JP2017503861A - Liquid vehicle for suspension of undelivered particles - Google Patents

Abstract

The present invention provides compositions comprising energy (eg, light) absorbing submicron particles (eg, nanoparticles comprising a silica core and a gold shell) and methods for delivering such particles by topical application. This delivery is facilitated by mechanical agitation (eg massage), acoustic vibrations in the range of 10 Hz to 20 kHz, ultrasound, repeated suction and pressurization and application of microjets. In addition or optionally, there is a step of applying a sufficient amount of liquid to the treatment site after sufficient evaporation of the formulation leaves a residue of particles on the surface of the skin. Thereafter, one or more steps that facilitate delivery of the particles to a portion of the skin are repeated. Ultimately, the particles are appropriately energy activated, thereby obtaining the desired therapeutic or clinical outcome.

Description

[Incorporation by reference]
This application includes subject matter that may be related to the subject matter described in US patent application Ser. No. 12 / 787,655, US Patent Application Publication No. 2012/0059307, and US Pat. No. 6,183,773, which references include: All of which are incorporated herein by reference. All or each of the publications and patent applications mentioned in this specification are hereby incorporated by reference in their entirety to the same extent as specifically and individually indicated to be incorporated herein by reference. It shall be part of the book.

  The present application recycles undelivered material by adding a liquid vehicle to resuspend or dissolve the material to deliver particles and other light absorbing materials into the pores. On how to improve.

  Acne vulgaris is a follicular skin disease characterized by the appearance of comedones, papules, nodules and cysts. A comedones is a state in which the hair follicle is blocked by a horn plug. An open face with visible horn plugs forms a “black head”. Closed comedones form a “white head” that often progresses to inflammatory papules, nodules and cysts. The presence of bacteria in the hair follicle can attract white blood cells to the hair follicle and cause an inflammatory response seen as papules (red bumps), pustules and nodules. Acne can be minor in the presence of few comedones or papules, or it can be highly inflammatory and leave an ugly scar. There is a need for improved methods of treating or ameliorating hair follicle skin diseases such as acne vulgaris.

  Selective photothermal decomposition, which involves the addition of a light-absorbing substance from the outside into sebaceous hair follicles, followed by laser irradiation, has been developed as a treatment for acne. As an example of the light absorbing material, there is a silica core: gold shell fine particle called nanoshell developed by Halas et al. Of Rice University. These materials can be expensive and it is desirable to reduce the amount used. Exemplary treatments include applying a suspension of particles to the surface of the skin and then performing a mechanical method such as massage or other techniques described below. In general, these particles are suspended in a liquid typically comprised of water, ethanol, diisopropyl adipate and polyethylene glycol. These are typically low viscosity formulations and, as mentioned above, the delivery of particles is assisted by one or more different techniques. The large flow of fluid containing particles from the skin surface through the pores to the target sebaceous hair follicle is the main method of particle transport. In this way, the fraction of particles delivered into the hair follicle is very small compared to the whole applied to the surface of the skin. For example, it is estimated that only about 1% of the particles applied to the facial skin can reach the hair follicle. Further, the fluid (vehicle) portion of the suspension evaporates in a short time, for example, in less than 1 minute. After sufficient evaporation, particle transport into sebaceous hair follicles is minimal or zero.

  What is needed is a way to make more efficient use of the particles in the formulation.

  As described below, the present invention provides methods for treating or ameliorating a follicular skin disease (eg, acne) in a subject (eg, human) and energy (eg, light) absorbing submicron particles. Compositions comprising (e.g. nanoparticles comprising a silica core and a gold shell) and methods for delivering such particles, for example, into hair follicles, sebaceous ducts and / or sebaceous glands, by topical application, these methods Provide use by.

  Accordingly, in one aspect, the invention provides a method for treating or ameliorating a follicular skin disease in a subject, wherein a formulation comprising submicron particles containing a light absorbing material is applied topically to the subject's skin. Applying to the process, mechanical agitation, acoustic vibration, ultrasound, alternating suction and pressure or microjet, skin follicles, sebaceous glands, sebaceous duct, infundibulum, A method comprising facilitating delivery of a substance into an eccrine tube or eccrine gland and energizing the submicron particles, thereby treating or ameliorating a hair follicular skin disease in a subject. provide.

  In another aspect, the present invention provides a method for improving the appearance of enlarged pores in a subject's skin, the method comprising locally applying a formulation comprising submicron particles containing a light-absorbing substance to the subject's skin; Promoting the delivery of substances to the hair follicles, sebaceous glands, sebaceous ducts or funnels of the skin by mechanical agitation, acoustic vibration, ultrasound, repeated suction and pressurization or microjet, and submicron particles Activating the energy, thereby improving the appearance of enlarged pores in the skin of the subject.

  In yet another aspect, the present invention provides a method for improving the appearance of a subject's oily skin, the method comprising locally applying a formulation comprising submicron particles containing a light-absorbing substance to the subject's skin, and a machine Promoting the delivery of submicron particles to the hair follicles, sebaceous glands, sebaceous ducts or funnels of the skin by mechanical stirring, acoustic vibration, ultrasound, repeated suction and pressurization or microjets; Activating the energy, thereby improving the appearance of the oily skin of the subject.

  In another aspect, the present invention is a method for permanent hair removal of a subject's hair comprising applying a light-absorbing substance locally to the subject's skin and activating the substance to thereby permanently remove the hair. And providing a method. In one embodiment, the hair is thin or thin hair with pigment. In another embodiment, the method further comprises topically applying a light-absorbing material to the subject's skin and depilating the hair from the subject's hair follicle before the material is energy activated.

  In another aspect, the present invention provides a method of treating hyperhidrosis by thermally damaging an eccrine gland or surrounding area, the method comprising locally applying a light absorbing material to the subject's skin, Energy activation, thereby permanently removing the eccrine glands and treating hyperhidrosis.

  In yet another aspect, the present invention provides a method for promoting the delivery of a light-absorbing substance to a target volume in a subject's skin to obtain a therapeutic effect, wherein the formulation comprising the light-absorbing substance Applying the substance locally to the skin and delivering the substance to a reservoir in the skin and irradiating the skin with a first series of light pulses to facilitate delivery of the substance into the target volume within the subject's skin And exposing the light absorbing material to a second series of light pulses, heating the material and thermally damaging the target volume to obtain a therapeutic effect.

  In yet another aspect, the present invention provides a method for promoting the delivery of a light-absorbing substance to a target volume within a subject's skin to obtain a therapeutic effect, wherein the formulation comprising the light-absorbing substance is locally applied to the subject's skin. Applying to the skin, facilitating delivery of the substance to the reservoir in the skin by mechanical agitation, and applying a series of low energy laser pulses, each pulse having a duration of 1 μs or less, Accelerating the delivery of the substance to the target volume in the skin by entering the target volume and exposing the light absorbing substance to a second series of low energy laser pulses, heating the substance and thermally damaging the target volume And obtaining a therapeutic effect.

  In yet another aspect, the present invention provides a method of treating or ameliorating a follicular skin disease in a subject, wherein a formulation comprising submicron particles containing a light absorbing material is applied topically to the subject's skin. The step of applying, the step of promoting the delivery of substances from the skin into the hair follicle by the acoustically generated microjet in the formulation, and the energy activation of the submicron particles, thereby reducing the follicular skin disease And a step of treating.

  In yet another aspect, the present invention is a method of treating or ameliorating a hair follicular skin disease in a subject comprising exposing the subject's skin to a formulation comprising sub-micron particles containing a light absorbing material; Promoting the delivery of substances from the skin into the hair follicles by cavitation induced by low-frequency ultrasound in the formulation near the surface of the skin adjacent to the hair follicles, and energizing the submicron particles And thereby treating a hair follicular skin disease.

  In yet another aspect, the present invention is a method for facilitating delivery of a light-absorbing substance to a target volume within the subject's skin, wherein a formulation comprising the light-absorbing substance is applied topically to the subject's skin, and the skin Delivering a substance to a reservoir in the target volume of the substance, facilitating delivery of the substance to the target volume in the subject's skin substantially via the transfollicular route, and a series of light pulses of the light absorbing substance And heating the substance to thermally damage the target volume to obtain a therapeutic effect.

  In another aspect, the invention provides a method of treating or ameliorating a follicular skin disease in a subject, wherein a formulation comprising particles of a light absorbing material is applied topically to the subject's skin; In order to selectively facilitate the delivery of the particles in the formulation mainly from the corresponding hair follicle into the sebaceous glands, the step of generating acoustic cavitation in the formulation and irradiating the particles with light to reduce hair follicular skin disease And a step of treating.

  In another aspect, the present invention is a method for treating or ameliorating a follicular skin disease in a subject, wherein a formulation comprising submicron particles containing a light absorbing material is applied topically to the subject's skin. Delivering the formulation into one or more sebaceous glands substantially via the trans-follicular route; energizing the submicron particles thereby treating hair follicular skin disease; Providing a method.

