% SDS / 20% propylene glycol and applied to human skin by massage or ultrasound. Dark-field images of horizontal planar sections taken at the lowest (20x) and highest (50x) magnifications were compared with (B) dilation of the follicular funnel and significant plasmon particle accumulation after ultrasound alone. (A) Shows that there is little accumulation of plasmon particles in the follicular funnel after massage alone.</figref><figref num="10">FIG. 10 depicts an embodiment of a cosmetic formulation of plasmon nanoparticles for sebaceous gland targeting. Plasmon nanoparticles with different shapes and coatings are formulated with 1% SDS / 20% propylene glycol and applied to human skin by massage + ultrasound, the skin is segmented in the horizontal plane for dark-field microscopy. It was. (A) Polyethylene glycol (PEG) coated nanorods (gold, dimensions 15 × 30 nm) were observed in a follicular funnel to a depth of up to 200 μm (white arrow). (B) Low concentrations (10 O.D.) of silica-coated nanoplates (silver, 200 nm in diameter) were observed up to 600 μm in follicles and sebaceous glands (perforated arrows). The inset shows sections without visible particles (scale bar 100 μm).</figref>
Physiological and pathophysiological tissue growth and remodeling biology, and changes in cell morphology are more complex than generally recognized and interact with biological compounds, physical forces and cell types. Including network.
The object of the subject matter described herein is a non-invasive and minimally moisturizing treatment of the skin and underlying tissue, or a composition, method for other accessible tissue gaps by the use of nanoparticles. And to provide the system. Treatments include, but are not limited to, hair removal, hair growth and regeneration, and skin rejuvenation or re-emergence, removal or reduction of warts, reduction of wrinkles, reduction of pores, removal of cellulite and other transdermal lipid deposits, Wart and fungal removal, thinning or removal of hyperplastic scars and scars containing keloids, abnormal pigmentation (such as Portwine's mother's spots), tattoo removal, and skin inconsistencies (eg, structure, color, tone, elasticity, etc.) In hydration). Other treatment or prevention methods are, but are not limited to, hyperhidrosis, anhidrosis, Frey's syndrome (taste sweating), Horner's syndrome, and Ross's syndrome, actinic keratosis, folliculous keratosis, dermatitis. Includes treatment of leukoplakia, psoriasis, psoriasis, lichen planus, eczema, alopecia, psoriasis, malignant or non-malignant skin tumors.
Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials similar to or equivalent to those described herein can be used in the practice or testing of the present disclosure, but methods and materials are described herein. Materials, methods and examples are exemplary only and are not intended to be limiting. Other features of the disclosure will become apparent from the following detailed description and claims.
As used herein, "administer" and "administer" are topical, dermis, subcutaneous, intradermal, intestinal, parenteral, rectal, nasal, intramuscular, intravenous, intraperitoneal, or otherwise. Includes providing or triggering a supply of material to a subject, such as through the pathways of.
A "suitable carrier" for a subject is any material that is physiologically compatible with the desired topical or route of administration to the vertebrate subject. The carrier can include a solid-based dry material with respect to the formulation; or the carrier can include a liquid or gel-based material with respect to the formulation into a liquid or gel form. The particular type of carrier, as well as the final formulation, depends in part on the route of administration and product type selected.
A "comparable amount" is an amount that is measurable relative to a given reference or standard.
The "component" of a pharmaceutical product includes any product or compound associated with or contained therein.
An "effective dose," "effective amount," or "therapeutic amount" is an amount sufficient to elicit the desired pharmacological, cosmetic, or therapeutic effect, and thus the disease or It provides effective prevention or treatment of the disorder and benefits vertebrate subjects.
"Therapeutic effect" or "therapeutically desirable effect" refers to a change in a domain or region that has been treated to show signs of being affected in the desired manner, eg, cancer treatment causes or destroys tumor cells. Stopping the growth of tumor cells, boil treatment causes a decrease in the number and / or severity of spots, hair removal treatment causes obvious hair loss, or wrinkle reduction treatment eliminates wrinkles.
An "isolated" biological component (such as a nucleic acid molecule, protein, or cell) is the other component from which the component was made, including any other protein, lipid, carbohydrate, and other component. Substantially isolated or purified away from biological components.
As used herein, "nanoparticle" generally refers to a particle having at least one dimension thereof, from about 0.1 nm to about 9000 nm.
As used herein, a "subject" or "patient" is any vertebrate species.
As used herein, a "substantially pure", "substantially separated" compound is substantially free of one or more other compounds.
A "target tissue" includes a region of an organism for which physical or chemical forces or changes are desired. As described herein, typical target tissues for the treatment of contusion include sebaceous glands, while typical target tissues for hair removal are hair follicle sebaceous gland units, hair follicles, and Includes hair follicles, or non-follicle epidermis. A "region" of a target tissue contains one or more components of the tissue. Typical target tissue regions include stem cell microenvironment, bulge, sebaceous gland, papillary line, cortex, epidermis, inner root sheath, outer root sheath, medulla oblongata, Huxley layer, Henle layer or pyloric muscle. The "domain" of the target tissue region includes basement membranes, extracellular matrix, cell surface proteins, non-binding proteins / analyzes, glycomatrices, glycoproteins, or lipid bilayers.
Compounds that are "substantially free" of some additional content lack most or all of the aforementioned content.
"Plasmon nanoparticles" are nanometer-sized metal structures in which localized surface plasmons are excited by light. These surface plasmons are surface electromagnetic waves that travel in a direction parallel to the metal / dielectric interface (eg, metal / atmosphere or metal / water).
"Light-absorbing nanomaterials" include nanomaterials that can demonstrate quantum size effects.
As described herein, compositions comprising plasmon nanoparticles for inducing selective thermal modulation in a target tissue are provided.
<Plasmon nanoparticles> Such a composition is 10<sup>9</sup>、10<sup>10</sup>、10<sup>11</sup>、10<sup>12</sup>、10<sup>13</sup>、10<sup>14</sup>、10<sup>15</sup>、10<sup>16</sup>About 10 particles, etc.<sup>9</sup>From about 10<sup>16</sup>Contains nanoparticles. Preferably, the composition is about 10<sup>11</sup>~ 10<sup>13</sup>As a result, the amount of particles localized to an effective 1 ml treatment volume is 10<sup>9</sup>From 10<sup>11</sup>Is. In certain embodiments where increased concentrations of nanoparticles relative to the target site are desired, the composition has an optical density of 10 O.D.-1000 O.D. (OD) or a particle concentration having an optical density of 1,000 OD or greater. Including. In some embodiments, these correspond to a concentration of nanoparticles greater than or equal to about 1-10% w / w.
Nanoparticles may be homogeneous or heterogeneous in size and other properties. The size of the nanoparticles is generally about 0.1 nm to about 5,000 nm in at least one dimension. Several variations in nanoparticle population size are expected. For example, the variation may be less than 0.01%, 0.1%, 0.5%, 1%, 5%, 10%, 15%, 25%, 50%, 75%, 100%, 200% or greater than 200%. is there. In certain embodiments where optimal plasmon resonance is desired, particle sizes in the range of about 10 nm to about 100 nm are provided. Alternatively, in embodiments where enhanced penetration of nanoparticles into target tissue regions such as hair follicles is desired, particle sizes in the range of about 100 nm to about 1000 nm are provided. Adjusting the particle size present in the composition is also a useful way to concentrate the composition of the target domain. Further, as described herein, nanoparticles having a size range of about 10 nm to about 100 nm are generally used as components of larger molecular structures in the range of about 100 nm to about 1000 nm. be able to. For example, plasmon nanoparticles can be surface coated to increase their size and incorporated into acceptable carriers, or crosslinked or aggregated with other particles or materials that give rise to larger particles. Can be done. In certain embodiments where at least one dimension of at least one nanoparticle in a solution of plasmon nanoparticles is less than 50-100 nm, the nanoparticle surface is designed to increase that dimension or particle to 50-100 nm or more. It can be coated with a matrix (eg silica) with a thickness of 10-100 nm or more. This increased dimensional magnitude can increase the delivery of all nanoparticles to the target site (eg, the hair follicle) and limit the delivery to the non-target site (eg, the dermis).
Important considerations when producing nanoparticles are 1) the zeta potential (positive, negative, or neutral) and charge density of the particles and the resulting composition; 2) the particles and the resulting composition. Hydrophilic / hydrophobic; 3) Adsorption layer (eg particle slip page) Includes plane)) presence; and 4) target cell adhesion properties. The nanoparticle surface can be functionalized by thiolated moieties having negative, positive or neutral charges (eg, carboxylic acids, amines, hydroxyl groups) in various proportions. In addition, anion-mediated surface coatings (eg, acrylate, citrate, etc.), surfactant coatings (eg, sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-1 / deceth-1 sulfate, lecithin, etc. And cetyltrimethylammonium bromide (CTAB), other surfactants including lipids, peptides), or protein / peptide coatings (eg albumin, ovalumin, egg protein, milk protein, other foods, plants, animals, bacteria, yeast, Alternatively, a recombinant inducible protein) can be used. Block copolymers are also useful. In addition, the usefulness of any other compound or material that adheres to the surface of light-absorbing particles to promote or prevent the interaction of certain molecules and improve particle entry into openings or follicles has been recognized. Will be. In some embodiments, the particle surface is unchanged. The adjustment of hydrophobicity to hydrophilicity is carried out by modifying the surface of the nanoparticles with chemicals known in the art, including silanes, isothiocyanates, short polymers (eg PEG), or functional hydrocarbons. .. Polymer chains of different lengths (eg, biopolymers such as proteins, polysaccharides, lipids and mixtures thereof; synthetic polymers such as polyethylene glycol, PLGA, etc.; and biopolymer synthetic mixtures) and recording densities are the adsorption layer of the particles / Useful for changing the slip surface.
Light absorption. Preferred nanoparticles have light absorption properties of about 10 nm to about 10,000 nm (eg, 100-500 nm). In a specific embodiment, the nanoparticles have light absorption useful for excitation by a standard laser device or other source of light. For example, nanoparticles absorb at a wavelength of about 755 nm (Alexandrite laser) in the range of about 800-810 nm (diode laser) or about 1064 nm (Nd: YAG laser). Similarly, nanoparticles absorb extremely pulsed light (IPL), for example, in the range of about 500 nm to about 1200 nm.
assembly. The nanoparticles provided herein may generally include a collection of unassembled nanoparticles. By "unassembled" nanoparticles, such collecting nanoparticles are directly (eg, particle-cell-particle, particle-protein-particle, particle-analyte-particle) by some intermediate (eg, particle-cell-particle, particle-protein-particle, particle-analyte-particle). Particle-particle) or indirectly, it means that they are not bonded to each other by physical force or chemical bond. In other embodiments, the nanoparticle composition is assembled into a trimmed array. In particular, such a trimmed array can include any three-dimensional array. In some embodiments, only some of the nanoparticles are assembled, eg, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 86, 90, 95, 99%, or more than 99% are assembled in a trimmed array. Nanoparticles are assembled by van der Waals attraction, London force, hydrogen bonds, dipole interactions, or covalent bonds, or a combination thereof.