  In yet another aspect, the present invention provides a method of treating or ameliorating a follicular skin disease in a subject, wherein a formulation comprising submicron particles containing a light absorbing material is applied topically to the subject's skin. Applying, promoting the delivery of substances to the hair follicles by cavitation induced by low frequency ultrasound near the surface of the skin adjacent to the hair follicles, and irradiating the submicron particles with light Treating or ameliorating hair follicular skin disease adjacent to submicron particles using the generated heat.

  The method aspects according to the present invention in the above aspects or other aspects of the invention described herein include a plurality of useful embodiments that can be universally applied in the method according to the invention described herein. .

  Thus, in one embodiment, delivery of the light absorbing material, eg, into a hair follicle, is facilitated by a microjet generated by ultrasound in the formulation.

  In another embodiment, energy activation of the submicron particles includes irradiating the submicron particles with light, thereby heating the particles.

  In another embodiment, the submicron particles are in the sebaceous gland during irradiation. In one embodiment, the submicron particles are substantially completely within the sebaceous gland during irradiation. In another embodiment, the submicron particles are in the sebaceous duct during irradiation. In yet another embodiment, the submicron particles are substantially completely within the sebaceous duct during irradiation. In yet another embodiment, the submicron particles are in a funnel that is involved in follicular skin disease.

  In certain embodiments, the light-absorbing substance in the formulation comprises a photoactive compound, a photodynamic therapy (PDT) prodrug or a PDT drug.

  In one embodiment, the application of ultrasound is performed at a frequency in the range of 20 kHz to 500 kHz. In another embodiment, application of ultrasound is performed at a frequency in the range of 20 kHz to 100 kHz. In yet another embodiment, application of ultrasound is performed at a frequency in the range of 20 kHz to 60 kHz. In yet another embodiment, application of ultrasonic energy occurs at a frequency in the range of 30 kHz to 50 kHz.

In one embodiment, the ultrasonic power density is about 0.5-50 W / cm ² . In another embodiment, the peak-to-peak amplitude displacement of the ultrasonic horn surface ranges from 0.5 to 30 microns.

  In certain other embodiments, the size of the submicron particles according to the present invention is selected to pass through the hair follicle and into the sebaceous gland of the hair follicle. In one embodiment, the hair follicle is a terminal hair follicle. In another embodiment, the hair follicle is a soft hair follicle. In yet another embodiment, the hair follicle is a sebaceous hair follicle.

  In one embodiment, the size of the submicron particles is from about 0.01 microns to about 1.0 microns. In another embodiment, the size of the submicron particles is from about 0.05 microns to about 0.25 microns.

  In one embodiment, the step of promoting further includes selecting the characteristics of the microjet generated by ultrasound such that bubbles of approximately the same size as the follicular pores are formed in the formulation. In another embodiment, the promoting step further comprises selecting cavitation characteristics induced by low frequency ultrasound such that bubbles of approximately the same size as the hair follicle are formed in the formulation.

  In other embodiments, the microjet generated by ultrasound in the formulation is generated within about 50 microns to about 100 microns from the surface of the subject's skin.

  In certain embodiments, delivery of the light absorbing material is facilitated by a process of immersion cavitation. In one embodiment, the promoting step generates cavitation within about 50-100 microns from the surface of the skin. In another embodiment, the stratum corneum portion of the subject skin portion that has undergone the delivery step remains intact. In certain other embodiments, for example, delivery of a light-absorbing substance into one or more sebaceous glands or hair follicles, for example, substantially via the transfollicular pathway, near the surface of the skin adjacent to the hair follicle It is promoted by cavitation induced by low frequency ultrasound. In one embodiment, the induced cavitation occurs from about 50 microns to about 100 microns from the surface of the skin. In another embodiment, the characteristics of the low frequency ultrasound are selected such that the stratum corneum remains intact with cavitation induced near the surface of the skin.

  In one embodiment, the follicular disease being treated is hyperhidrosis. In certain embodiments, the promoting step delivers particles into the eccrine gland via the eccrine gland duct.

  In other embodiments, the follicular disease to be treated is acne vulgaris. In yet other embodiments, the follicular disease to be treated is sebaceous hyperplasia. In yet another embodiment, the hair follicular disease to be treated is hirsutism.

  In one embodiment, the submicron particles are coated with PEG. In another embodiment, the particle has an absorption peak at a wavelength of 700-1100 nm. In another embodiment, the submicron particles have a shell to core ratio of about 1.05 to about 2.0.

  In another embodiment, the submicron particles are nanoparticles or nanoshells. In certain embodiments, the nanoparticle or nanoshell has a diameter of about 50 to about 300 nm (eg, 50, 75, 100, 125, 150, 175, 200, 250, 300 nm). In one embodiment, the nanoparticle or nanoshell has a diameter of about 50 to about 250 nm. In another embodiment, the nanoparticles have a diameter of about 150 nm.

  In another embodiment, the nanoparticles are coated with PEG.

  In yet another embodiment, the nanoparticles are nanoshells. In certain embodiments, the nanoparticles include a silica core and a gold shell.

  In certain embodiments, the submicron particles comprise about 0.5% to about 2% of the formulation. In one embodiment, the formulation comprises about 0.5 to about 2% of a suspension comprising nanoparticles. In another embodiment, the formulation comprises about 0.1 to about 10% of a suspension comprising nanoparticles.

  In one embodiment, the formulation contains a surfactant and / or is hydrophilic. In another embodiment, the formulation contains a surfactant and / or is lipophilic. In yet another embodiment, the formulation contains a surfactant and / or is a liposome. In certain embodiments, the surfactant is less than 10% of the formulation.

  In certain embodiments, the formulation includes a component that has the ability to solubilize lipids. In one embodiment, the component is ethanol.

  In one embodiment, the formulation comprises one or more of ethanol, isopropyl alcohol, propylene glycol, a surfactant and / or isopropyl adipate. In another embodiment, the formulation comprises hydroxypropylcellulose (HPC) and carboxymethylcellulose (CMC). In yet another embodiment, the formulation comprises any one or more of water, ethanol, propylene glycol, polysorbate 80, diisopropyl adipate, phospholipone and thickener.

  In certain embodiments, the formulation has an optical density of 5-500. In one embodiment, the formulation has an optical density of about 75. In another embodiment, the formulation has an optical density of about 125. In another embodiment, the formulation has an optical density of about 250.

  In certain embodiments, energy activation, eg, photoactivation, is performed with pulsed laser light that supplies light energy of a wavelength that is absorbed by the particles. In one embodiment, the pulsed laser light provides light energy at a wavelength that is preferentially absorbed by the particles. In another embodiment, energy activation is performed by a continuous laser that supplies light energy of a wavelength that is absorbed by the particles.

In one embodiment, the light energy has a wavelength range of about 700 to about 1100 nm. In a separate embodiment, the light energy has a fluence of less than about 100 J / cm ^2. In yet another embodiment, the light energy has a pulse duration of about 0.5 ms to 1000 ms.

  In certain embodiments, the skin is prepared for the method by heating, removing the contents of the hair follicles, and / or removing the hair. In one embodiment, the hair follicle contents are removed by a method that includes contacting the follicular pores with an adhesive polymer.

  In certain other embodiments, topically applied submicron particles are wiped from the skin prior to energy activation. In one embodiment, topically applied submicron particles are wiped from the skin using a fluid prior to application of light radiation. In another embodiment, the fluid is water, ethanol, acetone or a combination of two or more of water, ethanol and acetone. In another embodiment, the fluid may be composed of one or more of water, a solvent, a surfactant, and an alcohol.

  In certain other embodiments, the skin is heated to a temperature sufficient to assist hair follicle delivery before, during or after topical application. In one embodiment, the heating is performed by ultrasound. In another embodiment, the heating is performed with steam. In yet another embodiment, the heating is performed by hot pack. In yet another embodiment, the heating is performed with a steam towel. In general, heating is not sufficient to cause skin pain, tissue damage, burns or other heat related effects. In one embodiment, the temperature is about 35-44 ° C. In another embodiment, the temperature is about 40-44 ° C. In yet another embodiment, the temperature is about 42 ° C.

  In certain embodiments, the exposing step further comprises placing a large amount of the formulation in a container such that the formulation contacts the subject's skin. In one embodiment, the step of promoting further comprises placing an ultrasonic applicator in the container and dipping in the formulation.

  In one embodiment, the target volume is a sebaceous gland and the target volume is in the hair follicle under the skin.

  In another aspect, the present invention comprises a cosmetically acceptable carrier and an amount of a plurality of plasmon nanoparticles effective to induce thermal denaturation at a target tissue site with which the composition is in local contact. A composition is provided.

  In one embodiment, the plasmonic nanoparticles are activated by exposure to energy delivered from a nonlinear excitation surface plasmon resonance source to a target tissue site. In another embodiment, the plasmon nanoparticles comprise a composite material from a metal, metal composite, metal oxide, metal salt, conductor, superconductor, semiconductor, dielectric, quantum dot, or combinations thereof. In yet another embodiment, the large amount of plasmonic particles present in the composition comprises geometrically tuned nanostructures.