A "trimmed array" is an individual that can or cannot be patterned in the form of spheres, colloids, beads, ovals, squares, rectangles, fibers, wires, rods, shells, thin films, or flat surfaces. From the part, it can take the form of a macro structure. In contrast, "disturbed arrays" lack considerable macrostructure.
Geometrically adjusted nanostructures. The nanoparticles provided herein are currently known or can be formed in any shape that absorbs light and causes plasmon resonance in compositions with peak wavelengths or wavelengths from 200 nm to 10,000 nm. is there. In a non-limiting example, nanoparticles are spherical, elliptical, tubular, square, rectangular, rod-shaped, star-shaped, tubular, pyramidal, star-shaped, prismatic, triangular, branched, plate-shaped, or flat surface. It is formed as composed of. In a non-limiting example, plasmon particles include nanoplates, solid nanoshells, hollow nanoshells, nanorods, nanorices, nanospheres, nanofibers, nanowires, nanopyramids, nanoprisms, nanoplates, or combinations thereof. Plasmon particles present in the composition are defined as 5, 10, 15, 25, 50, 75, 80, 85, 90, 95, 98, 99, 99.9, or 99.9% more particles, in significant amounts. Includes geometrically adjusted nanostructures.
Composition. Nanoparticles include metals (eg gold, silver), metal composites (eg silver and silica, gold and silica), metal oxides (eg iron oxide, titanium oxide), metal salts (eg potassium oxalate, strontium chloride). ), Metallic compounds (eg titanium aluminum, alnico), conductors (eg copper, aluminum), electrical superconductors (eg yttrium barium copper oxide, bismus strontium calcium copper oxide), electrical semiconductors (eg copper) For example silicon, germanium), dielectrics (eg silica, plastic), or quantum dots (eg zinc sulfide, cadmium selenium). In a non-limiting example, the material is gold, silver, nickel, platinum, titanium, palladium, silicon, galadium. Alternatively, the nanoparticles include a metal and a dielectric, a metal and a semiconductor, or a composite material containing a metal and a semiconductor and a dielectric.
coating. Preferentially, the composition comprises coated nanoparticles.
<tables num="1A"><img file="JP2019123722A_D0001.tif" /></tables>
<tables num="1B"><img file="JP2019123722A_D0002.tif" /></tables>
Biomolecule. The composition may include peptides, nucleic acids, proteins, or antibodies. For example, a protein, antibody, peptide, or nucleic acid, protein, glycomatrix, or lipid, intercellular matrix, or basal membrane protein on the surface of a cell or stem cell that binds the protein of a follicular stem cell (eg, keratin 15). , Peptides, glycomatrix.
The charged part. The coated nanoparticles contain a charged portion, whereby the charge mediates enhanced or reduced binding to the components inside or outside the hair sac due to electrostatic or chemical interactions.
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<Description of target tissue> Topical and dermatological applications. Target tissues for topical and dermatological applications include the surface of the skin, epithelium and dermis. Diseases or illnesses suitable for treatment by topical and dermatological applications include contusion, warts, fungal infections, psoriasis, scar removal, hair removal, hair growth, reduction of hyperplastic scars or keloids, skin inconsistencies (eg, skin inconsistencies). Tissue, color, tone, elasticity, hydration), including malignant or non-malignant skin tumors.
As used herein, the term "boil" refers to boil vulgaris, as well as summer boil (acne aestivalis), confluent boil (acne conglobata), cosmetic boil (acne cosmetic), Fulminant boil, keloidalisnuchae boil, mechanical boil, miriarisnecrotica boil, necrotizing boil, chlor boil, drug-induced boil, scraped boil, halogen boil, facial disseminated boil Includes boil, pomade boil, tar boil, and topical boil. It also includes other forms of contusion and related skin disorders.
Subcutaneous application. Target tissues for subcutaneous application include adipose tissue and connective tissue below the integumentary system. Diseases or illnesses suitable for treatment by the application of subdermatological include wrinkles and tattoos. Other applications include skin rejuvenation and / or re-emergence, removal or reduction of cracks, and fat removal.
Often, a particular area of target tissue is a hair follicle, sebaceous gland, melocrine sweat gland, apocrine sweat gland, or arrector pili muscle, to which a particular domain is targeted. For example, the bulge area of the hair follicle is targeted. In one embodiment, the region containing hair follicle stem cells is of particular interest because the nanoparticles are useful for heat removal of hair follicle stem cells for hair removal. Thus, the target tissue region may include stem cell microenvironment, bulge, sebaceous gland, papillary line, cortex, epidermis, inner root sheath, outer root sheath, medulla oblongata, Huxley layer, Henle layer, or pyloric muscle. Each of these regions may contain cells, stem cells, basement membranes, extracellular matrix, growth factors, analytes, or other biological components that mediate hair follicle rejuvenation. Disintegration or destruction of these components has a therapeutic effect, eg, slows or stops the process of mediating hair regeneration, prevents the secretion of sebum from the sebaceous glands, damages or blocks tumor cells, Reduces the appearance of wrinkles. The structure can also be targeted adjacent to the desired target for removal, especially when heat can be effectively processed.
Localized domain. A composition comprising nanoparticles that are preferentially localized to the domain of the target tissue region of the mammalian subject to which the composition is administered is provided.
Target part. Nanoparticles can be designed to selectively bind to the domain of the target tissue. For example, nanoparticles are easily manipulated and linked to a domain by biological components in order to effectively target the nanoparticles to a target tissue domain. Preferably, the moiety comprises a stem cell component, a primordial cell, an extracellular matrix component, a basement membrane component, a hair shaft component, a follicular epithelial component, or a non-follicle epidermal component. Biological parts include proteins such as cell surface receptors, glycoproteins or intercellular matrix proteins, as well as carbohydrates, analysts, or nucleic acids (DNA, RNA), and membrane components (lipid bilayer components, endoplasmic reticulum). ) Is also included.
Delocalized domain. The nanoparticles present in the composition are preferentially delocalized away from the domain of the target tissue region. Delocalized domains include specific regions of tissue in which nanoparticles are substantially non-aggregated or, instead, more effectively removed from the domain. In a preferred embodiment, the delocalized domain is a non-follicle epithelium, dermis, hair follicle component (eg, hair stem cells, stem cell microenvironment, bulge, sebaceous glands, dermis papilla, cortex, epidermis, inner root sheath). , Outer root sheath, spinal cord, Huxley layer, Henle layer, pyloric muscle), hair follicle canal, sebaceous gland, sebaceous gland component, sebaceous gland cell, sebaceous cell component, or sebum.
Energy source. Non-linear excited surface plasmon resonance sources, including various sources of light emission or optics, are provided herein. Typical light sources include lasers (ion lasers, semiconductor lasers, Q-switch lasers, free-running lasers, or fiber lasers), light emitting diodes, lamps, sunlight, fluorescent sources or electroluminescent light sources. Typically, energy sources can emit radiation at wavelengths from about 100 to 200, 300, 400, 500, 1000, 2000, 5000 nm, and more than about 10,000 nm. Non-linear excited surface plasmon resonance sources can radiate electromagnetic radiation, ultrasonic waves, thermal energy, power energy, magnetic energy, or electrostatic energy. For example, the energy is about 0.00005 mW / cm<sup>2</sup>From about 1000 TW / cm<sup>2</sup>Intensity of radiation up to. Optimal intensities are chosen to induce high temperature gradients from plasmon nanoparticles in the region of about 10 microns to hundreds of microns in the surrounding tissue, but within a radius of about 100 microns or more from the nanoparticles. Has minimal residual effect when heating non-existent tissue. In certain embodiments, the thermal gradient of the difference between the target tissue region and another tissue region (eg, skin) is greater than 2-fold, 3-fold, 5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 100 times, or greater than 100 times.
Energy can be adjusted by monitoring the thermal gradient of heat on the surface of the skin with a thermal / infrared camera. As demonstrated herein, the methods and systems of the present disclosure provide excellent effects when surface plasmons are made on nanoparticles by the action of radiation. Typically, plasmons are made in one photon morphology, or instead two photon morphologies, multiple photon morphologies, gradual morphologies, or up-converted morphologies.
Radiation delivery. Non-linear Excited Surface Physical means of delivering energy from a plasmon resonance source to a target tissue region include fibers, waveguides, contact tips or a combination thereof.
An optical source is a CW optical source or pulse that is a single wavelength polarized (or instead non-polarized) optical source capable of emitting radiation at frequencies from about 200 nm to about 10,000 nm. Includes optical source. Alternatively, the optical source is a multi-wavelength polarized (or instead non-polarized) optical source capable of emitting radiation at wavelengths from about 200 nm to about 10,000 nm. A pulsed optical source can generally emit pulsed radiation at frequencies from about 1 Hz to about 1 THz. The pulsed optical source can have a duration of less than milliseconds, microseconds, nanoseconds, picoseconds, or femtoseconds. Optical sources can be combined with devices that cool the skin surface in order to reduce the heat of the particles or structures on the skin surface and to concentrate the heat on the components within the follicles or tissue structures in the deeper layers.
Nanoparticle-containing composition. Plasmon nanoparticles in certain embodiments are formulated in a variety of compositions to provide optimal percutaneous penetration into the target tissue. Preferentially, the nanoparticles are in a composition containing a 1-10% v / v surfactant (eg, sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-1 / deceth-1 sulfate). Prescribed in. Surfactants divide and emulsify sebum or other hydrophobic liquids to allow improved targeting of hydrophilic nanoparticles to hair follicles, funnels, sebaceous glands or other areas of the skin. To do. Surfactants also reduce the free energy required to deliver hydrophilic nanoparticles to small hydrophobic crevasses, such as the space between hair shafts and follicles, or sebaceous glands. Nanoparticle-containing compositions also include emulsions of various concentrations (1-20% w / v) in aqueous solutions, silicon / oil solvents, propylene glycol or creams (including, for example, alcohols, oils, paraffins, colloidal silica). obtain. In other embodiments, the formulation is a degradable or non-degradable polymer (eg, synthetic polylactide / co-glycolide copolymer, porous lauryllactame / caprolactam nylon copolymer, hydroxyethyl cellulose, polymeric electrolyte monolayer, or Instead, it comprises a natural hydrogel such as hyaluronic acid, gelatin, etc. In a further embodiment, the hydrogel PLGA, PEG-acrylate is included in the formulation, or a matrix component such as silica, polystyrene, or polyethylene glycol. Provided in the formulation Other formulations include components of surfactants, lipid bilayers, liposomes, or vesicles. Nanoparticles can include larger micron-sized particles.