  In one embodiment, the plasmonic particles absorb light, including nanoplates, solid nanoshells, hollow nanoshells, nanorods, nanorices, nanospheres, nanofibers, nanowires, nanopyramids, nanoprisms, nanostars or combinations thereof And includes any geometric shape currently known or to be formed that generates plasmon resonance at a desired wavelength. In another embodiment, the plasmon particle comprises silver, gold, nickel, copper, titanium, silicon, galadium, palladium, platinum or chromium.

  In one embodiment, cosmetically acceptable carriers include additives, colorants, emulsifiers, perfumes, humectants, polymerizable monomers, stabilizers, solvents or surfactants. In one particular embodiment, the surfactant is from the group consisting of sodium laureth 2-sulfate, sodium dodecyl sulfate, ammonium lauryl sulfate, octek-1 / deceth-1 sodium sulfate, lipids, proteins, peptides or derivatives thereof. Selected. In another specific embodiment, the surfactant is present in the composition in an amount of about 0.1 to about 10.0 w / w% of the carrier.

  In one embodiment, the solvent is selected from the group consisting of water, propylene glycol, alcohol, hydrocarbon, chloroform, acid, base, acetone, diethyl ether, dimethyl sulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, and ethyl acetate. The

  In another embodiment, the composition has at least about 10 O.D. at one or more peak resonance wavelengths. D. Plasmon particles having an optical density of

  In yet another embodiment, the plasmonic particles comprise a hydrophilic or aliphatic coating, the coating does not substantially adsorb to the skin of the mammalian subject, and the coating is polyethylene glycol, silica, silica oxide, polyvinyl Includes pyrrolidone, polystyrene, protein or peptide.

  In one embodiment, heat denaturation is injury, ablation, lysis, denaturation, deactivation, activation, induction of inflammation, activation of heat shock proteins, perturbation of cell signaling, or microcellularity at the target tissue site. Including destruction of the environment.

  In another embodiment, the target tissue site comprises a sebaceous gland, a sebaceous gland component, a sebum cell, a sebocyte component, a sebum or hair follicle funnel.

  In certain embodiments, the target tissue site comprises a bulge, hair bulb, stem cell, stem cell niche, dermal papilla, cortex, epidermis, hair sheath, medulla, pyloric muscle, Huxley layer or Henle layer.

  In another aspect, the present invention is a method of performing targeted ablation of tissue to treat a mammalian subject in need thereof, comprising i) a composition according to the present invention as described above on the skin of a subject. Administering locally to the surface; ii) providing an osmotic means for redistributing plasmon particles from the surface of the skin to a component of the dermal tissue; and iii) irradiating the surface of the skin with light. Providing a method.

  In one embodiment, the light source comprises mercury, xenon, deuterium or metal halide excitation, phosphorescence, incandescence, fluorescence, light emitting diode or sunlight.

  In another embodiment, the permeation means is pre-treatment with high frequency ultrasound, low frequency ultrasound, massage, iontophoresis, high pressure air flow, high pressure liquid flow, vacuum, fractional photopyrolysis or skin removal. Or a combination thereof.

Further in another embodiment, the irradiation is about 200nm~ about 10000nm light wavelengths, from about 1 to about 100 J / cm ² fluence of about 1 femtosecond to about 1 second pulse width and about 1Hz~ about repetition of 1THz of Includes light having a frequency.

  In another aspect, the present invention provides a cosmetically acceptable carrier, an effective amount of sodium dodecyl sulfate, and an amount effective to induce thermal damage to a target tissue site with which the composition is in local contact. Compositions comprising a plurality of plasmon nanoparticles are provided, wherein the nanoparticles are at least about 10 O.D at a resonance wavelength of about 810 nm or 1064 nm. D. The plasmonic particles have an optical density of about 5 to about 35 nm of silica coating, and acceptable carriers include water and propylene glycol.

  In yet another aspect, the present invention provides for a laser ablation of hair or for treating acne comprising a composition according to the present invention as described above and a plasmon energy source suitable for application to human skin. Provide a system for

  Various aspects of the present invention provide compositions, methods and systems for treating hair follicular skin diseases, as well as further effective utilization of the particles in the provided formulations or the treatment techniques described above.

It is a microscope picture which shows the heat damage of the part of a hair follicle epithelium and a sebaceous gland after delivering nanoshell suspension by massage. It is a photograph which shows the surface of the skin after apply | coating a nanoshell formulation and promoting delivery with an ultrasonic wave. Excess formulation was wiped from the skin before taking this picture. FIG. 5 is a photomicrograph showing a hair follicle filled with dark nanoshells after facilitating delivery with ultrasound. Nanoshells are not found in the epidermis or dermis. FIG. 3 is a photomicrograph showing the hair follicle and surrounding skin after ultrasonic delivery and laser irradiation of nanoshells visualized with hematoxylin and eosin (H & E staining). Selective thermal damage around the hair follicle is indicated by an additional black delineation line. It is a photograph which shows the surface of skin. Accumulation of nanoshells is seen in the hair follicle. It is a microscope picture which shows the hair follicle which nanoshell accumulates notably. FIG. 6 is a photomicrograph showing local thermal damage to hair follicles including sebaceous glands visualized using H & E staining. 2 is a table showing the effectiveness of delivering nanoshells and then laser treating back acne in human clinical trials.

  The present invention is useful for compositions containing light / energy absorbers for the treatment of hair follicular diseases and their local delivery to targets (eg, hair follicles, hair follicle funnels, sebaceous glands) It features a simple method.

[Definition]
Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd edition, 1994); The Cambridge Dictionary of Science, et al., 1989, Ed. References to Rieger et al. (Eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991) provide those skilled in the art with general definitions of many terms used in the present invention. To do. As used herein, the following terms have the meanings ascribed to them below, unless otherwise indicated.

  The term “ameliorate” means to reduce, inhibit, attenuate, reduce, prevent or stabilize the onset or progression of a skin disease or condition. One exemplary skin condition is acne vulgaris.

  The terms “compounds” and “materials” are used interchangeably and refer to an active moiety according to the present invention.

  The terms `` comprise '', `` comprising '', `` containing '', `` having '' and the like have the meaning ascribed to those terms in U.S. Patent Law Can mean `` includes '', `` including '', and the like, `` consisting essentially of '' or `` essentially ( `` consists essentially) '' also has the meaning ascribed to U.S. Patent Law, the term being open-ended, where the fundamental or novel characteristics of what is referred to are altered by the presence other than those mentioned. Unless otherwise stated, it is allowed to exist other than those mentioned, but prior art embodiments are excluded.

  The term “detect” refers to identifying the presence, absence or amount of an analyte to be detected.

  The term “effective amount” means the amount necessary to ameliorate the symptoms of the disease with respect to an untreated patient. The effective amount of an active compound used to practice the invention for therapeutic treatment of a disease will vary depending on the mode of administration, the age, weight and general health of the subject. Ultimately, the attending physician or attending veterinarian will decide the appropriate amount and dosage regimen. Such an amount is referred to as an “effective” amount.

  The term “energy activation” refers to stimulation by an energy source that causes thermal or chemical activity. Energy activation may be by any energy source known in the art. Exemplary energy sources include lasers, ultrasound, acoustic sources, flash lamps, ultraviolet light, electromagnetic wave sources, microwaves or infrared light. The energy absorbing material absorbs energy and becomes thermally or chemically active.

  The terms “light”, “light energy”, “optical energy” and “optical radiation” are used interchangeably herein.

  The term “obtaining”, such as the term “obtaining an agent”, includes synthesizing, purchasing, or otherwise obtaining the agent.

  The term “pharmaceutically acceptable carrier” means that the energy activatable substance according to the present invention carries it within or to a subject so that it can perform its intended function, Or means a pharmaceutically acceptable substance, composition or vehicle, eg liquid or solid filler, diluent, excipient, solvent or encapsulating substance involved in transport. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of substances that can be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose , Ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; Glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycols; esters such as ethyl oleate, ethyl laurate; agars; buffers such as water Magnesium and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and compatibility agent other non-toxic to be used in pharmaceutical formulations. Preferred carriers are surface-activities such that the energy activatable substance is carried into or around the pores, for example, into the sebaceous gland, into the horn plug, into the funnel and / or into the sebaceous gland and the funnel. And those capable of entering the pores by solvent transport.

  The term “reduce, reduce, reduce” means a negative change of at least 10%, 25%, 50%, 75% or 100%.

  The term “reference” means standard or control conditions.

  The term “subject” means a mammal, including but not limited to a human or non-human mammal, such as a cow, horse, dog, sheep or cat.

  Ranges described herein are understood to be shorthand for all values within the range. For example, the range of 1-50 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 , 47, 48, 49 or 50 are included to include any number, combination of numbers or subranges.

  The terms “treat”, “treating”, “treatment” and the like refer to reducing or ameliorating a disorder and / or symptoms associated therewith. It will be appreciated that treatment of a disorder or symptom does not require, but does not exclude, the disorder, symptom or symptoms associated therewith.

  The term “or” is understood to be inclusive unless explicitly stated or apparent from the context. The terms “a, an” and “the” are understood to be singular or plural as used herein unless explicitly stated or clear from the context. .

  The term “about” is understood to be within the normal tolerance in the art, eg, within the standard deviation of the mean, unless explicitly stated or apparent from the context. About 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%,. It can be understood as within 05% or 0.01%. Unless otherwise clear from context, all numerical values set forth herein are modified by the term “about”.

  The recitation of a list of chemical groups in any definition of a variable herein includes the definition of the variable as any single group or combination of listed groups. The recitation of one embodiment for a variable or aspect herein includes the combination as any single embodiment or with any other embodiment or portion thereof.

  Any composition or method described herein may be combined with any one or more of the other compositions and methods described herein.

[Onset mechanism of follicular diseases]
The sebaceous gland is a component of the pilosebaceous unit. They are located throughout the body, especially the face and upper trunk, and produce sebum, a lipid-rich secretion that covers the hair and epidermal surface. The sebaceous glands are involved in the pathogenesis of several diseases, the most frequent being acne vulgaris. Acne is characterized by obstruction of the hair follicle by a horn plug formed by abnormal detachment of the keratinocytes of the funnel (upper part of the hair follicle) in the situation where excessive sebum is produced by the hyperactive sebaceous glands It is a multifactorial disease.

  The funnel is an important site for the pathogenesis of many follicular diseases (eg, acne). There is evidence that abnormal growth and desquamation of funnel keratinocytes results in the formation of microcomedones, followed by clinically visible hair follicle “corn plugs” or comedones. Since the structure of the funnel is important for the pathogenesis of acne, it is possible to eliminate the lesion site by selectively destroying this part of the hair follicle with energy-activatable substance-assisted energy, for example, laser targeting. Or reduce.

[Local delivery of light / energy absorbing material]
The present invention provides for the delivery of light / energy-absorbing substances into the skin appendages of the hair follicle, in particular the funnel of the hair follicle and the sebaceous glands, by topical application. In one embodiment, such substances are useful for the treatment of follicular diseases, such as acne (eg, acne vulgaris). In another embodiment, such substances are useful for the treatment of eccrine symptoms such as hyperhidrosis. The introduction of energy-activatable substances into the sebaceous glands, followed by exposure to energy (light) having a wavelength corresponding to the absorption peak of the chromophore, increases the tissue's local light absorption and selective thermal damage of the sebaceous glands Happens.

  In another embodiment, a light-absorbing substance is applied to the subject's skin, facilitates delivery into the eccrine gland via the eccrine gland duct, and activates the substance to energize the eccrine gland or surrounding area. There is a treatment for hyperhidrosis by heat damage. The method thereby permanently removes the eccrine gland. In one embodiment, the method for treating hair follicular disease is a method for treating hyperhidrosis.

[Skin preparation]
Optionally, the skin is prepared by one or a combination of the following methods. Delivery of the light-absorbing material can be facilitated by hair loss that occurs prior to the topical application of the light-absorbing material.

  Optionally, the skin is degreased before applying the light absorbing compound. For example, acetone wipes are available from Sebacia, Inc. Before applying gold nanoshells (Dallas, GA), it is used to degrease the skin, in particular to remove sebum and hair follicle contents.

  In some subjects, delivery can be facilitated by reducing or removing follicle clogging prior to applying the light absorbing material. By removing the follicle clogging in this way, nanoshell delivery can be improved. In particular, the hair follicles of patients prone to acne are clogged with exfoliated keratinocytes, sebum and bacteria, P. Acnes. The hair follicle can be emptied by applying a vacuum. Other methods include strips with components such as cyanoacrylate strip, polyquaternium 37 (eg, biore pore clean strips). The polymer flows into the hair follicle and dries over time. When the dried polymer film is peeled off, the hair follicle contents are pulled out and the hair follicle is emptied.

  Optionally, the skin may be heated prior to applying the light absorbing material. By heating, the viscosity of sebum is reduced, and the sebum components can be liquefied. This can facilitate delivery of a light absorbing material (eg, formulated as a nanoshell) to the hair follicle.

[Local delivery of light-absorbing substances]
A light absorbing material, such as a non-toxic pigment (eg, indocyanine green or methylene blue) is applied topically to the skin after any desired preparation. Topically applied formulations containing light absorbing materials may include ethanol, propylene glycol, surfactants and acetone. Such additional components facilitate delivery into the hair follicle.

  Delivery of the light-absorbing material is facilitated by mechanical agitation, eg massage, acoustic vibration in the range 10 Hz to 20 kHz, ultrasound, repeated suction and pressurization and application of a jet. In one embodiment, the light absorbing material is delivered as nanoparticles, eg, nanoshells or nanorods that absorb light in the visible and near infrared regions of the electromagnetic spectrum. In another embodiment, the light absorbing material is a quantum dot. Preferably, the light absorbing material is formulated for local delivery in a form that facilitates hair follicle delivery. In one embodiment, such a formulation comprises water, ethanol, isopropyl alcohol, propylene glycol, a surfactant and isopropyl adipate, and related compounds. In one embodiment, the formulation is hydrophilic and contains a surfactant. In another embodiment, the formulation is lipophilic and contains a surfactant. In yet another embodiment, the composition is a liposome and contains a surfactant. In any of the above embodiments, the surfactant is less than 10% of the formulation. In another embodiment, the formulation is hydrophilic. In yet another embodiment, the formulation is lipophilic. In yet another embodiment, the composition is a liposome.

[Accelerated delivery by ultrasound]
Ultrasound was used to achieve transdermal delivery of the compound into the body. Ultrasound appears to generate shock waves and microjets due to bubble cavitation, forming channels in the skin and transporting molecules of interest. Previously, efforts have been made to deliver compounds through the stratum corneum. For example, small molecules that are less than 5 nm in size can be delivered through the stratum corneum. The rate of delivery from the stratum corneum decreases significantly with increasing particle size. For example, for particles having a size of 50 nm or more, the delivery rate through the stratum corneum is very low. However, this size is much smaller than the pore opening and the funnel of the hair follicle. For example, in some embodiments of the invention, a 150 nm size silica core and gold shell structure is used as a chromophore in treating symptoms affecting a subject. Such gold nanoshells are much smaller than the diameter of the funnel, but are difficult to deposit in the skin through the stratum corneum.

  From these findings, the funnel sebaceous gland system is selectively delivered so that a suitably sized light-absorbing substance is delivered first and then the infundibulo-sebaceous unit is selectively thermally damaged by pulsed laser irradiation. The target is the basis for acne treatment. Here, the ultrasound specifically facilitates the delivery of the light absorbing material into the hair follicle structure. Shock wave, microjet generation and streaming deliver light absorbing particles into the funnel of the hair follicle and the associated sebaceous glands and sebaceous glands.

  Ultrasound often involves heating the target organ skin. Some heating, such as heating up to about 42 ° C., can aid in the delivery of hair follicles. However, overheating is undesirable because it causes pain, tissue destruction and burns. In one embodiment, overheating can be avoided, for example, by cooling the skin. In another embodiment, the topically applied formulation or coupling gel may be cooled in advance or in parallel. Low duty cycles and repeated ultrasonic pulse bursts can also be used to avoid overheating, during which the body cools the skin receiving ultrasonic energy.

  In certain embodiments, the present invention provides two methods of ultrasound delivery. One is “contact ultrasound” and the other is “immersion ultrasound”.

  According to one embodiment of the contact ultrasonic method, the preparation according to the present invention is locally applied to the skin by extending it into a thin layer, and a horn that vibrates at an ultrasonic frequency is in close contact with the skin covered with the preparation. Contact.

  According to one embodiment of immersion ultrasound, a reservoir filled with the formulation is placed on the skin and immersed in it such that the horn does not contact the skin at a distance in the range of about 2 mm to about 30 mm, and then The horn is vibrated at an ultrasonic frequency.

  Acoustic cavitation is an action often observed by ultrasound in a liquid. In acoustic cavitation, sound waves apply a sinusoidal pressure to an existing cavity in the solution. During the negative pressure cycle, the liquid is pulled away at the “weak spot”. Such weak spots may be either pre-existing bubbles or solid nucleation sites. In one embodiment, a bubble is formed and grows until it reaches a critical size known as its resonance size (Leong et al., Acoustics Australia, 2011-acoustics. Asn.au, THE FUUNDAMENTALS OF POWER ULTRASOUND-A REVIEW. 54-63). According to Mitragotri (Biophys J. 2003; 85 (6): 3502 to 3512), the spherical collapse of the bubbles produces a high-pressure core that emits shock waves with amplitudes exceeding 10 kbar (Pecha and Gompf, Phys. Rev. Lett. 2000; 84: 1328-1330). In addition, non-spherical collapse of bubbles in the vicinity of the boundary such as the skin generates a microjet having a velocity of about 100 m / s (Popinet and Zaleski, 2002; J. Fluid. Mech. 464: 137-163). . Such bubble collapse phenomenon can assist in the delivery of substances into skin appendages such as hair and sebaceous hair follicles. Thus, various embodiments of the present invention optimize the bubble size prior to collapse to facilitate efficient delivery of light absorbing materials into the intended target (eg, sebaceous glands, hair follicles). An immersion ultrasonic method is provided.