Effective dose. As described herein, an effective dose of a nanoparticle-containing composition is, in some embodiments, of a particle that is required to produce an effective thermal gradient in the target tissue region. Including the amount, as a result, part of the target tissue region is acted upon by the thermal energy from the excited nanoparticles. The "minimum effective dose" is the smallest or lowest concentration of nanoparticles in the composition that is effective in achieving the desired biological, physical, and / or therapeutic effect. .. Preferentially, plasmon nanoparticles have an optical density of 10 O.D.-1,000 OD at one or more peak resonance wavelengths.
A cosmetically acceptable carrier. Cosmetological or pharmaceutical compositions are provided that have a plurality of plasmon nanoparticles and a cosmetically or pharmaceutically acceptable carrier. In general, the carrier and composition must be suitable for topical administration of the mammalian subject to the skin, so that the plasmon nanoparticles are in an amount effective for selective thermal modulation of the skin components. Exists. Priority, nanoparticles disrupt the skin barrier of the epidermis, emulsify sebum, improve the mixing of hydrophobic solutions with hydrophilic nanoparticles, and the hydrophobic areas of the skin (eg, hair shaft and surroundings). Entropic that delivers hydrophilic particles (between sheaths or follicles) Carriers containing 1-10% v / v surfactants (eg sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-1 / decline-1 sulfate) to allow reduction of barriers) Prescribed by. In some embodiments, the carrier is a polar or non-polar solvent. For example, suitable solvents are alcohols (eg n-butanol, isopropanol, n-propanol, ethanol, methanol), hydrocarbons (eg pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane). , Chloroform, diethyl-ether, water, water with propylene glycol, acids (eg acetic acid, formic acid), bases, acetone, isooctane, dimethyl sulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, ethyl acetate, tetramethylammonium hydroxide , Isopropanol and others. In other embodiments, an antioxidant that prevents the oxidation of unwanted materials, forms a chelate complex and emulsions (eg, egg yolk lecithin, sodium stearoyl lactylate, sodium bis (2-ethylhexyl-sulfosuccinate (AOT)). ), Other catalysts, emulsifiers, ionic or nonionic surfactants, supplements that inactivate the tracking of metal ions acting as cholesterol or phospholipids, materials, especially plastics Stabilizers such as UV stabilizers that protect against are provided. In a further embodiment, a composition having a cosmetically acceptable carrier is made so that the nanoparticles are substantially in the suspension. It is in.
Other components are optionally included, including emulsions, polymers, hydrogels, matrices, lipid bilayers, liposomes, or endoplasmic reticulum. In addition, inclusion of detectable colorants (eg pigments), air fresheners, moisturizers, and / or skin protectants is optional. In some examples, the formulation has a viscosity greater than or equal to 0.1-1000, less than or equal to, or in the range, as measured in millipascal seconds (mPa · s).
The amount of nanoparticles per milliliter in the composition is subject to modification for specific binding, 10<sup>9</sup>From 10<sup>18</sup>Range of particles up to, but generally 10 per milliliter<sup>11</sup>~ 10<sup>13</sup>Can be in the range of nanoparticles. In certain embodiments where increased concentrations of nanoparticles relative to the target site are desired, the composition comprises an optical density of 10 O.D.-1000 O.D., Or a particle density having an optical density greater than 1,000 OD. .. In some embodiments, these correspond to a concentration of nanoparticles of about 0.1-10% w / w or higher.
Prior to application of the nanoparticle formulation, the skin and hair follicles can be pre-treated to increase the delivery of nanoparticles to the target area. In some embodiments, the hair shaft is cut or removed by hair shearing, waxing, cyanoacrylate desquamation, calcium thioglycolate treatment, or other techniques for removing hair shafts and / or hair cysts. Will be done. The opening of active or inactive follicles can be blocked by plugs formed from corneocytes and / or other materials (eg, cell debris, soot, hydrocarbons, cosmetics). In some embodiments, a surface stripping action that includes a mechanical peeling action (eg, salt glow or microcrystal peeling) and a chemical peeling action (eg, an enzyme, alpha hydroxy acid or beta hydroxy acid). Pretreatment with is to remove the plug from the opening of the follicle to increase the targeting of the nanoparticle formulation to the target site within the hair sac.
In some embodiments, the nanoparticle formulation is a sponge coating tool, cloth coating tool, direct contact by hand or gloved hand, spray, aerosol, vacuum suction, high pressure airflow, or high pressure liquid flow, roller, brush, etc. Formulated for application by planar, semi-planar, wax, ultrasonic and other sonic forces, mechanical vibrations, hair shaft manipulation (including pulling, massage), physical forces, thermal manipulation, and other treatments. .. In some embodiments, the treatment of the nanoparticle formulation is performed alone, in combination, continuously or repeatedly 1-24 times. In other embodiments, the plasmon nanoparticles can be selectively localized to the first component of the skin, in which physical massage or pressure, ultrasound, or heat is the first component. Increases the selective localization of nanoparticles with respect to one component. In addition, the nanoparticles have a skin composition other than the first component, such as removal achieved with acetone, alcohol, water, air, skin exfoliation, chemical exfoliation, waxing, or reduction of plasmon compounds. It can be removed from the element. In addition, in some embodiments, the nanoparticles have a coating layer that increases the solubility of the nanoparticles in the carrier and / or reduces "stickiness" and accumulation in non-target regions. The subject matter described herein is also that at least one part of the outer surface of the nanoparticles is a polymer, polar monomer, non-polar monomer, biological compound, metal (eg, metal thin film, metal composite, metal oxide, etc. Alternatively, an embodiment is provided that is modified to include a layer of a metal salt), a dielectric, or a semiconductor. Alternatively, the outer surface modifications are polar, non-polar, charged, ionic, basic, acidic, reactive, hydrophobic, hydrophilic, antagonistic, or antagonistic. In certain embodiments where at least one dimension of at least one nanoparticle in a solution of plasmon nanoparticles is less than 50-100 nm, the nanoparticle surface is to increase that dimension or particle to 50-100 nm or more. , Can be coated with a matrix (eg silica) with a thickness of 10-100 nm or more. This increase
<Penetration Means> Preferably, the compositions of the present disclosure are administered topically. From the skin surface, using high-frequency ultrasound, low-frequency ultrasound, massage, ion-penetration therapy, high-pressure airflow, high-pressure fluid flow, vacuum, treatment with fractionated photothermal decomposition lasers or skin wear, or a combination thereof. Means for redistributing plasmon particles into hair follicles, hair follicle components, cystic funnels, sebaceous glands, or components of skin tissue, including sebaceous gland components, are provided herein. For example, the compositions include sponge coating tools, cloth coating tools, sprays, aerosols, vacuum suction, high pressure airflow, high pressure liquid flow, direct hand contact, ultrasonic and other sonic forces, mechanical vibrations, hair shaft manipulation ( It can be administered by use of physical force (including pulling, massage), physical force, thermal manipulation, or other treatments. The treatment of the nanoparticle preparation is performed alone, in combination, continuously or repeatedly 1-24 times.
<Cosmetic and Therapeutic Use of Plasmon Nanoparticles> In general terms, Applicants use nanoparticle-based treatment methods for the cosmetic and therapeutic treatment of dermatological diseases, disorders and disorders. Created a system and method.
<Acne Treatment> Acne is caused by a combination of diet, hormonal imbalance, bacterial infection (P. acnes), genetic predisposition, and other factors. The nanoparticle-based methods and systems described herein for contusion treatment can locally target the causative areas of the dermis, sebaceous glands and hair follicles, and thus chemical treatment (peroxide, hormones). , Antibiotics, retinoids, and anti-inflammatory compounds), skin scratching, phototherapy (laser, blue and red light treatment, or photodynamic treatment), or existing known in the art, including surgical procedures. Has advantages compared to the technology of.
In particular, laser-based techniques are gradually becoming a well-known treatment for follicles, but a considerable limitation is the lack of selective absorptive properties in natural pigments (eg fat, sebum) for specific wavelengths of light. As a result, selective heating of one cell, structure, or tissue component is not achieved without heating of adjacent off-target tissues, especially in the areas of sebaceous glands, funnels and hair follicles. The nanoparticles described herein allow the laser energy to be concentrated on specific cells, structures or components of tissue within the area of the sebaceous glands, funnels, or hair follicles due to selective photothermal damage. It provides significantly higher photothermal conversion than dyes.
The use of the materials and techniques described herein may provide a longer duration of contusion treatment than existing methodologies. In certain embodiments, coordinated selective removal of sebaceous glands or funnels is achieved as described herein. In particular, the plasmon nanoparticles are clearly localized to the area of the hair follicle or in close proximity to the sebaceous glands or funnel.
Plasmon nanoparticles exhibit strong absorption at wavelengths radiated by standard laser hair removers (eg, 755 nm, 810 nm, 1064 nm) in relation to the surrounding epidermal tissue. Therefore, irradiation of plasmon nanoparticles targeted by a laser beam induces thermal radiation from the particles to adjacent sebum, sebaceous glands, funnels, and other acne causing agents.
<Hair Removal> The nanoparticle-based methods and systems described herein for skin treatment include laser-based technology, chemical technology, electrolysis, electromagnetic technology, and mechanical technology (eg, brazing, tweezers). It has advantages over existing technologies known in the art. Such techniques do not adequately provide permanent hair removal across the width of the subject. In particular, subjects who have light on medium-pigmented hair are not well controlled by these techniques and suffer from side effects, including pain and lack of beneficial cosmetic effects, including hair removal. Laser-based techniques are well known in a variety of applications, but a considerable limitation is the lack of selective absorptive properties in natural pigments (eg, melanin) for specific wavelengths of light, resulting in tissue. Selective heating of one cell, structure or component of the is achieved without heating of adjacent off-target tissues. The nanoparticles described herein provide significantly higher photothermal conversion than natural dyes that allow laser energy to be concentrated on specific cells, structures or components of tissue due to selective photothermal damage.
More permanent reduction or removal of all hair types is provided herein in connection with hair removal procedures known in the art. In certain embodiments, coordinated selective removal of hair shafts and destruction of stem cells in the bulge region is provided as described herein. In particular, plasmon nanoparticles are clearly localized in the area of the hair follicle or approximate the bulge area, a stem cell-rich domain of the hair follicle. In addition, plasmon nanoparticles are localized at a close proximity of ~ 50-75% of the hair shaft structure.
Plasmon nanoparticles exhibit strong absorption at wavelengths radiated by standard laser depilatory devices (eg, 755 nm, 810 nm, 1064 nm) associated with the surrounding epidermal tissue. Therefore, irradiation of plasmon nanoparticles targeted by a laser beam induces thermal radiation from the particles to adjacent stem cells (or, in some cases, the structure of the hair shaft itself), disrupting cell death and normal regeneration pathways. Bring.