  The resonance size of the bubble depends on the frequency used for bubble generation. A simple approximate relationship between resonance and bubble size is F (Hz) × D (m) = 6 mHz (where F is the frequency in Hz and D is the bubble size (size) in m). Is given). In fact, the bubble diameter is usually smaller than the diameter predicted by this equation due to the non-linearity of bubble pulsation.

  Table 1 below shows the size of the bubble resonance size as a function of frequency calculated from the above relationship.

  A more accurate estimate of bubble size can be obtained from computer simulation of bubble vibration. For example, a study by Yasui (J. Acust. Soc. Am. 2002; 112: 1405-1413) investigated depth at three frequencies. The size of single bubble sonoluminescence (SBSL) stable bubbles is small and the range is shown in Table 2 below (estimated from Figures 1, 2 and 3 of Yasui, 2002).

For efficient delivery into the hair follicle with cavitation bubbles, there is a range of optimal cavitation bubble sizes. A strong cavitation shock wave generated by relatively large bubbles is required. However, if the bubble size is too large, a strong shock wave may be generated, the skin may be compressed, the pore size may be reduced, and efficient delivery to the target (eg, sebaceous gland, hair follicle) may be reduced. For example, if the bubble size is much larger than the follicle opening, the resulting shock wave compresses not only the pore opening but also the skin around the pore opening. This prevents efficient delivery into the hair follicle opening. Desirably, the bubble size should be approximately the same size as the target pore. The typical follicular pore size of human skin is estimated to be in the range of 12-300 microns. Thus, an advantageous ultrasonic frequency range is 20 kHz to 500 kHz. In another alternative, application of the ultrasonic frequency is in the range of 20 kHz to 100 kHz, 20 kHz to 60 kHz or even 30 kHz to 50 kHz. Desired power density is estimated to range from 0.5 to 50 / cm ^2. This is sufficient to generate cavitation bubbles in the desired size range.

  The term “immersion cavitation” is defined herein as the formation and collapse of cavitation bubbles by ultrasonic energy in a fluid formulation.

  In light of the above, the delivery of the light-absorbing substance into the hair follicle is selected by selecting the characteristics of the acoustically generated microjet so that air bubbles of approximately the same size as the follicular pores are formed in the formulation. A method of facilitating is also provided. By selecting the properties, the bubbles can be approximately the same size as a terminal hair follicle, soft hair follicle or sebaceous hair follicle. In another alternative implementation in light of the above description, by selecting the characteristics of cavitation induced by low frequency ultrasound so that air bubbles of approximately the same size as the hair follicle are formed in the formulation. Also provided is a method for facilitating delivery of a light-absorbing substance within a package. In one implementation, the hair follicle is a terminal hair follicle. In another implementation, the hair follicle is a vellus hair follicle. In yet another implementation, the hair follicle is a sebaceous hair follicle. In still other embodiments, ultrasound generated microjets or low frequency ultrasound induced cavitation occurs in formulations from about 50 microns to about 100 microns from the surface of the skin.

  In another embodiment, a method of treating or ameliorating a hair follicular skin disease in a subject is also provided. The method includes exposing the subject's skin to a formulation comprising submicron particles containing a light absorbing material. Next, there is a step of facilitating delivery of the substance from the skin into the hair follicle by cavitation induced by low frequency ultrasound in a formulation near the surface of the skin adjacent to the hair follicle. The submicron particles are then energy activated, thereby treating hair follicular skin disease. In one alternative, there may be a step of exposing the container by placing a large amount of the formulation in contact with the subject's skin. Furthermore, there is also a step of promoting the method by placing an ultrasonic applicator in a container and immersing it in the preparation.

  In yet another embodiment, a method is provided for facilitating delivery of a light absorbing material to a target volume within a subject's skin. The method includes the steps of topically applying a formulation comprising a light absorbing substance to the subject's skin and delivering the substance to a reservoir within the target volume of the skin. Next, there is a step of facilitating delivery of the substance to a target volume within the subject's skin substantially via the transfollicular route. Next, there is the step of exposing the light-absorbing substance to a series of light pulses, heating the substance and thermally damaging the target volume to obtain a therapeutic effect. In one alternative, the formulation has an optical density of 5-500. In another alternative, the formulation has an optical density of about 75. In yet another alternative, the formulation has an optical density of about 125. In yet another alternative, the formulation has an optical density of about 250. In one embodiment, the target volume is a sebaceous gland. In another embodiment, the target volume is in the hair follicle under the skin.

  In yet another embodiment, the step of promoting includes a step of immersion cavitation. In another alternative, a process is provided that uses immersion ultrasound to facilitate delivery into the sebaceous gland. In one alternative, the promoting step includes generating a microjet in the formulation. In one embodiment, cavitation is generated in the formulation and within about 50-100 microns from the skin surface by facilitating with ultrasound. In any of the methods described above, there is also the step of generating acoustic cavitation in the formulation to selectively facilitate delivery of the particles in the formulation into the sebaceous glands, primarily through the corresponding hair follicle. Thereafter, there is a step of irradiating the particles with light to treat a follicular skin disease. In one embodiment, the particles are formed to a size of about 0.01 microns to about 1 micron. In another embodiment, the particles are sized to enter or along the follicular pores. In yet other embodiments, the particles are about 50 nm to about 250 nm in diameter. In another embodiment, the particle is a nanoshell.

[Activity by energy (light)]
After topical application (eg, by mechanical agitation, ultrasound) and accelerated delivery, the upper skin is wiped to remove residual light absorbing material. Thereafter, energy (light) is irradiated. Light is absorbed by substances in the hair follicle or sebaceous glands, causing local heating. The light source depends on the absorber used. For example, for a nanoshell with a broad absorption spectrum tuned to a resonant wavelength of 800 nm, a light source such as 800 nm, 755 nm, 1064 nm or high intensity pulsed light (IPL) with appropriate filtering can be used. In one embodiment, the nanoparticles in suspension have an absorption peak at a wavelength of 700-1100 nm. Such pulse laser irradiation causes thermal damage to the tissue surrounding the substance. In one embodiment, the light energy has a fluence of less than about 100 J / cm ^2. Damage to fungal hair follicle stem cells and / or sebaceous glands improves hair follicle symptoms, such as acne. Such a method can be used not only for fine particles in suspension but also for small molecules dissolved in a solution. These may include drugs, photodynamic therapy (PDT) prodrugs or PDT drugs.

  Suitable energy sources include light emitting diodes, incandescent lamps, xenon arc lamps, lasers or sunlight. A suitable example of a continuous wave device is a diode, for example. Suitable flash lamps include, for example, pulsed dye lasers and alexandrite lasers. Some pulsed red dye lasers (504 and 510 nm) are typical lasers with wavelengths that are strongly absorbed in the epidermis and funnel by some chromophores, such as laser-sensitive dyes, but not in the sebaceous glands. A Q-switched neodymium (Nd): YAG laser with a wavelength of 1064 nm, which can also generate visible green light with a wavelength of 532 nm using a copper vapor laser (511 nm) and a potassium diphosphate crystal. Can be mentioned. In this process, selective photoactivation can be used in which an energy (light) source, eg, a laser, is matched to the wavelength of the absorption spectrum of the selected energy activatable material, preferably the color former.

  A high-concentration light-absorbing substance is more easily obtained in the funnel portion than the sebaceous gland duct and sebaceous gland having a high resistance to mass transport. Hair follicles containing sebaceous glands can be irreversibly damaged, relying solely on light absorption in principle other than the substance in the funnel. This is caused by keratinocyte damage in the hair follicle epithelium. High energy pulses can also be used to expand thermal damage and include outer root sheath stem cells, hair bulges, and sebaceous gland perimeters. However, such high energy should not cause unwanted side effects. Such side effects can also be mitigated by the use of epidermal cooling and long pulse durations ranging from about a few milliseconds up to 1000 ms.

  Acne can be improved by heat changes in the funnel itself and slight improvement of the sebaceous glands. The appearance of enlarged facial pores is a common problem for many people. This is typically due to enlargement of sebaceous glands, funnels, and pore openings. By heating tissue, especially collagen, the tissue contracts. The delivery of the nanoshell and its thermal targeting within the funnel sebaceous system, including the upper funnel, lower funnel and sebaceous glands, improves the appearance of enlarged pores.

[Formulation of energy absorbing substance]
The present invention provides a composition comprising a light / energy absorbing material for local delivery. In one embodiment, the particles in the composition are nanoparticles comprising a silica core and a gold shell. In yet another embodiment, the compound according to the invention comprises a silica core and a gold shell (150 nm). In another embodiment, the nanoshell used consists of a 120 nm diameter silica core, a 15 micron thick gold shell, with a total diameter of 150 nm.

  The nanoshell is covered with a 5000 MW PEG layer. The PEG layer prevents and / or reduces the aggregation of the nanoshell, thereby increasing the stability of the nanoshell suspension and extending the shelf life. In one embodiment, the nanoparticles have a diameter of about 50 to about 250 nm. In some embodiments, the ratio of the shell diameter to the core diameter of the particles used herein is from about 1.5 to about 2.0. In another embodiment, the particles in the formulation make up from about 0.5% to about 2% of the formulation.