<Non-malignant and malignant skin tumors> Laser therapy for the prevention and treatment of non-malignant, malignant, melanoma and non-melanoma skin cancers has received much attention in photodynamic therapy techniques, thereby photosensitive porphyrin. Is applied to the skin and is used to localize laser beams, generate active oxygen species, and destroy cancer cells by toxic radicals. For example, 5-ALA in combination with laser treatment is FDA-approved, widespread, and surgically approved by the FDA for the treatment of non-melanoma skin cancer actinic keratoses. Used out of indication for the treatment of untreated or recurrent basal cell carcinoma (BCC). However, this procedure causes the patient to have photosensitivity, inflammation, exfoliation, scarring, hypopigmentation and hyperpigmentation, and other side effects due to the nonspecific percutaneous uptake of porphyrin molecules. The nanoparticles described herein undergo significantly higher photothermal conversion than natural dyes and dyes that allow laser energy to be concentrated on specific cells, structures or components of tissue due to selective thermal modulation. provide.
The use of the materials and techniques described herein may provide a greater degree and duration of cancer treatment than existing methodologies. In certain embodiments, coordinated selective removal of specific target cells is described herein. In particular, plasmon nanoparticles are clearly localized to the area of the hair follicle that results from follicular bulge stem cells forming nodal basal cell carcinomas and other carcinomas. Plasmon nanoparticles can also be delivered to other tumor-causing target cells, such as the epithelium within the follicle, which contains the cells that are the source of superficial flat basal cell epithelioma.
Plasmon nanoparticles exhibit strong absorption at wavelengths radiated by standard laser depilatory devices (eg, 755 nm, 810 nm, 1064 nm) associated with the surrounding epidermal tissue. Therefore, irradiation of plasmon nanoparticles targeted by laser beams induces thermal radiation from the particles to adjacent keratinocytes, melanocytes, follicular bulge stem cells, cancer cells, or cancer cell precursors for cancer prevention and treatment. It results in suppression of cell death or cell proliferation.
Subcutaneous application. Target tissues for subcutaneous application include adipose tissue and connective tissue below the integumentary system. Diseases or illnesses suitable for treatment by the application of subcutaneous science include wrinkles and tattoos. Other applications include skin rejuvenation and / or re-emergence, removal or reduction of cracks, and fat removal.
Application of blood vessels. Target tissues for vascular application include arteries, arterioles, capillaries, veins, and veins. Diseases or diseases suitable for treatment by vascular application include spider veins, cardiopulmonary dysfunction, and vascular stenosis. In particular, venous abnormalities account for a significant proportion of cosmetic diseases or illnesses that affect blood vessels. Individuals with venous abnormalities, such as spider veins or incomplete venous valves, suffer from pain, pruritus, or unwanted aesthetics.
In addition, there are various indicators that removal of other blood vessels, including arteries, small arteries or capillaries, can provide therapeutic or cosmetic benefits, including: 1) Fat pads and / or fat cells. Removal of blood vessels that supply, 2) removal of blood vessels that support tumor / cancer cells, 3) removal of blood vessel bruise (port wine stain, hemangiomas, yellow spot stain), and 4) removal of the canal. Any other indicator that mediates tissue destruction and apoptosis, or necrosis of cells supported by those vessels for therapeutic or cosmetic benefits. A method of using the compositions described herein for the selective destruction of vascular components from plasmon nanoparticles localized or scattered in the blood is provided herein. To. Plasmon nanoparticles are introduced into the body by intravenous injection in combination with a pharmaceutically acceptable carrier as described above. The nanoparticles diffuse into the blood and, in some embodiments, localize to specific vascular tissue. The nanoparticles are subsequently activated by a laser or light-based system known in the art for the treatment of skin conditions such as hair removal or removal of spider veins. Alternatively, image-guided or non-image-guided fiber optic light guide-based laser or optical systems can be used to remove blood vessels or blood components in larger veins. In one embodiment, a dual functional device for injecting nanoparticles and administering light over an optical waveguide can be used. Activated nanoparticles can squeeze blood and adjacent tissues (blood vessels, blood vessel walls, endothelial cells, components on or within endothelial cells, endothelial basal membranes) up to excision temperatures (38-50 ° C and above). It heats the filling tissue, cells, or components that support the components of the cells, including and around the blood vessels, blood cells, blood cell components, other blood components).
A composition comprising a pharmaceutically acceptable carrier and multiple plasmon nanoparticles in an amount effective to induce thermal modulation of the blood vessel or target tissue region within the blood vessel to which the composition is contacted intravenously. Provided herein. In addition, the composition of plasmon nanoparticles may include means for targeting microvessels, selected from the group consisting of anti-microvascular endothelial cell antibodies and ligands for microvessel endothelial cell surface receptors. Also, a composition comprising a region of the target vascular bundle tissue and a plurality of plasmon nanoparticles and a pharmaceutically acceptable carrier under the condition that an effective amount of plasmon nanoparticles are localized in the domain of the target vascular region. The step of contacting with an object; and the step of exposing the target tissue region to energy delivered from a non-linear excitation surface plasmon resonance source in an effective amount to induce thermal modulation of the domain of the target vascular region. Also provided is a method of performing a thermal excision of the target vascular bundle tissue of a mammalian subject.
Oral and nasal application. Target tissues for oral application include the mouth, nose, pharynx, larynx and trachea. Diseases or diseases suitable for treatment by vascular application include oral cancer, polyps, throat cancer, nasal cancer, and Monniere Kuhn syndrome.
Application of endoscopy. Target tissues for the application of endoscopy include the stomach, small intestine, large intestine, rectum and anus. Diseases or diseases suitable for treatment by vascular application are gastrointestinal cancer, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, short bowel syndrome, or rumble whiplash, tropical sprue, streak , Includes infectious diseases such as celiac disease, enteritis, ulcers, Crohn's disease, and giant colon.
Method of thermal modulation. A method of performing thermal modulation of the target tissue region is provided. The nanoparticle composition comprises multiple plasmon nanoparticles under conditions where an effective amount of plasmon nanoparticles are localized to the domain of the target tissue region; and to induce thermal modulation of the domain of the target tissue region. The target tissue region is exposed to an effective amount of energy delivered from the non-linear excited surface plasmon resonance source.
Removal of non-specifically bound nanoparticles. Removal of nanoparticles localized on the surface of the skin can be performed by contacting the skin with acetone, alcohol, water, air, a debriding agent, or wax. Alternatively, physical wound cleaning may be performed. Alternatively, a reduction of plasmon compounds can be performed.
The amount of energy provided. The skin is cm, especially in the infrared range, by laser wavelengths of, for example, about 750 nm, 810 nm, 1064 nm, or other wavelengths.<sup>2</sup>Irradiated with 1-60 joules of fluence per hit. Various iteration rates are used, from continuous to pulsed, for example, 1-10Hz, 10-100Hz, 100-1000Hz. While some energy is reflected, it is an advantage of the subject matter described herein that a significant amount of energy is absorbed by the particles with a small amount absorbed by the skin. The nanoparticles are delivered to the hair follicles, funnels or sebaceous glands at a concentration sufficient for absorption, eg, 1.1-100 times more energy than other components of the skin in similar volumes. This is achieved in some embodiments by having a concentration of particles in the hair follicles that have absorbance at a laser peak of 1.1-100 times, which is associated with other skin components of similar volume. To.
Light-absorbing nanoparticles are utilized in combination with a laser or other excitation light source of suitable wavelength to allow adjustable destruction of target skin structures (eg, sebaceous glands, funnels, hair follicles). To. The laser beam can be applied continuously or in pulses with a single or multiple pulses of light. The intensity and distance of heating that causes photothermal damage is controlled by the intensity and duration of light exposure. In some embodiments, a pulsed laser is utilized to provide localized thermal destruction. In some such embodiments, pulses of different duration are 0.05, 0.1, 0.5, 1, 2, 5, 10, 20, 30, 50, 75, 100, 200, 300, 500, 1000 microns. It is provided to localize the thermally damaged area within the particle. The pulse is at least a femtosecond, picosecond, microsecond, or millisecond duration. In some embodiments, the peak temperatures achieved in the tissue from heating the nanoparticles are at least 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200 degrees Celsius. , 300, or 500 degrees. In some embodiments that utilize pulsed heating, high peak temperatures are those of macroscopic tissue above 0.1, 0.5, 1, 2, 3, 4, 5, 7, 9, 12, 15, 20 degrees Celsius. It is realized locally in the hair shaft without raising it. In some embodiments, short pulses (100 nanoseconds-1000 microseconds) are from particles incorporated to localize damage close to the particle location to target skin structures (eg, sebaceous glands and / or hair follicles). ) Is used to send a very high transient thermal gradient to and around it. In other embodiments, longer pulse lengths (1-500 ms) localize thermal energy away from localized particles to stem cells or other components of 100 μm or greater in the bulge region. Therefore, it is used to further send a thermal gradient from the target structure. cm<sup>2</sup>Fluence of 1-30 joules per fluence is generally sufficient to heat remove follicles with high particle concentration and therefore higher absorbance than skin (eg, 1.1-100 times per volume absorbance of skin). These fluences are often those currently in use (eg diodes: 25-40 J / cm).<sup>2</sup>, Alexandrite: 20J / cm<sup>2</sup>, Nd: YAG: 30-60J / cm<sup>2</sup>) Lower, less damage to non-follicle areas and potentially less pain.
Plasmon resonance system. A plasmon resonance system is provided that includes a surface containing multiple plasmon nanoparticles and a non-linear excitation light source. Preferably, the surface is a component of the skin targeted for cosmetic or therapeutic treatment (eg, a bulge area for hair removal, a funnel or sebaceous gland for the prevention of contusion). Also provided as components of the system are methods for delivering plasmon nanoparticles to the skin surface, such as coating tools, sprays, aerosols, vacuum suction, high pressure airflow, or high pressure liquid flow. In addition, methods are provided for localizing plasmon nanoparticles with respect to skin components such as hair follicles, bulge areas, sebaceous glands, funnels. Useful surface delivery means include devices that produce high frequency ultrasound, low frequency ultrasound, heat, massage, contact pressure, or a combination thereof.
In addition, a system is provided that includes removal means for removing nanoparticles on non-follicle-like parts of the skin. Removal means include at least one compound that reduces acetone, alcohol, water, air, chemical stripping, waxes, or plasmon compounds.
In addition, the systems of the present disclosure provide a non-linear excitation light source that produces a continuous wave or pulsed optical source. Alternatively, a non-linear excitation light source can generate electromagnetic radiation, ultrasonic waves, thermal energy, electrical energy, magnetic energy, or electrostatic energy. Non-linear excitation light source is about 0.00005 mW / cm<sup>2</sup>From about 1000 TW / cm<sup>2</sup>A system capable of irradiating nanoparticles having an intensity of up to is provided. In addition, the non-linear excitation source can function in one photon morphology, two photon morphologies, multiple photon morphologies, gradual morphology, or up-conversion morphology. Fibers, light guides, contact tips, or combinations thereof can be used in the system.
In some embodiments, the system includes a monitoring device such as a temperature sensor or thermal energy detector. In other embodiments, the system also includes controller means for adjusting a non-linear excitation light source (eg, a "feedback loop controller"). In a related embodiment, the system includes means for detecting a target tissue adjacent the temperature or the surface of the surface, wherein, the controller manually stage, lasting intensity and / or excitation of non-linear excitation light source Adjust the time. In such an embodiment, the controller means preferably adjusts the intensity of the non-linear excitation light source so that the first component of the hair follicle is associated with the second component of the hair follicle. Selectively heat excision. In a further embodiment, the cooling device is in direct contact with the skin during irradiation to minimize heating of the nanoparticles or skin on the surface, while the nanoparticles penetrate deeper into the follicles, skin, or sebaceous glands. Heat to a temperature at which adjacent tissue is selectively excised.
The skin is a typical target tissue. The skin preferably comprises a hair sac and / or sebaceous gland, where a non-linear excitation light source increases the temperature of the skin to 38 ° C, 39 ° C, 40 ° C, 41 ° C, 42 ° C, 43. Heat enough to reach temperatures above 37 ° C, such as ° C, 44 ° C, 45 ° C, 46 ° C, 47 ° C, 48 ° C, 49 ° C, about 50 ° C, or higher. It produces the energy that results in heating the skin in an amount that is effective in inducing thermal modulation of the hair sac, funnel, sebaceous glands, or their components.
Method of formulation. Also provided are methods of prescribing the nanoparticles of the present disclosure in a form suitable for use as described herein. In particular, the nanoparticle composition is made by: a) the step of forming a first mixture containing multiple nanoparticles and a first solvent; b) a first to form a second mixture. The step of exchanging the solvent with the second solvent; and c) the step of combining the second mixture with a cosmetically or pharmaceutically acceptable carrier; thereby forming a nanoparticle composition.
The process of exchange is optionally performed using liquid chromatography, solvent exchange system, centrifugation, precipitation, or perforation. Preferably, the nanoparticles are surfaces that have been modified through a controlled reduction or oxidation step. Such surface modifications may include coating steps such as light absorption of biological entities on the surface of monomers, polymers, or nanoparticles. Typically, the coating process involves bringing the nanoparticles into contact with an oxidizing environment. In addition, the coating process may include monomer polymerization to create a polymer coat.
The method described herein also involves dissolving the nanoparticles in a non-polar solvent to encapsulate the nanoparticles in the emulsion, followed by mixing the dissolved nanoparticles with a polar solvent. Including. In addition, the addition of surfactants at concentrations of 0.1-10% (eg sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-1 / deceth-1 sulfate) disrupts the skin barrier of the epidermis. , Can be used to emulsify sebum and allow improved mixing of hydrophilic nanoparticles in aqueous solution. In addition, nanoparticle enrichment such as centrifugation or lyophilization can be utilized. In addition, the nanoparticles can be pretreated by heat or radiation. Also provided is an optional step of joining a biological entity or a plurality of biological entities to nanoparticles. Such a bonding step may include a thiol, amine, or carboxyl bond of the biological entity to the nanoparticles.
Diseases and disorders. The present disclosure is for the treatment of wrinkles and other changes associated with photoaging or aging over time (commonly referred to as skin rejuvenation), and for the treatment of diseases, including skin diseases, contusion. To reduce related disorders such as liquor, folliculitis, pseudo-folliculitis, or proliferative or scaly scaly disorders such as psoriasis, to stimulate or reduce hair growth, and to cellulite, Reduced pigmentation such as irritation, liquor-like spots (PWS), bruise, hyperhidrosis, venous aneurysm, pigmentation problems, tattoos, white spots vulgaris, melanosis, scars, cracks, fungal infections, Can be used on human (or other animal) skin due to bacterial infections, dermatological inflammatory disorders, reduction of musculoskeletal problems (eg, tendonitis or arthritis), improving the treatment of surgical wounds And / or improve burn treatment to reduce and minimize scarring, improve circulation in the skin, etc.
The present disclosure may also help improve wound healing, including, but not limited to, chronic skin ulcers, diabetic ulcers, burn injuries, viral ulcers or disorders, periodontal disease and other dental disorders. The present disclosure also presents, in certain embodiments, non-ablative thermal wounding techniques for treating skin wrinkles, blemishes, cracks and other skin disorders. In the process of performing cosmetic surgery, including techniques), it helps to enhance the effectiveness of the device for making injuries or wounds. Under such circumstances, it may be preferable to use conventional non-resectable thermal treatment in combination with the methods of the present disclosure. The present application applies nanoparticles to enhance treatment so that in certain embodiments, removal of the stratum corneum (and perhaps additional epithelial layer) can prove effective for some treatment regimens. Used in combination with or without micro or surface excision, skin abrasions, or enzymatic or chemical stripping of the skin, or topical cosmetological applications. The methods of the present disclosure are, but are not limited to, contusion treatment, hair removal, hair growth / hair follicle irritation, reduction / prevention of malignant and non-malignant skin tumors, and skin. It is especially applicable to rejuvenation.
The dermatological treatment methods described herein are nanoparticle irradiation only, nanoparticle irradiation in combination with nanoparticles or microparticles, or nanoparticles with nanoparticles or compositions containing nanoparticles or microparticles and one or more therapeutic agents. It can be formed using particle irradiation. Such nanoparticle irradiation can be generated by any known nanoparticle generator, preferably a centralized nanoparticle generator capable of generating and irradiating a concentrated nanoparticle wave. ..
<p><Example 1: Generation of plasmon nanoparticles for thermal modulation> Nanorods, hollow nanoshells, silicon nanoshells, nanoplates, nanorices, nanowires, nanopyramids, nanoprisms, nanoplates, and the present description described herein. Plasmon nanoparticles containing other shapes known to the trader are made in the 1-1000 nm dimension range under conditions that promote deep follicular penetration with deep surface properties. Surface properties can vary on one or more (2, 3, or 4) different dimensions in order to increase the nanoparticle concentration of the target tissue domain. Penetration into the follicular openings of 10-200 μm can be maximized using the nanoparticles described herein. Here, nanoparticles sized in the range of about 10-100 nm are made and preferably assembled or formulated into a multiparticular structure with a size in the range of 100-300 nm. Alternatively, the coating (eg silica) grows on a uniparticular structure that increases the particle size to the range of 100-300 nm and above.</p><p> Surface-modified plasmon nanoparticles. Typical preparations for surface-modified plasmon nanoparticles are provided as follows. Plasmon nanoparticles are synthesized with a stable cetryltrimethylamonium bromide (CTAB) coating and 10.D to 100 through 1 to 3 cycles of centrifugation at 16,000 rcf by supernatant decanting. , 200, 300, 400, or 500 O.D. Alternatively, the nanoparticles coated with CTAB are concentrated and 250 Amol / L. Resuspend in 5-kDa methyl-polyethylene glycol (PEG) -thiol to produce PEG-coated nanoparticles. Verification that the PEG polymer stock is sufficiently reduced is performed using spectroscopy to measure the thiol activity of the polymer-thiol, which has 5,5-dithiobis (2-nitrobenzoic acid) against the DTT gradient. .. A solution of methyl-PEG-thiol and nanoparticles coated with CTAB was mixed for 1 hour at room temperature and then for 24 hours at 5 kDa in 4 L of distilled water. Dialysis was performed on MWCO. The dialyzed sample is processed through a 100-kDa filter to remove excess polymer. Quantification of the number of PEG polymers per particle is performed by surface modification of the nanoparticles with amino-PEG-thiol polymer and quantification of the number of amines by SPDP assay. For the test product, a solution of 100 O.D. of plasmon nanoparticles coated with CTAB is made in distilled water, and the plasmon nanoparticles coated with 100 O.D. PEG are prepared in distilled water, ethanol, DMSO, or mineral oil. create. Plasmon nanoparticles with a silica shell, for thicknesses of 5-50 nm and above, are made of silica such as tetra-ethyl-ortho-silicate (TEOS), sodium silicate, aminopropyletriethoxysilane (APTS). It is made by reacting a silicate with nanoparticles. In contrast, the vehicle-only formulation does not contain nanoparticles.</p><p> Embedded nanoparticles. The nanoparticles are embedded (or encapsulated) in a substance capable of producing a wide range of sizes and their size adjusted. Particle sizes in the 100-2000 nm range have been shown to enter the hair follicles without penetrating the dermis. Nanoparticles in silica, synthetic polylactide / co-glycolide copolymers, porous lauryl lactamin / caprolactam nylon copolymers, hydroxyethyl cellulose, polymeric electrolyte monolayers, or instead, without significantly altering plasmon resonance properties. Encapsulate in a natural hydrogel such as hyaluronic acid. The nanoparticles are embedded in the 100-2000 nm material without covalent attachment or by cross-linking amines, carboxyls or other components on the surface of the nanoparticles to the polymer structure. The surface of the 100-2000 nm material can be modified for optimal zeta potential, hydrophilicity / hydrophobicity, and / or adsorption layer by the techniques described herein. In addition, the shape of the aspect ratio of the polymer can be modified from the lowest to the highest to increase the concentration and penetration thickness of the embedded plasmon nanoparticles. Nanoparticles conveniently have an aspect ratio greater than about 1.</p><p><Example 2: Preparation of heat-cut plasmon nanoparticles for local delivery> Nanoparticles are prepared as in Example 1 using a suitable solvent (eg water, ethanol, dimethyl sulfoxide). A mixture containing multiple nanoparticles in water is concentrated to approximately 100-500 OOD and replaced with a new solvent by liquid chromatography, solvent exchange system, centrifugation, precipitation, or dialysis. Solvents include alcohols (eg n-butanol, isopropanol, n-propanol, ethanol, methanol), hydrocarbons (eg pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane), chloroform, diethyl-ether. , Water, acids (eg acetic acid, formic acid), bases, acetone, dimethylsulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, or ethyl acetate. The new solvent is combined with a cosmetically or pharmaceutically acceptable carrier, thereby forming a nanoparticle composition. In general, the particles and carrier will form an emulsion.</p><p> Provided is a plasmon nanoparticle preparation that amplifies or promotes the penetration of nanoparticles into hair follicles. In some embodiments, nanoemulsions and microemulsions facilitate division within lipid-rich skin compartments such as hair follicles. In some embodiments, the nanoparticles are subjected to disruption of the skin barrier of the epidermis, emulsification of sebum, and an improved mixture of hydrophilic nanoparticles in a hydrophobic solution, or hydrophobic spaces of the skin (eg, hair). Formulated in a composition containing a 0.5-2% v / v detergent to allow targeting (between the trunk and surrounding follicles). Nanoparticle formulations are also provided at various concentrations (1-20% w / v) in aqueous solutions, silicon / oil solvents, propylene glycol or creams (including, for example, alcohols, oils, paraffins, colloidal silica). In some embodiments, the light-absorbing nanoparticles are pH, temperature, osmolite concentration, viscosity, volatile, and prepared to improve the entry of the light-absorbing nanoparticles into the hair sac. It is used in solutions with other properties.