  The nanoparticles according to the present invention exhibit surface plasmon resonance, whereby incident light induces optical resonance of surface plasmons (electron vibrations) in the metal. The peak absorption wavelength can be “tuned” to the near infrared (IR) portion of the electromagnetic spectrum. These submicron-sized nanoparticles can penetrate the epidermal funnel, sebaceous ducts and sebaceous glands, minimizing penetration into the stratum corneum. In certain embodiments, selective transfollicular penetration of nanoparticles about 150-350 nm in diameter is achieved. In one aspect, a method for treating or ameliorating a hair follicular skin disease in a subject is provided. There is a step of topically applying to the subject's skin a formulation comprising submicron particles containing a light absorbing material. Next, there is the step of delivering the formulation into one or more sebaceous glands substantially via the transfollicular route. Next, there is the step of energy activating the submicron particles, thereby treating hair follicle skin diseases. In one embodiment, the portion of the stratum corneum within the portion of the skin that has undergone the delivery step remains intact. Still further, the delivery process is completed using an immersion ultrasound process, where the portion of the stratum corneum within the portion of the skin that has undergone the delivery process remains intact.

  Optionally, the light / energy absorbing material is provided in a vehicle that is formulated for local delivery. In one embodiment, the composition according to the present invention includes, but is not limited to, ethanol, isopropyl alcohol, propylene glycol, a surfactant such as polysorbate 80, phospholipon 90, polyethylene glycol 400 and isopropyl adipate. It is formulated with an agent that improves hair follicle delivery, including the above. In other embodiments, the composition according to the present invention includes one or more of one or more of the following, including, but not limited to, hydroxypropylcellulose (HPC) and carboxymethylcellulose (CMC) to improve formulation handling. Formulated with thickener.

  In the composition, wetting agents, emulsifiers, lubricants such as sodium lauryl sulfate and magnesium stearate, and colorants, mold release agents, coating agents, sweet fragrances, preservatives and antioxidants are present. Also good.

  Liquid dosage forms for topical administration of the composition according to the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, creams, lotions, ointments, suspensions and syrups. It is done. In addition to the active ingredient, liquid dosage forms are inert diluents commonly used in the art such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate. , Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, peach oil, almond oil and sesame oil), glycerol, tetrahydrofuryl Alcohols, fatty acid esters of polyethylene glycol and sorbitan, and mixtures thereof can be included.

  Suspensions contain, in addition to the active compounds, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and their Mixtures can be included.

  Ointments, pastes, creams and gels contain, in addition to the active compounds according to the invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, It can contain bentonite, silicic acid, talc, zinc oxide or mixtures thereof. The term “cream” is art-recognized and is intended to include semi-solid emulsion systems containing both oil and water. Oil-in-water creams are water miscible and are well absorbed by the skin, for example aqueous cream BP. Water-in-oil (oily) creams are immiscible with water and are therefore more difficult to remove from the skin. These creams are emollients, smooth and moisturize, for example oily cream BP. Both systems require the addition of natural or synthetic surfactants or emulsifiers.

  The term “ointment” is art-recognized and is intended to include a system having an oil or fat as its continuous phase. An ointment is a semi-solid anhydrous substance that is occlusive, softening and protective. Ointments limit transdermal water loss and are therefore hydrating and moisturizing. Ointments can be divided into two main groups: greasy, eg white soft paraffin (petroleum, petrolatum) and water soluble, eg macrogol (polyethylene glycol) ointment BP. The term “lotion” is art-recognized and is intended to include solutions typically used in dermatological applications. The term “gel” is art-recognized and includes a semi-solid permutation gelled with a high molecular weight polymer such as carboxypolymethylene (carbomer BP) or methylcellulose. It is intended and can be considered a semi-plastic aqueous lotion. They are typically non-greasy, water miscible, easy to apply and clean, and are particularly suitable for the treatment of hairy parts of the body.

Target monitoring
The condition or treatment of a subject having a skin disease or disorder can be monitored during treatment with the composition or method according to the invention. Such monitoring can be useful, for example, to assess the effectiveness of a particular drug or treatment plan in a patient. Treatments that promote skin health or improve skin appearance are considered particularly useful in the present invention.

[kit]
The present invention provides kits for the treatment or prevention of skin diseases or disorders, or symptoms thereof. In one embodiment, the kit comprises a pharmaceutical pack comprising an effective amount of a light / energy absorbing material [eg, a nanoshell (150 nm) with a silica core and a gold shell). Preferably, the composition is present in unit dosage form. In some embodiments, the kit includes a sterile container containing a therapeutic or prophylactic composition, such container being a box, ampoule, bottle, vial, tube, bag, pouch, blister pack or the like. Other suitable container forms known in the art may be used. Such containers may be made of plastic, glass, laminated paper, metal foil or other material suitable for holding the drug.

  Optionally, the compositions or combinations thereof according to the present invention are provided with instructions for administering them to a subject having or at risk of developing a skin disease or disorder. Instructions for use generally include information about the use of the composition for the treatment or prevention of skin diseases or disorders. In other embodiments, the instructions for use are a description of the compound or combination of compounds; acne, dermatitis, skin conditions associated with psoriasis, any other skin condition characterized by inflammation or bacterial infection or their Administration schedule and treatment for the treatment of symptoms; precautions; warnings; indications; contraindications for use; overdose information; side effects; animal pharmacology; clinical trials; and / or at least one of the references. Instructions for use may be printed directly on the container (if present), affixed to the container as a label, or provided in or with the container as a separate sheet, brochure, card or folder .

  The recitation of a list of chemical groups in any definition of a variable herein includes the definition of the variable as any single group or combination of listed groups. The recitation of one embodiment for a variable or aspect herein includes the combination as any single embodiment or with any other embodiment or portion thereof.

  The following examples are provided to illustrate the invention but do not limit the invention. Those skilled in the art will appreciate that the specific configurations provided below can be modified in various ways consistent with the invention described above, while retaining the important properties of the compounds or combinations thereof. It will be.

[Laser hair removal]
The invention features compositions and methods particularly useful for laser hair removal of lightly colored hair. In laser hair removal, a specific wavelength of light and pulse duration is used to minimize the impact on surrounding tissue and obtain an optimal effect on the target tissue. The laser can selectively heat melanin, a dark target substance, but can cause local damage to the hair follicles by not heating the rest of the skin. Since lasers target melanin, light, gray, and fine or fine hairs with low melanin levels are not efficiently targeted by existing laser hair removal methods. Efforts have been made to deliver various light absorbing materials, such as carbon particles, squid ink extract commercially known as melazine, or pigments into the hair follicle. These methods were largely ineffective.

  The present invention provides microparticles in the form of a suspension that is applied topically after skin preparation as outlined herein above. In particular, the skin is prepared by hair removal of the hair shaft and the light-absorbing substance is delivered to the hair follicle. Preferably, the formulation is optimized for follicular delivery by mechanical agitation over a period of time. After wiping the preparation from the upper part of the skin, laser irradiation is preferably performed while cooling the surface. The laser is pulsed with a wavelength that is absorbed by the particle or nanoshell with a pulse duration of about 0.5 ms to 400 ms or 0.5 ms to 1000 ms. This method permanently removes unpigmented or pale pigmented hair by destroying stem cells and other hair-growing organs present in the hair follicle bulges and hair bulb sites.

  The practice of the present invention, unless otherwise indicated, is well-understood by those skilled in the art and is conventional in molecular biology (including recombinant technology), microbiology, cell biology, biochemistry and immunology. Use technology. Such techniques are described in “Molecular Cloning: A Laboratory Manual”, 2nd edition (Sambrook, 1989); “Oligonucleotide Synthesis” (Gait, 1984); “Animal Cell Culture” (Fresh), 1987; “Enzymology” “Handbook of Experimental Immunology” (Weir, 1996); “Gene Transfer Vectors for Mammalian Cells” (Miller and Calos, 1987); “Current”. (Year); “PCR: The Polymerase Chain Reaction” (Mullis, 1994); “Current Protocols in Immunology” (Coligan, 1991). These techniques can be applied to the production of polynucleotides and polypeptides according to the present invention, and can be considered when producing and implementing the present invention as such. Techniques that are particularly useful for particular embodiments are discussed in the following sections.

  The following examples are set forth to provide those skilled in the art with a complete disclosure and description of how to perform and use the assay, screening and treatment methods of the invention, It is not intended to limit the scope of what the inventors regard as their invention.

[Example 1]
[Local delivery of nanoshells to the hair follicle epithelium for the treatment of follicular diseases]
An example of massage as a mechanical means of hair follicle delivery is shown. Nanoshell suspensions adjusted to 800 nm were massaged into the depigmented porcine skin of live pigs in vivo. After wiping off the suspension above the skin, laser energy was applied with parallel contact cooling. A biopsy was performed and a normal histological examination was performed. A micrograph of the histological examination is shown in FIG. There is thermal damage to the hair follicle epithelium and part of the sebaceous glands. Such damage is useful for treating follicular diseases, such as acne, or improving the appearance of a subject's oily skin.