</p><p> Formulations are prepared to maximize nanoparticle stability (degree of aggregation in solution), nanoparticle concentration, and nanoparticle absorbance (degree of laser-induced heating at different concentrations).</p><p> The formulation of plasmon nanoparticles is illuminated with a clinical laser having a wavelength that matches the peak absorption wavelength of the microparticles, and the formulation rapidly exceeds the temperature of thermal ablation and to a greater extent than conventional clinically absorbable dyes. Heat up to. Figure 2 shows 1064 nm, 20 J / cm<sup>2</sup>After exposure to a laser pulse of 55 ms, the temperature profile of the plasmon particles (peak absorption wavelength of 1020 nm) is compared with conventional clinical dye carbon lotions, melazine sprays and indocyanine greens. The temperature increase caused by the pulsed 1064 nm laser beam was more than 2.5 times greater with respect to the plasmon solution and was compared to conventional clinical dyes used at the same dilution (1: 1000 dilution from clinical concentration, Here, the clinical concentrations are: carbon 20-200 mg / ml, melazine 1 mg / ml, indocyanine green 5 mg / ml).</p><p><Example 3: Use of plasmon nanoparticles for thermal modulation of hair> Individuals with blonde hair, red hair, gray hair, or light-colored hair are not adequately treated by existing light-based hair removal techniques. A method of using the compositions described herein for the selective removal or reduction of untreated blonde, redhead, gray hair, or light colored hair is provided herein. The plasmon nanoparticles produced and formulated as described above are introduced into the target tissue area, generally the skin area, to achieve effective hair removal by a laser-based hair removal system known in the art. Activated.</p><p> In the hair follicles and / or near the components of the sebaceous glands, including the epithelial connections of the sebaceous ducts, sebum, and sebaceous glands, and / or near the bulge region, including the epithelial inner surface of the stem cells, stem cell microenvironment, bulge region, and / Or near the follicular follicles, construct an optimal particle size of 30-800 nm, including one or several plasmon nanoparticles, to achieve maximum penetration depth and concentration of plasmon nanoparticles. The nanoparticles that encapsulate the plasmon nanoparticles can be formulated from any number of polymers or matrices. In some embodiments, the formulations are degradable or non-degradable polymers such as synthetic polylactide / co-glycolide copolymers, porous lauryllactam / caprolactam nylon copolymers, hydroxyethylcellulose, polymer electrolyte monolayers, or Instead, it includes those in natural hydrogels such as hyaluronic acid, gelatin and others. In a further embodiment, hydrogel PLGA, PEG-acrylate is included in the formulation. Preferentially, matrix components such as silica, polystyrene or polyethylene glycol are provided in the formulation to improve particle stability and allow easy removal from the skin surface after application and follicular targeting. .. Other formulations include surfactants (eg, sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-1 / deceth-1 sulfate), lipid bilayers, liposomes, or endoplasmic reticulum components. Plasmon nanoparticles containing nanorods, nanoshells, nanospheres, nanoplates, or nanorices are encapsulated in or matrix of polymer or lipid-based nanoparticles or deposited on the particle surface. Alternatively, nanoparticles in a dimensional range larger than 100-250 nm, 250-500 nm, 800 nm-1500 nm, or 1500 nm can be used.</p><p> Skin pretreatment by mechanical or chemical exfoliation is used in some embodiments to remove hair plugs and "open" follicles for particle delivery. In addition, it can be shaved or waxed to create voids in the hair follicles to be filled with particles. The use of physical or thermal forces amplifies or promotes the penetration of light absorbing the nanoparticles and their conjugates into the hair follicles by partially causing the hair follicles to stretch prior to application of the nanoparticles. .. For example, ultrasonic and other sound forces, mechanical vibrations, hair shaft manipulations (including pulling), physical forces, heat manipulations, and other treatments, the entry of light-absorbing nanoparticles into the hair follicles. Use to improve. The treatment of the nanoparticle preparation is performed alone, in combination, continuously or repeatedly 1-24 times.</p><p> The applicator is used to uniformly apply the composition of nanoparticles to the follicles. The applicator can be a sponge, cloth, direct finger contact, tube, syringe, device applying suction, aerosol, spray, or other means known in the art. In one example, a formulation of 1 ml of plasmon nanoparticles at a concentration of 100 OOD with a peak resonance of 810 nm, by syringe, approximately 200 cm of the skin of an adult human subject.<sup>2</sup>Applies to the area of. The cloth is used to evenly distribute the solution over the skin area and into the hair follicles. A deep massage from a mechanical vibrator for 5 minutes with or without 1 MHz ultrasound is applied to deeply deliver the particles into the follicles. The particles, when irradiated by a diode (810 nm) laser, at a concentration sufficient to heat the skin with a radius of 100 μm at a temperature of 5-20 times greater increase than produced in similar volumes of adjacent skin. It penetrates down to 50-75% of the total length of the hair shaft. Acetone, ethanol, or wound cleansing agents can be used to reduce or prevent heat in the skin follicles and to remove all particles from the surface of the skin that have not accumulated in the follicles.</p><p> Nanoparticle formulations are examined in exobibo animal samples, exobibo human skin samples, and in vivo human skin, including the following assessments: 1) Depth of nanoparticle penetration into the hair sac; 2) Achieved particle concentration; 3) The degree of heat achieved at the delivered nanoparticle concentration; and 4) the effect of photothermal destruction, including temporary and permanent hair removal, 5) elimination of nanoparticles after treatment. To assess the depth of nanoparticle penetration, the surface of plasmon nanoparticles functionalized by fluorescent molecules is subjected to histological incision or follicular biopsy (removal of hair shaft) by fluorescence microscopy. Visualize. Alternatively, the plasmon nanoparticles are visualized directly by darkfield microscopy after a histological incision or follicular biopsy. To assess nanoparticle concentrations at various depths along the follicles, excised skin samples are separated by tape removal or heat-based techniques and the samples are separated by ICP-MS (inductively coupled plasma mass spectrometry). Dissolve for bulk analysis of metal concentration. The macroscopic degree of heating is validated by infrared thermography of skin samples and evaluation of skin sections exposed to laser exposure for thermal damage markers. Finally, follicular hair shaft, inner root sheath, outer root sheath By analyzing histological cell lesions at the target site, including the room sheath) and the bulge region containing the stem cell microenvironment, the effectiveness of photothermal destruction at the nanoparticle accumulation site can be measured. Target sites include stem cells that contribute to the growth of new hair. Permanent hair removal is fully achieved by the accumulation of plasmon nanoparticles to this depth as the bulge region is generally localized in the near-medium hair shaft (up to ~ 50% down in length). .. In some situations, nanoparticle delivery can also create a thermal gradient that emits light further down the hair shaft. Animal studies have removed uncolored hair by comparing thermal properties, thermal detachment of hair shafts, and thermal damage of bulge stem cells in treated hairless rodents, albino rodents, and black-haired rodents. It is useful for demonstrating the effect of hair. The effect on live human skin is measured by counting the number of hairs for 3 and 12 months in a row. Biopsies are taken from patients selected for 2, 4 and 6 weeks in a row to ensure that the nanoparticles are removed from the skin without being implanted in the dermis.</p><p> Hair follicle penetration of fluorescently labeled nanoparticles as measured using porcine extracutaneous implants and confocal imaging. A 25 mg / ml aqueous solution, silicon dioxide coated nanoparticles (200 nm diameter), with freshly thawed pig skin after excess nanoparticle suspension was removed and a manual massage was performed for 3 minutes. Made contact. An incision was made in the explant and exposed to confocal imaging. As shown in FIG. 3A, explant pieces were imaged at an angle to the hair follicles in a 60 μm plate; surface 1 shows the follicle funnel, while surface 2 shows the terminal region of the follicle. FIG. 3B demonstrates that a typical confocal image showing red nanoparticles (absorbance at 548 nm) is visible in superficial and deep follicles but not detectable in the cortical layer below the follicles. .. FIG. 3C shows high magnification imaging of red nanoparticles localized in deep follicles (~ 400 μm) and retained within said follicles. Green indicates tissue autofluorescence (488 nm).</p><p> Hair follicle penetration of plasmon nanoparticles measured using porcine skin and darkfield imaging. A 100 O.D. suspension of plasmon nanoparticles (200 nm diameter) in contact with freshly thawed pig skin after the excess nanoparticle suspension has been removed and a manual massage has been performed for 3 minutes. I let you. The procedure was repeated for a total of three applications and surface residues were removed by alternating several applications of water and ethanol (3-5). Skin samples were excised, fixed, incised along a horizontal plane and exposed to darkfield imaging. As shown in FIG. 4A, skin samples were divided and imaged horizontally with respect to hair follicles at various depths. In skin section images, plasmon nanoparticles were observed as a source of bright blue color points at depths up to 1.2 mm in porcine follicular space (Fig. 4B). Control samples without plasmon nanoparticles were clearly distinguished (Fig. 4C). ICP-MS is also performed on skin sections to assess nanoparticle concentrations at various depths along the follicle.</p><p> Hair follicle penetration of nanoparticles in hairless rodents, albino rodents and black-haired rodents. 8-week-old white-haired Swiss Webster mice (n = 3) are anesthetized with an injectable ketamine / xylazine solution, and the dorsal backskin and hair are washed and dried. Prior to drug administration, three 10 cm x 10 cm areas were distinguished by a permanent marker on each mouse: 1) electric razor, 2) Nair depilation reagent. Reagent), or 3) Warm wax / pine and expose to hair removal by application and exfoliation. Each mouse is treated with a pipette having up to 3 nanoparticle formulations at a quadruple 5-μl spot size per distinct skin area (up to 12 spots per area or 36 spots per mouse). Separate the exact spot location with a pen before pipetting. Massage the replica treatment spot on the left side of the back to the skin for 5 minutes, while applying the replica treatment spot on the right side of the back without massage. Thirty minutes after application, mice are sacrificed by carbon dioxide asphyxiation and cervical dislocation, the skin is carefully excised, and sections along the spot size demarcation are punctured. A skin biopsy is fixed with 10% paraformaldehyde, embedded with paraffin and cut across the microtome to 5 μm. Slides with attached paraffin sections are deparaffinized and stained with hematoxylin and eosin (H & E) or left unstained for dark field microscopy. Using H & E staining, photomicroscopy and / or darkfield microscopy, more than 50 follicles per formulation are imaged and scored in the follicles, along the hair shaft, in an estimated bulge stem cell microenvironment. Perform for skin sections for visible macroscopic nanoparticle accumulation at the site and at the depth of follicular scales. On successive histological sections, a silver enhancement staining kit based on sodium thiosulfate was used to enhance the plasmon nanoparticle signal by precipitation of metallic silver. obtain. Phase and darkfield micrographs are captured and used to record the depth of follicular penetration for each nanoparticle formulation and application. ICP-MS is also performed on skin sections to assess nanoparticle concentrations at various depths along the follicle.</p><p> Evaluation of photothermal fracture at the nanoparticle accumulation site. Treatment areas of porcine, human or mouse skin, clinical parameters (30-50 J / cm)<sup>2</sup>Irradiate with a laser that matches the peak absorption wavelength of the nanoparticles (eg, a 1064 nm YAG laser for 1020 nm plasmon particles) using 1 s exposure and a pulse width of 10-50 ms. To measure microscopic photothermal damage to target skin structures such as hair follicles and hair follicle bulge stem cells, 10 days after application and radiation, human subjects received lidocaine injection to paralyze the treated area. Carefully excise the skin and puncture the section along the spot size demarcation. Fresh human skin biopsies or explanted human and animal skin samples are fixed with 10% paraformaldehyde, embedded with paraffin, cut to 5 μm on a transverse microtome, or cut into 2%. It is fixed in a solution of Zamboni with picric acid and cryosectioned by freezing the gliding microtome. Slides with attached paraffin sections are deparaffinized and stained with hematoxylin and eosin (H & E). Histological sections are tested at various depths for markers of heat damage and inflammation. Hematoxylin and eosin (H & E) is used to image skin and follicular microanatomical structures and to show deterioration of hair shafts, sebaceous gland decline and cell vacuolization (indicating cell damage). Nitroblue tetrazolium chloride (NBTC), a lactate dehydrogenase stain lost by thermal damage to cells, is used to assess damage to keratinized cells. Cell damage in the follicles of skin samples receiving plasmon nanoparticles in addition to laser treatment is scored and compared to those receiving laser treatment alone. Treated live human skin is also clinically followed and first treated for 2 weeks to 3 months after plasmon nanoparticles + laser treatment, or during repeated plasmon nanoparticles + laser treatment. The baseline digital photographs obtained previously and the negative controls that received only laser treatment were compared. Note clinical observations of hair removal as well as erythema, edema, discomfort, irritation or scarring to measure the degree of nonspecific thermal damage.</p><p> The effect of plasmon particle coating on the specificity of delivery and photothermal heating. Preferentially, matrix components such as silica, polystyrene or polyethylene glycol are provided in the formulation to improve particulate stability and allow easy removal from the skin surface after application and follicular targeting. To do. Acetone, ethanol, or wound cleansing agents can be used to remove all particles from the surface of the skin that have not accumulated in the follicles, in order to reduce or prevent the heating of non-follicles in the skin. In FIG. 5, live human skin was treated with uncoated plasmon particles compared to silica-coated plasmon particles prior to comparison with laser-irradiated and particle-treated (laser-only) controls. Skin pretreatment, including razor dermabrasion (15 seconds, medium setting), to remove hair plugs and "open" follicles for particle delivery, both forearms I ran it on my department. 810 nm laser pulse (30 J / cm) on human forearm skin<sup>2</sup>Irradiated only by (Fig. 5A), 30ms, 2 passes), or after treatment with a formulation of uncoated plasmon nanoparticles of resonance at 830 nm in 20% propylene glycol (Fig. 5B). The plasmon nanoparticle formulation was applied by a 3-minute massage, repeated 3 times, and the skin surface was wiped with 3 alternating applications of water and ethanol prior to laser irradiation. Thirty minutes after laser irradiation, non-specific clinical burns were observed due to significant photothermal heating of the remaining uncoated particles on the skin surface (Fig. 5B). 1064 nm laser pulse (40 J / cm) on live human skin<sup>2</sup>, 55 ms, 3 passes) alone (Fig. 5C), or after treatment with a formulation of silica-coated plasmon nanoparticles of resonance at 1020 nm in 20% propylene glycol (Fig. 5D). The plasmon nanoparticle formulation was applied by a 3-minute massage, repeated 3 times, and the skin surface was wiped with 3 alternating applications of water and ethanol prior to laser irradiation. No evidence of skin burning or erythema was observed 30 minutes after laser irradiation, as the silica-coated particles could be sufficiently wiped from the skin surface (Fig. 5D). Enlarged photographs of silica-coated particles + laser-treated skin areas show specific photothermal damage (hair follicles) at the site targeted by the nanoparticles, without damage to surrounding or non-particle treated tissue. Peripheral erythema and edema) (Fig. 6).</p><p><Example 4: Use of plasmon nanoparticles for the treatment of follicles> For the treatment of vulgaris and other follicles and skin diseases such as follicles, but sebaceous glands, especially sebaceous glands and / or A method of using the compositions described herein for selective targeting of hair follicles is provided herein. The plasmon nanoparticles produced and formulated as described above are introduced into the target tissue area, generally the skin area, and activated by a laser-based system known in the art to achieve effective hair removal. To become.</p><p> In the hair follicles and / or near sebaceous gland components, including sebaceous ducts, sebum, and epithelial connections of sebaceous glands, and / or near stem cells, the stem cell microenvironment, near the bulge-increasing region, including the epithelial inner surface of the bulge region, and / Or build an optimal particle size of 100-800 nm, including one or several plasmon nanoparticles, to achieve maximum permeation depth and concentration of plasmon nanoparticles near follicular follicles. The nanoparticles that encapsulate the plasmon nanoparticles can be formulated from any number of polymers or matrices. In some embodiments, the formulations are degradable or non-degradable polymers such as synthetic polylactide / co-glycolide copolymers, porous lauryllactam / caprolactam nylon copolymers, hydroxyethylcellulose, polymer electrolyte monolayers, or Instead, it includes those in natural hydrogels such as hyaluronic acid, gelatin and others. In a further embodiment, hydrogel PLGA, PEG-acrylate is included in the formulation. Preferentially, matrix components such as silica, polystyrene or polyethylene glycol are provided in the formulation to improve particle stability and allow easy removal from the skin surface after application and follicular targeting. .. Preferentially, the formulation comprises a surfactant (eg, sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-1 / deceth-1 sulfate), lipid bilayer components, liposomes, or endoplasmic reticulum. .. Surfactants divide the skin barrier of the epidermis, emulsify sebum, improve the mixing of hydrophilic nanoparticles with hydrophobic solutions, and improve the hydrophobic areas of the skin (eg, hair shafts and surrounding sheaths). Or reduce the impairment of homogeneity delivering hydrophilic particles (between follicles). Plasmon nanoparticles containing nanorods, nanoshells, nanospheres, or nanorices can be encapsulated in polymer nanoparticles or matrices, or deposited on the particle surface. Alternatively, 100-250nm, 250-500nm, 800nm-1500n</p><p> The use of physical or thermal force causes the penetration of light into the hair follicles and / or sebaceous glands, which absorbs the nanoparticles and their conjugates by partially causing the hair follicles to dilate prior to application of the nanoparticles. Amplifies or promotes. For example, ultrasound, other sound forces, mechanical vibrations, hair shaft manipulations (including pulling), physical forces, thermal manipulations, and other treatments of light-absorbing nanoparticles, hair follicles and / or It is used to improve the entry into the sebaceous glands. The treatment of the nanoparticle preparation is performed alone, in combination, continuously or repeatedly 1-24 times.</p><p> Prior to application of plasmon nanoparticles, a pretreatment step of removing excess sebum from the surface of the skin can be performed using chemical and / or mechanical means. Skin pretreatment by mechanical or chemical replacement is used in some embodiments to remove hair plugs and "open" follicles for particle delivery. In addition, it can be shaved or waxed to create voids in the hair follicles to be filled with particles.</p><p> The applicator is used to uniformly apply the composition of nanoparticles to the follicles. The applicator can be a sponge, cloth, direct finger contact, tube, syringe, device applying suction, aerosol, spray, or other means known in the art. In one example, a formulation of 1 ml of plasmon nanoparticles at a concentration of 100 O.D. with a peak resonance of 810 nm was syringed approximately 200 cm of the skin of an adult human subject.<sup>2</sup>Applies to the area of. The cloth is used to evenly distribute the solution over the skin area and into the hair follicles. A massage from ultrasonic waves at 1 MHz for 5 minutes or from mechanical vibrations for 2 minutes without the ultrasound is applied to deliver the particles deep into the follicles. The particles, when irradiated by a diode (810 nm) laser, are sufficient to heat the skin within a radius of 100 μm at an increment temperature 5-20 times greater than that produced by similar volumes of adjacent skin. Penetrates the entire length of the hair shaft with less than ~ 50% at a high concentration. Acetone, ethanol, or wound cleansing agents can be used to reduce or prevent heat in the skin follicles and to remove all particles from the surface of the skin that have not accumulated in the follicles.</p><p> Delivery of plasmon nanoparticles to the sebaceous glands, measured using human abdominal skin and darkfield imaging. Human sebaceous glands are located within the hair follicle sebaceous system, which consists of hair, hair sac, arrector pili muscle and sebaceous glands. In Figure 7A, a human skin biopsy is performed to visualize the microanatomical structure of a typical hair follicle sebaceous gland system, including the hair follicles (HF), sebaceous glands (SG) and arrector pili muscle. Immunostain with antibodies against basement membrane markers (blue) and PGP9.5 (nerve markers, green). For delivery of nanoparticles to the hair follicles and sebaceous glands, for hair shaving to remove protruding hair, for microskin resection (15 seconds, intermediate setting) to remove hair plugs and keratinocytes, and for particle delivery. The skin is first pretreated by chemical depilation to "open" the follicular microwells. Suspension of excess nanoparticles in a 100 O.D. suspension of plasmon nanoparticles (200 nm diameter) formulated in 1% sodium dodecyl sulfate (SDS) and 20% propylene glycol (PG). The fluid was removed, a manual massage was performed for 3 minutes, followed by ultrasound (1 MHz) for 5 minutes, followed by contact with the resected human abdominal plasty skin. The procedure was repeated for a total of 3 applications and surface residues were removed by alternating 3-5 application of water and ethanol. Skin samples were excised, fixed, incised along a horizontal plane and exposed to darkfield imaging. Composition of plasmon nanoparticles with a cosmetically acceptable carrier of 1% SDS / 20% PG performed by massage and ultrasound as assessed by dark-field imaging of horizontal skin sections Can be delivered to human follicles, and specifically to the sebaceous glands, at a depth of 400-600 μm (Fig. 7B).