  One exemplary method of the above treatment includes topically applying to the subject's skin a formulation comprising submicron particles containing a light absorbing material. Next, there is the step of facilitating the delivery of the substance into the hair follicle, sebaceous gland, sebaceous duct or funnel of the skin by mechanical agitation, acoustic vibration, ultrasound, repeated suction and pressurization or microjet. Thereafter, there is a step of energy activating the submicron particles, thereby treating hair follicular skin diseases.

[Example 2]
[Local delivery of nanoshells to hair follicle epithelium for laser hair removal]
In preparation for laser hair removal, the porcine flank was removed by wax application. The skin was then heated and a vacuum was applied to empty the hair follicle contents of the skin. Next, fine particles of silica core and gold shell with a diameter of about 0.150 μm coated with PEG were delivered by massaging. The skin was wiped and material was removed from the top of the skin. This was then irradiated with a pulsed laser at 800 nm. Samples were removed, fixed in formalin and processed by normal histological examination (H & E staining). Thermal damage of the hair follicle structure was observed by histological examination.

[Example 3]
[Light-Pulse Induced Pressure Pulse Facilitated Delivery]
A formulation containing a light absorbing substance is applied to the upper skin. This can be accomplished by methods known in the art including, but not limited to, passive diffusion, heating, mechanical assistance, such as pressure pulses, vibration, acoustic coils, ultrasound, nozzles or combinations of the above. Move into the funnel of the glandular system. The light pulse is then applied with a handpiece incorporating a cold plate that can be pressed against the skin. When the substance is heated by the first light pulse, expansion occurs regardless of the formation of vapor bubbles. Thereby, a pressure pulse is generated. During the pressure pulse, pressure is applied to the skin with a chilled plate. Since pressure cannot escape from the skin, the substance reaches the sebaceous gland through a low resistance channel in the skin, for example, the sebaceous duct. This pulse typically has a short pulse duration, for example 1 ns to 1 ms, preferably 10 ns to 100 μs, so that the magnitude of the pressure pulse is maximized, for example through the formation of vapor bubbles. Once the substance enters the target sebaceous gland, it is irradiated with light with a pulse duration and a radiation exposure appropriate for the size of the target sebaceous gland. Heats the light-absorbing material, causing heat damage to the sebaceous glands, thus inactivating it, improving acne vulgaris and other follicular diseases and symptoms associated with the presence or activity of sebaceous glands.

  In a related manner, a series of low energy laser pulses with a pulse duration of 1 μs or less are used, preferably in the acoustic region of the pulse repetition frequency, to activate the particles. This activation causes the particles to be “stirred” vigorously, some of which enter the sebaceous glands from the funnel.

[Example 4]
[Use of ultrasound to deliver light-absorbing substances to hair follicles and sebaceous glands]
Pig ear skin was stored frozen. Before the experiment, it was thawed. The hair was depilated by waxing and a piece of pig ear was placed on the bottom of the cup with the skin facing up. There was filled a 150 nm diameter silica core / gold shell nanoshell formulation (Sebacia, Inc. Dallas, GA) having an optical density of about 250. A 20 kHz device horn manufactured by Sonics was immersed in the preparation so that the distance between the distal surfaces of the horn above the skin was about 5 mm. The diameter of the horn was 13 mm and the output was about 6W. Therefore, the power density during the on-time was 4.5 W / cm ² . The device was turned on at 50% duty cycle, 5s and 5s on and off times per cycle, respectively. Four cycles were applied. After the skin was wiped to remove the excess formulation, the skin was irradiated with a laser beam having a wavelength of 800 m at a spot of 9 mm × 9 mm, a total radiation exposure of about 50 J / cm ² and a pulse duration of 30 ms.

  The skin was observed with a dissecting microscope and a photograph was taken (FIG. 2). Cut through the hair follicle opening perpendicularly to the surface of the skin, the cut surface was observed with an optical microscope (FIG. 3). Several samples were placed in 10% formalin buffer and observed by routine histological examination (Figure 4).

  The skin was intact and undisturbed except that spots were observed at the follicular opening (FIG. 2). Upon cutting and microscopic observation, the presence of dark nanoshells was observed in the funnel of the hair follicle and in the sebaceous glands (FIG. 3). Nanoshells were not found in the epidermis or dermis around the hair follicle. Similarly, histological examination showed thermal damage of the follicle funnel and sebaceous glands (FIG. 4). There was no or minimal damage to the epidermis or dermis around the hair follicle.

  In one alternative embodiment, in a method using an ultrasonic horn used in immersion ultrasonics, the peak-to-peak amplitude displacement of the ultrasonic horn surface is in the range of 0.5 to 30 microns.

  In yet another aspect, it is provided that the size of the submicron particles is selected to pass through the hair follicle and into the sebaceous gland of the hair follicle. In one embodiment, the hair follicle is a terminal hair follicle. In another embodiment, the hair follicle is a vellus hair follicle. In yet another embodiment, the hair follicle is a sebaceous hair follicle. In yet a further implementation of the method according to the invention described herein, the size of the submicron particles is from about 0.01 microns to about 1.0 microns. In yet another exemplary embodiment, the submicron particle size is from about 0.05 microns to about 0.25 microns.

[Example 5]
[Accelerated delivery by ultrasound]
A transducer from APC International, McKeeville, PA, was driven by a sine wave 300Vp-p from a waveform generator and amplifier with a signal source impedance of 500Ω. A 150 OD diameter silica core: 250 OD formulation containing a gold shell (F78, Sebacia, Inc.) was applied topically to the skin of a depigmented pig ear. Thereafter, the upper surface was wiped, and laser irradiation was performed with an 800 nm Lumenis Lightsheer. The skin temperature was confirmed after application of ultrasound and it did not exceed 41 ° C.

  There was considerable accumulation of nanoshells in the hair follicle (FIG. 5). In FIG. 6, it cut | disconnected perpendicularly through the hair follicle and the cut surface was observed with the microscope. 1 shows an exemplary hair follicle. Significant accumulation of nanoshells was observed inside and outside the funnel.

  FIG. 7 shows the histological analysis of the sample. Local thermal damage to the hair follicle is observed, including thermal damage of the sebaceous glands (FIG. 7).

[Example 6]
[Human clinical efficacy demonstrated in back acne]
A clinical trial of back acne evaluated the effectiveness of delivering nanoshells locally followed by laser treatment. Nanoshells were applied topically to the back of each subject and laser treatment was initiated as described above. This treatment plan was given to each subject twice. Results were evaluated 12 weeks after the second treatment. Efficacy was determined by the number of weighted inflammatory lesions. The results are shown in FIG. This study of the back acne test shows that the treatment plan was clinically effective.

[Example 7]
[Human clinical efficacy demonstrated in sebaceous gland damage]
An IRB approved human clinical trial was conducted with 17 subjects with acne (6 men, 11 women). Subjects' age ranged from 18 to 40 years (average 24 years) (phototypes I to IV). Treatment was performed on an area of 1 square inch behind the ear (a sebaceous hair follicle). Nanoshells were delivered followed by laser treatment. There, the laser was adjusted to the absorption peak of the nanoshell [40-50 J / cm ² , 30 ms, 9 × 9 mm, light share (800 nm)]. Therapeutic efficacy was evaluated histologically with 31 biopsies, with 4-7 hair follicles present in each biopsy. A 4 mm punch biopsy was performed, cut continuously, and sebaceous hair follicle damage was visualized by H & E staining. Pain, erythema and edema were minimal. Local damage was observed in about 60% of sebaceous hair follicles. In some specimens, destruction of the entire sebaceous gland was observed. The average depth of thermal damage in the hair follicles was 0.47 mm (maximum 1.43 mm). No incidental damage to the epidermis or dermis was observed. In vivo histological examination, funnel, hair bulge and sebaceous gland damage were observed after treatment.

[Example 8]
[Ultrasonic-assisted delivery of photodynamic therapy (PDT) using aminolevulinic acid (ALA)]
In experiments with ultrasound, the hair follicle was easier to access to deliver the light-absorbing material than the stratum corneum. This seems to be due to the difference between the transport rate into the stratum corneum and the transport rate into the hair follicle. This difference can be exploited to facilitate selective delivery of smaller molecules. This method can be used either for chromophores in photothermal treatment regimes, or for photodynamic therapy with compounds or prodrugs that produce photodynamic effects. For example, conventional acne therapy, including ALA-PDT treatment, requires a long incubation time (approximately 3-4 hours) to deliver a sufficient concentration of ALA to the sebaceous glands to achieve the desired clinical efficacy. To do.

  This treatment results in significant adverse side effects including crusting of the epidermis, pain and persistent redness. This long incubation time delivers ALA to non-target areas of the epidermis and dermis. Ultrasound-assisted delivery can be achieved without this long incubation time and still a sufficient concentration is obtained in the target fungal sebaceous system. Ultrasonic delivery eliminates long incubation times, so ALA is hardly delivered to the epidermis and dermis other than the target. Following ultrasonic delivery, the ALA formulation may be removed from the surface of the skin. When sufficient time has passed to ensure that the concentration of photoactive substance has reached a sufficient level within the target volume, light irradiation is performed. In photothermal therapy, pulsed laser irradiation may be started immediately after delivery.