</p><p> A cosmetic formulation for the delivery of follicles and sebaceous glands in human skin. Preferentially, the formulation comprises a surfactant (eg, sodium dodecyl sulfate, sodium laureth 2-sulfate, ammonium lauryl sulfate, sodium octech-1 / deceth-1 sulfate), lipid bilayer components, liposomes, or endoplasmic reticulum. .. Surfactants divide the skin barrier of the epidermis and emulsify sebum to allow improved mixing of hydrophilic nanoparticles in hydrophobic solutions. Wetting agents such as propylene glycol are used to improve local viscosity and help maintain physiological pH. To demonstrate the efficacy and mechanism of typical cosmetic formulations for the delivery of human sebaceous glands, hair shears to remove protruding hair, microskin resections to remove hair plugs and keratinocytes (15 seconds, intermediate) The skin was first pretreated by chemical depilation, which "opens" the follicular microwells for particle delivery). Two separate 100 O.D. suspensions of plasmon nanoparticles (200 nm diameter) in 1% sodium dodecyl sulfate and 20% propylene glycol (SDS / PG), or 1% sodium laureth. -2-Prescribed in sulfate and 20% propylene glycol (SLES / PG). The formulation was contacted with two separate excised human abdominal skin samples, a 5-minute ultrasound followed by a 3-minute massage to deeply deliver the particles to the follicles. The procedure was repeated for a total of 3 applications and surface residues were removed by alternating 3-5 application of water and ethanol. Skin samples were excised, fixed, incised along a horizontal plane and exposed to darkfield imaging to assess particle delivery. A composition of plasmon nanoparticles with 1% SLES / 20% aesthetically acceptable carrier, administered by massage and ultrasound, as assessed by dark-field imaging of horizontal skin sections. It can be delivered to human follicles, and specifically to the sebaceous glands, at a depth of 400-600 μm (Fig. 8B).</p><p> Massage vs. ultrasound impact on nanoparticle delivery to human follicles and sebaceous glands. Ultrasonic and other sound forces, mechanical vibrations, hair shaft manipulations (including pulling), physical forces, thermal manipulations, and other treatments to the hair follicles and / or sebaceous glands of light-absorbing nanoparticles. It is used to improve the invasion of. Mechanical massage is a hair shaft Improves follicular permeation by'pumping'mechanisms), while ultrasound enhances percutaneous drug delivery through the lipid bilayer of the skin, foam formation, and temporary disruption of liquid mycloth triming. Hair shearing to remove protruding hair, microskin resection (15 seconds, intermediate setting) to remove hair plugs and keratinocytes, and particle delivery to characterize the effect of ultrasound-separated massage The skin is first pretreated by chemical depilation to "open" the follicular microwells. A suspension of 100 O.D. of plasmon nanoparticles (200 nm diameter) formulated in 1% sodium dodecyl sulfate (SDS) and 20% propylene glycol (PG) in three separate excised humans. It was contacted with an abdominal forming skin sample. In three treated human skin samples, massage alone was performed for 3 minutes and ultrasound (1 MHz) only for 5 minutes, or ultrasound followed by massage to deeply deliver the particles into the follicles. In the fourth sample, the particles were not applied to the skin. The procedure was repeated for a total of 3 applications and surface residues were removed by alternating 3-5 application of water and ethanol. Skin samples were excised, fixed, incised along a horizontal plane and exposed to darkfield imaging analysis to assess particle delivery. The composition of plasmon nanoparticles with 1% SLES / 20% aesthetically acceptable carrier administered by ultrasound, as assessed by dark-field imaging of horizontal skin sections, is both. For massage, more plasmon nanoparticles are delivered to the funnel, although the mechanism facilitates delivery (Fig. 9).</p><p> Additional plasmon nanoparticle formulations for follicular and sebaceous gland delivery in human skin. In some embodiments, plasmon nanoparticles include nanorods, nanoshells, nanospheres, or nanorices that are encapsulated in polymer nanoparticles or matrices or deposited on the surface of the particles. Preferentially, matrix components such as silica, polystyrene or polyethylene glycol are provided in the formulation to improve particle stability and allow easy removal from the skin surface after application and follicular targeting. .. Microskin resection to remove protruding hair shears, hair plugs and keratinocytes to demonstrate the shape and concentration of additional plasmon nanoparticles formulations for follicular, funnel and sebaceous gland delivery (15 seconds, The skin is first pretreated by chemical depilation that "opens" the follicular microwells for intermediate setting) and particle delivery. Separately, a 10 O.D. suspension of silica-coated nanoplates, a 30 O.D. suspension of plasmon nanorods coated with polyethylene glycol, and fluorescent silica particles, 1% sodium dodecyl sulfate. And formulated in 20% propylene glycol. The formulation was contacted with three separate excised human abdominal skin samples and a 3 minute massage was performed after 5 minutes of ultrasound (1 MHz) to deeply deliver the particles into the follicles. The procedure was repeated for a total of 3 applications and surface residues were removed by alternating 3-5 application of water and ethanol. Skin samples were excised, fixed, incised along a horizontal plane and exposed to darkfield imaging analysis to assess particle delivery. A composition of nanorods coated with polyethylene glycol (PEG) in a cosmetically acceptable carrier administered by ultrasound and massage, as assessed by dark-field imaging of horizontal skin sections. Gold (dimensions of 15 × 30 nm) was observed in a follicular funnel at a depth of 200 μm (Fig. 10A). Low concentration (10 O.D.</p><p> Assessment of photothermal destruction of sebaceous glands and target skin tissue. Nanoparticle formulations are tested on ex vivo animal skin samples, ex vivo human skin samples, and in vivo human skin as described in Example 3. By measuring the thermal damage to the sebaceous cells and the decrease in sebum production in the treated sebaceous glands, the effect of photothermal destruction at the nanoparticle accumulation site can be measured. To assess photothermal destruction, "shear to remove protruding hair, microskin excision to remove hair plugs and keratinocytes (15 seconds, intermediate setting) and follicular microwells for particle delivery" The human skin is first pretreated by "opening" chemical depilation. The skin is brought into contact with a 100 O.D. suspension of 810 nm resonant plasmon nanoparticles (200 nm diameter), followed by a 5 minute ultrasound (1 MHz) followed by a 3 minute massage to deliver the particles deep into the follicle. .. The procedure was repeated for a total of 3 applications and surface residues were removed by alternating 3-5 application of water and ethanol. Treated human skin sample with 810 nm laser (40 J / cm)<sup>2</sup>, 30 ms, 5 pulses) and compared to laser-treated humans. Human skin was biopsied, fixed in a solution of Zamboni with 2% picric acid, and cryoincised by freezing the gliding microtome. Slides with attached paraffin sections are deparaffinized and stained with hematoxylin and eosin (H & E). Histological sections are tested at various depths for markers of heat damage and inflammation. Hematoxylin and eosin (H & E) are used to image skin and follicular microanatomy and to show deterioration of hair shafts, sebaceous gland decline and cell vacuolation (indicating cell damage). Nitroblue tetrazolium chloride (NBTC), lactate dehydrogenase staining that is lost to cells by heat damage, can also be used to assess damage to keratinized cells vs. adipose gland cells. The intracellular colorant Oil-Red-O can be used to measure the oil content of lipids and sebum in treated samples. Sebum-absorbant to demonstrate sebum discharge rate and functional conversion during sebum flow Measure on skin in vivo using tapes) for 1-3 months in a row. Elimination and prevention of contusion lesions is measured by patient-reported results and counting contusion lesions for 1-3 months in a row.</p><p><Example 5: Preparation of heat-resected plasmon nanoparticles for vascular resection> The preparation was prepared for nanoparticle stability (degree of aggregation in solution), nanoparticle concentration, and nanoparticle absorbance previously injected into the bloodstream. Prepare to maximize (degree of laser-induced heating at different concentrations). Nanoparticles are produced as in Example 1 using a suitable solvent. A mixture containing multiple nanoparticles in water is concentrated to about 100-500 OD at peak absorbance and replaced with a new solvent by liquid chromatography, solvent exchange system, centrifugation, precipitation, or dialysis. Typical exchange solvents are 0.15 mol / L NaCl, 0.1 mol / L Na phosphate buffer (pH 7.2).</p><p><Example 6: Use of plasmon nanoparticles for thermal excision of blood vessel and microvessel components> Nanoparticle-containing compositions are typically administered intravascularly. Following such administration of plasmon nanoparticles, a laser harmonizing with the peak plasmon resonance of the particles (eg, 755 nm, 810 nm, or 1064 nm) is applied to heat the nanoparticles and surrounding tissue. Achieve thermal gradients using pulse widths of 10-100ns, 100ns-1ms, 1-10ms, 10100ms, 100-1000ms or continuous wave irradiation, and near particles or 20-200nm, 200nm-2μm, 2-20μm , 20-200 μm, 200 μm-2 mm particles are heated and localized. A temperature gradient of 20-200 nm is achieved from the individual particles. Supra mm A temperature gradient of millimeter) is achieved by the collective thermal deposition of many particles in veins with diameters of hundreds of microns and above. Irradiation is applied from one pulse to many pulses over a period of seconds to minutes. Cooling devices for the layers of the epidermis are used in association with irradiation to reduce pain and prevent heat damage elsewhere. Adjust the laser position, fluence, wavelength, angle of incidence, and irradiation pattern to achieve canal irradiation at specific depths between 0-10 mm, while avoiding heating of non-target vascular structures. Alternatively, a laser or light is administered through a fiber optic light path administered by a catheter to heat the particles in a larger vein.</p><p> In one embodiment, the side of the tissue is 2 W / cm after injection of PEG-nanorod by 810 nm peak plasmon resonance.<sup>2</sup>Irradiate with a beam diameter of 810 nm, 1 cm. Thermographic images are used to assess the surface temperature of the tissue immediately after irradiation.</p><p> Assessment of thermal damage to blood vessel, microvessel, or capillary component. After 30 minutes of application, the target vessel and surrounding supporting tissue (eg skin) are removed. The biopsy is fixed in 10% paraformaldehyde, embedded with paraffin and cut into 5-μm sections on a transverse microtome. Slides with attached paraffin sections are deparaffinized and stained with hematoxylin and eosin (H & E) or silver enhanced staining. H & E staining and photomicroscopy can be used to image one or several blood vessels, microvessels, and capillaries. Scoring is performed for visible thermal damage to the vascular structure. In addition, vascular staining (eg, CD31 staining) is performed to clearly identify vascular structures within the tissue sample.</p><p> As will be appreciated by those skilled in the art, the subject matter described herein can be embodied in other specific forms without departing from its spirit or essential qualities. Therefore, the aforementioned embodiments should be considered in all exemplary respects, without limitation to the inventions described herein.</p>
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| WO2009072657A1 | Cites | World Intellectual Property Organization (WIPO) | A | Search report | – |
| JOURNAL OF COLLOID AND INTERFACE SCIENCE, vol. 283, JPN6020010718, 2005, pages 392 - 396, ISSN: 0004236297 | Non-patent | – | – | Search report | – |
| PNAS, vol. 100, no. 23, JPN6020010720, 11 November 2003 (2003-11-11), pages 13549 - 13554, ISSN: 0004236298 | Non-patent | – | – | Search report | – |
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Titles2
- Japanese
- 標的とされた熱変調のための組成物及び方法
- English
- Compositions and Methods for Targeted Thermal Modulation
Classification
- CPC, 65
- A61N5/0616
- A61B18/06
- A61B18/203
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- A61K8/19
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- A61K41/0057
- A61K2800/622
- A61Q9/00
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- IPC, 22
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