  In another embodiment, the substance of interest (compound) is attached to the microparticle and delivered to the target volume. Light irradiation can be used to dissociate the substance and cause its diffusion and subsequent effects. Cavitation bubble formation is facilitated by the presence of “core” nanoparticles for bubble formation. Delivery may also be facilitated by the use of volatile components such as ethanol.

[Example 9]
[Formulation]
Various nanoshell formulations were tested in an ex vivo skin model. The test component was designed to improve delivery into the hair follicle. The formulation components were ethanol, isopropyl alcohol, propylene glycol, surfactants such as polysorbate 80, phospholipon 90, polyethylene glycol 400, isopropyl adipate. These were tested for compatibility with each other. Three types were identified: hydrophilic, lipophilic and liposomes. The absorption coefficient of the formulation is suggested to be in the range of 10 to 1000 cm- ¹ . Four example formulations were tested in an in vivo porcine skin model. The compositions are as shown in Table 3 below showing the four formulations tested in the human back acne test.

[Particle resuspension]
As noted above, there are a wide variety of treatments that involve applying one or more methods to apply a suspension containing the particles to the surface of the skin and then facilitate penetration of the formulation and particles into the desired treatment site. Including performing and then activating. These particles are suspended in a liquid typically comprised of water, ethanol, diisopropyl adipate and polyethylene glycol, as described above for the various formulations and compositions. These are typically low viscosity formulations and, as mentioned above, particle delivery is aided by techniques that facilitate penetration into the target site. In one embodiment, a large flow of fluid containing particles from the surface of the skin, through the pores and into the target sebaceous hair follicle is the main method of particle transport. In this way, the fraction of particles delivered into the hair follicle is very small compared to the whole applied to the surface of the skin. For example, it is estimated that only about 1% of the particles applied to the facial skin can reach the hair follicle. Further, the fluid (vehicle) portion of the suspension evaporates in a short time, for example, in less than 1 minute.

  In one embodiment, after sufficient evaporation, the transport of particles into the sebaceous hair follicle is minimal or zero. Therefore, there is a layer of black particles that remains on the surface of the skin. This residue comes from surface particles that were not pushed into the target site. This residue is wiped off before laser irradiation.

  As an alternative, the residue can be reused instead of wiped off by adding a suitable vehicle (ie a liquid or fluid to release particles from the dry surface of the skin), or Reassemble. In this way, a method is provided for “reusing” particles previously applied to one part of the surface of the skin to another part of the surface of the skin. Optionally, the reuse may be for the same treatment site. When the fluid or formulation delivering the particles is completely dry, a portion of the surface of the skin has a layer of particles. Thereafter, a cheaper liquid vehicle (similar to the previously used formulation but not containing expensive particulates) may be added to this surface rather than further applying the particle formulation. The user can resuspend the particles by introducing this vehicle. Then, once the pre-applied particles have re-flowed in suspension, they can be moved to another part of the surface of the skin using massage or other of the delivery techniques described above. Also good. For example, the particles may be applied to a portion of the face (eg, the left jaw). After complete drying, the particles are resuspended and moved to another part of the face (eg, right jaw). Thereafter, delivery may continue to be promoted using any of the techniques described above. Additionally or optionally, depending on the amount of reorganized particles, an amount of new particulate suspension may be added to the new site. Essentially, particles that remain on one part of the skin surface are used on another part of the skin surface.

  As another alternative, the method of applying a liquid vehicle described herein can be applied to particle recycling at the same treatment site. By continuing to reorganize the particles at the same treatment site, an increased delivery rate of particles into the target site can be achieved. In one example, the methods described herein are used to enhance delivery of the same treatment site into the hair follicle. It will be appreciated that the particle recycling method can be applied to insoluble particles and soluble materials such as dyes or drugs. In yet another embodiment, a method of delivering a substance that relies on a liquid phase to allow particles to enter the target pores and hair follicles is provided, where additional sites are treated by adding a vehicle to the dry suspension. . In addition, the above-described method may be adapted for the delivery of substances that depend on the liquid phase to allow the particles to enter the target pores and hair follicles, where additional delivery may dry the vehicle. It can be obtained by adding to a suspension.

  The examples and illustrations contained herein illustrate, by way of example and not limitation, specific embodiments in which the subject matter can be implemented. In one aspect, operation of the delivery device for delivery of delivery fluid is the desired therapy. In this case, the operation of the delivery device is a complete therapeutic operation. In another embodiment, the operation of the delivery device for delivery of the delivery fluid precedes or follows another therapy or another desired therapy. In this case, the operation and use of the delivery device is part of a multipart therapy. One particular example of multipart therapy includes fluids, formulation particles, shells, pharmaceuticals, liposomes, other therapeutic agents or pharmacological substances on the structure of the treatment site or delivery site, in the structure or There is the use of a delivery system to deliver into the structure and then further treat the delivery site or treatment site. In one particular example, a further treatment is to provide activation energy to the fluid, formulation or pharmacological substance. Exemplary fluids, formulations and treatments are described in US Pat. No. 6,183,773, US Pat. No. 6,530,944, US Patent Application Publication No. 2013/0315999 and US Patent Application Publication No. 2012/0059307. Each of which is hereby incorporated by reference in its entirety. Additionally or optionally, one or more of the operating parameters of the delivery device, and / or methods of using the delivery system described herein, may include one or more properties of the delivery fluid, components of the delivery fluid, or delivery used Modifications can be made based on the particles in the fluid.

[Other Embodiments]
From the foregoing description, it will be apparent that changes and modifications may be made so that the invention described herein is employed in various usages and situations. Such embodiments are also within the scope of the following claims.

  The recitation of a list of elements in any definition of a variable herein includes the definition of the variable as any single element or combination (or partial combination) of the listed elements. The recitation of an embodiment herein includes that embodiment as any single embodiment, or in combination with any other embodiments or portions thereof.

Claims (14)

A method of treating a subject's skin condition comprising:
a) topically applying a formulation comprising submicron particles containing a light-absorbing substance to the subject's skin;
b) facilitating delivery of the substance into the skin structure by mechanical agitation, acoustic vibration, ultrasound, repeated suction and pressurization or microjet;
c) applying a sufficient amount of liquid to the treatment site after the residue of particles remains on the surface of the skin by sufficient evaporation of the formulation;
d) repeating the promoting step for the portion of the skin treated in the applying step. A method of treating a subject's skin condition comprising:
a) topically applying a formulation comprising submicron particles containing a light-absorbing substance to the subject's skin;
b) facilitating delivery of the substance into the skin structure by mechanical agitation, acoustic vibration, ultrasound, repeated suction and pressurization or microjet;
c) treating the delivery fluid in a manner effective to move submicron particles from the surface of the subject's skin into the skin structure at least about 45 seconds after promoting delivery of the substance into the skin structure; Applying to the site. A method of treating a subject's skin condition comprising:
a) topically applying submicron particles comprising a light-absorbing material to the subject's skin;
b) delivering the submicron particles into the skin structure by mechanical agitation, acoustic vibration, ultrasound, repeated suction and pressurization or microjet;
c) applying a liquid to a treatment site in a manner effective to move submicron particles from the surface of the subject's skin into the skin structure.   2. The skin structure of claim 1, wherein the skin structure comprises at least one component selected from the group consisting of hair follicles, sebaceous glands, sebaceous ducts, funnels, eccrine glands, eccrine glands, apocrine glands and apocrine glands. Method.   The method according to claim 1, wherein the skin symptom comprises at least one selected from the group consisting of follicular skin disease, hyperhidrosis, enlarged pore appearance, oily skin, and unnecessary hair.   The method of claim 1, further comprising energy activating the submicron particles, thereby treating a skin condition of the subject.   The method of claim 1, wherein the liquid in the applying step is substantially the same as the formulation without the submicron particles.   2. The method of claim 1, wherein delivery of the substance into the skin structure is facilitated by a microjet generated by ultrasound in the formulation.   The method of claim 7, wherein energizing the submicron particles comprises irradiating the submicron particles.   The method according to claim 5, wherein the hair follicle is a terminal hair follicle, a soft hair follicle or a sebaceous hair follicle.   The method of claim 1, wherein the size of the submicron particles is from about 0.01 microns to about 1.0 microns.   The method of claim 1, wherein the size of the submicron particles is from about 0.05 microns to about 0.25 microns.   The method of claim 1, wherein the promoting step further comprises selecting a property of the microjet generated by ultrasound such that bubbles of approximately the same size as the follicular pores are formed in the formulation. . A method of treating a subject's skin condition comprising:
a) topically applying submicron particles comprising a light-absorbing material to the subject's skin;
b) delivering the submicron particles into the hair follicle, sebaceous gland, sebaceous duct or funnel of the skin by mechanical agitation, acoustic vibration, ultrasound, repeated suction and pressure or microjet;
c) applying a liquid to a treatment site by a method effective to move the submicron particles from the surface of the subject's skin into a hair follicle.